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Method for preparing travoprost intermediate

A technology of trifluoromethyl phenoxy and dimethyl methyl phosphate, which is applied in the field of preparation of travoprost intermediates, can solve the problems of difficulty in realizing industrial scale-up production, harsh reaction conditions and the like, and achieves easy post-processing, Simple operation, simple process effect

Active Publication Date: 2011-01-19
湖北远大天天明制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The reaction conditions of this method are harsh, and the reaction temperature is required to be between -60 and -55°C. After-treatment, high-vacuum fractional distillation must be carried out first, and then purified by silica gel chromatography column, which is difficult to realize industrial scale-up production.

Method used

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  • Method for preparing travoprost intermediate

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Experimental program
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Effect test

Embodiment 1

[0016] Add 12.5 g (0.1 mol) of dimethyl methyl phosphate, 200 ml of tetrahydrofuran and 25 g (0.1 mol) of ethyl (3-trifluoromethylphenoxy) acetate into a three-necked flask, and drop the temperature to -10°C Lithium diisopropylamide 16.1 g (0.15 mol), kept at -15 to -5 ° C for 5 hours, no raw material spots were detected by thin plate chromatography (developing agent ethyl acetate / petroleum ether = 1: 1), added dropwise 6 grams of acetic acid, raised to room temperature, concentrated to remove tetrahydrofuran, dissolved in water, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated and then distilled under reduced pressure (pressure 10Kp) to obtain 26.3 grams of the target product as a colorless to pale yellow oil The yield is 80%, and the purity is 98.06% (high performance liquid phase).

Embodiment 2

[0018] Add 17.4 g (0.14 mol) of dimethyl methyl phosphate, 250 ml of tetrahydrofuran and 25 g (0.1 mol) of ethyl (3-trifluoromethylphenoxy) acetate into a three-necked flask, cool down to -10°C and add dropwise Lithium diisopropylamide 22.5 grams (0.21 mole), keep-10~0 ℃ of reaction 2.5 hours, follow up and aftertreatment the same as embodiment 1 and obtain product 26.7 grams, yield 81%, purity 98.25% (HPLC ).

Embodiment 3

[0020] Add 31 grams (0.25 moles) of dimethyl methyl phosphate, 300 milliliters of tetrahydrofuran and 25 grams (0.1 moles) of ethyl (3-trifluoromethylphenoxy) acetate into a three-necked flask, drop the temperature to -10°C and add Lithium diisopropylamide 43 grams (0.40 mole), keep-10~-5 ℃ of reaction 4 hours, follow up and aftertreatment the same as embodiment 1 and obtain product 28.3 grams, yield 86%, purity 98.41% (high efficiency liquid Mutually).

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Abstract

The invention relates to a method for preparing a travoprost intermediate, which is prepared by performing a reaction of dimethyl methyl phosphonate, (3-trifluoromethyl phenoxyl) ethyl acetate and lithium diisopropylamide in an organic solvent. The method for preparing the travoprost intermediate has the advantages of simple process, mild reaction conditions, high yield and suitability for industrialized production.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a preparation method of a travoprost intermediate. Background technique [0002] Travoprost (Travoprost) is a PG drug approved by the US FDA in September 2006 for the treatment of primary open-angle glaucoma and ocular hypertension. 3-(3-trifluoromethylphenoxy)-2-oxopropyl phosphate dimethyl ester is a key intermediate for the preparation of travoprost. [0003] In the prior art, US3953435 discloses a method for preparing 3-(3-trifluoromethylphenoxy)-2-oxopropyl dimethyl phosphate, (3-trifluoromethylphenoxy)acetic acid Ethyl ester was reacted with dimethyl methyl phosphate in tetrahydrofuran / n-butyl lithium / n-hexane, and the yield was 67%. The reaction conditions of this method are harsh, and the reaction temperature is required to be between -60 and -55°C. After-treatment, high-vacuum fractional distillation must be carried out first, and then purified by silica gel c...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/40
Inventor 朱毅高永智周峰黄璐
Owner 湖北远大天天明制药有限公司
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