Preparing tofacitinib or its salt used for rheumatoid arthritis, involves reacting pyrimidine derivative with chloroacetaldehyde in alkali metal salt of organic acid, reacting 7H-pyrrolo[2,3-d]pyrimidine derivative with acid, and converting 7H-pyrrolo[2,3-d]pyrimidine-2,4-diol to tofacitinib or salt
	SAHU S; PATLE G T; LAD S M; HARATHI D N S; PATEL P; PALLE V R A
	2023-09-08
专利权人	GLENMARK LIFE SCI LTD (GLMK-C)
申请日期	2023-09-08
专利号	IN202321060507-A
成果简介	NOVELTY - Preparing tofacitinib or its salt of (IA), involves: (a) reacting 6-aminopyrimidine-2,4(1H,3H)-dione of (III) with chloroacetaldehyde of (IV) in the presence of an alkali metal salt of an organic acid and a base to obtain a salt of 7H-pyrrolo[2,3-d]pyrimidine-2,4-diol of (V); (b) treating the 7H-pyrrolo[2,3-d]pyrimidine-2,4-diol (V) with an acid to obtain 7H-pyrrolo[2,3-d]pyrimidine-2,4-diol of (VI); c) converting 7H-pyrrolo[2,3-d]pyrimidine-2,4-diol (VI) to tofacitinib; and (d) optionally, converting the tofacitinib to its salt of (IA); or (i) treating 7H-pyrrolo[2,3-d]pyrimidine-2,4-diol (VI) with a halogenating agent to obtain 2,4-dihalo-7H-pyrrolo[2,3-d]pyrimidine of (VII); (ii) reacting 2,4-dihalo-7H-pyrrolo[2,3-d]pyrimidine of (VII) with a tosylating agent; (iii) reacting 2,4-dichloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine (VIII) with (3R,4R)-1-trityl-N,4-dimethylpiperidin-3-amine of (IX). USE - Process for preparing tofacitinib, or its salt used in pharmaceutical composition for treating adult patients with rheumatoid arthritis, psoriatic arthritis and ulcerative colitis. No biological data given. ADVANTAGE - The process provides high purity, and ensure the safety, efficacy and consistency of the pharmaceutical composition. DETAILED DESCRIPTION - Preparing tofacitinib or its salt of formula (IA), involves: (a) reacting 6-aminopyrimidine-2,4(1H,3H)-dione of formula (III) with chloroacetaldehyde of formula (IV) in the presence of an alkali metal salt of an organic acid and a base to obtain a salt of 7H-pyrrolo[2,3-d]pyrimidine-2,4-diol of formula (V); (b) treating the 7H-pyrrolo[2,3-d]pyrimidine-2,4-diol (V) with an acid to obtain 7H-pyrrolo[2,3-d]pyrimidine-2,4-diol of formula (VI); c) converting 7H-pyrrolo[2,3-d]pyrimidine-2,4-diol (VI) to tofacitinib; and (d) optionally, converting the tofacitinib to its salt of (IA); or (i) treating 7H-pyrrolo[2,3-d]pyrimidine-2,4-diol (VI) with a halogenating agent to obtain 2,4-dihalo-7H-pyrrolo[2,3-d]pyrimidine of formula (VII); (ii) reacting 2,4-dihalo-7H-pyrrolo[2,3-d]pyrimidine of (VII) with a tosylating agent to obtain 2,4-dichloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine of formula (VIII); (iii) reacting 2,4-dichloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine with (3R,4R)-1-trityl-N,4-dimethylpiperidin-3-amine of formula (IX) to obtain pyrrolo[2,3-d]pyrimidine derivative of formula (X); (iv) reacting pyrrolo[2,3-d]pyrimidine derivative of (X) with a base followed by an acid to obtain chloro-N-methyl-N-[(3R,4R)-4-methyl piperidine-3-yl]-7-pyrolo[2,3-d]pyrimidine-4-amine of formula (XI); (v) converting chloro-N-methyl-N-[(3R,4R)-4-methyl piperidine-3-yl]-7-pyrolo[2,3-d]pyrimidine-4-amine to tofacitinib; and (vi) optionally, converting the tofacitinib to its salt (IA). A=citrate, tartrate, bitartrate, succinate, maleate, fumarate, and oxalate; M=sodium (Na), or potassium (K); Ts=tosyl; and X=Cl, Br or I. An INDEPENDENT CLAIM is included for a tofacitinib having 0.01-0.2 wt.% dimer impurity of formula (A) and trimer impurity of formula (B), which is prepared by the process.
IPC 分类号	A61K-031/519 ; A61P-035/00 ; C07D-487/04
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/20450
专题	中国科学院新疆生态与地理研究所
作者单位	GLENMARK LIFE SCI LTD (GLMK-C)
推荐引用方式 GB/T 7714	SAHU S,PATLE G T,LAD S M,et al. Preparing tofacitinib or its salt used for rheumatoid arthritis, involves reacting pyrimidine derivative with chloroacetaldehyde in alkali metal salt of organic acid, reacting 7H-pyrrolo[2,3-d]pyrimidine derivative with acid, and converting 7H-pyrrolo[2,3-d]pyrimidine-2,4-diol to tofacitinib or salt. IN202321060507-A[P]. 2023.

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