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Synthesis method of BTK inhibitor Acalabrutinib for treating chronic lymphocytic leukemia

A technology of lymphocytes and synthetic methods, applied in the field of medicinal chemical synthesis, can solve problems such as complex and cumbersome operations, unfavorable scale-up production and industrial promotion, and many impurities, and achieve the effects of simplified process flow, simplified operation, and high yield

Active Publication Date: 2017-12-29
SUZHOU FUSHILAI PHARMA CO LTD +1
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  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Due to the -NH on the pyrazine ring 2 As a reactive group, after several consecutive steps of reaction, multiple competitive side reactions will inevitably be caused, and more impurities will be introduced, which will adversely affect the quality and purification process of the downstream intermediates and final products, resulting in operational Complicated and cumbersome, it is not conducive to large-scale production and industrial promotion

Method used

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  • Synthesis method of BTK inhibitor Acalabrutinib for treating chronic lymphocytic leukemia
  • Synthesis method of BTK inhibitor Acalabrutinib for treating chronic lymphocytic leukemia
  • Synthesis method of BTK inhibitor Acalabrutinib for treating chronic lymphocytic leukemia

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] (1) Preparation of benzyl (S)-2-(8-aminoimidazo[1,5-a]pyrazin-3-yl)-1-pyrrolidinecarboxylate:

[0031] (S)-Benzyl 2-(8-chloroimidazo[1,5-a]pyrazin-3-yl)-1-pyrrolidinecarboxylate (10 g, 28 mmol) was dissolved in N-methylpyrrolidone (80 mL), Add ammonia water (168mmol) with a concentration of 28% by mass, and place the reaction mixture in a closed stainless steel reactor at 85°C and 2.5 atmospheric pressure to react for 6 hours. After the reaction is completed, cool to 40°C and release the pressure of the system, and slowly add water (50mL), cooled to 10°C, crystallized for 3h, filtered, and recrystallized from isopropanol to obtain (S)-2-(8-aminoimidazo[1,5-a]pyrazin-3-yl)-1 -benzyl pyrrolidinecarboxylate, off-white solid (8.5g), yield 90%, the reaction formula of this step is as follows:

[0032]

[0033] (2) Preparation of (S)-2-(8-tert-butoxycarbonylaminoimidazo[1,5-a]pyrazin-3-yl)-1-pyrrolidinecarboxylic acid benzyl ester:

[0034] (S)-2-(8-Aminoimidazo[1,5-a]py...

Embodiment 2

[0052] (1) Preparation of benzyl (S)-2-(8-aminoimidazo[1,5-a]pyrazin-3-yl)-1-pyrrolidinecarboxylate:

[0053] (S)-Benzyl 2-(8-chloroimidazo[1,5-a]pyrazin-3-yl)-1-pyrrolidinecarboxylate (15 g, 42 mmol) was dissolved in N-methylpyrrolidone (75 mL), Add ammonia water (273mmol) with a concentration of 28% by mass, and place the reaction mixture in a closed stainless steel reactor at 70°C and a pressure of 3 atmospheres to react for 8 hours. After the reaction is completed, cool to 40°C and release the pressure of the system, and slowly add water (50mL), cooled to 10°C, crystallized for 3h, filtered, and recrystallized from isopropanol to obtain (S)-2-(8-aminoimidazo[1,5-a]pyrazin-3-yl)-1 -benzyl pyrrolidinecarboxylate, off-white solid (12.9g), yield 91%, the reaction formula of this step is the same as that of Example 1.

[0054] (2) Preparation of (S)-2-(8-tert-butoxycarbonylaminoimidazo[1,5-a]pyrazin-3-yl)-1-pyrrolidinecarboxylic acid benzyl ester:

[0055] (S)-Benzyl 2-(8-ami...

Embodiment 3

[0067] (1) Preparation of benzyl (S)-2-(8-aminoimidazo[1,5-a]pyrazin-3-yl)-1-pyrrolidinecarboxylate:

[0068] (S)-Benzyl 2-(8-chloroimidazo[1,5-a]pyrazin-3-yl)-1-pyrrolidinecarboxylate (4.5g, 12.6mmol) was dissolved in N-methylpyrrolidone (70mL ), adding ammonia water (69.4mmol) with a concentration of 28% by mass percentage, the reaction mixture was placed in a closed stainless steel reactor and stirred for 4 hours at 90°C and 2 atmospheric pressure, and after the reaction was completed, it was cooled to 35°C and the system pressure was released. Slowly add water (50mL), cool to 10°C, crystallize for 3h, filter, and recrystallize from isopropanol to obtain (S)-2-(8-aminoimidazo[1,5-a]pyrazin-3-yl )-benzyl 1-pyrrolidinecarboxylate, off-white solid (3.9g), yield 92%, the reaction formula of this step is the same as that of Example 1.

[0069] (2) Preparation of (S)-2-(8-tert-butoxycarbonylaminoimidazo[1,5-a]pyrazin-3-yl)-1-pyrrolidinecarboxylic acid benzyl ester:

[0070] (S)...

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Abstract

A synthesis method of a BTK inhibitor Acalabrutinib for treating chronic lymphocytic leukemia comprises the steps as follows: preparing (S)-2-(8-aminoimidazo[1,5-a]pyrazine-3-yl)-1-pyrrolidinecarboxylic aci benzyl ester; preparing (S)-2-(8-tert-butoxycarbonylaminoimidazo[1,5-a]pyrazine-3-yl)-1-pyrrolidinecarboxylic acid benzyl ester; preparing (S)-2-(8-tert-butoxycarbonylamino-1-bromoimidazo[1,5-a]pyrazine-3-yl)-1-pyrrolidinecarboxylic acid benzyl ester; preparing (S)-2-(8-tert-butoxycarbonylamino-1-[4-(2-pyridylcarbamoyl)phenyl]imidazo[1,5-a]pyrazine-3-yl)-1-pyrrolidinecarboxylic acid benzyl ester; preparing (S)-2-(8-tert-butoxycarbonylamino-1-[4-(2-pyridylcarbamoyl)phenyl]imidazo[1,5-a]pyrazine-3-yl)pyrrolidine; preparing (S)-2-(8-tert-butoxycarbonylamino-1-[4-(2-pyridylcarbamoyl)phenyl]imidazo[1,5-a]pyrazine-3-yl)-1-(2-butynoyl)pyrrolidine; preparing Acalabrutinib. The yield is high, the process is simplified, and the synthesis method is green and environmentally friendly.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical chemical synthesis, and in particular relates to a synthesis method of Acalabrutinib, a BTK inhibitor for treating chronic lymphocytic leukemia. Background technique [0002] Acalabrutinib, a second-generation Bruton's tyrosine kinase (BTK) inhibitor, is a new anticancer drug developed by AstraZeneca for the treatment of chronic lymphocytic leukemia. Its chemical name is (S)-2-{8-amino-1-[4-(2-pyridylcarbamoyl)phenyl]imidazo[1,5-a]pyrazin-3-yl}-1 -(2-butynoyl)pyrrolidine, its chemical structural formula is: [0003] [0004] Acalabrutinib has been granted orphan drug qualification by the European Food and Drug Administration, and has received three orphan drug indications in a row, targeting chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL) and lymphoma cellular lymphoma. The drug works by permanently binding to BTK, part of a protein that...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 莫国宁查晓明
Owner SUZHOU FUSHILAI PHARMA CO LTD
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