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Acotiamide

January 12, 2016 12:05 pm / 4 Comments on Acotiamide

Acotiamide hydrochloride trihydrate
CAS#: 773092-05-0 (Acotiamide HCl hydrate, 1:1:3); 185104-11-4(Acotiamide HCl, 1:1); 185106-16-5 (Acotiamide free base)
Chemical Formula: C21H37ClN4O8S

Molecular Weight: 541.06
Elemental Analysis: C, 46.62; H, 6.89; Cl, 6.55; N, 10.36; O, 23.66; S, 5.93

Acotiamide, also known as YM-443 and Z-338, is a drug approved in Japan for the treatment of postprandial fullness, upper abdominal bloating, and early satiation due to functional dyspepsia. It acts as an acetylcholinesterase inhibitor. Note: The Approved drug API is a cotiamide HCl trihydrate (1:1:3)

N-(2-(diisopropylamino)ethyl)-2-(2-hydroxy-4,5-dimethoxybenzamido)thiazole-4-carboxamide hydrochloride trihydrate.

YM443; YM-443; YM 443; Z338; Z-338; Z 338; Acotiamide; Acotiamide hydrochloride trihydrate; Brand name: Acofide.

A peripheral acetylcholinesterase (AChE) inhibitor used to treat functional dyspepsia.

Acotiamide (YM-443, Z-338) is a drug approved in Japan for the treatment of postprandial fullness, upper abdominal bloating, and early satiation due to functional dyspepsia.^[1] It acts as an acetylcholinesterase inhibitor.

Acotiamide hydrochloride (acotiamide; N-[2-[bis(1-methylethyl) amino]ethyl]-2-[(2-hydroxy-4,5-dimethoxybenzoyl) amino] thiazole-4-carboxamide monohydrochloride trihydrate, Z-338) has been reported to improve meal-related symptoms of functional dyspepsia in clinical studies.

Acotiamide (Acofide(®)), an oral first-in-class prokinetic drug, is under global development by Zeria Pharmaceutical Co. Ltd and Astellas Pharma Inc. for the treatment of patients with functional dyspepsia. The drug modulates upper gastrointestinal motility to alleviate abdominal symptoms resulting from hypomotility and delayed gastric emptying. It exerts its activity in the stomach via muscarinic receptor inhibition, resulting in enhanced acetylcholine release and inhibition of acetylcholinesterase activity. Unlike other prokinetic drugs that are utilized in the management of functional dyspepsia, acotiamide shows little/no affinity for serotonin or dopamine D2 receptors. Acotiamide is the world’s first approved treatment for functional dyspepsia diagnosed by Rome III criteria, with its first approval occurring in Japan. Phase III trials in this patient population are in preparation in Europe, with phase II trials completed in the USA and Europe.

SYNTHESIS

EP 0870765; US 5981557; WO 9636619

Acylation of 2-aminothiazole-4-carboxylic acid ethyl ester (I) with 2,4,5-trimethoxybenzoyl chloride (II) produced the corresponding amide (III). The 2-methoxy group of (III) was then selectively cleaved by treatment with pyridine hydrochloride, yielding the 2-hydroxybenzamide (IV). Finally, displacement of the ethyl ester group of (IV) by N,N-diisopropyl ethanediamine (V) upon heating at 120 C furnished the target compound, which was isolated as the corresponding hydrochloride salt.

EP 0994108; WO 9858918

In a closely related procedure, acid chloride (II), prepared by treatment of 2,4,5-trimethoxybenzoic acid (VI) with SOCl2 in hot toluene, was condensed with aminothiazole (I), yielding amide (III). Displacement of the ethyl ester group of (III) by N,N-diisopropyl ethanediamine (V) furnished diamide (VII). Finally, upon formation of the hydrochloride salt of (VII) in isopropanol, the 2-methoxy group was simultaneously cleaved, directly leading to the title compound.

CN103709191A

Acotiamide hydrochloride, chemical name: N_ [2_ (diisopropylamino) ethyl] -2- [(2-hydroxy-4,5-dimethoxybenzoyl) amino ] thiazole-4-carboxamide hydrochloride, the following structure:

A test for the amine hydrochloride Japan Zeria Pharmaceutical Company and Astellas jointly developed acetylcholinesterase inhibitor class of prokinetic drugs, namely the treatment of functional dyspepsia drugs, is the world’s first approved specifically for the treatment of FD drugs, in June 2013 for the first time launched in Japan, under the trade name Acofide. Functional dyspepsia (Functional dyspepsia, FD) is a group of common symptoms include bloating, early satiety, burning sensation, belching, nausea, vomiting and abdominal discomfort and so difficult to describe, and no exact organic disease. Organic diseases because of lack of basic, functional dyspepsia harm to patients focus on the performance of gastrointestinal symptoms caused discomfort and possible impact on the quality of life in. Because some patients with functional dyspepsia symptoms caused by eating less, digestion and absorption efficiency is reduced, resulting in varying degrees of malnutrition (including nutrients are not full). With the people’s demands and improve the quality of life for functional dyspepsia know, the number of visits of the disease gradually increased, to become one of the most common disease of Gastroenterology partner waiting group. Such a high prevalence of functional dyspepsia treatment provides a huge market.

The present synthesis method has been reported in less divided into four methods are described below:

1, reference CN1084739C, synthetic route as shown below. Disadvantage of this patent is that: (I) using thionyl chloride and dichloroethane toxic, environmentally damaging substances; (2) demethylation low yield (64.6% to 86 reported in the literature %). Examples reported in this patent first and second step total yield was 84.6% and the total yield of the third-step reaction and recrystallization of 61%, the total yield of 51.6%.

The method, reported in the patent CN1063442C preparation A (page 25) reports (without reference to examples I and 6, referring to its general method). Patent CN102030654B (page 3) above: Step demethylation reaction generates a lot of by-products, it is difficult to take off only a selective protection of hydroxy groups, poor selectivity. Specific synthetic examples are shown below:

Preparation Method B 3 mentioned patent CN1063442C (prepared unprotected, p. 25), where the yield is very low two-step reaction. A test method for the preparation of amines referenced above example (Example 38) A test for specific preparation yield amine not mentioned in the text, but if you use the above method starting materials primary amino side reactions occur. Synthesis of solid concrete

Following is an example:

reported that patent CN101006040B in Method 4. The first step demethylation can also use titanium tetrachloride and aluminum chloride; the second reaction can also be used phenol / thionyl chloride. Synthetic route are higher yield and purity (total yield 73%).

The method of synthesis of the above methods 3 patent CN1063442C reported, though not suitable for the synthesis of amine A test, but may be modified on this basis.

the above patents, CN1084739 reagents using dichloroethane, toxic, environmentally destructive, and the total yield is low, is not conducive to industrial production; patent CN102030654B mentioned Step demethylation The reaction produces a lot of by-products, it is difficult to take off only selective hydroxy protecting group, the reaction selectivity, more side effects.

Example 4

[Amino-N- (2- tert-butoxycarbonyl group -4,5_ dimethoxybenzoyl)] _4_ Preparation of 2-methoxycarbonyl-1,3-thiazole: [0062] Step 1

2-hydroxy-4,5-dimethoxy-benzoic acid (100 g) was dissolved in dry toluene (400 ml) was added Boc20 (132 g) was stirred at rt for 3 hours at room temperature, was added a 10% aqueous citric acid (100 ml) and washed three times with purified water until neutral, dried over anhydrous sodium sulfate was added (20 g) and dried 8 hours, filtered, and the filtrate was added thionyl chloride (64 g) and N, N-dimethyl- carboxamide (0.19 ml), followed by stirring 80 ° C for 4 hours, the compound was added 2-amino-4-methoxycarbonyl-1,3-thiazole (85 g), stirred for 5 hours at 100 ° C, the reaction was completed After cooling to room temperature, the precipitated crystals were collected by filtration, crystals were added to 1.6 liters of water, 400 g of ice was added with stirring, and added a mass ratio of 10% sodium hydroxide aqueous solution adjusted to pH 7.5, followed by stirring for 3 hours at room temperature, filtered The crystals were collected, washed with water, 60 ° C and dried to give the title compound (170 g).

Hl-NMR (DMSO, 400MHz) δ: 1.34 (s, 3H), 1.37 (s, 3H), 1.40 (s, 3H), 3.77 (s, 3H),

3.82 (s, 3H), 3.88 (s, 3H), 7.17 (s, 1H), 7.50 (s, 1H), 7.95 (s, 1H), 11.45 (bs, 1H).

Step 2: 2- [N- (2- hydroxy-4,5-dimethoxybenzoyl) amino] -4- [(2_ diisopropylamino ethyl) – aminocarbonyl] -1 , Preparation of 3-thiazole hydrochloride

The 2- [N- (2- tert-butoxycarbonyl group -4,5_ dimethoxybenzoyl) amino] _4_ methoxycarbonyl _1,3_ thiazole prepared (170 g) and N , N- diisopropyl-ethylenediamine (162 ml), N, N- dimethylacetamide (162 ml) was stirred at 135 ° C for 8 hours and cooled, 1-butanol (1.7 liters), with 0.5N aqueous sodium hydroxide solution and washed with saturated brine, the mixture was concentrated under reduced pressure, methanol (1.7 l), hydrogen chloride gas under cooling and stirred for 5 hours, the precipitate was collected by filtration, the crystals were washed with 2-propanol and water do recrystallized from a mixed solvent, to give the title compound. Melting point: 160 ° C.

[0067] Hl- bandit R (DMSO, 400ΜΗζ) δ: 1.33 (d, J = 6.4Hz, 6H); 1.36 (d, J = 6.4,6H), 3.17-3.20 (m, 2H); 3.57-3.69 ( m, 4H), 3.77 (s, 3H), 3.82 (s, 3H), 6.89 (s, 1H), 7.50 (s, 1H), 7.91 (s, 1H); 8

• 74 (t, 1H, J = 5.9Hz); 9.70 (s, 1H); 11.80 (s, 1H); 12.05-12.15 (bs, 1H).

CN 104045606

http://google.com/patents/CN104045606B?cl=en

Example 1: A test preparation for the amine hydrochloride

In 500ml reaction flask was added 2,4, 5- trimethoxy benzoic acid (20 g, 94. 3mmol), 200 ml N, N- dimethylformamide. Was added TBTU (30.88 g, 113.2mmol), jealous% was added diisopropylethylamine (14.59g, 113. 2mmol), stirred at room temperature for 2 hours. Was added 2-aminothiazol 4-carboxylic acid methyl ester setback (14. 92 g, 94. 3mmol), DMAP (2. 30g, 18. 9mmol), was heated to 75 ° C, stirred for 24 hours. Added% Jealous diisopropylethylenediamine (27. 16g, 188. 6mmol), and heated to 140 ° C, stirred for 10 hours. After cooling, 400ml of n-butanol was added, stirred, allowed to stand for stratification. Take the upper, washed with saturated brine, 400ml, standing stratification. Take the upper, lower temperatures hydrogen chloride isopropanol solution of 120ml, precipitated solids. Vacuum filter cake into the oven blast 60 ° C and dried for 1 hour. A test was for amine hydrochloride (Compound V) 28. 5g, HPLC purity 99%, yield 62%.

1HNMR (400 MHz, dmso) 8 12.10 (s, 1H), 11.77 (s, 1H), 9.74 (s, 1H), 8.72 (t, / = 5.8 Hz, 1H), 7.88 (s, 1H) , 7.48 (s, 1H), 6.89 (s, 1H), 3.80 (s, 3H), 3.76 (s, 3H), 3.62 (d, / = 6.6 Hz, 4H), 3.16 (d, / = 6.4 Hz, 2H), 1.32 (dd, / = 13. 4,6. 3 Hz, 12H).

2 Example: A test preparation for the amine hydrochloride

added 2, 4, 5- trimethoxy benzoic acid (20g, 94. 3mmol) in 500ml reaction flask, 200ml% Jealous dimethylacetamide. Was added TBTU (30.88g, 113. 2mmol), was added diisopropylethylamine jealous% (14. 59g, 113. 2mmol)), followed by stirring at room temperature for 2 hours. Was added 2-aminothiazol-4-carboxylate (14. 92g, 94. 3mmol), DMAP (2. 3g, 18. 9mmol), was heated to 75 ° C, stirred for 24 hours. Added% Jealous diisopropylethylenediamine (27. 16g, 188. 6mmol), and heated to 140 ° C, stirred for 10 hours. After cooling, 400ml of n-butanol was added, stirred, allowed to stand for stratification. Take the upper, washed with saturated brine, 400ml, standing stratification. Take the upper, lower temperatures hydrogen chloride isopropanol solution of 120ml, precipitate a solid, vacuum filtration, cake into the oven blast 60 ° C and dried for 1 hour. A test was for amine hydrochloride (Compound V) 31. 7 g, HPLC purity 99%, yield 69%.

CN103387552A

A test for the amine hydrochloride (Z-338) is a new Ml Japan Zeria company’s original research, M2 receptor antagonist, for the treatment of functional dyspepsia clinic.

Chinese patent application describes doxorubicin hydrochloride CN200580028537 test for amines (Z-338) preparation, reaction

Process is as follows.

A test for the amine hydrochloride (z-338) Compound Patent Application (CN96194002.6) choosing 2,4,5-trimethoxy benzoic acid as a starting material first with 2-aminothiazol-4-carboxylate reacts 2- [(2-hydroxy-4,5-dimethoxybenzoyl) amino] -1,3-thiazole-4-carboxylate, 2-methyl-benzene and then removed, the yield of this method lower demethylation selectivity bad. So choose the first 2-methyl-removal before subsequent reaction better.

The first patent application CN200580028537 2_ hydroxyl _4,5_ dimethoxy benzoic acid and triphenyl phosphite placed in toluene, was added a few drops of concentrated sulfuric acid as a catalyst under reflux to give the intermediate 2-hydroxy – 4,5-dimethoxy-phenyl benzoate. After the above intermediate with 2-aminothiazol-4-carboxylate in place of toluene, was added triphenyl borate reacted, treated to give 2- [(2-hydroxy-4,5-dimethoxy- benzoyl) amino] -1,3-thiazole-4-carboxylate, and finally with N, N- diisopropylethylamine in toluene diamine salt in the system after the reaction.

Example 1

2 – [(2-hydroxy-4,5-dimethoxybenzoyl) amino] thiazole Synthesis _1,3_ _4_ carboxylate

[0030] triphosgene dissolved in 90ml CH2Cl2 19.0g placed in a four-necked flask, under N2 stream, the 2_ hydroxyl _4,5_ dimethoxy benzoic acid (22.2g) was dissolved in 150ml CH2Cl2 and 45ml pyridine, at four-necked flask temperature dropped 0_5 ° C under ice-salt bath. Dropping finished within 45min, kept cold stirred lOmin. After warm to room temperature (20 ° C) was stirred for 50min, the reaction was stopped. Pressure filtration, and the filtrate by rotary evaporation at room temperature to a constant weight, adding 35g 2- aminothiazol-4-carboxylate and 240ml 1,2_ dichloroethane and heated to reflux, the reaction 6h. After stopping the cooling, suction filtration, washed with methanol and the resulting solid was refluxed in 40ml, hot filtration to give a white solid 32.18g, yield 85%. M + Na + 361; 2M + Na + 699. [0031] Example 2

2 – [(2-hydroxy-4,5-dimethoxybenzoyl) amino] thiazole Synthesis _1,3_ _4_ carboxylate

triphosgene dissolved in 15ml CH2Cl2 placed 3.0g four-necked flask, under N2 stream, the 2_ hydroxyl _4,5_ dimethoxy benzoic acid (3.0g) was dissolved in pyridine 30ml CH2Cl2 and 61,111, in four-necked flask temperature dropped 0_5 ° C under ice-salt bath. 20min Upon completion, kept cold stirring lh. After warm to room temperature (20 ° C) and stirred overnight, 24h after stopping the reaction. Rotary evaporation at room temperature to a constant weight is added 3.5g 2- aminothiazol-4-carboxylate and 30ml 1,2- dichloroethane burning, heated to reflux, the reaction 6h. The solvent was evaporated after stopping, add 30ml methanol reflux filtration to give a white solid 4.1g, 20ml methanol was added to the mother liquor evaporated leaching and washing a white solid 0.85g. After the merger was solid 4.95g, yield 97%.

Example 3

2 – [(2-hydroxy-4,5-dimethoxybenzoyl) amino] thiazole Synthesis _1,3_ _4_ carboxylate

The diphosgene 3.0g was dissolved into 15ml CH2Cl2 four-necked flask, under N2 stream, the 2_ hydroxyl _4,5_ dimethoxy benzoic acid (3.0g) was dissolved in 30ml CH2Cl2 and 61,111 pyridine, Under ice-salt bath temperature dropped a four-necked flask 0_5 ° C. 20min Upon completion, kept cold stirring lh. After warm to room temperature (20 ° C) and stirred overnight, 24h after stopping the reaction. Rotary evaporation at room temperature to a constant weight is added 3.5g 2- aminothiazol-4-carboxylate and 30ml 1,2- dichloroethane burning, heated to reflux, the reaction 6h. After the solvent was evaporated and stopped by adding 30ml of methanol was refluxed for leaching to give a white solid 4.57g, yield 89.6%.

Example 4

2 – [(2-hydroxy-4,5-dimethoxybenzoyl) amino] thiazole Synthesis _1,3_ _4_ carboxylate

triphosgene dissolved in 15ml CH2Cl2 placed 3.0g four-necked flask, under N2 stream, the 2_ hydroxyl _4,5_ dimethoxy benzoic acid (3.0g) `pyridine was dissolved in 30ml CH2Cl2 and 61 111, Under ice-salt bath temperature dropped a four-necked flask 0_5 ° C. 20min Upon completion, kept cold stirring lh. After warm to room temperature (20 ° C) and stirred overnight, 24h after stopping the reaction. Rotary evaporation at room temperature to a constant weight is added 3.7g 2- aminothiazol-4-carboxylic acid ethyl ester and 30ml 1,2- dichloroethane burning, heated to reflux, the reaction 6h. The solvent was evaporated after stopping, add 30ml methanol reflux filtration to give a white solid 3.8g, 20ml methanol was added to the mother liquor evaporated leaching and washing a white solid 0.54g. After the merger was solid 4.34g, yield 81.4%. M + Na + 375.

Example 5

N- [2_ (diisopropylamino) ethyl] -2 – [(hydroxy -4,5_ 2_ dimethoxybenzoyl) amino] -1,3-thiazol-4-carboxamide amide hydrochloride

2 – [(2-hydroxy-4,5-dimethoxybenzoyl) amino] thiazole _4_ _1,3_ carboxylate and 1.5g IOml 1,4- dioxane placed in a four-necked flask, N2 gas shielded at 75 ° C was added dropwise 1.5ml N, N- diisopropyl-ethylenediamine, rose after reflux, the reaction was stirred for 6 hours. The reaction was stopped, the solvent was evaporated to dryness under reduced pressure, 30ml CH2Cl2 was added dissolved in 20ml10% NaCl solution was washed twice, and then the organic solvent was evaporated to dryness. IOml methanol was added, concentrated hydrochloric acid was added to adjust Xeon acidic. Evaporated methanol, washed with acetone to give the product 2.08g, yield 96.3%. M + H 451, MH 449.

Example 6

[0044] N- [2- (diisopropylamino) ethyl] -2 – [(hydroxy _4,5_ 2_ dimethoxybenzoyl) amino] -1,3-thiazol-4-carboxamide amide hydrochloride

PAPER

A Three-Step Synthesis of Acotiamide for the Treatment of Patients with Functional Dyspepsia

Kai Fu, Liu Yang, Qiu-Fen Wang, Fu-Xu Zhan, Bin Wang, Qian Yang, Zhi-Jia Ma, and Geng-Xiu Zheng^*

School of Chemistry and Chemical Engineering, University of Jinan, Jinan 250022, Shandong P.R. China

Org. Process Res. Dev., 2015, 19 (12), pp 2006–2011

DOI: 10.1021/acs.oprd.5b00256

Publication Date (Web): November 13, 2015

*E-mail: chm_zhenggx@ujn.edu.cn. Tel.: +8653182765841.

Abstract

A three-step synthesis of acotiamide is described. The agent is marketed in Japan for treatment of patients with functional dyspepsia. We designed a one-pot method to prepare the key intermediate 5a from 2 via an acyl chloride and amide and then reacted with 6 to obtain 1 under solvent-free condition. With the use of DCC, the unavoidable impurity 5b was also successfully converted into the desired 1. After isolation of 1, we carried forward to the next step of HCl salt formation, which was proved to be a very effective procedure for the removal of practically all major impurities. The process is cost-effective, simple to operate, and easy to scale-up.

http://pubs.acs.org/doi/abs/10.1021/acs.oprd.5b00256

see………….http://pubs.acs.org/doi/suppl/10.1021/acs.oprd.5b00256/suppl_file/op5b00256_si_001.pdf

References

Matsueda K, Hongo M, Tack J, Aoki H, Saito Y, Kato H (January 2010). “Clinical trial: dose-dependent therapeutic efficacy of acotiamide hydrochloride (Z-338) in patients with functional dyspepsia – 100 mg t.i.d. is an optimal dosage”. Neurogastroenterology and Motility : the Official Journal of the European Gastrointestinal Motility Society 22 (6): 618–e173. doi:10.1111/j.1365-2982.2009.01449.x. PMID 20059698.

: Mayanagi S, Kishino M, Kitagawa Y, Sunamura M. Efficacy of acotiamide in combination with esomeprazole for functional dyspepsia refractory to proton-pump inhibitor monotherapy. Tohoku J Exp Med. 2014;234(3):237-40. PubMed PMID: 25382232.

2: Zai H, Matsueda K, Kusano M, Urita Y, Saito Y, Kato H. Effect of acotiamide on gastric emptying in healthy adult humans. Eur J Clin Invest. 2014 Dec;44(12):1215-21. doi: 10.1111/eci.12367. PubMed PMID: 25370953.

3: Xiao G, Xie X, Fan J, Deng J, Tan S, Zhu Y, Guo Q, Wan C. Efficacy and safety of acotiamide for the treatment of functional dyspepsia: systematic review and meta-analysis. ScientificWorldJournal. 2014;2014:541950. doi: 10.1155/2014/541950. Epub 2014 Aug 12. PubMed PMID: 25197703; PubMed Central PMCID: PMC4146483.

4: Sun Y, Song G, McCallum RW. Evaluation of acotiamide for the treatment of functional dyspepsia. Expert Opin Drug Metab Toxicol. 2014 Aug;10(8):1161-8. doi: 10.1517/17425255.2014.920320. Epub 2014 May 31. PubMed PMID: 24881488.

5: Matsunaga Y, Tanaka T, Saito Y, Kato H, Takei M. [Pharmacological and clinical profile of acotiamide hydrochloride hydrate (Acofide(Â®) Tablets 100 mg), a novel therapeutic agent for functional dyspepsia (FD)]. Nihon Yakurigaku Zasshi. 2014 Feb;143(2):84-94. Review. Japanese. PubMed PMID: 24531902.

6: Nowlan ML, Scott LJ. Acotiamide: first global approval. Drugs. 2013 Aug;73(12):1377-83. doi: 10.1007/s40265-013-0100-9. Erratum in: Drugs. 2014 Jun;74(9):1059. Nolan, Mary L [corrected to Nowlan, Mary L]. PubMed PMID: 23881665.

7: Altan E, Masaoka T, FarrÃ© R, Tack J. Acotiamide, a novel gastroprokinetic for the treatment of patients with functional dyspepsia: postprandial distress syndrome. Expert Rev Gastroenterol Hepatol. 2012 Sep;6(5):533-44. doi: 10.1586/egh.12.34. Review. PubMed PMID: 23061703.

8: Nagahama K, Matsunaga Y, Kawachi M, Ito K, Tanaka T, Hori Y, Oka H, Takei M. Acotiamide, a new orally active acetylcholinesterase inhibitor, stimulates gastrointestinal motor activity in conscious dogs. Neurogastroenterol Motil. 2012 Jun;24(6):566-74, e256. doi: 10.1111/j.1365-2982.2012.01912.x. Epub 2012 Mar 19. PubMed PMID: 22429221.

9: Kusunoki H, Haruma K, Manabe N, Imamura H, Kamada T, Shiotani A, Hata J, Sugioka H, Saito Y, Kato H, Tack J. Therapeutic efficacy of acotiamide in patients with functional dyspepsia based on enhanced postprandial gastric accommodation and emptying: randomized controlled study evaluation by real-time ultrasonography. Neurogastroenterol Motil. 2012 Jun;24(6):540-5, e250-1. doi: 10.1111/j.1365-2982.2012.01897.x. Epub 2012 Mar 4. PubMed PMID: 22385472.

10: McLarnon A. Dyspepsia: Acotiamide can relieve symptoms of functional dyspepsia. Nat Rev Gastroenterol Hepatol. 2012 Jan 17;9(2):62. doi: 10.1038/nrgastro.2011.262. PubMed PMID: 22249733.

CN103665023A *	Dec 23, 2013	Mar 26, 2014	华润赛科药业有限责任公司	Synthetic method of acotiamide hydrochloride

CN103980226A *	May 10, 2014	Aug 13, 2014	杭州新博思生物医药有限公司	Acotiamide hydrochloride hydrate crystal form and preparation method thereof
CN104031001A *	Jun 30, 2014	Sep 10, 2014	山东诚创医药技术开发有限公司	Method for preparing 2-(N-(2,4,5-trimothoxyaniline) amino]-4-carbethoxy-1,3-thiazole by using one-pot process
CN104031001B *	Jun 30, 2014	Sep 30, 2015	山东诚创医药技术开发有限公司	一锅烩制备2-[n-(2,4,5-三甲氧基苯甲胺基)氨基]-4-乙氧羰基-1,3-噻唑的方法
CN104045606A *	Jul 11, 2014	Sep 17, 2014	杭州新博思生物医药有限公司	One-pot method for preparing acotiamide hydrochloride
CN104045606B *	Jul 11, 2014	Sep 30, 2015	杭州新博思生物医药有限公司	一锅法制备阿考替胺盐酸盐的方法

CN103665023A *	Dec 23, 2013	Mar 26, 2014	华润赛科药业有限责任公司	Synthetic method of acotiamide hydrochloride
CN104045606A *	Jul 11, 2014	Sep 17, 2014	杭州新博思生物医药有限公司	One-pot method for preparing acotiamide hydrochloride
CN104045606B *	Jul 11, 2014	Sep 30, 2015	杭州新博思生物医药有限公司	一锅法制备阿考替胺盐酸盐的方法

Acotiamide
Systematic (IUPAC) name

N-{2-[Bis(1-methylethyl)amino]ethyl}-2-{[(2-hydroxy-4,5-dimethoxyphenyl)carbonyl]amino}-1,3-thiazole-4-carboxamide
Clinical data
Legal status	Uncontrolled
Routes of administration	Oral
Identifiers
CAS Number	185106-16-5
ATC code	None
PubChem	CID: 5282338
ChemSpider	4445505
UNII	D42OWK5383
ChEMBL	CHEMBL2107723
Chemical data
Formula	C₂₁H₃₀N₄O₅S
Molecular mass	450.55 g/mol

Approval in Japan for Treating Functional Dyspepsia with Acofide®

Press Release

Tokyo, March 25, 2013 – Zeria Pharmaceutical Co., Ltd. (Tokyo: 4559; “Zeria”) and Astellas Pharma Inc. (Tokyo: 4503; “Astellas”) announced today that as of March 25, Zeria has obtained the marketing approval of Acofide® Tablets 100mg (nonproprietary name: acotiamide hydrochloride hydrate; “Acofide”; Zeria’sdevelopment code: “Z-338”; Astellas’s development code: “YM443”) for the treatment of functional dyspepsia(FD) from the Ministry of Health, Labour and Welfare in Japan. Acofide has been co-developed by both companies.

Acotiamide hydrochloride hydrate is a new chemical entity originated by Zeria, and inhibits peripheralacetylcholinesterase activities. Acetylcholine is an important neurotransmitter to regulate gastrointestinalmotility, and through the inhibition of degradation of acetylcholine, Acofide improves the impaired gastricmotility and delayed gastric emptying, and consequently the subjective symptoms of FD such as postprandialfullness, upper abdominal bloating, and early satiation.

Acofide, the world first FD treatment which demonstrated efficacy in the patients with FD diagnosed by the Rome III, will be launched in Japan ahead of the rest of the world.Also, since Acofide will be the first treatment with FD indication, Zeria and Astellas will co-promote Acofide for the sake of the increase of disease awareness of FD, the prompt market penetration, and the maximization of product potential.

In March 2008, Zeria and Astellas concluded the agreement for the co-development and co-marketing of Acofide and, subsequently conducted the co-development. In September 2010, Zeria submitted the application for marketing approval to the Ministry of Health, Labour and Welfare in Japan.

We believe that Acofide will contribute to alleviate the subjective symptoms and improve QOL of patients with FD.

Summary of Approval

Product name: Acofide® Tablets 100mg

Nonproprietary name: Acotiamide hydrochloride hydrate

Formulation: Tablet

Indication: Postprandial fullness, upper abdominal bloating, and early satiation due to functional dyspepsia

Dosage regimen: Normally in adults, 100mg of acotiamide hydrochloride hydrate is taken orally three times per day before a meal.

About Functional Dyspepsia (FD)

According to the Rome III, FD is a gastrointestinal disease comprised of subjective symptoms including postprandial fullness, early satiation and epigastric pain without any organic abnormality on gastrointestinal tract. The etiology of FD is still unclear, but it has been shown that delayed gastric emptying is closely associated with FD.

For inquiries or additional information

Zeria Pharmaceutical Co., Ltd.

Public Relations

TEL:+81-3-3661-1039, FAX:+81-3-3663-4203

http://www.zeria.co.jp/english

Astellas Pharma Inc.

Corporate Communications

TEL: +81-3-3244-3201, FAX:+81-3-5201-7473

http://www.astellas.com/en

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COC1=CC(O)=C(C=C1OC)C(=O)NC1=NC(=CS1)C(=O)NCCN(C(C)C)C(C)C

SKLB 1028, a novel oral multikinase inhibitor of EGFR, FLT3 and Abl,

January 12, 2016 5:45 am / Leave a comment

SKLB 1028

A multi-targeted inhibitor potentially for the treatment of leukemia and non small cell lung cancer.

SKLB-1028

Si Chuan University, 四川大学

CAS 1350544-93-2

9-isopropyl-N²-(4-(4-methylpiperazin-1-yl)phenyl)-N⁸-(pyridin-3-yl)-9H-purine- 2,8-diamine

2-N-[4-(4-methylpiperazin-1-yl)phenyl]-9-propan-2-yl-8-N-pyridin-3-ylpurine-2,8-diamine

9-Isopropyl-N2-[4-(4-methylpiperazin-1-yl)phenyl]-N8-(3-pyridyl)-9H-purine-2,8-diamine, 443.5474, C24H29N9, Preclinical

9-isopropyl-N²-(4-(4-methylpiperazin-1-yl)phenyl)-N⁸-(pyridin-3-yl)-9H-purine- 2,8-diamine. Yield 65.6 %. HPLC>98.6%. ¹H NMR(400 MHz, DMSO-d₆)： δ 9.22(s, 1H), 9.05(s, 1H), 8.94(d, J=2.8Hz, 1H), 8.39(s, 1H), 8.34(d, J=8.4Hz, 1H), 8.20(m, 1H), 7.63(d, J=8.8Hz, 2H), 7.37(m, 1H), 6.88 (d, J=8.8Hz, 2H), 4.88(m, 1H), 3.05(m, 4H), 2.45(m, 4H), 2.22(s, 3H), 1.69(s, 3H), 1.68(s, 3H)ppm。HRMS (ESI) m/z [M-H]- calcd for C₂₄H₂₉N₉: 443.2546, found: 442.2538………..Leukemia (2012), 26(8)

PATENT

WO 2011147066

Synthetic route is as follows:

Example reaction is as follows:

str1

Preparation of chloro-4-amino-5-nitro pyrimidine of Example 12-

Was added dropwise 2,4-dichloro-5-nitro-pyrimidine (lO Aqueous ammonia (8.0ml) and Ν, Ν- diisopropylethylamine (13.2ml) was dissolved in 150ml dichloromethane, 0 ° C when .Og) in dichloromethane (30ml) solution, after dropwise, maintaining the temperature of the reaction one hour, the precipitate was filtered off, the filter cake was recrystallized to give a yellow solid 8.1g, yield 90.1%

Product 1HNMR (400MHz, DMSO-i¾): δ 9.20 (s, 1H), 9.02 (s, 1H), 8.60 (s, lH) ppm

Preparation of pyrimidine

Isopropylamine (4.5ml) and Ν, Ν- diisopropylethylamine (13.2ml) was dissolved in 150ml of dichloromethane, was added dropwise 2,4-dichloro-5-nitro-pyrimidine at 0 ° C ( lO.Og) in dichloromethane (30ml) solution, after dropwise, maintaining the reaction temperature for half an hour, and purified by column chromatography to give a light yellow solid was 10.1g, 90.4% yield of product 1H NMR (400 MHz, CDCl ₃ ): [delta] 9.03 (s, 1H), 8.24 (s, 1H), 4.53 (m, 1H), 1.34 (d, J = 6.8 Hz, 6H) ppm ₀

Example 16, 4-amino-2- (4- (4-methyl-piperazin-1-yl) anilino) -5-nitro-pyrimidin embodiment

4- (4-methylpiperazine) aniline (3.8g) was added to the compound 2-l (3.5g) in n-butanol (150ml) solution, the reaction for 4.5 hours at 90 ° C, cooled to room temperature, filtered , washed, and dried to give a red solid (5.2g), a yield of 79.5%. Product ‘H NMR (400 MHz, CDCl ₃ ): [delta] 9.07 (s, 1H), 8.52 (s, 2H), 8.40 (s, 1H), 7.57 (s, 1H), 7.51 (s, 1H), 7.10 (m, 2H), 3.3 l (t, J = 4.8Hz, 4H), 2.81 (t, J = 4.8Hz, 4H), 2.30 (s, 3H) ppm.

Example 90,

9-isopropyl-2- (4- (4-methyl-piperazin-1-yl) anilino) -8- (pyridin-3-yl) -9H- purine

The compound 5- 7 (2.05g) was dissolved in dichloromethane (90ml), were added sequentially EDCI (2.3g), Ν, Ν- diisopropylethylamine (4.9ml), 3- pyridyl isothiocyanate ester (1.0g), stirred at room temperature for half an hour, then refluxed for 10 hours, TLC monitoring completion of the reaction the raw material 5-7 was cooled and purified by column chromatography to give a light red solid, yield 65.7%.

Product ESI-MS (m / z,%) 442.26 (MH) -. Ή NMR (400 MHz, DMSO-d ₆ ): [delta] 9.38 (s, IH), 9.13 (s, IH), 8.99 (s, IH), 8.40 (s, IH), 8.36 (d, J = 8.4 Hz, IH), 8.20 (d, J = 4.4Hz, IH), 7.70 (d, J = 8.8Hz, 2H), 7.37 (m, IH), 6.96 (d, J = 8.8Hz, 2H), 4.97-4.92 ( m, IH), 3.35 (s, 6H), 2.80 (s, 3H): 2.53 (s, 2H), 1.69 (s, 6H) ppm.

/////////SKLB 1028,

CN1CCN(CC1)c5ccc(Nc3nc4n(C(C)C)c(Nc2cccnc2)nc4cn3)cc5

New patent, WO 2016001885, Dr Reddy’s Laboratories Ltd, Eliglustat hemitartarate

January 12, 2016 3:33 am / Leave a comment

WO 2016001885

DR. REDDY’S LABORATORIES LIMITED [IN/IN]; 8-2-337, Road No. 3, Banjara Hills, Telangana, India Hyderabad 500034 (IN)

VELAGA, Dharma Jagannadha Rao; (IN).
PEDDY, Vishweshwar; (IN).
VYALA, Sunitha; (IN)

(WO2016001885) AMORPHOUS FORM OF ELIGLUSTAT HEMITARTARATE

Chemically Eliglustat is named N-[(1 R,2R)-2-(2,3-dihydro-1 ,4-benzodioxin-6-yl)-2-hydroxy-1 -(1 -pyrrolidinylmethyl)ethyl]-Octanamide(2R_!3R)-2,3-dihydroxybutanedioate and the hemitartarate salt of eliglustat has the structural formula as shown in Formula I.

Formula I

Eliglustat hemitartrate (Genz-1 12638), currently under development by Genzyme, is a glucocerebroside (glucosylceramide) synthase inhibitor for the treatment of Gaucher disease and other lysosomal storage disorders. Eliglustat hemitartrate is orally active with potent effects on the primary identified molecular target for type 1 Gaucher disease and other glycosphingolipidoses, appears likely to fulfill high expectations for clinical efficacy. Gaucher disease belongs to the class of lysosomal diseases known as glycosphingolipidoses, which result directly or indirectly from the accumulation of glycosphingolipids, many hundreds of which are derived from glucocerebroside. The first step in glycosphingolipid biosynthesis is the formation of glucocerebroside, the primary storage molecule in Gaucher disease, via glucocerebroside synthase (uridine diphosphate [UDP] – glucosylceramide glucosyl transferase). Eliglustat hemitartrate is based on improved inhibitors of glucocerebroside synthase, and is currently under development by Genzyme.

U.S. patent No. 7,196,205 discloses a process for the preparation of Eliglustat or a pharmaceutically acceptable salt thereof.

U.S. patent No. 6855830, 7265228, 7615573, 7763738, 8138353, U.S. patent application publication No. 2012/296088 discloses process for preparation of Eliglustat and intermediates thereof.

U.S. patent application publication No. 2013/137743 discloses (i) a hemitartrate salt of Eliglustat, (ii) a hemitartrate salt of Eliglustat, wherein at least 70% by weight of the salt is crystalline, (iii) a hemitartrate salt of Eliglustat, wherein at least 99% by weight of the salt is in a single crystalline form.

It has been disclosed earlier that the amorphous forms in a number of drugs exhibit different dissolution characteristics and in some cases different bioavailablity patterns compared to crystalline forms [Konne T., Chem pharm Bull., 38, 2003(1990)]. For some therapeutic indications one bioavailabihty pattern may be favoured over another. An amorphous form of Cefuroxime axetil is a good example for exhibiting higher bioavailability than the crystalline form.

Solid amorphous dispersions of drugs are known generally to improve the stability and solubility of drug products. However, such dispersions are generally unstable over time. Amorphous dispersions of drugs tend to convert to crystalline forms over time, which can lead to improper dosing due to differences of the solubility of crystalline drug material compared to amorphous drug material. The present invention, however, provides stable amorphous dispersions of eliglustat hemitartrate. Moreover, the present invention provides solid dispersions of eliglustat hemitartrate which may be reproduced easily and is amenable for processing into a dosage form.

There remains a need to provide solid state forms of eliglustat hemitartarate which are advantageous in a cost effective and environment friendly manner.

EXAMPLES

Example 1 : Preparation of amorphous form of eliglustat hemitartarate.

500mg of eliglustat hemitartarate was dissolved in 14 mL of dichloromethane at 26°C and stirred for 15 min. The solution is filtered to remove the undissolved particles and the filtrate is distilled under reduced pressure at 45°C. After distillation the solid was dried under vacuum at 45°C.

Example 2: Preparation of amorphous form of eliglustat hemitartarate.

500mg of eliglustat hemitartarate was dissolved in 70 mL of ethanol and stirred for 15 min at 25° – 30°C. The solution is filtered to remove the undissolved particles and the filtrate is distilled under reduced pressure at 48°C. After distillation the solid was dried under vacuum at 48°C.

Example 3: Preparation of amorphous form of eliglustat hemitartarate.

500mg of eliglustat hemitartarate was dissolved in 20 mL of methanol and stirred for 15 min at 25° – 30°C. The solution is filtered to remove the undissolved particles and the filtrate is distilled under reduced pressure at 48°C. After distillation the solid was dried under vacuum at 48°C.

Example 4: Preparation of a solid dispersion comprising an amorphous form of eliglustat hemitartarate and PVP-K30.

500mg of eliglustat hemitartarate and 500mg of PVP-K30 was dissolved in 20 mL of methanol and stirred for 10 min at 25° – 30°C. The solution is filtered to remove the undissolved particles and the filtrate is distilled under reduced pressure at 48°C. After distillation the solid is dried under vacuum at 48°C.

Example 5: Preparation of a solid dispersion comprising an amorphous form of eliglustat hemitartarate and hydroxy propyl cellulose.

500mg of eliglustat hemitartarate and 500 mg of hydroxy propyl cellulose was dissolved in 30 ml of methanol and stirred for 10 min at 25° – 30°C. The solution is distilled under reduced pressure at 49°C. After distillation the solid is dried under vacuum at 49°C.

Example 6: Preparation of a solid dispersion comprising an amorphous form of eliglustat hemitartarate and hydroxy propyl methyl cellulose.

500mg of eliglustat hemitartarate and 500 mg of hydroxy propyl methyl cellulose was dissolved in 30 mL of methanol and stirred for 10 min at 25° – 30°C. The solution is distilled under reduced pressure at 48°C. After distillation the solid is dried under vacuum at 48°C.

Example 7 Preparation of amorphous form of eliglustat hemitartarate.

3g of eliglustat hemitartarate was dissolved in 75 mL of methanol and stirred at 25°C for dissolution. The solution was filtered to remove the undissolved particles and the filtrate is subjected for spray drying at inlet temperature of 70°C and outlet temperature of 42°C to afford the title compound.

Example 8: Preparation of amorphous form of eliglustat hemitartarate.

500mg of eliglustat hemitartarate was dissolved in 30 mL of isopropanol and stirred at 56°C for dissolution. The solution was filtered to remove the undissolved particles and the filtrate is subjected to complete distillation under reduced pressure and drying at about 56°C to afford the title compound.

Example 9: Preparation of amorphous form of eliglustat hemitartarate.

1 g of eliglustat hemitartarate was provided in 40 mL of ethyl acetate and stirred at about 63°C. Then methanol (5 mL) is added at the same temperature to obtain clear solution which was filtered to remove the undissolved particles. Then additional quantity of methanol (5mL) is added to the filtrate and the filtrate was again filtered to remove particles. The obtained filtrate was subjected to complete distillation under reduced pressure and drying at about 57°C to afford the title compound.

Example 10: Preparation of amorphous form of eliglustat hemitartarate.

1 g of eliglustat hemitartarate was provided in 40 mL of acetone and stirred at about 55°C followed by addition of methanol (15 mL). The mixture is stirred at 55°C for clear solution and filtered to remove the undissolved particles. The obtained filtrate was subjected to complete distillation under reduced pressure and drying at about 57°C to afford the title compound.

Example 11 : Preparation of amorphous form of eliglustat hemitartarate.

1 g of eliglustat hemitartarate was provided in 25 mL of isopropyl alcohol and 25 mL of ethanol. The mixture was stirred at about 58°C for dissolution and filtered to remove the undissolved particles. The obtained filtrate was subjected to complete distillation under reduced pressure and drying at about 57°C to afford the title compound.

Example 12 Preparation of amorphous form of eliglustat hemitartarate.

5g of eliglustat hemitartarate was provided in 300 mL of isopropyl alcohol and stirred at about 59°C for dissolution. The solution was filtered to remove the undissolved particles and the filtrate is subjected for spray drying at inlet temperature of 65°C and outlet temperature of 37°C to afford the title compound according to Fig. 6

Example 13: Preparation of a solid dispersion comprising an amorphous form of eliglustat hemitartarate and Copovidone

500mg of eliglustat hemitartarate and 500mg of Copovidone were dissolved in 30 mL of methanol and stirred for clear solution, then filtered to make it particle free. The solvent from the filtrate was evaporated under reduced pressure at 45°C and obtained solid was subjected to drying at 45°C to afford the title solid. The resulting dispersion was found to be amorphous by X-ray powder diffraction.

Example 14: Preparation of a solid dispersion comprising an amorphous form of eliglustat hemitartarate and Copovidone

2g of eliglustat hemitartarate and 2g of Copovidone were dissolved in 100 mL of methanol and stirred for clear solution, then filtered to make it particle free. The solvent from the filtrate was subjected to spray drying at inlet temperature of 70 at 45°C and outlet temperature of 42°C to afford the title compound. The resulting dispersion was found to be amorphous by X-ray powder diffraction.

Example 15: Preparation of a solid dispersion comprising an amorphous form of eliglustat hemitartarate

2g of eliglustat hemitartarate was charged in 40 mL of methanol followed by addition of 2g of PVP K-30. The mixture was stirred for clear solution and filtered to make it particle free, the bed was washed with 20 mL of methanol. Then 2g of Syloid is added to the filtrate and filtrate is subjected to distillation under reduced pressure at about 57°C and obtained solid was subjected to drying at about 57°C to afford the title solid. The resulting dispersion was found to be amorphous by X-ray powder diffraction according to Fig. 7a. The said dispersion is kept at 25°C under 40% relative humidity for 24 hours and PXRD was recorded and found to be amorphous according to Fig 7b.

Example 16: Preparation of a solid dispersion comprising an amorphous form of eliglustat hemitartarate

2g of eliglustat hemitartarate was charged in 40 mL of methanol followed by addition of 2g of Copovidone. The mixture was stirred for clear solution and filtered to make it particle free, the bed was washed with 20 mL of methanol. Then 2g of Syloid is added to the filtrate and filtrate is subjected to distillation under reduced pressure at about 57°C and obtained solid was subjected to drying at about 57°C to afford the title solid. The resulting dispersion was found to be amorphous by X-ray powder diffraction according to Fig. 8a. The said dispersion is kept at 25°C under 40% relative humidity for 24 hours and PXRD was recorded and found to be amorphous according to Fig. 8b and D₉₀ of the resultant solid is about 437 microns.

Example 17: Preparation of a solid dispersion comprising an amorphous form of eliglustat hemitartarate and Syloid

1 g of eliglustat hemitartarate was dissolved in 25 ml_ of methanol and filtered to make it particle free. Then 1 g of Syloid 244 FPNF was added to the filtrate and solvent from the filtrate was evaporated under reduced pressure at 56°C and obtained solid was subjected to drying at 56°C to afford the title solid. The resulting dispersion was found to be amorphous by X-ray powder diffraction according to Fig. 9 and D₉₀ of the resultant solid is about 4 microns.

Example 18: Preparation of a solid dispersion comprising an amorphous form of eliglustat hemitartarate and Syloid

1 g of eliglustat hemitartarate was dissolved in 25 ml_ of methanol and filtered to make it particle free. Then 500mg of Syloid 244 FPNF was added to the filtrate and solvent from the filtrate was evaporated under reduced pressure at 56°C and obtained solid was subjected to drying at 56°C to afford the title solid. The resulting dispersion was found to be amorphous by X-ray powder diffraction.

PATENT

(WO2015059679) IMPROVED PROCESS FOR THE PREPARATION OF ELIGLUSTAT

WO2015059679

DR. REDDY’S LABORATORIES LIMITED [IN/IN]; 8-2-337, Road No. 3, Banjara Hills Hyderabad 500034 (IN)

JAVED, Iqbal; (IN).
DAHANUKAR, Vilas Hareshwar; (IN).
ORUGANTI, Srinivas; (IN).
KANDAGATLA, Bhaskar; (IN)

Eliglustat tartrate (Genz-1 12638) is a glucocerebroside (glucosylceramide) synthase inhibitor for the treatment of gaucher disease and other lysosomal storage disorders, which is currently under development.

Eliglustat is chemically known as 1 R, 2R-Octanoic acid [2-(2′, 3′-dihydro-benzo [1 , 4] dioxin-6′-yl)-2-hydroxy-1 -pyrrolidin-1 -ylmethyl]-ethyl]-amide, having a structural formula I depicted here under.

Formula I

Eliglustat hemitartrate (Genz-1 12638) development by Genzyme, is a glucocerebroside (glucosylceramide) synthase inhibitor for the treatment of Gaucher disease and other lysosomal storage disorders. Eliglustat hemitartrate is orally active with potent effects on the primary identified molecular target for type 1 Gaucher disease and other glycosphingolipidoses, appears likely to fulfill high expectations for clinical efficacy. Gaucher disease belongs to the class of lysosomal diseases known as glycosphingolipidoses, which result directly or indirectly from the accumulation of glycosphingolipids, many hundreds of which are derived from glucocerebroside. The first step in glycosphingolipid biosynthesis is the formation of glucocerebroside, the primary storage molecule in Gaucher disease, via glucocerebroside synthase (uridine diphosphate [UDP] – glucosylceramide glucosyl transferase). Eliglustat hemitartrate is based on improved inhibitors of glucocerebroside synthase.

U.S. patent No. 7,196,205 (herein described as US’205) discloses a process for the preparation of eliglustat or a pharmaceutically acceptable salt thereof. In this patent, eliglustat was synthesized via a seven-step process involving steps in that sequence: (i) coupling S-(+)-2-phenyl glycinol with phenyl bromoacetate followed by column chromatography for purification of the resulting intermediate, (ii) reacting the resulting (5S)-5-phenylmorpholin-2-one with 1 , 4-benzodioxan-6-carboxaldehyde to obtain a lactone, (iii) opening the lactone of the oxazolo-oxazinone cyclo adduct via reaction with pyrrolidine, (iv) hydrolyzing the oxazolidine ring, (v) reducing the amide to amine to obtain sphingosine like compound, (vi) reacting the resulting amine with octanoic acid and N-hydroxysuccinimide to obtain crude eliglustat, (vii) purifying the crude eliglustat by repeated isolation for four times from a mixture of ethyl acetate and n-heptane.

U.S. patent No. 6855830, 7265228, 7615573, 7763738, 8138353, U.S. patent application publication No. 2012/296088 disclose processes for preparation of eliglustat and intermediates thereof.

U.S. patent application publication No. 2013/137743 discloses (i) a hemitartrate salt of eliglustat, (ii) a hemitartrate salt of eliglustat, wherein at least 70% by weight of the salt is crystalline, (iii) a hemitartrate salt of Eliglustat, wherein at least 99% by weight of the salt is in a single crystalline form.

It is also an objective of the present application to provide an improved process for the preparation of eliglustat and a pharmaceutically acceptable salt thereof which is high yielding, simple, cost effective, environment friendly and commercially viable by avoiding repeated cumbersome and lengthy purification steps. It is a further objective of the present application to provide crystalline forms of eliglustat free base and its salts.

Example 6: Preparation of Eliglustat {(1 R, 2R)-Octanoic acid[2-(2′,3′-dihydro-benzo [1 , 4] dioxin-6′-yl)-2-hydroxy-1 -pyrrolidin-1-ylmethyl-ethyl]-amide}.

(1 R, 2R)-2-Amino-1 -(2′, 3′-dihydro-benzo [1 , 4] dioxin-6′-yl)-3-pyrrolidin-1 -yl-propan-1 -ol (15g) obtained from above stage 5 was dissolved in dry dichloromethane (150ml) at room temperature under nitrogen atmosphere and cooled to 10-15^° C. Octanoic acid N-hydroxy succinimide ester (13.0 g)was added to the above reaction mass at 10-15^° C and stirred for 15 min. The reaction mixture was stirred at room temperature for 16h-18h. Progress of the reaction was monitored by thin layer chromatography. After completion of reaction, the reaction mixture was cooled to 15°C and diluted with 2M NaOH solution (100 ml_) and stirred for 20 min at 20 °C. The organic layer was separated and washed with 2M sodium hydroxide (3x90ml).The organic layer was dried over anhydrous sodium sulphate (30g) and concentrated under reduced pressure at a water bath temperature of 45^°C to give the crude compound (20g).The crude is again dissolved in methyl tertiary butyl ether (25 ml_) and precipitated with Hexane (60ml). It is stirred for 10 min, filtered and dried under vacuum to afford Eliglustat as a white solid (16g). Yield: 74%, Mass (m/zj: 404.7 HPLC (% Area Method): 97.5 %, ELSD (% Area Method): 99.78%, Chiral HPLC (% Area Method): 99.78 %.

Example 7: Preparation of Eliglustat oxalate.

Eliglustat (5g) obtained from above stage 6 is dissolved in Ethyl acetate (5ml) at room temperature under nitrogen atmosphere. Oxalic acid (2.22g) dissolved in ethyl acetate (5ml) was added to the above solution at room temperature and stirred for 14h. White solid observed in the reaction mixture was filtered and dried under vacuum at room temperature for 1 h to afford Eliglustat oxalate as a white solid (4g). Yield: 65.46%, Mass (m/zj: 404.8 [M+H] ^+> HPLC (% Area Method): 95.52 %, Chiral HPLC (% Area Method): 99.86 %

G.V. Prasad, chairman, Dr Reddy’s Laboratories

//////////////New patent, WO 2016001885, Dr Reddy’s Laboratories Ltd, Eliglustat hemitartarate, WO 2015059679

Continuous ruthenium-catalyzed methoxycarbonylation with supercritical carbon dioxide

January 11, 2016 6:27 am / Leave a comment

Catal. Sci. Technol., 2016, Advance Article
DOI: 10.1039/C5CY01883H, Paper

Stefan Christiaan Stouten, Timothy Noel, Qi Wang, Matthias Beller, Volker Hessel
The methoxycarbonylation of cyclohexene with carbon dioxide over a ruthenium catalyst was realized in a micro flow system under supercritical conditions.

Continuous ruthenium-catalyzed methoxycarbonylation with supercritical carbon dioxide

http://pubs.rsc.org/en/Content/ArticleLanding/2016/CY/C5CY01883H?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2Fcy+%28RSC+-+Catalysis+Science+%26+Technology+latest+articles%29#!divAbstract

The methoxycarbonylation of cyclohexene with carbon dioxide over a ruthenium catalyst was realized in a micro flow system under supercritical conditions. Instead of the toxic and flammable carbon monoxide, this process utilizes carbon dioxide, thereby avoiding issues with bulk transportation of carbon monoxide as well as eliminating the need for safety precautions associated with the use of carbon monoxide. Obtained was a 77% yield of the ester product at 180 °C, 120 bar and with a 90 min residence time, which is over five times faster than for the same reaction performed under subcritical conditions in batch. An important factor for the performance of the system was to have a sufficiently polar supercritical mixture, allowing the catalyst to dissolve well. The optimal temperature for the reaction was 180 °C, as the activity of the system dropped considerably at higher temperatures, most likely due to catalyst deactivation.

Department of Chemical Engineering and Chemistry

ir. S.C. (Stefan) Stouten –

Address:

Technische Universiteit Eindhoven
P.O. Box 513
5600 MB EINDHOVEN

Department:: Department of Chemical Engineering and Chemistry
Section:: Micro Flow Chemistry and Process Technology
Positioncategory:: doctoral candidate (PhD) (PhD Stud.)
Position:: doctoral candidate
Room:: STW 0.
Email:: s.stouten@tue.nl

Volker Hessel

prof.dr. V. (Volker) Hessel

Address:

Technische Universiteit Eindhoven
P.O. Box 513
5600 MB EINDHOVEN

Chair:

Micro Flow Chemistry and Process Technology

Department:: Department of Chemical Engineering and Chemistry
Section:: Micro Flow Chemistry and Process Technology
Positioncategory:: Professor (HGL)
Position:: Full Professor
Room:: STW 1.45
Tel:: +31 40-247 2973
Tel (internal):: 2973
Email:: v.hessel@tue.nl

////////Continuous, ruthenium-catalyzed, methoxycarbonylation, supercritical carbon dioxide, flow reactor

NEW PATENT, WO2016001844, SUN PHARMACEUTICALS, AFATINIB DIMALEATE

January 11, 2016 5:45 am / Leave a comment

WO2016001844,

AMORPHOUS FORM OF AFATINIB DIMALEATE

SUN PHARMACEUTICAL INDUSTRIES LIMITED

VERMA, Shyam Sunder; (IN).
SINGH, Shravan Kumar; (IN).
SINGH, Kaptan; (IN).
PRASAD, Mohan; (IN)

Afatinib dimaleate is a tyrosine kinase inhibitor, chemically designated as 2-butenamide, N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(35)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4-(dimethylamino)-,(2£)-, (2Z)-2-butenedioate (1:2) having the structure depicted by Formula I.

Formula I

U.S. Patent Nos. RE43,431 and 6,251,912 provide processes for the preparation of afatinib dimaleate.

U.S. Patent No. 8,426,586 and PCT Publication Nos. WO 2012/121764 and WO

2013/052157 provide processes for the preparation of crystalline forms of afatinib and their salts.

Example: Preparation of an amorphous form of afatinib dimaleate

In a round bottom flask, a mixture of afatinib (3 g) and ethyl acetate (30 mL) was heated to about 65°C to obtain a turbid solution. In another round bottom flask, a mixture of maleic acid (1.6 g) and ethyl acetate (30 mL) was heated to about 50°C to obtain a clear solution. The maleic acid solution was added to the afatinib solution, and then the reaction mixture was heated at about 75°C to about 80°C. The reaction mixture was stirred at about 75°C to about 80°C for about 1 hour. The reaction mixture was cooled to about

20°C to obtain a sticky material. The sticky material was scratched with a spatula, and then the reaction mixture was further stirred at about 20°C to about 25°C for about 1 hour. The material obtained was filtered, and then washed with ethyl acetate (20 mL). The solid obtained was dried under vacuum at about 45°C to about 50°C for about 15 hours to obtain the amorphous form of afatinib dimaleate.

Yield: 2.5 g (56%)

Sun Pharma chief Dilip Shanghvi

///////

NEW PATENT, TICAGRELOR, DR. REDDY’S LABORATORIES LIMITED, WO 2016001851

January 11, 2016 4:00 am / 1 Comment on NEW PATENT, TICAGRELOR, DR. REDDY’S LABORATORIES LIMITED, WO 2016001851

WO 2016001851

DR. REDDY’S LABORATORIES LIMITED [IN/IN]; 8-2-337, Road No. 3, Banjara hills, Hyderabad, Telangana Hyderabad 500034 (IN)

DAHANUKAR, Vilas; (IN).
ELATI, Ravi Ram Chandrasekhar; (IN).
ORUGANTI, Srinivas; (IN).
RAPOLU, Rajesh Kumar; (IN).
KURELLA, Sreenivasulu; (IN)

The drug compound having the adopted name “ticagrelor” has chemical names: [1 S-(1 α,2α,3β(1 S^*,2R^*),5p)]-3-[7-[2-(3,4-difluorophenyl-cyclopropyl] amino]-5-(propylthio)-3H-1 ,2,3-triazolo[4,5-d]pyrimidin-3-yl)-5-(2-hydroxyethoxy)-cyclopentane-1 ,2-diol; or (1 S,2S,3fl,5S)-3-[7-{[(1 fl,2S)-2-(3,4-difluorophenyl) cyclopropyl]amino}-5-(propylthio)-3H 1 ,2,3]-triazolo[4,5-c/|pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclope ed by Formula I.

Formula I

Ticagrelor is the active ingredient in the commercially available BRILINTA® tablets for oral administration.

Ticagrelor and related compounds are disclosed in International Patent Application Publication Nos. WO 00/34283 and WO 99/05143 as pharmaceutically active Ρ₂τ (which are now usually referred to as P2Y12) receptor antagonists. Such antagonists can be used, inter alia, as inhibitors of platelet activation, aggregation, or degranulation. International Patent Application Publication Nos. WO 01 /92263 and WO 2010/030224 A1 , WO 2012085665 A2, WO 2012138981 A2 and WO 2013037942 A1 disclose processes for preparing ticagrelor.

The processes for the preparation of traizolo [4,5-d] pyrimidine derivatives preferably Ticagrelor and related compounds, described in the above mentioned prior art suffer from disadvantages since the processes involve tedious and cumbersome procedures such as lengthy and multiple synthesis steps, reactions under pressure and high temperature, longer reaction times, tedious work up procedures and multiple crystallizations or isolation steps, column chromatographic purifications and thus resulting in low overall yields of the product. Ticagrelor obtained by the processes described in the prior art does not have satisfactory purity and unacceptable amounts of impurities are formed along with Ticagrelor at various stages of the processes that are difficult to purify and thus get carried forward in the subsequent steps thus affecting the purity of final compound. Thus, there remains a need to prepare compounds of Formula I of high purity and in good yield while overcoming the drawbacks presented by the previously described processes.

Formula V Formula V”

In a preferred embodiment, present application provide compounds of Formula IV with specific groups i.e. compounds of Formula IV and Formula IV”,

Formula IV Formula IV”

In a preferred embodiment, present application provides a compound of Formula II with specific groups i.e. compounds of Formula ΙΓ and Formula II”,

Formula ΙΓ Formula II”

In a preferred embodiment, present application provides a compound of Formula l la with specific grou

Formula lla

Formula VII’ Formula VII”

In a preferred embodiment, present application provides compounds of Formula Vila with specific groups i.e. compounds of Formula Vila’ and Formula “,

Formula Vila’ Formula Vila”

G.V. Prasad, chairman, Dr Reddy’s Laboratories

EXAMPLES

EXAMPLE 1 : Preparation of 2-bromo-N,N-diphenylacetamide (FORMULA Vile).

A flask is charged with Ν,Ν-diphenyl amine (25 g) and dichloromethane (350 mL) under nitrogen atmosphere. The reaction mixture is cooled to 0°C followed by addition of solution of triethyl amine (20.7 mL) and bromoacetyl chloride (38.72 mL) in dichloromethane (181 mL). The mixture is cooled to room temperature and then stirred for about 16 hours. The completion of the reaction is monitored by TLC. The reaction mixture is diluted with dichloromethane (250 mL) and then washed with 0.5N aqueous hydrochloric acid solution (3×150 mL), brine (100 mL). The organic layer is separated and subjected to distillation under vacuum at 45°C. The obtained compound is recrystallized from hexane (250 mL) and methanol (100 mL) to afford the title compound.

EXAMPLE 2: Preparation of benzyl ((3aS,4R,6S,6aR)-6-(2-(diphenylamino)-2-oxoethoxy)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1 ,3]dioxol-4-yl)carbamate (FORMULA Vila).

A flask is charged with sodium hydride (2.85 mL, 60% dispersion in oil) and dimethyl formamide (10 mL) under nitrogen atmosphere. The reaction mixture is then cooled to -30°C followed by addition of a solution of benzyl

((3aS,4R,6S,6aR)-6-hydroxy-2,2-dimethyltetrahydro-4H-cyclopenta[d][1 ,3]dioxol-4-yl)carbamate (20 g) in dimethyl formamide (40 mL). The mixture is stirred at -30°C for about 45 minutes, then a solution of 2-bromo-N,N-diphenylacetamide (22.65 g) in dimethyl formamide (60 mL) is added at the same temperature. The reaction mixture is allowed to attain room temperature and stirred at the same for 3 hours and completion of the reaction is monitored by TLC. The reaction mixture is quenched with ice-cold water (200 mL) and extracted with ethyl acetate (3×150 mL). The organic layer is combined and washed with water (3×100 mL), brine (100 mL) and then organic layer is then subjected to complete distillation under vacuum at 45°C. The crude so obtained is treated with MTBE (150 mL) and stirred at room temperature for overnight followed by filtration of obtained solid to afford the title compound.

EXAMPLE 3: Preparation of 2-(((3aR,4S,6R,6aS)-6-amino-2,2-dimethyl tetrahydro-4H-cyclopenta[d][1 ,3]dioxol-4-yl)oxy)-N,N-diphenylacetamide (Formula VII)

A flask is charged with benzyl ((3aS,4R,6S,6aR)-6-(2-(diphenylamino)-2-oxoethoxy)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1 ,3]dioxol-4-yl)carbamate (15 g), ethanol (300 mL), 10% Pd/C (1.5 g) and ammonium formate (5.49 g). The reaction mixture is stirred at 80°C for 8 hours and completion of the reaction is monitored by TLC. Then reaction mixture is cooled to room temperature and filtered through celite bed, bed is washed with ethyl acetate (100 mL). The filtrate is subjected to complete distillation under vacuum at 45°C. Then ethanol (120 mL), L-tartaric acid (4.88 g) is added to the crude compound and mixture is stirred for 4 hours at room temperature. To the mixture, MTBE (300 mL) is added at the same temperature. The solvent is distilled under vacuum at 35°C to afford the gummy solid. Then MTBE (100 mL) is added to the gummy solid and mixture is stirred for 10-12 hours. The solid obtained is filtered and washed with MTBE (50 mL). The solid obtained is dissolved in water and sodium bicarbonate solution (200 mL) is added, desired compound is extracted in ethyl acetate (100 mL). The solvent is subjected to distillation (upto 40%) followed by addition of hexane (150 mL) and ethyl acetate (20 mL). The mixture is stirred at -10°C, then solid is recovered followed by drying under vacuum at 40°C. The crude compound is purified by column chromatography using methanol and dichloromethane (5:95) to afford the title compound.

EXAMPLE 4: Preparation of 2-(((3aR,4S,6R,6aS)-6-((5-amino-6-chloro-2- (propylthio)pyrimidin-4-yl)amino)-2,2-dimethyltetrahydro-4H-cyclopenta[d]

[1 ,3]dioxol-4-yl)oxy)-N,N-diphenylacetamide (Formula V)

A flask is charged with 4,6-dichloro-2-(propylthio)pyrimidin-5-amine (6.5 g),

2- (((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-4H-cyclopenta[d][1 ,3]dioxol-4-yl)oxy)-N,N-diphenylacetamide (10.39 g), sodium bicarbonate (9.13 g) and water. The mixture is stirred at 95-100°C for 15-20 hours till completion of the reaction (as monitored by TLC). Then water (20 mL) and ethyl acetate (25 mL) are added at room temperature. The layers are separated and aqueous layer is extracted with ethyl acetate (20 mL). The organic layers are combined and washed with brine solution (2×25 mL). The organic layer is subjected to complete distillation under vacuum at 40-45°C. The obtained crude compound is purified by column chromatography using ethyl acetate and hexane (30:70) to afford the title compound.

EXAMPLE 5: Preparation of 2-(((3aR,4S,6R,6aS)-6-(7-chloro-5-(propylthio)-3H-[1 ,2,3]triazolo[4,5-d]pyrimidin-3-yl)tetrahydro-4H-cyclopenta[d][1 ,3]dioxol-4-yl)oxy)-N,N-diphenylacetamide (Formula IV)

A flask is charged with 2-(((3aR,4S,6R,6aS)-6-((5-amino-6-chloro-2-(propylthio)pyrimidin-4-yl)amino)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1 ,3]dioxol-4-yl)oxy)-N,N-diphenylacetamide (6 g), acetic acid (30 mL) and water (6 mL). The mixture is cooled to 0 to -5°C followed by addition of addition of sodium nitrite solution (768 mg in 6 mL of water). The mixture is stirred for 1 hour at the same temperature and then mixture is allowed to attain room temperature, and further stirred for 1 hour. The completion of the reaction is monitored by TLC and then toluene (60 mL) is added. The layers are separated, organic layer is washed with saturated solution of potassium carbonate and subsequently organic layer is dried with sodium sulphate and used for next reaction.

EXAMPLE 6: Preparation of 2-(((3aR,4S,6R,6aS)-6-(7-(((1 R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1 ,2,3]triazolo[4,5-d]pyrimidin- 3- yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1 ,3]dioxol-4-yl)oxy)-N,N-diphenylacetamide (Formula II)

A flask is charged with (1 R,2S)-2-(3,4-difluorophenyl)cyclopropan-1 -amine mandelate (3.25 g), diisopropylethyl amine (6.1 mL), toluene (60 mL) and stirred for 30 minutes at room temperature. Then slowly, toluene layer containing 2-(((3aR,4S,6R,6aS)-6-(7-chloro-5-(propylthio)-3H-[1 ,2,3]triazolo[4,5-d]pyrimidin-3-yl)tetrahydro-4H-cyclopenta[d][1 ,3]dioxol-4-yl)oxy)-N,N-diphenylacetamide (60 mL) is added over a period of 10 minutes. The reaction mixture is stirred at room temperature for overnight and completion of the reaction is monitored by TLC. The reaction mixture is diluted with water (60 mL), layers are separated and aqueous layer is extracted with toluene (2×30 mL). The combined organic layers are washed with brine (60 mL) and then subjected to complete distillation under vacuum at 45°C to afford the crude compound. The crude compound is purified by column chromatography using ethyl acetate and hexane (80:20).

EXAMPLE 7: Preparation of 2-(((3aR,4S,6R,6aS)-6-(7-(((1 R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1 ,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1 ,3]dioxol-4-yl)oxy)ethan-1 -ol (Formula lib)

A flask is charged with 2-(((3aR,4S,6R,6aS)-6-(7-(((1 R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1 ,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1 ,3]dioxol-4-yl)oxy)-N,N-diphenylacetamide (3 g), THF (90 mL) and mixture is cooled to 0°C. Then portion wise, Lithium aluminium hydride (940 mg) is added over a period of 10 minutes and mixture is stirred at 0°C for 1 hour. The reaction mixture is then stirred at room temperature for 5 hours and progress of the reaction is monitored by TLC. Then mixture is cooled to 0-5°C and quenched with ice cold water (100 mL) and then diluted with ethyl acetate (30 mL). The layers are separated and organic layer after drying is used for next step.

EXAMPLE 8: Preparation of Ticagrelor (Formula I)

A flask is charged with organic layer containing 2-(((3aR,4S,6R,6aS)-6-(7-(((1 R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1 ,2,3] triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1 ,3]dioxol-4-yl)oxy)ethan-1 -ol (1 10 mL) and 2% hydrochloric acid solution (75 mL). The reaction mixture is stirred at room temperature for 48 hours and progress of the reaction is monitored by TLC. Then the reaction mixture is diluted with ethyl acetate (50 mL), layers are separated. The organic layer is sequentially washed with water (50 mL), brine solution (50 mL) followed by complete distillation under vacuum at 45°C. The crude compound is dissolved in ethyl acetate (12 mL) and then hexane (50 mL) is added. The mixture is stirred for 2 hours followed by isolation of solid by filtration. The obtained solid is dissolved in ethyl acetate (12 mL) and treated with charcoal followed by filtration. The filtrate is subjected to complete distillation and obtained solid is purified by column chromatography using ethyl acetate:hexane (1 :1 ) and methanohdichloromethane (5:95) to afford the title compound.

EXAMPLE 9: Preparation of 2-(((3aR,4S,6R,6aS)-6-(7-(((1 R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1 ,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1 ,3]dioxol-4-yl)oxy)ethan-1 -ol (Formula lib)

A flask is charged with 2-(((3aR,4S,6R,6aS)-6-(7-(((1 R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1 ,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1 ,3]dioxol-4-yl)oxy)-N,N-diphenylacetamide (100 mg), THF (3 mL) and cooled to 0-5°C followed by addition of Vitride (0.04 mL) at 0-5°C over a period of 5 minutes. The mixture is stirred at same temperature for 1 hour and progress of the reaction is monitored by TLC. Additional amount of Vitride (0.13 mL) is added to the mixture and stirred for additional 6 hours. After completion of reaction, reaction mixture is cooled to 0-5°C and quenched with saturated sodium potassium tartrate solution (10 mL) and extracted with ethyl acetate (20 mL). The organic layer is subjected to complete distillation under reduced pressure and obtained material is purified by column chromatography using ethyl acetate: hexane (1 :1 ) and methanohdichloromethane (5:95) to afford the title compound.

EXAMPLE 10: Preparation of 2-(((3aR,4S,6R,6aS)-6-(7-(((1 R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1 ,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1 ,3]dioxol-4-yl)oxy)acetaldehyde (Formula lib’)

A flask is charged with 2-(((3aR,4S,6R,6aS)-6-(7-(((1 R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1 ,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1 ,3]dioxol-4-yl)oxy)-N,N-diphenylacetamide (100 mg), THF (5 mL) and mixture is cooled to 0°C. Then portion wise, Lithium aluminium hydride (15 mg) is added over a period of 1 0

minutes and mixture is stirred at 0°C for 1 hour. The progress of the reaction is monitored by TLC. After completion of the reaction, mixture is quenched with ice cold water (5 mL) and diluted with ethyl acetate (10 mL). The layers are separated and organic layer after drying is subjected to complete distillation followed by purification using preparative TLC using 40% ethyl acetate in hexane to afford the title compound.

EXAMPLE 11 : Preparation of 2-bromo-1 -morpholinoethan-1 -one

A flask is charged with bromoacetyl bromide (25 mL), dichloromethane (500 mL) and mixture is stirred under nitrogen atmosphere. The reaction mixture is cooled to -25°C followed by slow addition of morpholine (72.7 mL in 500 mL of DCM) at the same temperature over a period of 30 minutes. The reaction mixture is stirred at -25°C for 15 minutes, then allowed to attain room temperature at which it is further stirred for 4 hours. The completion of the reaction is monitored by TLC and reaction mixture is sequentially washed with water (2×250 mL) and brine solution (2×100 mL). The organic solvent is subjected to distillation to afford the title compound.

EXAMPLE 12: Preparation of benzyl ((3aS,4R,6S,6aR)-2,2-dimethyl-6-(2-morpholino-2-oxoethoxy)tetrahydro-4H-cyclopenta[d][1 ,3]dioxol-4-yl)carbamate (Formula Vila”)

A flask is charged with sodium hydride (60%, 4.29 g), DMF (90 mL) and cooled to -30°C. Then, benzyl ((3aS,4R,6S,6aR)-6-hydroxy-2,2-dimethyltetrahydro-4H-cyclopenta[d][1 ,3]dioxol-4-yl)carbamate (30 g) is added to the reaction mixture at the same temperature over a period of 25 minutes and mixture is stirred at -30°C for 1 hour. Then 2-bromo-1 -morpholinoethan-1 -one (24.36 g) is added to the reaction mixture at -30°C over a period of 20 minutes and temperature is raised to room temperature. The mixture is stirred at RT for 1 hour. The progress of the reaction is monitored by TLC and after completion, the reaction mixture is quenched with ice cold water followed by extraction with ethyl acetate. The organic layer is separated and subjected to distillation to afford the title compound.

EXAMPLE 13: Preparation of 2-(((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-4H-cyclopenta[d][1 ,3]dioxol-4-yl)oxy)-1 -morpholinoethan-1 -one (Formula VII”)

A flask is charged with benzyl ((3aS,4R,6S,6aR)-2,2-dimethyl-6-(2-morpholino-2-oxoethoxy)tetrahydro-4H-cyclopenta[d][1 ,3]dioxol-4-yl)carbamate, ethanol (1 0 g), ammonium formate (4.35 g) and 10% Pd/C (1 g). The reaction mixture is heated to 80°C and then stirred for 2 hours. The progress of the reaction is monitored by TLC and after completion of the reaction, mixture is cooled to room temperature, filtered and washed with ethyl acetate (100 mL). The filtrate is distilled under reduced pressure and obtained compound is purified by column chromatography using methanol-DCM (5:95) to afford the title compound.

EXAMPLE 14: Preparation of 2-(((3aR,4S,6R,6aS)-6-((5-amino-6-chloro-2- (propylthio)pyrimidin-4-yl)amino)-2,2-dimethyltetrahydro-4H-cyclopenta[d]

[1 ,3]dioxol-4-yl)oxy)-1 -morpholinoethan-1 -one (Formula V”)

A flask is charged with 2-(((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-4H-cyclopenta[d][1 ,3]dioxol-4-yl)oxy)-1 -morpholinoethan-1 -one (8 g), water (24 mL) and stirred for 10 minutes. Then sodium bicarbonate (8.9 g), 4,6-dichloro-2-(propylthio)pyrimidin-5-amine (6.3 g) and water (24 mL) is added and mixture is heated to 95-100°C at which point it is stirred for 15 hours. The progress of the reaction is monitored by TLC and on completion reaction mixture is cooled to room temperature followed by addition of water (24 mL) and ethyl acetate (40 mL). The layers are separated and aqueous layer is extracted with ethyl acetate (20 mL). The organic layers are combined, washed with brine solution (2×40 mL) and subjected to distillation under vacuum at 45°C to afford the title compound.

EXAMPLE 15: Preparation of 2-(((3aR,4S,6R,6aS)-6-(7-chloro-5-(propylthio)-3H-[1 ,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1 ,3] dioxol-4-yl)oxy)-1 -morpholinoethan-1 -one (Formula IV”)

A flask is charged with 2-(((3aR,4S,6R,6aS)-6-((5-amino-6-chloro-2-(propylthio)pyrimidin-4-yl)amino)-2,2-dimethyltetrahydro-4H-cyclopenta[d]

[1 ,3]dioxol-4-yl)oxy)-1 -morpholinoethan-1 -one (4 g), acetic acid (20 mL) and stirred under nitrogen atmosphere for 10 minutes. Then water (8 mL) is added and mixture is cooled to -5 to 0°C followed by slow addition of sodium nitrite (650 mg). The mixture is stirred at 0°C for 1 hour and progress of the reaction is monitored by TLC. After completion of the reaction, mixture is extracted with toluene (40 mL and 20 mL). The combined toluene layer is sequentially washed with potassium

carbonate solution (40 mL) and brine solution (2×20 mL) followed by distillation under vacuum to afford the desired compound.

EXAMPLE 16: Preparation of 2-(((3aR,4S,6R,6aS)-6-(7-(((1 R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1 ,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1 ,3]dioxol-4-yl)oxy)-1 -morpholinoethan-1 -one (Formula II”)

A flask is charged with (1 R,2S)-2-(3,4-difluorophenyl)cyclopropan-1 -amine mandelate (2.5 g) and toluene (20 mL) followed by drop-wise addition of diisopropylethylamine (4.7 mL), then mixture is stirred for 10 minutes at RT. Then toluene layer containing 2-(((3aR,4S,6R,6aS)-6-(7-chloro-5-(propylthio)-3H-[1 ,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1 ,3] dioxol-4-yl)oxy)-1 -morpholinoethan-1 -one (4 g in 55 mL) is added to the above mixture and reaction mass is stirred for 15 hours at room temperature. The progress of the reaction is monitored by TLC followed by addition of water (20 mL) on completion of reaction. The layers are separated, aqueous layer is extracted with toluene (20 mL). The organic layers are combined, washed with brine solution (2×20 mL) and then subjected to distillation under vacuum at 45°C to afford the crude compound. The crude compound is purified by column chromatography using hexane to afford the title compound.

EXAMPLE 17: Preparation of 2-(((3aR,4S,6R,6aS)-6-(7-(((1 R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1 ,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1 ,3]dioxol-4-yl)oxy)ethan-1 -ol

A flask is charged with 2-(((3aR,4S,6R,6aS)-6-(7-(((1 R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1 ,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1 ,3]dioxol-4-yl)oxy)-1 -morpholinoethan-1 -one (1 g) in tetrahydrofuran (20 mL) and stirred under nitrogen atmosphere followed by addition of vitride (1 .53 mL) over a period of 10 minutes. The reaction mixture is stirred for 1 hour at room temperature and progress of the reaction is monitored by TLC. On completion, the mixture is quenched with sodium potassium tartrate (5 mL). The mixture is extracted with ethyl acetate (10 mL), then layers are separated and organic layer is subjected to distillation under vacuum at 45°C. The obtained material is dissolved in THF (20 mL) and slowly lithium aluminiumhydride (0.1 17 g) is added to the mixture at 0-5°C. Then mixture is stirred at room temperature for 1 hour and progress of the reaction is monitored by TLC. On completion of reaction, it is quenched with ice-cold water (20 mL) and extracted with ethyl acetate (15 mL). The layers are separated and organic layer is used for next step.

EXAMPLE 18: Preparation of Ticagrelor

EXAMPLE 19: Preparation of 2-(((3aR,4S,6R,6aS)-6-(7-chloro-5-(propylthio)-3H-[1 ,2,3]triazolo[4,5-d]pyrimidin-3-yl)tetrahydro-4H-cyclopenta[d][1 ,3]dioxol-4-yl)oxy)-N,N-diphenylacetamide (Formula IV)

A flask is charged with 2-(((3aR,4S,6R,6aS)-6-((5-amino-6-chloro-2-(propylthio)pyrimidin-4-yl)amino)-2,2-dimethyltetrahydro-4H-cyclopenta[d]

[1 ,3]dioxol-4-yl)oxy)-N,N-diphenylacetamide (5 g) and acetonitrile (50 mL) for clear solution. To this, isoamyl nitrite (1 .5 g) is added over a period of 5 minutes. The reaction mixture is maintained at room temperature for 5 hours and completion of the reaction is monitored by TLC. Then water (50 mL) and toluene (50 mL) are added and layers are separated. The aqueous layer is extracted with toluene (50 mL) and total organic layers are combined, subjected to distillation under vacuum to afford the title compound.

Anji Reddy

Mr G.V. Prasad, CEO, Dr. Reddy’s Labs

G V Prasad and Mr K. Satish Reddy

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NEW PATENT, TICAGRELOR, DR. REDDY’S LABORATORIES LIMITED, WO 2016001851

New Patent from Zydus Cadila, Canagliflozin, US 20160002275

January 11, 2016 3:45 am / Leave a comment

US-20160002275

CADILA HEALTHCARE LIMITED [IN]

DESAI, Sanjay Jagdish [IN]

PARIHAR, Jayprakash Ajitsingh [IN]

PATEL, Jagdish Maganlal [IN]

SURYAWANSHI, Uday Suresh [IN]

BHALALA, Jaisukh Bhupatbhai [IN]

(2S,3R,4R,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol is also known as Canagliflozin, is an inhibitor of subtype 2 sodium-glucose transport protein (SGLT2) which is chemically represented as compound of Formula (I).

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U.S. Pat. No. 7,943,788 B2 discloses canagliflozin and a process for its preparation.

U.S. Pat. No. 7,943,582 B2 (the ‘582 patent) discloses crystalline form of 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene hemihydrate and process for preparation thereof.

U.S. PG-Pub. No. 2011/0212905 discloses crystalline form of 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene hemihydrate and process for preparation thereof.

U.S. PG-Pub. Nos. 2009/0233874, 2010/099883 and 2008/0146515 discloses similar process for the preparation of canagliflozin substantially as same as shown in scheme-1 below.

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International (PCT) Publication No. WO 2011/079772 discloses a process for the preparation of canagliflozin by reduction of keto group of acetyl protected compound followed by hydrolysis.

U.S. PG-Publication No. 2014/0128595 discloses a process for the preparation of canagliflozin from anhydroglucopyranose derivative substantially as same as shown in scheme-2 below.

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The prior-art processes requires sequence of protection/deprotection of canagliflozin obtained in the course of the reactions and further purification or crystallization to obtain canagliflozin in reasonably pure form. This sequences of processes results in high amount of yield loss.

In view of the above prior art, there is provided a novel, efficient and convenient process for preparation of canagliflozin which is at least a useful alternative to the prior art as well as an efficient and convenient method for purification of canagliflozin without sequence of protection and deprotection.

Scheme-3.

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Ahmedabad-based pharma giant Cadila Healthcare’s chairman and managing director, Pankaj Patel,

EXAMPLES

Example-1Preparation of (3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (III)

In 500 mL three necked round bottomed flask equipped with mechanical stirrer, thermometer and addition funnel were added 2-(5-bromo-2-methylbenzyl)-5-(4-fluorophenyl)thiophene (Va) (5 g) and 150 mL toluene at 25° C. 1.5 mL (1.6M) n-butyl lithium in hexane was added dropwise at room temperature and the solution was stirred for 30 minutes. This solution was cooled to −78° C. and added dropwise to a solution of 3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one (IV) (6.4 g) in 100 mL toluene and the mixture was stirred for 3 hours. The reaction mixture was treated with 2.5 g methanesulfonic acid in 100 mL methanol and stirred for 1 hour. The reaction mass was warmed to 25° C. and then added to pre-cool saturated sodium bicarbonate solution and resulting mass was extracted with ethyl acetate. The extract was washed with brine, dried over Na₂SO₄and evaporated under reduced pressure to obtain compound of Formula (III).

Example-1APreparation of (3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (III)

In 500 mL three necked round bottomed flask equipped with mechanical stirrer, thermometer and addition funnel were added 2-(5-bromo-2-methylbenzyl)-5-(4-fluorophenyl)thiophene (Va) (5 g) and 150 mL toluene at 25° C. 1.5 mL (1.6M) n-butyl lithium in hexane was added dropwise at room temperature and the solution was stirred for 30 minutes. This solution was cooled to −78° C. and added dropwise to a solution of 3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one (IV) (6.4 g) in 100 mL toluene and the mixture was stirred for 3 hours. The reaction mixture was treated with 2.5 g methanesulfonic acid in 100 mL methanol and stirred for 1 hour. The reaction mixture warmed to room temperature and stirred for 8 hours. Saturated sodium bicarbonate solution was added to the reaction mixture and the separated aqueous layer was extracted with toluene. The organic layer was distilled to remove toluene and the residue was dissolved in 50 mL methylene dichloride, washed with brine, dried over Na₂SO₄and evaporated under reduced pressure to obtain residue. The residue was treated with 150 mL diisopropyl ether and stirred at 55° C. for 30 min, cooled, filtered and washed withdiisopropyl ether to obtain compound of Formula (III).

Example-1BPreparation of (3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (III)

In 5 L three necked round bottomed flask equipped with mechanical stirrer, thermometer and addition funnel were added 100 g 2-(5-iodo-2-methylbenzyl)-5-(4-fluorophenyl)thiophene (Vb), 114.35 g 3,4,5-tris((trimethylsilyl)oxy)-6-(((tri-methylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one (IV), 2 L toluene and 1 Ltetrahydrofuran at 30° C. The reaction mixture was cooled to −78° C. and 171.45 mL n-butyl lithium in hexane (1.6M) was added and the solution was stirred for 3 hours. The reaction mixture was treated with 94.16 g methanesulfonic acid in 1500 mL methanol and stirred for 1 hour. The reaction mixture warmed to 25° C. and stirred for 8 hours. The reaction mixture was cooled to 5° C. and saturated sodium bicarbonate solution was added to the reaction mixture and stirred for 30 min. The separated aqueous layer was extracted with toluene. The organic layer was distilled to remove toluene and the residue was dissolved in 300 mL methylene dichloride and 200 g silica gel of 60-120 mesh was added. The reaction mixture was stirred for 30 min at 30° C., washed with brine, dried over Na₂SO₄and evaporated under reduced pressure to obtain residue. The residue was treated with 1 L diisopropyl ether and stirred at 55° C. for 30 min, cooled, filtered and washed with diisopropyl ether to obtain compound of Formula (III).

Example-2APreparation of (3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-2-methoxy-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-3,4,5-triol (IIa1)

In 500 mL three necked round bottomed flask equipped with mechanical stirrer, thermometer and addition funnel were added 10 g compound of Formula (III), 80 mL methylene dichloride and 4.3 g N-methylmorpholine at −5 to 5° C. 2.7 g trimethylsilyl chloride was added slowly and stirred for 1 hour. After confirming the reaction completion TLC, 30 mL pre-cool water was slowly added, stirred and layers were separated. The separated aqueous layer was extracted with methylene dichloride and the combined organic layers were washed with 20% sodium dihydrogen phosphate dihydrate solution, water and brine. The organic layer was evaporated under reduced pressure to obtain compound of Formula (IIa).

Example-2BPreparation of (3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-2-methoxy-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-3,4,5-triol (IIa1)

In 1 L three necked round bottomed flask equipped with mechanical stirrer, thermometer and addition funnel were added 100 g compound of Formula (III) and 900 mL methanol at 30° C. and stirred for 1 hour. The reaction mixture was filtered to remove silica gel and washed with methanol. The filtrate was distilled under vacuum to remove methanol completely, 350 mL methylene dichloride and 42.63 g N-methylmorpholine were added to the residue and cooled to at −5 to 5° C., 34.34 g trimethylsilyl chloride was lot-wise added and stirred for 45 min. After confirming the reaction completion TLC, 300 mL pre-cool water was slowly added, stirred and layers were separated. The separated aqueous layer was extracted with methylene dichloride and the combined organic layers were washed with 20% sodium dihydrogen phosphate dihydrate solution, water and brine. The separated organic layer was dried over sodium sulfate and filtered to obtain compound of Formula (IIa1).

Example-3APreparation of Canagliflozin of Formula (I)

In 1 L three necked round bottomed flask equipped with mechanical stirrer, thermometer and addition funnel was added solution of compound (IIa) prepared in example-2B and cooled to −70° C. 8 mL triethylsilane and 5.5 mL boron trifluoridediethyl etherate were added dropwise within 1 hour maintaining the reaction temperature between −70° C. The reaction was warmed to −30° C. and stirred for 30 min. The reaction mixture was then added to freshly preparedsodium bicarbonate solution at 5° C. and then allowed to warm to room temperature and stirred for 20 mints to adjust the pH of 7-8. The reaction mass was then slowly added to cold water. The resulting mass was extracted with ethyl acetate. The combined organic layers were washed with saturated bicarbonatesolution, dried over Na₂SO₄and evaporated under reduced pressure to obtain canagliflozin having purity 86% by HPLC.

Example-3BPreparation of Canagliflozin of Formula (I)

In 2 L three necked round bottomed flask equipped with mechanical stirrer, thermometer and addition funnel was added the solution of compound (IIa) prepared in example-2B and cooled to −70° C. 67.38 g triethylsilane and 83.08 g boron trifluoridediethyl etherate were added dropwise within 1 hour maintaining the reaction temperature between −70° C. The reaction was warmed to −30° C. and stirred for 3 hours. The reaction mixture was then added to freshly prepared sodium bicarbonate solution at 5° C. and then allowed to warm to room temperature and stirred for 20 mints to adjust the pH of 7-8. The reaction mixture was then slowly added to cold water. The separated aqueous layer was extracted with 200 mL methylene dichloride. The combined organic layer was washed with 300 mL water and distilled completely to remove methylene dichloride. The resulting residue extracted with 500 mL ethyl acetate and stirred to obtain clear solution. The reaction mixture was treated with brine and saturated bicarbonate solution to separate the layers. The separated organic layer was dried over sodium sulfate, charcoalized and filtered. The filtrate is distilled to remove ethyl acetate completely under vacuum. The residue was dissolved in 300 mL methylene dichloride and 200 g silica gel of 60-120 mesh was added. The reaction mixture was stirred for 30 min at 30° C. and distilled completely under reduced pressure to obtain residue. The residue was treated with 500 L diisopropyl ether and stirred at 55° C. for 30 min, cooled, filtered and washed with diisopropyl ether to obtain canagliflozin (I) having purity 87% by HPLC.

Example-4Preparation of (3R,4S,5R,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-2-methoxy-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-3,4,5-triyl)tris(oxy)tris(trimethylsilane) (IIb1)

In 500 mL three necked round bottomed flask equipped with mechanical stirrer, thermometer and addition funnel were added 10 g compound of Formula (III), 100 mL methylene dichloride and 15 g N-methylmorpholine at 0 to 5° C. 12.7 g trimethylsilyl chloride was added slowly and stirred for 1 hour. After confirming the reaction completion by TLC, 300 mL pre-cool water was slowly added, stirred and layers were separated. The separated aqueous layer was extracted with methylene dichloride and the combined organic layers were washed with 20% sodium dihydrogen phosphate dihydrate solution, water and brine. The organic layer was evaporated under reduced pressure to obtain compound of Formula (IIb1).

Example-5Preparation of Canagliflozin

In 500 mL three necked round bottomed flask equipped with mechanical stirrer, thermometer and addition funnel was added 20 g compound (IIb1) prepared in example-4 and 100 mL methylene dichloride at −25° C. to −30° C. 11 mL triethylsilane and 7.8 mL boron trifluoridediethyl etherate was added drop wise within 1-2 hours maintaining the reaction temperature between −25° C. to −30° C. The reaction was stirred for 30 min and then allowed to warn to room temperature and stirred for 1.5-2 hours. The reaction mixture was then slowly added to cold water. The reaction mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated bicarbonate solution, dried over sodium sulfate and evaporated under reduced pressure to obtain canagliflozin having purity 86% by HPLC.

Example-6Purification of Canagliflozin

In 250 L three necked round bottomed flask equipped with mechanical stirrer, thermometer and addition funnel 10 g canagliflozin (purity 85%) and 100 mLtoluene were stirred to obtain a clear solution. 10 g Polyvinylpyrrolidone was added to the solution and stirred for 2-3 hours. The reaction mixture was filtered and washed with toluene. The solid was stirred in ethyl acetate and water mixture for 30 min. The separated ethyl acetate layer was evaporated to dryness to obtain pure canagliflozin. (7.1 g. Purity 96.55% by HPLC).

Example-7Purification of Canagliflozin

In 250 L three necked round bottomed flask equipped with mechanical stirrer, thermometer and addition funnel 10 g canagliflozin (purity 87%) and 100 mLtoluene were stirred in in a round bottom flask to obtain a clear solution. 10 g β-cyclodextrin was added to the solution and stirred for 2-3 hours. The reaction mixture was filtered and washed with toluene. The solid was stirred in ethyl acetate and water mixture for 30 min. The separated ethyl acetate layer was treated with activated carbon, filtered and evaporated to dryness to obtain pure canagliflozin. (7.9 g, Purity 98.93% by HPLC).

Example-8Purification of Canagliflozin

In 250 L three necked round bottomed flask equipped with mechanical stirrer, thermometer and addition funnel 10 g canagliflozin (purity 87%) and 0.25 g activated carbon were stirred in 100 mL toluene for 15-20 min and filtered. 10 g β-cyclodextrin was added to the filtrate and stirred for 2-3 hours. The reaction mixture was filtered and washed with toluene. The solid was stirred in isopropyl acetate and water mixture for 30 min. The separated isopropyl acetate layer was evaporated to dryness to obtain pure canagliflozin. (7.7 g, Purity 99.12% by HPLC).

Example-9Purification of Canagliflozin

In 250 L three necked round bottomed flask equipped with mechanical stirrer, thermometer and addition funnel, 10 g canagliflozin (purity 87%) and 100 mLtoluene were stirred to obtain a clear solution. 10 g hydroxy propyl methyl cellulose was added to the solution and stirred for 2-3 hour. The reaction mixture was filtered, washed with toluene. The solid was stirred in isopropyl acetate and water mixture for 30 min and dried to obtain pure canagliflozin. (Purity 97-98% by HPLC).

Example-10Purification of Canagliflozin

In 2 L three necked round bottomed flask equipped with mechanical stirrer, thermometer and addition funnel, 100 g canagliflozin (purity 87%) obtained in example-3B and 900 mL methanol were stirred for 45 min at 30° C. The reaction mixture was filtered to remove silica gel. The filtrate was distilled under vacuum completely below 45° C. 400 mL toluene was added and heated to 55° C. to obtain a clear solution. The reaction mixture was filtered and the filtrate was added 100 g β-cyclodextrine. The reaction mixture was heated at 75° C. for 30 min and cooled to 30° C. and further stirred for 30 min. 5 g canagliflozin β-cyclodextrin complex was added to the solution and further cooled to 5° C. The reaction mixture was stirred for 3 hours and filtered. The wet-cake was treated with 300 mL isopropyl acetate and heated at 75° C. for 30 min. The reaction mixture was cooled to 30° C. and stirred for 6 hours and further cooled to 5° C. and stirred for 3 hours. The reaction mixture was filtered and washed with isopropyl acetate and dried at 30° C. to obtain crystalline canagliflozin β-cyclodextrine complex having 40 g pure canagliflozin with 99% purity by HPLC.

Example-11Preparation of Amorphous Canagliflozin

In 1 L three necked round bottomed flask equipped with mechanical stirrer, thermometer and addition funnel, 100 g canagliflozin β-cyclodextrine (purity 98%) obtained in example-10 and 400 mL acetone were stirred for 30 min at 30° C. The reaction mixture was filtered to remove β-cyclodextrine. The filtrate was distilled under vacuum completely below 45° C. 400 mL acetone was added to the residue to get clear solution at 30° C. 5 g activated charcoal was added and stirred for 20 min. The reaction mixture was filtered and the filtrate was spray dried using JISL Mini spray drier LSD-48 keeping feed pump at 30 rpm, inlet temperature at 60° C., outlet temperature at 40° C. and 2 Kg/cm2 hot air supply. The product was collected from cyclone and is further dried at 40° C.±5° C. under vacuum for 12 hours to get 80 g of amorphous canagliflozin having 99.6% purity by HPLC.

WO2014195966

https://www.google.co.in/patents/WO2014195966A2?cl=un

Canagliflozin is inhibitor of sodium dependent glucose transporter inhibitor (SGLT) which is chemically represented as (25′,3i?,4/?,55^,,6 ?)-2-{3-[5-[4-Fluoro-phenyl]-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol having (I).

Formula (I)

U.S. Patent No, 7,943,788 B2 (the ‘788 patent) discloses canagliflozin or salts thereof and the process for its preparation.

U.S. Patent Nos. 7,943,582 B2 and 8,513,202 B2 discloses crystalline form of 1 -(P-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl] benzene hemihydrate and process for preparation thereof. The US ‘582 B2 and US ‘202 B2 further discloses that preparation of the crystalline form of hemi-hydrate canagliflozin typically involves dissolving in a good solvent (e.g. ketones or esters) crude or amorphous compound prepared in accordance with the procedures described in WO 2005/012326 pamphlet, and adding water and a poor solvent (e.g. alkanes or ethers) to the resulting solution, followed by filtration.

U.S. PG-Pub. No. 2013/0237487 Al (the US ‘487 Al) discloses amorphous dapagliflozin and amorphous canagliflozin. The US ‘487 Al also discloses 1:1 crystalline complex of canagliflozin with L-proline (Form CS1), ethanol solvate of a 1: 1 crystalline complex of canagliflozin with D-proline (Form CS2), 1 :1 crystalline complex of canagliflozin with L-phenylalanine (Form CS3), 1:1 crystalline complex of canagliflozin with D-proline (Form CS4).

The US ‘487 Al discloses preparation of amorphous canagliflozin by adding its heated toluene solution into n-heptane. After drying in vacuo the product was obtained as a white solid of with melting point of 54.7°C to 72.0°C. However, upon repetition of the said experiment, the obtained amorphous canagliflozin was having higher amount of residual solvents. Therefore, the amorphous canagliflozin obtained by process as disclosed in US ‘487 Al is not suitable for pharmaceutical preparations.

The US ‘487 Al further discloses that amorphous canagliflozin obtained by the above process is hygroscopic in nature which was confirmed by Dynamic vapor sorption (DVS) analysis. Further, it was observed that the amorphous form underwent a physical change between the sorption/desorption cycle, making the sorption/desorption behavior different between the two cycles. The physical change that occurred was determined to be a conversion or partial conversion from the amorphous state to a crystalline state. This change was supported by a change in the overall appearance of the sample as the humidity increased from 70% to 90% RH.

The canagliflozin assessment report EMA/718531/2013 published by EMEA discloses that Canagliflozin hemihydrate is a white to off-white powder^ practically insoluble in water and freely soluble in ethanol and non-hygroscopic. Polymorphism has been observed for canagliflozin and the manufactured Form I is a hemihydrate, and an unstable amorphous Form II. Form I is consistently produced by the proposed commercial synthesis process.

Therefore, it is evident from the prior art that the reported amorphous form of canagliflozin is unstable and hygroscopic as well as not suitable for pharmaceutical preparations due to higher amount of residual solvents above the ICH acceptable limits.

Hence, there is a need to provide a stable amorphous form of canagliflozin which is suitable for pharmaceutical preparations.

Crystalline solids normally require a significant amount of energy for dissolution due to their highly organized, lattice like structures. For example, the energy required for a drug molecule to escape from a crystal is more than from an amorphous or a non-crystalline form. It is known that the amorphous forms in a number of drugs exhibit different dissolution characteristics and in some cases different bioavailability patterns compared to the crystalline form (Econno T., Chem. Pharm. Bull., 1990; 38: 2003-2007). For some therapeutic indications, one bioavailability pattern may be favoured over another.

An amorphous form of some of the drugs exhibit much higher bioavailability than the crystalline forms, which leads to the selection of the amorphous form as the final drug substance for pharmaceutical dosage from development. Additionally, the aqueous solubility of crystalline form is lower than its amorphous form in some of the drugs, which may resulted in the difference in their in vivo bioavailability. Therefore, it is desirable to have amorphous forms of drugs with high purity to meet the needs of regulatory agencies and also highly reproducible processes for their preparation.

In view of the above, it is therefore, desirable to provide canagliflozin amorphous form as well as an efficient, economical and eco-friendly process for the preparation of highly pure canagliflozin amorphous form.

Example-l:

Preparation of amorphous form of Canagliflozin

In 100 ml three necked round bottomed flask equipped with mechanical stirrer, thermometer and addition funnel, 25.0 g of canagliflozin was dissolved in 250.0 mL of methanol mixture at 25°C to 30°C. The content was stirred for 30 minutes at 25°C to 30°C. To this, 1.0 g charcoal was added and stirred for 30 minutes at 25°C to 30°C. The content was filtered through Hyflo-supercel, and the Hyflo-supercel pad was washed with 50.0 mL methanol. The filtrate was concentrated under vacuum below 45°C followed by spray drying in JISL Mini spray drier LSD-48 under the below conditions. The product was collected from cyclone and is further dried at 55°C±5°C under vacuum for 16 hours to get 19.0 g of amorphous canagliflozin.

The spray-dried canagliflozin is amorphous in nature. The obtained product contains residual solvent well within ICH limit.

The obtained solid was amorphous canagliflozin as is shown by the X-ray diffraction pattern shown in FIG.1.

Example-2:

Preparation of amorphous form of Canagliflozin

In 100 ml three necked round bottomed flask equipped with mechanical stirrer, thermometer and addition funnel, 25.0 g of canagliflozin was dissolved in 250.0 mL of acetone mixture at 25°C to 3O°C. The content was stirred for 30 minutes at 25°C to 30°C. To this, 1.0 g charcoal was added and stirred for 30 minutes at 25°C to 30°C. The content was filtered through Hyflo-supercel, and the Hyflo-supercel pad was washed with 50.0 mL acetone. The filtrate was concentrated under vacuum below 45°C followed by spray drying in JISL Mini spray drier LSD-48 under the below conditions. The product was collected from cyclone and is further dried at 55°C±5°C under vacuum for 16 hours to get 20.0 g of amorphous canagliflozin.

The spray-dried canagliflozin is amorphous in nature. The compound is having residual acetone less than 0.5% by GC.

The obtained solid was amorphous canagliflozin as is shown by the X-ray diffraction pattern shown in FIG.2.

Example-3:

Preparation of amorphous form of canagliflozin

In 100 ml three necked round bottomed flask equipped with mechanical stirrer, thermometer and addition funnel, 10 g of canagliflozin was dissolved in 125 mL methanol and heated to obtain clear solution at 65°C. The solution was distilled to remove methanol completely. The compound thus obtained was amorphous canagliflozin.

Example-4:

Preparation of amorphous form of canagiiflozin

In 100 ml three necked round bottomed flask equipped with mechanical stirrer, thermometer and addition funnel, 10 g of canagiiflozin was dissolved in 125 mL acetone and heated to obtain clear solution at 65°C. The solution was distilled to remove acetone completely. The compound thus obtained was amorphous canagiiflozin. The compound is having residual acetone less than 0.5% by GC.

Example 5:

Preparation of amorphous form of canagiiflozin

In 100 ml three necked round bottom flask equipped with mechanical stirrer, thermometer and an addition funnel, canagiiflozin (0.5 gm, 1.02 mmol), PVP K-30 (4 gm, 8 times) and 88% methanol in water (12.5ml, 25V) were heated to 65-70°C to get clear solution. The reaction mixture was stirred for 1 hour, concentrated under vacuum (1.5 mbar) at 65-70°C and degassed under vacuum (1.5 mbar) for 1 hour at 70°C to obtain the title compound in amorphous form.

Example 6:

Preparation of amorphous form of canagiiflozin

In 100 ml three necked round bottom flask equipped with mechanical stirrer, thermometer and an addition funnel, canagiiflozin (0.5 gm, 1.02 mmol), HPMC-AS (1 gm, 2 times) in 88% methanol in water (12.5 ml, 25V) were heated at 65 to 70°C to get clear solution. The reaction mixture was stirred for 2 hours, concentrated under vacuum (1.5 mbar) at 70°C and degassed under vacuum (1.5 mbar) for lhr at 70°C to obtain the title compound in amorphous form.

Example-7:

Preparation of canagliflozin-L-Proline crystalline complex

In 100 ml three necked round bottomed flask equipped with mechanical stirrer, thermometer and addition funnel; 25.0 g of canagiiflozin, 6.06 g L-proline and 250 mL ethanol were heated to 75-80°C, stirred for 15 min and then cooled down to 25-30°C. The mass was filtered and washed with ethanol to obtain canagliflozin-L-proline crystalline complex.

Example-8:

Preparation of amorphous canagliflozin from canagliflozin-L-proline crystaUine complex

In 100 ml three necked round bottomed flask equipped with mechanical stirrer, thermometer and addition funnel 25.0 g of Canagliflozin-L-Proline Crystalline Complex and 250 mL of ethyl acetate were stirred to get a clear solution, washed with 2×150 mL of water and the organic layer was distilled. To the residue 100 mL of isopropyl acetate and 2.5 mL of water was added and heated to 75-80°C, stirred for 15 min and cooled down to 25-30°C. The mass filtered and washed with isopropyl acetate to obtain canagliflozin. The obtained canagliflozin was subjected to spray dyring under conditions of example-2 using acetone solvent to obtain amorphous canagliflozin. Purity > 99.5% by HPLC. The compound is having residual acetone less than 0.5% by GC.

The obtained solid was amorphous canagliflozin as shown by the X-ray diffraction pattern shown in FIG.2.

HPLC Purity of amorphous canagliflozin was measured by using following chromatographic conditions:

Equipment: Shimadzu LC2010C HPLC system equipped with a dual

wavelength UV-VIS detector or equivalent

Column: romasil C-8 (250mmx4.6 mm, 5 μπι) or equivalent

Flow rate: 1.5 mL/minute

Column oven temp.: 30°C

Wavelength: 210 nm

Injection Volume: 10 μΐ, .

Diluent: Mobile Phase A: Mobile Phase B (30:70)

Mobile Phase A: Buffer:Acetonitrile:Methanol (60:30: 10)

Mobile Phase B: Acetonitrile: Methanol (80:20)

Example-9:

Preparation of amorphous form of Canagliflozin as per Example-2 of US ‘487 Al In 100 ml three necked round bottomed flask equipped with mechanical stirrer, thermometer and addition funnel 25.0 g of canagliflozin and 150 mL of ethyl acetate were stirred to get clear solution. 100 mL of n-heptane was added to the solution and the reaction mixture was filtered and dried to obtain amorphous canagliflozin. The obtained amorphous canagliflozin were dried at 65°C under vacuum for 72 hours. The residual n-heptane was 44000 ppm by GC after 72 hours drying.

Example-10:

Replacing toluene with ethyl acetate in above example-9

In 100 ml three necked round bottomed flask equipped with mechanical stirrer, thermometer and addition funnel 25.0 g of canagliflozin and 150 mL of ethyl acetate were stirred to obtain clear solution. 100 mL of n-heptane was added to the solution and the reaction mixture was filtered and dried to obtain amorphous canagliflozin. The obtained amorphous canagliflozin were dried at 65°C under vacuum for 72 hours. The residual n-heptane was -44000 ppm by GC after 72 hours drying.

Example-11:

Replacing n-heptane with cyclohexane in above example-9

In 100 ml three necked round bottomed flask equipped with mechanical stirrer, thermometer and addition funnel 25.0 g of canagliflozin and 150 mL of ethyl acetate were stirred to obtain clear solution. 100 mL of cyclohexane was added to the solution and the reaction mixture was filtered and dried to obtain amorphous canagliflozin. The obtained amorphous canagliflozin were dried at 55°C under vacuum for 72 hours. The residual cyclohexane was >5000 ppm by GC after 72 hours drying.

Example-12:

Preparation of amorphous form of Canagliflozin

In 100 ml three necked round bottomed flask equipped with mechanical stirrer, thermometer and addition funnel; 25.0 g of canagliflozin and 250 mL of ethyl acetate were stirred to get clear solution and then ethyl acetate was removed under reduced pressure to obtain 20.0 g of amorphous canagliflozin. The obtained amorphous canagliflozin were dried at 55°C under vacuum for 72 hours. The residual ethyl acetate was -8450 ppm by GC after 72 hours drying.

///////////////New Patent, Zydus Cadila, Canagliflozin, US 20160002275

Shanghai Hengrui’s potent inhibitors of Human Uric Acid Transporter 1 (hURAT1)

January 10, 2016 5:22 am / Leave a comment

CID 86294127.png

MF	C ₁₄ H ₁₂ BrNO ₂ S
MW	338.21958 g / mol

1- (6-bromoquinolin-4-yl) sulfanylcyclobutane-1-carboxylic acid

CAS…….1638327-48-6

Cyclobutanecarboxylic acid, 1-[(6-bromo-4-quinolinyl)thio]-

COMING ………….

Image loading ...

MS m / z (ESI): 338.0 [M + l]

1H NMR (400 MHz, DMSO) δ 13.17 (s, 1H), 8.75-8.79 (m, 1H), 8.24 (s, 1H), 7.87-7.98 (m, 2H), 7.21-7.25 (m, 1H), 2.83-2.95 (m, 2H), 2.30-2.41 (m, 2H), 2.16-2.27 (m, 1H), 1.97-2.08 (m, 1H)

WO-2014183555-A1 / 2014-11-20

http://www.google.co.in/patents/WO2014183555A1?cl=en

PROCEDURE

6-bromo-quinoline-4-thiol

A mixture of 6-bromo-4-chloro-quinoline 3a (260 mg, 1.1 mmol, using known methods “Bioorganic &

Medicinal Chemistry Letters, 2012, 22 (4), 1569-1574 “prepared to give) and sodium sulfide (100 mg, 1.3 mmol) was added to 4 mL of N, N- dimethyl formamide, plus complete, heated 80 ° C, the reaction was stirred for 2 hours. To the reaction mixture was added 50 mL of water, 1 M hydrochloric acid was added dropwise to the reaction solution to pH 5-6, extracted with ethyl acetate (50 mL X 3), the combined organic phases, with no over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give the title product 6-bromo-quinolin-4-thiol 3b (257 mg, yellow oil), it was used directly in the next reaction.

The second step

L – ((6-bromo-quinolin-4-yl) thio) cyclobutyl carboxylate

Under an argon atmosphere, 6-bromo-quinolin-4-thiol 3b (257 mg, 1.1 mmol), 1- bromo-cyclobutyloxy embankment carboxylate (266 mg, 1.3 mmol) and cesium carbonate (371 mg, 1.1 mmol) were sequentially added to 5 mL of N, N- dimethylformamide and heated to 60 ° C, the reaction was stirred for 2 hours. The reaction solution was filtered, the filter cake washed with ethyl acetate (10 mL X 3) and the filtrate was concentrated under reduced pressure to give the title product l – ((6-bromo-quinolin-4-yl) thio) ethyl cyclobutyl 3c ( 300 mg, brown oil). Yield: 77%.

MS m / z (ESI): 368.2 [M + l]

1H MR (400 MHz, CDCl ₃ ) [delta] 8.67 (d, = 4.77 Hz, IH), 8.31 (d, = 2.13 Hz, IH), 7.94 (d, = 8.91Hz, IH), 7.78 (dd, = 9.03, 2.13Hz, IH), 7.15 (d, = 4.89Hz, IH), 4.16 (q, = 7.15Hz, 2H), 2.86-3.04 (m, 2H), 2.39-2.51 (m, 2H), 2.25-2.37 ( m, IH), 2.00-2.15 (m, IH), 1.16 (t, = 7.09Hz, 3H)

third step

L – ((6-bromo-quinolin-4-yl) thio) cyclobutyl acid

L – ((6-bromo-quinolin-4-yl) thio) ethyl cyclobutyl 3c (100 mg, 0.27 mmol) and lithium hydroxide monohydrate (23 mg, 0.55 mmol) was dissolved in 6 mL of tetrahydrofuran, ethanol and water (^ = 4: 1: 1) mixed solvent, the reaction was stirred for 3 hours. 1M hydrochloric acid was added dropwise to the reaction solution pH of 5 to 6, liquid separation, the aqueous phase was extracted (10 mL X 3) with dichloromethane, the combined organic phases, the organic phase was washed with a saturated sodium chloride solution (10 mL XI), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, the resulting A by thin layer chromatography in a developing solvent system, and the residue was purified to give the title product l – ((6-bromo-quinolin-4-yl) thio) cyclobutyl acid 3 (20 mg, white solid), yield: 22%.

MS m / z (ESI): 338.0 [M + l]

1H NMR (400 MHz, DMSO) δ 13.17 (s, 1H), 8.75-8.79 (m, 1H), 8.24 (s, 1H), 7.87-7.98 (m, 2H), 7.21-7.25 (m, 1H), 2.83-2.95 (m, 2H), 2.30-2.41 (m, 2H), 2.16-2.27 (m, 1H), 1.97-2.08 (m, 1H)

L – ((6-bromo-quinolin-4-yl) thio) cyclobutyl acid

First step

6-bromo-quinoline-4-thiol

A mixture of 6-bromo-4-chloro-quinoline 3a (260 mg, 1.1 mmol, a known method of “Bioorganic &

The second step

L – ((6-bromo-quinolin-4-yl) thio) ethyl cyclobutyl

Under an argon atmosphere, 6-bromo-quinolin-4-thiol 3b (257 mg, 1.1 mmol), 1- bromo-cyclobutyloxy embankment carboxylate (266 mg, 1.3 mmol) and cesium carbonate (371 mg, 1.1 mmol) were added to 5 mL of N, N- dimethylformamide and heated to 60 ° C, the reaction was stirred for 2 hours. The reaction mixture was filtered, the filter cake washed with ethyl acetate (10 mL X 3) and the filtrate was concentrated under reduced pressure to give the title product l – ((6-bromo-quinolin-4-yl) thio) ethyl cyclobutyl 3c ( 300 mg, brown oil). Yield: 77%.

MS m / z (ESI): 368.2 [M + l]

1H MR (400 MHz, CDC1 ₃₎ δ 8.67 (d, = 4.77Hz, IH), 8.31 (d, = 2.13Hz, IH), 7.94 (d, = 8.91Hz, IH), 7.78 (dd, = 9.03, 2.13Hz, IH), 7.15 (d, = 4.89Hz, IH), 4.16 (q, = 7.15Hz, 2H), 2.86-3.04 (m, 2H), 2.39-2.51 (m, 2H), 2.25-2.37 ( m, IH), 2.00-2.15 (m, IH), 1.16 (t, = 7.09Hz, 3H) Step

L – ((6-bromo-quinolin-4-yl) thio) cyclobutyl acid

L – ((6-bromo-quinolin-4-yl) thio) ethyl cyclobutyl 3c (100 mg, 0.27 mmol) and lithium hydroxide monohydrate (23 mg, 0.55 mmol) was dissolved in 6 mL of tetrahydrofuran, ethanol and water (^ = 4: 1: 1) mixed solvent, the reaction was stirred for 3 hours. 1M hydrochloric acid was added dropwise to the reaction solution pH of 5 to 6, liquid separation, the aqueous phase was extracted (10 mL X 3) with dichloromethane, the combined organic phases, the organic phase was washed with a saturated sodium chloride solution (10 mL XI), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, to the resulting thin layer chromatography using a developing solvent system A and the residue was purified to give the title product l – ((6-bromo-quinolin-4-yl) thio) cyclobutyl acid 3 (20 mg, white solid), yield: 22%. MS m / z (ESI): 338.0 [M + l]

1H NMR (400 MHz, DMSO) δ 13.17 (s, 1H), 8.75-8.79 (m, 1H), 8.24 (s, 1H), 7.87-7.98 (m, 2H), 7.21-7.25 (m, 1H), 2.83-2.95 (m, 2H), 2.30-2.41 (m, 2H), 2.16-2.27 (m, 1H), 1.97-2.08 (m, 1H)

SHANGHAI HENGRUI PHARM CO LTD

CYCLOALKYL ACID DERIVATIVE, PREPARATION METHOD THEREOF, AND PHARMACEUTICAL APPLICATION THEREOF

Discovery of potent and orally bioavailable inhibitors of Human Uric Acid Transporter 1 (hURAT1) and binding mode prediction using homology model

Jianbiao Peng ^, ,

Shanghai Hengrui Pharmaceutical Co. Ltd, 279 Wenjing Rd., Shanghai 200245, China

This Letter describes the Discovery of a series of potent inhibitors of Human Uric Acid Transporter 1 (hURATl). Lead generation via 3D pharmacophore Analysis and Optimization resulted in compound 41 . With an IC ₅₀ of 33.7 nM, 41 Also Demonstrated good Oral Bioavailability in RAT (74.8%) and displayed a consistent PK profile across all species tested (rat, dog and monkey).

http://www.sciencedirect.com/science/article/pii/S0960894X1530353X

doi: 10.1016 / j.bmcl.2015.12.040

Bioorganic & Medicinal Chemistry Letters

Volume 26, Issue 2 , 15 January 2016, Pages 277-282

Map of Shanghai Hengrui Pharmaceutical Co. Ltd

//////// Shanghai Hengrui, inhibitors of Human Uric Acid Transporter 1 (hURAT1), 1- (6-bromoquinolin-4-yl) sulfanylcyclobutane-1-carboxylic acid

c13cc (ccc3nccc1SC2 (C (= O) O) CCC2) Br

BMS 955829

January 9, 2016 1:39 pm / Leave a comment

(4R,5R)-5-(2,5-difluorophenyl)-4-(5-(phenylethynyl)pyridin-3-yl)oxazolidin-2-one

(4R,5R)-5(2,5-Difluorophenyl)-4-(5-(phenylethynyl)-3-pyridinyl)-1,3-oxazolidin-2-one

(4R,5R)-5-(2,5-difluorophenyl)- 4-(5-(phenylethynyl)pyridin-3-yl)oxazolidin-2-one.

cas 1375751-08-8
Chemical Formula: C22H14F2N2O2
Exact Mass: 376.1023

Bristol-Myers Squibb Company INNOVATOR

BMS-955829 is a Positive allosteric modulators (PAMs). BMS-955829 shows high functional PAM potency, excellent mGluR5 binding affinity, low glutamate fold shift, and high selectivity for the mGluR5 subtype. BMS-955829 is a potent mGluR5 PAM (EC50 = 2.6 ± 1.0 nM; n = 6), devoid of inherent mGluR5 agonist activity (EC50 > 30μM). The measured binding Ki of BMS-955829 was found to be 1.6 nM, which was in good agreement with its functional potency.

SYNTHESIS AND INTERMEDIATES…….https://www.google.co.in/patents/WO2012064603A1?cl=en

Intermediate 73

Diethyl 2,5-difluorobenzylphosphonate. A mixture of 2-(bromomethyl)-l,4- difluorobenzene (3 g, 14.49 mmol) and triethyl phosphite (7.72 ml, 43.5 mmol) was heated to 160 °C with stirring for 4 hours, cooled to ambient temperature and concentrated under high vacuum to remove most triethyl phosphite. The resulting residue was purified by column chromatography (20% to 30 % EtO Ac/Toluene) providing diethyl 2,5-difluorobenzylphosphonate (3.76 g, 13.52 mmol, 93 % yield) as colorless oil. ¾ NMR (500MHz, DMSO-d₆) δ 7.30 – 7.10 (m, 3H), 4.05 – 3.91 (m, 4H), 3.31 – 3.20 (m, 2H), 1.18 (t, J=7.0 Hz, 6H). MS Anal. Calcd. for [M+H]⁺ CiiHieFzOsP: 265.2; found 265.3.

Intermediate 74

(E)-3-Bromo-5-(2,5-difluorostyryl)pyridine. To a stirred solution of diethyl 2,5-difluorobenzylphosphonate (63.5 g, 240 mmol) and 5-bromonicotinaldehyde (50.7 g, 264 mmol) in tetrahydrofuran (1923 ml) was added potassium tert-butoxide in tetrahydrofuran (312 ml, 312 mmol) at -10 °C. After three hours, the reaction mixture was allowed to warm to ambient temperature and stirring was continued for another 16 hours at which time the reaction mixture was diluted with ether (800 mL) and washed with H₂O. The organic layer was dried over anhydrous magnesium sulfate, filered and concentrated to provide a yellow wax to which was added 300 mL of hexane and after sonication filtered to provide (is)-3-bromo-5-(2,5- difluorostyryl)pyridine (54 g, 173 mmol, 72.1%) as a white solid. ^XH NMR

(500MHz, DMSO-d₆) δ 8.78 (d, J=1.8 Hz, IH), 8.63 (d, J=2.1 Hz, IH), 8.44 (t, J=2.0 Hz, IH), 7.67 (ddd, J=9.4, 6.0, 3.2 Hz, IH), 7.56 – 7.48 (m, IH), 7.46 – 7.40 (m, IH), 7.34 (td, J=9.6, 4.6 Hz, IH), 7.24 (tt, J=8.3, 3.6 Hz, IH). MS Anal. Calcd. for [M+H]⁺ Ci₃H₉BrF₂N: 296.0; found 298.1

Intermediate 75

Tert-butyl (lR,2R)-l-(5-bromopyridin-3-yl)-2-(2,5-difluorophenyl)-2- hydroxyethylcarbamate. A solution of tert-butyl carbamate (4.18 g, 35.0 mmol) in propanol (39 ml) was sequentially treated with sodium hydroxide (1.376 g, 34.4 mmol) in water (72 ml) and tert-butyl hypochlorite (3.88 ml, 34.4 mmol). After 5 min of stirring, the reaction mixture was cooled to 0 °C. A solution of

(DHQD)₂PHAL (0.555 g, 0.677 mmol) in propanol (39 ml), a solution of (E)-3- bromo-5-(2,5-difluorostyryl)pyridine (3.34 g, 11.28 mmol) in propanol (68 ml) , and potassium osmate dihydrate (0.166 g, 0.451 mmol) were sequentially added. The reaction mixture was stirred for three additional hours at 0 °C, warmed to ambient temperature and after an additional 16 hours the light yellow homogenous solution was quenched with saturated aqueous sodium sulfite (100 mL). The aqueous phase was extracted with ethyl acetate( 2 X 50 mL), the combined organic phases were washed with brine (100 mL), dried over anhydrous magnesium sulfate and concentrated to afford a residue which was purified via column chromatography (25% to 40 % EtO Ac/Hex) to provide tert-butyl (7R,2R)-l-(5-bromopyridin-3-yl)-2- (2,5-difluorophenyl)-2-hydroxyethylcarbamate (2.2991 g, 5.09 mmol, 45.1 % yield) as an optically enriched mixture of enantiomers. ^XH NMR (500MHz, DIVISOR) δ 8.56 (d, J=1.8 Hz, IH), 8.40 (s, IH), 8.03 (s, IH), 7.52 (d, J=9.5 Hz, IH), 7.25 (br. s., IH), 7.10 (t, J=5.6 Hz, 2H), 5.89 (d, J=4.9 Hz, IH), 5.03 (t, J=5.0 Hz, IH), 4.83 (dd, J=8.9, 5.2 Hz, IH), 1.40 – 1.34 (m, 9H), MS Anal. Calcd. for [M+H]⁺

Ci₈H₂oBrF₂ 20₃: 429.1; found 431.3.

Intermediate 77

(lR,2R)-2-Amino-2-(5-bromopyridin-3-yl)-l-(2,5-difluorophenyl)ethanol To a stirred solution of tert-butyl tert-butyl (7R,2R,)-l-(5-bromopyridin-3-yl)-2-(2,5- difluorophenyl)-2-hydroxyethylcarbamate (2.30 g, 5.09 mmol) in methylene chloride (30 mL) was added HC1 in dioxane (30 ml, 120 mmol). The reaction mixture was placed in an oil bath set to 50 °C. After three hours, the reaction mixture was concentrated providing (7R,2R^-2-amino-2-(5-bromopyridin-3-yl)-l-(2,5- difluorophenyl)ethanol 2HC1 salt (2.10 g, 4.97 mmol, 98 % yield) as an optically enriched yellow wax. ^XH NMR (500MHz, DMSO-d₆) δ 8.95 (d, J=3.7 Hz, 2H), 8.64 (d, J=2.4 Hz, 1H), 8.45 (d, J=1.5 Hz, 1H), 8.31 (t, J=2.0 Hz, 1H), 7.47 – 7.09 (m, 3H), 7.04 (td, J=9.2, 4.4 Hz, 1H), 5.29 (d, J=9.2 Hz, 1H), 4.57 (dd, J=9.0, 5.3 Hz, 1H). Anal. Calcd. for [M+H]⁺ Ci₃H₁₂BrF₂N₂0: 329.0; found 331.2.

Intermediate 78

(4R,5R)-4-(5-Bromopyridin-3-yl)-5-(2,5-difluorophenyl)oxazotidin-2-one. To optically enriched (7R,2R)-2-amino-2-(5-bromopyridin-3-yl)-l-(2,5- difluorophenyl)ethanol, 2 HC1 (2.019 g, 4.82 mmol) in tetrahydrofuran (98 ml) was added diisopropylethylamine (2.95 ml, 16.87 mmol) and the resultant solution was stirred for ten mintues at ambient temperature, cooled to 0 °C and

carbonyldiimidazole (1.094 g, 6.75 mmol) was added. After an additional three hours at 0 °C the reaction mixture was warmed to ambient temperature and allowed to stir for another 16 hours. 2M ¾ in methanol (5ml) was added and after ten mintues the suspension was filtered and concentrated to a pink oil which was purified by column chromatography (25% to 40 % EtO Ac/Hex) providing (4R,5R)-4-(5- bromopyridin-3-yl)-5-(2,5-difluorophenyl)oxazolidin-2-one (1.353 g, 3.62 mmol, 75 % yield) as an optically enriched white solid. ¾ NMR (500MHz, DMSO-d₆) δ 8.80 – 8.68 (m, 1H), 8.55 (d, J=2.1 Hz, 2H), 8.16 (t, J=2.1 Hz, 1H), 7.46 – 7.28 (m, 3H), 5.71 – 5.58 (m, 1H), 5.02 (d, J=6.7 Hz, 1H). MS Anal. Calcd. for [M+H]⁺ Ci₄H₁₀BrF₂ 2O2: 355.0; found 357.2.

Intermediate 79

(4R,5R)-4-(5-Bromopyridin-3-yl)-5-(2,5-difluorophenyl)oxazotidin-2-one. Method – 2 A mixture of tert-butyl ((lR,2R)-l-(54oromopyridin-3-yl)-2-(2,5- difluorophenyl)-2-hydroxyethyl)carbamate and tert-butyl ((lR,2R)-2-(5- bromopyridin-3-yl)-l-(2,5-difluorophenyl)-2-hydroxyethyl)carbamate (about 6: 1 ratio) (101 g, 236 mmol) in tetrahydrofuran (590 mL) was cooled to -7 °C with a methanol/ice bath. To this mixture was added a solution of 1 M potassium tert- butoxide in tetrahydrofuran (590 mL, 590 mmol) via an addition funnel while maintaining the internal temperature < 3 °C. The reaction mixture was stirred with a cooling bath for 30 min and then allowed to warm up to room temperature. After 20 h, the reaction was deemed complete by LC/MS. The reaction mixture was concentrated to dryness to give crude product. Another identical scale reaction was performed. The crude products of the two batches were combined to work up together. They were treated with ethyl acetate (1.75 L) and water (1.75 L). The layers were separated. The organic layer was washed with brine (1.75 L), dried (sodium sulfate), and evaporated to give 161.5 g of crude product as a brown solid. This was purified by ISCO to give 67.1 g (42% yield). LC/MS (ES+) 355/357 (M+H, 100; Br isotope pattern); ^XH NMR (400MHz, CDCl₃) δ 8.75 (d, J=2.2 Hz, 1H), 8.53 (d, J=1.8 Hz, 1H), 7.97 (t, J=2.0 Hz, 1H), 7.29 – 7.23 (m, 1H), 7.18 – 7.09 (m, 2H), 6.40 (s, 1H), 5.56 (d, J=5.7 Hz, 1H), 4.84 (d, J=5.5 Hz, 1H); Calcd for

Ci₄H₉N₂BrF₂0₂: C, 47.34; H, 2.55; N, 7.86; Br, 22.50; F, 10.69. Found: C, 47.29; H, 2.61; N, 7.87; Br, 22.40; F, 10.37. Note: Chiral HPLC of the above sample showed 4.7% of the enantiomer. The (4S, 55) enantiomer can be purged by recrystallization from methanol to give > 99.9 ee with 67% recovery.

WO2012064603

https://www.google.co.in/patents/WO2012064603A1?cl=en

Scheme 1.

Pd(0)/Cu(l)/ TBAF Scheme 2.

cheme 4.

R’ = H, alkyl

Scheme 8.

cheme 11.

Scheme 12.

Scheme 14.

Scheme 15.

R” = H, alkyl R” = alkyl

cheme 16.

R’ = alky I

R” = alkyl

Scheme 17.

R’ = H, alkyl

R” = H, alkyl

Scheme 18.

R’ = H, alkyl R’ = H, alkyl

P T/US2011/059339

COMPD IS 185

Figure imgf000226_0001

Example 185

(4R, 5R)-5-(2, 5-difluorophenyl)-4-(5-(phenylethynyl)-3-pyridinyl)-l, 3-oxazolidin-2- one.

To a stirred solution of optically enriched (4R,5R)-4-(5-bromopyridin-3-yl)-5- (2,5-difluorophenyl)oxazolidin-2-one (1.25 g, 3.25 mmol) in triethylamine (70 mL) was added ethynylbenzene (0.592 mL, 5.28 mmol), copper(I) iodide (67 mg, 0.352 mmol), and triphenylphosphine (653 mg, 2.464 mmol). Nitrogen was bubbled through the mixture for 10 mintues before adding dichlorobis(triphenylphosphine)- palladium(II) (202 mg, 0.282 mmol) with continued nitrogen gas bubbling. After an additional 10 mintues the reaction mixtrue was heated to reflux for 16 hours, cooled to ambient temperature, diluted with EtOAc, washed with water (3X), brine, dried over magnesium sulfate, and concentrated in vacuo. Column chromatography (25% – -> 40% EtO Ac/Hex) provided optically enriched (4R,5R)-5-(2,5-difluorophenyl)-4- (5-(phenylethynyl)pyridin-3-yl)oxazolidin-2-one which was separated by chiral SFC chromatography (Chiralcel OJ-H preparative column, 30 x 250mm, 5μιη, Mobile Phase: 40% MeOH (0.1%DEA) in C0₂ @ 150Bar, Temp: 35°C, Flow rate: 70.0 mL/min. for 16 min, UV monitored @ 280 nM . tR = 9.23 min) to provide (1.38 g, 2.99 mmol, 85 % yield) of pure single enantiomer (4R,5R)-5-(2,5-difluorophenyl)- 4-(5-(phenylethynyl)pyridin-3-yl)oxazolidin-2-one.

‘H NMR (500 MHz, DMSO-i¾) δ ppm 8.77 (d, J=2.21 Hz, 1 H) 8.57 (s, 1 H) 8.56 (d, J=2.20 Hz, 1 H) 8.07 (t, J=2.05 Hz, 1 H) 7.58 – 7.66 (m, 2 H) 7.44 – 7.52 (m, 3 H) 7.39 – 7.45 (m, 1 H) 7.28 – 7.39 (m, 2 H) 5.67 (d, J=6.62 Hz, 1 H) 5.04 (d, J=6.62 Hz, 1 H). ¹³C NMR (126 MHz,

DMSO-i¾) δ ppm 157.28; 157.24 (d, J=240.70 Hz) 155.92 (d, J=245.20 Hz) 151.63; 147.70; 136.78; 135.02; 131.57; 129.43; 128.89; 126.63 (dd, J=14.99, 7.72 Hz) 121.51; 119.47; 117.83 (dd, J=23.60, 9.10 Hz) 117.50 (dd, J=24.50, 8.20 Hz); 114.60 (dd, J=26.34, 4.54 Hz); 92.86; 85.76; 78.12; 59.43;

LCMS (ESI) m/z calcd for C₂₂H₁₅F₂N₂0₂: 377.11, found 377.20[M+H]⁺;

HRMS (ESI) m/z calcd for

C₂₂H₁₅F₂N₂0₂: 377.1096, found 377.1096 [M+H]+.

SEE

WO2015054103, OXAZOLIDINONES AS MODULATORS OF MGLUR5

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=15257519640294865E18C0BA057EADF3.wapp1nA?docId=WO2015054103&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

PAPER

Positive allosteric modulators (PAMs) of the metabotropic glutamate receptor subtype 5 (mGluR5) are of interest due to their potential therapeutic utility in schizophrenia and other cognitive disorders. Herein we describe the discovery and optimization of a novel oxazolidinone-based chemotype to identify BMS-955829 (4), a compound with high functional PAM potency, excellent mGluR5 binding affinity, low glutamate fold shift, and high selectivity for the mGluR5 subtype. The low fold shift and absence of agonist activity proved critical in the identification of a molecule with an acceptable preclinical safety profile. Despite its low fold shift, 4 retained efficacy in set shifting and novel object recognition models in rodents.

Discovery and Preclinical Evaluation of BMS-955829, a Potent Positive Allosteric Modulator of mGluR5

Bristol-Myers Squibb Research & Development, 5 Research Parkway, Wallingford, Connecticut 06492, United States

ACS Med. Chem. Lett., Article ASAP

DOI: 10.1021/acsmedchemlett.5b00450

Publication Date (Web): January 4, 2016

*Tel: 1-203-677-7675. Fax: 1-203-677-7702. E-mail: fukang.yang@bms.com.

http://pubs.acs.org/doi/abs/10.1021/acsmedchemlett.5b00450

http://pubs.acs.org/doi/suppl/10.1021/acsmedchemlett.5b00450/suppl_file/ml5b00450_si_001.pdf

SEE…………http://orgspectroscopyint.blogspot.in/2016/01/bms-955829.html

///////BMS 955829, mGluR5, positive allosteric modulator, schizophrenia, cognition, neurotoxicity, Bristol-Myers Squibb

FC1=CC=C(C=C1[C@H]([C@@H](C2=CC(C#CC3=CC=CC=C3)=CN=C2)N4)OC4=O)F

AZD 2716

January 9, 2016 8:50 am / Leave a comment

AZD2716

CAS 1845753-81-2

MF C₂₄ H₂₃ N O_{3, MW 373.44}

[1,1′-Biphenyl]-3-propanoic acid, 2′-(aminocarbonyl)-α-methyl-5′-(phenylmethyl)-, (αR)-

Antiplaque candidate drug

AstraZeneca INNOVATOR

(R)-7(AZD2716) a novel, potent secreted phospholipase A₂ (sPLA₂) inhibitor with excellent preclinical pharmacokinetic properties across species, clear in vivo efficacy, and minimized safety risk. Based on accumulated profiling data, (R)-7 was selected as a clinical candidate for the treatment of coronary artery disease.

Chiral HPLC using a Chiralcel OJ 5 μm 20×250 mm
column with heptane/EtOH/formic acid ((10:90:0.1; 15 ml/min, 40 °C, 260 nm) as mobile
phase to yield (S)-7 and (R)-7

(R)-7:tR=5.8 min [α]D20 15.4 (c 0.5, ACN), 99.7 %ee. desired

(S)-7: tR=9.2 min. 99.0 % ee. undesired

LINK

http://pubs.acs.org/doi/suppl/10.1021/acsmedchemlett.6b00188

SYNTHESIS

¹H NMR (400 MHz, DMSO-d₆): δ 1.04 (d, J = 6.6 Hz, 3H), 2.55–2.68 (m, 2H), 2.95 (dd, J = 6.1, 12.8 Hz, 1H), 4.00 (s, 2H), 7.13–7.37 (m, 13H), 7.49–7.54 (m, 1H), 12.2 (s, br, 1H).

¹³C NMR (151 MHz, DMSO): δ 16.7, 39.1, 40.7, 41.0, 126.3, 126.4, 127.3, 127.8, 128.0, 128.2, 128.7, 128.9, 129.2, 130.3, 135.3, 139.2, 139.5, 140.5, 141.2, 142.7, 171.3, 177.1.

HRMS (ESI): [M + H]⁺ m/z calcd for C₂₄H₂₄NO₃ 374.1751, found 374.1748.

1H NMR

13C NMR

An Enantioselective Hydrogenation of an Alkenoic Acid as a Key Step in the Synthesis of AZD2716

Staffan Karlsson^*^†, Henrik Sörensen^†, Sören M. Andersen^†, Angele Cruz^†, and Per Ryberg^‡

^† CVMD iMed, Medicinal Chemistry, AstraZeneca R&D Mölndal, SE-431 83 Mölndal, Sweden

^‡SP Process Development, Box 36, SE-151 21 Södertälje, Sweden

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.5b00382………..http://pubs.acs.org/doi/abs/10.1021/acs.oprd.5b00382

http://pubs.acs.org/doi/suppl/10.1021/acs.oprd.5b00382/suppl_file/op5b00382_si_001.pdf

A classical resolution of a racemic carboxylic acid through salt formation and an asymmetric hydrogenation of an α,β-unsaturated carboxylic acid were investigated in parallel to prepare an enantiomerically pure alkanoic acid used as a key intermediate in the synthesis of an antiplaque candidate drug. After an extensive screening of rhodium- and ruthenium-based catalysts, we developed a rhodium-catalyzed hydrogenation that gave the alkanoic acid with 90% ee, and after a subsequent crystallization with (R)-1-phenylethanamine, the ee was enriched to 97%. The chiral acid was then used in sequential Negishi and Suzuki couplings followed by basic hydrolysis of a nitrile to an amide to give the active pharmaceutical ingredient in 22% overall yield.

Paper

Expedited structure-based optimization of the initial fragment hit 1 led to the design of (R)-7(AZD2716) a novel, potent secreted phospholipase A₂ (sPLA₂) inhibitor with excellent preclinical pharmacokinetic properties across species, clear in vivo efficacy, and minimized safety risk. Based on accumulated profiling data, (R)-7 was selected as a clinical candidate for the treatment of coronary artery disease.

Discovery of AZD2716: A Novel Secreted Phospholipase A₂ (sPLA₂) Inhibitor for the Treatment of Coronary Artery Disease

^†Cardiovascular and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit Departments of Medicinal Chemistry, ^‡Bioscience, ^§DMPK, ^∥Discovery Sciences Departments of Structure & Biophysics, ^⊥Reagents and Assay Development, and ^#Screening Sciences and Sample Management, Astrazeneca, Mölndal, Pepparedsleden 1, SE-431 83 Mölndal, Sweden

ACS Med. Chem. Lett., Article ASAP

DOI: 10.1021/acsmedchemlett.6b00188

*(F.G.) Phone: +1-212-4780-822. E-mail: fabrizio.giordanetto@deshawresearch.com., *(D.P.) Phone: +46 31 7065 663. E-mail:daniel.pettersen@astrazeneca.com.

http://pubs.acs.org/doi/full/10.1021/acsmedchemlett.6b00188

STR1

str2

akenoic acid as a key step in the sysnthesis of AZD2716. Org. Proc. Res. Dev. 2016, 20(2),
262-269).

/////////atherosclerosis, coronary artery disease, fragment screening, fragment-based drug discovery, Secreted phospholipase A₂, sPLA₂, AZD2716, AZD-2716, AZD 2716, PRECLINICAL

c1c(cc(c(c1)C(=O)N)c2cccc(c2)CC(C(=O)O)C)Cc3ccccc3

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A Three-Step Synthesis of Acotiamide for the Treatment of Patients with Functional Dyspepsia

Abstract

References

Approval in Japan for Treating Functional Dyspepsia with Acofide®

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PATENT

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Department of Chemical Engineering and Chemistry

ir. S.C. (Stefan) Stouten –

prof.dr. V. (Volker) Hessel

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Anji Reddy

G V Prasad and Mr K. Satish Reddy

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Discovery of potent and orally bioavailable inhibitors of Human Uric Acid Transporter 1 (hURAT1) and binding mode prediction using homology model

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COMPD IS 185

Discovery and Preclinical Evaluation of BMS-955829, a Potent Positive Allosteric Modulator of mGluR5

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AZD2716

SYNTHESIS

1H NMR

13C NMR

An Enantioselective Hydrogenation of an Alkenoic Acid as a Key Step in the Synthesis of AZD2716

Paper

Discovery of AZD2716: A Novel Secreted Phospholipase A2 (sPLA2) Inhibitor for the Treatment of Coronary Artery Disease

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Discovery of AZD2716: A Novel Secreted Phospholipase A₂ (sPLA₂) Inhibitor for the Treatment of Coronary Artery Disease