Asymmetric alcoholysis catalyzed by chiral thiourea amine salt

An asymmetric, thiourea ammonium salt technology, applied in the preparation of organic compounds, organic chemistry, organic chemical methods and other directions, can solve the problems of low yield, need to split, long synthesis route of pregabalin, etc., and achieves few steps. , mild reaction conditions, novel synthetic route effect

Inactive Publication Date: 2016-10-12
RAFFLES PHAMRMATECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] In order to solve the problems of long synthetic route of pregabalin, low yield in the production process, and the need for resolution in the pr

Method used

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  • Asymmetric alcoholysis catalyzed by chiral thiourea amine salt
  • Asymmetric alcoholysis catalyzed by chiral thiourea amine salt
  • Asymmetric alcoholysis catalyzed by chiral thiourea amine salt

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] 1. Catalytic asymmetric alcoholysis

[0039] Take a 100mL three-necked flask, add 3-isobutylglutaric anhydride (1.70g, 0.01mol), bromide (S)-2-(3(3,5-bis(trifluoro Methyl)phenyl)thioureido)-N,N,4-trimethyl-N-(4-bromobenzyl)pentan-1-ammonium (665mg, 1.0mmol), and 50 mL THF was added to dissolve the solid, Benzylthiol (1.50g, 0.012mol) was added under stirring at -10°C, reacted for 16h, the solvent was removed under reduced pressure, and purified by column chromatography to obtain 2.80g of thiol ester with a yield of 95% and an ee value of 94%. 1 H NMR (400MHz, CDCl 3 ): δ=0.80-0.87(6H), 1.13(2H), 1.55(1H), 2.25-2.40(3H), 2.50-2.60(2H), 4.34(2H), 7.26-7.42(5H), 10.70(1H ) ppm; MS (ESI) calcd for C 16 h 22 o 3 S(M + ):294.4; Found:295.2(M+H) + .

[0040] 2. Synthesis of benzyloxycarbamide methyl thiol ester

[0041] Take a 100mL three-necked flask, dissolve thiol ester (2.80g, 9.5mmol) in dry toluene at 25°C, add triethylamine (0.97g, 9.6mmol) and diphenylphosphor...

Embodiment 2

[0047] 1. Catalytic asymmetric alcoholysis

[0048] Take a 100mL three-necked flask, add 3-isobutylglutaric anhydride (1.70g, 0.01mol), chloride (S)-2-(3(3,5-bis(trifluoro Methyl)phenyl)thioureido)-N,N,4-trimethyl-N-(4-bromobenzyl)pent-1-ammonium (620mg, 1.0mmol), and added 50mL methyl tert-butyl Dissolve the solid in ether, add benzylmercaptan (1.50g, 0.012mol) under stirring at -10°C, react for 16h, remove the solvent under reduced pressure, and purify by column chromatography to obtain 2.84g of thiol ester with a yield of 96% and an ee value of 95 %. 1 H NMR (400MHz, CDCl 3 ): δ=0.80-0.87(6H), 1.10(2H), 1.55(1H), 2.25-2.40(3H), 2.50-2.60(2H), 4.34(2H), 7.26-7.40(5H), 10.70(1H ) ppm; MS (ESI) calcd for C 16 h 22 o 3 S(M + ):294.4; Found:295.2(M+H) + .

[0049] 2. Synthesis of benzyloxycarbamide methyl thiol ester

[0050] Take a 50mL three-necked flask, dissolve thiol ester (1.42g, 4.8mmol) in dry toluene at 25°C, add triethylamine (0.49g, 4.8mmol) and diphenylphos...

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Abstract

The invention provides asymmetric alcoholysis catalyzed by a chiral thiourea amine salt. The process includes the steps of: S1. subjecting 3-isobutylglutaric anhydride and mercaptan to asymmetric alcoholysis in the presence of a chiral thiourea amine salt catalyst to generate dextral mercaptide; S2. subjecting the dextral mercaptide obtained by asymmetric alcoholysis to reaction with diphenyl azidophosphate and benzyl alcohol in order to generate levo-benzyloxycarbonylaminomethyl mercaptide; and S3. hydrolyzing the levo-benzyloxycarbonylaminomethyl mercaptide under alkaline hydrogen peroxide condition to obtain levo-benzyloxycarbonylaminomethylhexanoic acid. The method provided by the invention does not use chemical resolution agent, the total yield is more than 50%, and the ee value is greater than 94%. The method has the advantages of novel synthesis route, few step, and mild reaction conditions.

Description

technical field [0001] The invention belongs to the field of chemical synthesis, and in particular relates to a chiral thiourea amine salt catalyzed asymmetric alcoholysis reaction. Background technique [0002] Pregabalin (CAS: 148553-50-8) is a gamma-aminobutyric acid (GABA) analogue with antiepileptic, analgesic and anxiolytic activities. In laboratory studies, the drug has anticonvulsant activity on various epilepsy models; the activity spectrum of animal models is similar to that of gabapentin, but the activity is 3 to 10 times that of gabapentin. [0003] There are many synthetic routes of pregabalin, which can be mainly divided into three types of synthetic routes, as follows: [0004] [0005] By synthesizing a racemic intermediate and then using a chiral resolution reagent, a chiral compound is obtained after resolution. The disadvantage of this type of synthesis is that the yield is low, and the other half of the enantiomer after resolution is not the target p...

Claims

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Application Information

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IPC IPC(8): C07C229/08C07C227/32
CPCC07B2200/07C07C227/32C07C269/06C07C327/22C07C327/30C07C229/08C07C271/22
Inventor 孙家强费安杰叶伟平徐俊烨
Owner RAFFLES PHAMRMATECH CO LTD
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