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A tofacitinib citrate purification method

A technology of tofacitinib and its refining method, which is applied in the direction of organic chemistry, organic chemistry, etc., can solve the problem of ineffective removal of impurities, and achieve the effect of simple operation and high yield

Active Publication Date: 2018-12-07
NANJING CHIA TAI TIANQING PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] After research, it was found that none of the refining methods reported in the literature can effectively remove the impurity G

Method used

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  • A tofacitinib citrate purification method
  • A tofacitinib citrate purification method
  • A tofacitinib citrate purification method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Example 1 Preparation of Tofacitinib Citrate Crude Product

[0026]

[0027] Add 40Kg of purified water into a 100L glass reactor, start stirring, and add 4Kg of (3R,4R)-N,4-dimethyl-1-(phenylmethyl)-3-piperidinamine hydrochloride (compound VI ), stirring to dissolve the system; then slowly add 9.49Kg of potassium carbonate powder, and stir for 10-20 minutes after the addition; then add 2.61Kg of 2,4-dichloro-7H pyrrole[2,3-D]pyrimidine (compound V). The temperature of the system is controlled at 100±5°C for 20-24 hours. Sampling by HPLC to monitor the reaction. After the reaction is completed, stop heating, cool the system to 20-30°C, centrifuge until almost no solvent comes out, rinse the filter cake with purified water, and centrifuge until no solvent comes out; beat the filter cake with 20Kg purified water for 0.5 hours , Centrifuge until almost no solvent comes out, rinse the filter cake with 8.0Kg purified water, centrifuge until no solvent comes out; add the ...

Embodiment 2

[0032] Embodiment 2 Refining of tofacitinib citrate

[0033] Add 100g of crude tofacitinib citrate (crude product content: 97.64%, impurity G content: 0.44%) and 200 mL of dimethyl sulfoxide into the reaction flask, heat up to 40°C, stir and dissolve until dissolved. Keep 40°C and add 3L of dichloromethane dropwise, after the dropwise addition, slowly cool down to 15°C, a white solid precipitates, keep stirring for 1 hour, filter and dry to obtain 95.0g pure product, yield 95.0%, HPLC detection, impurity G content 0.03% , Tofacitinib citrate purity 99.93%.

Embodiment 3

[0034] Example 3 Refining of Tofacitinib Citrate

[0035] Add 100g of crude tofacitinib citrate (crude content: 97.64%, impurity G content: 0.44%) and 100 mL of dimethyl sulfoxide into the reaction flask, raise the temperature to 45°C, and stir to dissolve until clear. Keep 45°C and add 3L of dichloromethane dropwise, after the dropwise addition, slowly cool down to 10°C, a white solid precipitates, keep stirring for 1 hour, filter and dry to obtain 94.8g of pure product, the yield is 94.8%, the content of impurity G is 0.03% by HPLC detection , Tofacitinib citrate purity 99.87%.

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Abstract

The invention belongs to the field of medicine synthesis and provides a tofacitinib citrate purification method which can effectively remove an impurity G. The method includes adding a tofacitinib citrate crude product to be purified into a mixed solvent, stirring and heating the mixture until the crude product is fully dissolved, cooling the mixture for crystallization, and performing filtrationand vacuum drying to obtain a purified tofacitinib citrate product. The method is simple to operate and suitable for industrial scale-up production, and has obvious impurity removing effects and a high yield.

Description

technical field [0001] The invention belongs to the field of drug synthesis, in particular to a method for refining tofacitinib citrate. Background technique [0002] Tofacitinib Citrate (English name Tofacitinib Citrate) is a new type of oral JAK pathway inhibitor developed by Pfizer. JAK / STAT is an important class of cytokine signal transduction pathway, which is associated with blood system diseases, tumors, rheumatoid It is associated with many diseases such as arthritis and psoriasis. Unlike most other rheumatoid arthritis (RA) therapeutic drugs that mainly act on extracellular targets, tofacitinib targets intracellular signal transduction pathways and acts on the core part of the cytokine network. Relieves symptoms and can also slow or stop the damage of the disease. The inhibitory effect of tofacitinib on JAK3 is 5-100 times that of JAK1 and JAK2. Tofacitinib is the first drug developed for the treatment of rheumatoid arthritis. [0003] Tofacitinib citrate was ap...

Claims

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Application Information

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IPC IPC(8): C07D487/04
CPCC07B2200/07C07D487/04
Inventor 石建超陈宏文郑礼康刘振峰王华萍柴雨柱徐丹朱春霞田舟山
Owner NANJING CHIA TAI TIANQING PHARMA
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