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Preparation method of tofacitinib citrate

A technology of tofacitinib and citric acid, applied in the field of synthetic drugs, can solve the problems of incomplete reaction, troublesome post-processing, long reaction time and the like, and achieve the effects of less reaction time, short synthesis steps and simple operation

Inactive Publication Date: 2015-04-22
NANJING CORE TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The disadvantage of this method is that the reaction time is longer, the reaction is not complete, and the post-processing is troublesome.

Method used

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  • Preparation method of tofacitinib citrate
  • Preparation method of tofacitinib citrate
  • Preparation method of tofacitinib citrate

Examples

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preparation example Construction

[0028] The preparation method of tofacitinib citrate of the present invention comprises the following steps:

[0029] (1) 8-13mol of compound I is added in the hydroiodic acid of stirring treatment, carries out displacement reaction, stirs, then

[0030] Then raise the temperature to room temperature and stir to obtain compound II;

[0031] (2) Dissolving 1-4mol of compound III in a solvent, adding a base, and performing neutralization reaction to obtain compound IV;

[0032] (3) Add compound II to react compound II and compound IV. During the reaction process, it is necessary to heat up and stir, then cool down, wash and beat under reflux to obtain compound V, which is tofacitinib citrate.

Embodiment 1

[0034] Take 339.5g of compound I whose chemical name is 4-chloro-7-toluenesulfonyl-7H-pyrrole[2,3-D]pyrimidine and add

[0035] In 100ml of 47% hydroiodic acid stirred at 0°C, the stirring time was 1h, and then the temperature was raised to room temperature and stirred for 5h. Then filter, separate and obtain the solid substance, then dissolve the obtained solid with dichloromethane, wash twice with saturated sodium chloride, dry over anhydrous sodium sulfate, and then rotary evaporate to dryness to obtain 439.1g chemically named as 4-iodo-7 -Compound II of tosyl-7H-pyrrolo[2,3-D]pyrimidine.

[0036] In a 1000mL round bottom flask, install a mechanical stirrer, a reflux condenser, and a thermometer, add 600mL of purified water to the round bottom flask, start stirring, and add 29.1g of (3R,4R)-1-benzyl-N,4 -Dimethylpiperidin-3-amine. Compound III of hydrochloride. After compound III is dissolved, slowly add 42.4 g of anhydrous sodium carbonate while stirring to prepare (3R,4R...

Embodiment 2

[0043] Take 246.9g of compound I whose chemical name is 4-chloro-7-toluenesulfonyl-7H-pyrrole[2,3-D]pyrimidine and add it to 100ml of 47% hydroiodic acid stirred at 0°C for 0.5h. Then raise the temperature to room temperature and stir for 4h. Then filter, separate and obtain the solid substance, then dissolve the obtained solid with dichloromethane, wash twice with saturated sodium chloride, dry over anhydrous sodium sulfate, and then rotary evaporate to dryness to obtain 319.4.5g chemical name of 4-iodo- Compound II of 7-tosyl-7H-pyrrolo[2,3-D]pyrimidine.

[0044]In a 1000mL round-bottomed flask, install a mechanical stirrer, a reflux condenser, and a thermometer. Add 600mL of N,N-dimethylformamide to the round-bottomed flask, start stirring, and add 58.2g of (3R,4R)- 1-benzyl-N,4-dimethylpiperidin-3-amine.Compound III of hydrochloride, after compound III is dissolved, slowly add anhydrous sodium bicarbonate 80g while stirring, to prepare chemical name (3R ,4R)-1-benzyl-N,4...

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Abstract

The invention belongs to the field of synthetic drugs and particularly relates to a preparation method of tofacitinib citrate. The preparation method comprises the following steps: (1) adding a compound I into hydroiodic acid to obtain a compound II; (2) dissolving the compound II in a solvent, and adding a base to obtain a compound IV; and (3) reacting the compound IV and the compound II to obtain a compound V, namely, tofacitinib citrate, wherein the compound I, the compound II, the compound III, the compound IV and the compound V have molecular structures as shown in the description. By the preparation method, the reaction time is greatly shortened, the post-treatment is simplified and the cost is reduced.

Description

technical field [0001] The invention belongs to the field of synthetic medicines, in particular to a preparation method of tofacitinib citrate. Background technique [0002] Rheumatoid arthritis can occur at any age, mostly in 30-60 years old, most common around 45 years old, and the incidence rate increases with age, and women are significantly higher than men. The incidence rate in my country is 0.32%-0.36%, and the global incidence rate is 0.5%-1.0%. According to this calculation, there are more than 4 million patients suffering from rheumatoid arthritis in my country. Rheumatoid arthritis is very harmful. If it is not treated in time, 75% of rheumatoid arthritis (RA) patients will experience bone destruction within two years of onset, and up to 80% of patients will experience disability after 20 years of illness; One-third of RA patients lost their working ability within 2 years after the onset of the disease. [0003] Unlike most other current RA therapeutic drugs th...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04C07C59/265C07C51/41
CPCC07D487/04C07C51/41C07C59/265
Inventor 王雪根何凌云李贻文汪洋金皓洁
Owner NANJING CORE TECH CO LTD
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