Preparing 5-bromo-4-(4-chlorothiophen-2-yl)thiazol-2-amine used for thrombocytopenia in adult patients with chronic liver disease, involves dissolving 2-amino-4-(4-chlorothiophen-2-yl)thiazole in solvent followed by adding brominating agent, isolating 5-bromo-4-(4-chlorothiophen-2-yl)thiazol-2-amine
	GADDE C; BONTU N R; BANDI C R; KALAPALA V R; UPPARAPALLI S K; PULLELA V S
	2023-09-19
专利权人	GRANULES INDIA LTD (GRAN-Non-standard)
申请日期	2023-09-19
专利号	IN202341062891-A
成果简介	NOVELTY - Preparing 5-bromo-4-(4-chlorothiophen-2-yl)thiazol-2-amine of (II), involves: (a) dissolving 2-amino-4-(4-chlorothiophen-2-yl)thiazole of (III) in a suitable solvent at a suitable temperature; (b) adding brominating agent to the solution at a suitable temperature; and (c) isolating 5-bromo-4-(4-chlorothiophen-2-yl)thiazol-2-amine of (II), which is a substantially free of dibromo impurity of (i), where molar ratio of brominating agent to 2-amino-4-(4-chlorothiophen-2-yl)thiazole (III) is 1: ≤ 1. USE - Improved process for preparing 5-bromo-4-(4-chlorothiophen-2-yl)thiazol-2-amine for used in avatrombopag maleate preparation for treating thrombocytopenia in adult patients with chronic liver disease. Test details are described but no results given. ADVANTAGE - The process is economical, easy to scale up, and commercially viable. DETAILED DESCRIPTION - Preparing 5-bromo-4-(4-chlorothiophen-2-yl)thiazol-2-amine of formula (II), involves: (a) dissolving 2-amino-4-(4-chlorothiophen-2-yl)thiazole of formula (III) in a suitable solvent at a suitable temperature; (b) adding brominating agent to the solution at a suitable temperature; and (c) isolating 5-bromo-4-(4-chlorothiophen-2-yl)thiazol-2-amine of formula (II), which is a substantially free of dibromo impurity of formula (i), where molar ratio of brominating agent to 2-amino-4-(4-chlorothiophen-2-yl)thiazole (III) is 1: ≤ 1. INDEPENDENT CLAIMS are included for: 1. an improved process for the preparation of avatrombopag free base of formula (Ia) or salts, which involves: (a) dissolving 2-amino-4-(4-chlorothiophen-2-yl)thiazole (III) in a suitable solvent at a suitable temperature; (b) adding brominating agent to the solution at a suitable temperature to provide 5-bromo-4-(4-chlorothiophen-2-yl)thiazol-2-amine (II); (c) reacting 5-bromo-4-(4-chlorothiophen-2-yl)thiazol-2-amine (II) with 1-cyclohexylpiperazine with a base in presence of a suitable solvent at a suitable temperature to provide 4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl)thiazol-2-amine of formula (IV); (d) condensing 4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl)thiazol-2-amine (IV) with chloro-6-(4-(ethoxycarbonyl) piperidin-1-yl)nicotinic acid of formula (V) and a suitable halogenating agent in presence of a suitable solvent, and followed by treating with a base at a suitable temperature to provide ethyl 1-(3-chloro-5-((4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl) thiazol-2-yl) carbamoyl) pyridin-2-yl)piperidine-4-carboxylate of formula (VI); and (e) hydrolyzing ethyl 1-(3-chloro-5-((4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl) thiazol-2-yl) carbamoyl) pyridin-2-yl)piperidine-4-carboxylate (VI) with a base in the presence of a suitable solvent to provide avatrombopag free base of formula (Ia) or salts, which is substantially free of bromo-Avatrombopag impurity of formula (ii), where molar ratio of brominating agent to (III) is 1: ≤1; 2. a crystalline form G of ethyl 1-(3-chloro-5-((4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl) thiazol-2-yl) carbamoyl) pyridin-2-yl)piperidine-4-carboxylate of (VI), which is characterized by its X-ray powder diffraction (XRPD) pattern having one or more peaks at 7.1, 11.1, 13.2, 14.3, 14.5, 15.0, 16.7, 17.5 and 21.3° 2θ± 0.2°; and 3. a process for the preparation of crystalline form G of ethyl 1-(3-chloro-5-((4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl) thiazol-2-yl) carbamoyl) pyridin-2-yl) piperidine-4-carboxylate of (VI), which involves: (a) dissolving ethyl 1-(3-chloro-5-((4-(4-chlorothiophen-2-yl)-5-(4-cyclohexyl piperazin-1-yl) thiazol-2-yl) carbamoyl) pyridin-2-yl) piperidine-4-carboxylate in a halogenated solvent, alcohol solvent, ether solvent or mixture; and (b) isolating crystalline form G of ethyl 1-(3-chloro-5-((4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl) thiazol-2-yl) carbamoyl) pyridin-2-yl) 20 piperidine-4-carboxylate of (VI); 4. a crystalline form K of avatrombopag free base of formula (Ia), which has XRPD pattern having one or more peaks at 5.9, 8.5, 8.9, 11.8, 12.8, 14.2, 14.7, 16.7, 21.6, and 21.9° 2θ± 0.2°; and 4. a process for the preparation of crystalline form K of avatrombopag free base of (Ia), which involves: (a) treating crystalline form G of compound of (VI) with a base in a suitable solvent to provide avatrombopag free base of (Ia); (b) dissolving the step-(a) solution in a hydrocarbon solvent; and (c) isolating crystalline form K of avatrombopag free base of (Ia).
IPC 分类号	A61K-031/426 ; A61P-007/04 ; C07D-417/14
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/20350
专题	中国科学院新疆生态与地理研究所
作者单位	GRANULES INDIA LTD (GRAN-Non-standard)
推荐引用方式 GB/T 7714	GADDE C,BONTU N R,BANDI C R,et al. Preparing 5-bromo-4-(4-chlorothiophen-2-yl)thiazol-2-amine used for thrombocytopenia in adult patients with chronic liver disease, involves dissolving 2-amino-4-(4-chlorothiophen-2-yl)thiazole in solvent followed by adding brominating agent, isolating 5-bromo-4-(4-chlorothiophen-2-yl)thiazol-2-amine. IN202341062891-A[P]. 2023.

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