MICONAZOLE NITRATE , Миконазол , ミコナゾール硝酸塩

 GENERIC, Uncategorized  Comments Off on MICONAZOLE NITRATE , Миконазол , ミコナゾール硝酸塩
Aug 072016


416.13             [22916478]

Miconazole Nitrate

            C18H14Cl4N2O.HNO3              479.14             [22832877]

ミコナゾール硝酸塩 JP16
Miconazole Nitrate

C18H14Cl4N2O▪HNO3 : 479.14








click on above image for clear view



1D 1H, n/a spectrum for Miconazole


2D [1H,1H]-TOCSY, n/a spectrum for Miconazole


1D DEPT90, n/a spectrum for Miconazole

1D DEPT135

1D DEPT135, n/a spectrum for Miconazole


2D [1H,13C]-HSQC

2D [1H,13C]-HSQC, n/a spectrum for Miconazole

2D [1H,13C]-HMBC

2D [1H,13C]-HMBC, n/a spectrum for Miconazole

2D [1H,1H]-COSY

2D [1H,1H]-COSY, n/a spectrum for Miconazole

2D [1H,13C]-HMQC

2D [1H,13C]-HMQC, n/a spectrum for Miconazole
Miconazole is an imidazole antifungal agent, developed by Janssen Pharmaceutica, commonly applied topically to the skin or tomucous membranes to cure fungal infections. It works by inhibiting the synthesis of ergosterol, a critical component of fungal cell membranes. It can also be used against certain species of Leishmania protozoa which are a type of unicellular parasites that also contain ergosterol in their cell membranes. In addition to its antifungal and antiparasitic actions, it also has some antibacterialproperties. It is marketed in various formulations under various brand names.

Miconazole is also used in Ektachrome film developing in the final rinse of the Kodak E-6 process and similar Fuji CR-56 process, replacing formaldehydeFuji Hunt also includes miconazole as a final rinse additive in their formulation of the C-41RA rapid access color negative developing process.
It is on the World Health Organization’s List of Essential Medicines, the most important medications needed in a basic health system.[1]

ALTERNATIVE ROUTES beginning with the racemic raw material will likely be more costly or more time-consuming to develop, Cox says. Crystallization might be tricky because the stereogenic center does not have a group that can readily undergo acid-base chemistry. Catalytic asymmetric chemistry will necessitate converting the raw material to an appropriate substrate and identifying effective, as well as usable, chemical catalysts or biocatalysts.
What happens to the unwanted enantiomer also depends on the economics. Reracemizing and feeding the racemate back into the process is ideal but not always practical. In the miconazole case, the raw material costs $32 per kg. It is unlikely that reracemizing would be less costly in this example, Cox explains.
People should not forget that the goal of chiral technologies–enantiopure product–also may be achieved with chemistry that already exists, notes David R. Dodds, founder of Dodds & Associates LLC, Manlius, N.Y., a consulting service for biotechnology and chemical companies. Process chemists seek the most robust, most productive, and least expensive synthetic route and aim to find it as fast as possible. Any reaction that can help reach this goal is useful. It is the overall process cost that will dictate which reactions will be used. And that cost covers not only reagents but also waste streams, utilities, equipment use, unit operations, and downstream requirements. Thus, it may be more commercially attractive to replace an elegant but expensive single reaction with several more mundane ones that have a lower total cost, he says. Such a situation is likely to arise when an asymmetric step requires an expensive chiral catalyst or chiral auxiliary.

Brief background information


Salt ATC Formula MM CAS
18 H 14 Cl 4 N 2 O 416.14 g / mol 22916-47-8
mononitrate A01AB09 
18 H 14 Cl 4 N 2 O ⋅ HNO 3 479.15 g / mol 22832-87-7



  • antifungal agent for topical use
  • antimycotic agent

Classes substance


  • Imidazoles, 1- (hlorfenetil) imidazoles

synthesis Way


Synthesis of a)

trade names


A country Tradename Manufacturer
Germany Castellani Hollborn
Daktar McNeil
Derma-Mikotral Rosen Pharma
Fungur HEXAL
Gyno-Daktar Janssen-Cilag, 1974
Gyno-Mikotral Rosen Pharma
Infektozoor Mundgel Infectopharm
Mikobeta betapharm
Mikotar Dermapharm
Mikoderm Engelhard
Mikotin Ardeypharm
Vobamik Almirall Hermal
France Daktapin Janssen-Cilag
Gyno-Daktapin Janssen-Cilag
Loramik Bioalliance
United Kingdom Gyno-Daktapin Janssen-Cilag
Italy Daktapin Janssen-Cilag
Mikonal Ecobi
Mikotef LPB
Miderm Mendelejeff
Nizakol PS Pharma
Pivanazolo Medestea
Prilagin Sofar
Japan Florid Mochida
USA Fungoid Pedinol
Ukraine GІNEZOL 7 Sagmel, Іnk., USA
MІKONAZOL-Darnitsa CJSC “Farmatsevtichna FIRMA” Darnitsa “, m. Kyiv, Ukraine
MІKOGEL BAT “Kiїvmedpreparat”, m. Kyiv, Ukraine
various generic drugs



  • ampoule 200 mg / 20 ml;
  • cream 1%, 2 g / 100 g 20 mg / g;
  • losyon 1%;
  • ointment 1%;
  • 2% oral gel;
  • Powder 2 g / 100 g 20 mg / g (in the form mononitrate);
  • solution of 20 mg / ml;
  • 100 mg suppositories;
  • Tablets of 250 mg (free base form);
  • vaginal cream 20 mg / g;
  • bottles of 400 mg / 40 ml



  1. Synthesis of a)
    • DAS 1,940,388 (Janssen; appl 8.8.1969;. USA-prior 19.8.1968, 23.7.1969.).
    • US 3,717,655 (Janssen; 20.2.1973; appl 19.8.1968.).
    • US 3,839,574 (Janssen; 1.10.1974; prior 23.7.1969.).

Miconazole nitrate was prepared by Godefori et
7]. Imidazole 1 was coupled with
brominated 2,4‑dichloroacetophenone 2 and the resulting ketonic product 3
was reduced with sodium borohydride to its corresponding alcohol 4. The
latter compound 4 was then coupled with 2,4-dichlorotoluene by sodium borohydride
in hexamethylphosphoramide (an aprotic solvent) which was then extracted with
nitric acid to give miconazole nitrate.



2-     Miconazole was also
prepared by Molina Caprile [8] as follows:
Phenyl methyl ketone 1 was brominated to give
1-phenyl-2-bromoethanone 2. Compound 2 was treated with
methylsulfonic acid to yield the corresponding methylsulfonate 3.
Etherification of 3 gave the a‑benzyloxy derivative 4 and compound 4 was
then chlorinated to give the 2,4‑dichlorinated derivative in both aromatic ring
systems 5. Compound 5 reacted with imidazole in dimethylformamide
to give miconazole 6 [7] which is converted to miconazole nitrate.


3-     Ye
et al reported that the reduction of 2,4-dichlorophenyl-2-chloroethanone
1 with potassium borohydride in dimethylformamide to give 90% a‑chloromethyl-2,4-dichlorobenzyl
alcohol 2. Alkylation of imidazole with compound 2 in dimethyl­formamide
in the presence of sodium hydroxide and triethylbenzyl ammonium chloride, gave
1-(2,4‑dichlorophenyl-2-imidazolyl)ethanol 3 and etherification of 3
with 2,4-dichlorobenzyl chloride under the same condition, 62% yield of
miconazole [9].
4-     Liao
and Li enantioselectively synthesized and studied the antifungal activity of
optically active miconazole and econazole. The key step was the
enantioselective reduction of 2‑chloro-1-(2,4-dichlorophenyl)ethanone catalyzed
by chiral oxazaborolidine [10].
5-     Yanez
et al reported the synthesiz of miconazole and analogs through a
carbenoid intermediate. The process involves the intermolecular insertion of
carbenoid species to imidazole from a‑diazoketones with copper acetylacetonate as the key
reaction of the synthetic route [11].
5-11 as 1-7
1.             E.F. Godefori and J. Heeres, Ger. Pat. 1,940,388
E.F. Godefori and J. Heeres, U.S. Pat. 3,717,655
E.F. Godefori, J. Heeres, J. van Cutsem and P.A.J.
Janssen, J. Med. Chem., 12, 784 (1969).
F. Molina Caprile, Spanish Patent ES 510870 A1
B. Ye, K. Yu and Q. Huang, Zhongguo Yiyao Gongye
, 21, 56 (1990).
Y.W. Liao and H.X. Li, Yaoxue Xuebao, 28,
22 (1993).
E.C. Yanez, A.C. Sanchez, J.M.S. Becerra, J.M.
Muchowski and C.R. Almanza, Revista de la Sociedad Quimica de Mexico, 48,
49 (2004).

MiconazoleTitle: Miconazole

CAS Registry Number: 22916-47-8
CAS Name: 1-[2-(2,4-Dichlorophenyl)-2-[(2,4-dichlorophenyl)methoxy]ethyl]-1H-imidazole
Additional Names: 1-[2,4-dichloro-b-[(2,4-dichlorobenzyl)oxy]phenethyl]imidazole
Molecular Formula: C18H14Cl4N2O
Molecular Weight: 416.13
Percent Composition: C 51.95%, H 3.39%, Cl 34.08%, N 6.73%, O 3.84%
Literature References: Prepn: E. F. Godefroi et al., J. Med. Chem. 12, 784 (1969); E. F. Godefroi, J. Heeres, DE 1940388;eidem, US 3717655 (1970, 1973 to Janssen). Clinical evaluation: Brugmans et al., Arch. Dermatol. 102, 428 (1970); Godts et al.,Arzneim.-Forsch. 21, 256 (1971). Review: P. Janssen, W. Van Bever, in Pharmacological and Biochemical Properties of Drug Substances vol. 2, M. E. Goldberg, Ed. (Am. Pharm. Assoc., Washington, DC, 1979) pp 333-354; R. C. Heel et al., Drugs 19, 7-30 (1980).
Derivative Type: Nitrate
CAS Registry Number: 22832-87-7
Manufacturers’ Codes: R-14889
Trademarks: Aflorix (Gramon); Albistat (Ortho); Andergin (ISOM); Brentan (Janssen); Conoderm (C-Vet); Conofite (Mallinckrodt); Daktar (Janssen); Daktarin (Janssen); Deralbine (Andromaco); Dermonistat (Ortho); Epi-Monistat (Cilag); Florid (Mochida); Fungiderm (Janssen); Fungisdin (Isdin); Gyno-Daktarin (Janssen); Gyno-Monistat (Cilag-Chemie); Micatin (J & J); Miconal Ecobi (Ecobi); Micotef (LPB); Monistat (Cilag-Chemie); Prilagin (Gambar); Vodol (Andromaco)
Molecular Formula: C18H14Cl4N2O.HNO3
Molecular Weight: 479.14
Percent Composition: C 45.12%, H 3.16%, Cl 29.60%, N 8.77%, O 13.36%
Properties: Crystals, mp 170.5° (Godefroi, Heeres, 1970); 184-185° (Godefroi).
Melting point: mp 170.5° (Godefroi, Heeres, 1970); 184-185° (Godefroi)
Derivative Type: (+)-Form nitrate
Properties: mp 135.3°. [a]D20 +59° (methanol).
Melting point: mp 135.3°
Optical Rotation: [a]D20 +59° (methanol)
Derivative Type: (-)-Form nitrate
Properties: mp 135°. [a]D20 -58° (methanol).
Melting point: mp 135°
Optical Rotation: [a]D20 -58° (methanol)
Therap-Cat: Antifungal (topical).
Therap-Cat-Vet: Antifungal (topical).
Keywords: Antifungal (Synthetic); Imidazoles.


  1. Jump up^ “WHO Model List of EssentialMedicines” (PDF)World Health Organization. October 2013. Retrieved 22 April 2014.
  2. Jump up^ British National Formulary ’45’ March 2003
  3. Jump up^ “Strange Beauty: Monistat Effectively Increases Hair Growth?”. Black Girl With Long Hair. Retrieved 12 April 2012.
  4. Jump up^ Ju, Jiang; Tsuboi, Ryoji; Kojima, Yuko; Ogawa, Hideoki (2005). “Topical application of ketoconazole stimulates hair growth in C3H/HeN mice”Journal of dermatology32: 243–247.
  5. Jump up^ S., Venturoli; O. Marescalchi; F. M. Colombo; S. Macrelli; B. Ravaioli; A. Bagnoli; R. Paradisi; C. Flamigni (April 1999). “A Prospective Randomized Trial Comparing Low Dose Flutamide, Finasteride, Ketoconazole, and Cyproterone Acetate-Estrogen Regimens in the Treatment of Hirsutism”The Journal of Clinical Endocrinology and Metabolism84 (4): 1304–1310. doi:10.1210/jc.84.4.1304. Retrieved 12 April 2012.
  6. Jump up^ Duret C, Daujat-Chavanieu M, Pascussi JM, Pichard-Garcia L, Balaguer P, Fabre JM, Vilarem MJ, Maurel P, Gerbal-Chaloin S (2006). “Ketoconazole and miconazole are antagonists of the human glucocorticoid receptor: consequences on the expression and function of the constitutive androstane receptor and the pregnane X receptor”. Mol. Pharmacol70 (1): 329–39. doi:10.1124/mol.105.022046PMID 16608920.
  7. Jump up^ Najm, Fadi J.; Madhavan, Mayur; Zaremba, Anita; Shick, Elizabeth; Karl, Robert T.; Factor, Daniel C.; Miller, Tyler E.; Nevin, Zachary S.; Kantor, Christopher (2015-01-01).“Drug-based modulation of endogenous stem cells promotes functional remyelination in vivo”Nature522 (7555). doi:10.1038/nature14335.
  8. Jump up^ United States Patent 5461068

External links




Miconazole ball-and-stick.png
Systematic (IUPAC) name
Clinical data
Trade names Desenex, Monistat, Zeasorb-AF
AHFS/ Monograph
MedlinePlus a601203
  • AU: A
  • US: C (Risk not ruled out)
  • In Australia, it is category A when used topically. In the US, the pregnancy category is C for oral and topical treatment.
Routes of
Legal status
Legal status
  • AU: S2 (Pharmacy only)
  • UK: POM (Prescription only)
  • US: OTC
  • Schedule 2 in Australia for topical formulations, schedule 3 (Aus) for vaginal use and for oral candidiasis, otherwise schedule 4 in Australia
Pharmacokinetic data
Bioavailability n/a
Metabolism n/a
Biological half-life n/a
Excretion n/a
CAS Number 22916-47-8 Yes
ATC code A01AB09 (WHO)A07AC01 (WHO)D01AC02 (WHO)G01AF04 (WHO)J02AB01 (WHO)S02AA13 (WHO)
PubChem CID 4189
DrugBank DB01110 Yes
ChemSpider 4044 Yes
KEGG D00416 Yes
ChEBI CHEBI:6923 Yes
Chemical data
Formula C18H14Cl4N2O
Molar mass 416.127 g/mol
Chirality Racemic mixture

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Arformoterol, (R,R)-Formoterol For Chronic obstructive pulmonary disease (COPD)

 GENERIC, Uncategorized  Comments Off on Arformoterol, (R,R)-Formoterol For Chronic obstructive pulmonary disease (COPD)
Aug 032016



  • MF C19H24N2O4
  • MW 344.405
Cas 67346-49-0
Chronic obstructive pulmonary disease (COPD)
  • Sunovion/Sepracor (Originator)
  • Asthma Therapy, Bronchodilators, Chronic Obstructive Pulmonary Diseases (COPD), Treatment of, RESPIRATORY DRUGS, beta2-Adrenoceptor Agonists
  • LAUNCHED 2007 , Phase III ASTHMA
Formamide, N-[2-hydroxy-5-[(1R)-1-hydroxy-2-[[(1R)-2-(4-methoxyphenyl)-1-methylethyl]amino]ethyl]phenyl]-

Arformoterol is a long-acting β2 adrenoreceptor agonist (LABA) indicated for the treatment of chronic obstructive pulmonary disease(COPD). It is sold by Sunovion, under the trade name Brovana, as a solution of arformoterol tartrate to be administered twice daily (morning and evening) by nebulization.[1]

Arformoterol inhalation solution, a long-acting beta2-adrenoceptor agonist, was launched in the U.S. in 2007 for the long-term twice-daily (morning and evening) treatment of bronchospasm in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema. The product, known as Brovana(TM), for use by nebulization only, is the first long-acting beta2-agonist to be approved as an inhalation solution for use with a nebulizer. The product was developed and is being commercialized by Sunovion Pharmaceuticals (formerly Sepracor)

Arformoterol ball-and-stick model

Bronchodilators, in particular β2-adrenoceptor agonists, are recognized as very effective drugs to treat asthma and other bronchospastic conditions. Important characteristics for these drugs are activity, selectivity, duration of action, and onset. While the first-generation drugs (e.g., isoprenaline or terbutaline) were relatively unselective and short-acting, the current drugs have either a fast onset but only a short duration of action of about 4 h (albuterol) or a slow onset (20 min) with a longer duration of action (salmeterol). Formoterol (IUPAC name:  3-formamido-4-hydroxy-α-[[N-(p-methoxy-α-methylphenethyl)amino]methyl]benzyl alcohol) is unique in that it not only is extremely potent and selective but also has a duration of up to 12 h and a rapid onset of 1−5 min. Most β2-adrenoceptor agonists are currently marketed as racemates despite regulatory preference and different biological activity of pure enantiomers. In the case of formoterol it has been shown that the (R,R)-isomer is 1000 times more active than the (S,S)-isomer


It is the active (R,R)-(−)-enantiomer of formoterol and was approved by the United States Food and Drug Administration (FDA) on October 6, 2006 for the treatment of COPD.

Arformoterol is a bronchodilator. It works by relaxing muscles in the airways to improve breathing. Arformoterol inhalation is used to prevent bronchoconstriction in people with chronic obstructive pulmonary disease, including chronic bronchitis and emphysema. The use of arformoterol is pending revision due to safety concerns in regards to an increased risk of severe exacerbation of asthma symptoms, leading to hospitalization as well as death in some patients using long acting beta agonists for the treatment of asthma.

Arformoterol is an ADRENERGIC BETA-2 RECEPTOR AGONIST with a prolonged duration of action. It is used to manage ASTHMA and in the treatment of CHRONIC OBSTRUCTIVE PULMONARY DISEASE.

 Arformoterol (Brovana)
Arformoterol is a beta2-Adrenergic Agonist. The mechanism of action of arformoterol is as an Adrenergic beta2-Agonist.
Arformoterol is a long-acting beta-2 adrenergic agonist and isomer of formoterol with bronchodilator activity. Arformoterol selectively binds to and activates beta-2 adrenergic receptors in bronchiolar smooth muscle, thereby causing stimulation of adenyl cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3′,5′-adenosine monophosphate (cAMP). Increased intracellular cAMP levels cause relaxation of bronchial smooth muscle and lead to a reduced release of inflammatory mediators from mast cells. This may eventually lead to an improvement of airway function.
Formoterol (Foradil) is a long acting β2-agonist used as a bronchodilator in the therapy of asthma and chronic bronchitis. The (R,R)-enantiomer has been shown to be more active than the other stereoisomers (R,S; S,R; and S,S) of formoterol. (R,R)-Formoterol is extremely potent and selective, having rapid onset (1−5 min) and long duration, and is 1000 times more active than the (S,S) isomer

Arformoterol tartrate

  • Molecular FormulaC23H30N2O10
  • Average mass494.492
  •  cas 200815-49-2
  • 183-185°C
Butanedioic acid, 2,3-dihydroxy-, (2R,3R)-, compd. with formamide, N-[2-hydroxy-5-[(1R)-1-hydroxy-2-[[(1R)-2-(4-methoxyphenyl)-1-methylethyl]amino]ethyl]phenyl]- (1:1) [ACD/Index Name]
N-{2-hydroxy-5-[(1R)-1-hydroxy-2-{[(1R)-2-(4-methoxyphenyl)-1-methylethyl]amino}ethyl]phenyl}formamide 2,3-dihydroxybutanedioate (salt)
N-[2-Hydroxy-5-[(1R)-1-hydroxy-2-[[(1R)-2-(4-methoxyphenyl)-1-methylethyl]amino] ethyl]phenyl]formamide (+)-(2R,3R)-Tartaric Acid; (-)-Formoterol 1,2-Dihydroxyethane-1,2-dicarboxylic Acid; (R,R)-Formoterol Threaric Acid; Arformoterol d-Tartaric Acid; Arformoterol d-α,β-Dihydroxysuccinic Acid
200815-49-2 CAS
Arformoterol tartrate (USAN)
Arformoterol Tartrate, can be used in the synthesis of Omeprazole (O635000), which is a proton pump inhibitor, that inhibits gasteric secretion, also used in the treatment of dyspepsia, peptic ulcer disease, etc. Itis also the impurity of Esomeprazole Magnesium (E668300), which is the S-form of Omeprazole, and is a gastric proton-pump inhibitor. Also, It can be used for the preparation of olodaterol, a novel inhaled β2-adrenoceptor agonist with a 24h bronchodilatory efficacy.





Example 1

Synthesis of (R,R)-Formoterol-L-tartrate Form D

A solution containing 3.9 g (26 mmol) of L-tartaric acid and 36 mL of methanol was added to a solution of 9 g (26 mmol) of arformoterol base and 144 mL methanol at C. Afterwards, the resulting mixture was seeded with form D and stirred at C. for 1 hour. It was then further cooled to C. for 1 hour and the product collected by filtration and dried under inlet air (atmospheric pressure) for 16 hours to provide 11.1 g (86% yield) (99.7% chemical purity, containing 0.14% of the degradation impurity (R)-1-(3-amino-4-hydroxyphenyl)-2-[[(1R)-2-(4-methoxyphenyl)-1-methylethy- l]amino]ethanol) of (R,R)-formoterol L-tartrate form D, as an off white powder. .sup.1H-NMR (200 MHz, d.sub.6-DMSO) .delta.: 1.03 (d, 3H); 2.50-2.67 (m, 5H); 3.72 (s, 3H); 3.99 (s, 2H); 4.65-4.85 (m, 1H); 6.82-7.15 (m, 5H); 8.02 (s, 1H); 8.28 (s, 1H); 9.60 (s, NH). No residual solvent was detected (.sup.1H-NMR).

PSD: d.sub.50=2.3 .mu.m.



Tetrahedron Letters, Vol. 38, No. 7, pp. 1125-1128, 1997
Enantio- and Diastereoselective Synthesis of all Four Stereoisomers of Formoterol



Taking Advantage of Polymorphism To Effect an Impurity Removal:  Development of a Thermodynamic Crystal Form of (R,R)-FormoterolTartrate

Chemical Research and Development, Sepracor Inc., 111 Locke Drive, Marlborough, Massachusetts 01752, U.S.A.
Org. Proc. Res. Dev., 2002, 6 (6), pp 855–862
DOI: 10.1021/op025531h


Abstract Image

The development and large-scale implementation of a novel technology utilizing polymorphic interconversion and crystalline intermediate formation of (R,R)-formoterol l-tartrate ((R,R)-FmTA, 1) as a tool for the removal of impurities from the final product and generation of the most thermodynamically stable crystal form is reported. The crude product was generated by precipitation of the free base as the l-tartrate salt in a unique polymorphic form, form B. Warming the resultant slurry effected the formation of a partially hydrated stable crystalline intermediate, form C, with a concomitant decrease in the impurity levels in the solid. Isolation and recrystallization of form C provided 1 in the thermodynamically most stable polymorph, form A.

 SYN 4


Formoterol, (+/-)N-[2-hydroxy-5-[1-hydroxy-2-[[2-(p-methoxyphenyl)-2-propylamino]ethyl]phenyl]-formamide, is a highly potent and β2-selective adrenoceptor agonist having a long lasting bronchodilating effect when inhaled. Its chemical structure is depicted below:
Figure imgb0001
Formoterol has two chiral centres, each of which can exist into two different configurations. This results into four different combinations, (R,R), (S,S), (S,R) and (R,S). Formoterol is commercially available as a racemic mixture of 2 diasteromers (R,R) and (S,S) in a 1:1 ratio. The generic name Formoterol always refers to its racemic mixture. Trofast et al. (Chirality, 1, 443, 1991) reported on the potency of these isomers, showing a decrease in the order of (R,R)>(R,S)≥(S,R)>(S,S). The (R,R) isomer, also known as Arformoterol, being 1000 fold more potent than the (S,S) isomer. Arformoterol is commercialised by Sepracor as Brovana
Formoterol was first disclosed in Japanese patent application (Application N° 13121 ) whereby Formoterol is synthesised by N-alkylation using a phenacyl bromide as described in the scheme below:
Figure imgb0002
Afterwards, a small number of methods have been reported so far, regarding the synthesis of the (R,R) isomer, also referred as (R,R)-Formoterol and Arformoterol.
Murase et al. [Chem. Pharm. Bull. 26(4) 1123-1129(1978)] reported the preparation of (R,R)-Formoterol from a racemic mixture of the (R,R) and (S,S) isomers by optical resolution using optically active tartaric acid. Trofast et al. described a method in which 4-benzyloxy-3-nitrostyrene oxide was coupled with a optically pure (R,R)- or (S,S)-N-phenylethyl-N-(1-p-methoxyphenyl)-2-(propyl)amine to give a diastereomeric mixture of Formoterol precursors. These precursors were further separated by HPLC in order to obtain pure Formoterol isomers. Both synthetic processes undergo long synthetic procedures and low yields.
Patent publication EP0938467 describes a method in which Arformoterol is prepared via the reaction of the optically pure (R) N-benzyl-2-(4-methoxyphenyl)-1-(methylethylamine) with an optically pure (R)-4-benzyloxy-3-nitrostyrene oxide or (R)-4-benzyloxy-3-formamidostyrene oxide followed by formylation of the amino group. This method requires relatively severe reaction conditions, 24 h at a temperature of from 110 up to 130 °C as well as a further purification step using tartaric acid in order to eliminate diastereomer impurities formed during the process.
WO2009/147383 discloses a process for the preparation of intermediates of Formoterol and Arformoterol which comprises a reduction of a ketone intermediate of formula:
Figure imgb0003
Using chiral reductive agent with an enantiomeric excess of about 98% which requires further purification steps to obtain a product of desired optical purity.
 R,R)-Formoterol (Arformoterol) or a salt thereof from optically pure and stable intermediate (R)-2-(4-Benzyloxy-3-nitro-phenyl)-oxirane (compound II), suitable for industrial use, in combination with optically pure amine in higher yields, as depicted in the scheme below:
Figure imgb0011

Compound (R, R)-1-(4-Benzyloxy-3-nitro-phenyl)-2-[[2-(4-methoxy-phenyl)-1-methylethyl]-(1-phenyl-ethyl)-amino]-ethanol (compound VI), having the configuration represented by the following formula:

Figure imgb0018

Examples(R)-2-(4-Benzyloxy-3-nitro-phenyl)-oxirane (II)

A solution of 90 g (0.25 mol) of (R)-1-(4-Benzyloxy-3-nitro-phenyl)-2-bromo-ethanol (compound I) in 320 mL of toluene and 50 mL of MeOH was added to a stirred suspension of 46 g (0.33 mol) of K2CO3 in 130 mL of toluene and 130 mL of MeOH. The mixture was stirred at 40°C for 20 h and washed with water (400 mL). The organic phase was concentrated under reduced pressure to a volume of 100 mL and stirred at 25 °C for 30 min. It was then further cooled to 0-5°C for 30 min. and the product collected by filtration and dried at 40 °C to provide 67.1 g (97% yield) (98% chemical purity, 100% e.e.) of compound II as an off-white solid. 1 H-NMR (200 MHz, CDCl3) δ: 2.80-2.90 (m, 2H); 3.11-3.20 (m, 2H), 3.80-3.90 (m, 1H); 5.23 (s, 2H); 7.11 (d, 2H); 7.41 (m, 5H), 7.76 (d, 2H).

Preparation of (R,R)-[2-(4-Methoxy-phenyl)-1-methyl-ethyl]-(1-phenyl-ethyl)-amine (III)

A solution of 13 g (78.6 mmol) of 1-(4-Methoxy-phenyl)-propan-2-one and 8.3 g (78.6 mmol) of (R)-1-Phenylethylamine in 60 mL MeOH was hydrogenated in the presence of 1.7 g of Pt/C 5% at 10 atm. and 30 °C for 20 h. The mixture was filtered though a pad of diatomaceous earth and concentrated under reduced pressure to give compound III as an oil. The obtained oil was dissolved in 175 mL of acetone, followed by addition of 6.7 mL (80.9 mmol) of a 12M HCl solution. The mixture was stirred at 23 °C for 30 min and at 0-5 °C for 30 min. The product collected by filtration and dried at 40 °C to provide 13.8 g of the hydrochloride derivate as a white solid. The obtained solid was stirred in 100 mL of acetone at 23 °C for 1h and at 0-5 °C for 30 min, collected by filtration and dried at 40 °C to provide 13.2 g of the hydrochloride derivate as a white solid. This compound was dissolved in 100 mL of water and 100 mL of toluene followed by addition of 54 mL (54 mmol) of 1N NaOH solution. The organic phase was concentrated to give 11.7 g (55% yield) (99% chemical purity and 100% e.e) of compound III as an oil.1H-NMR (200 MHz, CDCl3) δ: 0.88 (d, 3H); 1.31 (d, 3H), 2.40-2.50 (m, 1H); 2.60-2.80 (m, 2H); 3.74 (s, 3H); 3.90-4.10 (m, 1H); 6.77- 6.98 (m, 4H), 7.31 (s, 5H).

Synthesis of (R,R)-1-(4-Benzyloxy-3-nitro-phenyl)-2-[[2-(4-methoxy-phenyl)-1-methyl-ethyl]-(1-phenyl-ethyl)-amino]-ethanol (IV)

A 1-liter flask was charged with 50g (0.18 mol) of II and 50g (0.18 mol) of III and stirred under nitrogen atmosphere at 140 °C for 20 h. To the hot mixture was added 200 mL of toluene to obtain a solution, which was washed with 200 mL of 1N HCl and 200 mL of water. The organic phase was concentrated under reduced pressure to give 99 g (99% yield) (88% chemical purity) of compound IV as an oil. Enantiomeric purity 100%. 1H-NMR (200 MHz, CDCl3) δ: 0.98 (d, 3H); 1.41 (d, 3H), 2.60-2.90 (m, 4H); 3.20-3.30 (m, 1H); 3.74 (s, 3H); 4.10-4.20 (m, 1H); 4.30-4.40 (m, 1H), 5.19 (s, 2H); 6.69-7.42 (m, 16H); 7.77 (s, 1H).

Synthesis of (R, R)-1-(3-Amino-4-benzyloxy-phenyl)-2-[[2-(4-methoxy-phenyl)-1-methyl-ethyl]-(1-phenyl-ethyl)-amino]-ethanol (V)

A solution of 99 g (0.18 mol) of IV in 270 mL IPA and 270 mL toluene was hydrogenated in the presence of 10 g of Ni-Raney at 18 atm and 40 °C for 20 h. The mixture was filtered though a pad of diatomaceous earth and the filtrate was concentrated under reduced pressure to give 87 g (92% yield) (83% chemical purity, 100 % e.e.) of compound V as an oil. 1H-NMR (200 MHz, CDCl3) δ: 0.97 (d, 3H); 1.44 (d, 3H), 2.60-2.90 (m, 4H); 3.20-3.30 (m, 1H); 3.74 (s, 3H); 4.10-4.20 (m, 1H); 4.30-4.40 (m, 1H), 5.07 (s, 2H); 6.67-6.84 (m, 7H); 7.25-7.42 (m, 10H).

Synthesis of (R,R)-N-(2-Benzyloxy-5-{1-hydroxy-2-[[2-(4-methoxy-phenyl)-1-methyl-ethyl]-(1-phenyl-ethyl)-amino]-ethyl)-phenyl)-formamide (VI)

24 mL (0.63 mol) of formic acid was added to 27 mL (0.28 mol) of acetic anhydride and stirred at 50 °C for 2 h under nitrogen atmosphere. The resulting mixture was diluted with 100 mL of CH2Cl2 and cooled to 0 °C. A solution of 78 g (0.15 mol) of V in 300 mL de CH2Cl2 was slowly added and stirred for 1h at 0 °C. Then, 150 mL of 10% K2CO3 aqueous solution were added and stirred at 0 °C for 15 min. The organic phase was washed twice with 400 mL of 10% K2CO3 aqueous solution and concentrated under reduced pressure to give 80 g (97% yield, 100% e.e.) (75% chemical purity) of compound VI as an oil. 1H-NMR (200 MHz, CDCl3) δ: 0.98 (d, 3H); 1.42 (d, 3H), 2.60-2.90 (m, 4H); 3.20-3.30 (m, 1H); 3.75 (s, 3H); 4.10-4.20 (m, 1H); 4.30-4.40 (m, 1H), 5.09 (s, 2H); 6.67-7.41 (m, 17H); 8.4 (d, 1H).

Synthesis (R,R)-N-(2-Hydroxy-5-{1-hydroxy-2-[2-(4-methoxy-phenyl)-1-methyl-ethylamino]-ethyl}-phenyl)-formamide (VII)

A solution of 8.5 g (16 mmol) of VI, previous purified by column chromatography on silica gel (AcOEt/heptane, 2:3), in 60 mL ethanol was hydrogenated in the presence of 0.14 g of Pd/C 5% at 10 atm. and 40 °C for 20 h. The mixture was filtered though a pad of diatomaceous earth and concentrated under reduced pressure to give 5 g (93% yield) (91% chemical purity, 100% e.e.) of compound VII as foam. m. p.= 58-60 °C. 1H-NMR (200 MHz, d6-DMSO) δ: 0.98 (d, 3H); 2.42-2.65 (m, 5H); 3.20-3.40 (m, 1H); 3.71 (s, 3H); 4.43-4.45 (m, 1H); 6.77-7.05 (m, 5H); 8.02 (s, 1H), 8.26 (s, 1H).

Synthesis (R,R)-N-(2-Hydroxy-5-{1-hydroxy-2-[2-(4-methoxy-phenyl)-1-methyl-ethylamino]-ethyl}-phenyl)-formamide (VII)

A solution of 46 g (0.08 mol) of VI, crude product, was dissolved in 460 mL ethanol and hydrogenated in the presence of 0.74 g of Pd/C 5% at 10 atm. and 40 ° C for 28 h. The mixture was filtered though a pad of diatomaceous earth and the filtrate was concentrated under reduced pressure to give 24 g (83% yield) (77% chemical purity, 100% e.e.) of compound VII as a foam. m. p. = 58-60 °C. 1H-NMR (200 MHz, d6-DMSO) δ: 0.98 (d, 3H); 2.42-2.65 (m, 5H); 3.20-3.40 (m, 1H); 3.71 (s, 3H); 4.43-4.45 (m, 1H); 6.77-7.05 (m, 5H); 8.02 (s, 1H), 8.26 (s, 1H).

The HPLC conditions used for the determination of the Chemical purity % are described in the table below:

  • HPLC Column Kromasil 100 C-18
    Dimensions 0.15 m x 4.6 mm x 5 µm
    Buffer 2.8 ml TEA (triethylamine) pH=3.00 H3PO4 (85%) in 1 L of H2O
    Phase B Acetonitrile
    Flow rate 1.5 ml miN-1
    Temperature 40 °C
    Wavelength 230 nm

    The HPLC conditions used for the determination of the enantiomeric purity % are described in the table below:

    HPLC Column Chiralpak AD-H
    Dimensions 0.25 m x 4.6 mm
    Buffer n-hexane : IPA : DEA (diethyl amine) : H2O 85:15:0.1:0.1
    Flow rate 0.8 ml min-1
    Temperature 25 °C
    Wavelength 228 nm


Example 1

(R) -2- (4- benzyloxy-3-nitrophenyl) oxirane (I) (9. 86g, 36mmol) and (R) -I- (4- methoxy- phenyl) -N – [(R) -I- phenyl-ethyl] -2-amino-propane (II) (10. 8g, 40mmol) cast in the reaction flask, the reaction 20 hours at 140 ° C, the chiral Intermediate (III) (17. 3g, yield 88%). HPLC: de values ​​of> 90%; MS (ESI) m / z: 541 3 (M ++ 1); 1H-NMR (CDCl3):.. Δ 0. 96 (d, 3H), 1 49 (d, 3H ), 2 · 15 (q, 1Η), 2 · 67 (dq, 2H), 2. 99 (dq, 2H), 3. 74 (s, 3H), 4. 09 (d, 1H), 4. 56 (q, 1H), 5. 24 (s, 2H), 6. 77 (dd, 4H), 7. 10 (d, 1H), 7. 25-7. 5 (m, 11H), 7. 84 ( s, 1H).

 Example 2

 (R) -2- (4- benzyloxy-3-nitrophenyl) oxirane (I) (9. 86g, 36mmol) and (R) -I- (4- methoxybenzene yl) -N – [(R) -I- phenyl-ethyl] -2-amino-propane (II) (10. 8g, 40mmol) and toluene 100ml, 110 ° C0-flow reactor 36 hours, the solvent was distilled off succeeded intermediates (III) (16. 8g, yield 85%).

Example 3

(R) -2- (4- benzyloxy-3-nitrophenyl) oxirane (I) (9. 86g, 36mmol) and (R) -I- (4- methoxybenzene After [(R) -I- phenyl-ethyl] -2-amino-propane (II) (10. 8g, 40mmol) and dichloromethane 100ml, 30 ° C for 48 hours, and the solvent was distilled off – yl) -N succeeded intermediates (III) (15. Sg, yield 80%).

Example 4

 (R) -2- (4- benzyloxy-3-nitrophenyl) oxirane (I) (9. 86g, 36mmol) and (R) -I- (4- methoxybenzene yl) -N – [(R) -I- phenyl-ethyl] -2-amino-propane (II) (8. 75g, 32mmol) cast in the reaction flask, the reaction 20 hours at 140 ° C, the chiral intermediate form (III) (16. 3g, 83% yield).

Example 5

 (R) -2- (4- benzyloxy-3-nitrophenyl) oxirane (I) (9. 86g, 36mmol) and (R) -I- (4- methoxybenzene yl) -N – [(R) -I- phenyl-ethyl] -2-amino-propane (II) (14. 6g, 54mmol) cast in the reaction flask, the reaction 20 hours at 140 ° C, the chiral intermediate form (III) (17. 5g, 89% yield).




chirality 1991, 3, 443-50
Fumaric acid (0.138 mmol, 16 mg) was added to the residue dissolved in methanol. Evaporation of the solvent gave the
product (SS) W semifumarate (109 mg) characterized by ‘HNMR (4-D MSO) 6 (ppm) 1.00 (d, 3H, CHCH,), 4.624.70 (m, lH,
CHOH), 3.73 (s, 3H, OCH,), 6.M.9 (m, 3H, aromatic), 7.00 (dd,4H, aromatic), 6.49 (s, 1@ CH = CH fumarate). MS of disilylated
(SS) W: 473 (M +<H3,7%); 367 (M ‘<8H90, 45%); 310 61%). The (RSS) fraction was treated in the same manner
giving the product (R;S) W semifumarate, which was characterized by ‘H-NMR (4-DMSO) 6 (ppm) 1.01 (d, 3H, CHCH,),
3.76 (s, 3H, OC&), 6.49 (s, lH, CH=CH, fumarate) 6.M.9 (m, 3H, aromatic), 7.0 (dd, 4H, aromatic). MS of disilylated (R;S)
(M’X~~HIGNO1,7 %); 178 ( C I ~H~ ~N95O%,) ; 121 (CsH90, W. 473 (M’4H3, 5%); 367 (M’4gH90, 48%); 310
(M +–CI~HIGNO18, %); 178 (CIIHIGNO, 95%); 121 (CsH90, 52%). The structural data for the (RR) and (S;R) enantiomers
were in accordance with the proposed structures. The enantiomeric purity obtained for the enantiomers in each batch is
shown in Table 1.
The enantioselective reduction of phenacyl bromide (I) with BH3.S(CH3)2 in THF catalyzed by the chiral borolidine (II) (obtained by reaction of (1R,2S)-1-amino-2-indanol (III) with BH3.S(CH3)2 in THF) gives the (R)-2-bromo-1-(4-benzyloxy-3-nitrophenyl)ethanol (IV), which is reduced with H2 over PtO2 in THF/toluene yielding the corresponding amino derivative (V). The reaction of (V) with formic acid and Ac2O affords the formamide (VI), which is condensed with the chiral (R)-N-benzyl-N-[2-(4-methoxyphenyl)-1-methylethyl]amine (VII) in THF/methanol providing the protected target compound (VIII). Finally, this compound is debenzylated by hydrogenation with H2 over Pd/C in ethanol. The intermediate the chiral (R)-N-benzyl-N-[2-(4-methoxyphenyl)-1-methylethyl]amine (VII) has been obtained by reductocondensation of 1-(4-methoxyphenyl)-2-propanone (IX) and benzylamine by hydrogenation with H2 over Pd/C in methanol yielding racemic N-benzyl-N-[2-(4-methoxyphenyl)-1-methylethyl]amine (X), which is submitted to optical resolution with (S)-mandelic acid to obtain the desired (R)-enantiomer (VII).
Org Process Res Dev1998,2,(2):96

Large-Scale Synthesis of Enantio- and Diastereomerically Pure (R,R)-Formoterol

Process Research and Development, Sepracor Inc., 111 Locke Drive, Marlborough, Massachusetts 01752
Org. Proc. Res. Dev., 1998, 2 (2), pp 96–99
DOI: 10.1021/op970116o


(R,R)-Formoterol (1) is a long-acting, very potent β2-agonist, which is used as a bronchodilator in the therapy of asthma and chronic bronchitis. Highly convergent synthesis of enantio- and diastereomerically pure (R,R)-formoterol fumarate is achieved by a chromatography-free process with an overall yield of 44%. Asymmetric catalytic reduction of bromoketone 4 using as catalyst oxazaborolidine derived from (1R, 2S)-1-amino-2-indanol and resolution of chiral amine 3 are the origins of chirality in this process. Further enrichment of enantio- and diastereomeric purity is accomplished by crystallizations of the isolated intermediates throughout the process to give (R,R)-formoterol (1) as the pure stereoisomer (ee, de >99.5%).

(R,R)-formoterol fumarate (53.5 g, 70%) as white crystals:  mp = 139 °C dec; [α]20D = −45.5 (c = 1, H2O); ee, de > 99.5%; 1H NMR (300 MHz, DMSO-d6) δ (ppm) 9.64 (s), 9.35 (d), 8.55 (d), 8.29 (s), 8.15 (s), 7.14 (d, 2 H), 7.0 (m), 6.95 (d, 2 H), 6.51 (s, 1 H), 4.82 (m, 1 H), 3.72 (s, 3 H), 3.35 (m, 1 H), 3.10 (m, 3 H), 2.58 (m, 1 H), 2.50 (br s, 2 H), 1.06 (d, 3 H).

Anal. Calcd for C42H52N4O12:  C, 62.67; H, 6.51; N, 6.96. Found: C, 62.34; H, 6.57; N, 6.85.


The intermediate N-benzyl-N-[1(R)-methyl-2-(4-methoxyphenyl)ethyl]amine (IV) has been obtained as follows: The reductocondensation of 1-(4-methoxyphenyl)-2-propanone (I) with benzylamine (II) by H2 over Pd/C gives the N-benzyl-N-[1-methyl-2-(4-methoxyphenyl)ethyl]amine (III) as a racemic mixture, which is submitted to optical resolution with L-mandelic acid in methanol to obtain the desired (R)-enantiomer (IV). The reaction of cis-(1R,2S)-1-aminoindan-2-ol (V) with trimethylboroxine in toluene gives the (1R,2S)-oxazaborolidine (VI), which is used as chiral catalyst in the enantioselective reduction of 4-benzyloxy-3-nitrophenacyl bromide (VII) by means of BH3/THF, yielding the chiral bromoethanol derivative (VIII). The reaction of (VIII) with NaOH in aqueous methanol affords the epoxide (IX), which is condensed with the intermediate amine (IV) by heating the mixture at 90 C to provide the adduct (X). The reduction of the nitro group of (X) with H2 over PtO2 gives the corresponding amino derivative (XI), which is acylated with formic acid to afford the formamide compound (XII). Finally, this compound is debenzylated by hydrogenation with H2 over Pd/C in ethanol, providing the target compound.
The synthesis of the chiral borolidine catalyst (II) starting from indoline (I), as well as the enantioselective reduction of 4′-(benzyloxy)-3′-nitrophenacyl bromide (III), catalyzed by borolidine (II), and using various borane complexes (borane/dimethylsulfide, borane/THF and borane/diethylaniline), has been studied in order to solve the problems presented in large-scale synthesis. The conclusions of the study are that the complex borane/diethylaniline (DEANB) is the most suitable reagent for large-scale reduction of phenacyl bromide (III) since the chemical hazards and inconsistent reagent quality of the borane/THF and borane/dimethylsulfide complexes disqualified their use in large-scale processes. The best reaction conditions of the reduction with this complex are presented.

Formoterol is a long-acting β2-adrenoceptor agonist and has a long duration of action of up to 12 hours. Chemically it is termed as Λ/-[2-hydroxy-5-[1-hydroxy-2-[[2-(4- methoxyphenyl)propan-2-yl]amino]ethyl]phenyl]-formamide. The structure of formoterol is as shown below.

Figure imgf000003_0001

The asterisks indicate that formoterol has two chiral centers in the molecule, each of which can exist in two possible configurations. This gives rise to four diastereomers which have the following configurations: (R,R), (S1S), (S1R) and (R1S).

(R1R) and (S1S) are mirror images of each other and are therefore enantiomers. Similarly (S1R) and (R1S) form other enatiomeric pair.

The commercially-available formoterol is a 50:50 mixture of the (R1R)- and (S1S)- enantiomers. (R,R)-formoterol is an extremely potent full agonist at the β2-adrenoceptor and is responsible for bronchodilation and has anti-inflammatory properties. On the other hand (S,S)-enantiomer, has no bronchodilatory activity and is proinflammatory.

Murase et al. [Chem.Pharm.Bull., .26(4)1123-1129(1978)] synthesized all four isomers of formoterol and examined for β-stimulant activity. In the process, racemic formoterol was subjected to optical resolution with tartaric acid.

In another attempt by Trofast et al. [Chirality, 3:443-450(1991 )], racemic 4-benzyloxy-3- nitrostryrene oxide was coupled with optically pure N-[(R)-1-phenylethyl]-2-(4- methoxyphenyl)-(R)1-methylethylamine to give diastereomeric mixtures of intermediates, which were separated by column chromatography and converted to the optically pure formoterol.

In yet another attempt, racemic formoterol was subjected to separation by using a chiral compound [International publication WO 1995/018094].

WO 98/21175 discloses a process for preparing optically pure formoterol using optically pure intermediates (R)-N-benzyl-2-(4-methoxyphenyl)-1-methylethyl amine and (R)-4- benzyloxy-3-formamidostyrene oxide.

Preparation of optically pure formoterol is also disclosed in IE 000138 and GB2380996.

Example 7

Preparation of Arformoterol

4-benzyloxy-3-formylamino-α-[N-benzyl-N-(1-methyl-2-p- methoxyphenylethyl)aminomethyl]benzyl alcohol (120gms, 0.23M), 10% Pd/C (12 gms) and denatured spirit (0.6 lit) were introduced in an autoclave. The reaction mass was hydrogenated by applying 4 kg hydrogen pressure at 25-300C for 3 hrs. The catalyst was removed by filtration and the, clear filtrate concentrated under reduced pressure below 400C to yield the title compound. (63 gms, 80%).

Example 8

Preparation of Arformoterol Tartrate

Arformoterol base (60 gms, 0.17M), 480 ml IPA , 120 ml toluene and a solution of l_(+)- tartaric acid (25.6 gms, 0.17M) in 60 ml distilled water were stirred at 25-300C for 2 hrs and further at 40°- 45°C for 3 hrs. The reaction mass was cooled to 25-300C and further chilled to 200C for 30 mins. The solid obtained was isolated by filtration to yield the title compound. (60 gms, 70%),

The tartrate salt was dissolved in hot 50% IPA-water (0.3 lit), cooled as before and filtered to provide arformoterol tartrate. (30 gms, 50 % w/w). having enantiomeric purity greater than 99%.



Organic Process Research & Development 2000, 4, 567-570
 Modulation of Catalyst Reactivity for the Chemoselective Hydrogenation of a Functionalized Nitroarene: Preparation of a Key Intermediate in the Synthesis of (R,R)-Formoterol Tartrate………..

Modulation of Catalyst Reactivity for the Chemoselective Hydrogenation of a Functionalized Nitroarene:  Preparation of a Key Intermediate in the Synthesis of (R,R)-Formoterol Tartrate

Chemical Research and Development, Sepracor Inc., 111 Locke Drive, Marlborough, Massachusetts 01752, U.S.A.
Org. Proc. Res. Dev., 2000, 4 (6), pp 567–570
DOI: 10.1021/op000287k
In the synthesis of the β2-adrenoceptor agonist (R,R)-formterol, a key step in the synthesis was the development of a highly chemoselective reduction of (1R)-2-bromo-1-[3-nitro-4-(phenylmethoxy)phenyl]ethan-1-ol to give (1R)-1-[3-amino-4-(phenylmethoxy)phenyl]-2-bromoethan-1-ol. The aniline product was isolated as the corresponding formamide. The reaction required reduction of the nitro moiety in the presence of a phenyl benzyl ether, a secondary benzylic hydroxyl group, and a primary bromide, and with no racemization at the stereogenic carbinol carbon atom. The development of a synthetic methodology using heterogeneous catalytic hydrogenation to perform the required reduction was successful when a sulfur-based poison was added. The chemistry of sulfur-based poisons to temper the reacitivty of catalyst was studied in depth. The data show that the type of hydrogenation catalyst, the oxidation state of the poison, and the substituents on the sulfur atom had a dramatic effect on the chemoselectivity of the reaction. Dimethyl sulfide was the poison of choice, possessing all of the required characteristics for providing a highly chemoselective and high yielding reaction. The practicality and robustness of the process was demonstrated by preparing the final formamide product with high chemoselectivity, chemical yield, and product purity on a multi-kilogram scale.


Tetrahedron: Asymmetry 11 (2000) 2705±2717
An ecient enantioselective synthesis of (R,R)-formoterol, a potent bronchodilator, using lipases
Francisco Campos, M. Pilar Bosch and Angel Guerrero*
 formoterol (R,R)-1 as amorphous solid. Rf: 0.27 (SiO2, AcOEt:MeOH, 1:1).‰ Š20D=-41.5 (CHCl3, c 0.53).
IR, : 3383, 2967, 2923, 1674, 1668, 1610, 1514, 1442, 1247, 1033,815 cm^1.
1H NMR (300 MHz, CDCl3), : 8.11 (b, 1H), 7.46 (b, 1H), 6.99 (d, J=8.4 Hz, 2H), 6.9±6.7 (c, 4H), 4.46 (m, 1H), 4.34 (b, 3H interchangeable), 3.74 (s, 3H), 2.90±2.45 (c, 5H), 1.02 (d,J=5.7 Hz, 3H) ppm.
13C NMR (75 MHz, CDCl3), : 160.2, 158.3, 147.7, 133.4, 130.6, 130.2 (2C),125.7, 123.7, 119.5, 117.8, 114.0 (2C), 71.3, 55.3, 54.7, 53.6, 42.0, 19.4 ppm.
CI (positive, LC-MS)(m/z, %) 435 (M+1, 100).
The tartrate salt was prepared by dissolving 13.8 mg (0.04 mmol) of(R,R)-1 and 6.0 mg (0.04 mmol) of (l)-(+)-tartaric acid in 150 mL of 85% aqueous isopropanol.
The solution was left standing overnight and the resulting crystalline solid (7.6 mg) puri®ed on areverse-phase column (1 g, Isolute SPE C18) using mixtures of MeOH±H2O as eluent. The solventwas removed under vacuum and the aqueous solution lyophilized (^35C, 0.6 bar) overnight. The(l)-(+)-tartrate salt of (R,R)-1 showed an ‰ Š20D=-29.4 (H2O, c 0.61) (>99% ee based on the
reported value 34). 34=Hett, R.; Senanayake, C. H.; Wald, S. A. Tetrahedron Lett. 1998, 39, 1705.

Diethylanilineborane:  A Practical, Safe, and Consistent-Quality Borane Source for the Large-Scale Enantioselective Reduction of a Ketone Intermediate in the Synthesis of (R,R)-Formoterol

Chemical Research and Development, Sepracor Incorporated, 111 Locke Drive, Marlborough, Massachusetts 01752, U.S.A.
Org. Proc. Res. Dev., 2002, 6 (2), pp 146–148
DOI: 10.1021/op015504b


Abstract Image

The development of a process for the use of N,N-diethylaniline−borane (DEANB) as a borane source for the enantioselective preparation of a key intermediate in the synthesis of (R,R)-formoterol l-tartrate, bromohydrin 2, from ketone 3 on kilogram scale is described. DEANB was found to be a more practical, safer, and higher-quality reagent when compared to other more conventional borane sources:  borane−THF and borane−DMS.










Drugs R D. 2004;5(1):25-7.

Arformoterol: (R,R)-eformoterol, (R,R)-formoterol, arformoterol tartrate, eformoterol-sepracor, formoterol-sepracor, R,R-eformoterol, R,R-formoterol.


Sepracor in the US is developing arformoterol [R,R-formoterol], a single isomer form of the beta(2)-adrenoceptor agonist formoterol [eformoterol]. This isomer contains two chiral centres and is being developed as an inhaled preparation for the treatment of respiratory disorders. Sepracor believes that arformoterol has the potential to be a once-daily therapy with a rapid onset of action and a duration of effect exceeding 12 hours. In 1995, Sepracor acquired New England Pharmaceuticals, a manufacturer of metered-dose and dry powder inhalers, for the purpose of preparing formulations of levosalbutamol and arformoterol. Phase II dose-ranging clinical studies of arformoterol as a longer-acting, complementary bronchodilator were completed successfully in the fourth quarter of 2000. Phase III trials of arformoterol began in September 2001. The indications for the drug appeared to be asthma and chronic obstructive pulmonary disease (COPD). However, an update of the pharmaceutical product information on the Sepracor website in September 2003 listed COPD maintenance therapy as the only indication for arformoterol. In October 2002, Sepracor stated that two pivotal phase III studies were ongoing in 1600 patients. Sepracor estimates that its NDA submission for arformoterol, which is projected for the first half of 2004, will include approximately 3000 adult subjects. Sepracor stated in July 2003 that it had completed more than 100 preclinical studies and initiated or completed 15 clinical studies for arformoterol inhalation solution for the treatment of bronchospasm in patients with COPD. In addition, Sepracor stated that the two pivotal phase III studies in 1600 patients were still progressing. In 1995, European patents were granted to Sepracor for the use of arformoterol in the treatment of asthma, and the US patent application was pending.







Volume 19, Issue 3, March 2008, Pages 279–280

New method in synthesizing an optical active intermediate for (R,R)-formoterol

  • Key Laboratory of Drug Targeting Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu 610041, China\


(R)-1-(4-Methoxyphenyl)propan-2-amine 2a, an optical active intermediate for (R,R)-formoterol, was synthesized from d-alanine in 65% overall yield by using a simple route, which contained protecting amino group, cyclization, coupling with Grignard reagent, reduction and deprotection.


 IR spectra of (a) (R,R)-formoterol tartrate/form A, (b) (R,R)-formoterol tartrate/form B, (c) (R,R)-formoterol tartrate/form C.


Muller, P., et al.: Arzneimittel-Forsch., 33, 1685 (1983); Wallmark, B., et al.: Biochim. Biophys. Acta., 778, 549 (1984); Morii, M., et al.: J. Biol. chem., 268, 21553 (1993); Ritter, M., et al.: Br. J. Pharmacol., 124, 627 (1998); Stenhoff, H., et al.: J. Chromatogr., 734, 191 (1999), Johnson, D.A., et al.: Expert Opin. Pharmacother., 4, 253 (2003); Bouyssou, T., et al.: Bio. Med. Chem. Lett. 20, 1410, (2010);

External links

EP0390762A1 * 23 Mar 1990 3 Oct 1990 Aktiebolaget Draco New bronchospasmolytic compounds and process for their preparation
EP0938467A1 7 Nov 1997 1 Sep 1999 Sepracor, Inc. Process for the preparation of optically pure isomers of formoterol
EP1082293A2 20 May 1999 14 Mar 2001 Sepracor Inc. Formoterol polymorphs
WO2009147383A1 2 Jun 2009 10 Dec 2009 Cipla Limited Process for the synthesis of arformoterol
1 * HETT R ET AL: “Enantio- and Diastereoselective Synthesis of all Four Stereoisomers of Formoterol” TETRAHEDRON LETTERS, ELSEVIER, AMSTERDAM, NL LNKD- DOI:10.1016/S0040-4039(97)00088-9, vol. 38, no. 7, 17 February 1997 (1997-02-17), pages 1125-1128, XP004034214 ISSN: 0040-4039
2 * LING HUANG ET AL.: “The Asymmetric Synthesis of (R,R)-Formoterol via Transfer Hydrogenation with Polyethylene Glycol Bound Rh Catalyst in PEG2000 and Water” CHIRALITY, vol. 22, 30 April 2009 (2009-04-30), pages 206-211, XP002592699
3 MURASE ET AL. CHEM. PHARM. BULL. vol. 26, no. 4, 1978, pages 1123 – 1129
4 TROFAST ET AL. CHIRALITY vol. 1, 1991, page 443

Durham E-Theses A Solid-state NMR Study of Formoterol Fumarate

Arformoterol ball-and-stick model.png
Systematic (IUPAC) name
N-[2-hydroxy-5-[(1R)-1-hydroxy-2-[[(2R)-1-(4-methoxyphenyl) propan-2-yl]amino]ethyl] phenyl]formamide
Clinical data
Trade names Brovana
AHFS/ Monograph
MedlinePlus a602023
License data
  • US: C (Risk not ruled out)
Routes of
Inhalation solution fornebuliser
Legal status
Legal status
Pharmacokinetic data
Protein binding 52–65%
Biological half-life 26 hours
CAS Number 67346-49-0 Yes
ATC code none
PubChem CID 3083544
DrugBank DB01274 Yes
ChemSpider 2340731 Yes
ChEBI CHEBI:408174 Yes
Chemical data
Formula C19H24N2O4
Molar mass 344.405 g/mol




CAS Registry Number: 73573-87-2
CAS Name: relN-[2-Hydroxy-5-[(1R)-1-hydroxy-2-[[(1R)-2-(4-methoxyphenyl)-1-methylethyl]amino]ethyl]phenyl]formamide
Additional Names: 3-formylamino-4-hydroxy-a-[N-[1-methyl-2-(p-methoxyphenyl)ethyl]aminomethyl]benzyl alcohol; (±)-2¢-hydroxy-5¢-[(RS)-1-hydroxy-2-[[(RS)-p-methoxy-a-methylphenethyl]amino]ethyl]formanilide
Molecular Formula: C19H24N2O4
Molecular Weight: 344.40
Percent Composition: C 66.26%, H 7.02%, N 8.13%, O 18.58%
Literature References: Selective b2-adrenergic receptor agonist. Mixture of R,R (-) and S,S (+) enantiomers. Prepn: M. Murakamiet al., DE 2305092; eidem, US 3994974 (1973, 1976 both to Yamanouchi); K. Murase et al., Chem. Pharm. Bull. 25, 1368 (1977). Absolute configuration and activity of isomers: eidem, ibid. 26, 1123 (1978). Toxicity studies: T. Yoshida et al., Pharmacometrics26, 811 (1983). HPLC determn in plasma: J. Campestrini et al., J. Chromatogr. B 704, 221 (1997). Review of pharmacology: G. P. Anderson, Life Sci. 52, 2145-2160 (1993); and clinical efficacy: R. A. Bartow, R. N. Brogden, Drugs 55, 303-322 (1998).
Derivative Type: Fumarate dihydrate
CAS Registry Number: 43229-80-7
Manufacturers’ Codes: BD-40A
Trademarks: Atock (Yamanouchi); Foradil (Novartis); Oxeze (AstraZeneca)
Molecular Formula: (C19H24N2O4)2.C4H4O4.2H2O
Molecular Weight: 840.91
Percent Composition: C 59.99%, H 6.71%, N 6.66%, O 26.64%
Properties: Crystals from 95% isopropyl alcohol, mp 138-140°. pKa1 7.9; pKa2 9.2. Log P (octanol/water): 0.4 (pH 7.4). Freely sol in glacial acetic acid; sol in methanol; sparingly sol in ethanol, isopropanol; slightly sol in water. Practically insol in acetone, ethyl acetate, diethyl ether. LD50 in male, female, rats, mice (mg/kg): 3130, 5580, 6700, 8310 orally; 98, 100, 72, 71 i.v.; 1000, 1100, 640, 670 s.c.; 170, 210, 240, 210 i.p. (Yoshida).
Melting point: mp 138-140°
pKa: pKa1 7.9; pKa2 9.2
Log P: Log P (octanol/water): 0.4 (pH 7.4)
Toxicity data: LD50 in male, female, rats, mice (mg/kg): 3130, 5580, 6700, 8310 orally; 98, 100, 72, 71 i.v.; 1000, 1100, 640, 670 s.c.; 170, 210, 240, 210 i.p. (Yoshida)
Derivative Type: R,R-Form
CAS Registry Number: 67346-49-0
Additional Names: Arformoterol
Derivative Type: R,R-Form L-tartrate
CAS Registry Number: 200815-49-2
Additional Names: Arformoterol tartrate
Molecular Formula: C19H24N2O4.C4H6O6
Molecular Weight: 494.49
Percent Composition: C 55.86%, H 6.12%, N 5.67%, O 32.36%
Literature References: Prepn: Y. Gao et al., WO 9821175; eidem, US 6040344 (1998, 2000 both to Sepracor). Pharmacology: D. A. Handley et al., Pulm. Pharmacol. Ther. 15, 135 (2002).
Properties: Off-white powder, mp 184°.
Melting point: mp 184°
Therap-Cat: Antiasthmatic.
Keywords: ?Adrenergic Agonist; Bronchodilator; Ephedrine Derivatives.

//////Arformoterol, (R,R)-Formoterol, (R,R)-Formoterol-L-(+)-tartrate, 200815-49-2, Arformoterol tartrate , Brovana, UNII:5P8VJ2I235, Sepracor, Asthma Therapy, Bronchodilators, Chronic Obstructive Pulmonary Diseases, COPD ,  RESPIRATORY DRUGS, beta2-Adrenoceptor Agonists, Phase III, 2007, Sunovion




 GENERIC, Uncategorized  Comments Off on Gemfibrozil
Aug 022016


CAS: 25812-30-0
 5-(2,5-Dimethylphenoxy)-2,2-dimethylpentanoic acid
2,2-dimethyl-5-(2,5-xylyloxy)valeric acid
Manufacturers’ Codes: CI-719
Trademarks: Decrelip (Ferrer); Genlip (Teofarma); Gevilon (Pfizer); Lipozid (Pfizer); Lipur (Pfizer); Lopid (Pfizer)
MF: C15H22O3
MW: 250.33
Percent Composition: C 71.97%, H 8.86%, O 19.17%
Properties: Crystals from hexane, mp 61-63°. bp0.02 158-159°. LD50 in mice, rats (mg/kg): 3162, 4786 orally (Kurtz).
Melting point: mp 61-63°
Boiling point: bp0.02 158-159°
Toxicity data: LD50 in mice, rats (mg/kg): 3162, 4786 orally (Kurtz)
Therap-Cat: Antilipemic.


5-(2,5-Dimethylphenoxy)-2,2-dimethylpentanoic Acid

Gemfibrozil is classified as a fibric acid derivative and is used in the treatment of hyperlipidaemias. It has effects on plasma-lipid concentrations similar to those described under bezafibrate. The major effects of gemfibrozil have been a reduction in plasma-triglyceride concentrations and an increase in high-density lipoprotein (HDL) cholesterol concentrations. A reduction in very-low-density lipoprotein (VLDL)-triglyceride appears to be largely responsible for the fall in plasma triglyceride although reductions in HDL and low-density lipoprotein (LDL)-triglycerides have also been reported.
The effects of gemfibrozil on total cholesterol have been more variable: in general, LDL-cholesterol may be decreased in patients with pre-existing high concentrations and raised in those with low concentrations. The increase in HDL-cholesterol concentrations has resulted in complementary changes to the ratios of HDL-cholesterol to LDL-cholesterol and to total cholesterol. Gemfibrozil has successfully raised HDL-cholesterol concentrations in patients with isolated low levels of HDL-cholesterol but otherwise normal cholesterol concentrations.The Helsinki heart study assessed gemfibrozil for the primary prevention of ischaemic heart disease in middle-aged men with hyperlipidaemia. The usual dose, by mouth, is 1.2 g daily in two divided doses given 30 min before the morning and evening meals. Gemfibrozil is available as tablets for oral administration (Lopid: USP).

IR (KBr, cm–1): 2959.03, 2919.78, 2877.65, 1709.42, 1613.44, 1586.60, 1511.07, 1473.81, 1414.01, 1387.89, 1317.61, 1286.34, 1271.91, 1214.39, 1159.26, 1048.83, 996.57, 803.75;

1H NMR (DMSO, 500 MHz, δ ppm): 1.12 (s, 6H), 1.60 and 1.67 (m, 4H), 2.08 (s, 3H), 2.24 (s, 3H), 3.90 (t, 2H), 6.62 (d, 1H), 6.70 (s, 1H), 6.97 (d, 1H);

13C NMR and DEPT (DMSO, 500 MHz, δ ppm): 15.39 (CH3), 20.94 (CH3), 24.67 (CH2), 24.87 (CH3, CH3), 36.43 (CH2), 40.91 (C), 67.57 (CH2), 112.07 (CH), 120.45 (CH), 122.44 (C), 129.96 (CH), 135.93 (C), 156.43 (C), 178.56 (C);

MS M/Z (ESI): 251.16 [(MH)+].



Solvent:CDCl3Instrument Type:JEOLNucleus:1HFrequency:400 MHzChemical Shift Reference:TMS


1H NMR spectrum of C15H22O3 in CDCL3 at 400 MHz

Gemfibrozil is the generic name for an oral drug used to lower lipid levels. It belongs to a group of drugs known as fibrates. It is most commonly sold as the brand name, Lopid. Other brand names include Jezil and Gen-Fibro.


Gemfibrozil was selected from a series of related compounds synthesized in the laboratories of the American company Parke Davisin the late 1970s. It came from research for compounds that lower plasma lipid levels in humans and in animals.[1]


Therapeutic effects

Nontherapeutic effects and toxicities


Contraindications and precautions

  • Gemfibrozil should not be given to these patients:
    • Hepatic dysfunction
  • Gemfibrozil should be used with caution in these higher risk categories:
    • Biliary tract disease
    • Renal dysfunction
    • Pregnant women
    • Obese patients

Drug interactions

Environmental data

Gemfibrozil has been detected in biosolids (the solids remaining after wastewater treatment) at concentrations up to 2650 ng/g wet weight.[3] This indicates that it survives the wastewater treatment process.






The sodium isobutyrate (I) is metallated with lithium diisopropylamide, and the resulting compound is alkylated with 3- (2,5-dimethylphenoxy) propyl bromide.



Paul, L. C. 2,2-Dimethyl-ω-aryloxy alkanoic acids and salts and ester thereof. U.S. 3,674,836, 1972.


Production of Gemfibrozil
(1)2,5-Dimethylphenol and 1-Bromo-3-chloropropane reaction of 1-(2,5-dimethylphenoxy)-3-chloropropane. The reaction is carried out in toluene, adding new clean off reflux 5h. Just as follows:

Production of Gemfibrozil

(2)N/A can be used to manufacture Gemfibrozil.

Production of Gemfibrozil


Improved Process for Preparation of Gemfibrozil, an Antihypolipidemic

Chemical Research and Development, Aurobindo Pharma Ltd., Survey No. 71 and 72, Indrakaran (V), Sangareddy (M), Medak District-502329, Andhra Pradesh, India
Engineering Chemistry Department, AU College of Engineering, Andhra University, Visakhapatnam-530003, Andhra Pradesh, India
Org. Process Res. Dev., 2013, 17 (7), pp 963–966

An improved process for the preparation of gemfibrozil, an antihypolipodimic drug substance, with an overall yield of 80% and ∼99.9% purity (including three chemical reactions) is reported. Formation and control of possible impurities are also described. Finally, gemfibrozil is isolated from water without any additional solvent purification.


Literature References:

Serum lipid regulating agent. Prepn: P. L. Creger, DE 1925423; eidem, US 3674836 (1969, 1972, both to Parke, Davis).

Production: O. P. Goel, US 4126637 (1978 to Warner-Lambert).

Pharmacology: A. H. Kissebach et al.,Atherosclerosis 24, 199 (1976); M. T. Kahonen et al., ibid. 32, 47 (1979).

Series of articles on metabolism, clinical pharmacology, kinetics and toxicology: Proc. R. Soc. Med. 69, Suppl 2, 1-120 (1976).

Toxicity data: S. M. Kurtz et al., ibid. 15.

Clinical trial in hyperlipidemia: J. E. Lewis et al., Pract. Cardiol. 9, 99 (1983).

Clinical reduction of cardiovascular risk in patients with low HDL levels: H. B. Rubins et al., N. Engl. J. Med. 341, 410 (1999).


External links

Systematic (IUPAC) name
5-(2,5-dimethylphenoxy)-2,2-dimethyl-pentanoic acid
Clinical data
Trade names Lopid
AHFS/ Monograph
MedlinePlus a686002
  • Category C
Routes of
Legal status
Legal status
  • By Prescription
Pharmacokinetic data
Bioavailability Close to 100%
Protein binding 95%
Metabolism Hepatic (CYP3A4)
Biological half-life 1.5 hours
Excretion Renal 94%
Feces 6%
CAS Number 25812-30-0 Yes
ATC code C10AB04 (WHO)
PubChem CID 3463
DrugBank DB01241 Yes
ChemSpider 3345 Yes
UNII Q8X02027X3 Yes
KEGG D00334 Yes
ChEBI CHEBI:5296 Yes
Chemical data
Formula C15H22O3
Molar mass 250.333 g/mol

LOPID® (gemfibrozil tablets, USP) is a lipid regulating agent. It is available as tablets for oral administration. Each tablet contains 600 mg gemfibrozil. Each tablet also contains calcium stearate, NF; candelilla wax, FCC; microcrystalline cellulose, NF; hydroxypropyl cellulose, NF; hypromellose, USP; methylparaben, NF; Opaspray white; polyethylene glycol, NF; polysorbate 80, NF; propylparaben, NF; colloidal silicon dioxide, NF; pregelatinized starch, NF. The chemical name is 5-(2,5-dimethylphenoxy)2,2-dimethylpentanoic acid, with the following structural formula:


LOPID® (gemfibrozil) Structural Formula Illustration

The empirical formula is C15H22O3 and the molecular weight is 250.35; the solubility in water and acid is 0.0019% and in dilute base it is greater than 1%. The melting point is 58° –61°C. Gemfibrozil is a white solid which is stable under ordinary conditions.

/////////Gemfibrozil,  Antilipemic,  Fibrates, 25812-30-0,



ацетазоламид , أسيتازولاميد [, 乙酰唑胺 , ACETAZOLAMIDE

 GENERIC  Comments Off on ацетазоламид , أسيتازولاميد [, 乙酰唑胺 , ACETAZOLAMIDE
Aug 022016

ChemSpider 2D Image | acetazolamide | C4H6N4O3S2

ацетазоламид ,  أسيتازولاميد [,  乙酰唑胺 ,
CAS 59-66-5
Acetamide, N-(5-(aminosulfonyl)-1,3,4-thiadiazol-2-yl)-
MW 222.245,MF  C4H6N4O3S2
Title: Acetazolamide
CAS Registry Number: 59-66-5
CAS Name: N-[5-(Aminosulfonyl)-1,3,4-thiadiazol-2-yl]acetamide
Additional Names: 5-acetamido-1,3,4-thiadiazole-2-sulfonamide; 2-acetylamino-1,3,4-thiadiazole-5-sulfonamide
Manufacturers’ Codes: 6063
Trademarks: Acetamox (Tobishi-Santen); Atenezol (Tsuruhara); Défiltran (Gallier); Diamox (Barr); Didoc (Sawai); Diuriwas (IFI); Donmox (Horita); Edemox (Wassermann); Fonurit (Chinoin); Glaupax (Erco)
Molecular Formula: C4H6N4O3S2
Molecular Weight: 222.25
Percent Composition: C 21.62%, H 2.72%, N 25.21%, O 21.60%, S 28.85%
Literature References: Carbonic anhydrase inhibitor. Prepn: R. O. Roblin, J. W. Clapp, J. Am. Chem. Soc. 72, 4890 (1950); J. W. Clapp, R. O. Roblin, US 2554816 (1951 to Am. Cyanamid). HPLC determn in pharmaceuticals: Z. S. Gomaa, Biomed. Chromatogr. 7, 134 (1993). Effect on retinal circulation: S. M. B. Rassam et al., Eye 7, 697 (1993). Clinical trial in postoperative elevation of intraocular pressure: I. D. Ladas et al., Br. J. Ophthalmol. 77, 136 (1993). Comprehensive description: J. Parasrampuria, Anal. Profiles Drug Subs. Excip. 22, 1-32 (1993). Review of efficacy in acute mountain sickness: L. D. Ried et al.,J. Wilderness Med. 5, 34-48 (1994).
Properties: Crystals from water, mp 258-259° (effervescence). Weak acid. pKa 7.2. Sparingly sol in cold water. Slightly sol in alcohol, acetone. Practically insol in carbon tetrachloride, chloroform, ether. Soly (mg/ml): polyethylene glycol-400 87.81; propylene glycol 7.44; ethanol 3.93; glycerin 3.65; water 0.72.
Melting point: mp 258-259° (effervescence)
pKa: pKa 7.2
Derivative Type: Sodium salt
CAS Registry Number: 1424-27-7
Trademarks: Vetamox (Am. Cyanamid)
Therap-Cat: Antiglaucoma; diuretic; in treatment of acute mountain sickness.
Therap-Cat-Vet: Diuretic.
Keywords: Antiglaucoma; Carbonic Anhydrase Inhibitor; Diuretic; Sulfonamide Derivatives.
Starting reaction occurs in-between hydrazine hydrate and ammonium thiocyanate that produces 1, 2-bis (thiocarbamoyl) hydrazine which on further treatment with phosgene undergoesrearrangements, particularly  molecular rearrangement through loss of ammonia to form 5-amino-2-mercapto-1, 3, 4-thiadiazole. Upon acylation of 5-amino-2-mercapto-1, 3, 4-thiadiazole gives a corresponding amide which on oxidation with aqueous chlorine affords the 2-sulphonyl chloride. The final step essentially consists of amidation by treatment with ammonia.











14N NQR, 1H NMR and DFT/QTAIM study of hydrogen bonding and polymorphism in selected solid 1,3,4-thiadiazole derivatives

Corresponding authors
a»Jozef Stefan« Institute, Jamova 39, 1000 Ljubljana, Slovenia
Fax: +386 1 2517281
Tel: +386 1 4766576
bFaculty of Mathematics and Physics, University of Ljubljana, Jadranska 19, 1000 Ljubljana, Slovenia
cFaculty of Physics, Adam Mickiewicz University, Umultowska 85, 61-614 Poznań, Poland
Phys. Chem. Chem. Phys., 2010,12, 13007-13019

DOI: 10.1039/C0CP00195C,!divAbstract

Graphical abstract: 14N NQR, 1H NMR and DFT/QTAIM study of hydrogen bonding and polymorphism in selected solid 1,3,4-thiadiazole derivatives


The 1,3,4-thiadiazole derivatives (2-amino-1,3,4-thiadiazole, acetazolamide, sulfamethizole) have been studied experimentally in the solid state by 1H–14N NQDR spectroscopy and theoretically by Density Functional Theory (DFT). The specific pattern of the intra and intermolecular interactions in 1,3,4-thiadiazole derivatives is described within the QTAIM (Quantum Theory of Atoms in Molecules)/DFT formalism. The results obtained in this work suggest that considerable differences in the NQR parameters permit differentiation even between specific pure association polymorphic forms and indicate that the stronger hydrogen bonds are accompanied by the larger η and smaller ν and e2Qq/h values. The degree of π-electron delocalization within the 1,3,4-thiadiazole ring and hydrogen bonds is a result of the interplay between the substituents and can be easily observed as a change in NQR parameters at N atoms. In the absence of X-ray data NQR parameters can clarify the details of crystallographic structure revealing information on intermolecular interactions.

////////////ацетазоламид ,  أسيتازولاميد [,  乙酰唑胺 , ACETAZOLAMIDE




SPIRONOLACTONE, спиронолактон , سبيرونولاكتون , 螺内酯 ,

 GENERIC, Uncategorized  Comments Off on SPIRONOLACTONE, спиронолактон , سبيرونولاكتون , 螺内酯 ,
Jul 282016

Skeletal formula of spironolactone


Spironolactone, Supra-puren, Suracton, спиронолактон, سبيرونولاكتون ,

螺内酯 , Abbolactone, Aldactide, SNL, Spiroctanie, Sprioderm, Verospirone,  Opianin

7α-Acetylthio-17α-hydroxy-3-oxopregn-4-ene-21-carboxylic acid γ-lactone


(7a,17a)-7-(Acetylthio)-17-hydroxy-3-oxopregn-4-ene-21-carboxylic acid g-lactone
17-Hydroxy-7a-mercapto-3-oxo-17a-pregn-4-ene-21-carboxylic Acid g-Lactone Acetate
3-(3-Oxo-7a-acetylthio-17b-hydroxy-4-androsten-17a-yl)propionic Acid g-Lactone
 CAS 52-01-7

MF C24H32O4S, MW 416.573 Da

ChemSpider 2D Image | spironolactone | C24H32O4SSpironolactone, marketed under the brand name Aldactone among others, is a medication primarily used to treatfluid build-up due to heart failure, liver scarring, or kidney disease.[1] Other uses include high blood pressure, low blood potassium that does not improve with supplementation, early puberty, excessive hair growth in women,[1] and as a component of hormone replacement therapy for transgender women.[6] It is taken by mouth.[1]

Common side effects include electrolyte abnormalities particularly high blood potassium, nausea, vomiting, headache, a rash, and a decreased desire for sex. In those with liver or kidney problems extra care should be taken.[1]Spironolactone has not been well studied in pregnancy and should not be used to treat high blood pressure of pregnancy.[7] It is a steroid that blocks mineralocorticoid receptors. It also blocks androgen, and blocks progesterone. It belongs to a class of medications known as potassium-sparing diuretics.[1]

Spironolactone was introduced in 1959.[8][9] It is on the World Health Organization’s List of Essential Medicines, the most important medications needed in a basic health system.[10] It is available as a generic medication.[1] The wholesale cost in the developing world as of 2014 is between 0.02 and 0.12 USD per day.[11] In the United States it costs about 0.50 USD per day.[1]


Title: Spironolactone
CAS Registry Number: 52-01-7
CAS Name: (7a,17a)-7-(Acetylthio)-17-hydroxy-3-oxopregn-4-ene-21-carboxylic acid g-lactone
Additional Names: 17-hydroxy-7a-mercapto-3-oxo-17a-pregn-4-ene-21-carboxylic acid g-lactone, acetate; 3-(3-oxo-7a-acetylthio-17b-hydroxy-4-androsten-17a-yl)propionic acid g-lactone
Manufacturers’ Codes: SC-9420
Trademarks: Aldactone (Pharmacia & Upjohn); Aquareduct (Azupharma); Practon (Pfizer); Osyrol (Aventis); Sincomen (Schering AG); Spirobeta (Betapharm); Spiroctan (Ferlux); Spirolone (APS); Spironone (Dexo); Verospiron (Richter Gedeon); Xenalon (Mepha)
Molecular Formula: C24H32O4S
Molecular Weight: 416.57
Percent Composition: C 69.20%, H 7.74%, O 15.36%, S 7.70%
Literature References: Aldosterone antagonist. Prepn: Cella, Tweit, J. Org. Chem. 24, 1109 (1959); US 3013012 (1961 to Searle); Tweit et al., J. Org. Chem. 27, 3325 (1962). Activity and metabolic studies: Gerhards, Engelhardt, Arzneim.-Forsch. 13, 972 (1963). Crystal and molecular structure: Dideberg, Dupont, Acta Crystallogr. B28, 3014 (1972). Comprehensive description: J. L. Sutter, E. P. K. Lau, Anal. Profiles Drug Subs. 4, 431-451 (1975). Review of carcinogenetic risk: IARC Monographs 24, 259-273 (1980). Review of antiandrogen effects and clinical use in hirsutism: R. R. Tremblay, Clin. Endocrinol. Metab. 15, 363-371 (1986); of clinical efficacy in hypertension: A. N. Brest, Clin. Ther. 8, 568-585 (1986). Review of pharmacology: H. A. Skluth, J. G. Gums,DICP Ann. Pharmacother. 24, 52-59 (1990). Clinical trial in congestive heart failure: B. Pitt et al., N. Engl. J. Med. 341, 709 (1999).
Properties: Crystals from methanol, mp 134-135° (resolidifies and dec 201-202°). [a]D20 -33.5° (chloroform). uv max: 238 nm (e20200). Practically insol in water. Sol in alcohol; freely sol in benzene, chloroform. LD50 in rats, mice, rabbits (mg/kg): 790, 360, 870 i.p. (IARC, 1980).
Melting point: mp 134-135° (resolidifies and dec 201-202°)
Optical Rotation: [a]D20 -33.5° (chloroform)
Absorption maximum: uv max: 238 nm (e 20200)
Toxicity data: LD50 in rats, mice, rabbits (mg/kg): 790, 360, 870 i.p. (IARC, 1980)
Therap-Cat: Diuretic.
Therap-Cat-Vet: Diuretic.
Keywords: Aldosterone Antagonist; Diuretic; Steroids

Medical uses

Spironolactone is used primarily to treat heart failure, edematous conditions such as nephrotic syndrome or ascites in people with liver disease, essential hypertension, hypokalemia, secondary hyperaldosteronism (such as occurs with hepatic cirrhosis), and Conn’s syndrome (primary hyperaldosteronism). On its own, spironolactone is only a weak diuretic because it primarily targets the distal nephron (collecting tubule), where only small amounts of sodium are reabsorbed, but it can be combined with other diuretics to increase efficacy.

Spironolactone is an antagonist of the androgen receptor (AR) as well as an inhibitor of androgen production. Due to the antiandrogenic effects that result from these actions, it is frequently used off-label to treat a variety of dermatological conditions in which androgens, such as testosterone and dihydrotestosterone (DHT), play a role. Some of these uses include androgenic alopecia in men (either at low doses or as a topical formulation) and women, and hirsutism, acne, and seborrhea in women.[12] Spironolactone is the most commonly used drug in the treatment of hirsutism in the United States.[13] Higher doses of spironolactone are not recommended in males due to the high risk of feminization and other side effects. Similarly, it is also commonly used to treat symptoms of hyperandrogenism in polycystic ovary syndrome.[14]


Spironolactone (SL) is known to be a potent aldosterone antagonist at mineralocorticoid steroid hormone receptors, and it is widely used in humans for the treatment of essential hypertension, congestive heat failure and refractory edema or hyperaldosteronism. However, the prolonged use of SL is associated with undesirable endocrine side effects such as gynecomastia and lose of libido in men and menstrual irregularities in women due to interaction of SL with gonadal steroid hormone biosynthesis and target cell gonadal steroid receptors.

The nature and prevalence of the undesirable side effects limit the usefulness of spironolactone as a therapeutic agent. Gynecomastia or tender breast enlargement has been found to occur in 10% of hypertensive patients using spironolactone for therapy as compared to 1% of men in the placebo group. Recent studies by Pitt, et al. with spironolactone have shown that in patients with congestive heart failure (CHF) taking digoxin and a loop diuretic—spironolactone therapy in conjunction with digitalis and ACE inhibitor—reduces mortality by 30%. See Pitt, B., et al., The Effect of Spironolactone on Morbidity and Mortality in Patients with Severe Heart Failure, Randomized Aldactone Evaluation Study Investigors; N. Engl. J. Med., 1999, 341:709-717. These authors stated that the 30% reduction in the risk of death among patients in the group receiving spironolactone could be attributed to a lower risk of both death from progressive heart failure and sudden death from cardiac arrhythmic causes. In addition, they found that the frequency of hospitalization for worsening heart failure is 35% lower in the spironolacotone treated group than in the placebo group. These authors concluded that patients who received spironolactone had a significant improvement in the symptoms of severe heart failure caused by systolic left ventricular dysfunction. Overall, 8% of the patients in the spironolactone group discontinued treatment because of adverse events. The purpose of the present invention is to make available the individual chiral isomers of spironolactone that would be effective in treating CHF and in reducing hypertension, and at the same time would be devoid of undesirable side effects such as gynecomastia, lose of libido in men, and menstrual irregularities in women.

Spironolactone is the name commonly used for a specific spirolactone that has the full chemical name 17-hydroxy-7-alpha-mercapto-3-oxo-17-alpha-pregn-4-ene-21-carboxylic acid gamma-lactone acetate. The term “spirolactone” denotes that a lactone 10 ring (i.e., a cyclic ester) is attached to another ring structure in a spiro configuration (i.e., the lactone ring shares a single carbon atom with the other ring). Spirolactones that are coupled to steroids are the most important class of spirolactones from a pharmaceutical perspective, so they are widely referred to in the pharmaceutical arts simply as spirolactones. As used herein, “spironolactone” refers to a molecule comprising a lactone structure coupled via a spiro configuration to a steroid structure or steroid derivative.

Spironolactone, its activities, and modes of synthesis and purification are described in a number of U.S. patents, notably U.S. Pat. Nos. 3,013,012, 4,529,811 and 4,603,128.

Intracellular receptors (IRs) form a class of structurally-related genetic regulators that act as ligand-dependent transcription factors. See Evans, R. M., “The Steroid and Thyroid Hormone Receptor Superfamily”, Science, May 13, 1988; 240(4854):889-95. Steroid receptors are a recognized subset of the IRs, including the progesterone receptor (PR), androgen receptor (AR), estrogen receptor (ER), which can be referred to collectively as the gonadal steroid receptors, glucocorticoid receptor (GR), and mineralocorticoid receptor (MR). Regulation of a gene by such factors requires both the IR itself and a corresponding ligand that has the ability to selectively bind to the IR in a way that affects gene transcription.

Ligands for the IRs can include low molecular weight native molecules, such as the hormones aldosterone, progesterone, estrogen and testosterone, as well as synthetic derivative compounds such as medroxyprogesterone acetate, diethylstilbesterol and 19-nortestosterone. These ligands, when present the fluid surrounding a cell, pass through the outer cell membrane by passive diffusion and bind to specific IR proteins to create a ligand/receptor complex. This complex then translocates to the cell’s nucleus, where it binds to a specific gene or genes present in the cell’s DNA. Once bound to DNA, the complex modulates the production of the protein encoded by that gene. In this regard, a compound that binds to an IR and mimics the effect of the native ligand is referred to as an “agonist”, while a compound that binds to an IR and inhibits the effect of the native ligand is called an “antagonist”.

The therapeutic mechanism of action of spironolactone involves binding to intracellular mineralocorticoid receptors (MRs) in kidney epithelial cells, thereby inhibiting the binding of aldosterone. Spironolactone has been found to counteract the sodium reabsorption and potassium excretion effects of aldosterone and other mineralocorticoids. Spironolactone has also been shown to interfere with testosterone biosynthesis, has anti-androgen action and inhibits adrenal aldosterone biosynthesis. Large doses of spironolactone in children appear to decrease the testosterone production rate.

Spironolactone is found to exhibit intra-individual variability of pharmacokinetic parameters and it presumably belongs to the group of drugs with high inter-subject variability. Spironolactone has poor water solubility and dissolution rate.

In order to prolong the half-life and decrease the side effects associated with spironolactone, syntheses of spironolactone derivatives have been developed (e.g. synthesis of mexrenone, prorenone, spirorenone). Slight modifications of the spironolactone steroid skeleton, e.g. such as formation of 11β-allenic and epoxy compounds, have been shown to effect important variations in the affinity and specificity for the mineralocorticoid receptor. These results suggest that it is possible to develop spironolactone analogues that do not interact with the androgen receptor or cytochrome P-450 and are therefore free of spironolactone undesirable side-effects.


Figure US20090325918A1-20091231-C00003




REF 130, 150














Cella, John A.; Tweit, Robert C. (1959). Journal of Organic Chemistry 24: 1109. doi:10.1021/jo01090a019.

(See also part 1 and part 3)






The principal absorption peaks of the spectrum shown in Figure 5 were noted at 1765,
1693, 1673, 1240, 1178, 1135, 1123 and 1193 cm -1.












130 J.A. Cola, E.A. Brown, and R.R. Burtner, 3. Org. Chem., 24, 1109(1959).

 140 Remington’s: The Science and Practice of Pharmacy, 19 t~ edn.Volume II, K.G. Alfonso, ed.; Mack Publishing Co., Pennsylvania (1995) p.1048.
150. G. Anner and H. Wehrli (Ciba-Geigy, A.-G.), German Often 2,625,723 (cl.C07J21/00), Dec,1976; Swiss Appl. 75/7, 696, 13Jun. 1975; pp. 37.


    • High-Performance Liquid Chromatographic Conditions
      Column LiChrosorb RP-8, 5 μm. 150 × 4.6 mm I.D.
      Eluent Acetonitrile-0.05 M phosphate buffer, pH 4 (45:55)
      Flow-rate 1 ml/min
      Temperature 25° C.
      Detector UV detector, wavelength 286 nm or 271 nm
      Recorder Chart speed 0.5 cm/min
      Sample loop 10 μl
    • The concentration of canrenone is determined in plasma and urine samples by high-performance liquid chromatography (HPLC) with UV-detection. An aliquot of 300 ng of spironolactone derivative is added to the samples as internal standard, which are then extracted twice with 1 ml n-hexane-toluene (1:1, v/v). The organic phase is taken to dryness and re-dissolved in 250 μl HPLC eluent (methanol-water, 60:40, v/v). (25×4.6 mm; 5 μm). Detection is performed with the UV detector set at λ=285 nm.

Flurometric Method

    Five ml of water is a reagent blank and 5 ml of working standards containing 0.05 μg and 0.20 μg of SC-9376 are carried through the entire procedure. Lower sales are read vs. the 0.05 μg standard at full scale, and higher samples vs. the 0.20 μg standard. Fluorescence readings are proportional to the concentrations of the standards in this range.
      Pipette 0.2 ml of heparinized plasma into a 50-ml polyethylene-stoppered centrifuge tube, dilute to 5 ml with water and add 15 ml of methylene chloride (Du Pont refrigeration grade, redistilled). Shake for 30 seconds, centrifuge and discard the aqueous supernatant. Add 1 ml 0.1 N NaOH, shake 15 seconds, centrifuge and discard the supernatant. Transfer a 10-ml aliquot of the methylene chloride phase to another tube containing 2 ml of 65% aqueous sulfuric acid, shake 30 seconds, centrifuge and remove organic phase by aspiration. The material is allowed to stand at room temperature for about 1 hour and then about 1 ml of the sulfuric acid phase in transferred to a quartz cuvette. Fluorescence intensity is determined in an Aminco-Bowman spectrophotofluorometer (activation maximum, 465 nm).


    Gas Liquid Chromatography
    The GLC estimation is carried out on a Fractovap Model 251 series 2150 (Carlo Erba) instrument equipped with a Nickel-63 electron capture detector. A 6-foot, 0.4 mm internal diameter, U-shaped glass column, packed with OV-17 2% or XE-60 1% on gas chrom A, 100-120 mesh (Applied Science Lab) is conditioned for 3 days before use. Argon with 10% methane which passed through a molecular sieve before entering the column is used as the carrier gas. The conditions of analysis are: column 255° C., detector 275° C., carrier gas flow 30 ml/min. Samples are injected on the column with a 10 μl Hamilton syringe. The injector in not heated.


EXAMPLE 1Chiral Separation

The separation of 7 beta isomer of SL is schematically described below.


    • Figure US20090325918A1-20091231-C00004
      Chromatographic Method for Isolation of SL Isomers
      The basic method is described in Chan, Ky, et al., J. Chromatog, Nov. 15, 1991:571 (1-2) 291-297. The separation is performed using spectra-physics HPLC instrument and UV variable wavelength detector set at 254 nm. For chiral separation, the chromatographic column is either a pre-packed 25 mm×4.6 mm ID Cyclobond 1 (5 μm particle size), or a pre-packed 150 mm×4 mm ID Resolvosil BSA-7 column (5 μm) operated using the conditions described herein.
      Analysis of the isomers present in the peaks in the chromatograms and their chiral extract purity analysis can be determined in each case by high resolution NMR spectroscopy using a chiral shift reagent. Based on this information and the determination of molecular weight by mass spectrometry and/or optical activity, structural configuration is assigned to each isomer. Eluted samples of isomers may be re-chromatographed in order to obtain adequate quantities of isomers having desired optical purity for study. For future use, reference standards that are optically pure will be compared for confirmation of purity and identity to the isolated isomers that are obtained after their chromatographic separation.

EXAMPLE 2Chemical Synthesis of Optical Isomers

    As an example, the desire spironolactone 7-beta-isomer is synthesized following the scheme that is described below:
    • Figure US20090325918A1-20091231-C00005
      Diene (i) is prepared from commercially available starting materials using methods well known in the art of chemical synthesis.
      Diene (i) is treated with acetic acid and the mixture is heated to reflux to yield 7-alpha-acetate ester (ii). The 7-alpha-ester (ii) is further subjected to nucleophilic substitution, followed by hydrolysis to obtain the 7-beta-isomer (iii). The 7-beta-isomer (iii) is then esterified with an acyl halide in the presence of a base to generate the desired spironolactone 7-beta-isomer (iv).

EXAMPLE 3Preparation of Radiolabeled Probe Compounds of the Invention

      Using known methods, the compounds of the invention may be prepared as radiolabeled probes by carrying out their synthesis using precursors comprising at least one atom that is a radioisotope. The radioisotope is preferably selected from at least one of carbon (preferably


      C), hydrogen (preferably


      H), sulfur (preferably


    S), or iodine (preferably I). Such radiolabeled probes are conveniently synthesized by a radioisotope supplier specializing in customer synthesis of radiolabeled probe compounds. Such suppliers include Amersham Corporation, Arlington Heights, Ill.; Cambridge Isotope Laboratories, Inc., Andover, Mass.; SRI International, Menlo Park, Calif.; Wizard Laboratories, West Sacramento, Calif.; ChemSyn Laboratories, Lexena, Kans.; American Radiolabeled Chemicals, Inc., St. Louis, Mo.; and Moravek Biochemicals Inc., Brea, Calif.
      Tritium labeled probe compounds are also conveniently prepared catalytically via platinum-catalyzed exchange in tritiated acetic acid, acid-catalyzed exchange in tritiated trifluoroacetic acid, or heterogeneous-catalyzed exchange with tritium gas. Tritium labeled probe compounds can also be prepared, when appropriate, by sodium borotritide reduction. Such preparations are also conveniently carried out as a custom radiolabeling by any of the suppliers listed in the preceding paragraph using the compound of the invention as substrate.


    EXAMPLE 4Isolation and Purification Procedure
    The optical isomers of spironolactones may be isolated from fluid sample such as urine or blood as follows:
    Extraction from Urine
    The urine sample is extracted with dichloromethane and the extract washed with NaOH (0.1 N) and then with water to neutrality. The residue obtained after evaporation of the dichloromethane extract is purified on TLC in three different systems: benzene-acetone-water, (150:100:0.4); chloroform-ethanol, (90:10); ethyl acetate-cyclohexane-ethanol, (45:25:10), using aldosterone as reference standard.
      The extract is then purified by high performance liquid chromatography (HPLC) on a Waters 6000 A, 480 U.V. detector instrument with radial pressure. The extract is first run through a C


    10μ column using methanol-water (70:30) as the eluent, followed by a silica 5μ column using dichloromethane-methanol (95:5). In both cases, the rate of the eluent is 1.5 ml/min. A small part of the extract is subjected to heptafluorobutyrylation for GLC investigation.


  1.  “Spironolactone”. The American Society of Health-System Pharmacists. Retrieved Oct 24, 2015.
  2.  “Spironolactone: MedlinePlus Drug Information”. Retrieved 2016-01-20.
  3.  “Spironolactone”. Merriam-Webster Dictionary.
  4.  “Spironolactone”. Unabridged. Random House.
  5.  Harry G. Brittain (26 November 2002). Analytical Profiles of Drug Substances and Excipients. Academic Press. p. 309. ISBN 978-0-12-260829-2. Retrieved 27 May 2012.
  6.  Maizes, Victoria (2015). Integrative Women’s Health (2 ed.). p. 746.ISBN 9780190214807.
  7.  “Spironolactone Pregnancy and Breastfeeding Warnings”. Retrieved 29 November2015.
  8.  Camille Georges Wermuth (24 July 2008). The Practice of Medicinal Chemistry. Academic Press. p. 34. ISBN 978-0-12-374194-3. Retrieved 27 May 2012.
  9.  Marshall Sittig (1988). Pharmaceutical Manufacturing Encyclopedia. William Andrew. p. 1385. ISBN 978-0-8155-1144-1. Retrieved 27 May 2012.
  10.  “WHO Model List of EssentialMedicines” (PDF). World Health Organization. October 2013. Retrieved 22 April 2014.
  11.  “Spironolactone”. International Drug Price Indicator Guide. Retrieved 29 November2015.
  12.  Hughes BR, Cunliffe WJ (May 1988). “Tolerance of spironolactone”. The British Journal of Dermatology 118 (5): 687–91. doi:10.1111/j.1365-2133.1988.tb02571.x.PMID 2969259.
  13. Victor R. Preedy (1 January 2012). Handbook of Hair in Health and Disease. Springer Science & Business Media. pp. 132–. ISBN 978-90-8686-728-8.
  14.  Loy R, Seibel MM (December 1988). “Evaluation and therapy of polycystic ovarian syndrome”. Endocrinology and Metabolism Clinics of North America 17 (4): 785–813.PMID 3143568.


Skeletal formula of spironolactone
Ball-and-stick model of the spironolactone molecule
Systematic (IUPAC) name
7α-Acetylthio-17α-hydroxy-3-oxopregn-4-ene-21-carboxylic acid γ-lactone
Clinical data
Pronunciation /spɪˌrnəˈlæktn, sp, spə, ˈrɒ, n/or /ˌsprənˈlæktn/[2][3][4]
Trade names Aldactone
AHFS/ Monograph
MedlinePlus a682627
  • AU: B3
  • US: C (Risk not ruled out)
Routes of
Legal status
Legal status
Pharmacokinetic data
Protein binding 90%+[5]
Metabolism Hepatic CYP450
Biological half-life 1.3-2 hours
Excretion Urine, bile
CAS Number 52-01-7 Yes
ATC code C03DA01 (WHO)
PubChem CID 5833
DrugBank DB00421 Yes
ChemSpider 5628 Yes
UNII 27O7W4T232 Yes
KEGG D00443 Yes
ChEBI CHEBI:9241 Yes
Chemical data
Formula C24H32O4S
Molar mass 416.574 g/mol

///////Spironolactone, Supra-puren, Suracton, спиронолактон, سبيرونولاكتون ,

螺内酯 , Abbolactone, Aldactide, SNL, Spiroctanie, Sprioderm, Verospirone,  Opianin



Spray drying

 drugs, GENERIC, SYNTHESIS  Comments Off on Spray drying
Jun 042015

Laboratory-scale spray dryer.
A=Solution or suspension to be dried in, B=Atomization gas in, 1= Drying gas in, 2=Heating of drying gas, 3=Spraying of solution or suspension, 4=Drying chamber, 5=Part between drying chamber and cyclone, 6=Cyclone, 7=Drying gas is taken away, 8=Collection vessel of product, arrows mean that this is co-current lab-spraydryer

Spray drying is a method of producing a dry powder from a liquid or slurry by rapidly drying with a hot gas. This is the preferred method of drying of many thermally-sensitive materials such as foods and pharmaceuticals. A consistent particle size distribution is a reason for spray drying some industrial products such as catalysts. Air is the heated drying medium; however, if the liquid is a flammable solvent such as ethanol or the product is oxygen-sensitive then nitrogen is used.[1]

All spray dryers use some type of atomizer or spray nozzle to disperse the liquid or slurry into a controlled drop size spray. The most common of these are rotary disks and single-fluid high pressure swirl nozzles. Atomizer wheels are known to provide broader particle size distribution, but both methods allow for consistent distribution of particle size.[2] Alternatively, for some applications two-fluid or ultrasonic nozzles are used. Depending on the process needs, drop sizes from 10 to 500 µm can be achieved with the appropriate choices. The most common applications are in the 100 to 200 µm diameter range. The dry powder is often free-flowing.[3]

The most common spray dryers are called single effect as there is only one drying air on the top of the drying chamber (see n°4 on the scheme). In most cases the air is blown in co-current of the sprayed liquid. The powders obtained with such type of dryers are fine with a lot of dusts and a poor flowability. In order to reduce the dusts and increase the flowability of the powders, there is since over 20 years a new generation of spray dryers called multiple effect spray dryers. Instead of drying the liquid in one stage, the drying is done through two steps: one at the top (as per single effect) and one for an integrated static bed at the bottom of the chamber. The integration of this fluidized bed allows, by fluidizing the powder inside a humid atmosphere, to agglomerate the fine particles and to obtain granules having commonly a medium particle size within a range of 100 to 300 µm. Because of this large particle size, these powders are free-flowing.

The fine powders generated by the first stage drying can be recycled in continuous flow either at the top of the chamber (around the sprayed liquid) or at the bottom inside the integrated fluidized bed. The drying of the powder can be finalized on an external vibrating fluidized bed.

The hot drying gas can be passed as a co-current or counter-current flow to the atomiser direction. The co-current flow enables the particles to have a lower residence time within the system and the particle separator (typically a cyclone device) operates more efficiently. The counter-current flow method enables a greater residence time of the particles in the chamber and usually is paired with a fluidized bed system.

Alternatives to spray dryers are:[4]

  1. Freeze dryer: a more-expensive batch process for products that degrade in spray drying. Dry product is not free-flowing.
  2. Drum dryer: a less-expensive continuous process for low-value products; creates flakes instead of free-flowing powder.
  3. Pulse combustion dryer: A less-expensive continuous process that can handle higher viscosities and solids loading than a spray dryer, and that sometimes gives a freeze-dry quality powder that is free-flowing.

Spray dryer

Spray drying nozzles.

Schematic illustration of spray drying process.

A spray dryer takes a liquid stream and separates the solute or suspension as a solid and the solvent into a vapor. The solid is usually collected in a drum or cyclone. The liquid input stream is sprayed through a nozzle into a hot vapor stream and vaporised. Solids form as moisture quickly leaves the droplets. A nozzle is usually used to make the droplets as small as possible, maximising heat transfer and the rate of water vaporisation. Droplet sizes can range from 20 to 180 μm depending on the nozzle.[3] There are two main types of nozzles: high pressure single fluid nozzle (50 to 300 bars) and two-fluid nozzles: one fluid is the liquid to dry and the second is compressed gas (generally air at 1 to 7 bars).

Spray dryers can dry a product very quickly compared to other methods of drying. They also turn a solution, or slurry into a dried powder in a single step, which can be advantageous for profit maximization and process simplification.


The Spray Drying Process

The spray drying process is older than might commonly be imagined.  Earliest descriptions date from 1860 with the first patented design recorded in 1872. The basic idea of spray drying is the production of highly dispersed powders from a fluid feed by evaporating the solvent. This is achieved by mixing a heated gas with an atomized (sprayed) fluid of high surface-to-mass ratio droplets, ideally of equal size, within a vessel (drying chamber), causing the solvent to evaporate uniformly and quickly through direct contact.
Spray drying can be used in a wide range of applications where the production of a free-flowing powder is required. This method of dehydration has become the most successful one in the following areas:

  • Pharmaceuticals
  • Bone and tooth amalgams
  • Beverages
  • Flavours, colourings and plant extracts
  • Milk and egg products
  • Plastics, polymers and resins
  • Soaps and detergents
  • Textiles and many more

Almost all other methods of drying, including use of ovens, freeze dryers or rotary evaporators, produce a mass of material requiring further processing (e.g. grinding and filtering) therefore, producing particles of irregular size and shape. Spray drying on the other hand, offers a very flexible control over powder particle properties such as density, size, flow characteristics and moisture content.


Spray drying dia

Design and Control

The challenges facing both designers and users are to increase production, improve powder quality and reduce costs. This requires an understanding of the process and a robust control implementation.


Spray drying consists of the following phases:


  • Feed preparation: This can be a homogenous, pumpable and free from impurities solution, suspension or paste.
  • Atomization (transforming the feed into droplets): Most critical step in the process. The degree of atomization controls the drying rate and therefore the dryer size. The most commonly used atomization techniques are:

1. Pressure nozzle atomization: Spray created by forcing the fluid through an orifice. This is an energy efficient method which also offers the narrowest particle size distribution.
2. Two-fluid nozzle atomization: Spray created by mixing the feed with a compressed gas. Least energy efficient method. Useful for making extremely fine particles.
3. Centrifugal atomization: Spray created by passing the feed through or across a rotating disk. Most resistant to wear and can generally be run for longer periods of time.

  • Drying: A constant rate phase ensures moisture evaporates rapidly from the surface of the particle. This is followed by a falling rate period where the drying is controlled by diffusion of water to the surface of the particle.
  • Separation of powder from moist gas: To be carried out in an economical (e.g. recycling the drying medium) and pollutant-free manner. Fine particles are generally removed with cyclones, bag filters, precipitators or scrubbers.
  • Cooling and packaging.


A control system must therefore provide flexibility in the way in which accurate and repeatable control of the spray drying is achieved and will include the following features:


  • Precise loop control with setpoint profile programming
  • Recipe Management System for easy parameterisation
  • Sequential control for complex control strategies
  • Secure collection of on-line data from the system for analysis and evidence
  • Local operator display with clear graphics and controlled access to parameters


Spray drying often is used as an encapsulation technique by the food and other industries. A substance to be encapsulated (the load) and an amphipathic carrier (usually some sort of modified starch) are homogenized as a suspension in water (the slurry). The slurry is then fed into a spray drier, usually a tower heated to temperatures well over the boiling point of water.

As the slurry enters the tower, it is atomized. Partly because of the high surface tension of water and partly because of thehydrophobic/hydrophilic interactions between the amphipathic carrier, the water, and the load, the atomized slurry forms micelles. The small size of the drops (averaging 100 micrometers in diameter) results in a relatively large surface area which dries quickly. As the water dries, the carrier forms a hardened shell around the load.[5]

Load loss is usually a function of molecular weight. That is, lighter molecules tend to boil off in larger quantities at the processing temperatures. Loss is minimized industrially by spraying into taller towers. A larger volume of air has a lower average humidity as the process proceeds. By the osmosis principle, water will be encouraged by its difference in fugacities in the vapor and liquid phases to leave the micelles and enter the air. Therefore, the same percentage of water can be dried out of the particles at lower temperatures if larger towers are used. Alternatively, the slurry can be sprayed into a partial vacuum. Since the boiling point of a solvent is the temperature at which the vapor pressure of the solvent is equal to the ambient pressure, reducing pressure in the tower has the effect of lowering the boiling point of the solvent.

The application of the spray drying encapsulation technique is to prepare “dehydrated” powders of substances which do not have any water to dehydrate. For example, instant drink mixes are spray dries of the various chemicals which make up the beverage. The technique was once used to remove water from food products; for instance, in the preparation of dehydrated milk. Because the milk was not being encapsulated and because spray drying causes thermal degradation, milk dehydration and similar processes have been replaced by other dehydration techniques. Skim milk powders are still widely produced using spray drying technology around the world, typically at high solids concentration for maximum drying efficiency. Thermal degradation of products can be overcome by using lower operating temperatures and larger chamber sizes for increased residence times.[6]

Recent research is now suggesting that the use of spray-drying techniques may be an alternative method for crystallization of amorphous powders during the drying process since the temperature effects on the amorphous powders may be significant depending on drying residence times.[7][8]

Spray drying applications

Food: milk powder, coffee, tea, eggs, cereal, spices, flavorings, starch and starch derivatives, vitamins, enzymes, stevia, colourings, etc.

Pharmaceutical: antibiotics, medical ingredients, additives

Industrial: paint pigments, ceramic materials, catalyst supports, microalgae

Nano spray dryer

The nano spray dryer offers new possibilities in the field of spray drying. It allows to produce particles in the range of 300 nm to 5 μm with a narrow size distribution. High yields are produced up to 90% and the minimal sample amount is 1 mL.


Pharmaceutical Spray drying is a very fast method of drying due to the very large surface area created by the atomization of the liquid feed. As a consequence, high heat transfer coefficients are generated and the fast stabilisation of the feed at moderate temperatures makes this method very attractive for heat sensitive materials.

Spray drying provides unprecedented particle control and allows previously unattainable delivery methods and molecular characteristics. These advantages allow exploration into employing previously unattainable delivery methods and molecular characteristics.

Five things you might not know about spray drying

  1. Spray drying is suitable for heat sensitive materials
    Spray drying is already used for the processing of heat sensitive materials (e.g. proteins, peptides and polymers with low Tg temperatures) on an industrial scale. Evaporation from the spray droplets starts immediately after contact with the hot process gas. Since the thermal energy is consumed by evaporation, the droplet temperature is kept at a level where no harm is caused to the product.
  2. Spray drying turns liquid into particles within seconds
    The large surface of the droplets provides near instantaneous evaporation, making it possible to produce particles with a crystalline or amorphous structure. The particle morphology is determined by the operating parameters and excipients added to the feed stock.
  3. Spray drying is relatively easy to replicate on a commercial scale
    GEA Niro has been producing industrial scale spray drying plants for well over half a century. Our process know-how, products and exceptional facilities put us in a unique position to advise and demonstrate how products and processes will behave on a large scale.
  4. Spray drying is a robust process
    Spray drying is a continuous process. Once the set points are established, all critical process parameters are kept constant throughout the batch. Information for the batch record can be monitored or logged, depending on the system selected.
  5. Spray drying can be effectively validated
    The precise control of all critical process parameters in spray drying provides a high degree of assurance that the process consistently produces a product that meets set specifi cations.

The spray drying process

Spray drying is a very fast method of drying due to the very large surface area created by the atomization of the liquid feed and high heat transfer coefficients generated. The short drying time, and consequently fast stabilisation of feed material at moderate temperatures, means spray drying is also suitable for heat-sensitive materials.

As a technique, spray drying consists of four basic stages:

  1. Atomization: A liquid feed stock is atomized into droplets by means of a nozzle or rotary atomizer. Nozzles use pressure or compressed gas to atomize the feed while rotary atomizers employ an atomizer wheel rotating at high speed.
  2. Drying: Hot process gas (air or nitrogen) is brought into contact with the atomized feed guided by a gas disperser, and evaporation begins. The balance between temperature, flow rate and droplet size controls the drying process.
  3. Particle formation: As the liquid rapidly evaporates from the droplet surface, a solid particle forms and falls to the bottom of the drying chamber.
  4. Recovery: The powder is recovered from the exhaust gas using a cyclone or a bag filter. The whole process generally takes no more than a few seconds.



  1.  A. S. Mujumdar (2007). Handbook of industrial drying. CRC Press. p. 710. ISBN 1-57444-668-1.
  3.  Walter R. Niessen (2002). Combustion and incineration processes. CRC Press. p. 588. ISBN 0-8247-0629-3.
  4.  Onwulata p.66
  5.  Ajay Kumar (2009). Bioseparation Engineering. I. K. International. p. 179. ISBN 93-8002-608-0.
  6. Onwulata pp.389–430
  7.  Onwulata p.268
  8.  Chiou, D.; Langrish, T. A. G. (2007). “Crystallization of Amorphous Components in Spray-Dried Powders”. Drying Technology 25: 1427. doi:10.1080/07373930701536718.


Further reading

External links

Ahmednagar,  Maharashtra, India


Apr 102015

Venlafaxine structure.svg

CAS : 93413-69-5
CAS Name: 1-[2-(Dimethylamino)-1-(4-methoxyphenyl)ethyl]cyclohexanol
Additional Names: (±)-1-[a-[(dimethylamino)methyl]-p-methoxybenzyl]cyclohexanol; N,N-dimethyl-2-(1-hydroxycyclohexyl)-2-(4-methoxyphenyl)ethylamine; venlafexine
Molecular Formula: C17H27NO2
Molecular Weight: 277.40
Percent Composition: C 73.61%, H 9.81%, N 5.05%, O 11.54%
Venlafaxine (brand namesEffexorEffexor XR and Trevilor) is an antidepressant of the serotonin-norepinephrine reuptake inhibitor (SNRI) class.[3][4][5] This means it increases the concentrations of the neurotransmitters serotonin and norepinephrine in the body and the brain. First introduced by Wyeth in 1993, now marketed by Pfizer, it is licensed for the treatment of major depressive disorder (MDD), generalised anxiety disorder (GAD), panic disorder and social phobia.[6][7]
Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis have shown venlafaxine, alongside mirtazapineescitalopram and sertraline were significantly more efficacious.[8] Remission rates (defined as a HAM-D score of 7 or less) were 58% for venlafaxine plus mirtazapine.[9]
The rate of life-threatening or lethal outcomes for suicidal overdoses of venlafaxine is lower than for the TCAsMAOIs and bupropionand comparable to several of the SSRIs.[10] It is metabolised in the body into another antidepressant drug called desvenlafaxine (O-desmethylvenlafaxine) which is also sold as an antidepressant, under the brand name Pristiq.[11]
Both venlafaxine and paroxetine have been linked to the most severe discontinuation symptomes.
In 2007, venlafaxine was the sixth most commonly prescribed antidepressant on the U.S. retail market, with 17.2 million prescriptions.[12]


The chemical structure of venlafaxine is designated (R/S)-1-[2-(dimethylamino)-1-(4 methoxyphenyl)ethyl] cyclohexanol hydrochloride or (±)-1-[a [a- (dimethylamino)methyl] p-methoxybenzyl] cyclohexanol hydrochloride, and it has the empirical formula of C17H27NO2. It is a white to off-white crystalline solid. Venlafaxine is structurally and pharmacologically related to the atypical opioid analgesictramadol, and more distantly to the newly released opioid tapentadol, but not to any of the conventional antidepressant drugs, including tricyclic antidepressants, SSRIs, MAOIs, or RIMAs.[66]
Venlafaxine structure.svg
Systematic (IUPAC) name
Clinical data
Trade names Effexor XR, Effexor, Trevilor
AHFS/ monograph
Licence data US Daily Med:link
  • AU: B2
  • US: C
Pharmacokinetic data
Bioavailability 42±15%[1]
Protein binding 27±2% (parent compound), 30±12% (active metabolite,desvenlafaxine)[2]
Metabolism Hepatic (~50% of the parent compound is metabolised on first pass through the liver)[1][2]
Half-life 5±2 h (parent compound for immediate release preparations), 15±6 h (parent compound for extended release preparations), 11±2 h (active metabolite)[1][2]
Excretion Renal (87%; 5% as unchanged drug; 29% asdesvenlafaxine and 53% as other metabolites)[1][2]
93413-69-5 Yes
PubChem CID 5656
DrugBank DB00285 Yes
ChemSpider 5454 Yes
ChEBI CHEBI:9943 Yes
Chemical data
Formula C17H27NO2
277.402 g/mol
Derivative Type: Hydrochloride
CAS : 99300-78-4
Manufacturers’ Codes: Wy-45030
Trademarks: Effexor (Wyeth)
Molecular Formula: C17H27NO2.HCl
Molecular Weight: 313.86
Percent Composition: C 65.06%, H 8.99%, N 4.46%, O 10.20%, Cl 11.30%
Properties: White to off-white crystalline solid from methanol/ethyl acetate, mp 215-217°. Soly (mg/ml): 572 water. Partition coefficient (octanol/water): 0.43.
Melting point: mp 215-217°
Log P: Partition coefficient (octanol/water): 0.43
Derivative Type: (+)-Form
Properties: Crystals from ethyl acetate, mp 102-104°. [a]D25 +27.6° (c = 1.07 in 95% ethanol).
Melting point: mp 102-104°
Optical Rotation: [a]D25 +27.6° (c = 1.07 in 95% ethanol)
Derivative Type: (+)-Form hydrochloride
Manufacturers’ Codes: Wy-45655
Properties: Crystals from methanol/ether, mp 240-240.5°. [a]D25 -4.7° (c = 0.945 in ethanol).
Melting point: mp 240-240.5°
Optical Rotation: [a]D25 -4.7° (c = 0.945 in ethanol)
Derivative Type: (-)-Form
Properties: Crystals from ethyl acetate, mp 102-104°. [a]D25 -27.1° (c = 1.04 in 95% ethanol).
Melting point: mp 102-104°
Optical Rotation: [a]D25 -27.1° (c = 1.04 in 95% ethanol)
Derivative Type: (-)-Form hydrochloride
Manufacturers’ Codes: Wy-45651
Properties: Crystals from methanol/ether, mp 240-240.5°. [a]D25 +4.6° (c = 1.0 in ethanol).
Melting point: mp 240-240.5°
Optical Rotation: [a]D25 +4.6° (c = 1.0 in ethanol)
Therap-Cat: Antidepressant.
Keywords: Antidepressant; Serotonin Noradrenaline Reuptake Inhibitor (SNRI).



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Venlafaxine hydrochloride NMR spectra analysis, Chemical CAS NO. 99300-78-4 NMR spectral analysis, Venlafaxine hydrochloride H-NMR spectrum


Venlafaxine hydrochloride NMR spectra analysis, Chemical CAS NO. 99300-78-4 NMR spectral analysis, Venlafaxine hydrochloride C-NMR spectrum



Venlafaxine NMR spectra analysis, Chemical CAS NO. 93413-69-5 NMR spectral analysis, Venlafaxine H-NMR spectrum
Venlafaxine NMR spectra analysis, Chemical CAS NO. 93413-69-5 NMR spectral analysis, Venlafaxine C-NMR spectrum

Literature References: 
Serotonin noradrenaline reuptake inhibitor (SNRI). Prepn: G. E. M. Husbands et al., EP 112669US4535186 (1984, 1985 both to Am. Home Prods.); 
and resolution of isomers: J. P. Yardley et al., J. Med. Chem. 33, 2899 (1990). Receptor binding studies: E. A. Muth et al., Biochem. Pharmacol. 35, 4493 (1986). 
HPLC determn in biological fluids: D. R. Hickset al., Ther. Drug Monit. 16, 100 (1994).
Clinical pharmacokinetics: K. J. Klamerus et al., J. Clin. Pharmacol. 32, 716 (1992). 
Clinical trial in major depression: E. Schweizer et al., J. Clin. Psychopharmacol. 11, 233 (1991). 
Review of pharmacology and clinical efficacy in depression: S. A. Montgomery, J. Clin. Psychiatry 54, 119-126 (1993). 
Clinical trial in generalized anxiety disorder: A. J. Gelenberg et al., J. Am. Med. Assoc. 283, 3082 (2000).
: The views expressed are my personal and in no-way suggest the views
of the professional body or the company that I represent.
: The views expressed are my personal and in no-way suggest the views
of the professional body or the company that I represent.
: The views expressed are my personal and in no-way suggest the views
of the professional body or the company that I represent.



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Plerixafor………… immunostimulant used to mobilize hematopoietic stem cells in cancer patients.

 GENERIC, Uncategorized  Comments Off on Plerixafor………… immunostimulant used to mobilize hematopoietic stem cells in cancer patients.
Aug 252014

JM 3100.svg


cas 110078-46-1

CXCR4 chemokine antagonist

Stem cell mobilization [CXCR4 receptor antagonist]

A bicyclam derivate, highly potent & selective inhibitor of HIV-1 & HIV-2.

Bone marrow transplantation; Chronic lymphocytic leukemia; Chronic myelocytic leukemia; Myelodysplastic syndrome; Neutropenia; Sickle cell anemia

Plerixafor; Mozobil; AMD3100; 110078-46-1; Amd 3100; bicyclam JM-2987; AMD-3100; UNII-S915P5499N; JM3100
  • JKL 169
  • Mozobil
  • Plerixafor
  • SDZ SID 791
  • UNII-S915P5499N
Molecular Formula: C28H54N8
Molecular Weight: 502.78196
1,4,8,11-Tetraazacyclotetradecane, 1,1′-(1,4-phenylenebis(methylene))bis-
1,1′-[1,4-phenylenebis(methylene)]bis [1,4,8,11-tetraazacyclotetradecane]
1,1′- 1,4-phenylenebis-(methylene)!-bis-1,4,8,11-tetraazacyclotetradecane
Johnson Matthey (Innovator)
Plerixafor is a hematopoietic stem cell mobilizer. It is used to stimulate the release of stem cells from the bone marrow into the blood in patients with non-Hodgkin lymphoma and multiple myeloma for the purpose of stimulating the immune system. These stem cells are then collected and used in autologous stem cell transplantation to replace blood-forming cells that were destroyed by chemotherapy. Plerixafor has orphan drug status in the United States and European Union; it was approved by the U.S. Food and Drug Administration on December 15, 2008.

Mozobil (plerixafor injection) is a sterile, preservative-free, clear, colorless to pale yellow, isotonic solution for subcutaneous injection. Each mL of the sterile solution contains 20 mg of plerixafor. Each single-use vial is filled to deliver 1.2 mL of the sterile solution that contains 24 mg of plerixafor and 5.9 mg of sodium chloride in Water for Injection adjusted to a pH of 6.0 to 7.5 with hydrochloric acid and with sodium hydroxide, if required.

Plerixafor is a hematopoietic stem cell mobilizer with a chemical name l, 1′-[1,4phenylenebis (methylene)]-bis-1,4,8,11-tetraazacyclotetradecane. It has the molecular formula C28H54N8. The molecular weight of plerixafor is 502.79 g/mol. The structural formula is provided in Figure 1.

Figure 1: Structural Formula


MOZOBIL (plerixafor) Structural Formula Illustration


Plerixafor is a white to off-white crystalline solid. It is hygroscopic. Plerixafor has a typical melting point of 131.5 °C. The partition coefficient of plerixafor between 1octanol and pH 7 aqueous buffer is < 0.1.

Plerixafor (hydrochloride hydrate)

(CAS 155148-31-5)
Formal Name 1,​4-​bis((1,​4,​8,​11-​tetraazacyclotetradecan-​1-​yl)methyl)benzene,​ octahydrochloride
CAS Number 155148-31-5
Molecular Formula C28H54N8 • 8HCl • [XH2O]
Formula Weight 794.5
The α-chemokine receptor, CXCR4, on CD4+ T-cells is used by CXCR4-selective HIV forms as a gateway for T-cell infection. In mammalian cell signaling, CXCR4 activation promotes the homing of hematopoietic stem cells, chemotaxis and quiescence of lymphocytes, and growth and metastasis of certain cancer cell types. Plerixafor (hydrochloride) is a macrocyclic compound that acts as an irreversible antagonist against the binding of CXCR4 with its ligand, SDF-1 (CXCL12). It suppresses infection by HIV with an IC50 value of 1-10 ng/ml with selectivity toward CXCR4-tropic virus. Plerixafor mobilizes hematopoietic stem and progenitor cells for transplant better than the ‘gold standard’, G-CSF alone 4and synergizes with G-CSF. It also increases T-cell trafficking in the blood and spleen as well as the central nervous system. Plerixafor regulates the growth of primary and metastic breast cancer cells7 and inhibits dissemination of ovarian carcinoma cells.
Plerixafor hydrochloride (AMD-3100), a chemokine CXCR4 (SDF-1) antagonist, is launched in the U.S. for the following indications: to enhance mobilization of hematopoietic stem cells for autologous transplantation in patients with lymphoma and to enhance mobilization of hematopoietic stem cells for transplantation in patients with multiple myeloma.
In 2009, the product was approved in EU for these indications.AnorMED filed an orphan drug application for AMD-3100 with the FDA in January 2003 and received approval in July 2003 as immunostimulation for increasing the stem cells available in patients with multiple myeloma and non-Hodgkin’s lymphoma. Orphan drug status was also granted by the EMEA in October 2004 as a treatment to mobilize progenitor cells prior to stem cell transplantation.
In 2011, orphan drug designation was assigned by the FDA for the treatment of AML and by the EMA for the adjunctive treatment to cytotoxic therapy in acute myeloid leukemia.

Plerixafor (rINN and USAN, trade name Mozobil) is an immunostimulant used to mobilize hematopoietic stem cells in cancer patients. The stem cells are subsequently transplanted back to the patient. The drug was developed by AnorMED which was subsequently bought by Genzyme.



The molecule 1,1′-[1,4-phenylenebis(methylene)]bis [1,4,8,11-tetraazacyclotetradecane], consisting of two cyclam rings linked at the amine nitrogen atoms by a 1,4-xylyl spacer, was first synthesised by Fabbrizzi et al. in 1987 to carry out basic studies on the redox chemistry of dimetallic coordination compounds.[1] Then, it was serendipitously discovered by De Clercq that such a molecule, could have a potential use in the treatment of HIV[2] because of its role in the blocking of CXCR4, a chemokine receptor which acts as a co-receptor for certain strains of HIV (along with the virus’s main cellular receptor, CD4).[2]Development of this indication was terminated because of lacking oral availability and cardiac disturbances. Further studies led to the new indication for cancer patients.[3]


Peripheral blood stem cell mobilization, which is important as a source of hematopoietic stem cells for transplantation, is generally performed using granulocyte colony-stimulating factor (G-CSF), but is ineffective in around 15 to 20% of patients. Combination of G-CSF with plerixafor increases the percentage of persons that respond to the therapy and produce enough stem cells for transplantation.[4] The drug is approved for patients with lymphoma and multiple myeloma.[5]


Pregnancy and lactation

Studies in pregnant animals have shown teratogenic effects. Plerixafor is therefore contraindicated in pregnant women except in critical cases. Fertile women are required to use contraception. It is not known whether the drug is secreted into the breast milk. Breast feeding should be discontinued during therapy.[5]

Adverse effects

Nauseadiarrhea and local reactions were observed in over 10% of patients. Other problems with digestion and general symptoms like dizziness, headache, and muscular pain are also relatively common; they were found in more than 1% of patients. Allergies occur in less than 1% of cases. Most adverse effects in clinical trials were mild and transient.[5][6]

The European Medicines Agency has listed a number of safety concerns to be evaluated on a post-marketing basis, most notably the theoretical possibilities of spleen rupture and tumor cell mobilisation. The first concern has been raised because splenomegaly was observed in animal studies, and G-CSF can cause spleen rupture in rare cases. Mobilisation of tumor cells has occurred in patients with leukaemia treated with plerixafor.[7]

Phase III clinical development in combination with G-CSF (granulocyte colony-stimulating factor) is under way at Genzyme (which acquired the product through its acquisition of AnorMED in late 2006) in a stem cell mobilization regimen in non-Hodgkin’s lymphoma (NHL). The trials are designed to evaluate the potential of plerixafor in combination with G-CSF, to rapidly increase the number of peripheral blood stem cells capable of engraftment, thereby increasing the proportion of patients reaching a peripheral blood stem cell target and, as a result, reducing the number of apheresis sessions required for patients to collect a target number of peripheral blood stem cells. A phase I safety trial had been under way for the treatment of renal cancer, however, no recent development for this indication has been reported. An IND has been filed in the U.S. seeking approval to initiate clinical evaluation of the drug candidate to help repair damaged heart tissue in patients who have suffered heart attacks. Currently, an investigator-sponsored study is ongoing to evaluate plerixafor as a single agent in allogeneic transplant. AMD-3100, in combination with mitoxantrone, etoposide and cytarabine, is also in phase I/II clinical trials at the University of Washington for the treatment of acute myeloid leukemia (AML).

The University has also been conducting early clinical trials for increasing the stem cells available for transplantation in patients with advanced hematological malignancies, however, no recent developments on this trial have been reported. Genzyme has completed a phase I/II clinical study of plerixafor hydrochloride in combination with rituximab for the treatment of chronic lymphocytic leukemia. The former AnorMED had been developing plerixafor for the treatment of rheumatoid arthritis (RA), but no clinical development has been reported as of late. AnorMED was also developing plerixafor for the treatment of HIV, but discontinued the trials in 2001 due to abnormal cardiac activity and lack of efficacy.

By blocking CXCR4, a specific cellular receptor, plerixafor triggers the rapid movement of stem cells out of the bone marrow and into circulating blood. Once in the circulating blood, the stem cells can be collected for use in stem cell transplant. In terms of use for cardiac applications, there is clinical evidence that the presence of stem cells circulating in the bloodstream or directly injected into the hearts of patients who have suffered a heart attack may result in improved cardiac function.


Chemical properties

Plerixafor is a macrocyclic compound and a bicyclam derivative.[4] It is a strong base; all eight nitrogen atoms accept protons readily. The two macrocyclic rings form chelate complexes with bivalent metal ions, especially zinccopper and nickel, as well as cobalt and rhodium. The biologically active form of plerixafor is its zinc complex.[8]


Chemical structure for JM 3100

Three of the four nitrogen atoms of the macrocycle 1,4,8,11-tetraazacyclotetradecan are protected with tosyl groups. The product is treated with 1,4-dimethoxybenzene or 1,4-bis(brommethyl)benzene and potassium carbonate in acetonitrile. After cleaving of the tosyl groups with hydrobromic acid, plerixafor octahydrobromide is obtained.[9]

SEE   CHINESE JOURNAL OF MEDICINAL CHEMISTRY    2010 20 (6): 511-513   ISSN: 1005-0108   CN: 21-1313/R


0155g ( 8016% ), m p 129 ~ 131 e 。
( CDC l3 ) D: 7.28( s, 4H, A r-H ), 3.55 ( br s, 4H,A r-CH2 ), 2.82 ~ 2.52( m, 32H, NCH2, NHCH2 ),
1.86 ~ 1.68 ( m, 8H, CCH2C )。 ESI-M S m /z:
503.55 [M + H]+ 。







U.S. Pat. No. 5,021,409 is directed to a method of treating retroviral infections comprising administering to a mammal in need of such treatment a therapeutically effective amount of a bicyclic macrocyclic polyamine compound. Although the usefulness of certain alkylene and arylene bridged cyclam dimers is generically embraced by the teachings of the reference, no arylene bridged cyclam dimers are specifically disclosed.

WO 93/12096 discloses the usefulness of certain linked cyclic polyamines in combating HIV and pharmaceutical compositions useful therefor. Among the specifically disclosed compounds is 1,1′- 1,4-phenylenebis-(methylene)!-bis-1,4,8,11 tetraazacyclotetradecane (and its acid addition salts), which compound is a highly potent inhibitor of several strains of human immune deficiency virus type 1 (HIV-1) and type 2 (HIV-2).

European Patent Appln. 374,929 discloses a process for preparing mono-N-alkylated polyazamacrocycles comprising reacting the unprotected macrocycle with an electrophile in a non-polar, relatively aprotic solvent in the absence of base. Although it is indicated that the monosubstituted macrocycle is formed preferentially, there is no specific disclosure which indicates that linked bicyclams can be synthesized by this process.

U.S. Pat. No. 5,047,527 is directed to a process for preparing a monofunctionalized (e.g., monoalkylated)cyclic tetramine comprising: 1) reacting the unprotected macrocycle with chrominum hexacarbonyl to obtain a triprotected tetraazacyloalkane compound; 2) reacting the free amine group of the triprotected compound prepared in 1) with an organic (e.g., alkyl) halide to obtain a triprotected monofunctionalized (e.g., monoalkylated) tetraazacycloalkane compound; and 3) de-protecting the compound prepared in 2) by simple air oxidation at acid pH to obtain the desired compound. In addition, the reference discloses alternative methods of triprotection employing boron and phosphorous derivatives and the preparation of linked compounds, including the cyclam dimer 1,1′- 1,4-phenylenebis-(methylene)!-bis-1,4,8,11-tetraazacyclotetradecane, by reacting triprotected cyclam prepared as set forth in 1) above with an organic dihalide in a molar ratio of 2:1, and deprotecting the resultant compound to obtain the desired cyclam dimer.

J. Med. Chem., Vol. 38, No. 2, pgs. 366-378 (1995) is directed to the synthesis and anti-HIV activity of a series of novel phenylenebis(methylene)-linked bis-tetraazamacrocyclic analogs, including the known cyclam dimer 1,1′- 1,4-phenylenebis-(methylene)!-bis-1,4,8,11-tetraazacyclotetradecane. The cyclam dimers disclosed in this reference, including the afore-mentioned cyclam dimer, are prepared by: 1) forming the tritosylate of the tetraazamacrocycle; 2) reacting the protected tetraazamacrocycle with an organic dihalide, e.g., dibromo-p-xylene, in acetonitrile in the presence of a base such as potassium carbonate; and 3) de-protecting the bis-tetraazamacrocycle prepared in 2) employing freshly prepared sodium amalgam, concentrated sulfuric acid or an acetic acid/hydrobromic acid mixture to obtain the desired cyclam dimer, or an acid addition salt thereof.

Although the processes disclosed in U.S. Pat. No. 5,047,527 and the J. Med. Chem. reference are suitable to prepare the cyclam dimer 1,1′- 1,4-phenylene bis-(methylene)!-bis-1,4,8,11-tetraazacyclotetradecane, they involve the use of cyclam as a starting material, a compound which is expensive and not readily available. Accordingly, in view of its potent anti-HIV activity, a number of research endeavors have been undertaken in an attempt to develop a more practical process for preparing 1,1′- 1,4-phenylenebis-(methylene)!-bis-1,4,8,11-tetraazacyclotetradecane.



a) Preparation of the 1,4-phenylenebis-methylene bridged hexatosyl acylic precursor of formula III

To a 4-necked, round-bottom flask, equipped with a mechanical stirrer, heating mantle, internal thermometer and addition funnel, is added 43.5 g (0.25 mol) of N,N’-bis(3-aminopropyl) ethylenediamine and 250 ml of tetrahydrofuran. To the resultant solution is added, over a period of 30 minutes with external cooling to maintain the temperature at 20° C., 113.6 g (0.8 mol) of ethyl trifluoroacetate. The reaction mixture is then stirred at room temperature for 4 hours, after which time 52.25 ml. (0.3 mol) of diisopropylethylamine is added. The resultant reaction mixture is warmed to 60° C. and, over a period of 2 hours, is added a solution of 33.0 g (0.125 mol) of α,α’-dibromoxylene in 500 ml. of tetrahydrofuran. The reaction mixture is then maintained at a temperature of 60° C., with stirring, for an additional 2 hours after which time a solution of 62.0 g. (1.55 mol) of sodium hydroxide in 250 ml. of water is added. The resultant mixture is then stirred vigorously for 2 hours, while the temperature is maintained at 60° C. A solution of 152.5 g. (0.8 mol) of p-toluenesulfonyl-chloride in 250 ml. of tetrahydrofuran is then added, over a period of 30 minutes, while the temperature is maintained at between 20° C. and 30° C. The reaction is then allowed to proceed for another hour at room temperature. To the reaction mixture is then added 1 liter of isopropyl acetate, the layers are separated and the organic layer is concentrated to dryness under vacuum to yield the desired compound as a foamy material.

b) Preparation of the hexatosyl cyclam dimer of formula IV

To a 4-necked, round-bottom flask, equipped with a mechanical stirrer, heating mantle, internal thermometer and addition funnel, is added 114.6 g. (0.10 mol) of the compound prepared in a) above and 2.5 liters of dimethylformamide. After the system is degassed, 22.4 g. (0.56 mol) of NaOH beads, 27.6 g (0.2 mol) of anhydrous potassium carbonate and 5.43 g. (0.016 mol) of t-butylammonium sulfate are added to the solution, and the resultant mixture is heated to 100° C. and maintained at this temperature for 2.5 hours. A solution of 111.0 g (0.3 mol) of ethyleneglycol ditosylate in 1 liter of dimethylformamide is then added, over a period of 2 hours, while the temperature is maintained at 100° C. After cooling the reaction mixture to room temperature, it is poured into 4 liters of water with stirring. The suspension is then filtered and the filter cake is washed with 1 liter of water. The filter cake is then thoroughly mixed with 1 liter of water and 2 liters of ethyl acetate. The solvent is then removed from the ethyl acetate solution and the residue is re-dissolved in 500 ml. of warm acetonitrile. The precipitate that forms on standing is collected by filtration and then dried to yield the desired compound as a white solid.

c) Preparation of 1,1′- 1,4-phenylenebis-(methylene)!-bis-1,4,8,11-tetraazacyclotetradecane

In a 4-necked, round-bottom flask, equipped with a mechanical stirrer, heating mantle, internal thermometer and addition funnel, is added 26.7 g.(0.02 mol) of the compound prepared in b) above, 300 ml. of 48% hydrobromic acid and 1 liter of glacial acetic acid. The resultant mixture is then heated to reflux and maintained at reflux temperature, with stirring, for 42 hours. The reaction mixture is then cooled to between 22° C. and 23° C. over a period of 4 hours, after which time it is stirred for an additional 12 hours. The solids are then collected using suction filtration and added to 400 ml. of deionized water. The resultant solution is then stirred for 25 to 30 minutes at a temperature between 22° C. and 23° C. and filtered using suction filtration. After washing the filter pad with a small amount of deionized water, the solution is cooled to between 10° C. and 15° C. 250 g. of a 50% aqueous solution of sodium hydroxide is then added, over a period of 30 minutes, while the temperature is maintained at between 5° C. and 15° C. The resultant suspension is stirred for 10 to 15 minutes, while the temperature is maintained at between 10° C. and 15° C. The suspension is then warmed to between 22° C. and 23° C. and to the warmed suspension is added 1.5 liters of dichloromethane. The mixture is then stirred for 30 minutes, the layers are separated and the organic layer is slurried with 125 g. of sodium sulfate for 1 hour. The solution is then filtered using suction filtration, and the filtrate is concentrated under reduced pressure (40°-45° C. bath temperature, 70-75 mm Hg) until approximately 1.25 liters of solvent is collected. To the slurry is then added 1.25 liters of acetone, and the filtrate is concentrated under reduced pressure (40°-45° C. bath temperature, 70-75 mm Hg) until approximately 1.25 liters of solvent is collected. The slurry is then cooled to between 22° C. and 23° C. and the solids are collected using suction filtration. The solids are then washed with three 50 ml. portions of acetone and dried in a vacuum oven to obtain the desired compound as a white solid.


The following is an alternate procedure for the preparation of the 1,4-phenylenebis-methylene bridged hexatosyl acyclic precursor of formula III.

To a 3-necked, round-bottomed flask, equipped with a mechanical stirrer, heating mantle, internal thermometer and addition funnel, is added 3.48 g. (20 mmol) of N,N’-bis-(3-aminopropyl)ethylenediamine and 20 ml. of tetrahydrofuran. To the resultant solution is added, over a period of 20 minutes with external cooling to maintain the temperature at 20° C., 5.2 ml. (42 mmol) of ethyl trifluoroacetate. The reaction mixture is then stirred at room temperature for 1 hour, after which time a solution of 2.64 g. (10 mmol) of α,α’-dibromoxylene in 20 ml. of tetrahydrofuran is added. The resultant reaction mixture is then stirred at room temperature for 4 hours. A solution of 4.8 g. (120 mmol) of sodium hydroxide in 20 ml. of water is then added and the resultant mixture is warmed to 60° C. and maintained at this temperature, with vigorous stirring, for 2 hours. Over a period of 20 minutes, 13.9 g. (73 mmol) of p-toluenesulfonylchloride is then added portionwise, while the temperature is maintained at 20° C. The reaction is then allowed to proceed for another hour at room temperature. To the reaction mixture is then added 100 ml. of isopropyl acetate, the layers are separated and the organic layer is washed with saturated sodium bicarbonate aqueous solution. The solution is then condensed to 40 ml., cooled to 4° C. and kept at that temperature overnight. The resultant suspension is filtered and the solid is washed with 10 ml. of isopropyl acetate. The solvents are then removed from the filtrate to yield the desired compound as a brown gel.



Synthesis and structure-activity relationships of phenylenebis(methylene)linked bis-tetraazamacrocycles that inhibit HIV replication. Effects of macrocyclic ring size and substituents on the aromatic linker
J Med Chem 1995, 38(2): 366



New bicyclam-AZT conjugates: Design, synthesis, anti-HIV evaluation, and their interaction with CXCR-4 coreceptor
J Med Chem 1999, 42(2): 229


CN 102584732


Figure CN102584732BD00041

[0004] plerixafor (trade name Mozobil ™) was developed by the U.S. company Genzyme chemokine receptor 4 (CXCR4) antagonist specificity. The drug is a hematopoietic stem (progenitor) cell activator, and can stimulate hematopoietic stem cell proliferation and differentiation into functional blood circulation.

[0005] As the non-Hodgkin’s lymphoma (NHL) and multiple myeloma (Korea) most of the cases and the progress of cases to alleviate the need for autologous peripheral blood stem cell transplantation, and plerixafor joint G-CSF can significantly improve the number of patients with ⑶ 34 + cells, about 60% of the patient’s peripheral blood can ⑶ 34 + cells increased to ensure that the NHL and MM patients with autologous hematopoietic stem cell transplantation success.

[0006] U.S. FDA approval on December 15, 2008 its listing, clinical studies showed that the drug can greatly increase the number of white blood cells of patients and to promote hematopoietic stem cells from bone marrow to the blood flow, and granulocyte colony-stimulating factor (G-CSF ) have a synergistic effect; has been used in multiple myeloma and Hodgkin’s lymphoma patients with stem cell transplantation in clinical trials.

[0007] About plerixafor or synthetic analogs have some at home and abroad reported in the literature, there are J.0rg.Chem.2003, 68,6435-6436; J.Med Chem.1995, 38 (2): 366-378; J.SynthCommun.1998 ,28:2903-2906; Tetrahedron, 1989,45 (1) :219-226; Chinese Journal of Pharmaceuticals 2007,38 (6); World Patent W09634860A1; W09312096A1; U.S. Patent US5047527, US5606053, US5801281, US5064956, Chinese patent CN1466579A.

[0008] J.Med Chem.1995, 38 (2) = 366-378 relates to a preparation method comprises the following steps: a) forming a salt of trimethoxy benzene tetraaza macrocycles; 2) reacting the protected tetrazole hetero macrocycle in acetonitrile under the presence of a base such as potassium carbonate as dibromo-p-xylene is reacted with an organic dihalide; 3) using freshly prepared sodium amalgam, concentrated sulfuric acid or acetic acid / hydrobromic acid mixture deprotected target product.

[0009] US 5047527 relates to preparation of the cyclic four monofunctional amine, the method comprising: a) reacting the unprotected macrocycle of reaction with chromium hexacarbonyl to obtain protection tetraazadecalin three compounds; 2) 3 Protection of the free amino compound with an organic halide to obtain three-protected monofunctional tetraaza naphthenic compounds; 3) simple air oxidation, deprotection to obtain the desired product. [0010] J.Synth Commun.1998 ,28:2903-2906 describes an improved method for synthesizing intermediates Plerixafor, the method using phosphor protection, deprotection to give a smooth 1,1 ‘- [1,4 – phenylene bis (methylene)] _ two _1, 4,8,11 – tetraazacyclododecane fourteen burn.

[0011] US 5606053 relates to a process for preparing dimers 1, I ‘- [1,4 – phenylene bis (methylene)] – two -1,4,8,11 – tetraazacyclododecane-tetradecane method. The preparation of compounds include: 1) the four-amine as the starting material, obtained by acylation of toluene Juan acyclic intermediates and three xylene sulfonate and toluene sulfonate and toluene intermediates; 2) and xylene sulfonate and intermediates trimethylbenzene toluenesulfonic acid intermediates after alkylation separation dibromo xylene, toluene sulfonate and then obtain a non-cyclic dimers of six toluenesulfonic acylated; 3) six isolated bridged acyclic toluenesulfonic acid dimer form is reacted with ethylene glycol ditosylate three equivalents of cyclization; 4) deprotection to obtain the objective product was purified by hydrobromic acid and acetic acid.

[0012] US 5801281 relates to preparation of dimer 1, I ‘- [1,4 _-phenylene bis (methylene)] – two _1, 4,8,11

[0013] – tetraazacyclo tetradecane, comprising: a) reacting the acyclic tetraamine with 3 equivalents of ethyl trifluoroacetate, the reaction; 2) with 0.5 equivalents of the tri-dibromo-p-xylene-protected acyclic alkylation of the amine obtained form four non-cyclic dimers; 3) hydrolysis to remove the six trifluoroacetyl compound group; 4) acylation of the compound toluenesulfonic bridged tetraamine dimer; 5) B Juan xylene glycol ester cyclization; 6) and glacial acetic acid mixed with hydrobromic acid deprotection was the target product.

Under the [0014] US 5064956 discloses a multi-alkylated single-ring nitrogen of the compound prepared, the method involves reacting the unprotected macrocycle in an aprotic, relatively non-polar solvent in presence of alkali electrophilic reagent. Not mentioned in this document similar to the embodiment Seclin dimer synthesis.

[0015] Through the open Plerixafor synthetic route research and meta-analysis of the literature, mainly in the following four synthetic routes:

[0016] Route One, is 1,4,8,11 – tetraazacyclododecane cyclotetradecane as raw material, NI, N4, N8 three protected with 1,4 – bis (halomethyl) benzene-bridged deprotection to obtain the finished product. The following reaction scheme, wherein R is p-toluenesulfonyl group, a methanesulfonyl group, a trifluoroacetyl group, a tert-butoxycarbonyl group and the like:


Figure CN102584732BD00061

[0018] Route II is di (2 – aminopropyl) ethylenediamine as raw material, the ring and the reaction with 1,4 – bis (halomethyl) benzene-bridged, and then deprotection Bullock Suffolk.

[0019] Route 3 to 1,4,8,11 – tetraazacyclododecane cyclotetradecane as raw material, under anhydrous, anaerobic conditions, after the ring protection with 1,4 – bis (halomethyl ) benzene bridging, and then deprotection plerixafor. Synthesis scheme below, wherein R is P, Ni, etc.;

Figure CN102584732BD00071

[0021] line four, based on acrylate as starting material, first with ethylene diamine as raw material by Michael addition of the amine solution, then with malonate cyclization 1,4,8,11 – Tetraaza _5, 7,12 – three oxo cyclotetradecane by α, α ‘- dibromo-p-xylene bridging, the final deprotection plerixafor. Reaction Roadmap follows:


Figure CN102584732BD00081

[0023] The above synthesis route and the existing methods have the following disadvantages:

[0024] In an intermediate of the synthesis route, the existing technology, the need for column purification of the intermediates, low yield.

[0025] route to protect the stability of the two because of the strong, leading to the final deprotection step difficult, long production cycle, low yield, and finished organic residues can not be achieved within the standard limits.

Higher dry anaerobic demands [0026] Route 3 on, harsh reaction conditions, deprotection is not complete, intermediates need to repeatedly purified, low yield, after repeated recrystallization, finished monohetero difficult to control in 0.1% less.

[0027] Anhydrous ethylene diamine route and need four anhydrous THF, more stringent requirements on the process, and to use dangerous borane dimethyl sulfide, while the second step is only about 35% lower yield. Selectivity of the reaction is not high shortcomings, so do not be the most economical and reasonable synthetic route.

[0028] We prepared by Plerixafor prepared by methods disclosed above may Plerixafor single impurity of 0.1% or less is difficult to achieve, it is difficult to meet the quality requirements of the injection material, the same techniques can not reach the European Quality of ICH guidelines of the relevant technical requirements, low yield, high cost required for each step of the intermediate column to afford a large amount of solvent, time consuming, and the greater the elution solvent toxicity, is not suitable for industrial production.

(I) Preparation of 1,4,8 _ tris (p-toluenesulfonyl) -1,4,8,11 – tetraazacyclododecane-tetradecane: the raw 1,4,8,11 – tetraazacyclododecane cyclotetradecane suspended in methylene chloride, in the role of acid binding agent, at a temperature 10 ~ 30 ° C, p-toluenesulfonyl chloride and 3 ~ 8h, filtered, and the filtrate was collected and concentrated to dryness to obtain a residue; will have The residue of said C ^ C3 alkyl group in a mixed solvent of alcohol and an aprotic solvent, purification, crystallization segment greater than 95% purity of 1,4,8 – tris (p-toluenesulfonyl) _1, 4,8,11 – tetraaza cyclotetradecane;

[0032] (2) Preparation of 1,1 ‘- [1,4 – (phenylene methylene)] – two – [4,8,11 – tris (p-toluenesulfonyl)] -1,4, 8,11 – tetraazacyclododecane-tetradecane: A (I) the resulting 1,4,8 – tris (p-toluenesulfonyl) _1, 4,8,11 – tetraazacyclododecane-tetradecane, α, α two bromo-p-xylene in place of anhydrous acetonitrile, was added acid-binding agent, the reaction was refluxed under nitrogen for 5 to 24 hours; After the reaction was cooled to room temperature, the reaction mixture was then collected by filtration and the filter cake was purified to obtain a mixed solvent I , I, – [1,4 – (phenylene methylene)] – two – [4,8,11 – tris (p-toluenesulfonyl)] _1, 4,8,11 – tetraazacyclododecane ten four alkyl;

[0033] (3) Synthesis Plerixafor: A (2) the resultant I, 1’-[1,4 _ (phenylene methylene)] – two – [4,8,11 – tris (p-toluene sulfonyl)] -1,4,8,11 – tetraazacyclododecane myristic acid solution was added to the mixture, stirred and dissolved, the reaction was warmed to reflux for 10 to 24 hours, cooled, filtered, and filter cake was collected; the filter cake was dissolved in purified water, adjusted with sodium hydroxide solution or potassium hydroxide solution to the PH-12, filtered, and the filtrate was extracted with a halogenated solvent, and the organic layer was dried over anhydrous sodium sulfate and then filtered, the filtrate was concentrated under reduced pressure P Le Suffolk crude;

[0034] (4) Purification Plerixafor: Plerixafor the crude was dissolved into a solvent and heated to reflux to dissolve, filtered, and the crystallization solvent is added dropwise at 40 ~ 45 ° C crystallization 30min, filtered and the filtrate then cooled to 20 ~ 25 ° C crystallization I hour at O ​​~ 5 ° C crystallization three hours, filtered, and the filter cake was dried Plerixafor.

Plerixafor Preparation: 6 [0075] Implementation

[0076] The starting material 1,4,8,11 – tetraazacyclo tetradecane (5g, 25mmol) was suspended in dichloromethane (50g) was added N, N-diisopropylethylamine (7.5ml) , a solution of p-toluenesulfonyl chloride (10.8g, 56.5mmol) and methylene chloride (50g) in a solution of, at 25 ~ 30 ° C reaction temperature 3h, filtered, and the filtrate was collected and concentrated to dryness and to the residue in methanol (30g), toluene (IOg) was heated to reflux, filtered, and the filtrate was cooled to 40 ° C crystallization 30min, filtered to remove impurities little over protection, and the filtrate was added methyl tert-butyl ether (30g), stirring rapidly cooled to O ~ 5 ° C crystallization 3h, filtered, and dried to give 1,4,8 – tris (p-toluenesulfonyl) -1, 4,8,11 – tetraazacyclododecane-tetradecane (9.6g, 61.9%), purity of 97.2%.

[0077] The 4,8 _ tris (p-toluenesulfonyl) _1, 4,8,11 – tetraazacyclododecane-tetradecane (9g, 13.6mmol) α, α ‘- dibromo-p-xylene (1.81 g, 6.8mmol) in dry acetonitrile was placed (90ml) was added potassium carbonate (15.0g, 108.5mmol), the reaction was refluxed under nitrogen for 5 hours. Cooled to room temperature and filtered to collect the filter cake, was added anhydrous methanol (10ml), ethyl acetate (30ml), dichloromethane (IOml) hot melt, whereby the cooling crystallization, filtration, and dried under reduced pressure to obtain white solid (16. lg, 83%), purity 97.5%.

[0078] The intermediate obtained above (5g, 3.5mmol) was added to glacial acetic acid (25ml) and concentrated hydrochloric acid (25ml) was stirred until dissolved in the mixed solution was heated to reflux for 24 hours, cooled, collected by filtration cake. The filter cake was dissolved in purified water (20ml), adjusting the PH value of the solution with sodium hydroxide to 12, filtered, and the filtrate was extracted with dichloromethane (50mlX3), the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain sand Bullock Fu crude (1.4g, 79.5%), purity 98.6%.

[0079] The crude Plerixafor (1.4g) is placed in tetrahydrofuran (14g), heated to reflux to dissolve, filtered, and added dropwise n-hexane (42g), and 40 ~ 45 ° C crystallization 30min, filtered little solid, The filtrate was rapidly cooled to 20 ~ 25 ° C crystallization I hour and then at O ​​~ 5 ° C crystallization three hours, filtered, 45 ° C and dried under reduced pressure to obtain the finished Plerixafor (1.2g, 85.7%), purity 99.93 %, the largest single miscellaneous 0.04%.


Figure US08420626-20130416-C00014

wherein, n is 0 or 1, Ts is tosyl radical, P is trifluoroacetyl or p-tosyl radical;
To the NaOH solution of the starting material 7 is dropwise added ether solution of tosyl chloride. The system is stirred over night. A white solid is formed and filtrated. The filter cake is washed with water and ethyl ether, respectively, recrystallized to give a white solid intermediate of formula 8. To the dried acetonitrile solution of the compound of formula 8 is slowly dropwise added dried acetonitrile solution of 1,2-di-p-tosyloxypropane under reflux state, refluxed for 2-4 days, stood until room temperature. A white solid is precipitated and filtrated. The filter cake is washed with water and ethyl acetate, respectively, recrystallized to give a white solid compound of formula 9. The compound of formula 9 is dissolved in 90% concentrated sulfuric acid, allowed to react at 100° C. for 24-48 hours, stood until room temperature. To the reaction solution are dropwise added successively ethanol and ethyl ether. A white solid is precipitated, filtrated, dried, and dissolved in NaOH solution. The aqueous phase is extracted with chloroform. The chloroform phase is combined, concentrated, recrystallized to give a white solid compound of formula 10. To the chloroform solution of the compound of formula 10 and triethylamine is dropwise added chloroform solution of tosyl chloride. The mixture is allowed to react at room temperature over night, concentrated and column separated (eluant: dichloromethane/methanol system) to give a white solid compound of formula 11 (protective group is tosyl); or to the methanol solution of the compound of formula 10 is dropwise added ethyl trifluoroacetate. The mixture is allowed to react at room temperature over night, concentrated and column separated (eluant: ethyl acetate) to give a white solid compound of formula 11 (protective group is trifluoroacetyl);



Following subcutaneous injection, plerixafor is absorbed quickly and peak concentrations are reached after 30 to 60 minutes. Up to 58% are bound to plasma proteins, the rest mostly resides in extravascular compartments. The drug is not metabolized in significant amounts; no interaction with the cytochrome P450 enzymes or P-glycoproteins has been found. Plasma half life is 3 to 5 hours. Plerixafor is excreted via the kidneys, with 70% of the drug being excreted within 24 hours.[5]


In the form of its zinc complex, plerixafor acts as an antagonist (or perhaps more accurately a partial agonist) of the alpha chemokine receptor CXCR4 and an allosteric agonist ofCXCR7.[10] The CXCR4 alpha-chemokine receptor and one of its ligandsSDF-1, are important in hematopoietic stem cell homing to the bone marrow and in hematopoietic stem cell quiescence. The in vivo effect of plerixafor with regard to ubiquitin, the alternative endogenous ligand of CXCR4, is unknown. Plerixafor has been found to be a strong inducer of mobilization of hematopoietic stem cells from the bone marrow to the bloodstream as peripheral blood stem cells.[11]


No interaction studies have been conducted. The fact that plerixafor does not interact with the cytochrome system indicates a low potential for interactions with other drugs.[5]

Legal status

Plerixafor has orphan drug status in the United States and European Union for the mobilization of hematopoietic stem cells. It was approved by the U.S. Food and Drug Administration for this indication on December 15, 2008.[12] In Europe, the drug was approved after a positive Committee for Medicinal Products for Human Use assessment report on 29 May 2009.[7] The drug was approved for use in Canada by Health Canada on December 8, 2011.[13]


Small molecule cancer therapy

Plerixafor was seen to reduce metastasis in mice in several studies.[14] It has also been shown to reduce recurrence of glioblastoma in a mouse model after radiotherapy. In this model, the cancer surviving radiation are critically depended on bone marrow derived cells for vasculogenesis whose recruitment mediated by SDF-1 CXCR4 interaction is blocked by plerixafor.[15]

Use in generation of other stem cells

Researchers at Imperial College have demonstrated that plerixafor in combination with vascular endothelial growth factor (VEGF) can produce mesenchymal stem cells andendothelial progenitor cells in mice.[16]

Other uses

Blockade of CXCR4 signalling by plerixafor (AMD3100) has also unexpectedly been found to be effective at counteracting opioid-induced hyperalgesia produced by chronic treatment with morphine, though only animal studies have been conducted as yet.[17]

JM 3100.svg
JM 3100 3D.png
Systematic (IUPAC) name
1,1′-[1,4-Phenylenebis(methylene)]bis [1,4,8,11-tetraazacyclotetradecane]
Clinical data
AHFS/ Consumer Drug Information
MedlinePlus a609018
Pregnancy cat. (US)
Legal status -only (US)
Routes Subcutaneous injection
Pharmacokinetic data
Protein binding Up to 58%
Metabolism None
Half-life 3–5 hours
Excretion Renal
CAS number 110078-46-1
ATC code L03AX16
PubChem CID 65015
IUPHAR ligand 844
DrugBank DB06809
ChemSpider 58531 Yes
UNII S915P5499N Yes
Synonyms JM 3100, AMD3100
Chemical data
Formula C28H54N8 
Mol. mass 502.782 g/mol

(Plerixafor), chemical name: 1, I ‘- [I, 4_ phenylene ni (methylene)] – ni -1,4,

8,11 – tetraazacyclo tetradecane, its molecular structure is as follows:


Figure CN102653536AD00041

Synthesis of domestic and foreign literature in general, all require 1,4,8,11 – tetraazacyclo-tetradecane for 3 protection (eg of formula I), of the three methods are used to protect the p-toluenesulfonamide chloride, trifluoroacetic acid ko ko cool, tert-butyl carbonate ni. Use of p-toluenesulfonamide-protected deprotection step into strict step because deprotecting reagent (such as hydrobromic acid / glacial acetic acid, concentrated sulfuric acid, etc.) side reactions often occur.The use of trifluoroacetic acid ko ko ester protecting, since the trifluoromethyl group strongly polar ko, resulting fourth-NH unprotected decrease in activity, usually not fully reflect the subsequent reaction, thereby further into ー is introduced after deprotection difficult to remove impurities 1,4,8,11 – tetraazacyclo-tetradecane.

[0006] tert-butyl carbonate ni selective protection of the amino group is widely used (polyamines, amino acids, p printed tidic chains, etc.), but to use it for 1,4,8,11 – tetraazacyclo tetradecane rarely reported, abroad it for 1,4,8,11 – tetraazacyclo tetradecane protection coverage, we use the t-butyl carbonate brother attempted 3 protection, he was surprised to find that in certain conditions, the three protection up to 90% (see Figure I), with high selectivity, significantly higher than the reported domestic Boc protected

Selectivity of the reaction (see table below).


Figure CN102653536AD00051

[0008] 2 by three protection product with quite different polarity protection products, flash column chromatography using silica gel column to separate the protector 3 of sufficient purity, and deprotection conditions milder (only hydrochloric acid solution), in a certain extent reduce the incidence of side effects, so capable of synthesizing high purity products.


Figure CN102653536AD00052


Figure CN102653536AD00053


Figure CN102653536AD00061

xample I: 3Boc protection 1,4,8,11 _ tetraazacyclo Preparation tetradecane

[0048] 1,4,8,11 taken tetraazacyclo tetradecane _ 10g (0.05mol), and acetone – water (2: l) 50ml, tris ko amine 10. 119g (0. Lmol), ni ko isopropyl amine 3. 225g (0. 025mol), at room temperature was added dropwise tert-butyl carbonate, brother 38. 194g (0. 175mol), dropwise at room temperature after stirring for 24 hours, HPLC monitoring of the reaction. After completion of the reaction 50 ° C under reduced pressure to dryness to give a pale yellow oil, 150g on a silica gel column, and eluted with ko acid esters ko collecting ko ko acid ester liquid evaporated to dryness under reduced pressure to give a white foam 23. 12g, yield of 92.36%. 1HNMR (400MHz, CDCl3, 6 ppm): 1. 74 (2H, q, 5. 5);

I. 96 (2H, q, 6. 5); 2. 66 (2H, t, 5. 5); 2. 82 (2H, t, 5. 5); 3. 33 (4H, m); 3. 34 (2H, m); 3. 37 (2H, m), 3. 43 (4H, m).

[0049] Implementation Example 2: 6Boc protection Bullock Suffolk Preparation

[0050] Take 3Boc protection 1,4,8,11 _ tetraazacyclo tetradecane 20. 03g (0. 04mol), dissolved in anhydrous ko nitrile 400ml, anhydrous potassium carbonate 20g, aa ‘ni chlorine ni toluene 3.5012g (0.02mol), sodium iodide 75mg, at reflux for 24 hours under nitrogen, TLC monitoring of the reaction. After completion of the reaction, cooled to room temperature, filtered, the filter cake was washed with 200ml of ko nitrile, nitrile ko combined solution was evaporated to dryness under reduced pressure to give the protected Bullock 6Boc Suffolk 21. 20g, yield of 96.06%. Alcohol with ko – a mixed solvent of water and recrystallized to give a white solid. [0051] Implementation Example 3: Bullock Suffolk • 8HC1 • 3H20 Preparation of compounds

[0052] Protection Bullock Suffolk take 6Boc 20g, add methanol 200ml, stirring to dissolve, concentrated hydrochloric acid was added dropwise at room temperature, 60ml, was stirred at room temperature after the addition was complete 48 inches, TLC monitoring of the reaction. After completion of the reaction, filtration, the filter cake was dried 50 ° C under reduced pressure to give a white solid 13. 54g, yield of 88.04%.


Figure CN102653536AD00071


[0053] Implementation Example 4: Preparation of Suffolk Bullock…………Plerixafor BASE

[0054] Take Bullock Suffolk • 8HC1 • 3H20 compound 13. 54g, add water 40ml ultrasound to dissolve after stirring constantly with 50% sodium hydroxide solution to adjust the pH to 12 and filtered, the filter cake 50 ° C minus pressure and dried to give a white solid 7. 24g, yield 90.24 V0o

1H NMR (400MHz, CDCl3, 6 ppm): 1. 75 (4H, bs); 1. 87 (4H, bs); 2. 95-2. 51 (32H, m); 3. 54 (4H, s); 4. 23 (4H, bs); 7. 30 (4H, s). 

IR (KBr) 3280,2927,2883,2805,1458,1264,1117 cm,



NEW PATENT…………….WO-2014125499

Improved and commercially viable process for the preparation of high pure plerixafor base

Process for the preparation of more than 99.8% pure plerixafor base by HPLC. Also claims solid forms of plerixafor base and composition comprising the same. Appears to be the first filing from the assignee on this API. FDA Orange book lists US6987102 and US7897590, expire in July 2023.

Process for preparing 1,4,8,11-tetraazacyclotetradecane
Process for preparing 1,1′-[1,4-phenylenebis-(methylene)]-bis-1,4,8,11-tetraazacyclotetradecane
Aromatic-linked polyamine macrocyclic compounds with anti-HIV activity



Substituted benzodiazepines as inhibitors of the chemokine receptor CXCR4
Methods and compositions for the treatment or prevention of human immunodeficiency virus and related conditions using cyclooxygenase-2 selective inhibitors and antiviral agents
Process for preparation of N-1 protected N ring nitrogen containing cyclic polyamines and products thereof
Process for preparing 1,1′-[1,4-phenylenebis-(methylene)]-bis-1,4,8,11-tetraazacyclotetradecane


Antiviral methods employing double esters of 2′, 3′-dideoxy-3′-fluoroguanosine
Chemokine Receptor Modulators
Combination of CXCR4 Antagonist and Morphogen to Increase Angiogenesis
Chemokine receptor modulators
Chemokine receptor modulators
Compositions and methods for treating tissue ischemia
Treatment of viral infections using prodrugs of 2′,3-dideoxy,3′-fluoroguanosine



  1. Jump up^ Ciampolini, M.; Fabbrizzi, L.; Perotti, A.; Poggi, A.; Seghi, B.; Zanobini, F. (1987). “Dinickel and dicopper complexes with N,N-linked bis(cyclam) ligands. An ideal system for the investigation of electrostatic effects on the redox behavior of pairs of metal ions”.Inorganic Chemistry 26 (21): 3527. doi:10.1021/ic00268a022edit
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  10. Jump up^ Kalatskaya, I.; Berchiche, Y. A.; Gravel, S.; Limberg, B. J.; Rosenbaum, J. S.; Heveker, N. (2009). “AMD3100 is a CXCR7 Ligand with Allosteric Agonist Properties”.Molecular Pharmacology 75: 1240. doi:10.1124/mol.108.053389.PMID 19255243edit
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  12. Jump up^ “Mozobil approved for non-Hodgkin’s lymphoma and multiple myeloma” (Press release). Monthly Prescribing Reference. December 18, 2008. Retrieved January 3, 2009.
  13. Jump up^ Notice of Decision for MOZOBIL
  14. Jump up^ Smith, M. C. P.; Luker, K. E.; Garbow, J. R.; Prior, J. L.; Jackson, E.; Piwnica-Worms, D.; Luker, G. D. (2004). “CXCR4 Regulates Growth of Both Primary and Metastatic Breast Cancer”. Cancer Research 64 (23): 8604–8612. doi:10.1158/0008-5472.CAN-04-1844PMID 15574767edit
  15. Jump up^ Kioi, M.; Vogel, H.; Schultz, G.; Hoffman, R. M.; Harsh, G. R.; Brown, J. M. (2010).“Inhibition of vasculogenesis, but not angiogenesis, prevents the recurrence of glioblastoma after irradiation in mice”Journal of Clinical Investigation 120 (3): 694–705. doi:10.1172/JCI40283PMC 2827954PMID 20179352edit
  16. Jump up^ Pitchford, S.; Furze, R.; Jones, C.; Wengner, A.; Rankin, S. (2009). “Differential Mobilization of Subsets of Progenitor Cells from the Bone Marrow”. Cell Stem Cell 4 (1): 62–72. doi:10.1016/j.stem.2008.10.017PMID 19128793edit
  17. Jump up^ Wilson NM, Jung H, Ripsch MS, Miller RJ, White FA (March 2011). “CXCR4 Signaling Mediates Morphine-induced Tactile Hyperalgesia”Brain, Behavior, and Immunity 25(3): 565–73. doi:10.1016/j.bbi.2010.12.014PMC 3039030PMID 21193025.

External links


Synthetic routes to produce the novel chelators 2 and 3.

Theranostics 03: 0047 image No. 04

Theranostics 03: 0047 image No. 18






ncur_powerpoint Courtney.ppt 

… trials against cancer and for stem cell mobilization as “Mozobil” or “Plerixafor” …NMR studies of AMD-3100 suggest that complex configuration is important.

Mar 182014


CAS: 84371-65-3
17β-hydroxy-11β-(4-dimethylaminophenyl)-17α (Propa-1 ,2-dienyl) estra-4 ,9-dien-3-one.
17β-hydroxy-11β-(4-dimethylaminophenyl) 17α-(prop-2-ynyl) estra-4 ,9-dien-3-one.
RU-486; RU-38486, Mifegyne (HMR)
MF: C29H35NO2
MW: 429.59
C 81.08%, H 8.21%, N 3.26%, O 7.45%
mp 150°.
Optical Rotation: [a]D20 +138.5° (c = 0.5 in chloroform)
Progesterone receptor antagonist with partial agonist activity.
Mifeprex, Mifegyne, RU-486, Corlux, 84371-65-3, Mifepristonum [Latin], Mifepristona [Spanish], RU486, Mifepriston
Molecular Formula: C29H35NO2   Molecular Weight: 429.5937
A progestational and glucocorticoid hormone antagonist. Its inhibition of progesterone induces bleeding during the luteal phase and in early pregnancy by releasing endogenous prostaglandins from the endometrium or decidua. As a glucocorticoid receptor antagonist, the drug has been used to treat hypercortisolism in patients with nonpituitary CUSHING SYNDROME.

Mifepristone (or RU-486) is a synthetic steroid compound with both antiprogesterone and antiglucocorticoid properties. The compound is a 19-nor steroid with substitutions at positions C11 and C17 (17 beta-hydroxy-11 beta-[4-dimethylamino phenyl] 17 alpha-[1-propynyl]estra-4,9-dien-3-one), which antagonizes cortisol action competitively at the receptor level.

U.S. Pat. No. 4,386,085 (the ‘085 patent) discloses mifepristone starting from estra-5(10), 9(11)-diene-3,17-dione 3-ethylene acetal. The ‘085 patent discloses the purification of mifepristone by column chromatography using cyclohexane-ethyl acetate (7:3) mixture as an eluent. However, a drawback to the use of column chromatography is its unsuitability for industrial use.

Mifepristone is a progesterone receptor antagonist used as an abortifacient in the first months of pregnancy, and in smaller doses as an emergency contraceptive. Mifepristone is also a powerful glucocorticoid receptor antagonist, and has occasionally been used in refractory Cushing’s Syndrome(due to ectopic/neoplastic ACTH/Cortisol secretion). During early trials, it was known as RU-38486 or simply RU-486, its designation at the Roussel Uclaf company, which designed the drug. The drug was initially made available in France, and other countries then followed—often amid controversy. It is marketed under tradenames Korlym and Mifeprex, according to FDA Orange Book.

Mifepristone was the first antiprogestin to be developed and it has been evaluated extensively for its use as an abortifacient. The original target for the research group, however, was the discovery and development of compounds with antiglucocorticoid properties. It is these antiglucocorticoid properties that are of great interest in the treatment of severe mood disorders and psychosis.

In April 1980, as part of a formal research project at Roussel-Uclaf for the development of glucocorticoid receptorantagonists, chemist Georges Teutsch synthesized mifepristone (RU-38486, the 38,486th compound synthesized by Roussel-Uclaf from 1949 to 1980; shortened to RU-486); which was discovered to also be a progesterone receptor antagonist. In October 1981, endocrinologist Étienne-Émile Baulieu, a consultant to Roussel-Uclaf, arranged tests of its use for medical abortion in eleven women in Switzerland by gynecologist Walter Herrmann at theUniversity of Geneva‘s Cantonal Hospital, with successful results announced on April 19, 1982. On October 9, 1987, following worldwide clinical trials in 20,000 women of mifepristone with aprostaglandin analogue (initially sulprostone or gemeprost, later misoprostol) for medical abortion, Roussel-Uclaf sought approval in France for their use for medical abortion, with approval announced on September 23, 1988.

On October 21, 1988, in response to antiabortion protests and concerns of majority (54.5%) owner Hoechst AG of Germany, Roussel-Uclaf’s executives and board of directors voted 16 to 4 to stop distribution of mifepristone, which they announced on October 26, 1988. Two days later, the French government ordered Roussel-Uclaf to distribute mifepristone in the interests of public health.French Health Minister Claude Évin explained that: “I could not permit the abortion debate to deprive women of a product that represents medical progress. From the moment Government approval for the drug was granted, RU-486 became the moral property of women, not just the property of a drug company.” Following use by 34,000 women in France from April 1988 to February 1990 of mifepristone distributed free of charge, Roussel-Uclaf began selling Mifegyne (mifepristone) to hospitals in France in February 1990 at a price (negotiated with the French government) of $48 per 600 mg dose.

Mifegyne was subsequently approved in Great Britain on July 1, 1991, and in Sweden in September 1992, but until his retirement in late April 1994, Hoechst AG chairman Wolfgang Hilger, a devout Roman Catholic, blocked any further expansion in availability. On May 16, 1994, Roussel-Uclaf announced that it was donating without remuneration all rights for medical uses of mifepristone in the United States to the Population Council, which subsequently licensed mifepristone to Danco Laboratories, a new single-product company immune to antiabortion boycotts, which won FDA approval as Mifeprex on September 28, 2000.

On April 8, 1997, after buying the remaining 43.5% of Roussel-Uclaf stock in early 1997, Hoechst AG ($30 billion annual revenue) announced the end of its manufacture and sale of Mifegyne ($3.44 million annual revenue) and the transfer of all rights for medical uses of mifepristone outside of the United States to Exelgyn S.A., a new single-product company immune to antiabortion boycotts, whose CEO was former Roussel-Uclaf CEO Édouard Sakiz. In 1999, Exelgyn won approval of Mifegyne in 11 additional countries, and in 28 more countries over the following decade.

Mifepristone’s production and use as abortifacient may result in its release to the environment through various waste streams. If released to air, an estimated vapor pressure of 8.0X10-14 mm Hg at 25 deg C indicates mifepristone will exist solely in the particulate phase in the ambient atmosphere. Particulate-phase mifepristone will be removed from the atmosphere by wet and dry deposition. Mifepristone does not contain chromophores that absorb light at wavelengths >290 nm and therefore is not expected to be susceptible to direct photolysis by sunlight. If released to soil, mifepristone is expected to have no mobility based upon an estimated Koc of 89,000. Volatilization from water and moist soil surfaces is not expected to be an important fate process based upon an estimated Henry’s Law constant of 5.0X10-13 atm-cu m/mole. Mifepristone will not volatilize from dry soil surfaces based upon its vapor pressure. Biodegradation data were not available. If released into water, mifepristone is expected to adsorb to suspended solids and sediment based upon the estimated Koc. An estimated BCF of 2,800 suggests potential for bioconcentration in aquatic organisms is very high. Hydrolysis is not expected to be an important environmental fate process since this compound lacks functional groups that hydrolyze under environmental conditions. Occupational exposure to mifepristone may occur through inhalation and dermal contact with this compound at workplaces where mifepristone is produced or used. Exposure to the drug among the general population may be limited to those being administered the drug mifepristone, (an abortifacient).

3,3-(Ethylenedioxy)estra-5(10),9(11)-diene-17(beta)-one (I) could react with propynylmagnesium bromine (II) in the presence of THF to produce 3,3-(ethylenedioxy)-17(beta)-(propyn-1-yl)estra-5(10),9(11)-diene-17(beta)-ol (III), which is epoxidized with H2O2 in hexafluoroacetone-methylene chloride yielding 3,3-(ethylenedioxy)-17(beta)-(propyn-1-yl)-5(alpha),10(alpha)-epoxyestra-9(11)-en-17(beta)-ol (IV). The reaction of (IV) with 4-dimethylaminophenylmagnesium bromide (V) in THF affords 11(beta)-(4-dimethylaminophenyl)-3,3-(ethylenedioxy)-17(beta)-(propyn-1-yl)estra-9-en-17(beta)-ol (VI), which is finally deprotected by a treatment with HCl in metnanol.
 11β-[4(N,N-dimethylamino)phenyl]-17β-hydroxy-17α-(3-methyl-1-butynyl)-estra-4,9-dien-3-one from estra-5(10), 9(11)-diene-3,17-dione-cyclic-3-(1,2-ethanediylacetal) of the structural formula 2.
Figure US06512130-20030128-C00004

The compound of structural formula 2 can be prepared from (+)-estrone in seven steps. Methylation of hydroxy group at C-3 in (+)-estrone, reduction of 17-ketone to 17β-alcohol followed by Birch reduction of ring A and mild hydrolysis of the enol ether to afford estra-17β-hydroxy-5(10)-en-3-one in four steps (Ref: Wilds, A. L. and Nelson, N. A. J. Am. Chem. Soc. 1953, 75, 5365-5369). This compound in another three steps, namely bromination and dehydrobrominatlon, ketalisation followed by Oppenauer oxidation yield compound having structural formula 2 (Ref: Perelman, M; Farkas, E.; Fornefield, E. J.; Kraay, R. J. and Rapala, B. T. J. Am. Chem. Soc. 1960, 82, 2402-2403).

U.S. Pat. No. 4,386,085 describes the synthesis of steroids of the general formula mentioned therein

    EXAMPLE 15 17β-hydroxy-11β-(4-dimethylaminophenyl)-17α (Propa-1 ,2-dienyl) estra-4 ,9-dien-3-one.Step A: 11β-(4-dimethylaminophenyl) 3,3 – / 1,2-ethane diyl bis (oxy) / 17α-(propa-1 ,2-dienyl) estr-9-en-5α-17β-diol and 11β – (4 – dimethylaminophenyl) 3,3 – / 1,2-ethane diyl bis (oxy) / 17α-(prop-2-ynyl) estr-9-en-5α (-17β-diol. Preparation of lithium compound.

  • In 50 cm3 of anhydrous tetrahydrofuran at 0, +5 ° C, bubbled up Allène the absorption of 2.1 g. Cooled to -70 ° C. and 15 minutes in 23.9 cm3 of a 1.3 M solution of butyllithium in hexanne. The resulting mixture is stirred for 15 minutes at -70 ° C.


  • A solution of lithium derivative obtained above was added at -70 ° C in 25 minutes a solution of 3.5 g of the product obtained in Step A of Example 7 in 35 cm3 of anhydrous tetrahydrofuran. Stirred for 1 hour at -70 ° C, slowly poured into a saturated aqueous solution iced ammonium chloride. Extracted with ether, the organic phase washed with saturated sodium chloride, dried and the solvent evaporated. 3.4 g of product which was chromatographed on silica eluting with petroleum ether-ethyl acetate (1-1) to 1 mile triethylamine. Thus isolated: a) 1.73 g of isomer 17α-(propa-1 ,2-dienyl) F = 178 ° C. / Α / D = -32 ° ± 2 ° (c = 0.7% chloroform) b) 1.5 g of isomer 17o (- (prop-2-ynyl) F = 150 ° C. / α / D = -15 ° ± 2 ° (c = 0.9% chloroform).

Step B: 17β-hydroxy-11β-(4-dimethylaminophenyl)-17α (propa-1, 2 – dienyl) estra-4 ,9-dien-3-one.

  • Inert gas mixing 1.73 g of 17α isomer (- (propa-1, 2 – dienyl) obtained in Step A, 51.8 cm3 of 95% ethanol and 3.5 cm3 of 2N hydrochloric acid. stirred at 20 ° C for 1 hour, add 50 cm3 of methylene chloride and 50 cm3 of a 0.25 M solution of sodium bicarbonate, decanted, extracted with methylene chloride, washed with water, dried and the solvent evaporated. obtained 1.51 g of product was dissolved in 10 cm3 of methylene chloride hot. was added 15 cm3 of isopropyl ether, concentrated and allowed to stand. thus isolated 1.23 g of the expected product was crystallized again in methylene chloride-isopropyl ether. finally obtained 1.11 g of the expected product. F = 228 ° C.
    / Α / D – 139, 5 ° ± 3 ° (c = 0.8% chloroform). ANY ERROr MAIL ME
Prepn: J. G. Teutsch et al., EP 57115;eidem, US 4386085 (1982, 1983 both to Roussel-UCLAF).
Pharmacology: W. Herrmann et al., C.R. Seances Acad. Sci. Ser. 3294, 933 (1982).
Pituitary and adrenal responses in primates: D. L. Healy et al., J. Clin. Endocrinol. Metab. 57, 863 (1983).
Mechanism of action study: M. Rauch et al., Eur. J. Biochem. 148, 213 (1985).
Clinical study as abortifacient: B. Couzinet et al.,N. Engl. J. Med. 315, 1565 (1986); as postcoital contraceptive: A. Glasier et al., ibid. 327, 1041 (1992).
Review of mechanism of action and clinical applications: E. E. Baulieu, Science 245, 1351-1357 (1989).
Reviews: I. M. Spitz, C. W. Bardin, N. Engl. J. Med. 329, 404-412 (1993); R. N. Brogden et al., Drugs 45, 384-409 (1993).
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Pimecrolimus Пимекролимус…For treatment of mild to moderate atopic dermatitis.

 GENERIC  Comments Off on Pimecrolimus Пимекролимус…For treatment of mild to moderate atopic dermatitis.
Mar 092014



137071-32-0 cas 

(3S,4R,5S,8R,9E,12S,14S,15R,16S,18R,19R,26aS)- 3-{(E)-2-[(1R,3R,4S)-4-Chloro-3-methoxycyclohexyl]- 1-methylvinyl}-8-ethyl-5,6,8,11,12,13,14,15,16,17,

18,19,24,25,26,26a-hexadecahydro-5,19-dihydroxy- 14,16-dimethoxy-4,10,12, 18-tetramethyl-15,19-epoxy- 3H-pyrido[2,1-c][1,4]oxaazacyclotricosine-1, 7,20,21(4H,23H)-tetrone

The systematic name of pimecrolimus is (lR,9S,12S,13R,14S,17R,18E,21S,23S,24R,25S,27R)-12-[(lE)-2- {(1 R,3R,4S)-4-chloro-3-methoxycyclohexyl} – 1 -methylvinyl] – 17-ethyl- 1,14- dihydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-aza- tricyclo[]octacos-18-ene-2,3,10,16-tetraone.

Pimecrolimus is the 32 epichloro derivative of ascomycin.

Elidel, NCGC00167506-01,  DSSTox_CID_26674, DSSTox_RID_81811, DSSTox_GSID_46674, 137071-32-0, Tox21_112504
Molecular Formula: C43H68ClNO11   Molecular Weight: 810.45312
US2008085858 4-11-2008 Pharmaceutical Composition
Canada 2200966 2006-12-19 expiry   2015-10-26
United States 6423722 1998-12-26              2018-12-26


5912238 Jun 15, 2016
5912238*PED Dec 15, 2016
6352998 Oct 26, 2015
6352998*PED Apr 26, 2016
6423722 Jun 26, 2018
6423722*PED Dec 26, 2018

Viktor Gyollai, Csaba Szabo, “Methods of preparing pimecrolimus.” U.S. Patent US20060142564, issued June 29, 2006.

US20060142564 Link out


Pimecrolimus is an immunomodulating agent used in the treatment of atopic dermatitis (eczema). It is currently available as a topical cream, once marketed by Novartis, (however Galderma will be promoting the molecule in Canada in early 2007) under the trade name Elidel.



Pimecrolimus is an immunomodulating agent used in the treatment of atopic dermatitis (eczema). It is available as a topical cream, once marketed by Novartis (however, Galderma has been promoting the compound in Canada since early 2007) under the trade name Elidel.

Pimecrolimus ball-and-stick.png

Pimecrolimus is an ascomycin macrolactam derivative. It has been shown in vitro that pimecrolimus binds to macrophilin-12(also referred to as FKBP-12) and inhibits calcineurin. Thus pimecrolimus inhibits T-cell activation by inhibiting the synthesis and release of cytokines from T-cells. Pimecrolimus also prevents the release of inflammatory cytokines and mediators from mast cells.

Pimecrolimus is a chemical that is used to treat atopic dermatitis (eczema). Atopic dermatitis is a skin condition characterized by redness, itching, scaling and inflammation of the skin. The cause of atopic dermatitis is not known; however, scientists believe that it may be due to activation of the immune system by various environmental or emotional triggers. Scientists do not know exactly how pimecrolimus reduces the manifestations of atopic dermatitis, but pimecrolimus reduces the action of T-cells and mast cells which are part of the immune system and contribute to responses of the immune system. Pimecrolimus prevents the activation of T-cells by blocking the effects of chemicals (cytokines) released by the body that stimulate T-cells. Pimecrolimus also reduces the ability of mast cells to release chemicals that promote inflammation.

Pimecrolimus, like tacrolimus, belongs to the ascomycin class of macrolactam immunosuppressives, acting by the inhibition of T-cell activation by the calcineurin pathway and inhibition of the release of numerous inflammatory cytokines, thereby preventing the cascade of immune and inflammatory signals.[1] Pimecrolimus has a similar mode of action to that of tacrolimus but is more selective, with no effect on dendritic (Langerhans) cells.[2] It has lower permeation through the skin than topical steroids or topical tacrolimus[3] although they have not been compared with each other for their permeation ability through mucosa. In addition, in contrast with topical steroids, pimecrolimus does not produce skin atrophy.[4] It has been proven to be effective in various inflammatory skin diseases, e.g., seborrheic dermatitis,[5] cutaneous lupus erythematosus,[6]oral lichen planus,[7] vitiligo,[8] and psoriasis.[9][10] Tacrolimus and pimecrolimus are both calcineurin inhibitors and function as immunosuppressants.[11]

Ascomycin macrolactams belong to a new group of immunosuppressive, immunomodulatory and anti-inflammatory agents and include, e.g., ascomycin (FK520), tacrolimus (FK506) and pimecrolimus (ASM 981). The main biological effect of ascomycin macrolactams appears to be the inhibition of the synthesis of both Th1 and Th2-type cytokines in target cells.

As used herein, the term “ascomycin macrolactam” means ascomycin, a derivative of ascomycin, such as, e.g., tacrolimus and pimecrolimus, or a prodrug or metabolite of ascomycin or a derivative thereof.

Ascomycin, also called immunomycin, is a structurally complex macrolide produced by Streptomyces hygroscopicus. Ascomycin acts by binding to immunophilins, especially macrophilin-12. It appears that ascomycin inhibits the production of Th1 (interferon- and IL-2) and Th2 (IL-4 and IL-10) cytokines. Additionally, ascomycin preferentially inhibits the activation of mast cells, an important cellular component of the atopic response. Ascomycin produces a more selective immunomodulatory effect in that it inhibits the elicitation phase of allergic contact dermatitis but does not impair the primary immune response when administered systemically. The chemical structure of ascomycin is depicted below.

Figure US08536190-20130917-C00001

Tacrolimus (FK506) is a synthetic derivatives of ascomycin. As a calcineurin inhibitor, it works through the FK-binding protein and inhibits the dephosphorylation of nuclear factor of activated T cells (NFAT), thereby preventing the transport of the cytoplasmic component of NFAT to the cell nucleus. This leads to transcriptional inhibition of proinflammatory cytokine genes such as, e.g., interleukin 2, which are dependent on the nuclear factor of activated NFAT. The chemical structure of tacrolimus is depicted below.

Figure US08536190-20130917-C00002

Pimecrolimus, an ascomycin derivative, is a calcineurin inhibitor that binds with high affinity to the cytosolic receptor macrophilin-12, inhibiting the calcium-dependent phosphatase calcineurin, an enzyme required for the dephosphorylation of the cytosolic form of the nuclear factor of the activated T cell (NF-AT). It thus targets T cell activation and proliferation by blocking the release of both TH1 and TH2 cytokines such as IF-g, IL-2, -4, -5, and -10.3 It also prevents the production of TNF-a and the release of proinflammatory mediators such as histamine, hexosaminidase, and tryptase from activated mast cells.3 It does not have general antiproliferative activity on keratinocytes, endothelial cells, and fibroblasts, and in contrast to corticosteroids, it does not affect the differentiation, maturation, functions, and viability of human dendritic cells. The chemical structure of pimecrolimus is depicted below.

Figure US08536190-20130917-C00003

Pimecrolimus is an anti-inflammatory compound derived from the macrolactam natural product ascomycin, produced by certain strains of Streptomyces.

In January 2006, the United States Food and Drug Administration (FDA) announced that Elidel packaging would be required to carry a black box warning regarding the potential increased risk of lymph node or skin cancer, as for the similar drug tacrolimus. Whereas current practice by UKdermatologists is not to consider this a significant real concern and they are increasingly recommending the use of such new drugs.[12]

Importantly, although the FDA has approved updated black-box warning for tacrolimus and pimecrolimus, the recent report of the American Academy of Dermatology Association Task Force finds that there is no causal proof that topical immunomodulators cause lymphoma or nonmelanoma skin cancer, and systemic immunosuppression after short-term or intermittent long-term topical application seems an unlikely mechanism.[13] Another recent review of evidence concluded that postmarketing surveillance shows no evidence for this systemic immunosuppression or increased risk for any malignancy.[14] However, there are still some strong debates and controversies regarding the exact indications of immunomodulators and their duration of use in the absence of active controlled trials.[15] Dermatologists’ and Allergists’ professional societies, the American Academy of Dermatology[1], and the American Academy of Allergy, Asthma, and Immunology, have protested the inclusion of the black box warning. The AAAAI states “None of the information provided for the cases of lymphoma associated with the use of topical pimecrolimus or tacrolimus in AD indicate or suggest a causal relationship.”[2].

Click here for structure editor

Pimecrolimus binds with high affinity to macrophilin-12 (FKBP-12) and inhibits the calcium-dependent phosphatase, calcineurin. As a consequence, it inhibits T cell activation by blocking the transcription of early cytokines. In particular, pimecrolimus inhibits at nanomolar concentrations Interleukin-2 and interferon gamma (Th1-type) and Interleukin-4 and Interleukin-10 (Th2-type) cytokine synthesis in human T cells. Also, pimecrolimus prevents the release of inflammatory cytokines and mediators from mast cells in vitro after stimulation by antigen/lgE.

ELIDEL® (pimecrolimus) Cream 1% contains the compound pimecrolimus, the immunosuppressant 33-epi-chloro-derivative of the macrolactam ascomycin.

Chemically, pimecrolimus is (1R,9S,12S,13R,14S,17R,18E,21S,23S,24R,25S,27R)-12-[(1E)-2{(1R,3R,4S)-4-chloro-3-methoxycyclohexyl}-1-methylvinyl]-17-ethyl-1,14-dihydroxy-23,25 dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo[ 4,9]octacos-18-ene2,3,10,16-tetraone.

The compound has the empirical formula C43H68CINO11 and the molecular weight of 810.47. The structural formula is

Elidel® (pimecrolimus) Structural Formula Illustration

Pimecrolimus is a white to off-white fine crystalline powder. It is soluble in methanol and ethanol and insoluble in water.

Each gram of ELIDEL Cream 1% contains 10 mg of pimecrolimus in a whitish cream base of benzyl alcohol, cetyl alcohol, citric acid, mono- and di-glycerides, oleyl alcohol, propylene glycol, sodium cetostearyl sulphate, sodium hydroxide, stearyl alcohol, triglycerides, and water.

The second representative of the immunosuppressive macrolides for topical application – after tacrolimus (Protopic ®) – has 21 October in the trade. Pimecrolimus is approved for short-term and intermittent long-term treatment for patients aged two years who suffer from mild to moderate atopic dermatitis.

Pimecrolimus is a lipophilic derivative of macrolactam Ascomycin. The macrolides inhibit the production and release of pro-inflammatory cytokines by blocking the phosphatase calcineurin.The anti-inflammatory effect unfolds the drug in the skin. Since he is only minimally absorbed to not measurable, it hardly affects the local or systemic immune response. Therefore, the authorization neither restricts nor a maximum daily dose treatable area or duration of therapy.The cream can also be applied on the face, head and neck, and in skin folds, but not simultaneously with other anti-inflammatory topical agents such as glucocorticoids.

In studies in phases II and III patients aged three months and treated a maximum of one year.In two six-week trials involving 186 infants and young children as well as 403 children and adolescents, the verum symptoms and itching decreased significantly better than the cream base. Already in the first week of itching in 44 percent of children and 70 percent of the infants improved significantly. In adults, pimecrolimus was less effective than 0.1 percent betamethasone 17-valerate.

In the long-term treatment the verum significantly reduced the incidence of flares, revealed two studies with 713 and 251 patients. About a half and one year each about twice as many of the small patients were free of acute disease exacerbations than with the cream base (example: 61 versus 34 per cent of children, 70 versus 33 percent of infants older than six months). Moreover, the use of topical corticosteroids decreased significantly.

In a study of 192 adults with moderate to severe eczema half suffered six months no relapses more (24 percent with placebo). In the long-term therapy pimecrolimus was less effective than 0.1 percent triamcinolone acetonide cream and 1 percent hydrocortisone cream in adults.

The new topicum is-apart from burning and irritation at the application site – relatively well tolerated. It is neither kontaktsensibilisierend still phototoxic or sensitizing and does not cause skin atrophy. As in atopic Ekzen but usually a long-term therapy is necessary studies can reveal long-term adverse effects of the immunosuppressant on the skin only beyond one year.Also available from direct comparative studies between tacrolimus and pimecrolimus. They could help to delineate the importance of the two immunosuppressants.

Pimecrolimus (registry number 137071-32-0; Figure 1) is a macro lide having anti-inflammatory, antiproliferative and immunosuppressive properties. This substance is present as an active ingredient in the Elidel ® drug recently approved in Europe and in the USA for topical treatment of inflammatory conditions of the skin such as atopic dermatitis.

Figure imgf000002_0001

Figure 1: structural formula of pimecrolimus

19th Ed., vol. π, pg. 1627, spray-drying consists of bringing together a highly dispersed liquid and a sufficient volume of hot air to produce evaporation and drying of the liquid droplets. Spray-drying however is often limited to aqueous solutions unless special expensive safety measures are taken. Also, in spite of the short contact time, certain undesirable physical and chemical characteristics of the emerging solids are in particular cases unavoidable. The turbulence present in a spray-drier as a result of the moving air may alter the product in an undesirable manner. Modifications to the spray-drying technique are disclosed in WO 03/063821 and WO 03/063822. [00012] European Patent EP 427 680 Bl discloses a method of synthesizing amorphous pimecrolimus (Example 66a). The method yields amorphous pimecrolimus as a colorless foamy resin.

U.S. Patent No. US 6,423,722 discloses crystalline forms of pimecrolimus, such as form A, form B, etc. US 722 also contend that by performing example 66a from the European Patent EP 427 680 Bl, amorphous pimecrolimus is obtained.

The preparation of pimecrolimus was described for the first time in the patent application EP427680 on behalf of Sandoz. Used as raw material in such document is ascomycin (compound identified by registry number 11011-38-4), a natural product obtained through fermentation from Streptomyces strains (such as for example Streptomyces hygroscopicus var ascomyceticus, or Streptomyces hygroscopicus tsukubaensis N°9993). Pimecrolimus is obtained from the ascomycin through a sequence of four steps of synthesis (scheme 1)

Figure imgf000003_0001

Scheme 1 : synthesis process described in EP427680

From a structural point of view, pimecrolimus is the 33-epi-chloro derivative of ascomycin. As described in EP427680, the simultaneous presence – in the structure of ascomycin – of two secondary hydroxyl groups in position 24 and in position 33, requires the protection of the hydroxyl in position 24 before substituting the second hydroxyl in position 33 with an atom of chlorine.

In order to obtain the monoprotection of the hydroxyl in position 24 of ascomycin, such synthesis process provides for the preparation of 24,33-disilyl derivative and the subsequent selective removal of the silyl ester in position 33.

The high ratio between the silylating agent and the substrate and the non-complete selectivity of the subsequent step of deprotection requires carrying out two chromatographic purifications on the column of silica gel (Baumann K., Bacher M., Damont A., Hogenauer K., Steck A. Tetrahedron, (2003), 59, 1075-1087). The general yields of such synthesis process are not indicated in literature; an experiment by the applicant revealed that such yields amount to about 16% molar starting from ascomycin.

Other synthesis processes were recently proposed as alternatives to the synthesis of EP427680.

In particular, the International patent application WO2006040111 on behalf of Novartis provides for the direct substitution of the hydroxyl in position 33 of ascomycin with an atom of chlorine and a second alternative, described in the international patent application WO2006060614 on behalf of Teva, uses – as a synthetic intermediate – a sulfonate derivative in position 33 of ascomycin. Both the proposed synthetic alternatives are not entirely satisfactory in that in WO2006040111 the proposed halogenating agents (chlorophosphorane and N- chlorosuccinimide) are not capable, according to the same authors, of regioselectively substituting the hydroxyl function in position 33, while in WO2006060614 the quality characteristics of the obtained product are, even after chromatographic purification and/or crystallisation, low for a product to be used for pharmaceutical purposes (i.e. purity of 96% as described in the experimental part).

Generally, purified enzymatic systems may be used for the organic synthesis of polyfunctional molecules (Wang Y-F, Wong C-H. J Org Chem (1988) 53, 3127- 3129; Santaniello E., Ferraboschi P., Grisenti P., Manzocchi A. Chem. Rev. (1992), 92(5), 1071-140; Ferraboschi P., Casati S., De Grandi S., Grisenti P., Santaniello E. Biocatalysis (1994), 10(1-4), 279-88); WO2006024582). WO2007103348 and WO2005105811 describe the acylation of rapamycin in position 42 in the presence of lipase from Candida antartica.



Figure imgf000009_0001

Scheme 2: synthesis of pimecrolimus for enzymatic transesterification of ascomycin.

Figure imgf000013_0001

Scheme 3. Synthesis of pimecrolimus for enzyme-catalyzed alcoholysis from 33,24- diacetate of ascomycin

Example 1

Preparation of the 33-acetyl derivative of ascomvcin (compound I of scheme II)

Lipase from Candida antarctica (CAL B, Novozym 435) [0.140 g (2 U/mg)

FLUKA] was added to a solution of ascomycin (100 mg; 0.126 mmol) in toluene (8 ml) and vinyl acetate (4.5 eq; 0.473 g). The reaction is kept under stirring at the temperature of 30° C for 80 hrs then the enzyme is taken away for filtration and the filtrate is concentrated at low pressure to obtain 105 mg of 33-acetyl ascomycin.

A sample of such intermediate was purified for analytical purposes by chromatography on silica gel (n-hexane/acetone = 8/2 v/v as eluents) and thus crystallised by acetone/water.

The following analysis were carried out on such sample: 1H-NMR (500MHz) δ:

2.10 (CH3CO), 3.92 and 4.70 (24CH and 33CH); IR (cm-1): 3484.245, 2935.287,

1735.331, 1649.741, 1450.039,

1372.278; DSC: endotherm at 134.25° C; [α]D=-74,0° (c=0.5 CHCl3).

Spectrum of MS (ESI +): m/z: 856.4 (M+23; 100.0%)

Elementary analysis calculated for C45H7iNO13: C 64.80%; H, 8.58%; N, 1.68%;

O, 24.94%

Elementary analysis found: C 64.78%; H, 8.54%; N, 1.59%; O, 24.89%

Preparation of the 24-tgrt-butyldimethylsilylether-33 -acetyl derivative of ascomvcin (intermediate 24-silyl-33-Oac; compound II of scheme 2)

2,6-lutidine (0.29Og; 2.7 mmolels) and tert-butyldimethylsilyl triflate (0.238g; 0.9 mmoles) are added to a solution of 33-acetyl derivative of ascomycin (150 mg;

0.18 mmoles) in dichloromethane (5ml). The reaction is left under stirring at ambient temperature for 30 minutes. After this period the reaction mixture is washed with a solution saturated with sodium bicarbonate (5 ml) and organic phase obtained is washed in sequence with HCl 0.1N (5 ml 3 times) and with a solution at 30% of NaCl (5ml). The organic phase is anhydrified on sodium sulphate, filtered and concentrated to residue under vacuum to obtain 128 mg of product.

Spectrum of MS (ESI +): m/z: 970.5 (M+23; 100.0%)

1H-NMR (500 MHz) δ: 0.05 and 0.06 ((CHs)2Si), 0.90 ((CH3)3C-Si), 2.10

(CH3CO), 4.70 (33CH)

IR (cm-‘): 3462.948, 2934.450, 1739.236, 1649.937

Elementary analysis calculated for C51H85NOi3Si: C 64.59%; H, 9.03%; N, 1.48%; O, 21.93%

Elementary analysis found: C 64.50%; H, 9.05%; N, 1.41%; O, 21.88%

DSC= endoderma a 236,43° C. [α]D=-81,4° (c=0.5 CHCl3).

Preparation of 24-tert-butyldimethylsilylether of ascomycin (intermediate 24- silyl-33-OH; compound III of scheme 2) n-octan-1-ol (0.035g; 0.265 mmoles) and CAL B (Novozym 435) [0.100 g (2

U/mg) FLUKA] are added to a solution of 24-tert-butyldimethylsilylether-33- acetyl derivative of ascomycin (50 mg; 0.053 mmoles) in tert-butylmethylether (4 ml). The reaction is kept under stirring at the temperature of 40° C for 120 hours.

After this period the reaction mixture is filtered and the filtrate is evaporated to residue under vacuum to obtain a reaction raw product which is purified by chromatography on silica gel: 44 mg of product (0.048 mmoles) are recovered through elution with petroleum ether/acetone 7/3.

The chemical/physical properties of the obtained product match those of a reference sample obtained according to patent EP427680.

Preparation of 24-tert-butyldimethylsilylether-33-epi-chloro ascomycin

(intermediate 24-silyl-33-chloro; compound IV of scheme 2)

A solution of 24-silyl FR520, i.e. 24-silyl ascomycin (165 g; 0.18 moles) in anhydrous toluene (1.4 litres) and pyridine (50 ml) is added to a suspension of dichlorotriphenylphosphorane (99.95g) in anhydrous toluene (1.1 litres), under stirring at ambient temperature (20-25 °C) in inert atmosphere.

After adding, the reaction mixture is heated at the temperature of 60° C for 1 hour.

After this period the temperature of the reaction mixture is taken to 25° C and thus the organic phase is washed in sequence with water (1 time with 1 L) and with an aqueous solution of NaCl at 10% (4 times with 1 L each time), then it is anhydrified on sodium sulphate, filtered and concentrated under vacuum to obtain about 250 g of a moist solid of toluene. Such residue product is retaken with n- hexane (500 ml) and then evaporated to dryness (in order to remove the toluene present). The residue product is diluted in n-hexane (500 ml) under stirring at ambient temperature for about 45 minutes and then the undissolved solid taken away for filtration on buckner (it is the sub-product of dichlorophosphorane).

The filtrate is concentrated at low pressure to obtain 148.6 g of a solid which is subsequently purified by chromatography on silica gel (elution with n- heptane/acetone = 9/1) to obtain 123 g (0.13 moles) of product.

The chemical/physical properties of the obtained product match those described in literature (EP427680).

Preparation of the pimecrolimus from 24-fert-butyldimethylsilylether-33-epi- chloro ascomycin

The intermediate 24-silyl-33 chloro (123g; 0.13 Moles; compound IV of scheme

2) is dissolved under stirring at ambient temperature in a dichloromethane/methanol mixture=l/l=v/v (1.1 litres) then p-toluenesulfonic acid monohydrate (10.11 g) is added.

The reaction is kept under stirring at the temperature of 20-25° C for 72 hours, thus a solution of water (600 ml) and sodium bicarbonate (4.46 g) is added to the reaction mixture. The reaction mixture is kept under stirring at ambient temperature for 10 minutes, the organic phase is then prepared and washed with an aqueous solution at 10% of sodium chloride (600 ml).

The organic phase is anhydrified on sodium sulphate, filtered and concentrated under vacuum to obtain 119 g of raw pimecrolimus. Such raw product is purified by chromatography on silica gel (n-hexane/acetone as eluents) and thus crystallised by ethyl acetate, cyclohexane/water to obtain 66 g (81.5 mmoles) of purified pimecrolimus.

The chemical/physical data obtained matches the data indicated in literature.

Example 2

Preparation of ascomvcin 24.33-diacetate (intermediate 24, 33-diacetate; compound V of scheme 3)

DMAP (4.5 eq; 0.136 g) and acetic anhydride (4.5 eq; 0.114 g) are added to a solution of ascomycin (200 mg; 0.25 mmoles) in pyridine (2.5 ml), under stirring at the temperature of 0° C.

The reaction is kept under stirring for 1.5 hours at the temperature of 0° C then it is diluted with water and it is extracted with ethyl acetate (3 times with 5 ml). The organic extracts are washed with HCl 0.5 N (5 times with 10 ml), anhydrified on

Na2SO4 concentrated under vacuum.

The residue product was purified by chromatography on silica gel (n- hexane/acetone 8/2 v/v as eluent) to obtain ascomycin 24,32-diacetate (210 mg;

0.24 mmoles).

We carried out the following analysis on such purified sample:

1H-NMR (500 MHz) δ: 2.02 and 2.06 (2 CH3CO), 5.20 and 4.70 (24CH and


IR (Cm-1): 3462.749, 2935.824, 1734.403, 1650.739, 1449.091, 1371.079.

DSC: endothermic peak at 234.10° C ; [α]D=- 100.0° (C=0.5 CHCl3).

Spectrum of MS (ESI+): m/z: 898.4 (100.0%; m+23).

Elementary analysis calculated for C47H73NO14: C 64.44%; H 8.40%; N 1.60%; O


Elementary analysis found: C 64.55%; H 8.44%; N 1.61%; O 25.40%

Preparation of the 24-acetyl ascomycin (intermediate 24-acetate-33-OH; compound VI of scheme 3)

Lipase from Candida antartica (CAL B Novozym 435) [1.1 g (2 U/mg) FLUKA] is added to a solution of ascomycin 33,24-diacetate (500 mg; 0.57 mmol) in

TBDME (25 ml) and n-octan-1-ol (4.5 eq; 0.371 g). The reaction is kept under stirring at 30° C for 100 hours, then the enzyme is taken away for filtration and the obtained filtrate is concentrated under low pressure to obtain 425 mg (0.51 mmoles) of product.

A sample was purified for analytical purposes by chromatography on silica gel (n- hexane/acetone = 7:3 v/v as eluents) and thus crystallised by acetone/water.

We carried out the following analysis on such purified sample: 1H-NMR

(500MHz) δ: 2.05 (CH3CO); IR (an 1): 3491.528, 2935.860, 1744.728, 1710.227,

1652.310, 1448.662, 1371.335. DSC: endothermic peak at 134.68° C; [α]D=-

102.7° (c=0.5 CHCl3)

Spectrum of MS (ESI +): m/z: 856.4 (M+23; 100.0%)

Elementary analysis calculated for C45H71NO13: C 64.80%; H, 8.58%; N, 1.68%;

0, 24.94%

Elementary analysis found: C 64.71%; H, 8.49%; N, 1.60%; O, 24.97%

Preparation of the 24-acetyl-33epi-chloro ascomycin (intermediate 24-Acetate-33- chloro; compound VII of scheme 3) Supported triphenylphosphine (0.335 g; 1.1 mmoles) is added to a solution of 24- acetyl ascomycin (400 mg; 0.48 mmoles) in carbon tetrachloride (5 ml). The reaction mixture is kept under reflux for 3 hours then it is cooled at ambient temperature. The obtained suspension is filtered and the filtrate is concentrated to residue under vacuum to obtain 0.45g of reaction raw product which is purified by chromatography on silica gel: 163mg (0.19 mmoles) of product are obtained by elution with petroleum ether/acetone = 90/10.

1H-NMR δ: 2.08 (CH3CO); 4.60 (33CH); IR (Cm“1)= 3464.941, 2934.360,

1738.993, 1650.366, 1450.424, 1371.557; DSC: endothermic peak at 231.67° C

[α]D=-75.2° (c=0.5 CHCl3)

Spectrum of MS (ESI +): m/z: 874.3 (M+23; 100.0%)

Elementary analysis calculated for C45H70ClNO12: C 63.40%; H, 8.28%; Cl,

4.16%; N, 1.64%; O, 22.52%

Elementary analysis found: C 63.31%; H, 8.30%; Cl, 4.05%; N, 1.58%; O,


Preparation of pimecrolimus from 24-acetyl-33-epi-chloro ascomycin

A solution of 24-acetyl-33-epi-chloro ascomycin (200 mg; 0.23 mmoles; compound VII) in methanol (2 ml) and HCl 3N (1 ml) is stirred at ambient temperature for 40 hours. After this period, the reaction is neutralised with an aqueous bicarbonate solution, the methanol evaporated under vacuum. The mixture is extracted with dichloromethane (3 times with 5 ml), anhydrified on sodium sulphate, filtered and concentrated to residue to obtain a residue product which is purified by chromatography on silica gel (n-hexane/acetone as eluents) and thus crystallised by ethyl acetate, cyclohexane/water to obtain 78 mg of purified pimecrolimus (0.096 mmoles).

The chemical/physical characteristics of the obtained product matches the data indicated in literature for pimecrolimus.

Example 4 (comparative*)

Verification of the method of synthesis of pimecrolimus described in EP427680 Imidazole (508 mg) and tert-Butyldimethylsilylchloride (1.125 g) are added in portions to a solution of 2g (2.53 mmoles) of ascomycin in anhydrous N,N- dimethylformamide (40 ml). The reaction mixture is kept under stirring at ambient temperature for 4.5 days. The reaction is thus processed diluting it with ethyl acetate (200 ml) and processing it using water (5 x 100 ml). The organic phase is separated, anhydrified on sodium sulphate, filtered and evaporated to residue under vacuum to obtain a foamy raw product which is subsequently purified by chromatography on silica gel (1:30 p/p): 2.1 g (2.05 mmoles; yields 81% molars) of ascomycin 24,33 disilyl intermediate are obtained by elution with n- hexane/ethyl acetate 3/1. The chemical/physical data of such intermediate matches that indicated in EP427680.

2.1 g (2.05 mmoles) of ascomycin 24,33 disilyl intermediate are dissolved in a solution under stirring at the temperature of 0°C composed of acetonitrile (42 ml) and aqueous HF 40% (23.1 ml). The reaction mixture is kept under stirring at the temperature of 0°C for 2 hours then it is diluted with dichloromethane (30 ml). Then the reaction is washed in sequence with a saturated aqueous solution using sodium bicarbonate (30 ml) and water (30 ml). The separated organic phase is anhydrified on sodium sulphate, filtered and evaporated to residue under vacuum to obtain a foamy residue which is subsequently purified by chromatography on silica gel (1:30 p/p): 839 mg (0.92 mmoles; yields 45% molars) of ascomycin 24 monosilyl intermediate are obtained by elution with dichloromethane/methanol 9/1. The chemical/physical data of such intermediate matches that obtained on the compound III scheme 2 and matches the data of literature indicated in EP427680. A mixture of 839 mg (0.92 mmoles; yields 45% molars) of ascomycin 24 monosilyl intermediate, triphenylphosphine (337 mg) in carbon tetrachloride (36.4 ml) is heated under stirring under reflux for 15 hours. After this period the reaction mixture is evaporated to residue under vacuum to obtain a solid product purified by chromatography on silica gel (1:30 p/p): 535 mg (0.57 mmoles; yields 63% molars) of ascomycin 24 monosilyl intermediate, 33-chloro derivative are obtained by elution with n-hexane/ethyl acetate 2/1. The chemical/physical data of such intermediate matches those we obtained on compound IV scheme 2 and matches the data of literature indicated in EP427680.

535 mg (0.57 mmoles) of ascomycin 24 monosilyl intermediate, 33-chloro derivative are dissolved under stirring at ambient temperature in acetonitrile (16.4 ml) and aqueous HF 40% (0.44 ml). The reaction mixture is kept under stirring at ambient temperature for 45′ and then it is diluted with ethyl acetate (100 ml). The organic phase is thus washed in sequence with an aqueous solution of sodium bicarbonate (70 ml) with water (2 x 70 ml) and thus it is anhydrified on sodium sulphate, filtered and evaporated under vacuum to obtain a solid which is subsequently purified by chromatography on silica gel (1 :30 p/p): 323 mg (0.399 mmoles; yields 70% molars) of pimecrolimus is obtained by elution with n- hexane/ethyl acetate 2/3. The chemical/physical characteristics of the obtained product matches the data indicated in literature regarding pimecrolimus; the overall yield of the process is 16%.



Example 7: Preparation of amorphous pimecrolimus by precipitation [00094] 19,5 g purified pimecrolimus (colorless resin) was dissolved in 217 ml acetone at 4O0C and concentrated. Residue: 38,76 g. The residue was diluted with 6 ml distilled water with stirring. Finally 1 ml acetone was added. This solution was added slowly to 2 L chilled distilled water that was stirred efficiently. After the addition had been completed, the suspension was stirred 20 min at O0C. Then the solid was filtered and dried at 450C in vacuum oven overnight. Product: 15,65 g yellowish solid. Amorphous (XRD, DSC).

Example 8: Preparation of amorphous pimecrolimus by grinding

[00095] Procedure of grinding: 200 mg of Pimecrolimus sample was ground gently in an agate mortar using a pestle for half a minute. ,


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