Chemical synthesis method for R-2-hydroxy-4-phenylbutanoate

A technology of chemical synthesis of ethyl phenylbutyrate, applied in organic chemistry methods, chemical instruments and methods, organic chemistry, etc., can solve the problems of high atom economy, long reaction process cycle time, poor optical selectivity, etc.

Inactive Publication Date: 2009-04-22
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Although the biological method has a high optical yield, the consumption of organic solvents and water is large, the post-treatment is complicated, and the production efficiency is extremely low; while the chemical method consumes less solvent, and the atom economy in the whole process is high, but the disadvan

Method used

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  • Chemical synthesis method for R-2-hydroxy-4-phenylbutanoate
  • Chemical synthesis method for R-2-hydroxy-4-phenylbutanoate

Examples

Experimental program
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Effect test

Embodiment 1

[0022] In a 1-liter dry three-necked flask, add ethyl azodicarboxylate (0.12 mol), triphenylphosphine (0.12 mol), 20.8 g of ethyl S-2-hydroxy-4-phenylbutyrate (0.1 mol), p-nitrobenzoic acid (0.11 mol) and 500 milliliters of tetrahydrofuran, mechanically stirred for 5 hours, ended the reaction, then filtered, and the filtrate was concentrated to recycle tetrahydrofuran solvent, followed by recrystallization with ethyl acetate and petroleum ether to obtain 32 grams of R- Esterification intermediate. The intermediate was catalyzed by potassium carbonate (0.25 mole) in 300 milliliters of ethanol to carry out transesterification reaction for 12 hours, then filtered, the filtrate was neutralized with hydrochloric acid, extracted with dichloroethane after recovering the ethanol solvent, and the organic phase was recovered under normal pressure. Ethane was then distilled under reduced pressure, and the fractions at 100-108°C were collected at 40mmHg to obtain 18g of colorless liquid w...

Embodiment 2

[0024] In a 1-liter dry three-necked flask, sequentially add isopropyl azodicarboxylate (0.13 mol), triphenylphosphine (0.13 mol), 20.8 g of S-2-hydroxyl-4-phenylbutyric acid ethyl ester ( 0.1 mole), p-nitrobenzoic acid (0.13 mole) and 500 milliliters of toluene, mechanical stirring reaction 1 hour, finish reaction, filter subsequently, filtrate concentrates and reclaims toluene solvent, then obtains 32.3 grams of R with ethyl acetate and sherwood oil recrystallization - Esterification intermediates. The intermediate was catalyzed by potassium carbonate (0.20 moles) in 300 milliliters of ethanol to carry out transesterification reaction for 15 hours, then filtered, the filtrate was neutralized with hydrochloric acid, extracted with dichloroethane after recovering the ethanol solvent, and the organic phase was recovered under normal pressure. Carry out underpressure distillation after ethane, collect the cut of 100~108 ℃ at 40mmHg, obtain colorless liquid 17.7g, purity 99.0% (H...

Embodiment 3

[0026] In a 1-liter dry three-necked flask, sequentially add isopropyl azodicarboxylate (0.10 mol), triphenylphosphine (0.10 mol), 20.8 grams of S-2-hydroxyl-4-phenylbutyric acid ethyl ester ( 0.1 mole), p-nitrobenzoic acid (0.105 mole) and 500 milliliters of dichloroethane, mechanical stirring reaction 10 hours, finish reaction, filter subsequently, filtrate concentrates and reclaims dichloroethane solvent, then with ethyl acetate and sherwood oil Recrystallization gave 30.3 g of an R-esterified intermediate. The intermediate was catalyzed by potassium carbonate (0.25 mole) in 300 milliliters of ethanol to carry out transesterification reaction for 12 hours, then filtered, the filtrate was neutralized with hydrochloric acid, extracted with dichloroethane after recovering the ethanol solvent, and the organic phase was recovered under normal pressure. Carry out underpressure distillation after ethane, collect the cut of 100~108 ℃ at 40mmHg, obtain colorless liquid 15.5g, purity...

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Abstract

The invention discloses a chemical synthesis method for optical pure R-2-hydroxyl-4-phenyl ethyl butyrate. The chemical synthesis method comprises the following steps: in an organic solvent and in the presence of azodiformate and triphenylphosphine, S-2-hydroxyl-4-phenyl ethyl butyrate and paranitrobenzoic acid are reacted and then filtered; after the filtrate is condensed and the solvent is recycled, R-esterified intermediate is obtained by recrystallization; the intermediate is catalyzed in ethanol by potassium carbonate to be subjected to transesterification reaction and then filtered; the filtrate is neutralized by hydrochloric acid; after the solvent is recycled, the filtrate is extracted by ethylene dichloride which is then recycled by an organic phase; and the filtrate is distilled under reduced pressure to obtain the optical pure R-2-hydroxyl-4-phenyl ethyl butyrate with high yield. The synthesis method for the R-2-hydroxyl-4-phenyl ethyl butyrate has the advantages of safety, high efficiency, quick and convenient operation, high selectivity, good yield and low cost, simplicity, general use and suitability for industrialized production.

Description

technical field [0001] The invention relates to a preparation method of a pharmaceutical intermediate, in particular to a chemical synthesis method of ethyl R-2-hydroxy-4-phenylbutyrate. Background technique [0002] R-2-Hydroxy-4-phenylbutyric acid ethyl ester is synthesized from Benazepril, Enalapril, Lisinopril, Cilazapril, Peridole A key player in the treatment of hypertension and congestive heart failure drugs such as Perindopril, Quinapril, Spirapril and Ramipril sex intermediate. Due to the importance of ethyl R-2-hydroxy-4-phenylbutyrate in the synthesis of this class of drugs, its preparation has always been one of the hotspots of research at home and abroad, attracting many chemical science and technology workers to their preparation methods. Extensive research was conducted and a large number of preparation methods were reported. In summary, the methods mainly include biological and chemical methods, both of which include synthesis and resolution [Tetrahedron, ...

Claims

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Application Information

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IPC IPC(8): C07C69/73C07C67/333C07B53/00
Inventor 毛侦军戴西象林旭锋
Owner ZHEJIANG UNIV
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