AUTHOR OF THIS BLOG

DR ANTHONY MELVIN CRASTO, WORLDDRUGTRACKER

Eldecalcitol, an active vitamin D3 analog used to treat osteoporosis

 Uncategorized  Comments Off on Eldecalcitol, an active vitamin D3 analog used to treat osteoporosis
Jul 072016
 

 

 

 

Eldecalcitol

(1S,2S,3S,5Z)-5-[(2E)-2-[(1R,3aS,7aR)-1-[(2R)-6-hydroxy-6-methylheptan-2-yl]-7a-methyl-2,3,3a,5,6,7-hexahydro-1H-inden-4-ylidene]ethylidene]-2-(3-hydroxypropoxy)-4-methylidenecyclohexane-1,3-diol

(1R,2R,3R,5Z,7E)-2-(3-Hydroxypropyloxy)-9,10-secocholesta-5,7,10(19)-triene-1,3,25-triol

AC1O5QQ2;   CAS 104121-92-8;  AN-3697; ED 71, Edirol®
Molecular Formula: C30H50O5
Molecular Weight: 490.715 g/mol

APPROVED JAPAN , 2011-01-21, Chugai (Originator) , Roche,Taisho Toyama

Eldecalcitol was approved by Pharmaceuticals and Medicals Devices Agency of Japan (PMDA) on January 21, 2011. It was developed by Chugai Pharmaceutical (a member of Roche) and marketed as Edirol® by Chugai Pharmaceutical and Taisho.

Eldecalcitol is an orally active vitamin D analogue leading to greater absorption of bind calcium. It is usually used to treat osteoporosis.

Edirol® is available as capsule for oral use, containing 0.5 μg or 0.75 μg of free Eldecalcitol, and the recommended dose is 0.75 μg once daily.

ED-71, a vitamin D analog, is a more potent inhibitor of bone resorption than alfacalcidol in an estrogen-deficient rat model of osteoporosis. ED-71, effectively and safely increased lumbar and hip bone mineral density (BMD) in osteoporotic patients who also received vitamin D3 supplementation.

Eldecalcitol is a drug used in Japan for the treatment of osteoporosis.[1] It is an analog of vitamin D.[2] Osteoporosis is a common bone disease among the older generation, with an estimated prevalence of over 200 million people.[1] This condition often results in bone fractures due to abnormally low bone mass density, and is a leading cause of disability, especially among developed countries with longer average life spans. Osteoporosis is more common in women than with men.

 

 

AC1O5QQ2.pngEldecalcitol

Discovery

Chugai Pharmaceutical/Roche are the originators of the medicinal drug eldecalcitol through Taisho Pharmaceutical Holdings and Chugai Pharmaceutical. The trade name of eldecalcitol is Edirol, and its Chemical Abstracts Service (CAS) registry number is 104121-92-8. Eldecalcitol was approved for use in Japan on January 2011. The approval came from the Japanese Ministry of Health, Labor, and Welfare for the objective of a treatment for osteoporosis.[3]

Effects

Clinical trials have suggested that eldecalcitol, a vitamin D analog, has strong effects to reduce calcium reabsorption into the body from bones, therefore increasing bone mineral density, and to increase calcium absorption in intestines.[4] In animals, eldecalcitol inhibits the activity of osteoclasts for the function to reduce bone degradation for calcium, while still able to maintain osteoblast function so as to not hinder bone formation.[5] Unlike other vitamin D analogs, eldecalcitol does not significantly suppress parathyroid hormone levels, promising a better treatment for osteoporosis in comparison to other medications.[6] Bone mineral density increases with eldecalcitol use, in addition to strengthening bone structure. This occurs due to the function of the eldecalcitol drug, which decreases bone reabsorption as observed through a bone reabsorption marker. Bone geometry assessments show that eldecalcitol increases cortical bone area in patients with osteoporosis more so than other vitamin D analogs, such as alfacalcidol. There was also the maintenance of thickness of cortical bone mass, strongly indicating that eldecalcitol improves the strength and mass of bone, specifically cortical bone structure.[7] Adverse effects of eldecalcitol include an increase in blood and urinary calcium levels. Abnormally high levels of calcium can lead to problems associated with hypercalcemia.

Treatment for Osteoporosis

Eldecalcitol can be used for the treatment of hypocalcaemia or osteoporosis. Calcium absorption increases with the presence of eldecalcitol by the body, occurring in the intestines, which is useful for those who have low calcium levels. Eldecalcitol is more often used due to its effects to treat osteoporosis. In the aging population, the bone matrix becomes weakened through untreated osteoporosis. This leads to an increased risk of severe fractures that include spinal and hip fractures in addition to vertebral and wrist fractures. This creates a burden on the health care system due to a decline in the quality of life for the individuals that suffer from this condition. Some risk factors leading to the predisposition of developing osteoporosis are previous incidents of bone fractures and a reduction in bone mineral density.[1] These factors expectantly increase as age increases. Bone health is reliant on maintaining physiologically needed levels of calcium, where the body constantly maintains this calcium homeostasis through osteoblast and osteoclast activity. Osteoblast activity serves this function of maintaining appropriate calcium levels by depositing calcium in bones when blood calcium levels are above normal. In contrast, osteoclasts break down bone tissue to increase blood calcium levels if they are low.[8] This activity is performed after absorption of calcium by the body, which requires the actions of vitamin D. The active metabolite of vitamin D, calcitriol, performs its function through interactions with the calcitriol receptor. This nuclear hormone receptor is responsible for calcium absorption which, in turn, is involving in bone depletion and formation. The new analogs of vitamin D, such as eldecalcitol, are observed to have stronger effects in preventing bone loss, fractures, and falls in comparison to calcitriol.[9] Eldecalcitol is even more effective than its counterpart alfacalcidol, another vitamin D analog. Studies have shown eldecalcitol is more effective than alfacalcidol in preventing vertebral and wrist fractures, and even falls, with osteoporotic patients with vitamin D insufficiencies.[10] Eldecalcitol is also more effective at preventing fractures than vitamin D and calcium supplements.[1] Eldecalcitol increases calcium absorption for vitamin D deficient patients, and therefore could be used for osteoporosis treatment for all age groups.

Pharmacology

Analogs of vitamin D are being explored intensely for their regulatory effects on calcium metabolism with the purpose of treating osteoporosis, a skeletal disease associated with low bone mass and deterioration of bone tissue. Vitamin D is imperative for absorption of calcium to maintain bone strength.

Mechanism of Action

Eldecalcitol is an orally administered drug to patients, which binds to vitamin D receptors and binding protein for the goal of achieving greater specificity to bind calcium for its absorption. This greater affinity is 2.7-fold that of the active vitamin D form of calcitriol. Eldecalcitol is readily absorbed into the body, with a long elimination half-life of over eight hours, reaching maximum absorption in 3.4 hours.[1]

Dosage

Eldecalcitol is present in the form of pills for oral administration. In preclinical models with healthy male volunteers, oral doses of eldecalcitol ranged from 0.1 to 1.0 micrograms once daily to show an increase in bone mineral density.[11] Preclinical trials show improvements for doses at 0.5 and 0.75 micrograms, which are the recommended dosage amounts for the Edirol product as approved by the Japanese Ministry of Health, Labor, and Welfare for treating osteoporosis.[3]

Chemistry

The class of eldecalcitol is a vitamin D3 derivative. This molecule has a molecular weight of 490.71 grams per mole. The eldecalcitol analog of calcitriol, contains a hydroxypropyl group in the lower cyclohexane ring. The synthesis of eldecalcitol incorporates two units assembled together. The IUPAC names include (3S, 4S, 5R)-oct-1-en-7-yne-3,4,5-triol that is fused to a bicyclic system, (R)-6-((1R, 3aR, 7aR, E)-4-(bromomethylene)-7a-methyloctahydro-1H-inden-1-yl)-2-methylheptan-2-ol. The assembly process includes a Diels-Alder reaction to give the fully protected eldecalcitol. In order to get the parent molecule, the hydroxyl groups have to be deprotected. The chemistry of eldecalcitol allows for its binding 2.7-fold more potently than calcitriol. In addition, some vitamin D derivatives have been known to inhibit the serum parathyroid hormone. Eldecalcitol only weakly inhibits the serum parathyroid hormone, making it an even more appealing medicinal drug for its physiological uses in the treatment of osteoporosis.[3] Animal studies of eldecalcitol, in ovariectomized rats, show improvements in bone mass while lowering bone reabsorption to demonstrate its effectiveness in osteoporosis treatment.[5]

PAPER

Heterocycles,  Vol 92, No. 6, 2016, pp.1013-1029
Published online, 22nd March, 2016

DOI: 10.3987/REV-16-840
Diverse and Important Contributions by Medicinal Chemists to the Development of Pharmaceuticals: An Example of Active Vitamin D3 Analog, Eldecalcitol

Noboru Kubodera*

*International Institute of Active Vitamin D Analogs, 35-6, Sankeidai, Mishima, Shizuoka 411-0017, Japan

Abstract

Presented herein are diverse and important contributions by medicinal chemists to different stages of pharmaceutical development. The conceptual elements reviewed, which are intended for young chemists who engage in drug discovery research, draw upon the author’s experience in developing eldecalcitol, an active vitamin D3 analog used to treat osteoporosis. The review covers exploratory research for a lead candidate compound; process development for practical manufacturing; and synthesis of other compounds relevant to the program, such as tritiated compounds, postulated metabolites, and miscellaneous analogs for mode of action studies.

PAPER

Eldecalcitol [1α,25-dihydroxy-2β-(3-hydroxypropoxy)vitamin D3], an analog of calcitriol (1α,25-dihydroxyvitamin D3), possesses a hydroxypropoxy substituent at the 2β-position of calcitriol. Eldecalcitol has potent biological effects on bone disease such as osteoporosis. The marketing of eldecalcitol has very recently started in Japan. In consideration of this, we have been investigating practical synthesis of eldecalcitol for industrial-scale production. Eldecalcitol was initially synthesized in a linear manner. The 27-step linear sequence was, however, suboptimal due to its lengthiness and low overall yield (ca. 0.03%). Next, we developed a convergent approach based on the Trost coupling reaction, in which the A-ring fragment (ene-yne part obtained in 10.4% overall yield) and the C/D-ring fragment (bromomethylene part obtained in 27.1% overall yield) are coupled to produce the triene system of eldecalcitol (15.6%). Although the overall yield of the convergent synthesis was better than that of the linear synthesis, significant improvements were still necessary. Therefore, additional biomimetic studies were investigated. Process development for the practical production of eldecalcitol is described herein.

http://ar.iiarjournals.org/content/32/1/303/F3.expansion.html

Convergent synthesis of eldecalcitol (5) by coupling A-ring fragment 37 with C/D-ring fragment 40. Reagents and conditions: a: HO(CH2)3OH/t-BuOK, 120°C. b: t-BuCOCl/pyridine/CH2Cl2, rt. c: H2/Pd(OH)2/MeOH, rt. d: Me2C(OMe)2/TsOH/acetone, rt. e: DMSO/(COCl)2/CH2Cl2, −60°C. f: CH2=CHMgBr/THF, −60°C. g: t-BuCOCl/Et3N/DMAP/CH2Cl2, rt. h: 1 M HCl/MeOH, rt. i: Ph3P/DEAD/benzene, reflux. j: LiC ≡ CTMS/BF3-OEt2, −78°C. k: 10 N NaOH/MeOH, rt. l: TBSOTf/Et3N/CH2Cl2, 0°C. m: TESOTf/Et3N/CH2Cl2, 0°C. n: O3/CH2Cl2/MeOH, −78°C then NaBH4/MeOH, −78°C. o: NMO/TPAP/4Ams/CH2Cl2, rt. p: Ph3P+CH2BrBr/NaHMDS/ THF, −60°C to rt. q: (dba)3Pd2-CHCl3/PPh3/Et3N/toluene, reflux. r: TBAF/THF/toluene, reflux.

 

Industrial synthesis of alfacalcidol (4) and biomimetic synthesis of eldecalcitol (5) from cholesterol (42). Reagents and conditions: a: [Al(Oi-Pr)3]/cyclohexanone. b: DDQ/AcOEt. c: NaOEt/EtOH. d: NaBH4/MeOH/THF. e: Ac2O/DMPA/pyridine, rt. f: NBS/AIBN/n-hexane, reflux. g: γ-collidine/toluene, reflux. h: KOH/MeOH, rt. i: PTAD/CH2Cl2, rt. j: TBSCl/imidazole. k: MCPBA/CH2Cl2. l: DMI, 140°C. m: TBAF/THF. n: NaBH4/EtOH. o: 400 W high pressure mercury lamp/THF, 0°C then reflux without mercury lamp. p: HO(CH2)3OH/t-BuOK, 110°C. q: Microbial 25-hydroxylation.

 ROUTE1


1. Anticancer. Res. 2012, 32, 303-310.

2. Drugs. Fut. 2005, 30, 450-461.



1. Bioorg. Med. Chem. Lett. 1997, 7, 2871-2874.

2. Anticance. Res. 2009, 29, 3571-3578.

3. Heterocycles 2009, 77, 323-331.

4. Heterocycles 2006, 70, 295-307.


1. EP0503630A1.

2. Drugs Fut. 2005, 30, 450-461.


1. Bioorg. Med. Chem. 1998, 6, 2517-2523.

References

  1. Sanford, M; McCormack, PL (2011). “Eldecalcitol: A review of its use in the treatment of osteoporosis”. Drugs 71 (13): 1755–70. doi:10.2165/11206790-000000000-00000. PMID 21902297.
  2. Hatakeyama, S; Yoshino, M (2010). “Synthesis and preliminary biological evaluation of 20-epieldecalcitol [20-epi-1α,25-dihydroxy-2β-(3-hydroxypropoxy)vitamin D3: 20-epi-ED-71]”. The Journal of Steroid Biochemistry and Molecular Biology 121 (1–2): 25–28.doi:10.1016/j.jsbmb.2010.03.041. PMID 20304058.
  3. Robichaud; Stamford; Weinstein; McAlpine; Primeau; Lowe; Bernstein; Bronson; Manoj, Desai (2012). Annual Reports in Medicinal Chemistry 47 (1st ed.). San Diego: Elsevier Inc. pp. 529–531. ISBN 9780123964922.
  4. Nogachi, Y; Kawate, H; Nomura, M; Takayanagi, R (2013). “Eldecalcitol for the treatment of osteoporosis”. Europe PubMed Central 8: 1313–1321. doi:10.2147/CIA.S49825.
  5. Smith, S; Doyle, N; Boyer, M; Chouinard, L; Saito, H (2013). “Eldecalcitol, a vitamin D analog, reduces bone turnover and increases trabecular an cortical bone mass, density, and strength in ovariectomized cynomolgus monkeys”. Bone 57 (1): 116–122.doi:10.1016/j.bone.2013.06.005. PMID 23774444.
  6. Harada, S; Uno, S; Takahashi, F; Saito, H (2010). “Eldecalcitol is less effective in suppressing parathyroid hormone compared to calcitriol in vivo“. The Journal of Steroid Biochemistry and Molecular Biology 121 (1–2): 281–283.doi:10.1016/j.jsbmb.2010.04.001. PMID 20398764.
  7. Nakamura, T; Takano, T; Fukunaga, M; Shiraki, M; Matsumoto, T (2013). “Eldecalcitol is more effective for the prevention of osteoporotic fractures than alfacalcidol”. Journal of Bone and Mineral Metabolism 31 (4): 417–422. doi:10.1007/s00774-012-0418-5.PMC 3709079. PMID 23575909.
  8. Matsuo, K; Irie, N (2008). “Osteoclast-osteoblast communication”. Archives of Biochemistry and Biophysics 473 (2): 201–209. doi:10.1016/j.abb.2008.03.027.PMID 18406338.
  9. Saito, H; Takeda, S; Amizuka, N (2013). “Eldecalcitol and calcitriol stimulates ‘bone minimodeling,’ focal bone formation without prior bone resorption, in rat trabecular bone”.The Journal of Steroid Biochemistry and Molecular Biology 136 (1): 178–182.doi:10.1016/j.jsbmb.2012.10.004.
  10. Matsumoto, T; Ito, M; Hayashi, Y; Hirota, T; Tanigawara, Y; Sone, T; Fukunaga, M; Shiraki, M; Nakamura, T (2011). “A new active vitamin D3 analog, eldecalcitol, prevents the risk of osteoporotic fractures—A randomized, active comparator, double-blind study”. Bone49 (4): 605–612. doi:10.1016/j.bone.2011.07.011. PMID 21784190.
  11. Harada, S; Mizoguchi, T; Kobayashi, Y; Nakamichi, Y; Takeda, S; Sakai, S; Takahashi, F; Saito, H; Yasuda, H; Udagawa, N; Suda, T; Takahashi, N (2012). “Daily administration of eldecalcitol (ED-71), an active vitamin D analog, increases bone mineral density by suppressing RANKL expression in mouse trabecular bone”. Journal of Bone and Mineral Research 27 (1): 461–473. doi:10.1002/jbmr.555.
No. Major Technical Classification Publication No. Patent No. Legal Status Filling Date Estimated Expiry Date
1 Preparation CN85108857A CN1008368B Granted/expired 1985/12/4 2005/12/4
2 Crystal CN1223639A CN1216861C Granted 1997/6/16 2017/6/16
3 Preparation CN1637017A CN1276927C
Patent ID Date Patent Title
US7927613 2011-04-19 Pharmaceutical co-crystal compositions
US7323580 2008-01-29 CRYSTALS OF A VITAMIN D DERIVATIVE AND A METHOD FOR THE PREPARATION THEREOF
US7235679 2007-06-26 Crystals of a vitamin D derivative and a method for the preparation thereof
EP0924199 2006-05-10 CRYSTALS OF VITAMIN D DERIVATIVES AND PROCESS FOR THE PREPARATION THEREOF
US2005009794 2005-01-13 Crystals of a vitamin D derivative and a method for the preparation thereof
US6831183 2004-12-14 Crystals of a vitamin D derivative and a method for the preparation thereof
US6448421 2002-09-10 CRYSTALS OF VITAMIN D DERIVATIVES AND PROCESS FOR THE PREPARATION THEREOF
Eldecalcitol
Eldecalcitol.svg
Systematic (IUPAC) name
(1S,2S,3S,5Z,7E)-2-(3-Hydroxypropoxy)-9,10-secocholesta-5,7,10-triene-1,3,25-triol
Clinical data
Trade names Edirol
Identifiers
CAS Number 104121-92-8
ATC code None
PubChem CID 6438982
ChemSpider 4943418
Chemical data
Formula C30H50O5
Molar mass 490.715 g/mol

///////////eldecalcitol, active vitamin D3 analog,  treat osteoporosis, AC1O5QQ2, 104121-92-8,   AN-3697, ED 71, ED-71, Edirol®, PMDA, JAPAN

O[C@H]1CC(\C(=C)[C@H](O)[C@H]1OCCCO)=C\C=C2/CCC[C@]3([C@H]2CC[C@@H]3[C@H](C)CCCC(O)(C)C)C

OR

CC(CCCC(C)(C)O)C1CCC2C1(CCCC2=CC=C3CC(C(C(C3=C)O)OCCCO)O)C

 

Share
Oct 212015
 

Figure imgf000183_0001

TAK 272

C27 H41 N5 O4 . Cl H, 536.106

CAS.1202269-24-6. MonoHCl

1202265-90-4 DIHCL

Base cas…1202265-63-1
Metanesulfonate…1202266-34-9

Takeda Pharmaceutical Company Limited, INNOVATOR

 

see also…….http://newdrugapprovals.org/2015/10/20/tak-272-for-hypertension/
1-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)-piperidin-3-yl]-1H-benzimidazole-2-carboxamide

1- (4-methoxybutyl) -N- (2-methylpropyl) -N- [ (3S, 5R) -5- (morpholin-4-ylcarbonyl) piperidin-3-yl] -lH-benzimidazole-2-carboxamide dihydrochloride

N-Isobutyl-1-(4-methoxybutyl)-N-[5(R)-(morpholin-4-ylcarbonyl)piperidin-3(S)-yl]-1H-benzimidazole-2-carboxamide hydrochloride

1- (4-methoxybutyl) -N- (2- methylpropyl) -N – [(3S, 5R) -5- (morpholin-4-ylcarbonyl) piperidine-3 – yl] -1H- benzimidazole-2-carboxamide hydrochloride,

The compound is used as renin inhibitor for treating diabetic nephropathy and hypertension

Takeda’s TAK-272, was reported to be in phase II in October 2015), an oral renin inhibitor, for treating diabetic nephropathy and hypertension

  • 01 Apr 2015Takeda completes a phase I drug-drug interaction trial in Healthy volunteers in Japan (NCT02370615)
  • 18 Feb 2015Takeda plans a phase I drug-drug interaction trial in Healthy volunteers in Japan (NCT02370615)
  • 13 Feb 2015Takeda plans a phase I pharmacokinetics trial in Renal or Hepatic impairment patients in Japan (NCT02367872)
in Patent Document 1, a method for producing a synthetic intermediate of the above heterocyclic compound, the following methods are disclosed.

In the above method, the acid anhydride (BANC) from chiral dicarboxylic acid monoester ((-) – BMPA) were synthesized and then the carboxylic acid after conversion and hydrolysis reaction of the Z amine by the Curtius rearrangement of the carboxylic acid (BAPC) and it was then performs amidation by the condensation reaction with the amine (morpholine), is synthesized heterocyclic amide compound (BMPC). Further, Patent Document 2, the preparation of compounds useful as synthetic intermediates of the above heterocyclic compounds are disclosed.

(Wherein each symbol is as described in Patent Document 2.)

 TABLE In the above method, the acid anhydride of the formula (VI), in the presence of a chiral amine with the formula (VIIa) or (VIIb) is to produce a chiral dicarboxylic acid monoester compound, then reacted with an amine (R1-NH-R2) is subjected to amidation to, to produce a heterocyclic amide compound of the formula (VIII).

Patent literature

Patent Document 1: Patent No. 4,800,445 Patent
Patent Document 2: International Publication No. 2007/077005
 
SYNTHESIS…click on image to get clear view
T1
t2
T3
PATENT

WO2009154300

https://www.google.co.in/patents/WO2009154300A2?cl=en

INTERMEDIATES FOR CONSTRUCTION

Figure imgf000111_0001

USE THIS ONE

Figure imgf000180_0001Figure imgf000179_0001Figure imgf000165_0001

Figure imgf000182_0001Figure imgf000183_0001

Reference Example 31 tert-butyl (3S,5R)-3-[{ [1- (4-methoxybutyl) -lH-benzimidazol-2- yl] carbonyl} (2-methylpropyl) amino] -5- (morpholin-4- ylcarbonyl)piperidine-l-carboxylate and 1- (4-methoxybutyl) -N-

(2-methylpropyl) -N- [ (3S, 5R) -5- (morpholin-4- ylcarbonyl)piperidin-3-yl]-lH-benzimidazole-2-carboxamide

Figure imgf000182_0001

tert-Butyl (3S, 5R) -3-{ [ ( {2- [ (4- methoxybutyl) amino] phenyl}amino) (oxo) acetyl] (2- methylpropyl) amino} -5- (morpholin-4-ylcarbonyl) piperidine-1- carboxylate (9.11 g) was dissolved in acetic acid (50 ml), and the mixture was stirred at 😯0C for 15 hr. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, the residue was diluted with aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and a fraction eluted with ethyl acetate was concentrated under reduced pressure to give tert- butyl (3S, 5R) -3- [ { [1- (4-methoxybutyl) -lH-benzimidazol-2- yl] carbonyl } (2-methylpropyl) amino] -5- (morpholin-4- ylcarbonyl)piperidine-l-carboxylate (5.85 g) , and a fraction eluted with ethyl acetate-methanol (85:15) was concentrated under reduced pressure to give 1- (4-methoxybutyl) -N- (2- methylpropyl) -N- [ (3S, 5R) -5- (morpholin-4-ylcarbonyl) piperidin- 3-yl] -lH-benzimidazole-2-carboxamide (580 mg) . [0424] tert-butyl (3S,5R)-3-[{ [1- (4-methoxybutyl) -lH-benzimidazol-2- yl] carbonyl} (2-methylpropyl) amino] -5- (morpholin-4- ylcarbonyl ) piperidine-1-carboxylate 1H-NMR (CDCl3) δ 0.63-0.80 (2H, m) , 0.89-1.07 (4H, m) , 1.41- 1.59 (9H, m) , 1.59-1.80 (2H, m) , 1.87-2.23 (4H, m) , 2.30-2.98 (3H, m) , 3.21-3. 46 ( 6H, m) , 3.49-3. 91 (1OH, m) , 3. 95-4 . 47 (5H, m) , 7 . 18-7 . 51 (3H, m) , 7. 56-7 . 84 ( IH, m) .

MS (ESI+, m/e) 600 (M+l )

1- (4-methoxybutyl) -N- (2-methylpropyl) -N- [ (3S, 5R) -5- (morpholin- 4-ylcarbonyl)piperidin-3-yl] -lH-benzimidazole-2-carboxamide  BASE

1H-NMR (CDCl3) δ 0.64-0.74 (2H, m) , 0.95-1.07 (4H, m) , 1.43-

1.74 (3H, m) , 1.84-2.41 (4H, m) , 2.48-2.67 (IH, m) , 2.67-3.01

(3H, m), 3.03-3.44 (8H, m) , 3.47-3.78 (9H, m) , 4.06-4.46 (3H, m) , 7.28-7.47 (3H, m) , 7.62-7.81 (IH, m) . MS (ESI+, m/e) 500 (M+l)

Example 10

1- (4-methoxybutyl) -N- (2-methylpropyl) -N- [ (3S, 5R) -5- (morpholin-

4-ylcarbonyl) piperidin-3-yl] -lH-benzimidazole-2-carboxamide dihydrochloride

Figure imgf000183_0001

tert-Butyl (3S,5R)-3-[{ [1- (4-methoxybutyl) -IH- benzimidazol-2-yl] carbonyl} (2-methylpropyl) amino] -5-

(morpholin-4-ylcarbonyl)piperidine-l-carboxylate (5.85 g) was dissolved in methanol (20 ml) , 4M hydrogen chloride-ethyl acetate (20 ml) was added, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was concentrated, and the residue was diluted with aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and a fraction eluted with ethyl acetate- methanol (9:1) was concentrated under reduced pressure to give 1- (4-methoxybutyl) -N- (2-methylpropyl) -N- [ (3S, 5R) -5- (morpholin- 4-ylcarbonyl) piperidin-3-yl] -lH-benzimidazole-2-carboxamide (4.40 g) . The obtained 1- (4-methoxybutyl) -N- (2-methylpropyl) – N- [ (3S, 5R) -5- (morpholin-4-ylcarbonyl) piperidin-3-yl] -IH- benzimidazole-2-carboxamide (2.20 g) was dissolved in ethyl acetate (20 ml) , 4M hydrogen chloride-ethyl acetate (5 ml) and methanol (20 ml) were added, and the mixture was stirred at room temperature for 5 min. The reaction mixture was concentrated under reduced pressure to give the object product (2.52 g).

dihydrochloride

1H-NMR (DMSO-d6) δ 0.63-0.76 (2H, m) , 0.85-1.00 (4H, m) , 1.40-

1.60 (2H, m) , 1.68-1.89 (2H, m) , 1.93-2.17 (2H, m) , 2.20-2.44

(2H, m) , 2.81-3.81 (2OH, m) , 4.19-4.39 (3H, m) , 7.23-7.46 (2H, m) , 7.57-7.81 (2H, m) , 8.38-9.77 (2H, m) .

MS (ESI+, m/e) 500 (M+l)

Example 252

1- ( 4-methoxybutyl ) -N- ( 2-methylpropyl ) -N- [ ( 3S 1. 5R) -5- (morpholin- 4-ylcarbonyl ) piperidin-3-yl ] -lH-benzimidazole-2-carboxamide methanesulfonate

Figure imgf000586_0002

l-(4-Methoxybutyl) -N- (2-methylpropyl) -N- [ (3S,5R)-5- (morpholin-4-ylcarbonyl) piperidin-3-yl] -lH-benzimidazole-2- carboxamide (208 mg) was dissolved in ethyl acetate (2 ml) , a solution of methanesulfonic acid (40 μl) in ethyl acetate (1 ml) was added at 75°C, hexane (1 ml) was added, and the mixture was heated under reflux and stood at room temperature overnight. The precipitated crystals were collected by filtration, and dried at 7O0C for 3 hr to give the object product (158 mg) . MS (ESI+, m/e) 500 (M+l) melting point : 144.40C

EXTRAS IF REQD .………….

Example 32

methyl (3R, 5S)-5-[{ [1- (4-methoxybutyl) -lH-benzimidazol-2- yl] carbonyl} (2-methylpropyl) amino] piperidine-3-carboxylate dihydrochloride [0675]

Figure imgf000238_0001

MS (ESI+, m/e) 445 (M+l)

Example 33

(3R, 5S) -5- [ { [1- (4-methoxybutyl) -lH-benzimidazol-2- yljcarbonyl} (2-methylpropyl) amino] piperidine-3-carboxylic acid dihydrochloride

Figure imgf000238_0002

MS (ESI+, m/e) 431 (M+l)

Reference Example 29

{ [ ( 3S , 5R) -1- (tert-butoxycarbonyl ) -5- (morpholin-4- ylcarbonyl ) piperidin-3~yl ] ( 2-itιethylpropyl ) amino } (oxo ) acetic acid

Figure imgf000180_0001

To a solution of tert-butyl (3S,5R)~3-{ [ethoxy (oxo) acetyl] (2-methylpropyl) amino}-5- (morpholin-4- ylcarbonyl) piperidine-1-carboxylate (10.3 g) in ethanol (40 ml) was added 2M aqueous sodium hydroxide solution (22 ml) , and the mixture was stirred at room temperature for 6 hr. The reaction mixture was adjusted to pH 7 with IM hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (10.3 g) .

1H-NMR (CDCl3) δ 0.78-0.99 (6H, m) , 1.37-1.52 (9H, m) , 1.79- 2.16 (3H, m) , 2.38-3.86 (14H, m) , 3.93-4.43 (2H, m) . MS (ESI+, m/e) 442 (M+l)

Reference Example 28

tert-butyl (3S, 5R) -3-{ [ethoxy (oxo) acetyl] (2- methylpropyl ) amino } -5- (morpholin-4-ylcarbonyl) piperidine-1- carboxylate

Figure imgf000179_0001

To a solution of tert-butyl (3S, 5R) -3- [ (2- methylpropyl) amino] -5- (morpholin-4-ylcarbonyl) piperidine-1- carboxylate (9.24 g) and diisopropylethylamine (10.5 ml) in DMA (100 ml) was added dropwise ethyl chloroglyoxylate (3.4 ml) at 0°C. The reaction mixture was stirred at room temperature for 15 hr, and the reaction mixture was concentrated. An aqueous sodium bicarbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object product (10.3 g) . 1H-NMR (CDCl3) δ 0.84-1.00 (6H, m) , 1.37 (3H, q) , 1.42-1.53 (9H, m) , 1.80-2.19 (3H, m) , 2.26-2.42 (IH, m) , 2.59-2.96 (IH, in) , 2.97-3.30 (3H, m) , 3.37-3.92 (9H, m) , 4.01-4.26 (2H, m) , 4.26- 4.40 (2H, m) . MS (ESI4-, m/e) 470 (M+l)

Reference Example 22 tert-butyl (3S, 5R) -3- [ (2-methylpropyl) amino] -5- (morpholin-4- ylcarbonyl)piperidine-l-carboxylate

Figure imgf000165_0001

[0369] tert-Butyl (3S,5R)-3-{ [ (benzyloxy) carbonyl] aminoJ-5- (morpholin-4-ylcarbonyl)piperidine-l-carboxylate (58 g) and palladium (II) hydroxide-carbon (5 g) were suspended in methanol (400 ml) and the mixture was stirred under a hydrogen atmosphere (1 atom) at room temperature for 16 hr. The palladium catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue and acetic acid (8.8 ml) were dissolved in methanol (400 ml), 2- methylpropanal (14.0 ml) was added, and the mixture was stirred at room temperature for 1 hr. Sodium triacetoxyborohydride (40.4 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the concentrate was basified with 3.5M aqueous potassium carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (1:5) – ethyl acetate-hexane (1:1) was concentrated under reduced pressure to give the object product (33.3 g) .

1H-NMR (CDCl3) δ: 0.90 (6H, d) , 1.46 (9H, s) , 1.54 (IH, d) , 1.69 (IH, dt), 1.96-2.12 (2H, m) , 2.23-2.37 (IH, m) , 2.47 (3H, d) , 2.66 (IH, d) , 3.61 (IH, br s) , 3.55 (2H, d) , 3.69 (5H, ddd) , 4.01-4.46 (2H, m) .

Example 6 1-tert-butyl 3-methyl (3R, 5S) -5-aminopiperidine-l, 3- dicarboxylate [0318]

Figure imgf000154_0001

(3S, 5R) -1- (tert-Butoxycarbonyl) -5-(methoxycarbonyl)piperidine-3-carboxylic acid (2.83 g) was suspended in toluene (36 ml), diphenylphosphoryl azide (2.60 ml) and triethylamine (1.70 ml) were added, and the mixture was stirred at 100°C for 1 hr. The reaction mixture was cooled to room temperature, benzyl alcohol (1.53 ml) and triethylamine (7.00 ml) were added and the mixture was stirred at 80°C for 3 hr. The reaction mixture was concentrated, the residue was dissolved in ethyl acetate, and the solution was washed with water, 0.5M hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine in this order, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (1:3 – 3:1) was concentrated under reduced pressure. The obtained residue was dissolved in methanol (60 ml), 10% palladium carbon (50% in water) (150 mg) was added and the mixture was stirred under a hydrogen pressurization (5 atom) at ambient temperature and normal pressure for 5 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give the object product (1.83 g) as an oil.

1H-NMR (CDCl3) δ 1.22-1.43 (4H, m) , 1.46 (9H, s), 2.27-2.79 (4H, m) , 3.70 (3H, s) , 4.13 (2H, br s) [0320] In the same manner as in the method shown in Reference Example 6, the following compound (Reference Example 7) was obtained.

Reference Example 8

1-tert-butyl 3-methyl (3R, 5S) -5- [ (2- methylpropyl) amino] piperidine-1, 3-dicarboxylate [0325]

Figure imgf000155_0002

1-tert-Butyl 3-methyl (3R, 5S) -5-aminopiperidine-l, 3- dicarboxylate (1.83 g) , isobutyraldehyde (0.78 ml) and acetic acid (0.49 ml) were dissolved in methanol (50 ml), and the mixture was stirred at room temperature for 30 min. Sodium triacetoxyborohydride (3.80 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 7 hr. The reaction mixture was concentrated under reduced pressure, the concentrate was basified with aqueous sodium bicarbonate, and extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (1:1) – ethyl acetate 100% – ethyl acetate- methanol (9:1) was concentrated under reduced pressure to give the object product (1.42 g) as an oil.

1H-NMR (CDCl3) δ 0.90 (6H, d) , 1.22-1.38 (3H, m) , 1.46 (9H, s) , 1.69 (IH, dt), 2.23-2.39 (2H, m) , 2.44-2.59 (IH, m) , 2.47 (2H, d) , 2.74 (IH, br s) , 3.69 (3H, s) , 4.18-4.34 (2H, m)

Reference Example 27

N- (4-methoxybutyl) benzene-1, 2-diamine

Figure imgf000178_0002

To a solution of phenylenediamine (10.8 g) and 4- methoxybutyl methanesulfonate (9.11 g) in acetonitrile (100 ml) was added potassium carbonate (20.7 g) , and the mixture was stirred heated under reflux for 15 hr. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (35:65) was concentrated under reduced pressure to give the object product (5.44 g) . 1H-NMR (CDCl3) δ 1.67-1.82 (4H, m) , 3.13 (2H, t) , 3.24-3.39 (6H, m) , 3 . 38 -3 . 50 ( 2H, m) , 6 . 62 – 6 . 74 ( 3H, m) , 6 . 81 ( IH, in) . MS ( ESI+ , m/e ) 195 (M+l )

Reference Example 146 tert-butyl (3S, 5R) -3- [ { [1- (4-methoxybutyl) -lH-benzimidazol-2- yl]carbonyl} (2-methylpropyl) amino] -5- (morpholin-4- ylcarbonyl)piperidine-l-carboxylate

Figure imgf000290_0001

A solution of tert-butyl (3S, 5R) -3- [ (lH-benzimidazol-2- ylcarbonyl) (2-methylpropyl) amino] -5- (morpholin-4- ylcarbonyl)piperidine-l-carboxylate (200 mg) , 4-itιethoxybutyl methanesulfonate (107 mg) and cesium carbonate (254 mg) in N,N-dimethylacetamide (5 ml) was stirred at 60°C for 15 hr. After cooling to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate (10 ml*2) . The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (5:95 – 3:7) was concentrated under reduced pressure to give the object product (190 mg) . 1H-NMR (CDCl3) δ 0.63-0.80 (2H, m) , 0.89-1.07 (4H, m) , 1.41- 1.59 (9H, m) , 1.59-1.80 (2H, m) , 1.87-2.23 (4H, m) , 2.30-2.98 (3H, m) , 3.21-3.46 (6H, m) , 3.49-3.91 (1OH, m) , 3.95-4.47 (5H, m) , 7.18-7.51 (3H, m) , 7.56-7.84 (IH, m) . MS (ESI+, m/e) 600 (M+l)

ALTERNATE METHOD IN THIS PATENT

Figure imgf000106_0001

Figure imgf000127_0002

Reference Example 61

2- (trichloromethyl) -lH-benzimidazole

Figure imgf000211_0002

O-Phenylenediamine (25 g) was dissolved in acetic acid (750 ml), and methyl 2, 2, 2-trichloroacetimidate (28.5 ml) was added dropwise over 15 min. After stirring at room temperature for 1 hr, the reaction mixture was concentrated to about 150 ml, and poured into water (1500 ml) . The precipitated crystals were collected by filtration, washed with water (1000 ml) and suspended in toluene (500 ml) . The solvent was evaporated under reduced pressure. The residue was again suspended in toluene (500 ml) and the solvent was evaporated under reduced pressure. The residue was dried under reduced pressure to give the object product (51.8 g) . 1H-NMR (CDCl3) δ 7.31-7.45 (2H, m) , 7.49-7.55 (IH, m) , 7.89 (IH, d) , 9 . 74 ( IH, br s )

Reference Example 64

1-tert-butyl 3-methyl (3R, 5S) -5- [ (lH-benzimidazol-2- ylcarbonyl) (2-methylpropyl) amino] piperidine-1, 3-dicarboxylate

Figure imgf000212_0003

2- (Trichloromethyl) -lH-benzimidazole (19 g) and 1-tert- butyl 3-methyl (3R, 5S) -5- [ (2-methylpropyl) amino] piperidine- 1,3-dicarboxylate (25 g) were dissolved in THF (1200 ml), sodium hydrogen carbonate (67 g) and water (600 ml) were added, and the mixture was stirred at room temperature for 1 hr and at 5O0C for 1 hr. After evaporation of the solvent, the residue was extracted 3 times with ethyl acetate (700 ml) . The extract was washed successively with 10%-aqueous citric acid solution (500 ml) and brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure.

The residue was dissolved in ethyl acetate (1000 ml), subjected to basic silica gel column chromatography, and a fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object product (30.6 g) .

1H-NMR (CDCl3) δ 0.78-1.09 (6 H, m) , 1.17-1.55 (9 H, m) , 1.77-2.95 (5 H, m) , 3.11-3.79 (6 H, m) , 3.99-4.73 (4 H, m) , 7.24- 7.41 (2 H, m) , 7.45-7.59 (1 H, m) , 7.72-7.88 (1 H, m) , 10.66-10.98 (1 H, m)MS (ESI+, m/e) 459 (M+l)

Reference Example 69

1-tert-butyl 3-methyl (3R, 5S) -5- [ { [1- (4-methoxybutyl) -IH- benzimidazol-2-yl] carbonyl} (2-methylpropyl) amino] piperidine-1 , 3-dicarboxylate

Figure imgf000215_0003

1-tert-Butyl 3-methyl (3R, 5S) -5- [ (lH-benzimidazol-2- ylcarbonyl) (2-methylpropyl) amino] piperidine-1, 3-dicarboxylate (30 g) and 4-methoxybutyl methanesulfonate (12.5 g) were dissolved in DMA (600 ml), cesium carbonate (32 g) was added, and the mixture was stirred at 70°C for 12 hr. The reaction mixture was poured into ice water (1000 ml), and the mixture was extracted twice with ethyl acetate (1000 ml) . The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (1:4 – 1:1) was concentrated under reduced pressure to give the object product (28.7 g) .

1H-NMR (CDCl3) δ 0.76 (4H, d) , 1.01 (2H, d) , 1.30-1.52 (9H, m) , 1.58-2.07 (4H, m) , 2.10-2.93 (4H, m) , 3.27-3.75 (12H, m) , 4.06-4.57 (5H, m) , 7.26-7.48 (3H, m) , 7.79 (IH, d) MS (ESI+, m/e) 545 (M+l)

Example 71

1- (4-methoxybutyl) -N- (2-methylpropyl) -N- [ (3S, 5R) -5- (morpholin- 4-ylcarbonyl) piperidin-3-yl] -lH-benzimidazole-2-carboxamide

Figure imgf000291_0001

tert-Butyl (3S, 5R) -3- [{ [1- (4-methoxybutyl) -IH- benzimidazol-2-yl] carbonyl} (2-methylpropyl) amino] -5- (morpholin-4-ylcarbonyl)piperidine-l-carboxylate (5.85 g) was dissolved in methanol (20 ml) , 4M hydrogen chloride-ethyl acetate (20 ml) was added, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was concentrated, the residue was diluted with aqueous sodium bicarbonate,…and, the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and a fraction eluted with ethyl acetate- methanol (9:1) was concentrated under reduced pressure to give the object product (4.40 g) . MS (ESI+, m/e) 500 (M+l)

Example 101

1- (5-methoxypentyl) -N- (2-methylpropyl) -N- [ (3S, 5R) -5- (morpholin-4-ylcarbonyl) piperidin-3-yl] -lH-benzimidazole-2- carboxamide dihydrochloride

Figure imgf000345_0001

[1144] tert-Butyl (3S, 5R) -3- [ { [1- (5-methoxypentyl) -IH- benzimidazol-2-yl] carbonyl} (2-methylpropyl) amino] -5- (morpholin-4-ylcarbonyl)piperidine-l-carboxylate (123 mg) was dissolved in 4M hydrogen chloride-ethyl acetate (5 ml) , and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated, and the residue was subjected to reversed-phase preparative HPLC and the eluted fraction was concentrated under reduced pressure. The residue was diluted with aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. 4M Hydrogen chloride-ethyl acetate (1 ml) was added and the mixture was stirred for 5 min. The solvent was evaporated under reduced pressure to give the object product (76 mg) . MS (ESI+, m/e) 514 (M+l)

PATENT

WO2013122260

http://www.google.co.in/patents/WO2013122260A1?cl=en

PATENT

WO 2011158880

http://www.google.co.in/patents/WO2011158880A1?cl=en

Reference Example 1
1- (4-methoxybutyl) -N- (2- methylpropyl) -N – [(3S, 5R) -5- (morpholin-4-ylcarbonyl) piperidin-3-yl] -1H- benzimidazole -2 – carboxamide hydrochloride (A-type crystal)
tert- butyl (3S, 5R) -3 – [{[1- (4- methoxy-butyl) -1H- benzimidazol-2-yl] carbonyl} (2-methylpropyl) amino] -5- (morpholin-4- ylcarbonyl) was suspended dissolved piperidine-1-carboxylate The (300g) in 3N- hydrochloric acid water (1200mL) and Ethyl acetate (60mL), and stirred over 3 h at 25 ~ 35 ℃. After completion of the reaction, it was added ethyl acetate (2400mL) in the same temperature. After the addition, it was added 25% aqueous ammonia (600mL) with cooling. After the addition stirring and extracted the organic layer of 5% aqueous ammonia (600mL) was added and stirred. After stirring, the resulting organic layer it was concentrated until the solvent no longer distilled off. After concentrated, dissolved with ethyl acetate (1500mL), and transferred to solution to the crystallizer vessel, and washed with ethyl acetate (750mL). After washing, it was raised in stirring under 45 ~ 55 ℃. After raising the temperature, at the same temperature 4N- hydrogen chloride – it was dropped ethyl acetate (131.3mL). After dropping, it was to dissolve the precipitate at the same temperature. After dissolution confirmation, it was added heptane (750mL) at 40 ~ 50 ℃, after the addition, then cooled to 25 ~ 35 ℃. After cooling, the addition of A-type crystals of the seed crystals (300mg) which was obtained according to the method described in Example 265 of WO2009 / 154300, and stirred for 30 minutes or more. After stirring, the temperature was raised to 40 ~ 45 ℃, it was dropped heptane (1500mL). After the completion of the dropping, it was stirred at the same temperature. Then gradually cooled to 5 ℃ below, followed by stirring at the same temperature for 1 hour. After stirring, ethyl acetate and filtered crystals – heptane: washed with (1 1,600mL), to obtain a wet crystal. The obtained wet crystals dried under reduced pressure at 50 ℃, 1- (4- methoxybutyl) -N- (2- methylpropyl) -N – [(3S, 5R) -5- (morpholin-4-yl carbonyl) piperidin-3-yl] -1H- obtained a crystalline powder of benzimidazole-2-carboxamide hydrochloride (A-type crystal, 198.82g, 74.1% yield).  FINAL PRODUCT

TERT BUTYL DERIVATIVE, N-1 

Reference Example 4
tert- butyl (3S, 5R) -3 – [{[1- (4- methoxy-butyl) -1H- benzoimidazol-2-yl] carbonyl} (2-methylpropyl) amino] -5- (morpholin-4- ylcarbonyl) piperidine-1-carboxylate 1)

o- nitro aniline (50.0g, 0.362mol), tetrabutylammonium bromide (58.3g, 0.181mol), potassium bromide (43.1g, 0.362mol) in toluene (500mL ) and it was added. At a temperature of 20 ~ 30 ℃ 1- chloro-4-methoxy-butane (66.6g, 0.543mol) and, I was added to 50w / v% sodium hydroxide solution (145mL, 1.81mol). The reaction was heated to a temperature 85 ~ 95 ℃, and stirred for 6 hours. After cooling to a temperature 20 ~ 30 ℃, the reaction mixture water (250mL), 1N- aqueous hydrochloric acid (250mL × 2), 5w / v% aqueous solution of sodium bicarbonate (250mL), it was washed successively with water (250mL). After concentration under reduced pressure the organic layer to Contents (250mL), was added toluene (100mL), was obtained

N- (4- methoxy-butyl) -2-nitroaniline in toluene (350mL, 100% yield).
1 H-NMR (300MHz, CDCl 3) δ 1.64-1.89 (m, 4H), 3.25-3.39 (m, 2H), 3.35 (s, 3H), 3.44 (t, J = 6.1 Hz, 2H), 6.63 ( ddd, J = 8.5, 6.9, 1.2 Hz, 1H), 6.86 (dd, J = 8.5, 1.2 Hz, 1H), 7.43 (ddd, J = 8.5, 6.9, 1.5 Hz, 1H), 8.07 (br s, 1H ), 8.17 (dd, J = 8.5, 1.5 Hz, 1H).

2) N- (4-methoxy-butyl) -2-10 percent in nitroaniline of toluene solution (350mL) Pd / C (K-type, 50% water-containing product) (10.0g) and toluene (100mL) it was added. Hydrogen pressure of 0.1MPa, it was stirred for 3 hours at a temperature of 20 ~ 30 ℃. A stream of nitrogen, the catalyst was filtered, I was washed with toluene (100mL). After the water in the filtrate was separated off and adding magnesium sulfate (25.0g) at a temperature 20 ~ 30 ℃, and stirred at the same temperature for 30 minutes. Filtered over magnesium sulfate, washed with toluene (100mL), was obtained N- (4- methoxybutyl) -o- toluene solution of phenylenediamine (100% yield).
1 H NMR (500 MHz, CDCl 3) δ1.67-1.78 (m, 4H), 3.12-3.14 (m, 2H), 3.32 (br, 3H), 3.35 (s, 3H), 3.41-3.47 (m, 2H), 6.63-6.69 (m, 2H), 6.69-6.74 (m, 1H), 6.82 (td, J = 7.57, 1.58 Hz, 1H).

3) N- (4- methoxy-butyl) -o- After the toluene solution of phenylenediamine cooled to a temperature 0 ~ 10 ℃, acetic acid (65.2g, 1.09mol) and 2,2,2 trichloroacetimide acid methyl ( 70.3g, 0.398mol) and I were added. After stirring for 30 minutes at a temperature 0 ~ 10 ℃, it was stirred for 3 hours at a temperature of 20 ~ 30 ℃. The reaction was 5w / v% saline (250mL), 2N- aqueous hydrochloric acid / 5w / v% sodium chloride solution: a mixture of (1 1) (250mL × 2), 5w / v% aqueous solution of sodium bicarbonate (250mL), 5w / v It was washed successively with% saline solution (250mL). A stream of nitrogen, was added magnesium sulfate (25.0g) to the organic layer at a temperature 20 ~ 30 ℃, and stirred at the same temperature for 30 minutes. Filtered magnesium sulfate, and washed with toluene (100mL). The filtrate was concentrated under reduced pressure and the amount of contents (150mL). Stir the concentrated solution at a temperature 20 ~ 30 ℃, was allowed to precipitate crystals, was added dropwise heptane (750mL). The crystals bleeding is heated to a temperature 40 ~ 50 ℃, after stirring for 30 min, cooled to a temperature 0 ~ 10 ℃, and the mixture was stirred at the same temperature for 2 hours.The precipitated crystals were collected by filtration, toluene – heptane: was washed with (1 5,150 mL). And dried under reduced pressure at 40 ℃, it was obtained 1- (4-methoxy-butyl) -2-fine brown crystals of trichloromethyl -1H- benzimidazole (96.5g, 82.9% yield from o- nitroaniline).
1 H-NMR (300MHz, CDCl 3) δ: 1.68-1.85 (m, 2H), 1.99-2.17 (m, 2H), 3.37 (s, 3H), 3.48 (t, J = 6.1 Hz, 2H), 4.50 -4.65 (m, 2H), 7.27-7.49 (m, 4H), 7.82-7.93 (m, 1H).
. Anal Calcd for C 13 H 15 Cl 3 N 2 O:. C, 48.55; H, 4.70; N, 8.71; Cl, 33.07 Found: C, 48.30; H, 4.61; N, 8.74; Cl, 33.30.

4) pyridine-3,5-dicarboxylic acid (110g, 0.66mol), it was dropped methanol (660 mL) mixture of concentrated sulfuric acid at a temperature of 50 ℃ or less of (226.0g, 2.30mol). Thereafter, the mixture was stirred and heated to a temperature 55 ~ 65 ℃ 7 hours. The reaction was the temperature 40 ~ 50 ℃, was added water (220mL). And further dropping temperature 40-50 5% aqueous ammonia at ℃ (about 1.10L) was adjusted to pH8.0 ~ 8.5. After stirring at a temperature 40 ~ 50 ℃ 30 minutes and stirred for 1 hour and cooled to a temperature 0 ~ 10 ℃. Was collected by filtration precipitated crystals, methanol – water (1: 3,165mL), and washed successively with water (440mL). To obtain a white crystalline powder pyridine-3,5-dicarboxylic acid dimethyl and dried under reduced pressure at 50 ℃ (105.0g, 82.0% yield).
1 H-NMR (300 MHz, CDCl 3) δ 4.00 (s, 6H), 8.87 (s, 1H), 9.37 (s, 2H).
. Anal Calcd for C 9 H 9 NO 4:. C, 55.39; H, 4.65; N, 7.18; O, 32.79 Found: C, 55.42; H, 4.65; N, 7.16.

5) 1 L autoclave pyridine-3,5-dicarboxylic acid dimethyl (100g, 0.51mol) and was charged with dimethylacetamide (400mL), temperature 30 ℃ below with trifluoroacetic acid (59.2mL, after dropping the 0.77mol), 10% Pd-C (PE-type) the (20.0g) it was added. Hydrogen pressure of 0.5 ~ 0.7MPa, it was stirred for 12 hours at a temperature of 55 ~ 65 ℃. The catalyst was filtered off, it was washed with dimethylacetamide (50mL × 2). Triethylamine and the combined filtrates at a temperature 20 ~ 30 ℃ (77.8g, 0.77mol) was added dropwise, and adjusted to pH9.0 ~ 10.0. Temperature 30 ~ 40 ℃ by di -tert- butyl (134g, 0.614mol) was added dropwise and stirred at the same temperature for 2 hours. After the reaction mixture as a 20 ~ 30 ℃, it was added ethyl acetate (600mL), washed with water (900mL). The aqueous layer it was re-extracted with ethyl acetate (400mL). The combined organic layers 5w / v% citric acid -10w / v% sodium chloride solution (600mL), 3% aqueous sodium bicarbonate (600mL), and washed successively with water (600mL). Contents The organic layer (200mL) until it was concentrated under reduced pressure, methanol (250mL) was added to the concentrated solution, and then concentrated under reduced pressure until Contents (200mL). The addition of methanol (250mL) again concentrate, After concentration under reduced pressure until Contents (200mL), was added methanol (2.40L). The solution in water (18.5g, 1.03mol), cesium carbonate (417g, 1.28mol) was added and stirred for about 24 hours at a temperature 55 ~ 65 ℃. The reaction solution was the temperature 20 ~ 30 ℃, concentrated to Contents (700mL), it was added tetrahydrofuran (500mL). The solution temperature at 15 ~ 35 ℃ 2N- hydrochloric acid solution (1.28L, 2.56mol) was added dropwise and adjusted to pH3.0 ~ 3.5, and the mixture was stirred for 30 minutes at a temperature 20 ~ 30 ℃. Extracted with ethyl acetate (750mL × 2), and the organic layer was washed with 10w / v% aqueous sodium chloride solution (500mL × 3). Contents The organic layer (300mL) until it was concentrated under reduced pressure, to obtain a weight content by adding ethyl acetate (650mL).Heating the concentrate to a temperature of 55 ~ 65 ℃, it was added dropwise heptane (500mL). It cooled to a temperature 20 ~ 30 ℃ and stirred for 1 hour. The precipitated crystals were collected by filtration, ethyl acetate – heptane: was washed with (1 1,120mL). Dried under reduced pressure at 50 ℃ 1- (tert- butoxycarbonyl) to give a white crystalline powder of piperidine-3,5-dicarboxylic acid (113.3g, 80.9% yield).
1 H-NMR (300 MHz, DMSO-d 6) δ 1.40 (s, 9H), 1.44-1.61 (m, 1H), 2.21-2.26 (m, 1H), 2.31-2.41 (m, 2H), 4.10- 4.12 (m, 2H).
. Anal Calcd for C 12 H 19 NO 6:. C, 52.74; H, 7.01; N, 5.13; O, 35.13 Found: C, 52.96; H, 6.99; N, 5.39.

6) Under a nitrogen stream, 1- (tert- butoxycarbonyl) piperidine-3,5-dicarboxylic acid (5.00g, 18.3mmol) was suspended in tetrahydrofuran (10.0mL), trifluoroacetic acid anhydride at a temperature 20 ~ 30 ℃ It was dropping things (3.80mL, 27.5mmol). After the completion of the dropping, it was stirred for 1 hour at a temperature of 20 ~ 30 ℃. It was added dropwise heptane (20.0mL) at a temperature 20 ~ 30 ℃ the reaction solution, and stirred for 3 hours then cooled to a temperature 0 ~ 10 ℃. The precipitated crystals were collected by filtration, and washed with heptane (3.00mL). Dried under reduced pressure at 40 ℃ 2,4- dioxo-3-oxa-7-azabicyclo [3,3,1] white crystalline powder of nonane-7-carboxylic acid tert- butyl was obtained (4.03g, yield 86.1%).
1 H-NMR (300 MHz, CDCl 3) δ 1.43 (s, 9H), 1.93-1.99 (m, 1H), 2.40-2.46 (m, 1H), 3.06-3.11 (m, 4H), 4.50-4.54 ( m, 2H).
. Anal Calcd for C 12 H 17 NO 5:. C, 56.46; H, 6.71; N, 5.49; O, 31.34 Found: C, 56.51; H, 6.63; N, 5.69.

7) Under a nitrogen stream, quinidine (69.9g, 0.215mol) and was charged with tetrahydrofuran (200mL), and cooled to a temperature -5 ~ 5 ℃. At the same temperature 2,4-dioxo-3-oxa-7-azabicyclo [3,3,1] nonane-7-carboxylic acid tert- butyl (50.0g, 0.196mol) was added and washed with tetrahydrofuran (50.0mL) crowded. Temperature -5 ~ 5 methanol at ℃ (9.41g, 0.29 4mol) was added dropwise, and the mixture was stirred for 2 hours at a temperature -5 ~ 5 ℃. Ethyl acetate (350mL) to the reaction mixture, was by adding minute solution 20w / v% citric acid aqueous solution (250mL). The aqueous layer it was re-extracted with ethyl acetate (125mL × 2). The organic layers were combined 20w / v% aqueous solution of citric acid (250mL), I was washed successively with water (250mL × 2). The organic layer it was concentrated under reduced pressure. To the residue ethanol (100mL) was added ethyl acetate (450mL) was heated to a temperature 60 ~ 70 ℃, (R) – was added phenethylamine (23.7g, 0.196mol). Temperature 50-60 for one hour at ℃, 1 hour at a temperature of 20 ~ 30 ℃, it was stirred for 1 hour at a temperature of -5 ~ 5 ℃. The precipitated crystals were collected by filtration, ethanol – ethyl acetate: and washed with (2 9,100mL). And dried under reduced pressure at 50 ℃ (3S, 5R) -1- (tert- butoxycarbonyl) -5- (methoxycarbonyl) piperidin-3 to give a white crystalline powder of the carboxylic acid (1R) -1- phenylethylamine salt It was (55.7g, 69.6% yield).
1 H-NMR (300 MHz, DMSO-d 6) δ 1.42 (s, 9H), 1.43-1.51 (m, 3H), 2.06-2.14 (m, 1H), 2.21-2.26 (m, 1H), 2.39- 2.44 (m, 1H), 2.52-2.53 (m, 1H), 2.57 (br s, 2H), 3.64 (s, 3H), 4.12 (br s, 2H), 4.19-4.26 (m, 1H), 7.30- 7.40 (m, 3H), 7.45-7.48 (m, 2H).
. Anal Calcd for C 21 H 32 N 2 O 6:. C, 61.75; H, 7.90; N, 6.86; O, 23.50 Found: C, 61.54; H, 7.77; N, 6.86.

8) (3S, 5R) -1- (tert- butoxycarbonyl) -5- (methoxycarbonyl) piperidine-3-carboxylic acid (1R) -1- phenylethylamine salt (20.0g, 49.0mmol), methanol (20mL) and it was charged with water (80mL). Temperature 20-30 citric acid at ℃ (11.3g, 58.8mmol) was added dropwise a solution prepared by dissolving in water (20.0mL), and the mixture was stirred 1.5 hours at the same temperature. The precipitated crystals were collected by filtration and washed with water (60mL). And dried under reduced pressure at 50 ℃ (3S, 5R) -1- (tert- butoxycarbonyl) -5- give a white crystalline powder (methoxycarbonyl) piperidine-3-carboxylic acid (13.5g, 96.1% yield ).
1 H-NMR (300 MHz, CDCl 3) δ 1.40 (s, 9H), 1.46-1.59 (m, 1H), 2.22-2.27 (m, 1H), 2.37-2.45 (m, 2H), 2.63-2.73 ( m, 2H), 3.63 (s, 3H), 4.14 (br s, 2H), 12.51 (br s, 1H).
. Anal Calcd for C 13 H 21 NO 6:. C, 54.35; H, 7.37; N, 4.88; O, 33.41 Found: C, 54.14; H, 7.28; N, 4.85.

9) Under a nitrogen stream, (3S, 5R) -1- (tert- butoxycarbonyl) -5- (methoxycarbonyl) piperidine-3-carboxylic acid (30.0g, 104mmol), triethylamine (31.7g, 313mmol) and toluene ( It was charged with 180mL). Diphenylphosphorylazide at a temperature of 15 ~ 35 ℃ (28.7g, 313mmol) I was dropped a toluene (30.0mL) solution. After stirring at a temperature 30 ± 5 ℃ 30 minutes, and the mixture was stirred and heated to a temperature 65 ~ 75 ℃ 30 minutes. Temperature 60 ~ 70 ℃ in the benzyl alcohol (12.4g, 115mmol) it was dropped. To a temperature 80 ~ 90 ℃ was stirred and heated for 3 hours. The reaction mixture was cooled to a temperature 20 ~ 30 ℃, sodium nitrite (7.20g, 104mmol) and after stirring was added a solution prepared by dissolving in water (150mL) 1 hour, the aqueous layer was separated. The organic layer 5w / v% aqueous sodium bicarbonate solution (150mL), 20w / v% aqueous citric acid solution (150mL), washed successively with 5w / v% aqueous sodium chloride solution (150mL), the organic layer was concentrated under reduced pressure. The residue methanol (60.0mL) was added and concentrated under reduced pressure to. The more we went once in the same manner.To the residue was added methanol and the content amount of the (90.0g). Temperature 15 ~ 35 ℃ 2N- aqueous sodium hydroxide (62.6mL, 125mmol) was added and stirred for 1 hour at a temperature 30 ± 5 ℃. Temperature 20 ~ 30 ℃ in methanol (120mL), was added to 20w / v% aqueous citric acid solution (300mL), it was a pH3.0 ~ 3.5. After stirring for 30 minutes at a temperature 50 ~ 60 ℃, cooled to a temperature 20 ~ 30 ℃ and stirred for 1 hour. It was stirred for 1 hour at the temperature 0 ~ 10 ℃. The precipitated crystals were collected by filtration, and washed with water (90.0mL). And dried under reduced pressure at 50 ℃ (3R, 5S) -5 – {[(benzyloxy) carbonyl] amino} -1- (tert- butoxycarbonyl) to yield a white crystalline powder piperidine-3-carboxylic acid (35.0 g, 88.6% yield).
1 H-NMR (300 MHz, DMSO-d 6) δ 1.41 (s, 9H), 2.11 (d, J = 12.4 Hz, 1H), 2.40-2.48 (m, 4H), 2.62 (br s, 1H), 4.08 (t, J = 14.4 Hz, 2H), 5.04 (s, 2H), 7.31-7.41 (m, 5H), 12.53 (br s, 1H).
. Anal Calcd for C 19 H 26 N 2 O 6:. C, 60.30; H, 6.93; N, 7.40; O, 25.37 Found: C, 60.03; H, 6.99; N, 7.41.

10) Under a nitrogen stream, (3R, 5S) -5 – {[(benzyloxy) carbonyl] amino} -1- (tert- butoxycarbonyl) piperidine-3-carboxylic acid (30.0g, 79.3mmol), morpholine (7.60 g, 87.2mmol), 1- hydroxybenzotriazole monohydrate (2.43g, it was charged with 15.9mmol) and dimethylacetamide (90.0mL). Hydrochloride 1-ethyl at a temperature 20 ~ 30 ℃ -3- (3- dimethylaminopropyl) carbodiimide (16.7g, 87.1mmol) after addition and stirred for 1 hour at a temperature 45 ~ 55 ℃. Temperature 45 ~ 55 ℃ with tetrahydrofuran (90.0mL), sequentially dropwise addition of water (210mL), and stirred for 1 hour. After stirring for 1 hour and cooled to a temperature 20 ~ 30 ℃, were collected by filtration the precipitated crystals, tetrahydrofuran – water: washing with (1 3,120mL). And dried under reduced pressure at 50 ℃ tert- butyl piperidine -1- (3S, 5R) -3 – a white crystalline powder of {[(benzyloxy) carbonyl] amino} -5 (morpholin-4-yl-carbonyl) carboxylate It was obtained (32.7g, 92.3% yield).
1 H-NMR (300 MHz, DMSO-d 6) δ 1.41 (s, 9H), 1.49-1.57 (m, 1H), 1.87 (d, J = 12.3 Hz, 1H), 2.43 (br s, 1H), 2.63-2.71 (m, 1H), 2.79-2.83 (m, 1H), 3.37-3.54 (m, 9H), 3.89 (d, J = 11.5 Hz, 1H), 4.06 (br s, 1H), 5.03 (s , 2H), 7.30-7.38 (m, 5H).
. Anal Calcd for C 23 H 33 N 3 O 6:. C, 61.73; H, 7.43; N, 9.39; O, 21.45 Found: C, 61.59; H, 7.50; N, 9.43.

11) tert- Butyl piperidin -1- (3S, 5R) -3 – {[(benzyloxy) carbonyl] amino} -5- (morpholin-4-ylcarbonyl) carboxylate (30.0g, 67.0mmol), isobutyraldehyde (7.25g, 101mmol), it was charged with 10% Pd-C (PE type) (1.50g) and methanol (240mL).Hydrogen pressure of 0.2 ~ 0.3MPa, it was stirred for 4 hours at a temperature of 20 ~ 30 ℃. The catalyst is filtered off and washed with methanol (60.0mL). The filtrate was concentrated under reduced pressure, ethyl acetate was added (60.0mL), and concentrated under reduced pressure again. The residue ethyl acetate was added, followed by the amount of contents (360mL). Temperature 45-55 succinate by heating to ℃ (7.90g, 67.0mmol) was added. After stirring for 1 hour at a temperature 45 ~ 55 ℃, cooled to a temperature 20 ~ 30 ℃, and stirred for 1 hour. The precipitated crystals were collected by filtration, and washed with ethyl acetate (90.0mL). And dried under reduced pressure at 50 ℃ tert- butyl (3S, 5R) -3 – [(2- methyl-propyl) amino] -5- (morpholin-4-yl-carbonyl) piperidine – 1-carboxylate white crystals of alert succinate got sex powder (30.2g, 92.5% yield).
1 H-NMR (300 MHz, D 2 O) δ 1.02 (s, 3H), 1.04 (s, 3H), 1.47 (s, 9H), 1.97-2.09 (m, 2H), 2.26-2.30 (m, 1H ), 2.55 (s, 4H), 2.99 (d, J = 7.0 Hz, 2H), 3.23 (br s, 1H), 3.39-3.45 (m, 2H), 3.53-3.80 (m, 10H), 3.82-3.93 (br s, 1H).
. Anal Calcd for C 23 H 41 N 3 O 8:. C, 56.66; H, 8.48; N, 8.62; O, 26.25 Found: C, 56.48; H, 8.46; N, 8.39.

12) tert- Butyl (3S, 5R) -3 – [(2- methylpropyl) amino] -5- (morpholin-4-ylcarbonyl) piperidine – 1 – carboxylate succinate (30.3g, 62.2mmol), acetonitrile (60.0mL) and, it was charged with water (40.0mL). Then after stirring was added potassium carbonate (34.4g, 0.249mmol) 10 minutes, 1- (4-methoxybutyl) -2-trichloromethyl -1H- benzimidazole (20.0g, 62.2mmol) was added. After stirring for 2 hours at a temperature of 70 ~ 80 ℃, it was added dimethyl sulfoxide (15.0mL), and the mixture was stirred for 6 hours at a temperature 70 ~ 80 ℃. After cooling the reaction mixture to a temperature 20 ~ 30 ℃, water (120mL), it was separated and by adding toluene (240mL). The organic layer 10w / v% sodium chloride solution (100mL), 10w / v% aqueous solution of citric acid (100mL), it was washed sequentially with 10w / v% sodium chloride solution (100mL). The organic layer of activated carbon Shirasagi A a (1.0g) was added, and the mixture was stirred for 30 minutes at a temperature 20 ~ 30 ℃. Activated carbon was filtered, washed with toluene (40.0mL), and concentrated under reduced pressure of the filtrate to 110 mL. By heating to a temperature 35 ~ 45 ℃ was added dropwise heptane (280mL). At a temperature 35 ~ 45 ℃ tert- butyl (3S, 5R) -3 – [{[1- (4- methoxy-butyl) -1H- benzoimidazol-2-yl] carbonyl} (2-methylpropyl) amino] -5 – and the mixture was stirred for 1 hour at (morpholin-4-ylcarbonyl) piperidine-1-carboxylate was added to the same temperature the crystals (10mg) of the acrylate. Heptane (140mL) was stirred and added dropwise to 30 minutes at a temperature 35 ~ 45 ℃. It was cooled to a temperature 20 ~ 30 ℃ and stirred for 2 hours. The precipitated crystals were collected by filtration, toluene – heptane: was washed with (1 5,40.0mL). And dried under reduced pressure at 50 ℃ tert- butyl (3S, 5R) -3 – [{[1- (4- methoxy-butyl) -1H- benzoimidazol-2-yl] carbonyl} (2-methylpropyl) amino] – 5- (morpholin-4-ylcarbonyl) piperidine-1-carboxylate was obtained a pale yellowish crystalline powder of alert (27.7g, 74.2% yield).
1 H-NMR (300 MHz, CDCl 3) δ 0.68-0.80 (m, 3H), 0.96-1.08 (m, 3H), 1.31 (br s, 5H), 1.49 (s, 4H), 1.61-1.71 (m , 2H), 1.71 (br s, 0.5H), 1.92-2.05 (m, 3H), 2.05-2.24 (m, 2H), 2.45 (br s, 1H), 2.60 (br s, 1H), 2.72-2.96 (m, 2H), 3.26-3.35 (m, 3H), 3.35-3.47 (m, 2H), 3.47-3.73 (m, 10H), 4.02-4.26 (m, 2H), 4.26-4.34 (m, 1H) , 4.34-4.47 (m, 0.5H), 7.25-7.29 (m, 1H), 7.29-7.41 (m, 1H), 7.41-7.53 (m, 1H), 7.64 (br s, 0.5H), 7.79 (d , J = 8.2 Hz, 0.5H).
. Anal Calcd for C 32 H 49 N 5 O 6:. C, 64.08; H, 8.23; N, 11.68; O, 16.01 Found: C, 63.82; H, 8.12; N, 11.64.

PATENT

WO 2015156346

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=AEE60471E3EF3D2BBE2D20033D4D0CD7.wapp2nC?docId=WO2015156346&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=FullText

TAKEDA PHARMACEUTICAL COMPANY LIMITED [JP/JP]; 1-1, Doshomachi 4-chome, Chuo-ku, Osaka-shi, Osaka 5410045 (JP)

Provided is a method for producing a synthetic intermediate of a heterocyclic compound having a renin inhibitory activity and effective as a prophylactic or therapeutic drug against diabetic renal disease, hypertension, and the like. A method for producing a compound represented by formula (III-1a), (III-1b), (III-1c), and/or (III-1d) [where the symbols in the formulas are as defined in the description], or a salt thereof, said method characterized in that a compound represented by formula (Ia) or (Ib) [where the symbols in the formulas are as defined in the description] or a salt thereof is reacted with a compound represented by formula (II) [where the symbols in the formula are as defined in the description] or a salt thereof in the presence of an aluminum compound and a chiral amine compound.

in Patent Document 1, a method for producing a synthetic intermediate of the above heterocyclic compound, the following methods are disclosed.
Formula 2]

In the above method, the acid anhydride (BANC) from chiral dicarboxylic acid monoester ((-) – BMPA) were synthesized and then the carboxylic acid after conversion and hydrolysis reaction of the Z amine by the Curtius rearrangement of the carboxylic acid (BAPC) and it was then performs amidation by the condensation reaction with the amine (morpholine), is synthesized heterocyclic amide compound (BMPC). Further, Patent Document 2, the preparation of compounds useful as synthetic intermediates of the above heterocyclic compounds are disclosed.[Formula 3]

(Wherein each symbol is as described in Patent Document 2.)

 TABLE In the above method, the acid anhydride of the formula (VI), in the presence of a chiral amine with the formula (VIIa) or (VIIb) is to produce a chiral dicarboxylic acid monoester compound, then reacted with an amine (R1-NH-R2) is subjected to amidation to, to produce a heterocyclic amide compound of the formula (VIII).

Prior art documents

Patent literaturePatent Document 1: Patent No. 4,800,445 Patent

Patent Document 2: International Publication No. 2007/077005
Reference Example 1
3-oxabicyclo [3.3.1] nonane-2,4-dione
reaction vessel (1R, 3S) – was added to cyclohexane-1,3-dicarboxylic acid (10g) and THF (20mL), 5 It was cooled to ℃. It was added dropwise trifluoroacetic anhydride (8.19mL), and the mixture was stirred for about 1 hour. The reaction mixture was allowed to warm to room temperature, heptane (20mL) was added, up to 5 ℃ was cooled and stirred for about 30 minutes. The precipitate was filtered off, washed with heptane to give the title compound. Yield (6.7g)
Reference Example 2
(3S, 5R) – tert – butyl 3- (isobutyl-amino) -5- (morpholine-4-carbonyl) piperidine-1-carboxylic acid ester succinate
reactor in THF (240ml), (3S, 5R) -1- (tert – butoxycarbonyl) -5- (morpholine-4-carbonyl) piperidine-3-carboxylic acid (20.0g), triethylamine (12.2mL) and diphenylphosphoryl azide (15.1mL) They were charged and allowed to react for 1 hour at 60 ℃, cooled to 25 ℃. After cooling the THF (60ml) and sodium trimethyl silanolate (19.7g) to charged 0 ℃ separately reaction vessel, was added dropwise to this was allowed to react before the reaction solution over about 1 hour, 0 at 0 ℃. 5 hours it was allowed to react. 0 slowly added dropwise acetic acid (40mL) at ℃, After stirring for 10 minutes, was added ethanol (60ml) and isobutyraldehyde (5.3mL) at 25 ℃, and stirred for 10 minutes. Then added sodium borohydride (1.88g), and the mixture was stirred for 30 minutes, and further addition of sodium borohydride (1.88g) at 25 ℃, and the mixture was stirred for 30 minutes. After completion of the reaction, water (100mL) was added and stirred for 10 minutes at room temperature. The organic layer was concentrated, then added dropwise slowly toluene (140ml) and 5N aqueous sodium hydroxide solution (120ml), the layers were separated. After washing and addition of aqueous 1N sodium hydroxide (100ml) the organic layer was washed 1N aqueous sodium hydroxide (100ml) was added again organic layer. The aqueous layers were combined and extracted by addition of toluene (100ml). The organic layers were combined, washed with 10w / v% aqueous sodium chloride solution (100ml), and the organic layer was concentrated. It was added ethanol (100ml), after it was concentrated under reduced pressure until about 60ml, warmed to 60 ℃ by the addition of ethyl acetate (40ml). Was added succinic acid (6.9g), After stirring for 30 minutes, it was added dropwise ethyl acetate (200ml) at 60 ℃, and stirred for 30 minutes. After stirring for 1 hour at room temperature, and the mixture was stirred for 1 hour at 0 ℃. The crystals were collected by filtration and washed with a mixture of ethyl acetate / n-heptane (6/1) (60mL). The obtained crystals at an external temperature of 50 ℃ to constant weight and then dried under reduced pressure to give the title compound as almost white crystals. Yield (22.8g)
Example 1
(3S, 5R) -1- (tert – butoxycarbonyl) -5- (morpholin-4-ylcarbonyl) piperidine-3-carboxylic acid
the reaction vessel in chlorobenzene (7.5mL) and quinine (0.70g ) is added and stirred, it was added dropwise DIBAL1.0M hexane solution (2.16mL). The reaction mixture was cooled to -40 ℃, tert – butyl 2,4-dioxo-3-oxa-7-azabicyclo [3.3.1] was added nonane-7-carboxylic acid ester (0.50g), about 1 hour stirring. Was added chlorobenzene to another reaction vessel (2.5mL) and morpholine (0.17mL), the resulting solution was cooled to -40 ℃ was added dropwise to the previous reaction solution. After completion of the reaction, the mixture was separated with ethyl acetate and 10w / w% aqueous citric acid solution, and the resulting aqueous layer was re-extracted with ethyl acetate. The organic layers were combined, washed with 10w / w% saline, and concentrated to give the title compound. 1 H NMR (500 MHz, DMSO-D 6 ) delta ppm 1.41 (s, 9 H), 1.47 – 1.72 (M, 1 H), 1.89 – 2.10 (M, 1 H), 2.36 – 2.49 (M, 1 H ), 2.55 – 2.83 (m, 3 H), 3.40 – 3.50 (m, 2 H), 3.51 -.. 3.57 (m, 4 H), 3.59 (br s, 2 H), 3.83 – 4.04 (m, 1 H), 4.05 – 4.29 (m, 1 H), 12.52 (s, 1 H) optical purity of 94.3% EE <HPLC analytical conditions> column: CHIRALPAK IC (Co., Ltd. Daicel) column temperature: constant around 15 ℃ Temperature Mobile phase: A solution) 0.02 mol / L KH 2 PO 4 buffer solution (pH3.0): acetonitrile = 70: 30    B solution) 0.02 mol / L KH 2 PO 4 buffer solution (pH3.0): acetonitrile = 50 : 50 gradient program
Example 30 (1R, 3S) -3- (morpholin-4-ylcarbonyl) cyclopentanecarboxylic acid
(anhydride: 3-oxabicyclo [3.2.1] octane-2,4-dione; Amine: Morpholine ) 1 H NMR (500 MHz, DMSO-D 6 ) delta ppm 1.72 – 1.91 (M, 5 H), 2.04 (dt, J = 12.69, 7.84 Hz, 1 H), 2.65 – 2.74 (M, 1 H), 2.99 – 3.07 (m, 1 H), 3.42 – 3.51 (m, 4 H), 3.51 – 3.58 (m, 4 H), 11.96 – 12.17 (m, 1 H) optical purity of 52.3% EE <HPLC analysis conditions > column: CHIRALPAK IF (Co., Ltd. Daicel) column temperature: 15 ℃ constant temperature in the vicinity ofmobile phase: A solution) 0.02 mol / LKH 2 PO 4 buffer solution (pH3.0): acetonitrile = 70: 30     B solution) 0.02 mol / LKH 2 PO 4 buffer solution (pH3.0): acetonitrile = 50: 50 gradient Program
WO2010150840A1 24 Jun 2010 29 Dec 2010 Dainippon Sumitomo Pharma Co., Ltd. N-substituted-cyclic amino derivative
WO2011158880A1 15 Jun 2011 22 Dec 2011 Takeda Pharmaceutical Company Limited Crystal of amide compound
WO2012062687A1 * 7 Nov 2011 18 May 2012 F. Hoffmann-La Roche Ag Triazole derivatives and their use for neurological disorders
WO2013122260A1 14 Feb 2013 22 Aug 2013 Takeda Pharmaceutical Company Limited Tablet
CN103221402B * 7 Nov 2011 17 Jun 2015 霍夫曼-拉罗奇有限公司 三唑衍生物及其用于神经障碍的用途
US8329691 14 Oct 2008 11 Dec 2012 Takeda Pharmaceutical Company Limited Amide compounds and use of the same
US8389511 19 Dec 2008 5 Mar 2013 Dainippon Sumitomo Pharma Co., Ltd. Bicyclic heterocyclic derivative
US8658639 24 Jun 2010 25 Feb 2014 Dainippon Sumitomo Pharma Co., Ltd N-substituted-cyclic amino derivative
US8742097 2 Nov 2011 3 Jun 2014 Hoffmann-La Roche Inc. Triazole compounds I
US9018374 15 Jun 2011 28 Apr 2015 Takeda Pharmaceutical Company Limited Crystal of amide compound
US9090601 28 Jan 2010 28 Jul 2015 Millennium Pharmaceuticals, Inc. Thiazole derivatives

///////////TAK 272, Hypertension

Share

Lusutrombopag….Oral thrombopoietin (TPO) mimetic

 Phase 3 drug, Uncategorized  Comments Off on Lusutrombopag….Oral thrombopoietin (TPO) mimetic
Aug 202015
 

 

 LUSUTROMBOPAG.png

Lusutrombopag

(E)-3-[2,6-dichloro-4-[[4-[3-[(1S)-1-hexoxyethyl]-2-methoxyphenyl]-1,3-thiazol-2-yl]carbamoyl]phenyl]-2-methylprop-2-enoic acid

(S)-(-)-(E)-3-(2,6-dichloro-4-{4-[3-(1-hexyloxyethyl)-2-methyloxyphenyl]thiazol-2-ylcarbamoyl}phenyl)-2-methylacrylic acid

(2E)-3-{2,6-Dichloro-4-[(4-{3-[(1S)-1-(hexyloxy)ethyl]-2-methoxyphenyl}-1,3-thiazol-2-yl)carbamoyl]phenyl}-2-methylacrylic acid

UNII 6LL5JFU42F,  CAS 1110766-97-6,

D10476, MW591.546 , [US2010267783], MF C29H32Cl2N2O5S, S-888711

Shionogi & Co., Ltd.塩野義製薬株式会社 INNOVATOR

Optically active compound (C-3B)  Melting point: 142-145°C………….EP2184279B1

NMR (DMSO-d6) δ ppm: 12.97 (brs, 1H), 8.29 (s, 2H), 7.90 (dd, 1H, J = 1.8 Hz, 7.5 Hz), 7.72 (s, 1H), 7.35 – 7.40 (m, 2H), 7.26 (t, 1H, J = 7.5 Hz), 4.82 (q, 1H, J = 6.3 Hz), 3.62 (s, 3H), 3.16 – 3.37 (m, 2H), 1.69 (s, 3H), 1.18 – 1.51 (m, 11H), 0.82-0.87 (m, 3H) Optical rotation -4.5 degrees (DMSO, c = 1.001, 25°C)………….EP2184279B1

Optical rotation: -7.0 ± 0.5 degrees (CHCl3, c = 1.040, 21°C), NMR (CDCl3) δ ppm: 0.87 (3H, t, J = 6.8 Hz), 1.2 – 1.4 (6H, m), 1.48 (3H, d, J = 6.4 Hz), 1.52 – 1.64 (2H, m), 1.86 (3H, d, J = 1.4Hz)), 3.35 (2H, t, J = 6.7Hz), 3.55 (3H, s), 4.87 (1H, q, J = 6.3 Hz), 7.25 (1H, t, J = 7.7 Hz), 7.41 (1H, s), 7.49 (1H, dd, J = 7.9 Hz, J = 1.6 Hz), 7.51 (1H, dd, J = 7.5 Hz, J = 1.8 Hz), 7.65 (1H, d, J = 1.4 Hz), 8.33 (2H, s), 13.4 (2H, brs)………EP2184279B1

 

Thrombopoietin receptor agonist, Oral thrombopoietin (TPO) mimetic

  • 24 Mar 2015 Shionogi plans a phase III trial in Thrombocytopenia (in patients with chronic liver disease) in USA (NCT02389621)
  • 31 Dec 2014 Preregistration for Thrombocytopenia in Japan (PO)
  • 08 Nov 2013 Phase II development is ongoing in the US and the Europe

Process for preparing intermediates of an optically active 1,3-thiazole containing thrombopoietin receptor agonist  Also claims crystalline forms of lusutrombopag intermediates and a process for preparing lusutrombopag. Shionogi is developing lusutrombopag, a small-molecule thrombopoietin mimetic, as an oral tablet formulation for treating thrombocytopenia.

In December 2014, an NDA was submitted in Japan. In May 2015, the drug was listed as being in phase III development for thrombocytopenia in the US and Europe.

  

 

The lusutrombopag, a low molecular-human thrombopoietin receptor agonist, its chemical formula, “(E) -3- [2,6-Dichloro-4- [4- [3 – [(S) -1-hexyloxyethyl] – 2-methoxyphenyl] -thiazol- 2-ylcarbamoyl] -phenyl] is a -2-methylacrylic acid “. lusutrombopag is represented by the following chemical structural formula.

 

Figure JPOXMLDOC01-appb-C000001

 

Eltrombopag is represented by the following chemical structural formula.

Figure JPOXMLDOC01-appb-C000002

 

Avatrombopag is represented by the following chemical structural formula.

Figure JPOXMLDOC01-appb-C000003

 

 

Totrombopag choline is represented by the following chemical structural formula.

Figure JPOXMLDOC01-appb-C000004
C 3B IS THE COMPD OF ROT (-) AND S, E  FORM
Figure imgb0009
      Example 2 Synthesis of (R)-(E)-3-(2,6-dichloro-4-{4-[3-(1-hexyloxyethyl)-2-methyloxyphenyl]thiazol-2-ylcarbamoyl}phenyl)-2-methylacrylic acid (C-3A) (not included in the present invention) and (S)-(-)-(E)-3-(2,6-dichloro-4-{4-[3-(1-hexyloxyethyl)-2-methyloxyphenyl]thiazol-2-ylcarbamoyl}phenyl)-2-methylacrylic acid (C-3B)

    • According to the same method as in Example 1, an optically active compound (C-3A) and an opticallly active compound (C-3B) were synthesized from (RS)-(E)-3-(2,6-dichloro-4-{4-[3-(1-hexyloxyethyl)-2-methyloxyphenyl]thiazol-2-ylcarbamoyl}phenyl)-2-methylacrylic acid (B-3) obtained in Reference Example 3.

Optically active compound (C-3A)Melting point: 139-141°C   UNDESIRED

    • NMR (DMSO-d6) δ ppm: 12.97 (brs, 1H), 8.29 (s, 2H), 7.90 (dd, 1H, J = 1.8 Hz, 7.5 Hz), 7.72 (s, 1H), 7.35 – 7.40 (m, 2H), 7.26 (t, 1H, J = 7.5 Hz), 4.82 (q, 1H, J = 6.3 Hz), 3.62 (s, 3H), 3.16 – 3.37 (m, 2H), 1.69 (s, 3H), 1.18 – 1.51 (m, 11H), 0.82 – 0.87 (m, 3H) Optical rotaion +4.5 degrees (DMSO, c = 1.001, 25°C)

Optically active compound (C-3B)Melting point: 142-145°C  DESIRED

  • NMR (DMSO-d6) δ ppm: 12.97 (brs, 1H), 8.29 (s, 2H), 7.90 (dd, 1H, J = 1.8 Hz, 7.5 Hz), 7.72 (s, 1H), 7.35 – 7.40 (m, 2H), 7.26 (t, 1H, J = 7.5 Hz), 4.82 (q, 1H, J = 6.3 Hz), 3.62 (s, 3H), 3.16 – 3.37 (m, 2H), 1.69 (s, 3H), 1.18 – 1.51 (m, 11H), 0.82-0.87 (m, 3H) Optical rotation -4.5 degrees (DMSO, c = 1.001, 25°C)
      Example 4: Synthesis of (C-3B)

    • Figure imgb0021

First step: Synthesis of (S)-1-(3-bromo-2-methyloxyphenyl)ethane-1-ol (17)

    • Using the same method as that of the first step of Example 3, the compound (17) was obtained from the compound (16) at a yield 77%.
      Optical rotation: -23.5 ± 0.6 degrees (CHCl3, c = 1.050, 21°C)
      NMR (CDCl3) θ ppm: 1.49 (3H, d, J = 6.6 Hz), 2.33 (1H, brs), 3.88 (3H, s), 5.19 (1H, q, J = 6.4 Hz), 7.01 (1H, t, J = 7.9 Hz), 7.40 (1H, dd, J = 7.7 Hz, J = 1.1 Hz), 7.46 (1H, dd, J = 8.0 Hz, J = 1.4 Hz)

Second step: Synthesis of (S)-1-bromo-3-(1-hexyloxyethyl)-2-methyloxybenzene (18)

    • Using the same method as that of the second step of Example 3, the compound (18) was obtained from the compound (17) at a yield of 96%.
      Optical rotation: -29.8 ± 0.6 degrees (CHCl3, c = 1.055, 21°C)
      NMR (CDCl3) δ ppm: 0.87 (3H, t, J = 6.8 Hz), 1.2 – 1.4 (6H, m), 1.42 (3H, d, J = 6.5 Hz), 1.54 (2H, m), 3.29 (2H, m), 3.85 (3H, s), 4.78 (1H, q, J = 6.4 Hz), 7.02 (1H, t, J = 7.9 Hz), 7.39 (1H, dd, J = 7.8 Hz, J = 1.7 Hz), 7.45 (1H, dd, J = 7.9 Hz, J = 1.7 Hz)

Third step and fourth step: Synthesis of (S)-4-(3-(1-hexyloxyethyl)-2-methyloxyphenyl)thiazole-2-amine (20)

    • Using the same method as that of the fourth step of Example 3, the compound (19) was obtained from the compound (18), subsequently according to the same method as that of the fourth step, the compound (20) was obtained.

Compound (19)

    • NMR (CDCl3) δ ppm: 0.87 (3H, t, J = 6.9 Hz), 1.2-1.4 (6H, m), 1.45 (3H, d, J = 6.6 Hz), 1.55 (2H, m), 3.29 (2H, m), 3.78 (3H, s), 4.73 (2H, m), 4.80 (1H, q, J = 6.4 Hz), 7.24 (1H, t, J = 7.8Hz), 7.52 (1H, dd, J = 7.7 Hz, J = 1.8 Hz), 7.65 (1H, dd, J = 7.7 Hz, J = 1.8 Hz)

Compound (20)

  • Optical rotation: -4.2 ± 0.4 degrees (DMSO, c = 1.025, 21°C)
    NMR (CDCl3) δ ppm: 0.84 (3H, t, J = 7.0 Hz), 1.2 – 1.3 (6H, m), 1.35 (3H, d, J = 6.5 Hz), 1.48 (2H, m), 3.25 (2H, m), 3.61 (3H, s), 4.78 (1H, q, J = 6.4 Hz), 6.99 (2H, brs), 7.05 (1H, s), 7.16 (1H, t, J = 7.7 Hz), 7.27 (1H, dd, J = 7.5 Hz, J = 1.8 Hz), 7.81 (1H, dd, J = 7.6 Hz, J = 1.9 Hz)

 

      Fifth step: Synthesis of ethyl (S)-(E)-3-(2,6-dichloro-4-(4-(3-(1-hexyloxyethyl)-2-metyloxyphenyl)thiazol-2-ylcarbamoyl)phenyl)-2-methylacrylate (21)

    • Using the same method as that of the fifth step of Example 3, the compound (21) was obtained from the compound (20) at a yield of 94%.
      Optical rotation: +4.7 ± 0.4 degrees (CHCl3, c = 1.07, 21°C)
      NMR (CDCl3 ) δ ppm: 0.87 (3H, t, J = 6.9 Hz), 1.2 – 1.35 (6H, m), 1.38 (3H, t, J = 7.1
      Hz), 1.44 (3H, d, J = 6.4 Hz), 1.57 (2H, m), 1.77 (3H, d, J = 1.4 Hz), 3.30 (2H, m), 3.59 (3H, s), 4.31 (2H, q, J = 7.1 Hz), 4.83 (1H, q, J = 6.4 Hz), 7.17 (1H, t, J = 7.7 Hz), 7.42 (1H, d, J = 1.7 Hz), 7.42 (1H, dd, J = 7.7 Hz, J = 1.8 Hz), 7.51 (1H, s), 7.67 (1H, dd, J = 7.6 Hz, J = 1.7 Hz), 7.89 (2H, s), 10.30 (1H, brs)

Sixth step: Synthesis of (S)-(E)-3-(2,6-dichloro-4-(4-(3-(1-hexyloxyethyl)-2-metyloxyphenyl)thiazol-2-ylcarbamoyl)phenyl)-2-methylacrylic acid (C-3B)

  • Using the same method as that of the sixth step of Example 3, the compound (C-3B) was obtained from the compound (21) at a yield of 80%.
    Optical rotation: -7.0 ± 0.5 degrees (CHCl3, c = 1.040, 21°C)
    NMR (CDCl3) δ ppm: 0.87 (3H, t, J = 6.8 Hz), 1.2 – 1.4 (6H, m), 1.48 (3H, d, J = 6.4 Hz), 1.52 – 1.64 (2H, m), 1.86 (3H, d, J = 1.4Hz)), 3.35 (2H, t, J = 6.7Hz), 3.55 (3H, s), 4.87 (1H, q, J = 6.3 Hz), 7.25 (1H, t, J = 7.7 Hz), 7.41 (1H, s), 7.49 (1H, dd, J = 7.9 Hz, J = 1.6 Hz), 7.51 (1H, dd, J = 7.5 Hz, J = 1.8 Hz), 7.65 (1H, d, J = 1.4 Hz), 8.33 (2H, s), 13.4 (2H, brs)
  • Results of powder X-ray deffraction are shown in Fig. 5.
  • Diffraction angle of main peak: 2θ = 17.8, 21.1, 22.5, 23.3, 24.1, and 24.4 degrees

WO2005014561/EP1655291A1

 https://www.google.co.in/patents/EP1655291A1?cl=en

 

 

WO2014003155, claiming a composition comprising lusutrombopag, useful for treating thrombocytopenia.

https://www.google.co.in/patents/US20150148385?cl=en

.

WO  2015093586

Methods respectively for producing optically active compound having agonistic activity on thrombopoietin receptors and intermediate of said compound 

 

(Step 1) Synthesis of compound (VII ‘)  under a nitrogen atmosphere, it was dissolved compound 1 (2.00kg) in 1,2-dimethoxyethane (28.0kg). 25% LDA tetrahydrofuran – heptane – ethyl benzene solution (13.20kg) was added dropwise over 1 hour at -55 ℃, and stirred for 30 minutes. It was added dropwise over 40 minutes to 1,2-dimethoxyethane (3.0kg) solution of N- formyl morpholine (3.74kg) at -55 ℃, and stirred for 1 hour. 1,2-dimethoxyethane (3.0kg) solution of 2-phosphono-propanoic acid triethyl (3.74kg) was added dropwise over 45 minutes at 0 ℃, and stirred for 2 hours. 35% aqueous solution of sulfuric acid (15.8kg) was added dropwise over 40 minutes to the reaction solution. Water (16.0kg) was added and extracted. The resulting organic layer was washed with water (8.0kg), and the solvent was evaporated under reduced pressure. Acetonitrile (16.0kg) was added, and the mixture was stirred for 1 hour at 25 ℃, and the mixture was stirred and cooled to 0 ℃ 5 hours and 30 minutes. The precipitated crystals were collected by filtration, and washed with 5 ℃ acetonitrile (3.2kg). The resulting crystals it was dissolved in acetonitrile (16.0kg) at 75 ℃. It was cooled to 60 ℃, and the mixture was stirred for 30 minutes. Over 1 hour and then cooled to 30 ℃, and the mixture was stirred for 45 minutes. Over 40 minutes and then cooled to 5 ℃, and the mixture was stirred for 3 hours.The precipitated crystals were collected by filtration, and washed with 5 ℃ acetonitrile (3.2kg). The resulting crystals it was dissolved in acetonitrile (13.0kg) at 75 ℃. It was cooled to 60 ℃, and the mixture was stirred for 30 minutes. Furthermore, up to 30 ℃ over 1 hour and then cooled and stirred for 70 minutes. Over 30 minutes and then cooled to 5 ℃, and the mixture was stirred for 4 hours. I precipitated crystals were collected by filtration. Washed with 5 ℃ acetonitrile (3.2kg), and dried to give the compound (VII ‘) (1.63kg, 51.2% yield). NMR (CDCl 3 ) delta ppm: 8.07 (s, 2H), 7.47 (s, 1H), 4.32 (Q, 2H, J = 7.0 Hz), 1.79 (s, 3H), 1.38 (t, 3H, J = 7.0 Hz)  Results of powder X-ray diffraction and I shown in Figure 1 and Table 3. [Table 3]  In the powder X-ray diffraction spectrum, diffraction angle (2θ): 8.1 ± 0.2 °, 16.3 ± 0.2 °, 19.2 ± 0.2 °, 20.0 ± 0. 2 °, the peak was observed at 24.8 ± 0.2 °, and 39.0 ± 0.2 ° degrees.

 

(Synthesis of Compound (XI ‘))

(Step 2) Synthesis of Compound 4  under a nitrogen atmosphere over Compound 3 (3.00kg) and 1mol / L isopropylmagnesium chloride in tetrahydrofuran (11.40kg) 1 hour at 25 ℃ in The dropped, and stirred for 2 hours. 1mol / L isopropylmagnesium chloride in tetrahydrofuran solution (0.56kg) was added at 25 ℃, and stirred for 2 hours. To the reaction mixture N- methoxymethyl -N- methylacetamide the (1.45kg) was added dropwise over at 25 ℃ 40 minutes, and stirred for 80 minutes. 7% hydrochloric acid (9.7kg) was added to the reaction mixture, and the mixture was extracted with toluene (11.0kg). The resulting organic layer twice with water (each 7.5kg) washed, the solvent was evaporated under reduced pressure to give Compound 4 (2.63kg). NMR (CDCl 3 ) delta ppm: 7.69 (dd, 1H, J = 7.7 Hz, J = 1.5 Hz), 7.55 (dd, 1H, J = 7.7 Hz, J = 1.5 Hz), 7.05 (t, 1H, J = 7.7 Hz), 3.88 (s, 3H), 2.64 (s, 3H) ppm:

(Step 3) Synthesis of Compound 5  Under a nitrogen atmosphere, chloro [(1S Compound 4 (2.63kg), 2S) -N- ( p- toluenesulfonyl) -1,2-diphenyl-ethane diamine] (p- cymene) ruthenium (II) (28.6g), it was added to tetrahydrofuran (1.3kg) and triethylamine (880.0g). Formic acid (570.0g) was added dropwise over 6 hours at 40 ℃, and stirred for 1 hour. In addition 3.5% hydrochloric acid (14.4kg) to the reaction mixture, and the mixture was extracted with toluene (13.0kg).The organic layer was washed with 3.5% hydrochloric acid (14.4kg) and water (7.5kg), the solvent was concentrated under reduced pressure to obtain a toluene solution of Compound 5 (4.44kg).

(Step 4) Synthesis of Compound 6  under a nitrogen atmosphere, it was a potassium hydroxide (6.03kg) was dissolved in water (6.0kg). To the solution, it added tetrabutylammonium bromide (182.0g) and toluene solution of Compound 5 (4.44kg). 1-bromo-hexane (2.79kg) was added dropwise over 1 hour at 60 ℃, and the mixture was stirred for 4 hours. And extracted by adding water (4.4kg) to the reaction solution. The resulting organic layer was filtered through powdered cellulose and extracted with toluene (3.0kg) and water (7.6kg) to the filtrate. The solvent it was evaporated under reduced pressure from the organic layer. Toluene operation of evaporated under reduced pressure and the solvent by the addition of a (7.8kg) was repeated five times to obtain a toluene solution of Compound 6 (10.0kg).

(Step 5) Synthesis of Compound 7  under a nitrogen atmosphere, magnesium powder (301.0g), in tetrahydrofuran (1.3kg), the compound in toluene (6.4kg) and 1mol / L isopropylmagnesium chloride in tetrahydrofuran (432.0g) 6 In addition of the toluene solution (0.50kg) at 30 ℃, and the mixture was stirred for 2 hours. Toluene solution of Compound 6 (9.50kg) was added dropwise over 3 hours at 50 ℃, and stirred for 2 hours. 1-bromo-hexane (746.0g) was added at 50 ℃, and the mixture was stirred for 1 hour. It was added dropwise over 1 hour at 5 ℃ toluene (5.3kg) solution of 2-chloro -N- methoxy -N- methyl-acetamide (1.78kg), and stirred for 1 hour. 3.7% hydrochloric acid (16.7kg) was added to the reaction mixture, and the mixture was extracted. The obtained organic layer was washed with water (15.0kg), and concentrated under reduced pressure to give a toluene solution of Compound 7 (8.25kg).

 

(Step 6) Synthesis of Compound (II ‘)  under a nitrogen atmosphere, thiourea (1.03kg), in ethanol (1.2kg) and 65 ℃ toluene solution of compound 7 (8.25kg) in toluene (6.3kg) over 3 hours was added dropwise and stirred for 2 hours. The reaction solution was extracted by adding 0.7% hydrochloric acid (30.6kg), and washed twice with water (30.0kg). Ethanol in the organic layer (9.5kg), and extracted by addition of heptane (10.0kg) and 3.5% hydrochloric acid (5.9kg). The resulting aqueous layer with 4% hydrochloric acid (1.5kg) and ethanol (3.5kg) merged the aqueous layer was extracted from the organic layer, the ethanol was washed with heptane (10.0kg) (3.1kg) It was added. 8% aqueous sodium hydroxide (6.0kg) was added dropwise over at 5 ℃ 30 minutes, and stirred for 20 minutes. 8% aqueous sodium hydroxide (5.8kg) was added dropwise over a period at 5 ℃ 15 minutes.The precipitated crystals were collected by filtration, washed with 45% aqueous ethanol (10.9kg) and water (15.0kg) (crude crystals of Compound (II ‘)). The resulting crude crystals were dissolved in 50 ℃ in ethanol (8.1kg), over a period of 1 hour and then cooled to 10 ℃, and the mixture was stirred for 30 minutes. Water (10.0kg) over 2 hours was added dropwise and stirred for 30 minutes. The precipitated crystals were collected by filtration, washed with 50% aqueous ethanol (7.5kg) and water (10.0kg) (crystals of the compound after recrystallization from ethanol / water system (II ‘)). The resulting crystals were dissolved at 55 ℃ in toluene (1.6kg) and heptane (1.3kg), over 1 hour and cooled to 20 ℃, and stirred for 30 minutes. Heptane (6.3kg) over a period of 30 minutes was added dropwise and stirred for 15 minutes. The obtained crystals precipitated were collected by filtration, washed with a mixed solvent of toluene (0.3kg) and heptane (2.3kg), and dried to give compound (II ‘) (1.67kg, 44.5% yield) a (crystalline compound after recrystallization from toluene / heptane system (II ‘)).

NMR (CDCl 3 ) delta ppm: 0.84 (3H, t, J = 7.0 Hz), 1.2 – 1.3 (6H, M), 1.35 (3H, D, J = 6.5 Hz), 1.48 (2H, M), 3.25 ( 2H, m), 3.61 (3H, s), 4.78 (1H, q, J = 6.4 Hz), 6.99 (2H, brs), 7.05 (1H, s), 7.16 (1H, t, J = 7.7 Hz), 7.27 (1H, dd, J = 7.5 Hz, J = 1.8 Hz), 7.81 (1H, dd, J = 7.6 Hz, J = 1.9 Hz)  it is shown in Figure 2 and Table 4 the results of powder X-ray diffraction. [Table 4]  In the powder X-ray diffraction spectrum, diffraction angle (2θ): 12.5 ± 0.2 °, 13.0 ± 0.2 °, 13.6 ± 0.2 °, 16.4 ± 0. 2 °, 23.0 ± 0.2 °, a peak was observed at 24.3 ± 0.2 ° degrees.  Above, each of the compounds (II ‘) of the crude crystals, the ethanol / compound after recrystallization from water (II’) crystals and toluene / heptane compound after recrystallization from (II ‘) crystallographic purity of the results of the , Fig. 3, I 4 and 5 as well as Table 5. [Table 5](HPLC was measured by the above method A.)  As shown in the results of the above table, as compared to recrystallization from ethanol / water, recrystallized with toluene / heptane system, compounds having a high optical purity it is possible to manufacture a crystal of (II ‘).  Next, the above-mentioned compound (II ‘) of the crude crystals, the ethanol / compound after recrystallization from water (II’) crystals and toluene / heptane compound after recrystallization from (II ‘) results of crystals of HPLC of the respectively, Fig. 6, I 7 and 8 and Table 6. [Table 6] (units, .N.D shows the peak area of the (%). is, .HPLC to indicate not detected was measured by the above method B.)  As shown in the results of Table, with ethanol / water system Compared to recrystallization, recrystallization from toluene / heptane system is found to be efficiently remove organic impurities A and organic impurities B.

(Step 7) Compound ‘Synthesis of DMSO adduct of (VIII)  Under a nitrogen atmosphere, the compound (II ‘) (1.50kg) and compound (VII’) (1.43kg) in ethyl acetate (17.6kg) and triethylamine (1.09kg) were sequentially added, was dissolved.Diphenyl phosphorochloridate the (1.46kg) was added dropwise over 1 hour at 50 ℃, and the mixture was stirred for 3 hours. The reaction mixture was cooled to 25 ℃, after the addition of 2.6% hydrochloric acid (8.1kg), and extracted. The resulting organic layer to 6.3% aqueous solution of sodium hydroxide (3.2kg) and 14% aqueous sodium carbonate (5.2kg) was added and stirred for 20 minutes. Adjusted to pH7.5 with 8.3% hydrochloric acid and extracted. The organic layer it was washed with 4.8% sodium chloride aqueous solution (11.0kg). DMSO and (16.5kg) was added, and the mixture was concentrated under reduced pressure.DMSO and (5.8kg) was added, over a period at 40 ℃ 30 minutes was added dropwise water (0.9kg), and stirred for 1 hour. Over a period of 30 minutes, cooled to 25 ℃, and the mixture was stirred for 30 minutes. Over at 25 ℃ 30 minutes was added dropwise water (1.4kg), and the precipitated crystals were collected by filtration. After washing with 90% DMSO solution (10.0kg) and water (27.0kg), to obtain crystals of DMSO adduct and dried to Compound (VIII ‘) (2.98kg, 95.2% yield).

1H-NMR (CDCl 3 ) delta: 0.87 (t, J = 6.8 Hz, 3H), 1.20-1.34 (M, 6H), 1.37 (t, J = 7.1 Hz, 3H), 1.44 (D, J = 6.5 Hz , 3H), 1.52-1.59 (m, 2H), 1.77 (d, J = 1.3Hz, 3H), 2.62 (s, 6H), 3.28-3.34 (m, 2H), 3.59 (s, 3H), 4.31 ( q, J = 7.1Hz, 2H), 4.83 (q, J = 6.5Hz, 1H), 7.16 (t, J = 7.7Hz, 1H), 7.40-7.43 (m, 2H), 7.51 (s, 1H), 7.68 (dd, J = 7.7, 1.8Hz, 1H), 7.92 (d, J = 1.3Hz, 2H), 10.58 (s, 1H).  The results of the powder X-ray diffraction and I are shown in Figure 9 and Table 7. [Table 7]

In the powder X-ray diffraction spectrum, diffraction angle (2θ): 5.2 ° ± 0.2 °, 7.0 ° ± 0.2 °, 8.7 ° ± 0.2 °, 10.5 ° ± 0.2 °, 12.3 ° ± 0.2 °, 14.0 ° ± 0.2 °, 15.8 ° ± 0.2 °, 19.3 ° ± 0.2 °, 22.5 ° peak was observed to ± 0.2 ° and 24.1 ° ± 0.2 °.  TG / DTA analysis result it is shown in Figure 10.  Then, each result of HPLC of concentrated dry solid and the above DMSO adduct crystals described in the following Reference Examples 1, 11 and 12, 13 and 14, and I are shown in Table 8. [Table 8] (unit, .HPLC showing peak areas of (%) was measured by the above methods C.)  As shown in the results of the above Table, when compared with the extract, DMSO adduct of the compound (VIII ‘) The in the crystal, less residual organic impurities D, and it found to be about 56% removal.

(Step 8)  under nitrogen atmosphere, DMSO adduct of the compound (VIII ‘) and (2.50kg) it was dissolved in ethanol (15.8kg). 24% sodium hydroxide aqueous solution (1.97kg) was added dropwise over a period at 45 ℃ 30 minutes to the solution and stirred for 3 hours. The reaction mixture was cooled to 25 ℃, water was added (20.0kg) and ethanol (7.8kg). 18% hydrochloric acid (2.61kg) was added dropwise over at 25 ℃ 30 minutes, followed by addition of seed crystals prepared according to the method described in Patent Document 23. After stirring for 3 hours and allowed to stand overnight. Thereafter, the precipitated crystals were collected by filtration, to give after washing with 50% aqueous ethanol solution (14.2kg), and dried to a compound (XI ‘) (1.99kg, 93.9% yield).

NMR (CDCl 3 ) delta ppm: 0.87 (3H, t, J = 6.8 Hz), 1.2 – 1.4 (6H, M), 1.48 (3H, D, J = 6.4 Hz), 1.52 – 1.64 (2H, M), 1.86 (3H, d, J = 1.4Hz), 3.35 (2H, t, J = 6.7Hz), 3.55 (3H, s), 4.87 (1H, q, J = 6.3 Hz), 7.25 (1H, t, J = 7.7 Hz), 7.41 (1H, s), 7.49 (1H, dd, J = 7.9 Hz, J = 1.6 Hz), 7.51 (1H, dd, J = 7.5 Hz, J = 1.8 Hz), 7.65 (1H, d, J = 1.4 Hz), 8.33 (2H, s), 13.4 (2H, brs)  I is shown in Figure 15 the results of powder X-ray diffraction.

 

Patent Document 1: JP-A-10-72492 JP
Patent Document 2: WO 96/40750 pamphlet
Patent Document 3: JP-A-11-1477 JP
Patent Document 4: Japanese Unexamined Patent Publication No. 11-152276
Patent Document 5: International Publication No. 00/35446 pamphlet
Patent Document 6: JP-A-10-287634 JP
Patent Document 7: WO 01/07423 pamphlet
Patent Document 8: International Publication WO 01/53267 pamphlet
Patent Document 9: International Publication No. 02 / 059 099 pamphlet
Patent Document 10: International Publication No. 02/059100 pamphlet
Patent Document 11: International Publication No. 02/059100 pamphlet
Patent Document 12: International Publication No. 02/062775 pamphlet
Patent Document 13: International Publication No. 2003/062233 pamphlet
Patent Document 14: International Publication No. 2004/029049 pamphlet
Patent Document 15: International Publication No. 2005/007651 pamphlet
Patent Document 16: International Publication No. 2005/014561 pamphlet
Patent Document 17: JP 2005-47905 Japanese
patent Document 18: Japanese Patent Publication No. 2006-219480
Patent Document 19: Japanese Patent Publication No. 2006-219481
Patent Document 20: International Publication No. 2007/004038 pamphlet
Patent Document 21: International Publication No. 2007/036709 pamphlet
Patent Document 22: International Publication No. 2007/054783 pamphlet
Patent Document 23: International Publication No. 2009/017098 pamphlet

Non-Patent Document 1: Proceedings of the National Akademyi of Science of the United State of America (…. Proc Natl Acad Sci USA) 1992, Vol. 89, p 5640-5644.
Non-Patent Document 2: Journal of Organic (.. J. Org Chem) Chemistry 1984, Vol. 49, p 3856-3857.
Non-Patent Document 3: (.. J. Org Chem). Journal of Organic Chemistry, 1992, Vol. 57, p 6667-6669
Non-Patent Document 4:. Shinretto (Synlett) 2004 year Vol. 6, p 1092-1094

 

 

 

 

 

सुकून उतना ही देना प्रभू, जितने से जिंदगी चल जाये। औकात बस इतनी देना, कि औरों का भला हो जाये।

DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO …..FOR BLOG HOME CLICK HERE

 

Join me on Linkedin

View Anthony Melvin Crasto Ph.D's profile on LinkedIn

Join me on Facebook FACEBOOK

Join me on twitterFollow amcrasto on Twitter

Join me on google plus Googleplus

Join me on Researchgate

Anthony Melvin Crasto Dr.

 amcrasto@gmail.com

 

09b37-misc2b027LIONEL MY SON

He was only in first standard in school when I was hit by a deadly one in a million spine stroke called acute transverse mylitis, it made me 90% paralysed and bound to a wheel chair, Now I keep him as my source of inspiration and helping millions, thanks to millions of my readers who keep me going and help me to keep my son happy

सुकून उतना ही देना प्रभू, जितने से

जिंदगी चल जाये।

औकात बस इतनी देना,

कि औरों का भला हो जाये।

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL  

//////

phase 3, shionogi, japan, lusutrombopag, S 888711

CCCCCCOC(C)C1=CC=CC(=C1OC)C2=CSC(=N2)NC(=O)C3=CC(=C(C(=C3)Cl)C=C(C)C(=O)O)Cl

Share
Jul 032015
 

Teneligliptin.svg

TENELIGLIPTIN

Teneligliptin; 760937-92-6; UNII-28ZHI4CF9C; Teneligliptin (INN); 28ZHI4CF9C
MF C22H30N6OS
MW 426.5782 g/mol

Teneligliptin (INN; trade name Tenelia) is a pharmaceutical drug for the treatment of type 2 diabetes mellitus. It is approved for use in Japan.[1] It belongs to the class of anti-diabetic drugs known as dipeptidyl peptidase-4 inhibitors or “gliptins”.[2] {(2S,4S)-4-[4-(3-Methyl-1-phenyl-1H-pyrazol-5-yl)-1-piperazinyl]-2-pyrrolidinyl}(1,3-thiazolidin-3-yl)methanone

Teneligliptin was launched in Japan in 2012 by Mitsubishi Pharma and Daiichi Sankyo for the treatment of type 2 diabetes mellitus. In 2013, the indication was partially changed to include it as a combination therapy with existing oral hypoglycemic agents, such as biganides, alpha-glucosidaseinhibitors, rapid-acting insulin secretagogues, and insulin preparations, as well as sulfonylureas and thiazolidines that had been approved for the combination.

In 2014, the product was registered in KR for the treatment of type 2 diabetes mellitus.
In 2013, Mitsubishi Tanabe Pharma filed for approval in Japan for use of the compound as combination therapy for the treatment of diabetes type 2.

CAS  760937-92-6

Teneligliptin.png

3-{(2S,4S)-4-[4-(3-methyl-l -phenyl- 1 H- pyrazol-5-yl)- l-piperazinyl]-2-pyrrolidinylcarbonyl}-l , 3-thiazolidine is represented structurally by a compound of formula (I):

 

Figure imgf000003_0001

Teneligliptin (CAS 760937-92-6) is a novel, potent and long-lasting dipeptidyl peptidase-4 inhibitor in treatment of type 2 diabetes. Dipeptidyl-peptidase-4 (DPP- 4) inhibitor has been demonstrated to improve glycemic control, in particular postparandial hyperglycemic control.

Despite of their common mechanism of action, DPP-4 inhibitors show marked structural heterogeneity. DPP-4 inhibitors may be classified into peptidomimetic (i.e. sitagliptin, vildagliptin, saxagliptin, and anagliptin) and non-peptidomimetic (i.e. alogliptin and linagliptin) subtypes.

Teneligliptin, is chemically known as a 3- {((2S,4S)-4-(4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl)pyrrolidin-2-yl 25 carbonyl}thiazolidine hemipentahydrobromide hydrate and is peptidomimetic with the molecular formula of C22H30N6OS.2½HBr.xH2O and molecular weight of 642.88 g/mol for hemipentahydrobromide. The hydrate can be from mono to dihydrate.

U.S. Patent No. 7,074,794 B2 (the US ‘794) discloses teneligliptin as L-proline derivative and its pharmaceutically acceptable salts which exhibits a Dipeptidyl 5 peptidase IV (DPP-IV) inhibitory activity, which is useful for the treatment or prophylaxis of diabetes, obesity, HIV infection, cancer metastasis, dermopathy, prostatic hyperplasia, periodontitis, autoimmune diseases and the like.

The example-222 of the US ‘794 discloses the process for the preparation of teneligliptin as trihydrochloride salt U.S. Patent No. 8,003,790 B2 (the US ‘790) discloses salts of proline derivative, solvate thereof and production method thereof. In particular, the US ‘790 discloses 2.0 hydrochloride or 2.5 hydrochloride; 2.0 hydrobromide or 2.5 hydrobromide, and hydrates thereof teneligliptin.

The US ‘790 B2 further discloses different salts 15 of teneligliptin which are incorporated herein as reference in their entirety U.S. PG-Pub. No. 2011/0282058 A1 discloses salts of 3-{((2S,4S)-4-(4-(3-methyl- 1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl)pyrrolidin-2-ylcarbonyl}thiazolidine with mono-, di- and tri-basic acids or a solvate thereof. 20 International (PCT) publication No. WO 2012/165547 A1 discloses a process for preparation of teneligliptin and pharmaceutically acceptable salts thereof.

International (PCT) publication No. WO 2007/127635 A2 (the WO ‘635 A2) discloses a process for the preparation of diketo-piperazine and piperidine 25 derivatives. In particular, the WO ‘635 A2 discloses the process for preparation of 4-oxo-2-(thiazolidine-3-carbonyl)-pyrrolidine-1-carboxylic acid tert-butyl ester [herein compound (III)] by reacting piperazine with aryl halide.

International (PCT) publication No. WO 2012/099915 A1 (the WO ‘915 A1) 5 discloses the process for the preparation of deuterated thiazolidine derivatives. The WO ‘915 A1 also discloses the process for the preparation of 1-(3-methyl-1- phenyl-1H-pyrazol-5-yl)piperazine herein compound (V) by condensation of 5- chloro-3-methyl-1-phenyl-1H-pyrazole with piperazine.

Bioorganic & Medicinal Chemistry, 20(19), 5705-5719 (2012) discloses the process for the preparation of 1-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazine herein compound (V) by deprotection of Boc-protected 1-(3-methyl-1-phenyl-1Hpyrazol-5-yl)piperazine with triflouroacetic acid.

U.S. Patent Nos. 7,807,676 B2 and 7,807,671 B2 discloses a process for the preparation of 1-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazine by condensation of 5-chloro-3-methyl-1-phenyl-1H-pyrazole with piperazine in presence of n-BuLi in tetrahydrofuran. Bioorganic & Medicinal Chemistry, 14(11), 3662-3671 (2006),

Bioorganic & Medicinal Chemistry, 20(16), 5033-5041 (2012) and U.S. Patent Nos. 7,807,676 B2 and 7,807,671 B2 discloses a process for the preparation of (2S,4R)-tert-butyl 4-hydroxy-2-(thiazolidine-3-carbonyl)pyrrolidine-1-carboxylate by reacting (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid with 25 thiazolidine in presence of HOBT and EDC.HCl in dimethylformamide solvent.

Bioorganic & Medicinal Chemistry, 15(2), 641-655 (2007) discloses a process for the preparation of (2S,4R)-tert-butyl 4-hydroxy-2-(thiazolidine-3- carbonyl)pyrrolidine-1-carboxylate by treating (2S,4S)-tert-butyl 4-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-2-(3-thiazolidinylcarbonyl)pyrrolidine-1- carboxylate with tetrabutylammonium fluoride in tetrahydrofuran.

Bioorganic & Medicinal Chemistry, 20(19), 5705-5719 (2012) discloses the 5 process for the preparation of herein compound (II) after by reacting 1-(3-methyl- 1-phenyl-1H-pyrazol-5-yl)piperazine herein compound (V) with (2S,4R)-tert-butyl 4-hydroxy-2-(thiazolidine-3-carbonyl)pyrrolidine-1-carboxylate in presence of sodium triacetoxyborohydride. There is provided different alternative processes for the preparation of teneligliptin and intermediates thereof.

Bioorganic & Medicinal Chemistry, 20(19), 5705-5719 (2012) also discloses the process for the preparation of 4-[4-(5-methyl-2-phenyl-2H-pyrazol-3-yl)-piperazin- 1-yl]-2-(thiazolidine-3-carbonyl)pyrrolidine-1-carboxylic acid tert-butyl ester [herein compound (II)] after by reacting 1-(3-methyl-1-phenyl-1H-pyrazol-5- 15 yl)piperazine [herein compound (V)] with (2S,4S)-tert-butyl 4-[[(1,1- dimethylethyl)dimethylsilyl]oxy]-2-(3-thiazolidinylcarbonyl)pyrrolidine-1- carboxylate in presence of trifluoromethylsulfonic anhydride and diisopropylethylamine. 3 – [[(2S, 4S) -4- [4- (3- methyl-1-phenyl–1H- pyrazol-5-yl) -1-piperazinyl ] -2-pyrrolidinyl] carbamoyl] thiazolidine, having the formula below, is a very novel DPP-4 inhibitor potential.

Figure CN104177295AD00031

World Patent Application No. W02012099915 for Ge Lieting discloses a process for the preparation route is as follows:

Figure CN104177295AD00032

Journal B10rganic & Medicinal Chemistry, 2012, 20, 5705-5719 also discloses a preparation method for Ge Lieting, the route is as follows:

Figure CN104177295AD00041

[0009] 1- (3-methyl-1-phenyl-5-pyrazolyl) piperazine, was prepared for the Ge Lieting key intermediate. Journals B10rganic & Medicinal Chemistry, 2012,20,5705-5719 reported the preparation of the intermediates prepared route is as follows:

Figure CN104177295AD00042

[0011] The preparative route after the N-Boc-N- acetoacetyl piperazine phenylhydrazine and methanesulfonic acid in an ethanol solution of the reaction at room temperature 14h, concentrated under reduced pressure after addition of pyridine.Was added phosphorus oxychloride in pyridine, 20h post treatment reaction at room temperature the reaction system. The compound obtained above was then added trifluoroacetic acid was dissolved in methylene chloride after, after treatment at room temperature for 1.5h to give 1- (3-methyl-1-phenyl-5-pyrazolyl) piperazine.

The reaction process requires mesylate mesylate flammable, easy-absorbent deliquescence, and has a strong corrosive and irritating, easy to cause the body burns; phosphorus oxychloride, a highly toxic substance, water violent hair in the air smoke, hydrolyzed into phosphoric acid and hydrogen chloride, is very unstable, to operate a lot of trouble; trifluoroacetic acid is highly corrosive and irritant, can cause the body burns; low yield of the reaction (10%). Seeking a simple operation, high reaction yield, low cost and suitable for industrial production production process 1- (3-methyl-1-phenyl-5-pyrazolyl) piperazine has a very important role in the field of medicine.

…………………………………….

ten 1

ten 2 ten 3

ten 4

ten 1

ten 2

 

ten 4

 

since the capture is staggered, compd 165 is not clear in above pic see below

 

ten 3

 

 

…………

 

…………………….

CN104177295

reaction scheme in   http://www.google.com/patents/CN104177295A?cl=en

Figure CN104177295AD00043

Description: LR as Lawesson reagent (Lawesson Reagent), is a sulfur oxygen exchange reagent. The present invention provides a method for preparing key intermediates Ge Lieting method, comprising the steps of: (I) N-Boc-N- acetoacetyl piperazine Lawesson’s reagent in the presence of an organic solvent, with a phenylhydrazine of the formula occurs ⑴ reaction shown:

Figure CN104177295AD00051

(2) the step (1) The product was dissolved in an organic solvent, the following formula (II) in concentrated hydrochloric acid to deprotected shown:

Figure CN104177295AD00052
格列汀 refers to 1- (3-methyl-1-phenyl-5-pyrazolyl) piperazine
……………………………..

Volume 20, Issue 19, 1 October 2012, Pages 5705–5719

Full-size image (24 K)
…………………………………..

 

………………………..

http://www.google.co.in/patents/WO2015019238A1?cl=en

Example 5: Preparation of {(2^,.4^)-4-r4-(3-methyl-l-phenyl-lH-pyrazol-5-yl)piperazin- 1 -vHpyrrolidin-2-yl } ( 1.3 -thiazolidin-3 -vDmethanone hemipentahydrobromide hydrate (Formula II)

Activated carbon (10 g) was added to a solution of the residue (obtained in Example 4) in isopropyl alcohol (1000 mL) at 30°C to 35°C. The reaction mixture was filtered through a Hyflo® bed. The filtrate was heated to a temperature of 70°C to 75°C. Hydrobromic acid (48%; 168 g) was slowly added to the filtrate at 70°C to 75°C over a period of 10 minutes to 15 minutes. The reaction mixture was stirred for 2.5 hours at 70°C to 77°C. The progress of the reaction was monitored by HPLC. After completion of the reaction, the reaction mixture was cooled to a temperature of 20°C to 25 °C, and stirred at the same temperature for 60 minutes. The reaction mixture was filtered to obtain a solid. The solid obtained was washed with isopropyl alcohol (2 x 200 mL), and dried at 50°C under reduced pressure for 15 hours to obtain crude {(25*,45)-4-[4-(3-methyl-l-phenyl-lH- pyrazol-5 -yl)piperazin- 1 -yl]pyrrolidin-2-yl} ( 1 ,3 -thiazolidin-3 -yl)methanone

hemipentahydrobromide hydrate.

Yield: 90%

Example 6: Purification of {(2^’.4^)-4-r4-(3-methyl-l-phenyl-lH-pyrazol-5-yl)piperazin- 1 -yllpyrrolidin-2-yl } ( 1.3 -thiazolidin-3 -vDmethanone hemipentahydrobromide hydrate (Formula II)

A reaction mixture containing {(2S,4S)-4-[4-(3-methyl-l-phenyl-lH-pyrazol-5- yl)piperazin- 1 -yl]pyrrolidin-2-yl } ( 1 ,3 -thiazolidin-3 -yl)methanone

hemipentahydrobromide hydrate (100 g; prepared according to the process of Example 5) in ethanol (700 mL) was heated at 70°C to 75°C to obtain a solution. The solution was filtered at the same temperature. The filtrate was allowed to cool to a temperature of 65 °C to 68°C, and deionized water (10 mL) was added at the same temperature. The solution was cooled to a temperature of 55°C to 60°C, and stirred at the same temperature for 2 hours. The solution was further cooled to a temperature of 20°C to 25 °C, and stirred at the same temperature for 60 minutes to obtain a solid. The solid was filtered, washed with ethanol (100 mL), and dried at 45°C to 50°C under reduced pressure for 18 hours to 20 hours to obtain pure {(2S,4S)-4-[4-(3-methyl-l-phenyl-lH-pyrazol-5-yl)piperazin-l- yl]pyrrolidin-2-yl } ( 1 ,3 -thiazolidin-3 -yl)methanone hemipentahydrobromide hydrate .

Yield: 90%

HPLC Purity: 99.93%

WO2012099915A1 * 18 Jan 2012 26 Jul 2012 Hongwen Zhu Thiazolidine derivatives and their therapeutic use
WO2012165547A1 * 31 May 2012 6 Dec 2012 Mitsubishi Tanabe Pharma Corporation Method for manufacturing pyrazole derivative
WO2014041560A2 * 28 Aug 2013 20 Mar 2014 Glenmark Pharmaceuticals Limited; Glenmark Generics Limited Process for the preparation of teneligliptin
US7074794 10 Aug 2001 11 Jul 2006 Mitsubishi Pharma Corporation Proline derivatives and the use thereof as drugs
US8003790 17 Feb 2006 23 Aug 2011 Mitsubishi Tanabe Pharma Corporation Salt of proline derivative, solvate thereof, and production method thereof
US20050256310 * 12 May 2005 17 Nov 2005 Pfizer Inc Therapeutic compounds
EP1854795A1 * 17 Feb 2006 14 Nov 2007 Mitsubishi Pharma Corporation Salt of proline derivative, solvate thereof, and production method thereof
EP1894567A1 * 2 Jun 2006 5 Mar 2008 Mitsubishi Tanabe Pharma Corporation Concomitant pharmaceutical agents and use thereof
US20040106655 * 10 Aug 2001 3 Jun 2004 Hiroshi Kitajima Proline derivatives and the use thereof as drugs
 Patent Filing date Publication date Applicant Title
WO2015019238A1 * 28 Jul 2014 12 Feb 2015 Ranbaxy Laboratories Limited Process for the preparation of n-protected (5s)-5-(1,3-thiazolidin-3-ylcarbonyl)pyrrolidin-3-one
Patent Submitted Granted
Proline derivatives and use thereof as drugs [US7060722] 2005-11-03 2006-06-13
Proline derivatives and the use thereof as drugs [US7074794] 2004-06-03 2006-07-11
Proline derivatives and use thereof as drugs [US2006173056] 2006-08-03
SALT OF PROLINE DERIVATIVE, SOLVATE THEREOF, AND PRODUCTION METHOD THEREOF [US8003790] 2009-08-27 2011-08-23
METHOD OF TREATING ABNORMAL LIPID METABOLISM [US2010305139] 2010-12-02
COMBINED USE OF DIPEPTIDYL PEPTIDASE 4 INHIBITOR AND SWEETENER [US2010113382] 2010-05-06
CONCOMITANT PHARMACEUTICAL AGENTS AND USE THEREOF [US2009082256] 2009-03-26
PROPHYLACTIC/THERAPEUTIC AGENT FOR ABNORMALITIES OF SUGAR/LIPID METABOLISM [US2009088442] 2009-04-02
SALT OF PROLINE DERIVATIVE, SOLVATE THEREOF, AND PRODUCTION METHOD THEREOF [US2011282058] 2011-11-17
  1.  Joanne Bronson, Amelia Black, T. G. Murali Dhar, Bruce A. Ellsworth, and J. Robert Merritt. “Teneligliptin (Antidiabetic)”. Annual Reports in Medicinal Chemistry 48: 523–524. doi:10.1016/b978-0-12-417150-3.00028-4
  2.  Kishimoto, M (2013). “Teneligliptin: A DPP-4 inhibitor for the treatment of type 2 diabetes”Diabetes, metabolic syndrome and obesity : targets and therapy 6: 187–95. doi:10.2147/DMSO.S35682PMC 3650886PMID 23671395.

see gliptins at………….http://drugsynthesisint.blogspot.in/p/gliptin-series.html

http://organicsynthesisinternational.blogspot.in/p/gliptin-series-22.html

 

see gliptins at………….http://drugsynthesisint.blogspot.in/p/gliptin-series.html

http://organicsynthesisinternational.blogspot.in/p/gliptin-series-22.html

 

Share

Drug development, approval, manufacturing, and post-marketing…..Japan’s journey of a pharmaceutical product

 drugs, japan, Uncategorized  Comments Off on Drug development, approval, manufacturing, and post-marketing…..Japan’s journey of a pharmaceutical product
Sep 042014
 

Drug development, approval, manufacturing, and post-marketing

  • Development of a new drug involves a complicated process that requires a lot of time and enormous amounts of funding. In order to create one drug, you would need to evaluate approximately 700,000 candidates1). Of them, just one reaches the patients. Here, we will share how a new drug begins its journey, from the research and development of candidate compounds, to a product, to the patients, and how we are involved with drugs once the physician prescribes a drug to patients. We will explain what pharmaceutical companies call “the lifecycle of a drug.”
    1) from Japan Pharmaceutical Manufacturers Association DATABOOK 2013

The journey of a pharmaceutical product

1. Basic research

img

 

  • Conduct a research to discover new drug candidate substances and components and create new compounds. Most requires 2 to 3 years. This process also functions as an opportunity to research the yet-to-be-defined mechanisms of diseases, where the basic research conducted may not directly lead to a new drug. Discovering a seed for a new drug is like looking for a piece diamond on the bottom of the deep ocean, where these highly uncertain basic research and drug development research could become the base in identifying several million candidate elements. After this process, a screening method to narrow down potential substances will be developed, and several of the candidate substances move on to the next process.
  • There are two types of research, collaborative research and sponsored research, where pharmaceutical companies and others provide funding support.
    The research is conducted after an official contract is exchanged with universities and others.
    Collaborative research:(Joint research expenses in the JPMA Transparency Guideline)
    Research institutions such as universities and investigators of pharmaceutical companies and others conduct a research cooperatively.
    Sponsors such as pharmaceutical companies entrust research institutions such as universities to conduct the research, where accomplishments are reported to the sponsors.
    Image result for kiyomizu dera

    The journey of a pharmaceutical product

    2. Development

    1) Non-clinical trial

    • CMC: Quality
      CMC stands for Chemistry, Manufacturing and Control. Design and research for manufacturing procedures, specifications and stability tests are carried out.
    • A process to investigate the efficacy and safety of candidate drug compounds. An animal testing is conducted for pharmacokinetics, pharmacological and toxicity tests. The next trials are conducted based on data obtained from this first process. This process takes about 3 to 5 years.
    • The trial is required to be conducted based on GLP for non-clinical trial regarding safety of pharmaceutical products.

    2) Clinical trial

    • The clinical trial is conducted by pharmaceutical companies and others based on the Pharmaceutical Affairs Law, in order to have a new drug approved or to apply for a new indication for an existing drug. Other than clinical trials conducted by pharmaceutical companies with an objective of approval application, there are trials called investigator-led clinical trials which are conducted by physicians and medical institutions for the purpose of the approval application.
    • The trial process investigates the efficacy and safety of the candidate compound on humans. The clinical trial is conducted mainly in 3 steps, Phase I, Phase II and Phase III. This process takes approximately 3 to 10 years. It is required to conduct the trials based on the GCP.
      Phase I trial (human pharmacology study) :
      Confirms mainly the compound’s safety among healthy people
      Phase II trial (exploratory study) :
      Confirms the drug’s administration method and administration amount among a small number of patients
      Phase III trial (confirmatory trial) :
      Confirms the drug’s efficacy and safety among numerous patients

The journey of a pharmaceutical product

3. NDA and regulatory approval application

  • The enormous amount of data gathered on candidate compounds so far is compiled into an approval application document and submitted to the regulatory authority in each country/region. In Japan, it is submitted to the Ministry of Health, Labour and Welfare (MHLW). The Pharmaceuticals and Medical Devices Agency (PMDA) will conduct a strict review from a scientific standpoint, and once the efficacy and safety of the candidate compound is confirmed, it will obtain approval by the MHLW as a new drug to be manufactured and distributed.
  • The PMDA website provides a detailed explanation on the complicated and wide-ranging process from application to approval.

 

Image result for meiji shrine

 

 The journey of a pharmaceutical product

  • 4. Production, Quality, Information Provision & Product Distribution

    1) Manufacturing of newly approved drugs and the quality control process.

    In every process of the drug development, from manufacturing to shipping and transportation after shipments, there are strict standards in place, ranging from those defined by the Pharmaceutical Affairs Law, those that require approval from regulatory agencies, and unique standards set within companies.

    • Approval and inspection of manufacturing site: Under the Pharmaceutical Affairs Law, a GMP compatibility investigation is required for a new drug to be approved. This is an investigation that also confirms that the manufacturing site has the building, facility and administrative system to constantly manufacture the product which has been guaranteed its efficacy, safety and homogeneity.
      GMP investigation is conducted regularly as well as unscheduled, in addition to the investigation conducted at the time of approval.
    • The manufacturing process begins from the measuring of raw materials: (Chugai Pharmaceutical “Manufacturing of active pharmaceutical ingredient/solid drug factory”)
    • Decision on shipment: Some products, such as vaccines and blood products, require a national test per lot and may take time for it to be shipped out.
      National test process for vaccines

    2) Product distribution and provision of information

 

Image result for golden pavilion kyoto

The journey of a pharmaceutical product

5. Post manufacturing and distribution

  • Conduct surveys and trials on appropriate use, in order to confirm the new drug’s efficacy and safety in a regular and a daily medical setting that cannot be obtained from a clinical trial conducted for the drug’s approval. For example, through post-manufacturing and distribution clinical trials and post-manufacturing and distribution surveys, collect information on adverse reaction and the drug quality, and communicate assessment and analysis results to medical facilities.
  • Making changes to items listed in the application material submitted to obtain marketing approval, requires companies to submit an approval application for partial approval and obtain an approval per the Pharmaceutical Affairs Law.
  • The reporting system of adverse reactions and infectious diseases based on the Pharmaceutical Affairs Law, is for pharmaceutical companies and healthcare practitioners such as physicians and pharmacists to report the MHLW. The objective for this is to appropriately collect adverse reaction, infectious diseases and default information of pharmaceutical products and others in approved medical facilities such as hospitals, and promptly conduct safety measures.
  • Pharmaceutical companies, in order to promote academic research and provide aid for the research, supports research institutions such as universities, hospitals and medical academic conferences. As an academic research aid, it provides scholarship donations to universities and others. For example, in order to promote case reports that communicate product usage experience by expert physicians for products that have been in the market for 3 to 5 years since post-manufacturing and distribution, pharmaceutical companies will bring together a seminar through donations to the medical academic conferences and co-host seminars with academic conferences. Through such activities, it will promote the products’ safety and appropriate usage post-manufacturing and distribution.
  • There are also clinical research and clinical trials that are led by physicians and medical facilities conducted after a product’s post-manufacturing. Some physician-led clinical trials do not have an objective to apply for approval, but rather are conducted by physicians and researchers in order to provide the best treatment to patients and promote evidence-based medicine.

……………………………………………………………………………….

  • The various steps in this process are usually conducted by pharmaceutical companies alone. However, at times accomplishments are made through a cooperative effort with universities and medical institutions. In order for cooperative research with universities and medical institutions to steadily progress, and for new drugs to be created as a result, companies sometimes contribute by providing funding to the research. The types of funding provided are presented in the table below. Also, for certain items an example is illustrated and explained in each process within the “product lifecycle,” and is hyperlinked to the cost items of each member companies’ disclosure target within the JPMA‘s “Transparency guideline for the relationship between corporate activities and medical facilities and others.
  • The progress of each process within the “product lifecycle” is managed by adhering to various laws and self-regulations. We will explain the process of drug development that at times is considered complicated, to the manufacturing and distribution of new drugs, and related laws and regulations to adhere to. The following table shows one part of the product lifecycle chart.
    Product lifecycle and requirements overviewProduct lifecycle and requirements overview

 

Terminology: Product lifecycle and related laws

news image

  • PAL:Pharmaceutical Affairs Law
    A Law regulating matters related to the manufacturing, distribution, standards and screening, handling and advertising regulation and others for healthcare products, quasi-drugs, cosmetics and medical devices in Japan. (Law No. 145, Aug. 10, 1960).
  • GLP:Good Laboratory Practice
    A standard for conducting non-clinical studies on the safety of drugs. It is a standard regarding animal studies in non-clinical studies, particularly regulated for toxicity studies.
  • CMC:Chemistry, Manufacturing and Control
    Information regarding Chemistry, Manufacturing and Control. It refers to the integrated concept of researches for drug substance process, drug development, and quality assessment, as well as works related to those researches. The pharmaceutical companies’ CMC includes a wide range of work from non-clinical studies, clinical studies to regulatory approval applications.
  • GCP:Good Clinical Practice
    A standards regarding the implementation of clinical trial for pharmaceutical products.
  • ICH:International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use
    A project that brings together regulatory authorities in Europe, Japan and the United States. The purpose is to make recommendations on ways to achieve greater harmonisation in the interpretation and application of technical guidelines and requirements for product registration.
  • GMP:Good Manufacturing Practice
    A ministry ordinance related to standards for the manufacturing management and quality management of pharmaceutical products and quasi-drugs. It refers to the standard for the manufacturing management and quality management at manufacturing facilities of pharmaceutical products and others.
  • PV:Pharmacovigilance
    Activities related to the safety monitoring of pharmaceutical products. It refers to the careful monitoring and continuous surveillance of the safety of an approved product during its life on the market.
  • GQP:Good Quality Practice
    A standard on the quality management of pharmaceutical products and others.
  • GDP:Good Distribution Practice
    A standard on pharmaceutical product distribution.
  • GPSP:Good Post-marketing Study Practice
    A standard on the implementation of the pharmaceutical products’ post-marketing surveillance and study.
  • GVP:Good Vigilance Practice
    A standard on the safety management of pharmaceutical products and others after manufacturing and distribution.

 

Sources:

Image result for imperial palace tokyo

 Image result for sensoji

Share

Japanese researchers develop new 30-minute method to detect Ebola virus

 Uncategorized  Comments Off on Japanese researchers develop new 30-minute method to detect Ebola virus
Sep 042014
 
Ebola

Researchers from the Nagasaki University in Japan have developed a new method to detect the presence of Ebola virus in 30 minutes.

The new method is claimed to allow doctors to rapidly diagnose the infection.

Professor Jiro Yasuda and team was quoted by AFP as saying that the newly developed process is cheaper than the system, which is currently in use in West Africa where the virus has already claimed around 1,500 lives.

Yasuda said: “The new method is simpler than the current one and can be used in countries where expensive testing equipment is not available.

Japanese researchers develop new 30-minute method to detect Ebola virus

http://www.pharmaceutical-technology.com/news/newsjapanese-researchers-develop-new-30-minute-method-detect-ebola-virus-4360875?WT.mc_id=DN_News
Researchers from the Nagasaki University in Japan have developed a new method to detect the presence of Ebola virus in 30 minutes.

Tokyo (AFP) – Japanese researchers said Tuesday they had developed a new method to detect the presence of the Ebola virus in 30 minutes, with technology that could allow doctors to quickly diagnose infection.

Professor Jiro Yasuda and his team at Nagasaki University say their process is also cheaper than the system currently in use in west Africa where the virus has already killed more than 1,500 people.

“The new method is simpler than the current one and can be used in countries where expensive testing equipment is not available,” Yasuda told AFP by telephone.

“We have yet to receive any questions or requests, but we are pleased to offer the system, which is ready to go,” he said.

Yasuda said the team had developed what he called a “primer”, which amplifies only those genes specific to the Ebola virus found in a blood sample or other bodily fluid.

Using existing techniques, ribonucleic acid (RNA) — biological molecules used in the coding of genes — is extracted from any viruses present in a blood sample.

This is then used to synthesise the viral DNA, which can be mixed with the primers and then heated to 60-65 degrees Celsius (140-149 Fahrenheit).

If Ebola is present, DNA specific to the virus is amplified in 30 minutes due to the action of the primers. The by-products from the process cause the liquid to become cloudy, providing visual confirmation, Yasuda said.

Currently, a method called polymerase chain reaction, or PCR, is widely used to detect the Ebola virus, which requires doctors to heat and cool samples repeatedly and takes up to two hours.

“The new method only needs a small, battery-powered warmer and the entire system costs just tens of thousands of yen (hundreds of dollars), which developing countries should be able to afford,” he added.

The outbreak of the Ebola virus, transmitted through contact with infected bodily fluids, has sparked alarm throughout western Africa and further afield.

JAPAN

 

Share

Mitsubishi Tanabe Pharma Corp. and Daiichi Sankyo Co. Ltd., announced that Mitsubishi Tanabe Pharma has received approval to manufacture and market the SGLT2 inhibitor, Canaglu tablets (canagliflozin hydrate) 100 mg in Japan

 japan  Comments Off on Mitsubishi Tanabe Pharma Corp. and Daiichi Sankyo Co. Ltd., announced that Mitsubishi Tanabe Pharma has received approval to manufacture and market the SGLT2 inhibitor, Canaglu tablets (canagliflozin hydrate) 100 mg in Japan
Jul 082014
 

 

 

NEWS

Diabetes Drug Receives MMA in Japan

Mitsubishi Tanabe Pharma Corp. and Daiichi Sankyo Co. Ltd., announced that Mitsubishi Tanabe Pharma has received approval to manufacture and market the SGLT2 inhibitor, Canaglu tablets (canagliflozin hydrate) 100 mg in Japan, for the treatment of patients with type 2 diabetes mellitus. Read more…

http://www.dddmag.com/news/2014/07/diabetes-drug-receives-mma-japan?et_cid=4034150&et_rid=523035093&type=headline

FULL STORY
Share
Dec 182013
 

TOFOGLIFLOZIN

托格列净

CSG-452, R-7201, RG-7201

CAS..1201913-82-7 monohydrate

903565-83-3 (anhydrous)

(1S,3′R,4′S,5′S,6′R)-6-(4-Ethylbenzyl)-6′-(hydroxymethyl)-3′,4′,5′,6′-tetrahydro-3H-spiro[2-benzofuran-1,2′-pyran]-3′,4′,5′-triol hydrate (1:1)

PMDA Pharmaceuticals and Medical Devices Agency, Japan Approved mar24, 2014

 

THERAPEUTIC CLAIM Treatment of diabetes mellitus
CHEMICAL NAMES
1. Spiro[isobenzofuran-1(3H),2′-[2H]pyran]-3′,4′,5′-triol, 6-[(4-ethylphenyl)methyl]-3′,4′,5′,6′-tetrahydro-6′-(hydroxymethyl)-, hydrate (1:1), (1S,3’R,4’S,5’S,6’R)-
2. (1S,3’R,4’S,5’S,6’R)-6-[(4-ethylphenyl)methyl]-6′-(hydroxymethyl)-3′,4′,5′,6′-tetrahydro-3H-spiro[2-benzofuran-1,2′-pyran]-3′,4′,5′-triol monohydrate
3. (1S,3’R,4’S,5’S,6’R)-6-[(4-ethylphenyl)methyl]-3′,4′,5′,6′-tetrahydro-6′-(hydroxymethyl)-
spiro[isobenzofuran-1(3H),2′-[2H]pyran]-3′,4′,5′-triol monohydrate

(3S,3’R,4’S,5’S,6’R)-5-[(4-ethylphenyl)methyl]-6′-(hydroxymethyl)spiro[1H-2-benzofuran-3,2′-oxane]-3′,4′,5′-triol;hydrate

MW404.5, MF C22H26O6

INNOVATOR  Chugai Pharmaceuticals

Sanofi, kowa

Deberza®………..KOWA/Apleway®……………SANOFI

CODE DESIGNATION CSG 452

Tofogliflozin (USAN, codenamed CSG452) is an experimental drug for the treatment of diabetes mellitus and is being developed byChugai Pharma in collaboration with Kowa and Sanofi.[1] It is an inhibitor of subtype 2 sodium-glucose transport protein (SGLT2), which is responsible for at least 90% of the glucose reabsorption in the kidney. As of September 2012, the drug is in Phase III clinical trials.[2][3]

Tofogliflozin is an SGLT-2 inhibitor first launched in 2014 in Japan by Sanofi and Kowa for the oral treatment of type II diabetes.

The product was discovered by Chugai and was licensed to Roche in 2007. In 2011, this license agreement was terminated. In 2012, the product was licensed to Kowa and Sanofi by Chugai Pharmaceutical in Japan for the treatment of diabetes type 2. In 2015, the license between Kowa and Chugai was expanded for developments and marketing of the agent in the U.S. and the E.U.

Chemistry

The active moiety or anhydrous form (ChemSpider ID: 28530778, CHEMBL2110731) has the chemical formula C22H26O6 and amolecular mass of 386.44 g/mol.

The United States Adopted Name tofogliflozin applies to the monohydrate, which is the form used as a drug.[4] The International Nonproprietary Name tofogliflozin applies to the anhydrous compound[5] and the drug form is referred to as tofogliflozin hydrate.

Several drugs are available for the treatment of type 2 diabetes mellitus (T2DM), but few patients achieve and maintain glycaemic control without weight gain and hypoglycaemias. Sodium glucose co-transporter 2 (SGLT-2) inhibitors are an emerging class of drugs with an original mechanism of action involving inhibition of renal glucose reabsorption. Two agents of this class, dapagliflozin and canagliflozin, have already been approved, although we need more data on cardiovascular outcomes along with bladder and breast cancer. Tofogliflozin is a further SGLT-2 inhibitor, which exhibits the highest selectivity for SGLT-2, the most potent antidiabetic action and a reduced risk of hypoglycaemia. Recently, a 52-week, multicentre, open-label, randomised controlled trial in Japanese T2DM patients has shown that tofogliflozin exhibits adequate safety and efficacy as monotherapy or as add-on treatment in patients suboptimally controlled with oral agents. Despite the very promising characteristics of this new drug, important questions remain to be answered, mainly additional data on safety outcomes and potential beneficial effects of tofogliflozin, for instance in prediabetes and diabetic nephropathy. Moreover, it would be welcome to examine the utility of its therapeutic use in combination with insulin and metformin.

Tofogliflozin has recently demonstrated safety and efficacy as monotherapy or add-on treatment . This is very important, granted our expectations of SGLT-2 inhibitors as useful alternative oral hypoglycaemic agents. Although important questions remain to be answered, the results of the new trial add to the importance of SGLT-2 inhibitors as a useful new class of oral hypoglycaemic agents.

 

CLIP

There are two scalable synthetic routes reported to prepare tofogliflozin.2 An efficient production synthesis of tofogliflozin hydrate from alcohol 2 was first described by Murakata et al. (Scheme 1, route 1).2a In 2016, Ohtake et al. reported an improved synthetic route, which achieved in just 7 linear steps (Scheme 1, route 2).2b They selected the optimal protecting groups for the purpose of chemoselective activation and crystalline purification, and obtained the pure tofogliflozin in a good overall yield. However, these methods suffer from several drawbacks. Firstly, some reagents, such as BH3 (Scheme 1, route 2) and 2-Methoxyproene (3, Scheme 1), are toxic or highly volatile. Meanwhile, the use of Palladium reagents may lead to an excess of residual heavy metal in the final product. Secondly, manufacturing costs in these methods are high due to the application of expensive raw materials and reagents. Last but not least, the key tactical stages that involve Br/Li exchange of aryl bromide followed by addition to gluconolactone 5 need the cryogenic conditions (< -60 oC), and this method is not suitable for industrial production. Herein, we report a newly developed synthetic method for tofogliflozin hydrate starting from readily available raw materials and affording good overall yield.

SCHEME 2 FOR

 

2. (a) Murakata, M.; Ikeda, T.; Kimura, N.; Kawase, A.; Nagase, M.; Yamamoto, K.; Takata, N.; Yoshizaki, S.; Takano, K. Crystal of spiroketal derivative, and process for production thereof. European Appl. EP 2308886 A1, April 13, 2011. (b) Ohtake, Y.; Emura, T.; Nishimoto, M.; Takano, K.; Yamamoto, K.; Tsuchiya, S.; Yeu, S.; Kito, Y.; Kimura, N.; Takeda, S.; Tsukazaki, M.; Murakata, M.; Sato, T. J. Org. Chem. 2016, 81, 2148.

 

 

Antidiabetic mechanism of SGLT-2 inhibitors.

CLIP

Ohtake, Y.; Sato, T.; Kobayashi, T.; Nishimoto, M.; Taka, N.; Takano, K.; Yamamoto, K.; Ohmori, M.; Yamaguchi, M.; Takami, K.; Yeu, S.-H.; Ahn, K.-H.; Matsuoka, H.; Morikawa, K.; Suzuki, M.; Hagita, H.; Ozawa, K.; Yamaguchi, K.; Kato, M.; Ikeda, S. J. Med. Chem. 2012, 55, 7828−7840

DOI: 10.1021/acs.joc.5b02734 J. Org. Chem. 2016, 81, 2148−2153

STR1

 

STR1

(1S,3′R,4′S,5′S,6′R)-6-[(4-Ethylphenyl)methyl]-6′-(hydroxymethyl)-3′,4′,5′,6′-tetrahydro-3H-spiro[2-benzofuran-1,2′- pyran]-3′,4′,5′-triol (1, tofogliflozin).

To a solution of 17b (89.9 g, 145 mmol) in DME (653 mL) and MeOH (73.0 mL), 2 N NaOH aq. solution (726 mL, 1.45 mol) was added dropwise for 1 h at waterbath temperature. After stirring at rt for 1 h, 2 N H2SO4 aq. solution (436 mL) was added slowly to the mixture. Water (700 mL) was added to the mixture, and the resultant mixture was extracted with AcOEt (500 mL × 2). The resultant organic layer was washed with brine (1.00 L) and then dried over anhydrous Na2SO4 (250 g). The mixture was concentrated in vacuo to obtain 1 (57.3 g, quant) as a colorless amorphous solid;

[α]D 26 +24.2° (c 1.02, MeOH);

1 H NMR (400 MHz, CD3OD) δ: 1.19 (3H, t, J = 7.6 Hz), 2.58 (2H, q, J = 7.6 Hz), 3.42−3.47 (1H, m), 3.63−3.67 (1H, m), 3.75−3.88 (4H, m), 3.95 (2H, s), 5.06 (1H, d, J = 12.5 Hz), 5.12 (1H, d, J = 12.5 Hz), 7.07−7.14 (4H, m), 7.17−7.23 (3H, m);

13C NMR (100 MHz, CD3OD) δ: 16.3, 29.4, 42.3, 62.8, 71.9, 73.4, 74.9, 76.2, 76.4, 111.6, 121.8, 123.6, 128.9, 129.9, 131.1, 139.7, 139.9, 140.2, 142.6, 143.2;

MS (ESI) m/z: 387 [M + H]+ ; HRMS (ESI) calcd for C22H27O6 [M + H]+ 387.1802, found 387.1801

DOI: 10.1021/acs.joc.5b02734 J. Org. Chem. 2016, 81, 2148−2153

Ohtake, Y.; Sato, T.; Kobayashi, T.; Nishimoto, M.; Taka, N.; Takano, K.; Yamamoto, K.; Ohmori, M.; Yamaguchi, M.; Takami, K.; Yeu, S.-H.; Ahn, K.-H.; Matsuoka, H.; Morikawa, K.; Suzuki, M.; Hagita, H.; Ozawa, K.; Yamaguchi, K.; Kato, M.; Ikeda, S. J. Med. Chem. 2012, 55, 7828−7840

 

 

str1

 

 

 

SGLT2 inhibitors inhibitors represent a novel class of agents that are being developed for the treatment or improvement in glycemic control in patients with type 2 diabetes. Glucopyranosyl-substituted benzene derivative are described in the prior art as SGLT2 inhibitors, for example in

WO 01/27128, WO 03/099836, WO 2005/092877, WO 2006/034489,

WO 2006/064033, WO 2006/117359, WO 2006/117360,

WO 2007/025943, WO 2007/028814, WO 2007/031548,

WO 2007/093610, WO 2007/128749, WO 2008/049923, WO 2008/055870, WO 2008/055940.

 

PATENTS

WO 2006080421

WO2009154276A1

WO 2011074675

WO 2012115249

 

Papers

Chinese Chemical Letters, 2013 ,  vol. 24,  2  pg. 131 – 133

Journal of Medicinal Chemistry, 2012 ,  vol. 55,  17  pg. 7828 – 7840

NMR

STR1

STR1
WO 2011074675

Figure JPOXMLDOC01-appb-C000048

1 H-NMR (CD 3 OD) δ: 1.19 (3H, t, J = 7.5Hz), 2.59 (2H, q, J = 7.5Hz) ,3.42-3 .46 (1H , m), 3.65 (1H, dd, J = 5.5,12.0 Hz) ,3.74-3 .82 (4H, m), 3.96 (2H, s), 5.07 (1H , d, J = 12.8Hz), 5.13 (1H, d, J = 12.8Hz) ,7.08-7 .12 (4H, m) ,7.18-7 .23 (3H, m) .
MS (ESI +): 387 [M +1] +.

 

 

Second set

http://pubs.acs.org/doi/full/10.1021/jm300884k

J. Med. Chem., 2012, 55 (17), pp 7828–7840

DOI: 10.1021/jm300884k

1H NMR (400 MHz, CD3OD) δ: 1.20 (3H, t, J = 7.6 Hz), 2.58 (2H, q, J = 7.6 Hz), 3.42–3.47 (1H, m), 3.63–3.67 (1H, m), 3.75–3.88 (4H, m), 3.95 (2H, s), 5.06 (1H, d, J = 12.3 Hz), 5.12 (1H, d, J = 12.5 Hz), 7.07–7.14 (4H, m), 7.17–7.23 (3H, m).

13C NMR (100 MHz, CD3OD) δ: 16.3, 29.4, 42.3, 62.8, 71.9, 73.4, 74.9, 76.2, 76.4, 111.6, 121.8, 123.6, 128.9, 129.9, 131.1, 139.7, 139.9, 140.2, 142.6, 143.2.

MS (ESI): 387 [M + H]+. HRMS (ESI), m/z calcd for C22H27O6 [M + H]+ 387.1802, found 387.1801.

THIRD SET

(1S,3′R,4′S,5′S,6′R)-6-[(4-Ethylphenyl)methyl]-6′-(hydroxymethyl)-3′,4′,5′,6′-tetrahydro-3H-spiro[2-benzofuran-1,2′- pyran]-3′,4′,5′-triol (1, tofogliflozin).

To a solution of 17b (89.9 g, 145 mmol) in DME (653 mL) and MeOH (73.0 mL), 2 N NaOH aq. solution (726 mL, 1.45 mol) was added dropwise for 1 h at waterbath temperature. After stirring at rt for 1 h, 2 N H2SO4 aq. solution (436 mL) was added slowly to the mixture. Water (700 mL) was added to the mixture, and the resultant mixture was extracted with AcOEt (500 mL × 2). The resultant organic layer was washed with brine (1.00 L) and then dried over anhydrous Na2SO4 (250 g). The mixture was concentrated in vacuo to obtain 1 (57.3 g, quant) as a colorless amorphous solid;

[α]D 26 +24.2° (c 1.02, MeOH);

1 H NMR (400 MHz, CD3OD) δ: 1.19 (3H, t, J = 7.6 Hz), 2.58 (2H, q, J = 7.6 Hz), 3.42−3.47 (1H, m), 3.63−3.67 (1H, m), 3.75−3.88 (4H, m), 3.95 (2H, s), 5.06 (1H, d, J = 12.5 Hz), 5.12 (1H, d, J = 12.5 Hz), 7.07−7.14 (4H, m), 7.17−7.23 (3H, m);

13C NMR (100 MHz, CD3OD) δ: 16.3, 29.4, 42.3, 62.8, 71.9, 73.4, 74.9, 76.2, 76.4, 111.6, 121.8, 123.6, 128.9, 129.9, 131.1, 139.7, 139.9, 140.2, 142.6, 143.2;

MS (ESI) m/z: 387 [M + H]+ ; HRMS (ESI) calcd for C22H27O6 [M + H]+ 387.1802, found 387.1801

DOI: 10.1021/acs.joc.5b02734 J. Org. Chem. 2016, 81, 2148−2153

Ohtake, Y.; Sato, T.; Kobayashi, T.; Nishimoto, M.; Taka, N.; Takano, K.; Yamamoto, K.; Ohmori, M.; Yamaguchi, M.; Takami, K.; Yeu, S.-H.; Ahn, K.-H.; Matsuoka, H.; Morikawa, K.; Suzuki, M.; Hagita, H.; Ozawa, K.; Yamaguchi, K.; Kato, M.; Ikeda, S. J. Med. Chem. 2012, 55, 7828−7840

 

PATENT

Prepn

WO 2011074675

[Example 1] (1S, 3’R, 4’S, 5’S, 6’R) -6 – [(4 – ethyl-phenyl) methyl] -3 ‘, 4’, 5 ‘, 6′-tetrahydro- -6′-(hydroxymethyl) – spiro [isobenzofuran -1 (3H), 2’-[2H] pyran] -3 ‘, 4′, one of the preparation step [compound of formula (IX)] 5’-triol Preparation of methanol (2 – hydroxymethyl-phenyl – bromo-4)

 

Figure JPOXMLDOC01-appb-C000042

 

To the mixing solution (1mol / L, 78.9kg, 88.4mol) of borane-tetrahydrofuran complex in tetrahydrofuran (6.34kg, 61.0mol) and, trimethoxyborane, two tetrahydrofuran (33.1kg) in – bromoterephthalic was added at below 30 ℃ solution (7.5kg, 30.6mol) of the acid, and the mixture was stirred for 1 hour at 25 ℃. Then cooled to 19 ℃ The reaction mixture was stirred for 30 minutes and added a mixed solution of tetrahydrofuran and methanol (3.0kg) of (5.6kg). In addition to methanol (15.0kg) in the mixture was kept for a while.

Again, to the mixing solution (1mol / L, 78.9kg, 88.4mol) of borane-tetrahydrofuran complex in tetrahydrofuran (6.34kg, 61.0mol) and, trimethoxyborane, two tetrahydrofuran (33.0kg) in – was added at below 30 ℃ solution (7.5kg, 30.6mol) of bromo terephthalic acid, and the reaction was carried out for 1 hour at 25 ℃. Then cooled to 18 ℃ The reaction mixture was stirred for 30 minutes and added a mixed solution of tetrahydrofuran and methanol (3.0kg) of (5.6kg). After addition of methanol (15.0kg) in the mixture is combined with the reaction mixture obtained in the previous reaction, and then the solvent was distilled off under reduced pressure. After addition of methanol (36kg) residue was obtained, and the solvent was evaporated under reduced pressure. Furthermore, (54 ℃ dissolved upon confirmation) which was dissolved by warming was added to methanol (36kg) to the residue. After cooling to room temperature the solution was stirred for 30 minutes added water (60kg). After addition of water (165kg) In addition to this mixture was cooled to 0 ℃, and the mixture was stirred for one hour. Centrifuge the obtained crystals were washed twice with water (45kg), and dried for 2 hours under reduced pressure to give (11.8kg, 54.4mol, 89% yield) of the title compound.

1 H-NMR (DMSO-d 6) δ: 4.49 (4H, t, J = 5.8Hz), 5.27 (1H, t, J = 5.8Hz), 5.38 (1H, t, J = 5.8Hz), 7.31 (1H, d, J = 7.5Hz), 7.47 (1H, d, J = 7.5Hz), 7.50 (1H, s).

Preparation of benzene (ethoxy methyl – methyl – – methoxy-1 1) – bromo-1 ,4 – 2:2 process bis

 

Figure JPOXMLDOC01-appb-C000043

 

(- Bromo-4 – 2-hydroxyethyl methyl phenyl) in tetrahydrofuran (57kg) in the solution (8.0kg, 36.9mol) of methanol, I added (185.12g, 0.74mol) of pyridinium p-toluenesulfonate. After cooling to -15 ℃ below the mixture, 2 – was added at -15 ℃ or less (7.70kg, 106.8mol) methoxy propene, and the mixture was stirred 1 h at -15 ~ 0 ℃. Was added aqueous potassium carbonate (25 wt%, 40kg) and the reaction mixture was warmed to room temperature and separate the organic layer was added toluene (35kg). After washing with water (40kg) The organic layer was evaporated under reduced pressure. Was dissolved in toluene (28kg) and the residue obtained was obtained as a toluene solution of the title compound.

1 H-NMR (CDCl 3) δ: 1.42 (6H, s), 1.45 (6H, s), 3.24 (3H, s), 3.25 (3H, s), 4.45 ( 2H, s), 4.53 (2H, s), 7.28 (1H, dd, J = 1.5,8.0 Hz), 7.50 (1H, d, J = 8.0Hz), 7. 54 (1H, d, J = 1.5Hz).
MS (ESI +): 362 [M +2] +.

Preparation of on – (3R, 4S, 5R, 6R) -3,4,5 – tris (trimethylsilyloxy)-6 – trimethylsilyloxy methyl – tetrahydropyran-2: Step 3

 

Figure JPOXMLDOC01-appb-C000044

 

Glucono -1,5 – – D-(+) in tetrahydrofuran (70kg) in the solution (35.8kg, 353.9mol) of N-methylmorpholine (7.88kg, 44.23mol) and lactone, chlorotrimethylsilane ( was added at 40 ℃ less 29.1kg, and 267.9mol), and the mixture was stirred for 2 hours at 30 ~ 40 ℃ resulting mixture. Was cooled to 0 ℃ the reaction mixture was added toluene (34kg) water (39kg), and the organic layer was separated. Twice sodium dihydrogen phosphate aqueous solution (5 wt%, 39.56kg) in, washed once with water (39kg) the organic layer the solvent was evaporated under reduced pressure. Was dissolved in toluene (34.6kg) and the residue obtained was obtained as a toluene solution of the title compound.

1 H-NMR (CDCl 3) δ: 0.13 (9H, s), 0.17 (9H, s), 0.18 (9H, s), 0.20 (9H, s), 3.74- 3.83 (3H, m), 3.90 (1H, t, J = 8.0Hz), 3.99 (1H, d, J = 8.0Hz), 4.17 (1H, dt, J = 2 .5,8.0 Hz).

Step 4: (1S, 3’R, 4’S, 5’S, 6’R) -3 ‘, 4’, 5 ‘, 6′-tetrahydro -6,6′ – bis (hydroxymethyl) – spiro [ (3H), 2’-[2H] pyran] -3 ‘, 4′, 5’-Preparation of triol isobenzofuran-1

 

Figure JPOXMLDOC01-appb-C000045

 

(Methyl – – – methoxy 1-ethoxy-methyl) – bromo-1 ,4 – 2 prepared in step 2 bis cooled to below -10 ℃ toluene solution of benzene, hexane solution to (15 wt% n-butyl lithium , was added at below 0 ℃ 18.2kg, and 42.61mol), and the mixture was stirred 1.5 h at 5 ℃ resulting mixture. (10.5kg, 40.7mol), was added tetrahydrofuran (33.4kg) then magnesium bromide diethyl ether complex in the mixture, and the mixture was stirred for 1 hour at 25 ℃. Was added at below -10 ℃ toluene solution of the on – tris (trimethylsilyloxy) -6 – – 3,4,5 cooled to -15 ℃ below the mixture prepared in step 3 trimethylsilyloxy methyl – tetrahydropyran-2 was. After stirring 0.5 h at -15 ℃ or less, poured into 20% aqueous ammonium chloride solution to (80kg) of this solution, and the organic layer was separated. After washing with water (80kg) and the organic layer obtained, and the solvent was evaporated under reduced pressure. I was dissolved in methanol (43kg) residue was obtained. Was stirred for 1 hour at 20 ℃ was added (1.4kg, 7.4mol) and p-toluenesulfonic acid monohydrate in the mixture. Thereafter, it was stirred for another hour and cooled to 0 ℃, centrifuged crystals obtained was washed with methanol (25kg), and dried for 8 hours at reduced pressure under 40 ℃, (5.47kg, yield the title compound I got 50%) rate.

1 H-NMR (DMSO-d 6) δ :3.20-3 .25 (1H, m) ,3.41-3 .45 (1H, m) ,3.51-3 .62 (4H, m) , 4.39 (1H, t, J = 6.0Hz) ,4.52-4 .54 (3H, m), 4.86 (1H, d, J = 4.5Hz), 4.93 (1H, d, J = 5.5Hz), 4.99 (1H, d, J = 12.5Hz), 5.03 (1H, d, J = 12.5Hz), 5.23 (1H, t, J = 5 .8 Hz) ,7.24-7 .25 (2H, m), 7.29 (1H, dd, J = 1.5,8.0 Hz).

Step 5: (1S, 3’R, 4’S, 5’S, 6’R) -6 – [(methoxycarbonyl) methyl] -3 ‘, 4’, 5 ‘, 6′-tetrahydro-3’ , 4 ‘, 5′-tris (methoxycarbonyl) oxy-6′-[(methoxycarbonyl) methyl] – Preparation of [(3H), 2’-[2H] pyran isobenzofuran] spiro

 

Figure JPOXMLDOC01-appb-C000046

 

(1S, 3’R, 4’S, 5’S, 6’R) – tetrahydro -6,6 ‘- bis (hydroxymethyl) – spiro [isobenzofuran -1 (3H), 2’-[2H] pyran ] -3 ‘, 4′, 5’-triol 4 (5.3kg, 17.8mol) and – dissolved in acetonitrile (35kg) (13.7kg, 112.1mol) a chloroformate, in the solution of dimethylaminopyridine I was added at 12 ℃ or less (10.01kg, 105.9mol) methyl. Heated to 20 ℃, After stirring for 1 h, was added ethyl acetate (40kg) and water (45kg), and the organic layer was separated and the mixture. Once (45.4kg) aqueous solution consisting of (9.01kg) sodium chloride and potassium hydrogen sulfate (1.35kg), sodium chloride aqueous solution (weight 10%, 44.5kg), sodium chloride aqueous solution (the organic layer was washed successively 20% by weight, in 45.0kg), and the solvent was evaporated under reduced pressure. Was dissolved in ethylene glycol dimethyl ether (18kg) and the residue obtained was then evaporated under reduced pressure. Was dissolved in ethylene glycol dimethyl ether (13.2kg) again and the residue obtained was obtained as ethylene glycol dimethyl ether solution of the title compound. I was used as it was in the six step.

1 H-NMR (CDCl 3) δ: 3.54 (3H, s), 3.77 (6H, s), 3.811 (3H, s), 3.812 (3H, s), 4.23 ( 1H, dd, J = 2.8,11.9 Hz), 4.32 (1H, dd, J = 4.0,11.9 Hz) ,4.36-4 .40 (1H, m), 5.11 -5.24 (5H, m), 5.41 (1H, d, J = 9.8Hz), 5.51 (1H, t, J = 9.8Hz), 7.25 (1H, d, J = 7.5Hz), 7.42 (1H, d, J = 7.5Hz), 7.44 (1H, s).
MS (ESI +): 589 [M +1] +, 606 [M +18] +.

Step 6: (1S, 3’R, 4’S, 5’S, 6’R) -6 – [(4 – ethyl-phenyl) methyl] -3 ‘, 4’, 5 ‘, 6’-tetrahydro-3 ‘4’, 5′-tris (methoxycarbonyl) oxy-6′-[(methoxycarbonyl) methyl] – Preparation of [(3H), 2′-[2H] pyran isobenzofuran] spiro

 

Figure JPOXMLDOC01-appb-C000047

 

[(Methoxycarbonyl) methyl] -3 ‘, 4’, 5 ‘, 6’-tetrahydro – (1S, 3’R, 4’S, 5’S, 6’R) -6 which had been prepared in Step 5 – 3 ‘, 4′, 5′-tris (methoxycarbonyl) oxy-6′-[(methoxycarbonyl) methyl] – spiro [isobenzofuran -1 (3H), 2’-[2H] pyran] Ethylene glycol dimethyl ether in solution, 2 – (2.46kg, 17.8mol), 4 butanol (25kg), anhydrous potassium carbonate – – methyl-2 were sequentially added (3.73kg, 24.9mol) ethyl phenyl boronic acid, in the reaction vessel was replaced with argon atmosphere, was bubbled with argon mixture. To the mixture – after the addition (0.72kg, 0.88mol) and palladium (II) chloride dichloromethane adduct [1,1 ‘-bis (diphenylphosphino) ferrocene], it was replaced with argon again inside of the vessel, one at 80 ℃ I was stirring time. After cooling, I added sequentially (0.859kg, 5.3mol) of ethylene glycol dimethyl ether (9.85kg), ethyl acetate (19kg), N-acetyl-L-cysteine ​​in the mixture. After stirring for 2.5 h the mixture was filtered and added Celite (5.22kg), and washed with ethyl acetate (78kg) and the filter residue. The combined washings and filtrate, and the solvent is evaporated off under reduced pressure, and in addition (0.58kg, 3.6mol) and ethanol (74kg), N-acetyl-L-cysteine ​​residue was obtained, which is heated to 70 ℃ or I was dissolved residue is then. After addition of water (9.4kg) in the solution, cooled to 60 ℃, and the mixture was stirred for 1 h. After confirming solid precipitated, cooled to 0 ℃ from 60 ℃ over 2.5 hours or more The mixture was stirred for 1 hour or more at 5 ℃ less. Centrifuge the resulting solid was washed twice with a mixture of water (35kg) and ethanol (55kg). Was dissolved at 70 ℃ ethanol (77kg) again, wet powder was obtained (10.21kg), cooled to 60 ℃ added water (9.7kg), and the mixture was stirred for 1 h. After confirming solid precipitated, cooled to 0 ℃ from 60 ℃ over 2.5 hours or more, and the mixture was stirred for 1 hour or more at 5 ℃ less. (9.45kg, dry powder rate 8.47kg, 13.7mol which was centrifuged obtained crystals were washed with a mixture of water (32kg) and ethanol (51kg), was obtained as a moist powder the title compound, 77% overall yield from the previous step).

1 H-NMR (CDCl 3) δ: 1.20 (3H, t, J = 7.5Hz), 2.60 (2H, q, J = 7.5Hz), 3.50 (3H, s), 3 .76 (3H, s), 3.77 (3H, s), 3.81 (3H, s), 3.96 (2H, s), 4.23 (1H, dd, J = 2.8,11 .9 Hz), 4.33 (1H, dd, J = 4.5,11.9 Hz) ,4.36-4 .40 (1H, m) ,5.11-5 .20 (3H, m), 5 .41 (1H, d, J = 10.0Hz), 5.51 (1H, t, J = 10.0Hz) ,7.07-7 .11 (4H, m), 7.14 (1H, d, J = 7.8Hz), 7.19 (1H, dd, J = 1.5,7.8 Hz), 7.31 (1H, d, J = 1.5Hz).
MS (ESI +): 619 [M +1] +, 636 [M +18] +.

Step 7: (1S, 3’R, 4’S, 5’S, 6’R) -6 – [(4 – ethyl-phenyl) methyl] -3 ‘, 4’, 5 ‘, 6’-tetrahydro-6 , 4 ‘, 5′-Preparation of triol’ – -3 [(3H), 2′-[2H] pyran isobenzofuran] spiro – (hydroxymethyl) ‘

 

Figure JPOXMLDOC01-appb-C000048

 

(1S, 3’R, 4’S, 5’S, 6’R) -6 – [(4 – ethyl-phenyl) methyl] -3 ‘, 4’, 5 ‘, 6′-tetrahydro-3’, 4 ‘, 5′-tris (methoxycarbonyl) oxy-6′-[(methoxycarbonyl) methyl] – wet powder spiro [(3H), 2’-[2H] pyran isobenzofuran -1] (8.92kg, In addition at 20 ℃ (4mol / L, 30.02kg, the 104.2mol) aqueous solution of sodium hydroxide, 1 hour the reaction mixture to a solution of (28kg) ethylene glycol dimethyl ether dry end conversion 8.00kg, of 12.9mol) the mixture was stirred. And the organic layer was separated by addition of water (8.0kg) in the mixture. The ethyl acetate aqueous sodium chloride solution (25 wt%, 40kg) and a (36kg) in the organic layer and the aqueous layer was removed after washing. The washed again aqueous sodium chloride solution (25 wt%, 40kg) in the organic layer was evaporated under reduced pressure. Were added and acetone (32.0kg) water (0.8kg) residue was obtained. After the solvent was evaporated under reduced pressure, dissolved in acetone (11.7kg) in water (15.8kg) and the residue obtained was cooled to below 5 ℃. Was added below 10 ℃ water (64kg) to the mixture, and the mixture was stirred for 1 hour at below 10 ℃. Centrifuge the resulting crystals were washed with a mixture of water (8.0kg) and (1.3kg) acetone. For 8 hours through-flow drying 13 ~ 16 ℃ temperature ventilation, under the conditions of 24-33% relative humidity the wet powder, the monohydrate crystal (3.94kg, 9.7mol, 75% yield) of the title compound I was obtained as: (4.502 wt% water content).

Method of measuring the amount of water:
Analysis: coulometric KF titration analyzer: trace moisture measurement device manufactured by Mitsubishi Chemical Corporation Model KF-100
Anolyte: Aqua micron AX (manufactured by Mitsubishi Chemical Corporation)
Catholyte: Aqua micron CXU (manufactured by Mitsubishi Chemical Corporation)

1 H-NMR (CD 3 OD) δ: 1.19 (3H, t, J = 7.5Hz), 2.59 (2H, q, J = 7.5Hz) ,3.42-3 .46 (1H , m), 3.65 (1H, dd, J = 5.5,12.0 Hz) ,3.74-3 .82 (4H, m), 3.96 (2H, s), 5.07 (1H , d, J = 12.8Hz), 5.13 (1H, d, J = 12.8Hz) ,7.08-7 .12 (4H, m) ,7.18-7 .23 (3H, m) .
MS (ESI +): 387 [M +1] +.

 

PATENT

US20110306778

Example 1 Synthesis of 1,1-anhydro-1-C-[5-(4-ethylphenyl)methyl-2-(hydroxymethyl)phenyl]-β-D-glucopyranose Step 1: Synthesis of 3,4,5-tris(trimethylsilyloxy)-6-trimethylsilyloxymethyl-tetrahydropyran-2-one

 

Figure US20110306778A1-20111215-C00017

 

To a solution of D-(+)-glucono-1,5-lactone (7.88 kg) and N-methylmorpholine (35.8 kg) in tetrahydrofuran (70 kg) was added trimethylsilyl chloride (29.1 kg) at 40° C. or below, and then the mixture was stirred at a temperature from 30° C. to 40° C. for 2 hours. After the mixture was cooled to 0° C., toluene (34 kg) and water (39 kg) were added thereto. The organic layer was separated and washed with an aqueous solution of 5% sodium dihydrogen phosphate (39.56 kg×2) and water (39 kg×1). The solvent was evaporated under reduced pressure to give the titled compound as an oil. The product was used in the next step without further purification.

1H-NMR (CDCl3) δ: 0.13 (9H, s), 0.17 (9H, s), 0.18 (9H, s), 0.20 (9H, s), 3.74-3.83 (3H, m), 3.90 (1H, t, J=8.0 Hz), 3.99 (1H, d, J=8.0 Hz), 4.17 (1H, dt, J=2.5, 8.0 Hz).

Step 2: Synthesis of 2,4-dibromo-1-(1-methoxy-1-methylethoxymethyl)benzene

 

Figure US20110306778A1-20111215-C00018

 

Under a nitrogen atmosphere, to a solution of 2,4-dibromobenzyl alcohol (40 g, 0.15 mol) in tetrahydrofuran (300 ml) was added 2-methoxypropene (144 ml, 1.5 mol) at room temperature, and then the mixture was cooled to 0° C. At the same temperature, pyridinium p-toluenesulfonic acid (75 mg, 0.30 mmol) was added and the mixture was stirred for 1 hour. The reaction mixture was poured into a saturated aqueous solution of sodium hydrogen carbonate cooled to 0° C., and extracted with toluene. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the titled compound as an oil in quantitative yield. The product was used in the next step without further purification.

1H-NMR (CDCl3) δ: 1.44 (6H, s), 3.22 (3H, 4.48 (2H, s), 7.42 (1H, d, J=8.0 Hz), 7.44 (1H, dd, J=1.5, 8.0 Hz), 7.68 (1H, d, J=1.5 Hz).

Step 3: Synthesis of 2,3,4,5-tetrakis(trimethylsilyloxy)-6-trimethylsilyloxymethyl-2-(5-(4-ethylphenyl)hydroxymethyl-2-(1-methoxy-1-methylethoxymethyl)phenyl)tetrahydropyran

 

Figure US20110306778A1-20111215-C00019

 

Under a nitrogen atmosphere, 2,4-dibromo-1-(1-methoxy-1-methylethoxymethyl)benzene (70 g, 207 mmol), which was obtained in the previous step, was dissolved in toluene (700 mL) and t-butylmethyl ether (70 ml), and n-butyllithium in hexane (1.65 M, 138 ml, 227 mmol) was added dropwise at 0° C. over 30 minutes. After the mixture was stirred for 1.5 hours at 0° C., the mixture was added dropwise to a solution of 3,4,5-tris(trimethylsilyloxy)-6-trimethylsilyloxymethyl-tetrahydropyran-2-one (Example 1, 108 g, 217 mol) in tetrahydrofuran (507 ml) at −78° C., and the reaction mixture was stirred for 2 hours at the same temperature. Triethylamine (5.8 ml, 41 mmol) and trimethylsilyl chloride (29.6 ml, 232 mmol) were added thereto, and the mixture was warmed to 0° C. and stirred for 1 hour to give a solution containing 2,3,4,5-tetrakis(trimethylsilyloxy)-6-trimethylsilyloxymethyl-2-(5-bromo-2-(1-methoxy-1-methylethoxymethyl)phenyl)tetrahydropyran.

The resulting solution was cooled to −78° C., and n-butyllithium in hexane (1.65 M, 263 ml, 434 mmol) was added dropwise thereto at the same temperature. After the mixture was stirred at −78° C. for 30 minutes, 4-ethylbenzaldehyde (62 ml, 455 mmol) was added dropwise at −78° C., and the mixture was stirred at the same temperature for 2 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the organic layer was separated, and washed with water. The solvent was evaporated under reduced pressure to give a product containing the titled compound as an oil (238 g). The product was used in the next step without further purification.

A portion of the oil was purified by HPLC (column: Inertsil ODS-3, 20 mm I.D.×250 mm; acetonitrile, 30 mL/min) to give four diastereomers of the titled compound (two mixtures each containing two diastereomers).

Mixture of Diastereomers 1 and 2:

1H-NMR (500 MHz, CDCl3) δ: −0.47 (4.8H, s), −0.40 (4.2H, s), −0.003-0.004 (5H, m), 0.07-0.08 (1314, m), 0.15-0.17 (18H, m), 1.200 and 1.202 (3H, each t, J=8.0 Hz), 1.393 and 1.399 (3H, each s), 1.44 (3H, s), 2.61 (2H, q, J=8.0 Hz), 3.221 and 3.223 (3H, each s), 3.43 (1H, t, J=8.5 Hz), 3.54 (1H, dd, J=8.5, 3.0 Hz), 3.61-3.66 (1H, m), 3.80-3.85 (3H, m), 4.56 and 4.58 (1H, each d, J=12.4 Hz), 4.92 and 4.93 (1H, each d, J=12.4 Hz), 5.80 and 5.82 (1H, each d, J=3.0 Hz), 7.14 (2H, d, J=8.0 Hz), 7.28-7.35 (3H, m), 7.50-7.57 (2H, m).

MS (ESI+): 875 [M+Na]+.

Mixture of Diastereomers 3 and 4:

1H-NMR (500 MHz, toluene-d8, 80° C.) δ: −0.25 (4H, s), −0.22 (5H, s), 0.13 (5H, s), 0.16 (4H, s), 0.211 and 0.214 (9H, each s), 0.25 (9H, s), 0.29 (9H, s), 1.21 (3H, t, J=7.5 Hz), 1.43 (3H, s), 1.45 (3H, s), 2.49 (2H, q, J=7.5 Hz), 3.192 and 3.194 (3H, each s), 3.91-4.04 (4H, m), 4.33-4.39 (2H, m), 4.93 (1H, d, J=14.5 Hz), 5.10-5.17 (1H, m), 5.64 and 5.66 (1H, each s), 7.03 (2H, d, J=8.0 Hz), 7.28-7.35 (3H, m), 7.59-7.64 (1H, m), 7.87-7.89 (1H, m).

MS (ESI+): 875 [M+Na]+.

Step 4: Synthesis of 1,1-anhydro-1-C-[5-(4-ethylphenyl)hydroxymethyl-2-(hydroxymethyl)phenyl]-β-D-glucopyranose

 

Figure US20110306778A1-20111215-C00020

 

Under a nitrogen atmosphere, the oil containing 2,3,4,5-tetrakis(trimethylsilyloxy)-6-trimethylsilyloxymethyl-2-(5-(4-ethylphenyl)hydroxymethyl-2-(1-methoxy-1-methylethoxymethyl)phenyl)tetrahydropyran (238 g), which was obtained in the previous step, was dissolved in acetonitrile (693 ml). Water (37 ml) and 1N HCl aq (2.0 ml) were added and the mixture was stirred at room temperature for 5.5 hours. Water (693 ml) and n-heptane (693 ml) were added to the reaction mixture and the aqueous layer was separated. The aqueous layer was washed with n-heptane (693 ml×2), and water was evaporated under reduced pressure to give a product containing water and the titled compound (a diastereomer mixture) as an oil (187 g). The product was used in the next step without further purification.

1H-NMR (500 MHz, CD3OD) δ: 1.200 (3H, t, J=7.7 Hz), 1.201 (3H, t, J=7.7 Hz), 2.61 (2H, q, J=7.7 Hz), 3.44-3.48 (1H, m), 3.63-3.68 (111, m), 3.76-3.84 (4H, m), 5.09 (1H, d, J=12.8 Hz), 5.15 (1H, d, J=12.8 Hz), 5.79 (1H, s), 7.15 (2H, d, J=7.7 Hz), 7.24 and 7.25 (1H, each d, J=8.4 Hz), 7.28 (2H, d, J=7.7 Hz), 7.36 (1H, dd, J=8.4, 1.5 Hz), 7.40-7.42 (114, m).

MS (ESI+): 425 [M+Na]+.

Step 5: Synthesis of 1,1-anhydro-1-C-[5-(4-ethylphenyl)methyl-2-(hydroxymethyl)phenyl]-β-D-glucopyranose (crude product)

 

Figure US20110306778A1-20111215-C00021

 

To a solution of the oil containing 1,1-anhydro-1-C-[5-(4-ethylphenyl)hydroxymethyl-2-(hydroxymethyl)phenyl]-β-D-glucopyranose (187 g), which was obtained in the previous step, in 1,2-dimethoxyethane (693 ml) was added 5% Pd/C (26 g, 6.2 mmol, water content ratio: 53%), and the mixture was stirred in the atmosphere of hydrogen gas at room temperature for 4 hours. After filtration, the filtrate was evaporated under reduced pressure to give an oil containing the titled compound (59 g). The purity of the resulting product was 85.7%, which was calculated based on the area ratio measured by HPLC. The product was used in the next step without further purification.

1H-NMR (CD3OD) δ: 1.19 (3H, t, J=7.5 Hz), 2.59 (2H, q, J=7.5 Hz), 3.42-3.46 (1H, m), 3.65 (1H, dd, J=5.5, 12.0 Hz), 3.74-3.82 (4H, m), 3.96 (2H, s), 5.07 (1H, d, J=12.8 Hz), 5.13 (1H, d, J=12.8 Hz), 7.08-7.12 (4H, m), 7.18-7.23 (3H, m).

MS (ESI+): 387 [M+1]+.

Measurement Condition of HPLC:

Column: Cadenza CD-C18 50 mm P/NCD032

Mobile phase: Eluent A: H2O, Eluent B: MeCN

Gradient operation: Eluent B: 5% to 100% (6 min), 100% (2 min)

Flow rate: 1.0 mL/min

Temperature: 35.0° C.

Detection wavelength: 210 nm

Step 6: Synthesis of 1,1-anhydro-1-C-[5-(4-ethylphenyl)methyl-2-(hydroxymethyl)phenyl]-2,3,4,6-tetra-O-methoxycarbonyl-β-D-glucopyranose

 

Figure US20110306778A1-20111215-C00022

 

Under a nitrogen atmosphere, to a solution of the oil containing 1,1-anhydro-1-C-[5-(4-ethylphenyl)methyl-2-(hydroxymethyl)phenyl]-β-D-glucopyranose (59 g) and 4-(dimethylamino)pyridine (175 g, 1436 mmol) in acetonitrile (1040 ml) was added dropwose methyl chloroformate (95 ml, 1231 mmol) at 0° C. The mixture was allowed to warm to room temperature while stirred for 3 hours. After addition of water, the mixture was extracted with isopropyl acetate. The organic layer was washed with an aqueous solution of 3% potassium hydrogensulfate and 20% sodium chloride (three times) and an aqueous solution of 20% sodium chloride, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. To the resulting residue was added ethanol (943 mL) and the mixture was heated to 75° C. to dissolve the residue. The mixture was cooled to 60° C. and a seed crystal of the titled compound was added thereto. The mixture was cooled to room temperature and stirred for 1 hour. After precipitation of solid was observed, water (472 ml) was added thereto, and the mixture was stirred at room temperature for 2 hours. The resulting crystal was collected by filtration, washed with a mixture of water and ethanol (1:1), and dried under reduced pressure to give the titled compound (94 g). To the product (91 g) was added ethanol (1092 ml), and the product was dissolved by heating to 75° C. The solution was cooled to 60° C. and a seed crystal of the titled compound was added thereto. The mixture was cooled to room temperature and stirred for 1 hour. After precipitation of solid was observed, water (360 ml) was added thereto, and the mixture was stirred at room temperature for 2 hours. The resulting crystal was collected by filtration, washed with a mixture of water and ethanol (1:1), and dried under reduced pressure to give the titled compound [83 g, total yield from 2,4-dibromo-1-(1-methoxy-1-methylethoxymethyl)benzene used in Step 3: 68%].

1H-NMR (CDCl3) δ: 1.20 (3H, t, J=7.5 Hz), 2.60 (2H, q, J=7.5 Hz), 3.50 (3H, s), 3.76 (3H, s), 3.77 (3H, s), 3.81 (3H, s), 3.96 (2H, s), 4.23 (1H, dd, J=2.5, 11.8 Hz), 4.33 (1H, dd, J=4.5, 12.0 Hz), 4.36-4.40 (1H, m), 5.11-5.20 (3H, m), 5.41 (1H, d, J=10.0 Hz), 5.51 (1H, t, J=10.0 Hz), 7.07-7.11 (4H, m), 7.14 (1H, d, J=7.5 Hz), 7.19 (1H, dd, J=1.5, 7.8 Hz), 7.31 (1H, d, J=1.5 Hz).

MS (ESI+): 619 [M+1]+, 636 [M+18]+.

Another preparation was carried out in the same manner as Step 6, except that a seed crystal was not used, to give the titled compound as a crystal.

Step 7: Synthesis of 1,1-anhydro-1-C-[5-(4-ethylphenyl)methyl-2-(hydroxymethyl)phenyl]-β-D-glucopyranose

 

Figure US20110306778A1-20111215-C00023

 

To a solution of 1,1-anhydro-1-C-[5-(4-ethylphenyl)methyl-2-(hydroxymethyl)phenyl]-2,3,4,6-tetra-O-methoxycarbonyl-β-D-glucopyranose (8.92 kg as wet powder, corresponding to 8.00 kg of dry powder) in 1,2-dimethoxyethane (28 kg) was added a solution of sodium hydroxide (4 mol/L, 30.02 kg) at 20° C., and the mixture was stirred for 1 hour. Water (8.0 kg) was added to the mixture and the layers were separated. To the organic layer were added an aqueous solution of 25% sodium chloride (40 kg) and ethyl acetate (36 kg). The organic layer was separated, washed with an aqueous solution of 25% sodium chloride (40 kg), and the solvent was evaporated under reduced pressure. The purity of the resulting residue was 98.7%, which was calculated based on the area ratio measured by HPLC. To the resulting residue were added acetone (32.0 kg) and water (0.8 kg), and the solvent was evaporated under reduced pressure. To the resulting residue were added acetone (11.7 kg) and water (15.8 kg), and the solution was cooled to 5° C. or below. Water (64 kg) was added to the solution at 10° C. or below, and the mixture was stirred at the same temperature for 1 hour. The resulting crystal was collected by centrifugation, and washed with a mixture of acetone (1.3 kg) and water (8.0 kg). The resulting wet powder was dried by ventilation drying under a condition at air temperature of 13 to 16° C. and relative humidity of 24% to 33% for 8 hours, to give a monohydrate crystal (water content: 4.502%) of the titled compound (3.94 kg). The purity of the resulting compound was 99.1%, which was calculated based on the area ratio measured by HPLC.

1H-NMR (CD3OD) δ: 1.19 (3H, t, J=7.5 Hz), 2.59 (2H, q, J=7.5 Hz), 3.42-3.46 (1H, m), 3.65 (1H, dd, J=5.5, 12.0 Hz), 3.74-3.82 (4H, m), 3.96 (2H, s), 5.07 (1H, d, J=12.8 Hz), 5.13 (1H, d, J=12.8 Hz), 7.08-7.12 (4H, m), 7.18-7.23 (311, m).

MS (ESI+): 387 [M+1]+.

Measurement Condition of HPLC:

Column: Capcell pack ODS UG-120 (4.6 mm I.D.×150 mm, 3 μm, manufactured by Shiseido Co., Ltd.)

Mobile phase: Eluent A: H2O, Eluent B: MeCN

Mobile phase sending: Concentration gradient was controlled by mixing Eluent A and Eluent B as indicated in the following table.

 

TABLE 1
Time from
injection (min) Eluent A (%) Eluent B (%)
0 to 15 90→10 10→90
15 to 17.5 10 90
17.5 to 25 90 10

 

Flow rate: 1.0 mL/min

Temperature: 25.0° C.

Detection wavelength: 220 nm

Method for Measurement of Water Content:

Analysis method: coulometric titration method

KF analysis apparatus: Type KF-100 (trace moisture measuring apparatus manufactured by Mitsubishi Chemical Corporation)

Anode solution: Aquamicron AX (manufactured by Mitsubishi Chemical Corporation)

Cathode solution: Aquamicron CXU (manufactured by Mitsubishi Chemical Corporation)

 

 

PATENT

US20090030006

The compound of the present invention can be synthesized as shown in Scheme 1:

 

Figure US20090030006A1-20090129-C00005
Figure US20090030006A1-20090129-C00006

 

wherein R11 and R12 have the same meaning as defined above for substituents on Ar1, A is as defined above, and P represents a protecting group for a hydroxyl group.

CLIP

Tofogliflozin hydrate (Deberza)
Tofogliflozin hydrate, which is a sodium-glucose co-transporter 2 inhibitor, was approved in Japan for the treatment of type 2 diabetes
at the same time as luseogliflozin hydrate (XIX). The drug was discovered by Chugai Pharmaceutical and jointly developed
with Sanofi-Aventis and Kowa.263

Tofogliflozin hydrate reduces glucose levels by inhibiting the reuptake of glucose by selectively
inhibiting SGLT2, and plays a key role in the reuptake of glucose in the proximal tubule of the kidneys.264–266 The synthetic
approach described in Scheme 48 represents the largest scale reported to date in a patent application.263,266–268

Reduction of commercially available 2-bromoterephtalic acid (268, Scheme 48) through the use of trimethoxyborane and borane-THF proceeded in 89% yield to afford diol 269.

Subjection of this compound to 2-methoxypropene (270) under acidic conditions generated bis-acetonide 271. This bromide then underwent lithium–halogen exchange followed by exposure to magnesium bromide and treatment with lactone 272 (which was prepared by persilylation of commercially available (3R,4S,5S,6R)-3,4,5-trihydroxy-6-hydroxymethyl)tetrahydro-2Hpyran-2-one (277, Scheme 49).

This mixture was worked up with aqueous ammonium chloride and upon treatment with p-TsOH in methanol resulted in spiroacetal 273. Next, global protection of all alcohol functionalities within 273 was affected by reaction with methylchloroformate and DMAP in acetonitrile.

The benzyl carbonate within 274 was selectively exchanged via Suzuki coupling with 4-ethylphenylboronic acid (275) to afford methylene dibenzyl system 276. Subsequent treatment with aqueous sodium hydroxide in methanol followed by crystallization from 1:6 acetone and water furnished the desired product tofogliflozin hydrate (XXXIV) in 75% yield.

STR1

STR1

263 Takamitsu, K.; Tsutomu, S.; Masahiro, N. WO Patent 2006080421A1, 2006.
264. http://www.info.pmda.go.jp/shinyaku/P201400036/index.html.
265. Pafili, K.; Papanas, N. Expert Opin. Pharmacother. 2014, 15, 1197.

266. Ohtake, Y.; Sato, T.; Kobayashi, T.; Nishimoto, M.; Taka, N.; Takano, K.;Yamamoto, K.; Ohmori, M.; Yamaguchi, M.; Takami, K.; Yeu, S. Y.; Ahn, K. H.;Matsuoka, H.; Morikawa, K.; Suzuki, M.; Hagita, H.; Ozawa, K.; Yamaguchi, K.;Kato, M.; Ikeda, S. J. Med. Chem. 2012, 55, 7828.
267. Murakata, M.; Ikeda, T.; Kawase, A.; Nagase, M.; Kimura, N.; Takeda, S.;Yamamoto, K.; Takano, K.; Nishimoto, M.; Ohtake, Y.; Emura, T.; Kito, Y. WOPatent 2011074675A1, 2011.
268. Murakata, M.; Takuma, I.; Nobuaki, K.; Masahiro, N.; Kawase, A.; Nagase, M.;Yamamoto, K.; Takata, N.; Yoshizaki, S. WO Patent 2009154276A1, 2009.

 

Paper

A Scalable Synthesis of Tofogliflozin Hydrate

Pharmaceutical Research Center, Disha Pharmaceutical Group Co., Ltd., Weihai 264205, China
Org. Process Res. Dev., Article ASAP
Abstract Image

A newly process for the synthesis of tofogliflozin hydrate, a sodium-glucose cotransporter type 2 (SGLT2) inhibitor, was described. Three improvements were achieved, including the development of a regioselective Friedel–Crafts reaction, a high-yield reduction, and a mild metal–halogen exchange. These improvements ultimately resulted in the isolation of tofogliflozin hydrate as a white solid in >99% purity (HPLC area) and 23% overall yield after 12 steps without column chromatography.

 

 Tofogliflozin hydrate white solid with 99.56% purity by HPLC. Water content: 4.47%.

Mp: 71−80 oC. [α]20 D =  +23.9 (c = 1.0, CH3OH).

1H NMR (400 MHz, CD3OD) δ 7.23-7.18 (m, 3H), 7.12-7.08(m, 4H), 5.13 (d, J = 12.4 Hz, 1H), 5.07 (d, J = 12.4 Hz, 1H), 3.96 (s, 2H), 3.83-3.73 (m, 4H), 3.65 (dd, J = 11.9, 5.5 Hz, 1H), 3.41-3.47 (m, 1H), 2.59 (q, J = 7.6 Hz, 2H), 1.19 (t, J = 7.6 Hz, 3H).

13C NMR (100 MHz, CD3OD) δ 143.2, 142.6, 140.2, 139.9, 139.7, 131.2, 129.9, 128.9, 123.6, 121.8, 111.6, 76.4, 76.2, 74.9, 73.4, 71.9, 62.8, 42.3, 29.5, 16.3.

HRMS (ESI) m/z: [M+H]+ Calcd for C22H27O6 387.1802; Found 387.1805.

IR (KBr, cm-1) ν: 3362, 2962, 2927, 1637, 1513, 1429, 1095, 1034, 808, 770. Spectroscopic data were identical with those reported.1b, 2

1. (a) Suzuki, M.; Honda, K.; Fukazawa, M.; Ozawa, K.; Hagita, H.; Kawai, T.; Takeda, M.; Yata, T.; Kawai, M.; Fukuzawa, T.; Kobayashi, T.; Sato, T.; Kawabe, Y.; Ikeda, S. J. Pharmacol. Exp. Ther. 2012, 341, 692.

(b) Ohtake, Y.; Sato, T.; Kobayashi, T.; Nishimoto, M.; Taka, N.; Takano, K.; Yamamoto, K.; Ohmori, M.; Yamaguchi, M.; Takami, K.; Yeu, S.-H.; Ahn. K.-H.; Matsuoka, H.; Morikawa, K.; Suzuki, M.; Hagita, H.; Ozawa, K.; Yamaguchi, K.; Kato, M.; Ikeda, S. J. Med. Chem. 2012, 55, 7828.

(c) Ikeda, S.; Takano, Y.; Cynshi, O.; Tanaka, R.; Christ, A. D.; Boerlin, V.; Beyer, U.; Beck, A.; Ciorciaro, C.; Meyer, M.; Kadowaki, T. Diabetes, Obesity and Metabolism 2015, 17, 984.

2. (a) Murakata, M.; Ikeda, T.; Kimura, N.; Kawase, A.; Nagase, M.; Yamamoto, K.; Takata, N.; Yoshizaki, S.; Takano, K. Crystal of spiroketal derivative, and process for production thereof. European Appl. EP 2308886 A1, April 13, 2011.

(b) Ohtake, Y.; Emura, T.; Nishimoto, M.; Takano, K.; Yamamoto, K.; Tsuchiya, S.; Yeu, S.; Kito, Y.; Kimura, N.; Takeda, S.; Tsukazaki, M.; Murakata, M.; Sato, T. J. Org. Chem. 2016, 81, 2148.

References

  1.  Chugai Pharmaceutical: Development Pipeline
  2.  Nagata, T.; Fukazawa, M.; Honda, K.; Yata, T.; Kawai, M.; Yamane, M.; Murao, N.; Yamaguchi, K.; Kato, M.; Mitsui, T.; Suzuki, Y.; Ikeda, S.; Kawabe, Y. (2012). “Selective SGLT2 inhibition by tofogliflozin reduces renal glucose reabsorption under hyperglycemic but not under hypo- or euglycemic conditions in rats”. AJP: Endocrinology and Metabolism 304 (4): E414–E423. doi:10.1152/ajpendo.00545.2012.PMID 23249697.
  3.  Ohtake, Y.; Sato, T.; Kobayashi, T.; Nishimoto, M.; Taka, N.; Takano, K.; Yamamoto, K.; Ohmori, M.; Yamaguchi, M.; Takami, K.; Yeu, S. Y.; Ahn, K. H.; Matsuoka, H.; Morikawa, K.; Suzuki, M.; Hagita, H.; Ozawa, K.; Yamaguchi, K.; Kato, M.; Ikeda, S. (2012). “Discovery of Tofogliflozin, a NovelC-Arylglucoside with anO-Spiroketal Ring System, as a Highly Selective Sodium Glucose Cotransporter 2 (SGLT2) Inhibitor for the Treatment of Type 2 Diabetes”. Journal of Medicinal Chemistry 55 (17): 7828–7840. doi:10.1021/jm300884k.PMID 22889351.
  4.  Statement on a nonproprietary name adopted by the USAN council: Tofogliflozin.
  5.  http://www.who.int/entity/medicines/publications/druginformation/innlists/RL65.pdf
Tofogliflozin monohydrate
Tofogliflozin monohydrate skeletal 3D.svg
Systematic (IUPAC) name
(1S,3′R,4′S,5′S,6′R)-6-(4-Ethylbenzyl)-6′-(hydroxymethyl)-3′,4′,5′,6′-tetrahydro-3H-spiro[2-benzofuran-1,2′-pyran]-3′,4′,5′-triol hydrate (1:1)
Legal status
Legal status
  • Investigational
Identifiers
CAS Number 1201913-82-7
903565-83-3 (anhydrous)
ATC code None
PubChem CID 46908928
ChemSpider 28527871
KEGG D09978
ChEMBL CHEMBL2105711
Synonyms CSG452
Chemical data
Formula C22H28O7
Molar mass 404.45 g/mol

//////////TOFOGLIFLOZIN, 托格列净 , CSG-452, R-7201, RG-7201, 1201913-82-7  , 903565-83-3, oral hypoglycaemic agentsSGLT-2 inhibitorstype 2 diabetes mellitus, Deberza

CCc1ccc(cc1)Cc2ccc3c(c2)[C@]4([C@@H]([C@H]([C@@H]([C@H](O4)CO)O)O)O)OC3.O

The glucopyranosyl-substituted benzene derivatives are proposed as inducers of urinary sugar excretion and as medicaments in the treatment of diabetes.

The term “canagliflozin” as employed herein refers to canagliflozin, including hydrates and solvates thereof, and crystalline forms thereof and has the following structure:

Figure US20130035281A1-20130207-C00013

The compound and methods of its synthesis are described in WO 2005/012326 and WO 2009/035969 for example. Preferred hydrates, solvates and crystalline forms are described in the patent applications WO 2008/069327 for example.

atigliflozin, including hydrates and solvates thereof, and crystalline forms thereof and has the following structure:

Figure US20130035281A1-20130207-C00014

The compound and methods of its synthesis are described in WO 2004/007517 for example.

ipragliflozin, including hydrates and solvates thereof, and crystalline forms thereof and has the following structure:

Figure US20130035281A1-20130207-C00015

The compound and methods of its synthesis are described in WO 2004/080990, WO 2005/012326 and WO 2007/114475 for example.

tofogliflozin, including hydrates and solvates thereof, and crystalline forms thereof and has the following structure:

Figure US20130035281A1-20130207-C00016

The compound and methods of its synthesis are described in WO 2007/140191 and WO 2008/013280 for example.

remogliflozin and prodrugs of remogliflozin, in particular remogliflozin etabonate, including hydrates and solvates thereof, and crystalline forms thereof. Methods of its synthesis are described in the patent applications EP 1213296 and EP 1354888 for example.

sergliflozin and prodrugs of sergliflozin, in particular sergliflozin etabonate, including hydrates and solvates thereof, and crystalline forms thereof. Methods for its manufacture are described in the patent applications EP 1344780 and EP 1489089 for example.

luseoghflozin, including hydrates and solvates thereof, and crystalline forms thereof and has the following structure:

Figure imgf000031_0002

ertugliflozin, including hydrates and solvates thereof, and crystalline forms thereof and has the following structure:

Figure imgf000031_0003

and is described for example in WO 2010/023594.

The compound of the formula

Figure imgf000032_0001

is described for example in WO 2008/042688 or WO 2009/014970.

Dapagliflozin

Figure US20130096076A1-20130418-C00001

The compound is described for example in WO 03/099836. Crystalline forms are described for example in WO 2008/002824.

Remogliflozin and Remogliflozin Etabonate

Figure US20130096076A1-20130418-C00002

The compound is described for example in EP 1354888 A1.

Sergliflozin and Sergliflozin Etabonate

Figure US20130096076A1-20130418-C00003

The compounds are described in EP 1 329 456 A1 and a crystalline form ofSergliflozin etabonate is described in EP 1 489 089 A1.

1-Chloro-4-(β-D-glucopyranos-1-yl)-2-(4-ethyl-benzyl)-benzene

Figure US20130096076A1-20130418-C00004

The compound is described in WO 2006/034489.

(1S)-1,5-anhydro-1-[5-(azulen-2-ylmethyl)-2-hydroxyphenyl]-D-glucitol

Figure US20130096076A1-20130418-C00005

The compound (4-(Azulen-2-ylmethyl)-2-(β-D-glucopyranos-1-yl)-1-hydroxy-benzene) is described in WO 2004/013118 and WO 2006/006496. The crystalline choline salt thereof is described in WO 2007/007628.

(1S)-1,5-anhydro-1-[3-(1-benzothien-2-ylmethyl)-4-fluorophenyl]-D-glucitol

Figure US20130096076A1-20130418-C00006

The compound is described in WO 2004/080990 and WO 2005/012326. A cocrystal with L-proline is described in WO 2007/114475.

Thiophen Derivatives of the Formula (7-1)

Figure US20130096076A1-20130418-C00007

wherein R denotes methoxy or trifluoromethoxy. Such compounds and their method of production are described in WO 2004/007517, DE 102004063099 and WO 2006/072334.

1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene

Figure US20130096076A1-20130418-C00008

The compound is described in WO 2005/012326. A crystalline hemihydrate is described in WO 2008/069327.

Spiroketal Derivatives of the Formula (9-1)

Figure US20130096076A1-20130418-C00009

wherein R denotes methoxy, trifluoromethoxy, ethoxy, ethyl, isopropyl or tert. butyl. Such compounds are described in WO 2007/140191 and WO 2008/013280.

Share

Is poor Research the Cause of the Declining productivity of the pharmaceutical Industry An Industry in need of a Paradigm shift

 Uncategorized  Comments Off on Is poor Research the Cause of the Declining productivity of the pharmaceutical Industry An Industry in need of a Paradigm shift
Jul 212013
 

 

picked up from a japanes site

創薬パラダイム・シフト:プロセス重視からサイエンス重視へ転換せよ

Sams-Dodd F. Is poor research the cause of the declining productivity of the pharmaceutical industry? An industry in need of a paradigm shift.
Drug discovery today. 2012;00(00):1–7. 

Available at:http://linkinghub.elsevier.com/retrieve/pii/S1359644612003674

過去20年の創薬パラダイムであるターゲットベースの創薬は、何千億円の投資の割にはそれほど効果的ではなかったと言われている。なぜこれほどまでに機能しなかったのか?ここでは従来の手法の失敗確率の高い理由を知り、生産性向上のための創薬手法の転換を提案する。たとえば、ターゲット選定の段階で、多くの研究者は選択的な化合物を目指そうとするが、癌のキナーゼ研究を見てもわかるように、薬効を示すのはマルチのターゲットによって複数のシグナルを同時に作用する事に発揮する場合も多い。また、製薬企業では薬効につながる明確なMOAを必要とする傾向にあるが、実際には精神疾患の薬剤のようにMOAが十分に説明できずに使,,,,,,,,,,,,,,,,,,see below a translation

 


Available at: http:// linkinghub.elsevier.com/retrieve/pii/S1359644612003674

It is said that drug discovery of target-based drug discovery is a paradigm of the past 20 years, was not very effective in what percent of one hundred billion yen of investment. Why did not work so much? You know why a high failure probability of the conventional method, we propose the transformation of drug discovery techniques to improve productivity in this case.

 For example, at the stage of target selection, many researchers trying to aim at compounds selective, but as can be seen from kinase cancer research, and shows a medicinal action at the same time a plurality of signals by the target multi- If you want to demonstrate to that you often. Further, it tends to require a clear MOA leading to efficacy in pharmaceutical companies, but the MOA is used to not be fully described as drug mental illness often actually in practice. Movement of proteins in vivo actually that it is not so simple many MOA to be described coherently At first glance also, also, may be used instead of different views depending on the specifications of interpretation in practice. 

If you prove that it is selective for off-target of 100 kinds about the compound that is optimized in a single mechanism, if there is action on targets unknown other, it is that there is a clinically significant after we In some cases, it can be seen. Next is to evaluate and to build the flow of screening MOA and target Once you have decided, but it is also not necessarily the one that bridges the screening and clinical actually.

 Case of cancer cells, and so extrapolate clinical efficacy in inhibition of proliferation activity, but are those far removed from the actual in vivo in most cases, the process itself is continuously evaluated by routine work ends as a waste of time not money. If you choose to use compound somehow, animal disease model is not possible to accurately predict clinical outcome. Uncertainties like this a lot, theme 97% never fail downright non-clinical. Rather than biology and disease clearly, feeling had focused on the process is undeniable drug discovery paradigm of current. Important thing originally, is to to centered on principles and appropriate science focused on disease in clinical, it is to re-build process on it. 

Reorganization research and development are important, it is not able to change the nature of the disease where you have reorganized matter. Therefore, it is a secondary or if the organization. The new research paradigms consider the process to focus on the disease, it is necessary to apply the three principles. One of them is the process of science-based.Science is made ​​up by systematic law, which is evidenced by the accumulation of observation and experiment without prejudice. It’s that you have to often is that is do we need to note here, discussions would begin while not to suspect the hypothesis and doctrine that are major premise. 

For example, the earth if the major premise that it is a flat, what’s there in the flat world of another fall from the tip of the flat earth?Question that will come out. However, if you can dispel the assumption by the belief that there is no basis to recognize the shape of the earth, it is possible to pursue science in the right direction in a totally different perspective. This same is true for drug discovery research. For example, if a certain phenomenon is to work, it would no longer consider the direction of the other.

Cause of schizophrenia may be mentioned a theory that based on the excess dopamine hyperactivity as an example.May develop the symptoms of schizophrenia-like D amphetamine is allowed to release dopamine, this concept is the basis that it has a D2 antagonism dopamine psychotropic drugs many. However, it is said, not the D amphetamine contraindicated, psychotropic drugs long-term treatment is also lead to enhanced dopamine system schizophrenia many patients. However, the fact that you have these, never to be little consideration on the grounds that would be go against the doctrine of dopamine hypothesis. In other words, the doctrine would be to blind us to the alternative hypothesis essentially. 

This same is true with respect to Alzheimer’s.When the doctrine of a certain hypothesis is treated as the principles, facts that go against the doctrine is ignored, hypothesis another is neglected, progress of science’s delayed in order to look away from the truth. Hypothesis became a doctrine becomes absolute only and is deified as the Bible. Fact defeat the hypothesis that even came out after another, the cause interpreted as another factor, never wake up until push forward until you collapse in clinical late as a result. Hypothesis that build on doctrine the wrong does not lead only in the wrong direction all. 

Simply because I admit to know that the earth is a sphere, a new way of science he is cut open. In addition, reductionism approach dominant also should be noted in the discussion of science. Element has a plurality of by influencing the complex in vivo, originally, it is not possible to understand the living body to focus on a single element. For example, to understand the engine of the car, there is a need to disconnect the engine from the mirror and the door, however, they are not able to understand the engine itself and accidentally disconnect without knowing the function of important and bolts cylinder engine. Multi-target has been spotlighted in the drug synergy effect by the action of more than one is because the expected effect even insufficient for single target. That it kept asking the research many times, to re-examine the design of the experiment is important in decision-making, but is in surprisingly poor. Schizophrenia negative symptoms model of phencyclidine-induced and model of cerebral infarction has become a problem much that there is no reproducibility by the lab.

In the process of science-based, it will continue to refine while obtaining conclusive evidence to do the practice and discussion is important. Clinical success rate is low, it sifted the hypothesis as much as possible in the process of advancing the research, better should remain. The second principle is that the customers know. Be patient with the customer for the pharmaceutical companies. It is not possible to produce products that are competitive by knowing the limit disease, condition, existing drugs. Even on the researchers know the needs of the patient, taking into closer contact with the doctor is important. Principles of the third, is to understand the risks. The acceptable risk, it is not what we deal with the risk, that is, whether to undertake the corresponding risk, the only pass to avoid the discussion if not. First of all drug discovery are those difficult, many programs to fail in the mid-way is typical for the pharmaceutical companies. 

However, it should be avoided risk, such as notice and a predictable if you even care, because he turn away the failure of such a future, because it should not be happening that failure waiting to happen after we some. A few years ago, pharmaceutical companies some had considered mGluR5 antagonists as an anti-anxiety drug. This MOA was expected as much anti-anxiety drug, but the side effects of psychotic disorders such as hallucinations and delusions has been concern on the other hand. However, was never to be fully verified until the compound drop in its side effects in Phase 1 this concern. Many pharmaceutical companies are in was not able to deal with known risks. 

Any pharmaceutical company, and the last would complete the study because of the common “because other companies are doing” and, nobody did not want to press the stop button. Pharmaceutical companies had been wiped out by the results of the problem banzai charge of pharmaceutical companies which can be called reckless risk-taking took place waiting to happen in clinical trials. To avoid this situation, the practice of the process of due diligence scientific is the essential. Inspection with no bias due to opposition support and opinion is carried out in this process. And verified by experiment hypothesis that there is sufficient scientific reason to support (1) project, if you can dispel the uncertain surface with a (2) simple additional experiments, and (3) key in this process it is determined Uruka about, you can reduce the risk of later on in (4) checkpoint. Researchers lament “factor of the disease is too complex” and the “because there is no way of doing the other”, the researchers would start the research been sticking to the one target. 

However, you should know that a little time, to discuss the clinical symptoms of the disease, you only need to discuss the screening method of Japan before, and there is also a problem that can be resolved

Share

Japanese MHLW clears Roche’s Avastin as glioblastoma therapy

 Uncategorized  Comments Off on Japanese MHLW clears Roche’s Avastin as glioblastoma therapy
Jun 212013
 
Japanese MHLW clears Roche’s Avastin as glioblastoma therapy
The Japanese Ministry of Health, Labour and Welfare (MHLW) has cleared Roche’s Avastin (bevacizumab) as a combination therapy and monotherapy to treat the aggressive form of brain cancer glioblastoma…

read all at

http://regulatoryaffairs.pharmaceutical-business-review.com/news/japanese-mhlw-clears-roches-avastin-as-glioblastoma-therapy-170613

 

Share
Follow

Get every new post on this blog delivered to your Inbox.

Join other followers: