Check patentability & draft patents in minutes with Patsnap Eureka AI!

Preferential crystallization preparation method of chiral alpha-phenylethyl alcohol

A technology that preferentially crystallizes and phenethyl alcohol is applied in organic chemical methods, separation/purification of hydroxyl compounds, organic chemistry, etc. It can solve the problems of low reaction concentration, poor atom economy, cumbersome operation, etc., and achieve high product yield and easy operation. Simple, high-purity effect

Active Publication Date: 2016-01-13
XIHUA UNIV +1
View PDF9 Cites 4 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] (1) Enzymatic asymmetric catalytic hydrolysis method (US7858643B2, WO2009036404A): 2,6-dichloro-3-fluoroacetophenone is used as raw material and chemically reduced to the corresponding 2,6-dichloro-3-fluorobenzene Ethanol, then alcohol and acetic anhydride esterified by enzymatic hydrolysis can get R-alcohol and S-ester, then R-alcohol is mesylated, acetyl group is substituted to get S-ester, S-ester is hydrolyzed to get (S)- 1-(2,6-dichloro-3-fluorophenyl)ethanol; this method has a long reaction cycle and low reaction concentration, which is not conducive to industrial production, and the selectivity is not high
[0006] (2) Chemical resolution method: split after esterification with Boc-L-proline (CN201210038110.8, CN200910262815.6); or split with chiral phenylethylamine after reacting with phthalic anhydride (CN201410275671. 9); long steps, low yield, poor atom economy
[0009] (1) Enzymatic asymmetric catalytic hydrolysis method: using biological enzyme KRED-101 as a catalyst (Practical Methods for Biocatalysis and Biotransformations, 2010; 273-275) or using methanol transfer hydrogen method (IndianPatAppl, 2005CH01159, 2007-09-07) to catalyze 3,5 - asymmetric reduction of bis(trifluoromethyl)acetophenone to R-3,5-bis(trifluoromethyl)phenethyl alcohol, while the enzyme-catalyzed kinetic resolution method utilizes the enzyme-selective catalytic 3,5 -Synthesis of R-3,5-bistrifluoromethylphenethyl alcohol with bistrifluoromethylphenethyl alcohol (Progress in Chemical Industry, 2013, 32 (11); 2691-2694), these several biocatalytic methods all exist cost-effective. high disadvantage
[0010] (2) Chemical synthesis method: asymmetric catalytic reduction of 3,5-bis(trifluoromethyl)acetophenone to (R)-3,5-bis(trifluoromethyl) using Ru and other noble metal complexes as catalysts Phenylethyl alcohol (Organic Process Research & Development, 2007, 11 (3): 519-523; FineChemicals, 2013, 30 (4), 468-470), this method has the disadvantages of expensive metal catalyst and low optical purity of the product
This method is cumbersome to operate and requires chromatographic purification, which is not suitable for large-scale industrial applications

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
  • Preferential crystallization preparation method of chiral alpha-phenylethyl alcohol
  • Preferential crystallization preparation method of chiral alpha-phenylethyl alcohol
  • Preferential crystallization preparation method of chiral alpha-phenylethyl alcohol

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 2

[0044] The screening of embodiment 2 primary crystallization conditions

[0045] Take 30 g of the compound (2) prepared in Example 1, add different types and different amounts of solvents, heat and dissolve at 40 ° C, prepare solutions with different concentrations, cool naturally, add 1 S-seed crystal, and stand for crystallization After 10 hours, filter and dry, weigh, calculate the yield and check the ee value by chiral liquid phase. The chromatographic conditions for detection are: AD-H; n-hexane (0.1% acetic acid): isopropanol = 80:20; 0.3ml / L; 254nm; 30°C.

[0046] The screening conditions are shown in Table 1.

[0047] Table 1 Screening test of primary crystallization conditions

[0048] solvent

[0049] The results show that when the solvent is petroleum ether, the yield and ee value of the primary crystallization product are significantly better than other solvents. At the same time, when solvent: solute (mL / g) = 3.5, the effect is the best.

Embodiment 3

[0050] Example 3 Resolution and Preparation of (S)-1-(2,6-dichloro-3-fluorophenyl)ethanol by preferential crystallization method

[0051]

[0052] (1) Primary crystallization

[0053]Take 30g of compound (2) prepared in Example 1 and add 105mL of petroleum ether, stir and heat at 40°C under argon to dissolve; add 1 grain of (S)-1-(2,6-dichloro-3-fluorobenzene Base) ethanol seed crystal, after 45min, the seed crystal became smaller obviously; after 1 hour, the seed crystal disappeared; after 3.5h, a white solid precipitated out (precipitated first at the bottom of the bottle); after 10h, no solid precipitated anymore; Dry, weighing 20g, yield is 66.7%; Through chiral liquid phase detection ee: 60.5% (detection condition AD-H; Normal hexane (0.1% acetic acid): Virahol=80:20; 0.3ml / L; 254nm ; 30°C).

[0054] (2) Secondary crystallization

[0055] Take 30g of the compound obtained from one crystallization, add 105mL of petroleum ether, stir and heat at 40°C under argon, and ...

Embodiment 4

[0062] Example 4 Resolution and Preparation of (R)-1-(2,6-dichloro-3-fluorophenyl)ethanol by preferential crystallization method

[0063]

[0064] (1) Primary crystallization

[0065] Take 30g of compound (2) prepared in Example 1 and add 105mL of petroleum ether, stir and heat at 40°C under argon to dissolve; add 1 grain of (R)-1-(2,6-dichloro-3-fluorobenzene Base) ethanol seed crystal, after 45min, the seed crystal became smaller obviously; after 1 hour, the seed crystal disappeared; after 3.5h, a white solid precipitated out (precipitated first at the bottom of the bottle); after 10h, no solid precipitated anymore; Dry, weighed 22g, the yield was 73.3%; according to the aforementioned chromatographic conditions, ee: 62.5% was detected by chiral liquid phase.

[0066] (2) Secondary crystallization

[0067] Take 30g of the compound obtained from one crystallization, add 105mL of petroleum ether, stir and heat at 45°C under argon, and dissolve; put 1 seed crystal of (R)-1...

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 method for preparing chiral alpha-phenylethyl alcohol. The method is a preferential crystallization method implemented by taking petroleum ether as a solved, is simple and convenient to operate, is high in product yield and purity, and can obtain a high-purity product with the ee value of more than or equal to 99.5% by virtue of 3 times of crystallization, thereby being suitable for large-scale industrial production.

Description

technical field [0001] The invention relates to a method for preparing chiral α-phenylethanol by preferential crystallization. Background technique [0002] Chiral α-phenylethanol is a key intermediate in the preparation of various drugs, such as the following Crizotinib intermediate - (S)-1-(2,6-dichloro-3-fluorobenzene base) ethanol and aprepitant (Aprepitant) intermediate - (R)-3,5-bis(trifluoromethyl)phenylethanol: [0003] [0004] For (S)-1-(2,6-dichloro-3-fluorophenyl)ethanol, the preparation methods in current literature mainly contain the following types: [0005] (1) Enzymatic asymmetric catalytic hydrolysis method (US7858643B2, WO2009036404A): 2,6-dichloro-3-fluoroacetophenone is used as raw material and chemically reduced to the corresponding 2,6-dichloro-3-fluorobenzene Ethanol, then alcohol and acetic anhydride esterified by enzymatic hydrolysis can get R-alcohol and S-ester, then R-alcohol is mesylated, acetyl group is substituted to get S-ester, S-ester ...

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): C07C29/78C07C33/46
CPCC07B2200/07C07C29/78C07C33/46
Inventor 王周玉吴鹏程蒋珍菊徐志宏翁光林谭平刘斯宇王伟
Owner XIHUA UNIV
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