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Method for preparing beta-N-methylamino-L-alanine

A technology of alanine and methylamino, which is applied in the field of preparation of β-N-methylamino-L-alanine (BMAA), can solve problems such as low yield, unstable performance of intermediates, and difficult separation of products. Achieve the effect of simple process operation and low raw material cost

Active Publication Date: 2019-02-22
KANGHUA SHANGHAI DRUG RES DEV CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0014] The purpose of the present invention is to provide a preparation method of β-N-methylamino-L-alanine, which mainly solves the unstable performance of intermediates, easy side reactions, difficult separation of products and low yield in existing synthetic methods. and other technical issues

Method used

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  • Method for preparing beta-N-methylamino-L-alanine
  • Method for preparing beta-N-methylamino-L-alanine
  • Method for preparing beta-N-methylamino-L-alanine

Examples

Experimental program
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Effect test

Embodiment 1

[0040] (1): Add 108.5 g (0.5 mol) N-acetylaminomalonate diethyl ester, (72.6 g, 0.6 mol) N-methylbenzylamine and 48.8 mL (0.65 mol) mass hundred 37% aqueous formaldehyde solution was added and stirred at room temperature for 4 hours. 100 mL of water was added to quench the reaction, and then extracted three times with 600 mL of ethyl acetate, the organic phase was washed three times with water, saturated sodium bicarbonate solution and saturated brine successively, dried over anhydrous sodium sulfate, and concentrated to obtain 183 g of intermediate 1. figure 1 , colorless oil, yield ~100%, directly to the next step reaction.

[0041] (2): Dissolve 183g (0.5 mol) of intermediate 1 in 300 mL of ethanol, add a solution made of 22 g (0.55 mol) of sodium hydroxide and 1L of water, stir and heat under reflux for 12 hours. After cooling, the reaction solution was washed three times with ethyl acetate, acidified with 1N dilute hydrochloric acid to Ph=4, concentrated to dryness to ob...

Embodiment 2

[0045] Example 2: The molar ratio of diethyl acetamidomalonate and N-methylbenzylamine used in step (1) is 1:1, and the rest are the same as in Example 1. Steps (1), (2) and (3) are combined Yield 33%.

Embodiment 3

[0046] Example 3: The sodium hydroxide used in step (2) is 2eq, and the rest are the same as in Example 1. The combined yield of steps (1), (2) and (3) is 38%.

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Abstract

The invention relates to a method for preparing beta-N-methylamino-L-alanine. The technical problems that the conventional preparation method is low in yield, long in route and difficult in chiral control and the like are mainly solved. According to the technical scheme of the invention, the method for preparing beta-N-methylamino-L-alanine comprises the following steps: carrying out a Mannich reaction on diethyl acetamidomalonate, N-methylbenzylamine and an aqueous solution of formaldehyde to obtain an intermediate I; performing alkaline hydrolysis on the intermediate I, and performing decarboxylation to obtain an intermediate 2; performing palladium carbon catalytic debenzylation on the intermediate 2 in the presence of Boc anhydride, and performing Boc protection to obtain an intermediate 3; reacting the intermediate 3 in the presence of L-acetylase so as to obtain an L-isomer, and performing Boc protection to obtain an intermediate 4; and performing Boc- deprotection on the intermediate 4 in the presence of hydrogen chloride, and forming hydrochloride, thereby obtaining the chemically pure and optically pure final product beta-N-methylamino-L-alanine.

Description

technical field [0001] The invention relates to a preparation method of β-N-methylamino-L-alanine (BMAA). Background technique [0002] β-N-methylamino-L-alanine (β-N-methylamino-L-alanine, BMAA) is a naturally occurring, neurotoxic non-protein amino acid. It was first discovered in a kind of algae, and the study found that most cyanobacteria (cyanobacteria) can produce this neurotoxin. Studies in recent years have shown that it plays an important role in the metabolism of fat and fatty acids, muscle growth, production of immune hemoglobin and antibodies, manufacturing and processing of cell membranes, and synthesis of sheaths surrounding nerve cells. Now it is widely used in the research of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Parkinsonism dementia complex (PDC) and Alzheimer's disease (Alzheimer disease, AD), The global incidence of these neurodegenerative diseases increases gradually with the aging of the population. [0003] β-N-meth...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C231/12C07C233/47C07C269/04C07C271/22C12P13/02C07C227/20C07C229/26
CPCC07B2200/07C07C227/20C07C231/12C07C269/04C12P13/02C07C233/47C07C271/22C07C229/26
Inventor 徐红岩董建海袁伟芳
Owner KANGHUA SHANGHAI DRUG RES DEV CO LTD
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