A kind of preparation method of lisinopril intermediate

An intermediate and hydroxyl technology, which is applied in the field of preparation of lisinopril intermediates, can solve the problems of high refining difficulty, high cost, and low yield, and achieve the effects of environmental friendliness, mild conditions, and cost reduction

Active Publication Date: 2018-01-09
SUZHOU LEAD BIOTECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0017] The technical problem to be solved by the present invention is that the preparation (R)-HPBE in the prior art has high cost, harsh preparation conditions, complicated preparation process, low yield and high difficulty in refining, and then provides a low-cost, easy-to-prepar The preparation method of the lisinopril intermediate with high yield and high product purity

Method used

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  • A kind of preparation method of lisinopril intermediate
  • A kind of preparation method of lisinopril intermediate
  • A kind of preparation method of lisinopril intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] The lisinopril intermediate prepared in this example is (R)-2-hydroxy-4-phenylbutyric acid ethyl

[0044]

[0045] Esters have the following structure:

[0046] The above-mentioned ethyl (R)-2-hydroxy-4-phenylbutyrate uses cheap and easy-to-obtain benzaldehyde and pyruvic acid as raw materials, through condensation, biological enzyme-catalyzed asymmetric reduction, double bond hydrogenation and esterification in four efficient steps Reactive synthesis, the synthetic route is as follows:

[0047]

[0048] Its preparation method is specifically:

[0049] (1) Under a nitrogen atmosphere, 21.2 g of benzaldehyde was dissolved in 15 mL of methanol, the reaction system was lowered to 0°C and 17.2 g of pyruvic acid was added while maintaining this temperature. The methanol solution of potassium hydroxide (16.8g potassium hydroxide is dissolved in the methanol of 60mL) is slowly added dropwise, and the temperature of the reaction system is controlled below 15°C. After t...

Embodiment 2

[0054] This example is the same as the preparation method of (R)-2-hydroxy-4-phenylbutyric acid ethyl ester described in Example 1, the only difference is that step (2) is: take the product obtained in the above step 1) Add 10 g of potassium unsaturated ketoacid and 20 mL of isopropanol to a 250 mL reactor filled with 80 mL of 0.2M PBS buffer at pH=6.0 and stir evenly, then add 6N hydrochloric acid dropwise to adjust the pH of the system to 6.0. Add 0.25 g of ketoreductase powder (purchased from Suzhou Pivot Biotechnology Co., Ltd.: Product No. YHADH047) and NADP+0.01 g in sequence, and stir at 30° C. for 24 hours. The reaction conversion rate is >92% as monitored by HPLC. After the reaction was completed, 6N hydrochloric acid was slowly added dropwise to the reaction system to adjust the pH to 1, and 50 mL of ethyl acetate was added to stir for 0.5 hour, filtered, the filtrate was separated into layers, and the organic phase was taken. The aqueous phase was extracted twice wi...

Embodiment 3

[0056] The preparation method of (R)-2-hydroxyl-4-phenylbutyric acid ethyl ester of the present embodiment may further comprise the steps:

[0057] (1) Under an inert gas, dissolve benzaldehyde in an organic solvent, add pyruvic acid at a temperature of 0°C, keep the temperature at 15°C, slowly drop a strong alkali methanol solution, and keep the temperature at 20°C after the addition is complete , stirred and reacted for 12h, after the reaction was completed, the reaction solution was filtered, and the obtained yellow solid was washed with methanol and ether to obtain the unsaturated keto acid;

[0058] Wherein, the organic solvent is methanol; the inert gas is nitrogen; the strong base is potassium hydroxide;

[0059] It should be noted that, as an alternative implementation of this embodiment, the above-mentioned 0°C can be replaced by any value between -5°C and 5°C; the above-mentioned 15°C can also be any value lower than 15°C; the above-mentioned 20°C can be replaced by ...

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Abstract

The invention provides a method for preparing a lisinopril intermediate. The lisinopril intermediate is (R)-2-hydroxyl-4-phenylbutyrate. The method has the advantages that the lisinopril intermediate is made of inexpensive and easily available raw materials which are benzaldehyde and pyruvic acid, four-step efficient reaction including condensation, biological enzyme catalytic asymmetric reduction, double-bond hydrogenation and esterification is carried out on the benzaldehyde and the pyruvic acid, and accordingly an optically pure target product (R)-HPBE [(R)-2-hydroxyl-4-phenylbutyrate] can be ultimately obtained at the overall yield of 83%.

Description

technical field [0001] The present invention relates to a kind of preparation method of lisinopril intermediate, belongs to the technical field of biopharmaceutical and biochemical industry. Background technique [0002] Lisinopril, chemically known as N-{N-[(S)-1-carboxy-3-phenylpropyl]-L-lysyl}-L-proline, is used to treat various degrees of Drugs for hypertension and renohypertension may also be used alone or in combination with diuretics and digitalis to treat congestive heart failure. One of the brands of this medicine and compound preparation (hydrochlorothiazide) was developed by Merck & Co. of the United States, and was approved by the FDA on December 29, 1987 and on February 16, 1989, and its trade names were respectively Prinivil and Prinzide; One brand is AstraZeneca Zestril, which was approved by the FDA on June 9, 1993. The drug has low toxic and side effects, high drug efficacy and good selectivity, and has become one of the best-selling drugs for treating car...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C69/732C07C67/08C12P7/42
CPCC07C51/353C07C51/36C07C67/08C12P7/42C07C59/84C07C69/732
Inventor 谢新开黄晓飞张金鑫张瑞杰
Owner SUZHOU LEAD BIOTECH CO LTD
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