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Preparation method of enclomiphene

A technology of enclomiphene and mixed solvent is applied in the field of preparation of enclomid, can solve the problems of unsuitability for industrial production, complicated operation process, low splitting efficiency, etc., achieves good industrial application prospect, simple operation, easy operation and the like. The effect of recycling

Inactive Publication Date: 2017-08-11
SHANGHAI DUDE MEDICAL SCI & TECH CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] (2) E.M.Dolginova, G.M.Kadatskii and others in the synthesis and biological study of the cis-and trans-isomers of clomiphene citrate and some intermediates of its synthesis. In the article, the method of physical crystallization was used to obtain relatively high purity (98% ) trans-isomer enclomid, but this method has low resolution efficiency, long resolution time and repeated resolution many times, complicated operation process, and is not suitable for industrial production

Method used

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  • Preparation method of enclomiphene

Examples

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Embodiment 1

[0056] Embodiment 1: the preparation of Clomiphene cis-trans isomer mixture

[0057]

[0058] N,N-diethyl-2-[4-(1,2-diphenylethenyl)phenoxy]ethylamine hydrochloride (59.8g, content 92%) was dissolved in 730mL of dichloromethane, After adding 20.35 g of N-chlorosuccinimide at one time, it was heated to reflux and reacted in the dark for 6 hours. HPLC monitors that the reaction of raw materials is complete. In HPLC, the cis peak area ratio is 24.50%, and the trans peak area ratio is 61.26%. The reaction solution is washed twice with 436 ml of excess 2% sodium hydroxide aqueous solution, washed with water, washed with saturated saline, and dried. After concentration, 50.0 g of a mixture of cis and trans isomers of clomiphene was obtained, with a purity of 85.76% and a crude yield of 78.2%.

Embodiment 2

[0059] Embodiment 2: Preparation of cis-trans isomer mixture of clomiphene citrate

[0060] Dissolve 25.0 g of the cis-trans isomer mixture of clomiphene obtained in Example 1 in 25 mL of absolute ethanol, add 12.18 g of anhydrous citric acid, heat up to reflux reaction for 5 minutes after the addition, and cool down naturally until the room temperature is 20°C No solid precipitated, continued to stir for half an hour after cooling in an ice bath, precipitated a white viscous solid, added 50 mL of tert-butyl methyl ether to dilute, continued to stir in an ice bath for half an hour, filtered, washed the solid with a small amount of tert-butyl methyl ether, and dried to obtain clomiphene citrate Salt 30.8g, yield 97.53%.

Embodiment 3

[0061] Embodiment 3: the preparation of clomiphene malonate cis-trans isomer mixture

[0062] With reference to the method of Example 2, 12.6 g of the corresponding cis-trans isomer mixture of clomiphene malonate was prepared, with a yield of 93.7%.

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Abstract

The invention relates to a preparation method of enclomiphene. The preparation method comprises steps as follows: (1) clomiphene or salt thereof and racemic 1,1'-binaphthyl-2,2'-diyl hydrogenphosphate are subjected to a reaction in alcohol solvents containing ether solvents, and an enclomiphene and 1,1'-binaphthyl-2,2'-diyl hydrogenphosphate compound in a solid form is obtained; (2) the enclomiphene and 1,1'-binaphthyl-2,2'-diyl hydrogenphosphate compound in a solid form is subjected to a free reaction, and enclomiphene is prepared. With the alcohol solvents containing the ether solvents as splitting solvents, enclomiphene and the splitting solvents can form a solid compound which is directly separated out from the splitting solvents, the flowability of a reaction system is improved, and the enclomiphene preparation method with better industrial application prospects is provided, and by means of the preparation method, the splitting yield is high, the purity of a split product is high, the cost is low and environmental pollution is low.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a preparation method of enclomid. Background technique [0002] Clomiphene is a selective estrogen receptor modulator similar in structure to tamoxifen, which binds to estrogen receptors and blocks normal estrogen feedback on the hypothalamus and subsequent negative feedback on the pituitary, Causes an increase in luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Clomid can be used to treat anovulatory female infertility, and it is suitable for those who have a certain level of estrogen in the body. Clomiphene for medicinal use is a mixture of two geometric isomers, including the cis isomer (Zuclomiphene) and the trans isomer (enclomiphene), in which the cis Isomers account for about 30%-50%. [0003] [0004] Ernst et al., J.Pharmaceut.Sci.65:148 (1976) have demonstrated that the trans isomer of clomiphene is antiestrogenic (AE), while the cis isome...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C213/10C07C217/20
CPCC07C213/10C07C217/20
Inventor 柴民军孔锐苏彩娟袁哲东刘学民张爱明张喜全
Owner SHANGHAI DUDE MEDICAL SCI & TECH CO LTD
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