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Method for practical synthesizing optically active alpha amino pimelic acid ester or monoester

An aminopimelic acid ester, optically active technology, applied in chemical instruments and methods, organic chemistry, bulk chemical production, etc., can solve the problems of unsuitability for industrial production, harsh reaction conditions, and low utilization of raw materials, and achieve easy Effects of magnification, easy access to raw materials, and simple raw materials

Active Publication Date: 2007-12-26
CHANGZHOU HEQUAN PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The technical problem to be solved in the present invention is: develop a kind of synthetic technique of practical optically active α-aminopimelic acid ester or α-aminopimelic acid monoester, avoid the long synthetic route that exists in the existing technique, and the reaction conditions are relatively Harsh, low raw material utilization rate, poor enantioselectivity, high cost, difficult to scale up, not suitable for industrial production and other shortcomings

Method used

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  • Method for practical synthesizing optically active alpha amino pimelic acid ester or monoester
  • Method for practical synthesizing optically active alpha amino pimelic acid ester or monoester
  • Method for practical synthesizing optically active alpha amino pimelic acid ester or monoester

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Experimental program
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Effect test

Embodiment 1

[0016] 1. Synthesis of 5-Hydroxy-N-Boc-prosthenic acid ethyl ester

[0017]

[0018] Dissolve L-N-Boc-ethyl pyroglutamate 1 (30 g, 117 mmol) in anhydrous THF, cool to -78°C in a dry ice-acetone bath, and slowly add DIBAL-H toluene solution (1 M, 233mL, 233mmol), the rate of addition was controlled so that the addition was completed within 1 hour. After the dropwise addition, the reaction solution was continuously stirred for 45 minutes and monitored by TLC. After the reaction was complete, isopropanol was slowly added to quench the reaction, then an aqueous solution of potassium sodium tartrate was added, and the reaction solution was continuously stirred for 20 minutes. The layers were left to stand, the aqueous phase was extracted with ether, the organic phases were combined, washed with saturated brine, anhydrous MgSO 4 After drying and concentration, 5-hydroxy-N-Boc-proline ethyl ester 2 (29.5 g, 97.6%) was obtained, which was directly put into the next reaction withou...

Embodiment 2

[0029] 1. Synthesis of 5-Hydroxy-N-Boc-prosthenic acid ethyl ester

[0030]

[0031] Dissolve L-N-Boc-ethyl pyroglutamate 1 (30g, 117mmol) in anhydrous THF, cool to -78°C in a dry ice-acetone bath, slowly add DIBAL-H toluene solution (1M, 233mL, 233mmol), control the rate of addition to make it dropwise in 1 hour. After the dropwise addition, the reaction solution was continuously stirred for 45 minutes and monitored by TLC. After the reaction was complete, isopropanol was slowly added to quench the reaction, then an aqueous solution of potassium sodium tartrate was added, and the reaction solution was continuously stirred for 20 minutes. The layers were left to stand, the aqueous phase was extracted with ether, the organic phases were combined, washed with saturated brine, anhydrous MgSO 4 After drying and concentration, 5-hydroxy-N-Boc-proline ethyl ester 2 (29.5 g, 97.6%) was obtained, which was directly put into the next reaction without further purification.

[0032]...

Embodiment 3

[0042] 1. Synthesis of 5-Hydroxy-N-Boc-prosthenic acid ethyl ester

[0043]

[0044] Dissolve L-N-Boc-ethyl pyroglutamate 1 (10g, 39mmol) in anhydrous THF, cool to -78°C in a dry ice-acetone bath, then slowly add LiBEt 3 H solution in THF (1M, 47mL, 47mmol), the rate of addition was controlled so that the addition was completed within 10 minutes. After the dropwise addition, the reaction solution continued to stir for 30 minutes, and was monitored by TLC. After the reaction was complete, slowly added saturated NaHCO 3 Quenches the reaction. After warming up to 0°C, slowly add 30% H 2 o 2 , continued to stir for 30 minutes, concentrated under reduced pressure, the residue was diluted with EtOAc, washed with saturated brine, and the aqueous phase was extracted twice with EtOAc. Mixed organic phase, Na 2 SO 4 Dry, filter, and concentrate the filtrate to obtain 5-hydroxy-N-Boc-proline ethyl ester.

[0045] 2. Synthesis of diethyl L-2-aminohept-5-enedioic acid

[0046] ...

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Abstract

This invention relates to a method for synthesizing optically active alpha-aminopimelic acid ester or monoester. The method comprises: reducing ethyl L-N-Boc-pyroglutamate to obtain hemiacetal, performing Wittig reaction to obtain corresponding olefin, and hydrogenating to obtain L-2-aminopimelic acid ester or L-2-aminopimelic acid monoester. The method has such advantages as simple synthesis rotine, reasonable process, high enantio selectivity, high optical purity of the product, and abundant raw material, and can be used for mass production of L-2-aminopimelic acid ester or L-2-aminopimelic acid monoester. The method solves the problems of long synthesis rotine, expensive reagents, low enantio selectivity, and unable mass production faced by the present synthesis process.

Description

Technical field: [0001] The present invention relates to the practical synthesis of optically active α-aminopimelic acid esters or monoesters. Background technique: [0002] Recently, unnatural amino acids with extended carbon chains on the backbone of natural aspartic acid (2-aminosuccinic acid) and glutamic acid (2-aminoglutaric acid): 2-aminoadipic acid, 2-amino Pimelic acid, 2-aminosuberic acid, etc. are widely used in medicinal chemistry and organic synthesis, and this field has attracted more and more attention from chemical researchers. L-2,6-diaminopimelic acid, as a precursor for lysine biosynthesis, has important biological activities. And L-2-aminopimelate can be used in the synthesis of L-2,6-diaminopimelic acid. [0003] At present, the synthesis methods of L-2-aminopimelate mainly include enzymatic kinetic resolution (Chem.Pharm.Bull, 1994, 59, 3676) and asymmetric catalytic hydrogenation of aldehydes derived from glutamic acid after Wittig reaction. (J.Org....

Claims

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Application Information

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IPC IPC(8): C07C229/36C07C227/18
CPCY02P20/55
Inventor 缪伟徐卫良张治柳马汝建陈曙辉李革
Owner CHANGZHOU HEQUAN PHARMA CO LTD
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