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Novel synthetic process of tofacitinib citrate

A technology of tofacitinib and synthesis process, applied in the field of medicine, can solve problems such as long time and low yield, and achieve the effects of improving yield, reasonable route and mild reaction conditions

Inactive Publication Date: 2016-02-24
NINGBO LIWAH PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But the synthesis of starting material-1 (reaction of the first step) takes a long time and the yield is low

Method used

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  • Novel synthetic process of tofacitinib citrate
  • Novel synthetic process of tofacitinib citrate
  • Novel synthetic process of tofacitinib citrate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Embodiment 1 synthetic intermediate-1:

[0045] 1g of N-methyl-N-((3R,4R)-4-methyl-1-benzyl-3-piperidinyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (from Starting material-1) and 0.2g of 10% palladium carbon were added to a three-necked reaction flask, 30ml of anhydrous methanol was added to stir and disperse, and 0.187g of ammonium formate was added. The temperature was raised to reflux, and the reaction was carried out for 2 hours, and the reaction was monitored by TLC.

Embodiment 2

[0046] Embodiment 2 synthetic intermediate-1:

[0047] 1g of N-methyl-N-((3R,4R)-4-methyl-1-benzyl-3-piperidinyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (from Starting material-1) and 0.2g of 10% palladium carbon were added to a three-necked reaction flask, 30ml of anhydrous methanol was added to stir and disperse, and 0.561g of ammonium formate was added. The temperature was raised to reflux, and the reaction was carried out for 2 hours, and the reaction was monitored by TLC.

Embodiment 3

[0048] Embodiment 3 synthetic intermediate-1:

[0049] 1g of N-methyl-N-((3R,4R)-4-methyl-1-benzyl-3-piperidinyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (from Starting material-1) and 0.2g of 10% palladium carbon were added to a three-necked reaction flask, 30ml of anhydrous methanol was added to stir and disperse, and 0.748g of ammonium formate was added. The temperature was raised to reflux, and the reaction was carried out for 2 hours, and the reaction was monitored by TLC.

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Abstract

The invention discloses a novel synthetic process of tofacitinib citrate. The novel synthetic process comprises the steps that 1, an initial raw material-1, 10% of palladium on carbon, absolute methanol and ammonium formate are mixed in a reaction container, and reacting is carried out to obtain a midbody-1; 2, the midbody-1 prepared in the step 1 is dissolved into absolute ethyl alcohol, an initial raw material-2 is added, reacting is carried out at the reaction temperature of 20 DEG C to 50 DEG C, reaction liquid is purified to obtain a crude midbody-2 after reacting is finished, and the crude midbody-2 is refined to obtain a refined midbody-2; 3, the refined midbody-2 is subjected to heating reflux and dissolved clarification through absolute ethyl alcohol, a citric acid water solution is dropwise added, and reacting continues to be carried out at the temperature of 50 DEG C to 90 DEG C; then the mixture is slowly cooled to 20 DEG C to 45 DEG C, and stirring and devitrification are carried out; crystals are filtered and washed with ethyl alcohol, drying is carried out under reduced pressure at the temperature of 40 DEG C to 60 DEG C, and white crude tofacitinib citrate is obtained. The chemical synthetic process is more reasonable in route, and the reaction conditions are milder.

Description

technical field [0001] The medicine of the present invention, in particular, relates to a novel synthesis process of tofacitinib citrate. Background technique [0002] The compound patent WO2001 / 042246 of tofacitinib citrate was applied on 2000.10.23, and the published synthetic route is as follows: [0003] Compound patent WO2001 / 042246, application date: 2000.10.23 [0004] [0005] Synthetic route of tofacitinib citrate [0006] The compound has a patented route, a stable process, easy-to-obtain raw materials, and cheap reagent prices. However, the synthesis of starting material-1 (reaction in the first step) takes a long time and the yield is low. Therefore, it is necessary to find a new synthesis process of tofacitinib citrate with high yield and suitable for industrial production. Contents of the invention [0007] The technical problem to be solved by the present invention is to provide a novel synthesis process of tofacitinib citrate. The synthesis process ...

Claims

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Application Information

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IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 王腾峰吕波孙卓亚张旭胡艳嫔
Owner NINGBO LIWAH PHARM CO LTD
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