Preparing edoxaban tosylate monohydrate for reducing risk of stroke, comprises condensing 2-amino-5-chloropyridine with ethyl oxalyl chloride, condensing obtained compound with tert-butyl (2-amino-5-(dimethyl carbamoyl)cyclohexyl)carbamate oxalate followed by performing salt formation of free base
	DHARMENDHAR R N; CHILUKURI V R; ETTABOINA V; NADAKUDITY S K; AMBABHAI V N; RAO S M
	2023-09-14
专利权人	NEULAND LAB LTD (NEUL-Non-standard)
申请日期	2023-09-14
专利号	IN202341061785-A
成果简介	NOVELTY - Preparing edoxaban tosylate monohydrate (I) comprises: (i) condensing 2-amino-5-chloropyridine (2) with ethyl oxalyl chloride (3) to obtain ethyl 2-((5-chloropyridin-2-yl)amino)-2-oxoacetate (4); (ii) condensing compound (4) with tert-butyl ((1R,2S,5S)-2-amino-5-(dimethyl carbamoyl) cyclohexyl) carbamate oxalate (5) to obtain tert-butyl ((1R,2S,5S)-2-(2-((5-chloropyridin-2-yl)amino)-2-oxoacetamido)-5 (dimethyl carbamoyl)-cyclohexyl) carbamate (6); (iii) deprotecting compound (6) to obtain N1-((1S,2R,4S)-2-amino-4-(dimethyl carbamoyl) cyclohexyl)-N2-(5-chloropyridin-2-yl)oxalamide (7); (iv) condensing compound (7) with 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride (8) to obtain edoxaban free base (9); and (v) performing salt formation of compound (9) in presence of p-toluenesulfonic acid hydrate to obtain edoxaban tosylate monohydrate (I). USE - Method for preparing edoxaban tosylate monohydrate for reducing risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. No biological data given. ADVANTAGE - The method provides edoxaban tosylate with high yield and high purity, without the requirement of special purification step, recrystallization, and workup procedures, in simple and cost-effective manner. DETAILED DESCRIPTION - Preparing edoxaban tosylate monohydrate of formula (I) comprises: (i) condensing 2-amino-5-chloropyridine of formula (2) with ethyl oxalyl chloride of formula (3) in presence of dimethylformamide and water to obtain ethyl 2-((5-chloropyridin-2-yl)amino)-2-oxoacetate of formula (4); (ii) condensing compound (4) with tert-butyl ((1R,2S,5S)-2-amino-5-(dimethyl carbamoyl) cyclohexyl) carbamate oxalate of formula (5) in presence of dimethyl sulfoxide, diisopropylamine, and water to obtain tert-butyl ((1R,2S,5S)-2-(2-((5-chloropyridin-2-yl)amino)-2-oxoacetamido)-5 (dimethyl carbamoyl)-cyclohexyl) carbamate of formula (6); (iii) deprotecting compound (6) in presence of acid, base and solvent to obtain N1-((1S,2R,4S)-2-amino-4-(dimethyl carbamoyl) cyclohexyl)-N2-(5-chloropyridin-2-yl)oxalamide of formula (7) (in-situ); (iv) condensing compound (7) with 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride of formula (8) in presence of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, hydroxybenzotriazole and water, base and solvent to obtain N1-(5-chloropyridin-2-yl)-N2-((1S,2R,4S)-4-(dimethylcarbamoyl)-2-(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamido) cyclohexyl) oxalamide (edoxaban free base) of formula (9); and (v) performing salt formation of compound (9) in presence of p-toluenesulfonic acid hydrate, methylene chloride, ethanol and water to obtain N1-(5-chloropyridin-2-yl)-N2-((1S,2R,4S)-4-(dimethylcarbamoyl)-2-(5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]-pyridine-2-carboxamido) cyclohexyl) oxalamide 4-methyl benzenesulfonate hydrate (edoxaban tosylate monohydrate) (I). INDEPENDENT CLAIMS are included for: a method for preparing ethyl 2-((5-chloropyridin-2-yl)amino)-2-oxoacetate (4), which comprises condensing compound (2) with compound (3) in presence of dimethylformamide and water; and a method for preparing tert-butyl ((1R,2S,5S)-2-(2-((5-chloropyridin-2-yl)amino)-2-oxoacetamido)-5 (dimethyl carbamoyl)-cyclohexyl) carbamate (6).
IPC 分类号	A61K-031/444 ; A61P-007/02 ; C07D-211/74 ; C07D-213/81 ; C07D-495/04 ; C07D-513/04
国家	印度
专业领域	医药卫生
语种	英语
成果类型	专利
文献类型	科技成果
条目标识符	http://119.78.100.226:8889/handle/3KE4DYBR/20405
专题	中国科学院新疆生态与地理研究所
作者单位	NEULAND LAB LTD (NEUL-Non-standard)
推荐引用方式 GB/T 7714	DHARMENDHAR R N,CHILUKURI V R,ETTABOINA V,et al. Preparing edoxaban tosylate monohydrate for reducing risk of stroke, comprises condensing 2-amino-5-chloropyridine with ethyl oxalyl chloride, condensing obtained compound with tert-butyl (2-amino-5-(dimethyl carbamoyl)cyclohexyl)carbamate oxalate followed by performing salt formation of free base. IN202341061785-A[P]. 2023.

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