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Preparation method of flibaserin intermediate

A flibanserin and intermediate technology, which is applied in the field of preparation of flibanserin intermediates, can solve the problems of many side reactions, low reaction selectivity, high irritation and the like, and achieves improved reaction selectivity and product yield High, easy-to-use effects

Inactive Publication Date: 2017-06-20
广州隽沐生物科技股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

1-Bromo-2-chloroethane has low reaction selectivity, many side reactions, and complex post-treatment
1-bromo-2-chloroethane is a highly toxic reagent, and chloroacetyl chloride used in another method is also a highly toxic, highly irritating corrosive solvent, these reagents are not environmentally friendly, and are not conducive to industrialization Production

Method used

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  • Preparation method of flibaserin intermediate
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  • Preparation method of flibaserin intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Preparation of 2-(4-(3-trifluoromethylphenyl)piperazine-1-ethanol

[0027] (1) Add 1-(3-trifluoromethylphenyl)piperazine hydrochloride (35.0g, 0.131mol), NaOH (13.1g, 0.328mol) and 280ml of ethanol into a 250ml reaction flask, and stir;

[0028] (2) Add 2-bromoethanol (32.8g, 0.26mol), heat to reflux, and monitor the end point of the reaction with thin-layer chromatography;

[0029] (3) Filter the reactant, wash the filter residue with 100ml ethanol, combine the eluate and the filtrate, concentrate under reduced pressure, add water to the concentrated gain, and add NaOH to adjust the pH to be greater than 11, and stir;

[0030] (4) Extract with dichloromethane (150ml*2), extract twice, combine the organic layers, wash with saline (200ml*2), and then dry with anhydrous sodium sulfate;

[0031] (5) Filtration, concentration under reduced pressure to obtain 34.6 g of yellow oily substance 2-(4-(3-trifluoromethylphenyl)piperazine-1-ethanol, the yield reached 96% after dete...

Embodiment 2～16

[0033] The amount of each raw material in Examples 2 to 16, the process parameters of the preparation process and the 2-(4-(3-trifluoromethylphenyl)piperazine-1-ethanol output and yield are as shown in Table 1:

[0034] Table 1

[0035]

Embodiment 17

[0037] Preparation of Intermediate II

[0038] (1) Add 2-(4-(3-trifluoromethylphenyl)piperazine-1-ethanol (33.0g, 0.12mol), DCM (330ml) into a 500ml reaction flask, stir, and cool in an ice-water bath. This patent The DCM used in is dichloromethane;

[0039] (2) DCM solution (30ml) of thionyl chloride (57.0g, 0.479mol) was added dropwise, and the temperature was raised to reflux for 2h after the addition;

[0040] (3) Concentrate under reduced pressure after the reaction is completed, add ethanol to the concentrated product for recrystallization, and obtain 38.0 g of white solid powder, and the yield of intermediate II reaches 96% after detection.

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Abstract

The invention discloses a method belonging to the field of heterocyclic compounds, and concretely relates to a preparation method of a flibaserin intermediate. The preparation method comprises the following steps of (1) dissolving 1-(3-trifluoromethylphenyl) piperazine hydrochloride in a solvent a, and reacting with 2-halogenated ethanol or ethylene oxide in the presence of alkali to obtain 2-(4-(3-trifluoromethylphenyl) piperazine-1-ethanol; (2) reacting the 2-(4-(3-trifluoromethylphenyl) piperazine-1-ethanol with a chloride agent compound to obtain a compound as shown in a formula I. According to the preparation method, the reaction selectivity is improved, the generation of impurities is reduced, the product purity is improved, and the preparation method is simple and convenient to operate, environmentally-friendly, and beneficial for industrialized mass production.

Description

technical field [0001] The invention belongs to the field of heterocyclic compounds, and in particular relates to a preparation method of a flibanserin intermediate. Background technique [0002] Flibanserin, a 5-HT1α agonist and 5-HT2α antagonist, was studied as an antidepressant in the early days. In August 2015, flibanserin tablets developed by Sprout Approved by the FDA for the treatment of sexual desire disorder in premenopausal women, it is the first chemical drug to be marketed in the world for the treatment of female sexual desire disorder. [0003] The chemical name of flibanserin is: 1-[2-(4-(3-trifluoromethyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzo Imidazol-2-one, disclosed in European Patent Application EP0526434 as the hydrochloride salt, has the following chemical structure: [0004] [0005] There are few reports about the synthetic route and preparation method of flibanserin. European patent EP1414816 discloses a method for preparing flibans...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D295/073
CPCC07D295/073
Inventor 邹小燕蔡云峰李秋丽张荷明
Owner 广州隽沐生物科技股份有限公司
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