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Preparation method of flibanserin

A technology of flibanserin and trifluoromethyl phenyl is applied in the field of organic synthesis route design and the preparation of raw materials and intermediates, and can solve the problems of difficulty in obtaining raw materials of the synthesis route, high control and cost, and many reaction steps. , to achieve the effect of fast and convenient preparation process, high product yield and high product purity

Active Publication Date: 2015-09-23
SUZHOU LIXIN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] Analyzing the above two synthetic routes and preparation methods, although the second part solves the problem of the source of piperazine derivatives, the problem of the source of benzimidazolone and the coexistence of multiple active reaction sites still exist, making the whole synthetic route There are still disadvantages such as difficult to obtain raw materials, many reaction steps, difficult to control side reactions and high cost.

Method used

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  • Preparation method of flibanserin
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  • Preparation method of flibanserin

Examples

Experimental program
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Effect test

Embodiment 1

[0034] Add m-aminobenzotrifluoride (8.5g, 50mmol), tris(2-chloroethyl)amine (12.2g, 60mmol), potassium carbonate (6.9g, 50mmol) and 150mL of n-butanol in the reaction flask, and heat up to 115- 120° C., stirred for 24 hours, and TLC detected that the reaction was complete. The reaction solution was concentrated, dissolved in dichloromethane, washed twice with water, the organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Obtained 6.7 g of yellow-green oil N-(3-trifluoromethylphenyl)-N'-(2-chloroethyl)-piperazine (II), yield 45.9%, EI-MS m / z: 293 [M+H] + .

Embodiment 2

[0036] After stirring and dissolving m-aminobenzobenzotrifluoride (8.5g, 50mmol), tris(2-bromoethyl)amine (33.4g, 100mmol) and ether 50mL, pour it into a solid phase reactor equipped with 100g of basic alumina , after stirring evenly, remove the solvent by bubbling with nitrogen gas, seal it, raise the temperature to 145-150°C, and stir for 1-2 hours to react. After cooling, the resulting mixture was washed successively with 200 mL of a 5% sodium methoxide / methanol solution and 200 mL of dichloromethane. The solutions were combined and concentrated to obtain 13.2 g of light brown viscous liquid N-(3-trifluoromethylphenyl)-N'-(2-bromoethyl)-piperazine (II), yield 78.6%, EI -MS m / z: 337[M+H] + .

Embodiment 3

[0038] Add N-(3-trifluoromethylphenyl)-N'-(2-bromoethyl)-piperazine (II) (6.7g, 20mmol), o-nitroaniline (2.8g, 20mmol) into the reaction flask ), cuprous iodide (0.38g, 2mmol), diisopropylethylamine (0.52g, 4mmol) and N,N-dimethylformamide 50mL, heated to 100-110°C under stirring, and reacted for 5 hours, TLC detects that the reaction is complete. Cool down to 50-60°C, filter, and wash the filter cake with ethyl acetate. The filtrate was washed with brine and water, concentrated, and recrystallized from ethyl acetate and n-hexane (1:1) to obtain a yellow solid N-(3-trifluoromethylphenyl)-N'-[2-(N-(2 -Nitrophenyl)amino)ethyl]-piperazine (III) 6.4 g, yield 81.2%. EI-MS m / z: 395[M+H] + , δ3.04-3.87 (m, 8H), 3.90-4.06 (m, 4H), 5.42 (brs, 1H), 6.73-7.78 (m, 8H).

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Abstract

The invention discloses a preparation method of flibanserin. The preparation method uses trifluoromethylbenzene, triamine (2-halogen ethyl) and ortho-nitroaniline which are easy to obtain as raw materials and adopts classical elementary reactions such as cyclization, substitution, reduction and condensation, so that the flibanserin is prepared. The raw materials of the preparation method are easy to obtain, the technology is succinct, the yield is high, the preparation method is economical and environment-friendly, and a new preparation way is provided for the industrial production of the flibanserin.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis route design and preparation of raw materials and intermediates, and particularly relates to a preparation method of flibanserin, a drug that can reduce 5-hydroxytryptamine that inhibits libido and improves female libido. Background technique [0002] Flibanserin (Flibanserin) is funded by Boehringer Ingelheim (Boehringer Ingelheim) of Germany, a joint research of the University of North Carolina, the University of Virginia, the Women's Health Center of the Ottawa Hospital in Canada and the University of Pavia in Italy. Drugs to increase libido in women. The drug completed Phase III clinical trials in November 2009 and submitted a new drug application. However, Boehringer Ingelheim terminated the research and development of the project in October 2010 based on the feedback of follow-up routine research results. In December 2013, Spour Pharmaceuticals appealed to the U.S. Food and Drug ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D235/26
CPCC07D235/26
Inventor 许学农
Owner SUZHOU LIXIN PHARMA
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