Tipifarnib

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Jan 082015

Tipifarnib

6-[(R)-Amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone;

(R)-(+)-R 115777; Zarnestra; 192185-68-5

zarnestra, 192185-72-1, R115777, R-115777, IND 58359, UNII-MAT637500A

192185-72-1, 192185-68-5

Molecular Formula: C27H22Cl2N4O

Molecular Weight: 489.39578 g/mol

cas

192185-72-1, 192185-68-5 (racemate), 192185-70-9 (racemic; diHCl), 192185-69-6 (racemic; fumarate)

R115777 is a substance that is being studied in the treatment of acute myeloid leukemia (AML) and other types of cancer. It belongs to the family of drugs called farnesyltransferase inhibitors. It is also called tipifarnib and Zarnestra.

Tipifarnib (trade name Zarnestra) is a farnesyltransferase inhibitor that is being investigated in patients 65 years of age and older with newly diagnosed acute myeloid leukemia (AML). It inhibits the Ras kinase in a post translational modification step before the kinase pathway becomes hyperactive. It inhibits prenylation of the CxxX tail motif, which allows Ras to bind to the membrane where it is active. Without this step the protein cannot function.

It is also being tested in clinical trials in patients in certain stages of breast cancer.^[1]

For treatment of progressive plexiform neurofibromas associated with Neurofibromatosis type I, it successfully passed phase one clinical trials but was suspended (NCT00029354) in phase two.^[2]^[3] The compound was discovered by and is under investigation byJohnson & Johnson Pharmaceutical Research & Development, L.L.C, with registration number R115777.

Approval process

Tipifarnib was submitted to the FDA by Johnson & Johnson for the treatment of AML in patients aged 65 and over with a New Drug Application (NDA) to the Food and Drug Administration (FDA) on January 24, 2005.

In June 2005, the FDA issued a “not approvable” letter for tipifarnib.^[4]

Farnesyltransferase inhibitors block the main post-translational modification of the Ras protein, thus interfering with its localization to the inner surface of the plasma membrane and subsequent activation of the downstream effectors. Although initially developed as a strategy to target Ras in cancer, farnesyltransferase inhibitors have subsequently been acknowledged as acting by additional and more complex mechanisms that may extend beyond Ras involving GTP-binding proteins, kinases, centromere-binding proteins and probably other farnesylated proteins.

A particular farnesyltransferase inhibitor is described in WO 97/21701, namely (R)-(+)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone. The absolute stereochemical configuration of the compound was not determined in the experiments described in the above-mentioned patent specification, but the compound was identified by the prefix “(B)” to indicate that it was the second compound isolated from column chromatography. The compound thus obtained has been found to have the (R)-(+)-configuration. This compound will be referred to below by its published code number R115777 and has the following formula (V).

R115777 (Tipifarnib) is a potent, orally active inhibitor of farnesylprotein transferase. It is one of the most advanced of the farnesylprotein transferase inhibitors currently reported to be in clinical development, being one of the agents that have progressed to phase III studies.

R115777 has been found to have very potent activity against neoplastic diseases. Antineoplastic activity in solid tumors, such as breast cancer, as well as in haematological malignancies, such as leukemia, have been observed. Also combination studies have been carried out demonstrating that R115777 can be safely combined with several highly active anticancer drugs.

In WO 01/53289, the racemates (±) (4-(3-chloro-phenyl)-6-[(6-chloro-pyridin-3-yl)-(4-methoxy-benzylamino)-(3-methyl-3H-imidazol-4-yl)-methyl]-1-cyclopropylmethyl-1H-quinolin-2-one (racemate 1) and (±) 4-(3-chloro-phenyl)-6-[(6-chloro-pyridin-3-yl)-[(4-methoxy-benzylidene)-amino]-(3-methyl-3H-imidazol-4-yl)-methyl]-1-cyclopropylmethyl-1H-quinolin-2-one (racemate 2) are prepared.

After chiral molecule separation using column chromatography, either the benzylamino or the benzilidine moiety of the resulting (+) and/or (−) enantiomers are converted to an amino group under acidic conditions.

In WO 97/21701, it is described (on page 9, line 7-14) that intermediates of formula (XIII), can be prepared by reacting an intermediate of formula (XIV), wherein W is an appropriate leaving group, such as, for example, halo, with an intermediate ketone of formula (XV). In WO 97/21701, it is described that this reaction can be performed by converting the intermediate of formula (XV) into an organometallic compound, by stirring it with a strong base such as butyl lithium and subsequently adding the intermediate ketone of formula (XV). It is further indicated that although this reaction gives at first instance a hydroxy derivative (i.e. R⁸is hydroxy), said hydroxy derivative can be converted into other intermediates wherein R⁸has another definition by performing art-known (functional group) transformations. The drawings of the compounds of formula (XIII), (XV) and (XIV) have been taken over from WO 97/21701 and the substituents in these drawings are as defined in WO 97/21701.

In WO 97/21701, it is also described (from page 7 line 32, to page 8 line 6) that the compounds of formula (XVI), wherein R is C_1-6alkyl, R^{(2-8, 16-19)}can be a substituent chosen from lists as defined in WO 97/21701 and R¹has a meaning as defined in WO 97/21701 apart from hydrogen, may be prepared by hydrolysing an intermediate ether of formula (XIII), according to art-known methods, such as stirring the intermediate of formula (XIII) in an aqueous acid solution. An appropriate acid can be for instance hydrochloric acid. Subsequently the resulting quinolinone, wherein R¹is hydrogen, may be transformed into a quinolinone of formula (XVI) by art-known N-alkylation. The drawings of the compounds of formula (XIII) and (XVI) have been taken over from WO 97/21701 and the substituents in these drawings are as defined in WO 97/21701.

The synthesis of R115777 as originally described in WO 97/21701, is presented in scheme 1.

Herein, in step 1, the intermediate 1-methyl imidazole in tetrahydrofuran, is mixed with a solution of n-butyllithium in a hexane solvent to which is added chlorotriethylsilane (triethylsilyl chloride), followed by a further addition of n-butyllithium in hexane, the resulting mixture being cooled to −78° C. before the addition of a solution of a compound of formula (I), i.e. 6-(4-chlorobenzoyl)-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone in tetrahydrofuran. The reaction mixture is subsequently brought to room temperature, and then hydrolysed, extracted with ethyl acetate and the organic layer worked up to obtain a compound of formula (II), i.e. (±)-6-[hydroxy(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone.

In step 2, the hydroxy compound of formula (II) is chlorinated with thionylchloride to form a compound of formula (III), i.e. (±)-6-[chloro(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone.

In step 3, the chloro compound of formula (III) is treated, with NH₄OH in tetrahydrofuran to form the amino compound of formula (IV), i.e. (±)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone.

In step 4, the amino compound of formula (IV) is separated into its enantiomers by chiral column chromatography over Chiracel OD (25 cm; eluent: 100% ethanol; flow: 0.5 ml/min; wavelength: 220 nm). The pure (B)-fractions are collected and recrystallised from 2-propanol resulting in R115777, the compound of formula (V).

However, the procedure described in WO97/21701 has a number of disadvantages. For example, during the first step, the procedure results in the undesired formation of a corresponding compound of formula (XI), i.e. 6-[hydroxy(4-chlorophenyl)(1-methyl-1H-imidazol-2-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone), in which the imidazole ring is attached to the remainder of the molecule at the 2-position of the ring, instead of the desired 5-position. At the end of the procedure, this results in the formation of a compound of formula (XII), i.e. 6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-2-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone.

Furthermore, the purification of compound (V) using chiral chromatography is expensive and disadvantageous in view of the large amounts of solvent needed and the specialised equipment required to perform a large scale chiral chromatography.

Another process for the synthesis of R115777 as described in WO 02/072574, is presented in scheme 2.

Herein, in step 1, 1-methyl imidazole in tetrahydrofuran is mixed with a solution of n-hexyllithium in a hexane solvent to which is added tri-iso-butylsilyl chloride, followed by a further addition of n-hexyllithium in hexane. The compound of formula (I) in tetrahydrofuran is then added to the reaction mixture, keeping the temperature between −5° C. and 0° C. The resulting product of formula (II) is isolated by salt formation.

In step 2, the chlorination reaction is effected by treatment of the compound of formula (II) with thionyl chloride in 1,3-dimethyl-2-imidazolidinone.

In step 3, the chloro compound of formula (III) is treated with a solution of ammonia in methanol. After the addition of water, the compound of formula (IV), precipitates and can be isolated.

In step 4, the compound of formula (IV) can be reacted with L-(−)-dibenzoyl tartaric acid (DBTA) to form the diastereomeric tartrate salt with formula (VI) i.e. R-(−)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone [R—(R*,R*)]-2,3-bis(benzoyloxy)butanedioate (2:3).

Finally, in step 5, the compound of formula (VI) is treated with aqueous ammonium hydroxide, to form the crude compound of formula (V) which is then purified by recrystallisation from ethanol to the pure compound (V).

PatentSubmittedGrantedNOVEL IV FORMULATION OF TIPIFARNIB [US2009042935]2009-02-12

Novel IV formulation of tipifarnib [US2007093449]2007-04-26

Medical devices to treat or inhibit restenosis [US2005154451]2005-07-14

FARNESYL PROTEIN TRANSFERASE INHIBITORS WITH IN VIVO RADIOSENSITIZING PROPERTIES [WO0001411]2000-01-13

Patent	Submitted	Granted
Process for the preparation of imidazole compounds [US6844439]	2004-07-15	2005-01-18
TREATMENT OF MITOCHONDRIAL DISORDERS USING A FARNESYL TRANSFERASE INHIBITOR [US2010331363]	2010-12-30
TREATMENT OF MITOCHONDRIAL DISORDERS USING A FARNESYL TRANSFERASE INHIBITOR [US2011060005]	2011-03-10
Diastereoselective Synthesis Process with 6-Bromo-4-(3-Chlorophenyl)-2-Methoxy-Quinoline [US7572916]	2007-12-20	2009-08-11
Anti-cancer phosphonate analogs [US7452901]	2006-04-13	2008-11-18
Diastereoselective Synthesis Process for the Preparation of Imidazole Compounds [US7456287]	2007-10-11	2008-11-25
Diastereoselective Addition of Lithiated N-Methylimidazole on Sulfinimines [US7524961]	2007-12-20	2009-04-28
Therapeutic phosphonate compounds [US7645747]	2006-11-23	2010-01-12
TREATMENT OF PROTEINOPATHIES USING A FARNESYL TRANSFERASE INHIBITOR [US2010160372]	2010-06-24
ANTI-CANCER PHOSPHONATE ANALOGS [US2010022467]	2010-01-28

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http://www.google.co.in/patents/US7572916

EXAMPLE A.1 a) Preparation of N-[(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methylene)]-2-methyl-2-propanesulfinamide [(S(R)] (Compound 25)

Ti(OEt)₄(0.0162 mol) was added to a mixture of (4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methanone (0.0032 mol) and (R)-(+)-2-methyl-2-propane-sulfinamide (0.0032 mol) in DCE (7 ml). The mixture was stirred and refluxed for 6 days, then cooled to room temperature. Ice water was added. The mixture was filtered over celite. Celite was washed with DCM. The organic layer was extracted with saturated sodium chloride. The organic layer was separated, dried (MgSO₄), filtered, and the solvent was evaporated. This fraction was purified by column chromatography over silica gel (40 μm) (eluent: DCM/MeOH/NH₄OH 97/3/0.5), yielding 0.475 g of compound 25 (46%).

The compound N-[(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methylene)]-2-methyl-2-propanesulfinamide [(S(S)] can be obtained in an analogous way.

b) Preparation of N-[(4-chlorophenyl)((4-(3-chlorophenyl)-2-methoxy-quinoline-6-yl)(1-methyl-1H-imidazole-5-yl)methyl]-2-methyl-2-propanesulfinamide [S(R)] (Compound 26)

n-Butyllithium (0.00081 mol) in hexane, was added dropwise at −78° C. to a mixture of 6-bromo-4-(3-chlorophenyl)-2-methoxy-quinoline (0.00081 mol) in THF (3 ml) under nitrogen flow. The mixture was stirred at −78° C. for 30 minutes. A solution of compound 25 (0.00065 mol) in THF (0.6 ml) was added. The mixture was stirred at −78° C. for 1 hour and 30 minutes, poured out into ice water and extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. This fraction was purified by column chromatography over silica gel (40 μm)(eluent: DCM/MeOH/NH₄OH 97/3/0.1). The pure fractions were collected and the solvent was evaporated, yielding 0.138 g (36%) of compound 26, melting point 153° C.

The compound N-[(4-chlorophenyl)((4-(3-chlorophenyl)-2-methoxy-quinoline-6-yl)(1-methyl-1H-imidazole-5-yl)methyl]-2-methyl-2-propanesulfinamide [S(S)] can be obtained in an analogous way

c) Preparation of (S)-1-(4-chlorophenyl)-1-[4-(3-chlorophenyl)-2-methoxy-quinoline-6-yl]-1-(1-methyl-1H-imidazole-5-yl)-methylamine (Compound 27)

Hydrochloric acid in isopropanol was added to a solution of compound 26 (0.000018 mol) in methanol (4.2 ml). The mixture was stirred at room temperature for 30 minutes. The mixture was added to potassium carbonate (10%) on ice and extracted with ethyl acetate. The organic layer was separated, washed with a solution of saturated sodium chloride, dried (MgSO₄), filtered, and evaporated giving 0.086 g (100%) of compound 27, melting point 96° C., enantiomeric excess 88%.

d) Preparation of (S)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1H)-quinolin-2-one (Compound 28)

Compound 27 (0.00038 mol) in hydrochloric acid 3N (9.25 ml) and THF (9.25 ml), was stirred at 60° C. for 24 hours and evaporated, giving 0.18 g (100%) of compound 28, melting point 210° C.

EXAMPLE A.2 a) Preparation of N-[(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methylene)]-p-toluenesulfinamide [(S(S)](Compound 29)

Ti(OEt)₄(0.0419 mol) was added to a mixture of (4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methanone (0.0084 mol) and (S)-(+)-p-toluenesulfinamide (0.0084 mol) in DCE (18 ml). The mixture was stirred and refluxed for 7 days, then cooled to room temperature. Ice water was added. The mixture was filtered over celite. Celite was washed with DCM. The organic layer was extracted with saturated sodium chloride. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. This fraction was purified by column chromatography over silica gel (40 μm) (eluent: DCM/MeOH/NH₄OH 97/3/0.5), yielding 1.15 g of compound 29 (38%).

The compound N-[(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methylene)]-p-toluenesulfinamide [(S(R)] can be obtained in an analogues way.

B. Preparation of Final Compounds

EXAMPLE B.1 a) Preparation of (S)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone (Compound 30)

Compound 28 (0.00038 mol) was added to a solution of THF (1.8 ml) and NaOH 10N (1.8 ml). BTEAC (0.0019 mol) and methyliodide (0.00076 mol) were added and the mixture was stirred for 2 hours at room temperature. EtOAc was added. The organic layer was separated, dried (MgSO₄), filtered, and evaporated giving 0.149 g (83%) of compound 30, enantiomeric excess 86%.

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Cyclization of 3- (3-chlorophenyl) -N-phenyl-2-propenamide (I) by means of polyphosphoric acid (PPA) at 100 C gives 4- (3-chlorophenyl) -1,2,3,4-tetrahydroquinolin- 2-one (II), which is condensed with 4-chlorobenzoic acid (III) by means of PPA at 140 C to yield 6- (4-chlorobenzoyl) -4- (3-chlorophenyl) -1,2,3,4 -tetrahydroquinolin-2-one (IV). The dehydrogenation of (IV) by means of Br2 in bromobenzene at 160 C affords 6- (4-chlorobenzoyl) -4- (3-chlorophenyl) quinolin-2 (1H) -one ( V), which is methylated with iodomethane and NaOH / benzyltrimethylammonium chloride in THF to provide 6- (4-chlorobenzoyl) -4- (3-chlorophenyl) -1-methylquinolin-2 (1H) -one (VI). Condensation of compound (VI) with 1-methylimidazole (VII) by means of butyllithium in THF gives the triaryl carbinol (VIII), which is finally treated with ammonia in THF to afford R-115777.

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paper

Org. Lett., Article ASAP

DOI: 10.1021/ol503292p

http://pubs.acs.org/doi/full/10.1021/ol503292p

Quinolinone derivatives were constructed via a Pd-catalyzed C–H bond activation/C–C bond formation/cyclization cascade process with simple anilines as the substrates. This finding provides a practical procedure for the synthesis of quinolinone-containing alkaloids and drug molecules. The utility of this method was demonstrated by a formal synthesis of Tipifarnib.

synthesis

http://pubs.acs.org/doi/suppl/10.1021/ol503292p/suppl_file/ol503292p_si_001.pdf

References

Angibaud, P.; Venet, M.; Filliers, W.; Broeckx, R.; Ligny, Y.; Muller, P.;Poncelet, V.; End, D. Eur. J. Org. Chem. 2004, 479.

see………….http://onlinelibrary.wiley.com/doi/10.1002/ejoc.200300538/abstract

(b) Filliers, W.; Broeckx, R.;Angibaud, P. U.S. patent, US7572916, 2009.

Oleocanthal for treating pain

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Jan 062015

“Oleocanthal” is specifically deacetoxydialdehydic ligstroside aglycone, which exists as a single isomer (enantiomer). The (-)-enantiomer is the natural product and has the following chemical formula:

http://www.google.com/patents/EP2583676A1?cl=en

The Trustees of The University of Pennsylvania,

Monell Chemical Senses Center,

Russell S. J. Keast, Qiang Han, Amos B. Smith Iii, Gary K. Beauchamp, Paul A. S. Breslin, Jianming Lin,

In 1993, Montedoro and co-workers reported the isolation of a new class of phenolic compounds (1-4), including the dialdehydic and aldehydic forms of ligstroside (5) and oleuropeine (6) from virgin olive oils (Montedoro, G. et al. (1993) J. Agric. Food Chem. 41:2228-2234) (See Figure 1 for structures). These phenolic compounds comprise important minor constituents of virgin olive oils that have been implicated in the organoleptic characteristics including bitterness, pungency, and astringency (Andrewes, P. et al. (2003) J. Agric. Food Chem. 57:1415-1420 ).
In addition, these agents have been suggested to contribute to the oxidative stability of virgin olive oil and as such are associated with health benefits of olive oils, specifically their antioxidant/anticancer activities (Owen, R.W. et al. (2000) Food Chem. Toxicology 38:647-659; Owen, R.W. et al. (2000) Eur. J. Cancer 36(10):1235-1247; Baldioli, M. et al. (1996) J. Am. Oil Chem. Soc. 73(11):1589-1593; Manna, C. et al. (2002) J. Agric. Food Chem. 50(22):6521-6526).
Similar structural features have been reported in the constituents of the Jasminum (Somanadhan, B. et al. (1998) Planta Medica 64:246-50; Takenaka, Y. et al. (2002) Chem. & Pharm. Bull 50(3):384-389) and related plant species (Takenaka, Y. et al. (2002) Phytochemistry 59(7):779-787). It has been shown that both ibuprofen and a Mediterranean diet (i.e., high in olive oil) both decrease the risk/incidence for breast and lung cancer.
In 2003, Busch and co-workers at Unilever Research and Development Vlaardingen (The Netherlands) identified deacetoxydialdehydic ligstroside aglycone as a principal contributor to the potent pungent (burning) sensation at the back of throat associated with high quality virgin olive oils (Andrewes, P. et al. (2003) J. Agric. Food Chem. 57:1415-1420). Studies at Firmenich, Inc., reached the same conclusion (Firmenich, Inc. study). The structure of 1 was assigned,

employing a series of 1 and 2D NMR experiments (Andrewes, P. et al. (2003) J. Agric. Food Chem. 57:1415-1420), in conjunction with comparison to literature data (Montedoro, G. et al. (1993) J. Agric. Food Chem. 41:2228-2234). The absolute stereochemistry remained undetermined. That 1 was responsible for the strong pungent (burning) sensation at the back of the throat was based on an extensive series of HPLC fraction analysis, omission analysis and correlation, and hydrolysis studies, in conjunction with human sensory studies. Andrewes et al., however, acknowledged that “a coelution compound causing the burning sensation” could not be eliminated without completing a synthesis of 1, which they stated to be “extremely challenging.”

EXAMPLES

Example 1: Isolation of deacetoxydialdehydic ligstroside aglycone “Oleocanthal”A. Synthesis of Oleocanthal

Retrosynthetically, we envisioned both enantiomers of (1) to derive from the enantiomeric forms of cyclopentanediols (7) via oxidative cleavage of the diol moiety (Scheme 1). The requisite cyclopentanediols (7) in turn would be prepared from cyclopentanones (+)- and (-)-(10), via alkylation to introduce stereoselectively the side chain from the convex face, followed by stereoselective Wittig ethylnation and removal of the acetonide moiety (Scheme 1).

(5) Initially (+)- and (-)-cyclopentanones (10) were prepared via the sulfoximine and/or enzymatic protocols introduced and developed by Johnson (Johnson, C.R. and T. Penning (1988) J. Am. Chem. Soc. 110:4726-4735; Johnson, C.R. (1998) Acc. Chem. Res. 31:333-341). Although effective on modest scale (10-100mg), the requirement for gram quantities of the oleocanthals demanded that we secure for more scalable routes to (10). Towards this end, we optimized a hybrid of synthetic approaches (Moon, H. et al. (2002) Tetrahedron: Asym. 13(11):1189-1193; Jin, Y. et al. (2003) J. Org. Chem. 68(23):9012-9018; Yang, M. (2004) J. Org. Chem. 69(11):3993-3996; Palmer, A. et al. (2001) Eur. J. Org. Chem. 66(7):1293-1308; Paquette, L. and S. Bailey (1995) J. Org. Chem. 60:7849-7856) as outlined in Scheme 2. Importantly, both enantiomers of (10) could be prepared in multi-gram quantities in 7 steps, with an overall efficiency of 40% from inexpensive D-(-)-ribose. Key elements of both sequences entailed vinyl Grignard addition to the enantiomers of aldehyde (12), followed in turn by ring closing metathesis (RCM), PCC oxidation and hydrogenation (Scheme 2).
Alkylation of (+)- and (-)- cyclopentanone (10) with methyl bromoacetate was then anticipated to proceed from the less hindered convex face of the bicyclic skeleton to install the side chain in a stereoselective fashion. Initial attempts however to alkylate (-)-(8) with methyl bromoacetate employing LDA in the presence of HMPA furnished only a complex mixture containing only trace amounts of (-)-(16). Neither addition of Cu(I) (Johnson, C.R. and T. Penning (1988) J. Am. Chem. Soc. 110:4726-4735) reportedly to suppress side reactions, nor the use of the corresponding tin enolate [generated by treatment of (-)-(10) in THF with LDA, followed by HMPA and tributyltin chloride (Suzuki, M. et al. (1985) J. Am. Chem. Soc. 107:3348; Nishiyama, H. et al. (1984) Tetrahedron Lett. 25:223)] improved the situation. Alkylation of the zinc enolate of (-)-(10) [generated by treatment of (-)-(10) in THF with 1.1 eq. LHMDS, followed in turn by HMPA (3.0 eq.) and dimethyl zinc (Morita, Y. et al. (1989) J. Org. Chem. 54:1787-1788) (1.0 eq.)] with methyl bromoacetate, however consistently furnished (-)-(16) in 55-60% yield as a single diastereomer (this reaction was fairly clean except some baseline materials. Using t-butyl bromoacetate instead of methyl bromoacetate did not improve the yield) (Scheme 3).
Wittig ethylnation of (-)-(16) was next achieved with ethyltriphenylphosphine bromide. Best results were obtained employing LDA as the base at -45°C. Although excellent stereoselectivity (ca., 10:1 E:Z) favoring the E-isomer (-)-(17) was achieved, the yield was only modest (42%), presumably due to the ease of enolization of (-)-(16) (Edmunds, M. “The Wittig Reaction” In MODERN CARBONYL OLEFINATION, Takeda, Ed., John Wiley & Sons, New Jersey, 2004). Interestingly, the stereoselectivity varied dramatically with reaction temperature. At 0°C, the E:Z selectivity was 3.3:1, while at room temperature the selectivity was 1.6:1. Assignment of the E geometry of the olefin was based on NMR NOE analysis (Scheme 4).
Hydrolysis of ester (-)-(17) (LiOH/THF/H₂O) next afforded acid (-)-(18), which was subjected to Mitsunobu esterification (Mitsunobu, O. (1981) Synthesis 1-28) with 4-hydroxyphenethyl alcohol to furnish phenol (-)-(19) in 92% yield. As expected, the Mitsunobu reaction proceeded with complete chemoselectivety at the primary hydroxyl (Appendino, G. et al. (2002) Org. Lett. 4:3839-3841). Completion of the synthesis of (-)-oleocanthal (1) was then achieved via liberation of the vicinal diol moiety (4N HCl/acetonitrile), followed by oxidative cleavage (NaIO₄); (-)-oleocanthal (1) was identical in all respects (e.g., ¹H and ¹³C NMR, IR and HRMS) with an authentic sample isolated from virgin olive oil, the latter possessing spectral data identical to that reported in the literature (Montedoro, G. et al. (1993) J. Agric. Food Chem. 41:2228-2234). The structural assignment of (1) was also confirmed by COSY NMR analysis. Synthetic (-)-(1) displayed a small negative optical rotation ([α]²⁵D -0.78, c = 0.9, CHCl₃) identical to that obtained from a sample isolated from virgin olive oil ([α]²⁵ _D -0.9, c = 2.0, CHCl₃). Thus the stereochemistry of (-)-oleocanthal (1) is 3S, 4E. The enantiomer of the natural product (+)-(1) was prepared via a similar reaction sequence beginning with (+)-(10) to furnish (+)-1 ([a]²⁵ _D +0.73, c = 0.55, CHCl₃) (Scheme 5).
In summary, an effective, scalable synthesis of both enantiomers of oleocanthal (1) has been achieved, each in 13 steps (7 % overall yield) from inexpensive (D)-(-)-ribose, requiring only 6 chromatographic separations. The structural similarity of oleocanthal to a number of related natural products (Somanadhan, B. et al. (1998) Planta Medica 64:246-50; Takenaka, Y. et al. (2002) Chem. & Pharm. Bull. 50(3):384-389; Takenaka, Y. et al. (2002) Phytochemistry 59(7):779-787) suggests that the synthetic approach presented here should also be applicable to their construction.

Figure 3 shows the synthetic scheme of (-)-oleocanthal.

Figure 4 shows the synthetic scheme of (+)-oleocanthal.

Meclinertant (SR48692)

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Dec 312014

2-[[1-(7-chloroquinolin-4-yl)-5-(2,6-dimethoxyphenyl)pyrazole-3-carbonyl]amino]adamantane-2-carboxylic acid

Meclinertant (SR-48692) is a drug which acts as a selective, non-peptide antagonist at the neurotensin receptor NTS₁, and was the first non-peptide antagonist developed for this receptor.^[1]^[2] It is used in scientific research to explore the interaction between neurotensin and other neurotransmitters in the brain,^[3]^[4]^[5]^[6]^[7]^[8] and produces anxiolytic, anti-addictive and memory-impairing effects in animal studies.^[9]^[10]^[11]^[12]

PatentSubmittedGranted1-(7-chloroquinolin-4-yl)pyrazole-3-carboxamide N-oxide derivatives, method of preparing them, and their pharmaceutical compositions [US5561234]1996-10-01

Substituted 1-naphthyl-3-pyrazolecarboxamides which are active on neurotensin [US5585497]1996-12-17

3-amidopyrazole derivatives, process for preparing these and pharmaceutical composites containing them [US5420141]1995-05-30

Substituted 1-naphthyl-3-pyrazolecarboxamides which are active on neurotensin, their preparation and pharmaceutical compositions containing them [US5523455]1996-06-04

3-amidopyrazole derivatives, process for preparing these and pharmaceutical compositions containing them [US5607958]1997-03-04

3-amidopyrazole derivatives, process for preparing these and pharmaceutical compositions containing them [US5616592]1997-04-01

3-amidopyrazole derivatives, process for preparing these and pharmaceutical compositions containing them [US5635526]1997-06-03

Substituted 1-phenyl-3-pyrazolecarboxamides active on neurotensin receptors, their preparation and pharmaceutical compositions containing them [US5965579]1999-10-12

Systematic (IUPAC) name
2-([1-(7-Chloro-4-quinolinyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carbonyl]amino)admantane-2-carboxylic acid
Clinical data
Legal status	?
Identifiers
CAS number	146362-70-1
ATC code	?
PubChem	CID 119192
IUPHAR ligand	1582
UNII	5JBP4SI96H
Chemical data
Formula	C₃₂H₃₁Cl N₄O₅
Mol. mass	587.064

A Machine-Assisted Flow Synthesis of SR48692: A Probe for the Investigation of Neurotensin Receptor-1 (pages 7917–7930)

Dr. Claudio Battilocchio, Benjamin J. Deadman, Dr. Nikzad Nikbin, Dr. Matthew O. Kitching, Prof. Ian R. Baxendale and Prof. Steven V. Ley

Article first published online: 16 APR 2013 | DOI: 10.1002/chem.201300696

Flow and pharmaceuticals? An investigation into whether machine-assisted technologies can be of true help in the multistep synthesis of a potent neurotensin receptor-1 probe, Meclinertant (SR48692; see structure), is reported.

Meclinertant (SR 48692)
We developed an improved synthesis of the neurotensin antagonist biological probe SR 48692. The preparation includes an number of chemical conversions and strategies involving the use of flow chemistry platforms which helped overcome some of the limiting synthetic transformations in the original chemical route .

Meclinertant (SR 48692): The synthesis of neurotensin antagonist SR 48692 for prostate cancer research I.R. Baxendale, S. Cheung, M.O. Kitching, S.V. Ley, J.W. Shearman Bio. Org. Med. Chem. 2013, 21, 4378-4387.

A synthesis of the neurotensin 1 receptor probe Merclinertant (SR48692) has been reported using a range of continuous flow through synthesis, in-line reaction monioring and purification techniques. This strategy has been contrasted with a more conventional batch synthesis approach.

Notably the safe use of phosgene gas (generated in situ), the superheating of solvents to accelerate reaction rates, the processing of a reagent suspension under continuous flow-through conditions and the application of semi-permeable membrane technology to facilitate work-up and purification were all techniques that could be beneficially applied in the synthetic scheme.

C. Battilocchio, B. J. Deadman, N. Nikbin, M. O. Kitching, I. R. Baxendale, S. V. Ley, Eur. J. Chem., 2013, DOI: 10.1002/chem.201300696

…………………….

Abstract:

An improved synthesis of the molecule SR 48692 is presented and its use as a neurotensin antagonist biological probe for use in cancer research is described. The preparation includes an number of enhanced chemical conversions and strategies to overcome some of the limiting synthetic transformations in the original chemical route.

The Synthesis of Neurotensin Antagonist SR 48692 for Prostate Cancer Research.Bioorg. Med. Chem. 2013, 21, 4378-4387.

Link: 10.1016/j.bmc.2013.04.075Baxendale, I. R.; Cheung, S.; Kitching, M. O.; Ley, S. V. Shearman, J. W.

/////////////////////////////

Meclinertant, Reminertant, SR-48692
The condensation of 2′,6′-dimethoxyacetophenone (I) with diethyl oxalate (II) by means of sodium methoxide in refluxing methanol gives the dioxobutyrate (III), which is cyclized with 7-chloroquinoline-4-hydrazine (IV) in refluxing acetic acid yielding the pyrazole derivative (V). The hydrolysis of the ester group of (V) with KOH in refluxing methanol/water affords the corresponding carboxylic acid (VI), which is finally treated with SOCl2 in refluxing toluene and condensed with 2-aminoadamantane-2-carboxylic acid.

EP 0477049; FR 2665898; JP 1992244065; US 5420141; US 5607958; US 5616592; US 5635526; US 5744491; US 5744493

…………………………….

Gully D, Canton M, Boigegrain R, Jeanjean F, Molimard JC, Poncelet M, Gueudet C, Heaulme M, Leyris R, Brouard A (January 1993).“Biochemical and pharmacological profile of a potent and selective nonpeptide antagonist of the neurotensin receptor”. Proceedings of the National Academy of Sciences of the United States of America 90 (1): 65–9. doi:10.1073/pnas.90.1.65. PMC 45600. PMID 8380498.
Gully D, Jeanjean F, Poncelet M, Steinberg R, Soubrié P, Le Fur G, Maffrand JP (1995). “Neuropharmacological profile of non-peptide neurotensin antagonists”. Fundamental & Clinical Pharmacology 9 (6): 513–21. doi:10.1111/j.1472-8206.1995.tb00528.x.PMID 8808171.
Rostene W, Azzi M, Boudin H, Lepee I, Souaze F, Mendez-Ubach M, Betancur C, Gully D (April 1997). “Use of nonpeptide antagonists to explore the physiological roles of neurotensin. Focus on brain neurotensin/dopamine interactions”. Annals of the New York Academy of Sciences 814: 125–41. doi:10.1111/j.1749-6632.1997.tb46151.x. PMID 9160965.
Jump up^ Jolas T, Aghajanian GK (August 1997). “Neurotensin and the serotonergic system”. Progress in Neurobiology 52 (6): 455–68.doi:10.1016/S0301-0082(97)00025-7. PMID 9316156.
Jump up^ Dobner PR, Deutch AY, Fadel J (June 2003). “Neurotensin: dual roles in psychostimulant and antipsychotic drug responses”. Life Sciences73 (6): 801–11. doi:10.1016/S0024-3205(03)00411-9. PMID 12801600.
Jump up^ Chen L, Yung KK, Yung WH (September 2006). “Neurotensin selectively facilitates glutamatergic transmission in globus pallidus”.Neuroscience 141 (4): 1871–8. doi:10.1016/j.neuroscience.2006.05.049. PMID 16814931.
Petkova-Kirova P, Rakovska A, Della Corte L, Zaekova G, Radomirov R, Mayer A (September 2008). “Neurotensin modulation of acetylcholine, GABA, and aspartate release from rat prefrontal cortex studied in vivo with microdialysis”. Brain Research Bulletin 77 (2–3): 129–35. doi:10.1016/j.brainresbull.2008.04.003. PMID 18721670.
Petkova-Kirova P, Rakovska A, Zaekova G, Ballini C, Corte LD, Radomirov R, Vágvölgyi A (December 2008). “Stimulation by neurotensin of dopamine and 5-hydroxytryptamine (5-HT) release from rat prefrontal cortex: possible role of NTR1 receptors in neuropsychiatric disorders”.Neurochemistry International 53 (6–8): 355–61. doi:10.1016/j.neuint.2008.08.010. PMID 18835308.
Griebel G, Moindrot N, Aliaga C, Simiand J, Soubrié P (December 2001). “Characterization of the profile of neurokinin-2 and neurotensin receptor antagonists in the mouse defense test battery”. Neuroscience and Biobehavioral Reviews 25 (7–8): 619–26. doi:10.1016/S0149-7634(01)00045-8. PMID 11801287.
Tirado-Santiago G, Lázaro-Muñoz G, Rodríguez-González V, Maldonado-Vlaar CS (October 2006). “Microinfusions of neurotensin antagonist SR 48692 within the nucleus accumbens core impair spatial learning in rats”. Behavioral Neuroscience 120 (5): 1093–102. doi:10.1037/0735-7044.120.5.1093. PMID 17014260.
Felszeghy K, Espinosa JM, Scarna H, Bérod A, Rostène W, Pélaprat D (December 2007). “Neurotensin receptor antagonist administered during cocaine withdrawal decreases locomotor sensitization and conditioned place preference”. Neuropsychopharmacology 32 (12): 2601–10. doi:10.1038/sj.npp.1301382. PMC 2992550. PMID 17356568.
Lévesque K, Lamarche C, Rompré PP (October 2008). “Evidence for a role of endogenous neurotensin in the development of sensitization to the locomotor stimulant effect of morphine”.European Journal of Pharmacology 594 (1–3): 132–8. doi:10.1016/j.ejphar.2008.07.048. PMID 18706409.

ANTIMALARIAL PIPELINE

Uncategorized 1 Response »

Dec 292014

Malaria, a devastating infectious disease caused by Plasmodium spp., leads to roughly 655,000 deaths per year, mostly of African children. To compound the problem, drug resistance has emerged to all classical antimalarials and may be emerging for artemisinin-based combination therapies. To address the need for new antimalarials with novel mechanisms, several groups carried out phenotypic screening campaigns to identify compounds inhibiting growth of the blood stages of Plasmodium falciparum. In this review, we describe the characterization of these compounds, explore currently ongoing strategies to develop lead molecules, and endorse the concept of a “malaria box” of publicly accessible active compounds.

Malaria is a mosquito-borne disease that kills roughly 655,000 people every year, mostly young children in Africa. Malaria affects roughly 215 million patients annually (World Health Organization, 2011), and approximately one third of the world’s population is at risk for contracting the disease. The World Health Organization has announced a new campaign for global malaria eradication (Wells et al., 2009).

Mosquito-borne diseases are usually controlled by a combination of vector control, vaccines, and chemotherapy. In the case of malaria, economical vector control strategies, including insecticide-impregnated bed nets and localized spraying, have been deployed with success (Okumu and Moore, 2011). Additionally, progress is being made toward effective vaccines with the RTSS vaccine from GlaxoSmithKline (GSK), giving some protection (Schwenk and Richie, 2011). Nonetheless, chemotherapy remains the dominant component of malaria control. Unfortunately, clinical resistance has emerged for most available drugs (Petersen et al., 2011), and there are recent indications of the emergence of resistance to the artemisinin components of artemisinin-based combination therapies, which are a cornerstone of current antimalarial treatment strategies (Dondorp et al., 2009, Mok et al., 2011, Saralamba et al., 2011 and Veiga et al., 2011).

Therefore, new antimalarials are urgently needed. The focus of the discovery process is on new medicines that are structurally distinct from existing drugs, act by novel mechanisms, and avoid being acted upon by drug transporters overexpressed or overactive in multi-drug-resistant malaria. In the late 2000s, three groups, one in academia (St. Jude Children’s Research Hospital) (Guiguemde et al., 2010) and two in industry (GSK [Gamo et al., 2010] and Novartis [Plouffe et al., 2008]), identified novel leads using screening campaigns measuring the growth inhibitory potential of compounds acting on Plasmodium falciparum co-cultured during its asexual stages in human erythrocytes.

In this review, we discuss the driving force for conducting these screens; the results, including similarities and differences between the compounds identified; and the need for further innovation and work in understanding the underlying cellular and physiologic mechanisms by which the new classes of antimalarials work.

SEE………...http://cdn.thehoopla.com/images/68/0/raw/Gobal.Malaria.Pipeline.2013.pdf

Volume 19, Issue 1, 27 January 2012, Pages 116–129

doi:10.1016/j.chembiol.2012.01.004

http://www.sciencedirect.com/science/article/pii/S1074552112000178

High-Priority Series from Each Group

Series Example	Institution	Development Stage
Dihydropyridine SJ000025081	SJCRH	Lead optimization
Diaminonaphthoqinone SJ000030570	SJCRH	Lead optimization
Dihydroisoquinoline SJ000101247	SJCRH	Preclinical
Carboxamide GSK2611622A	GSK	Lead optimization
Indoline TCMDC-139046	GSK	Lead optimization
Alkylpyrazole TCMDC-134142	GSK	Lead optimization
Thienopyrazole TCMDC-123580	GSK	Lead optimization
Aminopiperidine TCMDC-124833	GSK	Lead optimization
Spiroindolone NITD609	Novartis	Phase I
Imidazolo piperazine	Novartis	Preclinical
Benzamide	Novartis	Lead optimization
Pyrimidine-4,6-diamine	Novartis	Lead optimization

In retrospective analysis, it is clear that each group independently detected most of the chemotypes present in this table, but, although uncoordinated, each group focused later efforts on a restricted set of series identified from their screens

Chemical structures of anti–malarials

Anthony et al. Malaria Journal 2012 11:316 doi:10.1186/1475-2875-11-316

http://www.malariajournal.com/content/11/1/316

CMI 977, LDP 977

Uncategorized Comments Off

Dec 272014

CMI 977

C16-H19-F-N2-O4

322.3341

Millennium (Originator), Taisho (Licensee)

(2S,5S)-1-[4-[5-(4-Fluorophenoxymethyl)tetrahydrofuran-2-yl]-3-butynyl]-1-hydroxyurea 175212-04-1 CMI-977 is a potent 5-lipoxygenase inhibitor that intervenes in the production of leukotrienes and is presently being developed for the treatment of chronic asthma. It is a single enantiomer with an all–trans (2S,5S) configuration. Of the four isomers of CMI-977, the S,Sisomer was found to have the best biological activity and was selected for further development. The enantiomerically pure product was synthesized on a 2-kg scale from (S)-(+)-hydroxymethyl-γ-butyrolactone.

CytoMed, Inc. announced y the initiation of Phase I clinical trials for CMI-977, its orally active therapeutic product for the treatment of asthma. CMI-977 inhibits the 5-lipoxygenase (5-LO) cellular inflammation pathway to block the generation of leukotrienes, which play a key role in triggering bronchial asthma. The Company also announced that it has received a U.S. patent covering a number of 5-LO inhibitor compounds, including CMI-977, and their use in treating inflammatory and other disorders.
"Asthma is a chronic, persistent inflammatory disease of the airways characterized by coughing and wheezing. These symptoms are induced by the release of inflammatory mediators, including leukotrienes, from inflammatory cells in the lining of the airways," said Colin Scott, Vice President, Clinical and Regulatory Affairs of CytoMed. "CMI-977 inhibits the production of all classes of leukotrienes by inhibiting the 5-LO pathway. Preclinical studies of CMI-977 have shown similar efficacy to steroid treatment in reducing inflammation, without any evidence of the significant toxicity that has been associated with long-term use of steroids."
"CytoMed's product development strategy focuses on leveraging its expertise in molecular biology, medicinal chemistry and pharmacology to develop a broad range of product candidates," commented Thomas R. Beck, M.D., Chairman and CEO of CytoMed. "Moving our second product into the clinic is a significant step towards the Company's goal of developing a portfolio of safe and efficacious anti-inflammatory compounds." The Company's lead product, CMI-392, is currently in Phase II studies in collaboration with Stiefel Laboratories as a topical treatment for inflammation-related skin disorders.
The Phase I trial of CMI-977, which involves 56 healthy human volunteers, is being conducted at a single site. The double blind, randomized, escalating single dose study is designed to assess CMI-977's safety and tolerability.
The Company plans to complete the study in mid-1998. Over 14.6 million Americans suffer from chronic asthma. The disease is characterized by a widespread narrowing of the airways due to a contraction (spasm) of smooth muscle and overproduction of mucous, which blocks the air passages. These changes are caused by the release of spasmogens and vasoactive substances, including leukotrienes. Current long-term therapies include corticosteroids, which function by non-selectively suppressing a variety of cellular pathways that initiate inflammation. Steroids, while often effective, are associated with significant adverse side effects. CMI- 977 is a leukotriene modulator, part of a new class of drugs designed to
provide patients with a viable alternative to steroids.
CytoMed, Inc. is a growing biopharmaceutical company committed to the discovery and development of novel proprietary products for the treatment of inflammatory disease. The Company has three products in clinical or preclinical stage of development: CMI-392 in Phase II studies for the treatment of inflammatory skin disorders in collaboration with Stiefel
Laboratories; CMI-977, an orally active product in Phase I clinical trials for the treatment of asthma; and CMI-CAB-2, in late-stage preclinical development for the treatment of acute pulmonary and cardiovascular inflammation. To date, the Company has been funded primarily by investments from institutional and venture investors including Schroder Ventures, Oracle Strategic Partners, Atlas Venture, CIP Capital, BioAsia Investors, WPG Farber, Gateway Ventures, HealthCare Ventures and New York Life Insurance.

Org. Proc. Res. Dev., 1999, 3 (1), pp 73–76

DOI: 10.1021/op980209l

http://pubs.acs.org/doi/abs/10.1021/op980209l

…………………………

PAPER

A practical gram scale asymmetric synthesis of CMI-977 is described. A tandem double elimination of an α-chlorooxirane and concomitant intramolecular nucleophilic substitution was used as the key step. Jacobsen hydrolytic kinetic resolution and Sharpless asymmetric epoxidation protocols were applied for the execution of the synthesis of the key chiral building block.

Enantioselective gram scale synthesis of CMI-977 has been described using the tandem sequence of α-chloroepoxide fragmentation and intramolecular nucleophilic substituion as the key step. Combinations of Jacobsen’s hydrolytic kinetic resolution and Sharpless asymmetric epoxidation were explored on the way to achieve the key intermediate.

http://www.sciencedirect.com/science/article/pii/S0957416603001575 ………………………………. The reaction of oxirane (I) with vinylmagnesium bromide in THF gives 1-(4-fluorophenoxy)-4-penten-2(S)-ol (II), which is treated with ethyl vinyl ether and mercuric trifluoroacetate to yield the vinyl ether (III). The cyclization of (III) by means of Grubb’s catalyst in refluxing benzene affords the dihydrofuran (IV), which is treated with benzenesulfinic acid in dichloromethane to give the sulfone (V). The reaction of (V) with the acetylenic tetrahydropyranyl ether (VI) by means of isopropylmagnesium bromide in THF yields the expected addition product (VII), which is treated with TsOH to eliminate the tetrahydropyranyl group and provide the alcohol (VIII). The condensation of (VIII) with N,O-bis (phenoxycarbonyl)hydroxylamine (IX) by means of PPh3 and DEAD in THF affords the protected carbamate derivative (X), which is finally treated with ammonia in methanol.http://www.chemdrug.com/databases/8_0_sluqxnnnfcuabcvj.html

Synthesis 2000, 4, 557

””””””””””””””””””””

J. Braz. Chem. Soc. vol.24 no.2 São Paulo Feb. 2013

http://dx.doi.org/10.5935/0103-5053.20130024

http://www.scielo.br/scielo.php?pid=S0103-50532013000200003&script=sci_arttext Asthma is a chronic inflammatory disease of the respiratory system that results in the reduction or even the obstruction of air flow into the lungs.¹ Over the last 40 years, there have been sharp increases in the global prevalence of asthma and the mortality due to this condition. In 2006, approximately 300 million people worldwide developed asthma, and there are approximately 180,000 deaths annually.² In Brazil, asthma is the third most common cause of hospitalization in the Brazilian Unified Health System (SUS).³ The underdiagnosis and undertreatment of this disease have motivated the scientific community to search for new target-specific drugs to treat asthma and related respiratory diseases.⁴ The compound CMI-977 (LDP-977) (1) was discovered by Cyto-Med Inc., USA,⁵ and has been demonstrated to be a prominent candidate for the treatment of chronic asthma (Figure 1). This compound inhibits the 5-lipoxygenase pathway, thus blocking the production of leukotrienes.⁶ LDP-977 (1), containing a THF-2,5-trans-substituted ring with a (2S,5S) configuration, is orally active, and exhibits a good safety profile, a high degree of potency and excellent oral bioavailability relative to the three other stereoisomers.⁵

(2S,5S)-trans-5-[(4-Fluorophenoxy)methyl]-2-(4-N-hydroxyureidyl-1-butynyl)tetrahydrofuran, CMI-977 Over the years, several synthetic routes have been proposed for the stereoselective synthesis of the THF moiety present in CMI-977 (1) (Scheme 1).^5,7,8 Intermediate 4 was prepared by Cyto-Med Inc., USA, using the first synthetic route developed,⁵ which involved a chiral pool approach for the creation of the C9 stereogenic center (Scheme 1). A nucleophilic attack involving an oxonium electrophile intermediate, obtained from 3, produced C6, but a disappointing low degree of selectivity was observed. In a similar oxonium strategy, Ley and co-workers⁷ employed an anomeric oxygen to promote the carbon rearrangement of an alkynyltributylstannane to access the THF unit, but their reaction also exhibited low selectivity (Scheme 1). Other similar strategies have led to similar results.⁸ Gurjar et al.⁹ reported a new stereoselective approach that installs the stereocenters at C6 and C9 in 6 using both Jacobsen hydrolytic kinetic resolution (HKR) and a Sharpless asymmetric epoxidation step (Scheme 1). The formation of a tandem propargyl alkoxide followed by intramolecular substitution resulted in the creation of the key tetrahydrofuran ring intermediate 7. Ley and co-workers¹⁰ also explored a similar tandem strategy providing the Retrosynthetic analysis of CMI-977 (LDP-977) (1) suitable intermediate 11, which in turn afforded the key fragment 7. These two new approaches were clearly Our disconnection approach began with a superior for the construction of the 2,5-anti THF unit as higher levels of diastereoselectivity were achieved. However, numerous steps are involved in these synthetic epoxide routes. In this paper, it is described our approach for the total synthesis of CMI-977 (LDP-977) (1). The biological importance of the target molecule and its structural features inspired us to devise a more concise and diastereoselective route to achieve the THF-2,5-trans ring of intermediate 7. Results and Discussion Retrosynthetic analysis of CMI-977 (LDP-977) (1) Our disconnection approach began with a long-established strategy for the insertion of the N-hydroxy urea moiety by alkylation involving acetylene 7 and epoxide 13, followed by a Mitsunobu-like reaction involving alcohol 4 and hydroxycarbamate 12 (Scheme 2).^9,10 The terminal acetylene 7 can be assembled via Seyferth-Gilbert homologation (using the Ohira-Bestmann protocol)¹¹ involving the aldehyde prepared from alcohol 14. It was intended to create the trans-THF configuration in our key fragment 14 using a Mukaiyama oxidative cyclization protocol with homoallylic alcohol 15.¹² The functional groups in fragment 15 could be installed starting from commercially available and inexpensive 4-fluorophenol 16, rac-epichlorohydrin 17 and allylbromomagnesium 18, in a strategy similar to that applied by Gurjar et al.⁹ Preparation of the key fragment 14 Our approach to the total synthesis of CMI-977 (LDP-977) (1) began with the reaction of p-fluorophenol 16 with rac-epichlorohydrin 17 in the presence of KOH, providing rac-5 in 97% yield (Scheme 3).¹³ The epoxide rac-5was resolved by hydrolytic kinetic resolution under Jacobsen conditions,¹⁴ using the catalyst (R, R)-(salen)Co^III(OAc) (19, 0.5 mol%) and H₂O (0.57 equiv) in tert-butyl methyl ether, providing (S)-5 in a 48% yield.⁹ The next step involved the epoxide ring-opening of (S)-5 with allylmagnesium bromide (18), providing homoallylic alcohol 15 in a quantitative yield (Scheme 4). The subsequent oxidative cyclization of 15 according to the Mukaiyama protocol,¹² mediated by the Co(modp)₂ (20) (30 mol%) catalyst,¹⁵ provided trans-THF 14 as the only observed diastereoisomer in an 84% yield.⁸ This approach has proven to be a powerful strategy for accessing the 2,5-trans-THF unit in a highly diastereoselective fashion. Preparation of the key fragment 4 and conclusion of the synthesis The alcohol 14 was then oxidized to aldehyde 21 under Parikh-Doering conditions, followed by Seyferth-Gilbert homologation¹⁶ using the Ohira-Bestmann reagent 22,¹¹ assembling the terminal acetylene 7 in a 75% yield over two steps (Scheme 5). The ¹H NMR and ¹³C NMR spectra and the optical rotation of trans-THF 7 matched the reported values for this compound.⁹ Next, the treatment of 7 with n-BuLi and ethylene oxide 13 led to alcohol 4 in a 70% yield. As shown in Scheme 5, the preparation of hydroxycarbamate 26 (53% yield), followed by its acetylation using acetyl chloride 27, provided 12 in a quantitative yield. A Mitsunobu-like reaction between alcohol 4 and N-hydroxycarbamate 12 provided 23 in a 93% yield. Finally, 23 was ammonolysed with NH₃·MeOH, yielding CMI-977 as a white solid in a 38% yield. The spectral and physical data of the synthetic sample were in complete agreement with those reported in the literature.^5,7-9

SPECTRAL DATA (2S,5S)-trans-5-[(4-Fluorophenoxy)methyl]-2-(4-N-hydroxyureidyl-1-butynyl)tetrahydrofuran, CMI-977 (1) To a round-bottomed flask, it was added 15 (85 mg, 0.19 mmol) at 0 ºC. Then, NH₃ (2 mL, 14 mmol, 7 mol L^-1in MeOH) was added, and the mixture was stirred at 0 ºC for 36 h. The reaction was concentrated under reduced pressure and purified by flash column chromatography using a mixture of CHCl₃/MeOH (20:1) as the eluent, providing the compound CMI-977 (1) (24 mg, 0.074 mmol) as a colorless solid in a 38% yield; mp 106-107 ºC, 106-107 ºC;⁹

[α]_D²⁰ -40 (c 1.1, MeOH), [α]_D -46.0 (c 1.1, MeOH);⁹

¹H NMR (CDCl₃, 250 MHz) δ 1.19 (s, 1H), 1.67-1.81 (m, 1H), 1.86-1.98 (m, 1H), 2.08-2.21 (m, 2H), 2.46 (t, 2H, J 6.5 Hz), 3.60 (t, 2H, J 6.8 Hz), 3.77-3.89 (m, 2H), 4.34-4.43 (m, 1H), 4.63-4.67 (m, 1H), 5.48 (s, 2H), 6.74-6.92 (m, 4H), 8.60 (br, 1H);

¹³C NMR (CDCl₃, 150.9 MHz) δ 17.2 (CH₂), 27.7 (CH₂), 33.3 (CH₂), 48.7 (CH₂), 69.1 (CH), 70.7 (CH₂), 76.9 (CH), 80.7 (C₀), 82.9 (C₀), 115.5 (CH), 115.7 (CH), 115.9 (CH), 154.8 (C₀), 156.6 (C₀), 158.2 (C₀), 161.7 (C₀);

IR (film) ν_max/cm^-1 3445, 3331, 3178, 2918, 2878, 1639, 1583, 1512, 1454, 1362, 1302, 1229, 1097, 1078, 1038, 937, 827, 762;

HRMS (ESI-TOF) m/z [M + H]⁺ for C₁₆H₂₀FN₂O₄ calcd. 323.1407, observed 323.1438.

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Sun, X. S.; Wasley, J. W. F.; Qiu, J; Blonder, J. P.; Stout, A. M.; Green, L. S.; Strong, S. A.; Colagiovanni, D. B.; Richards, J. P.; Mutka, S. C.; Chun, L.; Rosenthal, G. J.; ACS Med. Chem. Lett. 2011,2, 402; [ Links ]

Semko, C. M.; Chen, L.; Dressen, D. B.; Dreyer, M. L.; Dunn, W.; Farouz, F. S.; Freedman, S. B.; Holsztynska, E. J.; Jefferies, M.; Konradi, A. K.; Liao, A.; Lugar, J.; Mutter, L.; Pleiss, M. A.; Quinn, K. P.; Thompson, T.; Thorsett, E. D.; Vandevert, C.; Xu, Y.-Z.; Yednock, T. A.; Bioorg. Med. Chem. Lett .2011,21,1741. [ Links ]

5. Cai, X.; Hwang, S.; Killan, D.; Shen, T. Y.; US pat. 5,648,486 1997; [ Links ] Cai, X.; Grewal, G.; Hussion, S.; Fura, A.; Biftu, T.; US pat. 5,681,966 1997; [ Links ]

Cai, X.; Cheah, S.; Eckman, J.; Ellis, J.; Fisher, R.; Fura, A.; Grewal, G.; Hussion, S.; Ip, S.; Killian, D. B.; Garahan, L. L.; Lounsbury, H.; Qian, C.; Scannell, R. T.; Yaeger, D.; Wypij, D. M.; Yeh, C. G.; Young, M. A.; Yu, S.; Abs. Pap. Am. Chem. Soc.,1997,214,214-MEDI. [ Links ]

6. Cai, X.; Chorghade, M. S.; Fura, A.; Grewal, G. S.; Juaregui, K. A.; Lounsbury, H. A.; Scannell, R. T.; Yeh, C. G.; Young, M. A.; Yu, S.; Org. Process Res. Dev. 1999,3,73.

7. Dixon, D. J.; Ley, S. V.; Reynolds, D. J.; Chorghade, M. S.; Synth. Commun. 2000,30, 1955; [ Links ]Dixon, D. J.; Ley, S. V.; Reynolds, D. J.; Chorghade, M. S.; Indian J. Chem., Sect B 2001,40,1043.

8. Chorgade, M. S.; Gurjar, M. K.; Adikari, S. S.; Sadalapure, K.; Lalitha, S. V. S.; Murugaiah, A. M. S.; Radhakrishna, P.; Pure Appl. Chem. 1999,71, 1071; [ Links ] Gurjar, M. K.; Murali Krishna, L.; Sridhar Reddy, B.; Chorghade, M. S.; Synthesis 2000, 557; [ Links ] Chattopadhyay, A.; Vichare, P.; Dhotare, B.;Tetrahedron Lett. 2007,48,2871.

9. Gurjar, M. K.; Murugaiah, A. M. S.; Radhakrishna, P.; Ramana, C. V.; Chorghade, M. S.; Tetrahedron: Asymmetry 2003,14,1363.

10. Sharma, G. V. M.; Punna, S.; Prasad, T. R.; Krishna, P. R.; Chorghade, M. S.; Ley, S. V.; Tetrahedron: Asymmetry 2005,16,1113.

…………………………………………………

read

Pure Appl. Chem., Vol. 71, No. 6, pp. 1071-1074, 1999.

http://pac.iupac.org/publications/pac/pdf/1999/pdf/7106×1071.pdf

Full text – pdf 322 kB – IUPAC

………………………………………………… US 5703093; US 5792776; WO 9600212 Ether (III) was prepared by condensation of (S)-4-(hydroxymethyl)butyrolactone (I) and 4-fluorophenol (II) in the presence of diisopropylazodicarboxylate (DIAD) and triphenylphosphine under Mitsunobu conditions. Then, reduction of lactone (III) with DIBAL-H in toluene at -78 C gave lactol (IV), which was converted to silyl ether (V) by treatment with tert-butyldimethylsilyl chloride (TBDMS-Cl) and imidazole. Subsequent reaction of (V) with TBDMS-Br in CH2Cl2 at -78 C, followed by condensation with the lithium acetylide derived from acetylene (VI), yielded compound (VII) as a mixture of isomers. Chromatographic separation of the mixture provided the desired trans isomer, which was deprotected by treatment with tetra-n-butylammonium fluoride to give alcohol (VIII). This was then condensed with N,O-bis(phenoxycarbonyl)hydroxylamine (IX) in the presence of DIAD and Ph3P to furnish the hydroxamic acid derivative (X). Finally, concomitant deprotection of the O-phenoxycarbonyl group and substitution of the remaining phenoxy group for an amino group by treatment with methanolic ammonia in a pressure tube, provided the title compound.http://www.chemdrug.com/databases/8_0_sluqxnnnfcuabcvj.html …………………………………………………. PAPER

Title:	A short and efficient stereoselective synthesis of the potent 5-lipoxygenase inhibitor, CMI-977^†
Authors:	Dixon, Darren J Ley, Steven V Reynolds, Dominic J Chorghade, Mukund S
Issue Date:	Nov-2001
Publisher:	NISCAIR-CSIR, India
Abstract:	A short and efficient synthesis of the potent 5-lipoxygenase inhibitor CMI-977 has been accomplished, utilising an oxygen to carbon rearrangement of an anomerically linked alkynyl stannane tetrahydrofuranyl ether derivative as the key step.
Page(s):	1043-1053
CC License:	CC Attribution-Noncommercial-No Derivative Works 2.5 India

Source:	IJC-B Vol.40B(11) [November 2001]

Files in This Item:

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IJCB 40B(11) 1043-1053.pdf		3.03 MB	Adobe PDF	View/Open

http://nopr.niscair.res.in/bitstream/123456789/22437/1/IJCB%2040B%2811%29%201043-1053.pdf ……………………………………………….

http://www.google.com.ar/patents/US20080081835 Specific inhibitors of 5-LO that may be mentioned include the following.

- (1) Zileuton (synonyms: A-64077, ABT 077, Zyflo®), described in, for example, EP 0 279 263, U.S. Pat. No. 4,873,259, Int. J. Immunopharmacol. 14, 505 (1992), Br. J. Cancer 74, 683 (1996) and Am. J. Resp. Critical Care Med. 157, Part 2, 1187 (1998).

- (2) A-63162, described in, for example, Anticancer Res. 14, 1951(1994).

- (3) A-72694.

- (4) A-78773, described in, for example, Curr. Opin. Invest. Drugs 2, 69 (1993).

- (5) A-79175 (the R-enantiomer of A 78773), described in, for example, Carcinogenesis 19, 1393 (1998) and J. Med. Chem. 40, 1955 (1997).

- (6) A-80263.

- (7) A-81834.

- (8) A-93178

- (9) A-121798, described in, for example, 211th Am. Chem. Soc. Meeting. 211: abstr. 246, 24 Mar. 1996.
- (10) Atreleuton (synonyms ABT-761 and A-85761), described in, for example, Exp. Opin. Therap. Patents 5 127 (1995).

- (11) MLN-977 (synonyms LPD-977 and CMI-977), described in, for example, Curr. Opin. Anti–Inflamm. &Immunomod. Invest. Drugs 1, 468 (1999). This, as well as similar compounds are described in U.S. Pat. No. 5,703,093.

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WO 0001381 The reaction of 4-fluorophenol (I) with epichlorohydrin (II) by means of K2CO3 in refluxing acetone gives 2-(4-fluorophenoxymethyl)oxirane (III), which is submitted to an enantioselective ring opening with the Jacobsen (R,R)-catalyst yielding a mixture of the (R)-diol (IV) and unaltered epoxide (V), easily separated by column chromatography. The reaction of (IV) with tosyl chloride and pyridine in dichloromethane affords the primary monotosylate (VI), which is converted into the chiral epoxide (VII) by reaction with NaH in THF/DMF. The reaction of (VII) with allylmagnesium bromide (VIII) in ethyl ether gives the 2-hexenol derivative (IX), which is treated with benzenesulfonyl chloride and DMAP yielding the sulfonate (X). The ozonolysis of (X) with ozone in dichloromethane affords the aldehyde (XI), which is condensed with ethoxycarbonylmethylene(triphenyl)phosphorane (XII) yielding the 2-heptenoic ester (XIII). The reduction of (XIII) with diisobutylaluminum hydride (DIBAL) in toluene/dichloromethane provides the 2-hepten-1-ol (XIV), which is epoxidized with cumene hydroperoxide in the presence of diisopropyl (+)-tartrate and Ti(Oi-Pr)4 in dichloromethane to give the chiral epoxyalcohol (XV). The reaction of (XV) with triphenylphosphine/CCl4 in chloroform affords the corresponding chloride (XVI). …………………………………….

WO 0001381 Intermediate (XVI) is treated with BuLi and diisopropylamine in THF giving the chiral acetylenic tetrahydrofuran (XVII). The addition of ethylene oxide (XVIII) to the terminal acetylene of (XVII) by means of BF3/Et2O in THF gives the 3-butyl-1-ol derivative (XIX), which is condensed with N,O-bis(phenoxy- carbonyl)hydroxylamine (XX) by means of PPh3 and diisopropylazodicarboxylate (DIAD) in THF yielding the final intermediate (XXI). Finally, this compound is treated with ammonia in methanol to obtain the target urea derivative.

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poster

http://www.prp.rei.unicamp.br/pibic/congressos/xxcongresso/paineis/092085.pdf

SÍNTESE TOTAL DO CMI-977 (LDP-977), UM PODEROSO AGENTE ANTIASMÁTICO
Lui Strambi Farina (IC), Marco Antonio Barbosa Ferreira (PG) e Luiz Carlos Dias (PQ)*
INSTITUTO DE QUÍMICA, UNIVERSIDADE ESTADUAL DE CAMPINAS, C.P. 6154, 13084-971, CAMPINAS, SP, BRASIL
*ldias@iqm.unicamp.br
Agência Financiadora: Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPQ).
Palavras-Chave: Síntese orgânica, Tetrahidrofuranos, CMI-977 (LDP-977)

……………………………

Synthesis of (+)-Muricatacin and a Formal Synthesis of CMI-977 from l-Malic Acid

https://www.thieme-connect.de/DOI/DOI?10.1055/s-0033-1338934

A total synthesis of (+)-muricatacin and a formal synthesis of CMI-977 have been achieved using commercially available l-malic acid based on our furan approach to oxacyclic systems, the proven scope of which is thus broadened.

(S)-(+)-3-HYDROXY-2,2-DIMETHYLCYCLOHEXANONE

spectroscopy, SYNTHESIS, Uncategorized Comments Off

Dec 192014

(S)-(+)-3-hydroxy-2,2-dimethylcyclohexanone

bp 85–87°C at 3.7 mm, [α]²¹D + 23.0° (CHCl₃, c 2.0)

The spectral properties of (S)-(+)-3-hydroxy-2,2-dimethylcyclohexanone are as follows:

IR v_max (film) cm⁻¹: 3470 (s), 1705 (s), 1120 (m), 1055 (s), 985 (s), 965 (m);

¹H NMR (250 MHz, CDCl₃) δ: 1.11 (s, 3 H), 1.15 (s, 3 H), 1.60–1.71 (m, 1 H), 1.76–1.86 (m, 1 H), 1.96–2.05 (m, 2 H), 2.16 (br s, 1 H), 2.35–2.45 (m, 2 H), 3.69 (dd, 1 H, J = 7.6, 2.9);

¹³C NMR (76 MHz, CDCl₃) δ: 19.7, 20.7, 22.9, 29.0, 37.3, 51.3, 77.8, 215.3.

The optical purity of (S)-(+)-3-hydroxy-2,2-dimethylcyclohexanone can be determined by HPLC analysis.

The (S)-α-methoxy-α-trifluoromethylphenylacetate (MTPA ester) is prepared according to the reported procedure:³ HPLC analysis (Column, Nucleosil^® 50-5, 25 cm × 4.6 mm; eluant, hexane : THF = 30 : 1, 1.03 mL/min; detected at UV 256 nm) retention time 35.6 min (98.0–99.4%) and 29.6 min (0.6–(2.0%). Therefore, the optical purity is determined to be 96.0–98.8% ee.

Analysis of the MTPA ester of this product by 250 MHz ¹H NMR and capillary GLC (12.5 m, 5% methyl silicone column) failed to detect any more of the minor diastereomer than would have been expected from the purity (98% ee) of the MTPA-Cl employed.

NOTE….Intermediate is

2,2-dimethylcyclohexane-1,3-dione bp 92–97°C (4 mm)

37–38°C.

The spectra are as follows: ¹H NMR (250 MHz, CDCl₃) δ: 1.29 (s, 6 H), 1.93 (5 lines, 2 H, J = 6.5), 2.67 (t, 4 H, J = 6.9); ¹³C NMR (76 MHz, CDCl₃) δ: 18.1, 22.3, 37.4, 61.8, 210.6.

Natural products synthesized from (S)-3-hydroxy-2,2-dimethylcyclohexanone

References and Notes

Department of Agricultural Chemistry, The University of Tokyo, Yayoi 1-1-1, Bunkyo-Ku, Tokyo 113, Japan.
Mekler, A. B.; Ramachandran, S.; Swaminathan, S.; Newman, M. S. Org. Synth., Coll. Vol. V 1973, 743, 3.
Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512.
Kieslich, K. “Microbial Transformations of Non-Steroid Cyclic Compounds;” Georg Thieme; Stuttgart, 1976, pp. 28–31.
Lu, Y.; Barth, G.; Kieslich, K.; Strong, P. D.; Duax, W. L.; Djerassi, C. J. Org. Chem. 1983, 48, 4549.
Mori, K.; Mori, H. Tetrahedron 1985, 41, 5487.
Yanai, M.; Sugai, T.; Mori, K. Agric. Biol. Chem. 1985, 49, 2373.
Mori, K.; Watanabe, H. Tetrahedron 1986, 42, 273.
Mori, K.; Nakazono, Y. Tetrahedron 1986, 42, 283.
Mori, K.; Mori, H.; Yanai, M. Tetrahedron 1986, 42, 291.
Mori, K.; Tamura, H. Tetrahedron 1986, 42, 2643.
Sugai, T.; Tojo, H.; Mori, K. Agric. Biol. Chem. 1986, 50, 3127.
Mori, K.; Mori, H. Tetrahedron 1986, 42, 5531.
Mori, K.; Mori, H. Tetrahedron 1987, 43, 4097.
Mori, K.; Komatsu, M. Liebigs Ann. Chem. 1988, 107.

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Lexipafant

Uncategorized Comments Off

Dec 162014

Lexipafant

CAS : 139133-26-9

N-Methyl-N-[[4-[(2-methyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl]phenyl]sulfonyl]-L-leucine ethyl ester

N-methyl-N-[[a-(2-methyl-1H-imidazo[4,5-c]pyridin-1-yl)-p-tolyl]sulfonyl]-L-leucine ethyl ester

N-Methyl-N-[4-(2-methyl-1H-imidazo[4,5-c]pyridin-1-ylmethyl)phenylsulfonyl]-L-leucine ethyl ester

Manufacturers’ Codes: BB-882

DO6
GR-167089
ISV-611

UNII-H14917M9YW

Trademarks: Zacutex (Brit. Biotech)

MF: C23H30N4O4S

M Wt: 458.57

Percent Composition: C 60.24%, H 6.59%, N 12.22%, O 13.96%, S 6.99%

Properties: White crystalline solid from ethyl acetate, mp 105°. [a]D20 -6.7° (c = 2.0 in CDCl3).

Melting point: mp 105°

Optical Rotation: [a]D20 -6.7° (c = 2.0 in CDCl3)

Therap-Cat: Anti-inflammatory. (Nonsteroidal); Platelet Activating Factor Antagonist.

Lexipafant is a platelet-activating factor (PAF) antagonist that was in early clinical development at DevCo for the oral treatment of dementia and motor function disorders in HIV patients, intravenous treatment of acute pancreatitis, as well as for the prevention of certain serious renal and neurological complications experienced by patients undergoing cardiac surgery, including stroke. However, no recent developments of the drug candidate have been reported by the company.

Lexipafant was also being studied at British Biotech (now Vernalis) for the intravenous treatment of pancreatitis, but development for this indication was discontinued. In 2002, DevCo obtained from British Biotech exclusive rights to develop, manufacture and sell lexipafant for the treatment of human disease, excluding the fields of oncology and ophthalmology.

……………………………

http://www.google.com.ar/patents/EP0543858B1?cl=en

……………………………………………

WO 1993016075

http://www.google.com/patents/WO1993016075A1?cl=en

………………………………

WO 1995013064

http://www.google.com/patents/EP0727995A1?cl=en

Literature References:

Platelet activating factor (PAF) antagonist. Prepn: M. Whittaker, A. Miller, WO 9203422; eidem, US5200412 (1992, 1993 both to British Bio-Technology).

Structure-activity report: M. Whittaker et al., J. Lipid Mediators Cell Signalling 10, 151 (1994).

Pharmacology: F. M. Abu-Zidan et al., Pharmacol. Toxicol. 78, 23 (1996).

Clinical evaluation in acute pancreatitis: A. N. Kingsnorth et al., Br. J. Surg. 82, 1414 (1995).

ANTHONY MELVIN CRASTO

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RABEPRAZOLE SPECTRAL VISIT

SYNTHESIS, Uncategorized Comments Off

Dec 092014

1H NMR RABEPRAZOLE

RAB standard: (DMSOd6 400 MHz) δ 8.28 (d, 1H, J=5.56 Hz), 7.46 (m, 2H), 6.93 (d, 1H, J=5.68 Hz), 6.88 (m, 2H), 4.57 (AB, 2H, J=12.88 Hz), 4.10 (t, 2H, J=6.19 Hz), 3.49 (t, 2H, J=6.32 Hz), 3.25 (S, 3H), 2.17 (S, 3H), 1.98 (quin., 2H, J=6.19 Hz) ¹³C NMR (DMSOd6, 101 MHz) δ 162.61, 152.41, 147.95, 146.62, 121.74, 118.20, 117.32, 105.92, 68.30, 64.92, 59.64, 57.96, 28.67, 10.83.

The ¹H spectrum for the RAB starting material is shown with peaks labelled and integrated. Data were collected on a 400 MHz NMR in DMSOd6, corrected to TMS by residual non-deuterated solvent.

Figure S13 COSY NMR spectrum of RAB

The COSY spectrum for the RAB starting material is shown. This was used to assign the methoxypropoxy carbon chain δ 1.98, 3.49 and 4.10. Data were collected on a 400 MHz NMR in DMSOd6, corrected to TMS by residual non-deuterated solvent.

Figure S14 HMBC spectrum of RAB

The spectrum shows the long range coupling of ¹H to ¹³C nuclei. Coupling is observed between the 3-methyl group and the AB system, and between the various hydrogens on the alkyl chain.

Evaluation of antispasmodic activity of different Shodhit guggul using different shodhan process

Ayurveda, Uncategorized Comments Off

Dec 092014

Evaluation of antispasmodic activity of different Shodhit guggul using different shodhan process

Rachana Kamble, Sadhana Sathaye, DP Shah
University Institute of Chemical Technology, N. Parekh Marg, Matunga, Mumbai-400 019, India

According to ayurvedic texts shodhan vidhi is an important process which enhances the biological activity of a compound and reduces the toxicity at the same time. Before incorporating into formulations, guggul is processed using Shodhan vidhi involving different shodhan dravyas like gulvel, gomutra, triphala, dashmul. We have evaluated the antispasmodic activity of guggul on ileum of guinea pig and Wistar rats. The animals were sacrificed and ileum tissue of guinea pig and rat was isolated and tested for antispasmodic activity using different spasmogens like acetylcholine, histamine and barium chloride. It was observed that the different shodhit guggul (shudha guggul) i.e. processed using different shodhan vidhi, showed good antispasmodic activity as compared to Ashudha guggul. When acetylcholine was used as spasmogen, gulvel and triphala shodhit guggul showed good antispasmodic activity than other shodhit guggul. Thus shodhan vidhi enhances the therapeutic properties of guggul.
Kamble R, Sathaye S, Shah D P. Evaluation of antispasmodic activity of different Shodhit guggul using different shodhan process. Indian J Pharm Sci 2008;70:368-72
URL:
Kamble R, Sathaye S, Shah D P. Evaluation of antispasmodic activity of different Shodhit guggul using different shodhan process. Indian J Pharm Sci [serial online] 2008 [cited 2014 Dec 9];70:368-72. Available from: http://www.ijpsonline.com/text.asp?2008/70/3/368/43005

Sadhana Sathaye

Associate professor of Pharmacy(Pharmacology) at Institute Of Chemical Technology

in.linkedin.com/pub/sadhana-sathaye/14/290/84a

SPIN SPIN COUPLING

Uncategorized Comments Off

Dec 032014

The source of spin-spin coupling

The ¹H-NMR spectra that we have seen so far (of methyl acetate and para-xylene) are somewhat unusual in the sense that in both of these molecules, each set of protons generates a single NMR signal. In fact, the ¹H-NMR spectra of most organic molecules contain proton signals that are ‘split’ into two or more sub-peaks. Rather than being a complication, however, this splitting behavior actually provides us with more information about our sample molecule.

Consider the spectrum for 1,1,2-trichloroethane. In this and in many spectra to follow, we show enlargements of individual signals so that the signal splitting patterns are recognizable.

The signal at 3.96 ppm, corresponding to the two H_a protons, is split into two subpeaks of equal height (and area) – this is referred to as adoublet. The H_b signal at 5.76 ppm, on the other hand, is split into three sub-peaks, with the middle peak higher than the two outside peaks – if we were to integrate each subpeak, we would see that the area under the middle peak is twice that of each of the outside peaks. This is called a triplet.

The source of signal splitting is a phenomenon called spin-spin coupling, a term that describes the magnetic interactions between neighboring, non-equivalent NMR-active nuclei. In our 1,1,2 trichloromethane example, the H_a and H_b protons are spin-coupled to each other. Here’s how it works, looking first at the H_a signal: in addition to being shielded by nearby valence electrons, each of the H_a protons is also influenced by the small magnetic field generated by H_b next door (remember, each spinning proton is like a tiny magnet). The magnetic moment of H_b will be aligned with B₀ in (slightly more than) half of the molecules in the sample, while in the remaining half of the molecules it will be opposed to B₀. The B_eff ‘felt’ by H_a is a slightly weaker if H_b is aligned against B₀, or slightly stronger if H_b is aligned with B₀. In other words, in half of the molecules H_a is shielded by H_b (thus the NMR signal is shifted slightly upfield) and in the other half H_a isdeshielded by H_b(and the NMR signal shifted slightly downfield). What would otherwise be a single H_a peak has been split into two sub-peaks (a doublet), one upfield and one downfield of the original signal. These ideas an be illustrated by a splitting diagram, as shown below.

Now, let’s think about the H_bsignal. The magnetic environment experienced by H_b is influenced by the fields of both neighboring H_aprotons, which we will call H_a1 and H_a2. There are four possibilities here, each of which is equally probable. First, the magnetic fields of both H_a1 and H_a2 could be aligned with B₀, which would deshield H_b, shifting its NMR signal slightly downfield. Second, both the H_a1 and H_a2 magnetic fields could be aligned opposed to B₀, which would shield H_b, shifting its resonance signal slightly upfield. Third and fourth, H_a1 could be with B₀ and H_a2 opposed, or H_a1opposed to B₀ and H_a2 with B₀. In each of the last two cases, the shielding effect of one H_aproton would cancel the deshielding effect of the other, and the chemical shift of H_b would be unchanged.

So in the end, the signal for H_b is a triplet, with the middle peak twice as large as the two outer peaks because there are two ways that H_a1and H_a2 can cancel each other out.

Now, consider the spectrum for ethyl acetate:

We see an unsplit ‘singlet’ peak at 1.833 ppm that corresponds to the acetyl (H_a) hydrogens – this is similar to the signal for the acetate hydrogens in methyl acetate that we considered earlier. This signal is unsplit because there are no adjacent hydrogens on the molecule. The signal at 1.055 ppm for the H_c hydrogens is split into a triplet by the two H_b hydrogens next door. The explanation here is the same as the explanation for the triplet peak we saw previously for 1,1,2-trichloroethane.

The H_bhydrogens give rise to a quartet signal at 3.915 ppm – notice that the two middle peaks are taller then the two outside peaks. This splitting pattern results from the spin-coupling effect of the three H_c hydrogens next door, and can be explained by an analysis similar to that which we used to explain the doublet and triplet patterns.

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By now, you probably have recognized the pattern which is usually referred to as the n + 1 rule: if a set of hydrogens has n neighboring, non-equivalent hydrogens, it will be split into n + 1 subpeaks. Thus the two H_b hydrogens in ethyl acetate split the H_c signal into a triplet, and the three H_c hydrogens split the H_b signal into a quartet. This is very useful information if we are trying to determine the structure of an unknown molecule: if we see a triplet signal, we know that the corresponding hydrogen or set of hydrogens has two `neighbors`. When we begin to determine structures of unknown compounds using ¹H-NMR spectral data, it will become more apparent how this kind of information can be used.

Three important points need to be emphasized here. First, signal splitting only occurs between non-equivalent hydrogens – in other words, H_a1 in 1,1,2-trichloroethane is not split by H_a2, and vice-versa.

Second, splitting occurs primarily between hydrogens that are separated by three bonds. This is why the H_a hydrogens in ethyl acetate form a singlet– the nearest hydrogen neighbors are five bonds away, too far for coupling to occur.

Occasionally we will see four-bond and even 5-bond splitting, but in these cases the magnetic influence of one set of hydrogens on the other set is much more subtle than what we typically see in three-bond splitting (more details about how we quantify coupling interactions is provided in section 5.5B). Finally, splitting is most noticeable with hydrogens bonded to carbon. Hydrogens that are bonded to heteroatoms (alcohol or amino hydrogens, for example) are coupled weakly – or not at all – to their neighbors. This has to do with the fact that these protons exchange rapidly with solvent or other sample molecules.

Below are a few more examples of chemical shift and splitting pattern information for some relatively simple organic molecules.

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Coupling constants

Chemists quantify the spin-spin coupling effect using something called the coupling constant, which is abbreviated with the capital letterJ. The coupling constant is simply the difference, expressed in Hz, between two adjacent sub-peaks in a split signal. For our doublet in the 1,1,2-trichloroethane spectrum, for example, the two subpeaks are separated by 6.1 Hz, and thus we write ³J_a-b = 6.1 Hz.

The superscript 3 tells us that this is a three-bond coupling interaction, and the a-b subscript tells us that we are talking about coupling between H_a and H_b. Unlike the chemical shift value, the coupling constant, expressed in Hz, is the same regardless of the applied field strength of the NMR magnet. This is because the strength of the magnetic moment of a neighboring proton, which is the source of the spin-spin coupling phenomenon, does not depend on the applied field strength.

When we look closely at the triplet signal in 1,1,2-trichloroethane, we see that the coupling constant – the `gap` between subpeaks – is 6.1 Hz, the same as for the doublet. This is an important concept! The coupling constant ³J_a-b quantifies the magnetic interaction between the H_a and H_b hydrogen sets, and this interaction is of the same magnitude in either direction. In other words, H_a influences H_b to the same extent that H_b influences H_a. When looking at more complex NMR spectra, this idea of reciprocal coupling constants can be very helpful in identifying the coupling relationships between proton sets.

Coupling constants between proton sets on neighboring sp³-hybridized carbons is typically in the region of 6-8 Hz. With protons bound to sp²-hybridized carbons, coupling constants can range from 0 Hz (no coupling at all) to 18 Hz, depending on the bonding arrangement.

For vinylic hydrogens in a trans configuration, we see coupling constants in the range of ³J = 11-18 Hz, while cis hydrogens couple in the ³J= 6-15 Hz range. The 2-bond coupling between hydrogens bound to the same alkene carbon (referred to as geminal hydrogens) is very fine, generally 5 Hz or lower. Ortho hydrogens on a benzene ring couple at 6-10 Hz, while 4-bond coupling of up to 4 Hz is sometimes seen between meta hydrogens.

Fine (2-3 Hz) coupling is often seen between an aldehyde proton and a three-bond neighbor. Table 4 lists typical constant values.

Complex coupling

In all of the examples of spin-spin coupling that we have seen so far, the observed splitting has resulted from the coupling of one set of hydrogens to just one neighboring set of hydrogens. When a set of hydrogens is coupled to two or more sets of nonequivalent neighbors, the result is a phenomenon called complex coupling. A good illustration is provided by the ¹H-NMR spectrum of methyl acrylate:

First, let’s first consider the H_c signal, which is centered at 6.21 ppm. Here is a closer look:

With this enlargement, it becomes evident that the Hc signal is actually composed of four sub-peaks. Why is this? H_c is coupled to both H_aand H_b , but with two different coupling constants. Once again, a splitting diagram can help us to understand what we are seeing. H_a istrans to H_c across the double bond, and splits the H_c signal into a doublet with a coupling constant of ³J_ac = 17.4 Hz. In addition, each of these H_c doublet sub-peaks is split again by H_b (geminal coupling) into two more doublets, each with a much smaller coupling constant of²J_bc = 1.5 Hz.

The result of this `double splitting` is a pattern referred to as a doublet of doublets, abbreviated `dd`.

The signal for H_a at 5.95 ppm is also a doublet of doublets, with coupling constants ³J_ac= 17.4 Hz and ³J_ab = 10.5 Hz.

The signal for H_b at 5.64 ppm is split into a doublet by H_a, a cis coupling with ³J_ab = 10.4 Hz. Each of the resulting sub-peaks is split again by H_c, with the same geminal coupling constant ²J_bc = 1.5 Hz that we saw previously when we looked at the H_c signal. The overall result is again a doublet of doublets, this time with the two `sub-doublets` spaced slightly closer due to the smaller coupling constant for the cisinteraction. Here is a blow-up of the actual H_bsignal:

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When constructing a splitting diagram to analyze complex coupling patterns, it is usually easier to show the larger splitting first, followed by the finer splitting (although the reverse would give the same end result).

When a proton is coupled to two different neighboring proton sets with identical or very close coupling constants, the splitting pattern that emerges often appears to follow the simple `n + 1 rule` of non-complex splitting. In the spectrum of 1,1,3-trichloropropane, for example, we would expect the signal for H_b to be split into a triplet by H_a, and again into doublets by H_c, resulting in a ‘triplet of doublets’.

H_a and H_c are not equivalent (their chemical shifts are different), but it turns out that ³J_ab is very close to ³J_bc. If we perform a splitting diagram analysis for H_b, we see that, due to the overlap of sub-peaks, the signal appears to be a quartet, and for all intents and purposes follows the n + 1 rule.

For similar reasons, the H_c peak in the spectrum of 2-pentanone appears as a sextet, split by the five combined H_b and H_d protons. Technically, this ‘sextet’ could be considered to be a ‘triplet of quartets’ with overlapping sub-peaks.

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In many cases, it is difficult to fully analyze a complex splitting pattern. In the spectrum of toluene, for example, if we consider only 3-bond coupling we would expect the signal for H_b to be a doublet, H_d a triplet, and H_c a triplet.

In practice, however, all three aromatic proton groups have very similar chemical shifts and their signals overlap substantially, making such detailed analysis difficult. In this case, we would refer to the aromatic part of the spectrum as a multiplet.

When we start trying to analyze complex splitting patterns in larger molecules, we gain an appreciation for why scientists are willing to pay large sums of money (hundreds of thousands of dollars) for higher-field NMR instruments. Quite simply, the stronger our magnet is, the more resolution we get in our spectrum. In a 100 MHz instrument (with a magnet of approximately 2.4 Tesla field strength), the 12 ppm frequency ‘window’ in which we can observe proton signals is 1200 Hz wide. In a 500 MHz (~12 Tesla) instrument, however, the window is 6000 Hz – five times wider. In this sense, NMR instruments are like digital cameras and HDTVs: better resolution means more information and clearer pictures