Preparing methyl {4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamate (vericiguat) comprises reacting 2-(5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)pyrimidine-4,5,6-triamine with reagent
	PENUMATI N R; PRADEEP R; RAMPRASAD A K; NAGARAJU C
	2023-09-27
专利权人	MAITHRI DRUGS PRIVATE LTD (MAIT-Non-standard)
申请日期	2023-09-27
专利号	IN202341064963-A
成果简介	NOVELTY - Preparing methyl {4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamate (vericiguat) (I) comprises (f) converting 5-fluoro-3-amino-1H-pyrazolo[3,4-b]pyridine (4) to 5-fluoro-1H-pyrazolo[3,4-b]pyridine compound (5); (g) converting compound (5) to 5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b] pyridine compound (6); (h) reacting compound (6) with reagent to obtain 5-fluoro-1-(2-fluorobenzyl)-3-cyano-1H-pyrazolo[3,4-b] pyridine (7); (i) reacting compound (7) with reagent to obtain 5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboximidamide (8); (j) converting compound (8) to (E)-2-(5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-5-(phenyldiazenyl)pyrimidine-4,6-diamine (9); (k) converting compound (9) to 2-(5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)pyrimidine-4,5,6-triamine (10); (l) reacting compound (10) with reagent to obtain compound (I). USE - Preparing methyl {4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamate. No biological data given. ADVANTAGE - The method provides methyl {4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamate with high purity of 99%, and high yield, without nitroso amine impurities, in efficient and cost-effective manner. DETAILED DESCRIPTION - Preparing methyl {4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamate of formula (I) comprises: (a) reacting 2,6-dichloro-5-fluoronicotinonitrile of formula (A) in presence of suitable reagent, and solvent to obtain 2,6-dichloro-3-fluoropyridin-5-amide of formula (1); (b) reacting compound (1) in presence of suitable reagent, and solvent to obtain 6-chloro-3-fluoropyridin-5-amide of formula (2); (c) reacting compound (2) with suitable reagent, and solvent to obtain 6-chloro-3-fluoropyridin-5-nitrile of formula (3); (d) optionally reacting compound 2,6-dichloro-5-fluoronicotinonitrile with suitable reagent, and solvent to obtain compound (3); (e) reacting compound (3) with suitable reagent, solvent to obtain 5-fluoro-3-amino-1H-pyrazolo[3,4-b]pyridine of formula (4); (f) reacting compound (4) with suitable reagent, solvent to obtain 5-fluoro-1H-pyrazolo[3,4-b]pyridine compound of formula (5); (g) reacting compound (5) with suitable reagent, solvent to obtain 5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b] pyridine compound of formula (6); (h) reacting compound (6) with suitable reagent, solvent to obtain 5-fluoro-1-(2-fluorobenzyl)-3-cyano-1H-pyrazolo[3,4-b] pyridine of formula (7); (i) reacting compound (7) with suitable reagent, solvent to obtain 5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboximidamide of formula (8) or its salts; (j) reacting compound (8) with suitable reagent, solvent to obtain (E)-2-(5-fluoro-1-(2-fluoro benzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-5-(phenyldiazenyl)pyrimidine-4,6-diamine of formula (9) or its salts; (k) reacting compound (9) with suitable reagent, solvent to obtain 2-(5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)pyrimidine-4,5,6-triamine of formula (10) or its salts; (l) reacting compound (10) with suitable reagent, solvent to obtain compound (I) or their salts; and (m) optionally purifying the compound obtained in the above steps with suitable acid, base in suitable solvent to obtain the pure compound (I). X=Cl, Br, or I. INDEPENDENT CLAIMS are included for: 1. a method-2 for preparing crystalline form of compound (I), which comprises: (i) dissolving compound (I) in dimethyl sulfoxide; (ii) adding the solution obtained in step (i) to oxalic acid in acetone or ethyl acetate; (iii) isolating the compound obtained in step (ii) as vericiguat oxalic acid salt; (iv) treating the compound obtained in step (iii) with ammonia or sodium carbonate in water to obtain pure compound (I); (v) optionally treating the compound obtained in step (iii) with mixture of dimethyl sulfoxide and aqueous sodium bicarbonate solution or mixture of dimethyl sulfoxide-ethanol and aqueous sodium bicarbonate or mixture of ethanol and aqueous sodium bicarbonate solution to obtain pure crystalline form of compound (I); and 2. vericiguat, which has particle size distribution D90 of less than 300 µm, D50 of less than 150 µm, and D10 of less than 75 µm.
IPC 分类号	A61K-031/506 ; A61P-015/10 ; A61P-015/12 ; A61P-043/00 ; A61P-007/02 ; A61P-009/10 ; A61P-009/12 ; C07D-471/04
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/20214
专题	中国科学院新疆生态与地理研究所
作者单位	MAITHRI DRUGS PRIVATE LTD (MAIT-Non-standard)
推荐引用方式 GB/T 7714	PENUMATI N R,PRADEEP R,RAMPRASAD A K,et al. Preparing methyl {4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamate (vericiguat) comprises reacting 2-(5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)pyrimidine-4,5,6-triamine with reagent. IN202341064963-A[P]. 2023.

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