Synthesis method of larotrectinib intermediate

A synthetic method and intermediate technology, applied in the field of drug synthesis, can solve the problems of difficulty in product purification and difficult removal of triphenylphosphine oxide, and achieve the effects of reduced production costs, easy availability of raw materials, and simple operation

Active Publication Date: 2020-07-10
ANHUI DEXINJIA BIOPHARM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] This route is a brand-new synthetic route, but highly toxic sodium azide is used in the azidation reaction, and sodium azide is explosive at the same time, and triphenylphosphine is used in the Staudinger reaction. The product triphenylphosphine oxide is difficult to remove, which causes great difficulty in the purification of the product

Method used

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  • Synthesis method of larotrectinib intermediate
  • Synthesis method of larotrectinib intermediate
  • Synthesis method of larotrectinib intermediate

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Experimental program
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Effect test

Embodiment 1

[0026] Add 50g of 4-chloro-1-(2,5-difluorophenyl)butan-1-one (1eq) (purchased from Shanghai Haohong Biomedical Technology Co., Ltd.) into a 500mL autoclave, add 200mL of tetrahydrofuran, and pass Add liquid ammonia, maintain the pressure of the reaction system at 0.4 MPa, react at 55°C for 4 hours, cool to room temperature 20-25°C, add 25mL of water under normal pressure, then slowly add formic acid dropwise, adjust the pH to 4.0, and continue stirring at room temperature for 4-5 hours , concentrate the solvent, add water 100mL and 150mL ethyl acetate to extract, separate layers, wash the organic phase with water once, dry, and concentrate to obtain a colorless or light yellow oil, namely 5-(2,5-difluorophenyl)-3, 4-Dihydro-2H-pyrrole (III), the two-step total yield is 93%, and the gas phase purity is 98.5%.

Embodiment 2

[0028] Add 50g of 4-chloro-1-(2,5-difluorophenyl)butan-1-one (1eq) (purchased from Shanghai Haohong Biomedical Technology Co., Ltd.) into a 500mL autoclave, add 250mL of ethanol, and pass Add liquid ammonia, maintain the pressure of the reaction system at 0.5 MPa, react at 60°C for 4 hours, cool to room temperature 20-25°C, add 25mL of water under normal pressure, then slowly add formic acid dropwise, adjust the pH to 3.5, and continue stirring at room temperature for 4-5 hours , concentrate the solvent, add water 100mL and 150mL ethyl acetate to extract, separate layers, wash the organic phase with water once, dry, and concentrate to obtain a colorless or light yellow oil, namely 5-(2,5-difluorophenyl)-3, 4-Dihydro-2H-pyrrole (III), the two-step total yield is 92%, and the gas phase purity is 98.2%.

Embodiment 3

[0030] Add 50g of 4-chloro-1-(2,5-difluorophenyl)butan-1-one (1eq) (purchased from Shanghai Haohong Biomedical Technology Co., Ltd.) into a 500mL autoclave, add 250mL of ethanol, and pass Add liquid ammonia, normal pressure, react at 60°C for 4 hours, and the liquid phase control shows no reaction.

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Abstract

The invention discloses a synthesis method of a larotrectinib intermediate, and belongs to the field of drug synthesis. The method uses 4-chloro-1-(2, 5-difluorophenyl)butane-1-one (I) as the raw material to synthesize 5-(2, 5-difluorophenyl)-3, 4-dihydro-2H-pyrrole (III) through ammonolysis and ring closing one-pot method. The invention provides the synthesis method of the larotrectinib intermediate. The method is controllable in reaction process, easy to operate and high in yield.

Description

technical field [0001] The invention belongs to the field of medicine synthesis, and relates to a synthesis method of an antineoplastic drug larotretinib intermediate 5-(2,5-difluorophenyl)-3,4-dihydro-2H-pyrrole (III). Background technique [0002] Larotrectinib (LOXO-101) trade name is Vitrakvi, and its Chinese name is: Larotrectinib or Larotrectinib. It is an ATP-competitive, oral selective inhibitor for the tropomyosin-related kinase (TRK) family Three subtypes of the receptor (TRKA, B and C) have 50% inhibitory concentrations in the nanomolar range. On November 27, 2018, the FDA accelerated the approval of the pan-cancer targeted drug Vitrakvi (larotrectinib) jointly developed by Bayer and Loxo Oncology for the treatment of adults and children with locally advanced or metastatic solid tumors carrying NTRK gene fusions. [0003] Mechanism of action: It is a tropomyosin receptor kinase (TRK) inhibitor, which can highly specifically inhibit the three proteins of TRKA, TRK...

Claims

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Application Information

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IPC IPC(8): C07D207/20
CPCC07D207/20
Inventor 张启龙汪崇文高令峰王红磊许坤郑庚修
Owner ANHUI DEXINJIA BIOPHARM
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