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A kind of preparation method of tofacitinib compound

A technology for tofacitinib and compounds, applied in the field of drug preparation, can solve the problems of unsuitability for industrial production, long preparation process route, long reaction period and the like, and achieve the effects of convenient post-processing operation, easy industrialization, and short reaction time

Active Publication Date: 2019-12-20
SHANDONG LUOXIN PHARMA GRP HENGXIN PHARMA CO LTD +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This route also has a long preparation process route, a long reaction cycle, and high cost, which is not suitable for industrial production.

Method used

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  • A kind of preparation method of tofacitinib compound
  • A kind of preparation method of tofacitinib compound
  • A kind of preparation method of tofacitinib compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Preparation of Compound III

[0034] In a 250mL three-neck flask, sequentially add 14.9g of 4-methylpiperidin-3-one hydrochloride (II), 50mL of distilled water and 50mL of toluene, cool to 0-5°C in an ice bath, stir, and weigh 8.41g Potassium hydroxide was added to the reaction flask in batches, the reaction time was 2 hours, the ice bath was removed, and 12.6 g of benzyl chloride was added dropwise at room temperature. After 30 minutes, the dropwise addition was completed, and the stirring was continued, and the reaction was heated to reflux for 6 hours. After the end, the mixture was allowed to stand for stratification, the organic phase was separated, washed with water, anhydrous sodium sulfate, filtered, and the solvent toluene was evaporated under reduced pressure to obtain 19.31 g of a colorless liquid with a yield of 95.46% and an HPLC purity of 99.76%.

Embodiment 2

[0036] Preparation of Compound III

[0037] In a 250mL three-neck flask, sequentially add 14.96g of 4-methylpiperidin-3-one hydrochloride (II), 50mL of distilled water and 50mL of toluene, cool to 0-5°C in an ice bath, stir, and weigh 16.8g Sodium hydroxide was added to the reaction bottle in batches, the reaction time was 2 hours, the ice bath was removed, and 19 g of benzyl chloride was added dropwise at room temperature. After 30 minutes, the dropwise addition was completed, and the stirring was continued, heated to reflux for 6 hours, and the reaction was completed. After standing still, the organic phase was separated, washed with water, anhydrous sodium sulfate, filtered, and the solvent toluene was distilled off under reduced pressure to obtain 19.81 g of a colorless liquid with a yield of 97.23% and a purity of 98.37% by HPLC.

Embodiment 3

[0039] Preparation of Compound III

[0040] In a 250mL three-necked flask, add 14.96g of 4-methylpiperidin-3-one hydrochloride (II), 50mL of distilled water and 50mL of toluene in sequence, cool to 0-5°C in an ice bath, stir, and weigh potassium carbonate 27.64g was added to the reaction flask in batches, the reaction time was 2h, the ice bath was removed, and 15.2g of benzyl chloride was added dropwise at room temperature. After 30min, the benzyl chloride was added dropwise. Continue to stir, and heated to reflux for 6h, and the reaction was over. After standing, the organic phase was separated, washed with water, anhydrous sodium sulfate, filtered, and the solvent toluene was evaporated under reduced pressure to obtain 17.68 g of a colorless liquid with a yield of 87.34% and an HPLC purity of 97.26%.

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Abstract

The invention discloses a tofacitinib compound preparation method. Under alkali and solvent existence condition, 4-methyl piperidine-3-ketamine hydrochloride (II) and benzyl chloride are subjected toa reaction to obtain a compound III, acid catalysis is carried out to obtain a compound V, and steps of asymmetric catalytic hydrogenation, deprotection, and condensation are carried out to obtain a final product tofacitinib (I), the preparation method has the advantages of short technical process, mild reaction condition, high overall yield and purity, and less by-product, and is suitable for industrial preparation.

Description

technical field [0001] The invention relates to a preparation method of a tofacitinib compound, which belongs to the technical field of medicine preparation. Background technique [0002] Tofacitinib, the chemical name is 3-{(3R,4R)-4-methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino] Piperidin-1-yl}-3-oxopropionitrile is a new type of Janus kinase inhibitor developed by Pfizer, which can effectively inhibit the activity of JAK1 and JAK3 and block the signal transduction of various inflammatory cytokines . In November 2012, it was approved for marketing by the US FDA, and tofacitinib citrate (trade name: Xeljanz) was recognized by the US Food and Drug Administration as a "breakthrough therapy" and approved for marketing for inadequate response or intolerance to methotrexate treatment A novel oral JAK inhibitor in adult patients with moderately to severely active rheumatoid arthritis. Studies have shown that tofacitinib has a good therapeutic effect on various inflamm...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 侯俊凯张晗黄青艳
Owner SHANDONG LUOXIN PHARMA GRP HENGXIN PHARMA CO LTD