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Clomiphene synthesis using a single solvent

A technology of organic solvents and solutions, which is applied in the preparation of organic compounds, aminohydroxy compounds, carboxylates, etc., and can solve problems such as difficult assembly lines

Inactive Publication Date: 2016-11-02
REPROS THERAPEUTICS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The current method used to prepare clomiphene requires isolation of intermediates and solvent changes, making the method difficult to streamline

Method used

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  • Clomiphene synthesis using a single solvent
  • Clomiphene synthesis using a single solvent
  • Clomiphene synthesis using a single solvent

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0025] by 1 -{4-[2-(Diethylamino)ethoxy]phenyl}-1,2-diphenylethanol Preparation of trans-clomiphene citrate

[0026] dehydration

[0027] 1-{4-[2-(Diethylamino)ethoxy]phenyl}-1,2-diphenylethanol (6) dissolved in ethanol containing excess hydrochloric acid was refluxed at 50°C for 3 hours. The solvent and excess hydrochloric acid were removed in vacuo and the residue was dissolved in dichloromethane. 2-{4-[(Z)-1,2-diphenylethenyl]phenoxy}-N,N-diethylethylammonium hydrochloride (7) is obtained.

[0028] Chlorination

[0029] The hydrochloride (7) solution obtained above was treated with 1.05 equivalents of N-chlorosuccinimide and stirred at room temperature for about 20 hours. Reaction completion was confirmed by HPLC. The hydrochloride salt was converted to the free base by addition of saturated aqueous bicarbonate solution. The mixture was stirred at room temperature for 30 minutes, then the phases were separated and the organic phase was evaporated in vacuo. 2-{4-...

example 2

[0034] Synthesis of Clomiphene Using a Single Solvent

[0035] Step 1 - Dehydration of 1-{4-[2-(diethylamino)ethoxy]phenyl}-1,2-diphenylethanol to form sulfuric acid Hydrogen 2-{4-[(Z)-1,2-diphenylvinyl]phenoxy}-N,N-diethylethylammonium (7)

[0036] The synthetic route described in Example 1 used HCl for the dehydration step and ethanol at 50°C as solvent. Due in part to the more favorable corrosion properties of sulfuric acid, sulfuric acid was investigated as an alternative to HCl for the dehydration step (as described in Example 1). Dichloromethane (chlorinated methane) was investigated as an alternative solvent for the dehydration step as this would eliminate the need to remove the ethanol solvent prior to the chlorination step.

[0037] Mix 1-{4-[2-(diethylamino)ethoxy]phenyl}-1,2-diphenylethanol (6) (6.60g, 16.9mmol) and 66mL (1×10 3mmol) of methyl chloride was charged to a 100 mL 3-neck round bottom flask equipped with a temperature probe and a stir bar to give ...

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Abstract

The present invention provides a one-pot method for synthesizing clomiphene (a mixture of the isomers cis-clomiphene and trans-clomiphene) utilizing a single solvent. In a preferred embodiment, the single solvent is dichloromethanc (DCM, also known as methylene chloride). The present invention provides an improved method for synthesizing clomiphene and purifying clomiphene isomers.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of US Provisional Application No. 61 / 951,316, filed March 11, 2014, the contents of which are incorporated herein by reference. technical field [0003] The present invention relates to a process for the synthesis of clomiphene and the purification of the trans isomer of clomiphene. Background technique [0004] Clomid is a selective estrogen receptor modulator related to tamoxifen. Clomiphene is a mixture of two geometric isomers, cis-clomiphene (or zuclomiphene) and trans-clomiphene (or enclomiphene). Clomid is currently approved as a mixture of cis and trans isomers, with the cis isomer present at about 30% to 50% (Merck Manual), for inducing ovulation in anovulatory women . [0005] Methods of synthesizing clomiphene are known in the art. For example, US Patent No. 2,914,563 (the contents of which are incorporated herein by reference) describes the preparation of clomiphene ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/138
CPCC07C213/10C07B2200/09C07C59/265C07C213/08C07C217/18C07C51/412
Inventor J.S.波多尔斯基K.苏
Owner REPROS THERAPEUTICS
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