Preparation method of JAKs inhibitor drug tofacitinib

A technology of tofacitinib and inhibitors, which is applied in the field of preparation of JAKs inhibitor drug tofacitinib, can solve the problems of long synthetic route, not suitable for large-scale production, high production cost, etc., and achieve simple operation and easy control of purity , the effect of little pollution

Inactive Publication Date: 2016-07-06
NANTONG CHANGYOO PHARMATECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

This process has a long synthetic route, and is applied to expensive reagents such as rhodium catalysts, resulting in high production costs, and high-risk reagents such as lithium aluminum hydride are not suitable for large-scale production

Method used

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  • Preparation method of JAKs inhibitor drug tofacitinib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] (1) Preparation of Compound II:

[0022] Add 190g of 2,4-dichloro-7H pyrrole[2,3-D]pyrimidine, 280g of potassium carbonate, 1000mL of acetonitrile into the reaction flask, stir, heat to 45°C, then dropwise add 250g of benzyl bromide; °C reaction, TLC monitoring reaction. After the reaction is complete, cool to room temperature, evaporate most of the solvent, add 1000mL water and 2000mL ethyl acetate, stir, let stand for liquid separation, extract the aqueous layer with 800mL ethyl acetate, combine organic phases, dry over anhydrous sodium sulfate, and reduce pressure Concentrate to dryness, add 800mL of methyl tert-butyl ether to make a slurry, and obtain 255g of solid product Compound II.

[0023] (2) Preparation of Compound IV:

[0024] Add 200g (3R,4R)-N,4-dimethyl-1-(phenylmethyl)-3-piperidinamine hydrochloride, 210g 7-benzyl-2,4-dichloro- 7H pyrrole[2,3-D]pyrimidine (Compound II), 160g of potassium carbonate, 500mL of ethanol and 1000mL of water, stirred and rai...

Embodiment 2

[0032] (1) Preparation of Compound II:

[0033] Add 150g of 2,4-dichloro-7H pyrrole[2,3-D]pyrimidine, 205g of N,N-diisopropylethylamine, 600mL of N,N-dimethylformamide into the reaction flask, stir and heat to 45°C , and then dropwise added 152g of benzyl chloride; after dropping, the temperature was raised to 90°C for reaction, and the reaction was monitored by TLC. After completion of the reaction, cool to room temperature, add 1000mL of water and 1500mL of ethyl acetate, stir, stand still for liquid separation, extract the water layer twice with 1000mL of ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, and concentrate to dryness under reduced pressure. Add 600mL of isopropyl ether and make a slurry to obtain 204g of solid product Compound II.

[0034](2) Preparation of Compound IV:

[0035] Add 160g (3R,4R)-N,4-dimethyl-1-(phenylmethyl)-3-piperidinamine hydrochloride, 168g 7-benzyl-2,4-dichloro- 7H pyrrole[2,3-D]pyrimidine, 93g piperidine, a...

Embodiment 3

[0043] (1) Preparation of Compound II:

[0044] Add 190g of 2,4-dichloro-7H pyrrole[2,3-D]pyrimidine, 153g of triethylamine, 1000mL of DMSO into the reaction flask, stir, heat to 45°C, then dropwise add 207g of benzyl bromide; °C reaction, TLC monitoring reaction. After the reaction is complete, cool to room temperature, evaporate most of the solvent, add 1000mL water and 2000mL ethyl acetate, stir, let stand for liquid separation, extract the aqueous layer with 800mL ethyl acetate, combine organic phases, dry over anhydrous sodium sulfate, and reduce pressure Concentrate to dryness, add 800mL of methyl tert-butyl ether to make a slurry, and obtain 250g of solid product Compound II.

[0045] (2) Preparation of Compound IV:

[0046] Add 200g (3R,4R)-N,4-dimethyl-1-(phenylmethyl)-3-piperidinamine hydrochloride, 230g 7-benzyl-2,4-dichloro- 7H pyrrole[2,3-D]pyrimidine (Compound II), 133g of N,N-diisopropylethylamine, 500mL of ethanol and 1000mL of water, stirred and raised to r...

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Abstract

The invention discloses a preparation method of JAKs inhibitor drug tofacitinib, which is characterized in that it comprises the following steps: (1) using 2,4-dichloro-7H pyrrole [2,3-D] pyrimidine as a raw material, Under the action of base, react with halobenzyl to prepare compound II; (2) (3R,4R)-N,4-dimethyl-1-(phenylmethyl)-3-piperidinamine hydrochloride React with 7-benzyl-2,4-dichloro-7H pyrrole [2,3-D] pyrimidine under the action of a base to prepare compound IV; (3) the compound IV obtained in step (2) is catalyzed under the action of a metal catalyst Hydrogenation reaction to obtain compound V; (4) Compound V obtained in step (3) is coupled and docked with cyanoacetic acid under the action of a condensing agent to obtain compound VI; (5) Compound VI obtained in step (4) is prepared by salting with citric acid Get tofacitinib. The synthesis route of the method is short, the reaction process of each step is easy to operate, the solvent can be recycled and used mechanically, the pollution is small, and it is suitable for large-scale industrial production.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a preparation method of the JAKs inhibitor drug tofacitinib. Background technique [0002] Tofacitinib, Tofacitnib, the Chinese chemical name is 3-{(3R,4R)-4-methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino] Piperidin-1-yl}-3-oxopropionitrile citrate; CAS number: 1193037-88-0. Tofacitinib is a Janus kinase (JAKs) inhibitor developed by Pfizer. On November 6, 2012, the U.S. Food and Drug Administration (FDA) approved the marketing of tofacitinib citrate (Xeljanz) for moderately to severely active rheumatoid patients who have insufficient response or intolerance to methotrexate treatment. A novel oral JAK inhibitor for the treatment of adult patients with rheumatoid arthritis (RA). The structural formula is as follows: [0003] . [0004] Rheumatoid arthritis is a common systemic autoimmune disease, characterized by chronic progressive non-suppurative inflammati...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61P19/02A61P29/00
CPCY02P20/584C07D487/04
Inventor 李泽标刘杰潘婧张磊严军吕连岭
Owner NANTONG CHANGYOO PHARMATECH CO LTD
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