Supercharge Your Innovation With Domain-Expert AI Agents!

Biological enzyme resolution method for preparing optically pure (S)-5-(4-fluorophenyl)-5-hydroxypentanoate

A technology of methyl hydroxyvalerate and methyl acetoxyvalerate, which is applied in the field of biocatalytic preparation of chiral drug intermediates, can solve problems such as effective utilization and inability to recycle splits, achieve high optical purity, and improve resolution The effect of high efficiency and high yield

Inactive Publication Date: 2012-07-25
重庆惠健生物科技有限公司
View PDF5 Cites 9 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method can obtain the chirally pure target product (ee 99%), but (4S)-4-phenyl-3-[(5R)-5 -(4-Fluorophenyl)-5-acetoxypentanoyl]-1,3-oxazol-2-one During the hydrolysis and oxidation of 5-acetoxy, the mother nucleus is partially hydrolyzed, causing the other half to fail Efficient utilization through loop splitting

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Biological enzyme resolution method for preparing optically pure (S)-5-(4-fluorophenyl)-5-hydroxypentanoate
  • Biological enzyme resolution method for preparing optically pure (S)-5-(4-fluorophenyl)-5-hydroxypentanoate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Example 1 ( RS )-5-(4-fluorophenyl)-5-hydroxypentanoic acid methyl ester preparation

[0026] Add 42g (0.2mol) of p-fluorobenzoylbutyric acid into 400ml of anhydrous methanol, cool in an ice bath to 0°C, slowly add 29ml (0.4mol) of thionyl chloride dropwise, keep the temperature below 10°C during the dropwise addition, and drop After addition, reflux at 50°C for 2-3 hours, distill methanol and thionyl chloride under reduced pressure, dissolve the residue with 150ml ethyl acetate, wash with 150ml saturated sodium bicarbonate and 150ml saturated brine, and dry over anhydrous sodium sulfate , and concentrated to dryness to obtain 40 g of methyl p-fluorobenzoyl butyrate (light yellow solid), with a yield of 89%.

[0027] Add 22.4g (0.1mol) of methyl p-fluorobenzoylbutyrate into 300ml of anhydrous methanol, cool in an ice bath to 0°C, add 3.8g (0.1mol) of sodium borohydride in batches, react at room temperature for 20min, and finish the reaction with 1mol / L dilute hydroch...

Embodiment 2

[0028] Example 2 ( RS )-5-(4-fluorophenyl)-5-hydroxypentanoic acid methyl ester resolution

[0029] Add ( RS )-5-(4-fluorophenyl)-5-hydroxypentanoic acid methyl ester 11.3g (0.05mol), Lipozyme TL IM 5.65g, vinyl acetate 8.6g (0.1mol), methyl tert-butyl ether 60ml, React at 40 °C on a shaking table (160 r / min) for 72 h. After the reaction was completed, the enzyme was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (n-hexane:ethyl acetate=1:1, V / V) to obtain ( S )-5-(4-fluorophenyl)-5-hydroxypentanoic acid methyl ester 5.1g, yield 45%, ee 99%, ( R )-5-(4-fluorophenyl)-5-acetoxyvaleric acid methyl ester 6.16g, yield 46%, ee 99%.

Embodiment 3

[0030] Example 3 ( R )-5-(p-Fluorophenyl)-5-acetoxyvaleric acid methyl ester racemization

[0031] Add 6.16g ( R )-5-(4-fluorophenyl)-5-acetoxypentanoic acid methyl ester (0.023mol), 20ml tetrahydrofuran and 2mol / L sodium hydroxide solution 46ml (0.092mol), react at room temperature for 1h, and use Adjust the pH to 2-3 with 2mol / L hydrochloric acid, extract with ethyl acetate (2×100ml), wash with 100ml saturated brine, dry over anhydrous sodium sulfate, and concentrate to obtain 4.63g ( R )-5-(p-fluorophenyl)-5-hydroxypentanoic acid, yield 95%.

[0032] Add ( R )-5-(4-fluorophenyl)-5-hydroxypentanoic acid 4.63g (0.022mol), 40ml dimethylformamide and 16.8g pyridinium dichromate (0.022mol), react for 3h, add 100ml ethyl acetate ester, the organic layer was washed with 100ml of saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain 3.7g of p-fluorobenzoyl butyric acid, with a yield of 80%.

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

The invention discloses a biological enzyme resolution method for preparing optically pure (S)-5-(4-fluorophenyl)-5-hydroxypentanoate. The method uses fluorobenzoyl butyrate to synthetize (S)-5-(4-fluorophenyl)-5-hydroxypentanoate by methyl esterification and chemical reduction, then uses immobilized lipase to carry out enantioselective resolution to obtain enantiomerically pure (S)-5-(4-fluorophenyl)-5-hydroxypentanoate and (R)-5-(4-fluorophenyl)-5-acetoxypentanoate. The invention also provided a method for preparing p-fluorobenzoyl butyric acid by racemization through hydrolysis and oxidation of (R)-5-(4-fluorophenyl)-5-acetoxypentanoate, and the method realizes cyclic utilization of a by-product. The method provided by the invention is low in cost, high in yield and optical purity and environment-friendly, and is suitable for industrial production of (S)-5-(4-fluorophenyl)-5-hydroxypentanoate.

Description

technical field [0001] A preparation of optically pure ( S )-5-(4-Fluorophenyl)-5-Hydroxypentanoic acid methyl ester bioenzyme resolution. technical field [0002] The invention relates to the technology of preparing chiral pharmaceutical intermediates by biocatalysis, especially the method of obtaining optical isomers of compounds by using biological enzymes. Background technique [0003] Ezetimibe (Ezetimble, chemical name: 1-(4-fluorophenyl)-(3 R )-[3-(4-fluorophenyl)-(3 S )-hydroxypropyl]-(4 S )-(4-hydroxyphenyl)-2-propionolactam), is a new type of cholesterol absorption inhibitor developed by Schering-Plough Pharmaceutical Company, which was first launched in the United States in 2002 for the treatment of hyperlipidemia. Among the many synthetic routes of ezetimibe, (4 S )-4-Phenyl-3-[(5 S )-5-(4-fluorophenyl)-5-hydroxypentanoyl]-1,3-oxazol-2-one is its key intermediate. The intermediate is mainly prepared by chemical (biological) asymmetric reduction method ...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
IPC IPC(8): C12P41/00C12P7/62
Inventor 夏仕文林晖陈永正方国兰陈义文徐红梅
Owner 重庆惠健生物科技有限公司
Features
  • R&D
  • Intellectual Property
  • Life Sciences
  • Materials
  • Tech Scout
Why Patsnap Eureka
  • Unparalleled Data Quality
  • Higher Quality Content
  • 60% Fewer Hallucinations
Social media
Patsnap Eureka Blog
Learn More

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic, Popular Technical Reports.

© 2025 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com