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Tofacitinib intermediate preparation method and method for preparing tofacitinib or its salt by using tofacitinib intermediate preparation method

A technology for tofacitinib and medicinal salts is applied in the field of pharmaceutical synthesis, which can solve the problems of low product purity and difficult evaporation of water, and achieve the effects of reducing production costs, reducing the introduction of impurities, and overcoming the complexity of the preparation process.

Inactive Publication Date: 2015-07-08
HEBEI GUOLONG PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the water is not easy to evaporate to dryness, so that the purity of the product is low

Method used

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  • Tofacitinib intermediate preparation method and method for preparing tofacitinib or its salt by using tofacitinib intermediate preparation method
  • Tofacitinib intermediate preparation method and method for preparing tofacitinib or its salt by using tofacitinib intermediate preparation method
  • Tofacitinib intermediate preparation method and method for preparing tofacitinib or its salt by using tofacitinib intermediate preparation method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] Preparation of N-methyl-N-((3R,4R)-4-methylpiperidin-3-yl)-7H-pyrrolo[2,3-D]pyrimidin-4-amine (compound of formula I)

[0041]

[0042] Add 35 g of compound II, 175 ml of acetonitrile, and 142 ml of hydrochloric acid (1 mol / L, relative molar weight is 1.5) into a dry 500 ml hydrogenation reactor. After stirring until completely dissolved, add 3.98g Pd(OH) 2 / C (the trade name is palladium hydroxide / carbon, purchased from Beijing Bailingwei Technology Co., Ltd., wherein the palladium content is 20%, the water content is 50%, and the relative molar weight is 0.03). First replace the air in the reactor with nitrogen three times, and then replace the nitrogen in the reactor with hydrogen three times. Under the hydrogen pressure of 0.1MPa, the reactor is heated to 70°C-75°C, and the reaction is continued for 9h.

[0043] Add about 3 cm of diatomaceous earth to the Buchner funnel and moisten it with acetonitrile. After the reaction was completed, the reaction solution wa...

Embodiment 2

[0048] Preparation of N-methyl-N-((3R,4R)-4-methylpiperidin-3-yl)-7H-pyrrolo[2,3-D]pyrimidin-4-amine (compound of formula I): With reference to Example 1, wherein with 95ml concentration is 1mol / L sulfuric acid (with H + Calculate, relative molar weight is 2) replace hydrochloric acid as inorganic acid, replace 175ml acetonitrile with 350ml ethanol as organic solvent, and hydrogen pressure is 0.3MPa. The reaction time was 9 hours, the HPLC purity of the product was 98.98%, and the yield was 83%.

Embodiment 3

[0050] Preparation of N-methyl-N-((3R,4R)-4-methylpiperidin-3-yl)-7H-pyrrolo[2,3-D]pyrimidin-4-amine (compound of formula I): Referring to Example 1, wherein 11.05g of platinum carbon (trade name is platinum carbon, purchased from Beijing Bailingwei Reagent Co., Ltd., the platinum content is 5%, and the relative molar weight is 0.03) replaces palladium carbon as a catalyst. The reaction time is 8 hours, the HPLC purity is 99.32%, and the yield is 92%.

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Abstract

The invention provides a N-methyl-N((3R,4R)-4-methyl piperidine-3-group)-7H-pyrrolo[2,3-D]pyrimidine-4-amine (tofacitinib intermediate)preparation method and a method for preparing tofacitinib or its salt by using the tofacitinib intermediate preparation method. The tofacitinib intermediate preparation method can dissolve a compound in a formula (II) in a mixed solvent system of an acidic solvent and an organic solvent, and then a hydrogenation reaction is carried out under existence of palladium carbon or platinum carbon catalyst, thereby a compound in a formula (1) can be obtained. The method is simple to operate, and the tofacitinib intermediate yield is high. The invention also relates to the compound in the formula (1) prepared by the method and tofacitinib or its medicinal salt prepared by the compound.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to N-methyl-N-((3R,4R)-4-methylpiperidin-3-yl)-7H-pyrrolo[2,3-D]pyrimidine-4- A method for preparing amine and a method for preparing tofacitinib or a salt thereof by using the same. 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, 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; Among patients with working abi...

Claims

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Application Information

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IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 曲继广魏赛丽孙雪梅赵毅莎印杰李彪马辉
Owner HEBEI GUOLONG PHARMA CO LTD
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