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Enzymatic synthesis method of bimatoprost intermediate

A technology of bimatoprost and synthetic method, which is applied in the field of biopharmaceuticals, can solve the problems of unfriendly environment and low chiral purity, and achieve the effects of simple and convenient operation, high optical purity and high yield

Active Publication Date: 2021-03-12
JIANGSU ALPHA PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] The more synthetic routes reported by bimatoprost mainly include the following steps, for example, the synthetic route disclosed in US2005209337, wherein the carbonyl chiral reduction is prepared by chemical methods, a large amount of organic solvents are used, it is not friendly to the environment, and the chiral low purity

Method used

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  • Enzymatic synthesis method of bimatoprost intermediate
  • Enzymatic synthesis method of bimatoprost intermediate
  • Enzymatic synthesis method of bimatoprost intermediate

Examples

Experimental program
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Embodiment 1

[0035] In the reaction flask, add oxalyl chloride (8.0ml, 0.08mol) and dichloromethane (160ml) sequentially under nitrogen protection, cool to -75~-65°C, add DMSO (16.0ml, 0.22mol) dropwise, and keep the temperature at -75 After stirring for 1 h at ~-65°C, slowly add compound V (16.0 g, 58 mmol) in dichloromethane solution (140 ml) dropwise. After continuing to stir for 1 h, slowly add triethylamine (40 ml) dropwise, and heat up to -50 React at ℃ for 2 hours, monitor until the reaction of the raw materials is complete, quench the reaction with 10% sodium dihydrogen phosphate aqueous solution (200ml), separate the liquids after stirring, wash the organic phase with saturated sodium chloride solution (100ml×3), and wash with anhydrous sulfuric acid After sodium drying and filtration, the dichloromethane solution of compound VI was obtained for future use (among them, the purity of compound VI was 98.5%, the yield was 92.7%, and it is used now).

Embodiment 2

[0037] In the reaction flask, lithium chloride (8.6g, 0.25mol), (2-oxo-4-phenylbutyl) dimethyl phosphate (24.0g, 0.094mol) and acetonitrile (170ml) were added successively under nitrogen protection. , cooled to -10~0°C, DIPEA (25ml, 0.14mol) was added dropwise, and after stirring evenly, the dichloromethane solution (500ml, 0.09 mol), add in about 0.5h, react for about 2-3h, monitor until the reaction is complete, wash with saturated sodium chloride solution (160ml×3), filter after drying with anhydrous sodium sulfate, spin the filtrate to get a light yellow solid , adding petroleum ether (30ml), beating and filtering to obtain white powder compound III (23.5g, purity 94.8%, yield 95.2%).

Embodiment 3

[0039]Add compound III (20.8g, 51.2mmol) and methanol (200ml) in turn to the reaction flask. After stirring and dissolving, add potassium carbonate powder (6.4g, 44.8mmol), control the temperature at 20-25°C, and react for about 3.5h , monitor until the reaction is complete. Add 1mol / L hydrochloric acid (about 75ml) to the obtained reaction solution to adjust the pH of the mixed solution to 6, then add water (120ml), extract with methyl tert-butyl ether (320ml×4), combine the organic phases, add methanesulfonate Acid (960l) was stirred for 45min, washed successively with saturated sodium bicarbonate solution (320ml×2) and saturated sodium chloride solution (320ml), dried over anhydrous sodium sulfate and filtered, and the filtrate was evaporated to dryness under reduced pressure to obtain a colorless oil compound II (16.5 g, 98.5% purity, 96.4% yield).

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Abstract

The invention relates to an enzymatic synthesis method of a bimatoprost intermediate, which comprises the following steps: (1) cooling a mixed solution of oxalyl chloride and dichloromethane to -75 to-65 DEG C, adding dimethyl sulfoxide and a compound V, reacting for 1.5-3 hours, adding triethylamine, heating the solution to -55 to -45 DEG C, and reacting to prepare a compound IV; (2) dissolvingdimethyl (2-oxo-4-phenyl-butyl) phosphate and lithium chloride in acetonitrile, cooling the mixture to -10 to 0 DEG C, and adding N,N-diisopropylethylamine and the compound IV for chemical reaction toprepare a compound III; (3) carrying out chemical reaction on the compound III and potassium carbonate at 20-25 DEG C to prepare a compound II; and (4) with the compound II as a substrate, carrying out a biological catalytic reaction in the presence of ketocarbonyl reductase acetone powder to generate a compound I. The specific synthesis route is as follows: the compound I is shown in the specification.

Description

technical field [0001] The invention belongs to the technical field of biopharmaceuticals, and relates to a biocatalytic synthesis method of a bimatoprost intermediate. Background technique [0002] Bimatoprost (bimatoprost) is a prostaglandin fatty acid amide analogue developed by Allergan Company. It was approved by the FDA in 2001 for the treatment of glaucoma, and has good intraocular pressure-lowering effect and safety. Later, it was verified that it also has the effect of growing eyelashes and treating male baldness. It was approved by the FDA in 2008 to grow eyelashes. [0003] The more synthetic routes reported by bimatoprost mainly include the following steps, for example, the synthetic route disclosed in US2005209337, wherein the carbonyl chiral reduction is prepared by chemical methods, a large amount of organic solvents are used, it is not friendly to the environment, and the chiral Low purity. [0004] Contents of the invention [0005] The purpose of the...

Claims

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Application Information

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IPC IPC(8): C12P7/22
CPCC12P7/22Y02P20/55
Inventor 陈本顺石利平叶金星徐春涛张维冰李大伟程瑞华郭炳华钱若灿何义何伟
Owner JIANGSU ALPHA PHARM CO LTD
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