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Improved tofacitinib synthesis method and impurity preparation method

A synthetic method, the technology of tofacitinib, which is applied in the field of medicinal chemistry, can solve the problems of tofacitinib degradation and other problems, and achieve the effect of easy removal and quality improvement

Inactive Publication Date: 2020-12-18
HANGZHOU HUADONG MEDICINE GRP PHARMA RES INST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] The purpose of the present invention is to overcome the defects in the prior art that are prone to produce difficult-to-separate impurities and the post-treatment process will cause the degradation of tofacitinib, and provide an improved synthesis method of tofacitinib and a method for preparing impurities

Method used

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  • Improved tofacitinib synthesis method and impurity preparation method
  • Improved tofacitinib synthesis method and impurity preparation method
  • Improved tofacitinib synthesis method and impurity preparation method

Examples

Experimental program
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Effect test

Embodiment 1

[0035] Add 6.0 g of Compound I, 1.2 g of 10% Pd / C, 48.0 g of ammonium formate, and 72 ml of methanol into the reaction flask, heat to 65° C., and keep stirring for 9 h. After the reaction was complete, it was filtered, extracted with dichloromethane and ethyl acetate, washed with water and distilled under reduced pressure to obtain 3.0 g of white powder Compound II with a yield of 68.2%.

[0036] Add 3.0 g of Compound II, 1.4 g of ethyl cyanoacetate, 1.2 g of DBU, and 10 ml of n-butanol into the reaction flask, raise the temperature to 60-65°C, and keep stirring for 8-9 hours. After the reaction was complete, it was lowered to room temperature, added with water, extracted with ethyl acetate, concentrated and dried to obtain 1.6 g of light yellow tofacitinib crude product, with a yield of 62.8%.

[0037] The impurity formula A was separated from the compound II by chromatographic separation, which accounted for 32.6% by weight of the product. As the reaction time increases, th...

Embodiment 2

[0039] Add 40 g of Compound I, 8 g of 10% Pd / C, 233 g of formic acid, and 480 ml of methanol into the reaction flask, heat to 67-70°C, and keep stirring for 4-5 hours. After the reaction was complete, it was cooled to room temperature and filtered. After the filtrate was concentrated under reduced pressure, the pH was adjusted to 14 by adding 30% aqueous sodium hydroxide solution, and the aqueous phase was washed with ethyl acetate. Then methanol was added to the water phase, and the reaction was stirred at 50-60°C for 4h. After the reaction was complete, dichloromethane was added for extraction three times, the liquid was separated, the organic phase was concentrated until no distillate was present, and then dried to obtain 24.1 g of compound II as a white solid powder with a yield of 82.4%. Impurity formula A was not detected.

[0040] Add 20g of compound II, 18.4g of ethyl cyanoacetate, 12.4g of DBU, and 100ml of tetrahydrofuran into the reaction flask, heat up to 60-65°C,...

Embodiment 3

[0042] Add 40 g of compound I, 8 g of 10% Pd / C, 320 g of ammonium formate, and 480 ml of methanol into the reaction flask, heat to 67-70°C, and keep stirring for 4-5 hours. After the reaction was complete, it was cooled to room temperature and filtered. After the filtrate was concentrated under reduced pressure, the pH was adjusted to 13 by adding 30% aqueous sodium hydroxide solution, and the aqueous phase was washed with ethyl acetate. Then methanol was added to the water phase, and the reaction was stirred at 55-60°C for 4h. After the reaction was complete, dichloromethane was added for extraction three times, the liquid was separated, the organic phase was concentrated until no distillate was present, and then dried to obtain 22.3 g of compound II as a white solid powder. Yield 76.2%. Impurity formula A was not detected.

[0043] Add 20g of compound II, 18.4g of ethyl cyanoacetate, 12.4g of DBU, and 100ml of tetrahydrofuran into the reaction flask, heat up to 60-65°C, an...

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Abstract

The invention discloses an improved tofacitinib synthesis method and an impurity preparation method. According to the improved tofacitinib synthesis method, by controlling the pH value of the reactionliquid, an impurity shown in the formula A is decomposed into a compound II, meanwhile, formic acid in the reaction liquid exists in a salt mode and is easy to remove, and the reaction yield and thetofacitinib quality are effectively improved. Meanwhile, the invention further provides a synthesis method of the impurity A, the impurity A can be synthesized through the method, and the quality of tofacitinib is detected and controlled.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to an improved synthesis method of tofacitinib and a preparation method of impurities. Background technique [0002] Tofacitinib, the chemical name is N-methyl-N-[(3R,4R)-1-cyanoacetyl-4-methylpiperidin-3-yl]-7H-pyrrolo[2, 3-d] pyrimidin-4-amine, a JAK inhibitor developed by Pfizer, can effectively inhibit the activities of JAK1 and JAK3. At present, tofacitinib is widely used in the treatment of rheumatoid arthritis, and can also be used as an autoimmune disease drug and immunosuppressant. [0003] The compound patent CN1195755C of Tofacitinib discloses a synthetic method, as shown below. [0004] [0005] The reaction route has high yield, stable process and easy-to-obtain raw materials. However, the debenzylation reaction needs to be carried out under the condition of pressurized hydrogen, which has high requirements on the safety of the equipment and has grea...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 金燕芬杨建科孙丽蕊方秋鲍粤华
Owner HANGZHOU HUADONG MEDICINE GRP PHARMA RES INST
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