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Method for purifying bimatoprost

A bimetrexed and purification method technology, applied in the field of preparing high-purity bimetrexed, can solve the problems of high cost, unfavorable production scale-up, complicated operation and the like, achieves mild conditions, simple and convenient operation, and overcomes the complicated process of removing impurities Effect

Active Publication Date: 2018-05-29
YAOPHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Removing the 5,6-trans isomer by preparative chromatography not only has low purification efficiency and high cost, but also requires the addition of special equipment for production, which is not conducive to production scale-up
[0009] CN104370786 provides a method of forming a prostaglandin compound into a macrolide and then removing the 5,6-trans isomer, although this method can reduce the 5,6-trans isomer to no detection, But the involved esterification of this method, multiple operation steps such as hydrolysis, recrystallization, amination, column chromatography, deprotection, operation are more loaded down with trivial details, and the total yield is counted by compound V, to bimatoprost finished product, only has About 33.5%
[0010] Considering that the generation of 5,6-trans isomer in the process of preparing bimatoprost is inevitable, and the existing technology has limited ability to remove it, and the cost is relatively high, therefore, in order to use the drug more safely and reduce production cost, it is necessary to develop a method that can effectively and conveniently remove 5,6-trans isomer impurities and prepare high-purity bimatoprost

Method used

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  • Method for purifying bimatoprost

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Preparation of Crude Bimatoprost

[0032] Compound IV was prepared according to the method described in EP2495235, and compound VII was prepared according to the method described in Org. Lett., 2015, 17(3), pp 504-507.

[0033] Add 37.8g (3.5eq) of compound V to the reaction flask, add 50mL of tetrahydrofuran, stir evenly and cool down to -10°C, dissolve 18g (7eq) of potassium tert-butoxide in 50mL of tetrahydrofuran and add it dropwise to the reaction solution, controlling the temperature not to exceed -10°C, after adding and keeping warm for 30min, dissolve 7g (1eq) of compound VII in 50mL of tetrahydrofuran, add dropwise to the reaction solution, return to room temperature for about 2h after adding, TLC (EA / MeOH=100:5) to monitor the completion of the reaction, go to Add 200mL saturated ammonium chloride solution to the reaction solution, stir to dissolve and separate the liquids, extract the aqueous phase with 200mL ethyl acetate, combine the organic phases, wash wi...

Embodiment 2

[0035] Preparation of tert-butyldimethyl bimatoprost

[0036] Dissolve 9g (1eq) of crude bimatoprost in 90mL of dichloromethane, add 13.0g (4eq) of TBSCl, 6.6g (4.5eq) of imidazole, stir and react overnight, add 90mL of saturated ammonium chloride solution to the reaction solution, divide liquid, the organic phase was washed with 90mL saturated brine, dried with 50g of anhydrous sodium sulfate, and then concentrated to obtain about 18g of a yellow oil, which was chromatographed on a 500g 200-300 mesh silica gel column, eluent (n-heptane / ethyl acetate = 12:1) to obtain 15 g of tert-butyldimethyl bimatoprost, which was detected by HPLC with a purity of 99.92%, a yield of 91.5%, and a 5,6-trans isomer impurity content of 0.05%.

Embodiment 3

[0038] Preparation of tert-butyldiphenyl bimatoprost

[0039] Dissolve 9g (1eq) crude bimatoprost in 90mL dichloromethane, add 23.8g (4eq) TBDPSCl, 6.6g (4.5eq) imidazole, stir and react overnight, add 90mL saturated ammonium chloride solution to the reaction solution, divide liquid, the organic phase was washed with 90mL saturated brine, dried with 50g of anhydrous sodium sulfate, and then concentrated to obtain about 30g of a yellow oil, which was chromatographed on a 600g 200-300 mesh silica gel column, eluent (n-heptane / ethyl acetate=12 :1), to obtain 23 g of tert-butyldiphenyl bimatoprost, yield: 94.3%, HPLC detection, purity 99.91%, 5,6-trans isomer impurity content 0.04%.

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Abstract

The invention provides a method for removing 5,6-trans isomer impurities from crude bimatoprost. Through derivation and column chromatography of the crude bimatoprost, the 5,6-trans isomer impuritiesare removed; then through dissociation, high-purity bimatoprost is obtained; the high-purity bimatoprost can be further recrystallized.

Description

technical field [0001] The invention relates to a purification method of bimatoprost, which is used for preparing high-purity bimatoprost. Background technique [0002] Bimatoprost (Bimatoprost) is a prostaglandin analog, which is clinically used to reduce intraocular pressure in patients with open-angle glaucoma or ocular hypertension; Bimatoprost has the effect of promoting eyelash growth and is used to promote The growth of eyelashes in patients with rare eyelashes; bimatoprost also has the effect of activating prostaglandin F2a receptors in hair follicles and promoting hair growth. This mechanism of action is expected to be curative in the field of male baldness. The chemical name of bimatoprost is (Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(1E,3S)-3-hydroxy-5-phenyl-1 -pentenyl]cyclopentyl]-5-N-ethylheptenamide, the chemical structural formula is as follows: [0003] [0004] WO1996010407, WO2002096898, EP1886992, US20090163596, Org. Lett., 2015, 17(3), pp 504-507 and o...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C405/00
CPCC07C405/0041
Inventor 陈英杰刘念冉海琳吴佳
Owner YAOPHARMA CO LTD
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