Preparation method of tofacitinib impurity

A technology of tofacitinib and impurities, which is applied in the fields of drug synthesis and drug quality research, can solve the problems of low compound yield, severe reaction conditions, and difficult to control, and achieves high yield, simple process, and easy separation and purification. Effect

Inactive Publication Date: 2021-06-08
SHANGHAI SCIENPHARM CO LTD
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  • Application Information

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Problems solved by technology

However, during the hydrolysis process, the cyano group will be hydrolyzed into amide and acid, and the amide bond is easily hydrolyzed during the reaction process, and concentrated sulfuric acid and high temperature reaction are required, the reaction conditions are severe, it is not easy to control, and the yield of the compound is low

Method used

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  • Preparation method of tofacitinib impurity
  • Preparation method of tofacitinib impurity
  • Preparation method of tofacitinib impurity

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Experimental program
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Effect test

Embodiment 1

[0058] Tofacitinib impurity 3-((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl )-3-oxopropionic acid preparation. The synthesis process is as figure 1 shown; the specific steps are as follows:

[0059] A, the preparation of the compound shown in formula (Ⅲ);

[0060] Add 9.5 g (29.8 mmol) of the compound represented by formula (II) into 95 mL of dichloromethane, add 12.1 g (119.4 mmol) of triethylamine, and stir. The temperature was lowered to 0-5° C., and a solution of 6.5 g (47.8 mmol) of methyl 3-chloro-3-oxopropionate in dichloromethane (10 mL) was added dropwise. After the dropwise addition, the temperature was naturally raised to 20-30°C. After 3 hours of reaction, the temperature was lowered to 0-5°C, and 5mL of water was added to quench the reaction, and 2N dilute hydrochloric acid was added dropwise to adjust the pH value to 5-6. The liquid was separated, and the organic phase was sequentially Wash with saturated sodium bicarbonate ...

Embodiment 2

[0068] Tofacitinib impurity 3-((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl )-3-oxopropionic acid preparation

[0069] A, the preparation of the compound shown in formula (Ⅲ);

[0070] Add 1 g (3.1 mmol) of the compound represented by formula (II) into 5 mL of dichloromethane, add 1.11 g (11.0 mmol) of triethylamine, and stir. The temperature was lowered to 0-5° C., and a solution of 0.5 g (3.8 mmol) of methyl 3-chloro-3-oxopropionate in dichloromethane (2 mL) was added dropwise. After the dropwise addition, naturally raise the temperature to 20-30°C, after 2-3 hours of reaction, cool down to 0-5°C, add 2mL water to quench the reaction, add dilute hydrochloric acid dropwise to adjust the pH value to 5-6, separate liquid, organic phase Washed with saturated sodium bicarbonate and saturated brine, dried the organic phase with an appropriate amount of anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and purif...

Embodiment 3

[0074] Tofacitinib impurity 3-((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl )-3-oxopropionic acid preparation

[0075] A, the preparation of the compound shown in formula (Ⅲ);

[0076] Add 1 g (3.1 mmol) of the compound represented by formula (II) into 20 mL of dichloromethane, add 2.22 g (22.0 mmol) of triethylamine, and stir. The temperature was lowered to 0-5°C, and a solution of 857 mg (6.3 mmol) of methyl 3-chloro-3-oxopropionate in dichloromethane (3 mL) was added dropwise. After the dropwise addition, the temperature was naturally raised to 20-30°C. After 3 hours of reaction, the temperature was lowered to 0-5°C, and 2 mL of water was added to quench the reaction. Dilute hydrochloric acid was added dropwise to adjust the pH value to 5-6. Wash with saturated sodium bicarbonate and saturated brine, dry the organic phase with an appropriate amount of anhydrous sodium sulfate, filter, concentrate to dryness under reduced pressure, and pu...

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Abstract

The invention provides a preparation method of a tofacitinib impurity, and relates to the field of drug synthesis and drug quality research. The preparation method comprises the steps of dissolving N-methyl-N-((3R, 4R)-4-methylpiperidine-3-yl)-7H-pyrrolo [2, 3-d] pyrimidine-4-amine dihydrochloride in a first organic solvent, and reacting with methyl 3-chloro-3-oxopropionate under the catalysis of an acid-binding agent to obtain 3-((3R, 4R)-4-methyl-3-(methyl (7H-pyrrolo [2, 3-d] pyrimidine-4-yl) amino) piperidine-1-yl)-3-oxopropionic acid methyl ester,dissolving the product in a second organic solvent, adding an alkaline reagent, and adjusting the pH value to be acidic, thereby obtaining the tofacitinib impurity. The tofacitinib impurity is 3-((3R, 4R)-4-methyl-3-(methyl (7H-pyrrolo [2, 3-d] pyrimidine-4-yl) amino) piperidine-1-yl)-3-oxopropionic acid. The method is simple, and the product is high in yield and purity.

Description

technical field [0001] The present invention relates to the field of drug synthesis and drug quality research, in particular to a method for preparing tofacitinib impurities, in particular to a tofacitinib (chemical name: N-methyl-N-[(3R, 4R)- A method for preparing related substances of 1-cyanoacetyl-4-methylpiperidin-3-yl]-7-H-pyrrolo[2,3-d]pyrimidin-4-amine). Background technique [0002] Tofacitinib, the chemical name is N-methyl-N-[(3R,4R)-1-cyanoacetyl-4-methylpiperidin-3-yl]-7-H-pyrrolo[ 2,3-d] pyrimidine-4-amine, is a kind of anti-rheumatoid arthritis oral inhibitor developed by Pfizer (Pfrizer), its citrate (tofacitinib citrate, Tofacitinib Citrate) It has passed Phase III clinical trials, and was approved for marketing by the US Food and Drug Administration (FDA) on November 6, 2012, and was approved for marketing by the Japanese Pharmaceuticals and Medical Devices Agency (PMDA) on March 25, 2013. On March 22, it was approved for marketing by the European Medicin...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 刘娇彭典金李惠谢军姜春阳
Owner SHANGHAI SCIENPHARM CO LTD
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