Novel process for preparing flibanserin

A technology of flibanserin and new technology, which is applied in the field of new technology for the preparation of drug flibanserin, and can solve the problems of difficult industrialization, unsimplified and cumbersome reaction process, etc.

Inactive Publication Date: 2017-09-26
葵花药业集团北京药物研究院有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] This route uses m-aminotrifluorotoluene as a raw material, adopts the method of post-synthesizing imidazolone, and synthesizes flibanserin through four steps. This route uses very toxic amino a

Method used

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  • Novel process for preparing flibanserin
  • Novel process for preparing flibanserin
  • Novel process for preparing flibanserin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Preparation of Intermediate 1

[0032] Add 1-benzyl-2-benzimidazolone (10 g, 0.044 mol) into 50 mL of dehydrated DMF, cool in an ice bath to 10 ° C, control the temperature below 20 ° C and slowly add 2 g (60%) of sodium hydride, add Stir at room temperature for 3 hours, cool to below 5°C and add 1,2-dibromoethane (16.5 g, 0.088 mol) dropwise, return to room temperature and stir for 3 hours, then pour the reaction solution into ice water and extract with dichloromethane. The extract was washed with water, dried, filtered and evaporated to dryness to obtain 10.8 g of the product with a yield of 73%.

Embodiment 2

[0034] Preparation of Intermediate 1

[0035] Add 1-benzyl-2-benzimidazolone (10g, 0.044mol) into 50mL of DMF, cool in an ice bath to 10°C, control the temperature below 20°C and slowly add 5g of potassium hydroxide, and stir at room temperature for 3 Hours later, 1,2-dibromoethane (16.5 g, 0.088 mol) was added dropwise and stirred at room temperature for 3 hours. The reaction solution was poured into ice water, extracted with dichloromethane, the extract was washed with water, dried, filtered and evaporated to dryness to obtain Product 8.9g, yield 60%.

Embodiment 3

[0037] Synthesis of Intermediate 2

[0038] Intermediate 1 (30g, 0.0905mol) and 1-(3-trifluoromethylphenyl)piperazine salt (24.1g, 0.0905mol) were added to 200mL acetone, stirred at room temperature for 15 minutes, and 20g of potassium hydroxide was added Raise the temperature to reflux, react for 12 hours, cool down to room temperature, put the reaction solution into 1L of water, add 300mL of dichloromethane to extract twice, combine the organic layers, dry over sodium sulfate, filter, evaporate the filtrate to dryness, add 300mL of methanol and water mixture, Stir at room temperature for 3 hours, filter with suction, and dry the product at room temperature to obtain 27.9 g of the product with a yield of 64%.

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Abstract

The invention discloses a novel process for preparing flibanserin. The process comprises the following steps: taking 1-benzyl or substituted benyl-2-benzimidazolone as a raw materials; reacting the raw material with 1,2-dibromoethane to generate an intermediate 1; reacting the intermediate 1 with 1-(3-trifluoromethyl-phenyl) piperazine salt to generate an intermediate 2; and adding hydrogen into the intermediate 2 to remove a protecting group in the presence of a catalyst to obtain the flibanserin. Raw materials in the method are low in price and are easily obtained, an operation method is simple, the reaction conditions are gentle, and the novel process for preparing the flibanserin has potential industrial value.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a new preparation process of flibanserin, a medicine for improving female libido. Background technique [0002] Flibanserin, a drug used to increase libido in women, reduces libido-inhibiting serotonin to increase libido-stimulating dopamine levels. The drug was first developed by Boehringer Ingelheim in Germany and later transferred to Sprout of the United States. On August 18, 2015, Addyi (flibanserin) of Sprout was approved by the FDA. Drugs for sexual desire disorders in women. [0003] In the published literature at present, the synthetic method of flibanserin mainly contains following three kinds [0004] Method 1: The representative patent WO199303016 is the earliest method to synthesize flibanserin. The synthetic route is as follows [0005] [0006] This route takes 1-benzyl-2-benzimidazolone as raw material, first reacts with 1,2-dichloroethane to ge...

Claims

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Application Information

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IPC IPC(8): C07D235/26
CPCC07D235/26Y02P20/55
Inventor 闫启强曲韵智彭晓云付宏伟
Owner 葵花药业集团北京药物研究院有限公司
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