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Method for large-scale preparation of tafluprost

A tafluprost and fluorination technology, which is applied in the field of large-scale preparation of tafluprost, can solve the problems of many side effects, etc., and achieve the effect of reducing the generation of impurities and timely and reasonable quenching

Pending Publication Date: 2021-01-12
ZHEJIANG JIANFENG PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Because tafluprost is a highly active compound, the impurity may be a highly active compound, and even the activity is many times higher than that of tafluprost. If the purity is not enough, there will be many side effects

Method used

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  • Method for large-scale preparation of tafluprost

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0020] 1. Oxidation reaction: Add 109.4g of trichloroacetonitrileuric acid (TCCA), 1.3L of dimethyl carbonate and 325mL of ethyl acetate into the reaction flask, stir and cool down to between 0°C and 5°C. Add tetramethylpiperidine nitrogen oxide (TEMPO0.74g) into the system, and then add corylactone. After reacting for 1.5 hours, the reaction solution was added to the suspension of sodium thiosulfate pentahydrate, dipotassium hydrogen phosphate trihydrate and water to quench the reaction, filter with suction, wash the filter cake with dimethyl carbonate, and let the filtrate stand The layers were separated, and the organic phase was dried by adding anhydrous sodium sulfate and stirring. The filtrate was concentrated to dryness under reduced pressure to obtain 117.3 g of intermediate III.

[0021] 2. Condensation reaction 1: Add 17.57g of sodium hydride and 1.76L of tetrahydrofuran into the reaction bottle, start stirring, cool down to -5°C to 0°C, and drop 103.1g of 2-carbony...

example 2

[0032] Refined Purification:

[0033] Reverse-phase column chromatography: use a dynamic axial compression column to The pore diameter of carbon octadeca is used as filler, and the mobile phase is acetonitrile-ammonium acetate-water solution (10:1:10). Dissolve 42 grams of tafluprost crude product, pass through the column, collect relevant effluents, and concentrate to dryness under reduced pressure.

[0034] Normal-phase column chromatography: The mobile phase was dissolved in n-hexane-isopropanol (8:2), and passed through a COSMOSILCHIRAL 5C 20ID×250mm column. The relevant effluent was collected and concentrated to dryness under reduced pressure. 35.28 g was obtained, and the content of tafluprost detected by HPLC was 99.9%. Impurity A: 0.021%, impurities B, C, D, F, G not detected, unknown maximum single impurity 0.065%, total impurity: 0.086%

example 3

[0036] Refined Purification:

[0037] Reverse-phase column chromatography: use a dynamic axial compression column to The pore diameter of carbon octadeca is used as a filler, and the mobile phase is acetonitrile-ammonium acetate-water solution (10:1:10). Dissolve 35 grams of tafluprost crude product, pass through the column, collect relevant effluents, and concentrate to dryness under reduced pressure.

[0038] Normal-phase column chromatography: The mobile phase was dissolved in n-hexane-isopropanol (8:2), and passed through a COSMOSILCHIRAL 5C 20ID×250mm column. The relevant effluent was collected and concentrated to dryness under reduced pressure. 24.71 g was obtained, and the content of tafluprost detected by HPLC was 99.9%. Impurity A: 0.020%, impurities B, C, D, F, G not detected, unknown maximum single impurity 0.062%, total impurity: 0.082%

[0039] Chemical name of each impurity:

[0040] Impurity A: (5E)-7-[(1R,2R,3R,5S)-2-[(1E)-3,3-difluoro-4-phenoxy-1-buten-1-y...

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Abstract

The invention discloses a method for industrially preparing tafluprost. The method comprises the following steps: taking Corey lactone as an initial raw material, oxidizing, condensing, fluorinating,deprotecting, reducing, re-condensing, esterifying and refining to obtain the tafluprost, according to the method for large-scale preparation of the tafluprost provided by the invention, a reversed-phase and normal-phase preparative column purification technology is used, a molecular group evacuation technology is adopted, and a molecular group'evacuation agent 'is added into a mobile phase, so that a relatively good effect is achieved, in addition, a trichloroacetonitrile uric acid(TCCA)reagent is adopted in an oxidation method, and the yield of the tafluprost is improved. The use of variousreaction quenching agents is also the characteristic of the method, and the timely and reasonable quenching of the reaction has certain significance for reducing the generation of impurities.

Description

technical field [0001] The invention relates to a method for large-scale preparation of tafluprost, which belongs to the technical field of chemical drug preparation. Background technique [0002] Tafluprost, the chemical name is (5Z)-7-[(1R,2R,3R,5S).2-[(1E)-3,3-difluoro-4-phenoxy-1-butene- 1-yl]-3,5-dihydroxycyclopentyl]-5-heptenoic acid isopropyl ester, a novel PGF2 derivative, as a selective PG receptor agonist for the reduction of open-angle glaucoma Or elevated intraocular pressure in patients with ocular hypertension, with high safety and small adverse reactions, it is the latest generation of anti-glaucoma prostaglandin drugs. The drug is a preservative-free eye drop jointly developed and marketed by Asahi Glass Co., Ltd. and Santen Pharmaceutical Co., Ltd., and was approved for marketing in Denmark and Germany on June 30, 2008. [0003] The synthesis method of tafluprost mainly uses corylide as the starting material, and synthesizes the target compound through oxi...

Claims

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Application Information

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IPC IPC(8): C07C405/00
CPCC07C405/00C07D307/935C07C2601/08
Inventor 蒋晓萌黄金龙庞雄宗悦喜施存元林军倪乐平徐春柳
Owner ZHEJIANG JIANFENG PHARM CO LTD
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