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Preparation method of biphenyl alanine derivative

A technology for biphenylalanine and derivatives, which is applied in the field of preparation of biphenylalanine derivatives, can solve the problems of low atom utilization, high price, and high cost, and achieve low requirements for equipment and low price in the process , the effect of mild reaction conditions

Active Publication Date: 2015-06-24
迪嘉药业集团股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] The disadvantage of this route is that it uses expensive and difficult-to-obtain N-(diphenylmethylenyl)aminoacetic acid methyl ester as a raw material, and after hydrolysis, the diphenylmethyl group with a larger molecular weight is removed, and the atom utilization is low, resulting in cost increase

Method used

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  • Preparation method of biphenyl alanine derivative
  • Preparation method of biphenyl alanine derivative
  • Preparation method of biphenyl alanine derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] Toluene (300mL), glycine methyl ester hydrochloride (50g, 0.40mol), triethylamine (44.5g, 0.44mol), anhydrous magnesium sulfate (48.1g, 0.40mol), benzaldehyde (38.2g, 0.36mol ) into a 1000mL three-neck flask in turn, react at 30°C for 2h, filter out insoluble matter, add 300mL of water to the organic layer, stir for 10min, and separate the layers to obtain a toluene solution of compound (formula iii).

[0043] Add potassium hydroxide (44.9g, 0.8mol) and 4-chloromethylbiphenyl (77.04g, 0.38mol) to the toluene solution of compound (formula iii), react at 30°C for 1h, add water 300mL, stir for 10min, Separate the layers, add 200mL 6M dilute hydrochloric acid to several layers, stir at room temperature for 1h, separate the layers, and wash the aqueous layer with saturated Na 2 CO 3 The pH of the solution was adjusted to 7~8, a large amount of white solid was precipitated, and 79.6 g of biphenylalanine methyl ester (formula i) was obtained by filtration, with a purity (HPLC...

Embodiment 2

[0045] Toluene (300mL), glycine methyl ester hydrochloride (50g, 0.40mol), triethylamine (44.5g, 0.44mol), anhydrous magnesium sulfate (48.1g, 0.40mol), benzaldehyde (40.32g, 0.38mol ) into a 1000mL three-neck flask in turn, react at 30°C for 4h, filter out insoluble matter, add 300mL of water to the organic layer, stir for 10min, and separate the layers to obtain a toluene solution of compound (formula iii).

[0046] Add potassium hydroxide (44.9g, 0.8mol) and 4-chloromethylbiphenyl (81.1g, 0.4mol) to the toluene solution of compound (formula iii), react at 30°C for 1h, add water 300mL, stir for 10min, Separate the layers, add 200mL 6M dilute hydrochloric acid to several layers, stir at room temperature for 1h, separate the layers, and wash the aqueous layer with saturated Na 2 CO 3 The pH of the solution was adjusted to 7~8, a large amount of white solid was precipitated, and 83.8 g of biphenylalanine methyl ester (formula i) was obtained by filtration, with a purity (HPLC)...

Embodiment 3

[0048] Toluene (300mL), glycine methyl ester hydrochloride (50g, 0.40mol), triethylamine (44.5g, 0.44mol), anhydrous magnesium sulfate (48.1g, 0.40mol), benzaldehyde (46.7g, 0.44mol ) into a 1000mL three-neck flask in turn, react at 30°C for 6h, filter out insoluble matter, add 300mL of water to the organic layer, stir for 10min, and separate the layers to obtain a toluene solution of compound (formula iii).

[0049] Add potassium hydroxide (44.9g, 0.8mol) and 4-chloromethylbiphenyl (89.21g, 0.44mol) to the toluene solution of compound (formula iii), react at 35°C for 1h, add water 300mL, stir for 10min, Separate the layers, add 200mL 6M dilute hydrochloric acid to several layers, stir at room temperature for 1h, separate the layers, and wash the aqueous layer with saturated Na 2 CO 3 The pH of the solution was adjusted to 7~8, a large amount of white solid was precipitated, and 84.0 g of biphenylalanine methyl ester (formula i) was obtained by filtration, with a purity (HPLC...

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Abstract

The invention relates to a preparation method of a compound represented by the formula (i); and the compound represented by the formula (i) is prepared by taking glycine methyl ester or hydrochloride thereof as the starting material through benzaldehyde protection, benzyl chloride biphenyl alkylation and deprotection. According to the invention, the starting material is easy to obtain and low in cost; furthermore, an intermediate related in the reaction process is unnecessary to separate and purify; the preparation method is simple to operate and moderate in reaction condition; and therefore, the preparation method is applied to industrialized mass production.

Description

technical field [0001] The invention relates to a preparation method of biphenylalanine derivatives. Background technique [0002] Compounds with the structure of biphenylalanine derivatives are an important class of pharmaceutical intermediates, especially as inhibitors of some enzymes in vivo, such as neprilysin inhibitors, neutral endopeptidase inhibitors, etc. [0003] There are three main methods for preparing biphenylalanine: [0004] 1) Using biphenyl monoformaldehyde and hydantoin as starting materials, biphenylalanine was obtained through condensation, reduction, and hydrolysis (see WO2007083776): [0005] [0006] The disadvantage of this route is that expensive Pd / C is needed in the reduction process, and the reaction conditions are relatively harsh, requiring 10-20 atmospheres, which requires high equipment requirements. [0007] 2) Biphenylalanine derivatives were prepared by condensation, decarboxylation, esterification, reduction, and -Boc protection usin...

Claims

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Application Information

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IPC IPC(8): C07C227/18C07C229/36
Inventor 丛日刚刘庆春沈文丽刘彦彬孙建王化冰
Owner 迪嘉药业集团股份有限公司
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