Method for preparing methyldopa by directly hydrolyzing 5-methyl-5-(3,4-dimethoxybenzyl)hydantoin with acid

A technology of dimethoxybenzyl and hydantoin, applied in chemical instruments and methods, cyanide reaction preparation, organic compound preparation, etc., can solve the problems of purity, yield decrease, and increase of by-products, etc.

Active Publication Date: 2014-12-24
ZHEJIANG CHIRAL MEDICINE CHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the hydantoin method, an important disadvantage of hydrolyzing hydantoin with BaOH is that the hydrolyzed product needs to be mixed with DL-α-methyl-(3,4-dimethoxyphenyl)-α-amino Barium propionate undergoes an exchange reaction, and then undergoes complicated post-treatment of the intermediate product to remove the barium sulfate generated to obtain DL-α-methyl-(3,4-dimethoxyphenyl)-α-aminopropyl acid, and, in the further high-temperature hydrolysis demethylation stage of hydrobromic acid, the oxidative properties of residual sulfuric acid make the polyphenol-like structure after demethylation produce a variety of chemical reactions under high temperature and oxidation conditions, and the structure of some compounds Unknown changes increase by-products and decrease purity and yield

Method used

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  • Method for preparing methyldopa by directly hydrolyzing 5-methyl-5-(3,4-dimethoxybenzyl)hydantoin with acid
  • Method for preparing methyldopa by directly hydrolyzing 5-methyl-5-(3,4-dimethoxybenzyl)hydantoin with acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] In a three-necked flask equipped with a thermometer, a stirrer and a reflux condenser, add 4.3g (0.016mol) of 5-methyl-5-(3,4-dimethoxybenzyl)hydantoin, add 36% 24.3 g (0.24 mol) of concentrated hydrochloric acid in an oil bath was then slowly heated to 65-70°C (40 minutes) and stirred for 6 hours, then heated to 100-110°C (to achieve vigorous reflux) and stirred for 24 hours. After the reaction was completed, N was directly introduced into the reaction mixture slowly. 2 , while extracting excess HCl by distillation under reduced pressure. Adjust the pH of the solution with ammonia water and solids appear, stir until the pH is constant. Then, carefully adjust the pH to 6, let stand for 1 hour, and filter the solid. The solid was washed with 4×25ml of acetone to obtain a white solid. It was then vacuum dried at 50°C for 5 hours. Obtain product DL-2-amino-3-(3,4-dihydroxyphenyl)-2-methyl-propionic acid (C 10 h 13 NO 4 ·H 2 o 1.5 ) is 3.57 grams of methyldopa, yie...

Embodiment 2

[0034] In a three-necked flask equipped with a thermometer, a stirrer and a reflux condenser, add 4.3g (0.016mol) of 5-methyl-5-(3,4-dimethoxybenzyl)hydantoin, adding 47% 41.4 g (0.24 mol) of hydrobromic acid, then slowly heated in an oil bath to 65-70°C (40 minutes), stirred and reacted for 6 hours, then heated to 100-120°C (reaching vigorous reflux), stirred and reacted for 18 hours. After the reaction was completed, N was directly introduced into the reaction mixture slowly. 2 , while extracting excess hydrobromic acid by distillation under reduced pressure. Adjust the pH of the solution with ammonia water and solids appear, stir until the pH is constant. Then, carefully adjust the pH to 6, let stand for 1 hour, and filter the solid. The solid was washed with 4×25ml of acetone to obtain a white solid. It was then vacuum dried at 50°C for 5 hours. Obtain product DL-2-amino-3-(3,4-dihydroxyphenyl)-2-methyl-propionic acid (C 10 h 13 NO 4 ·H 2 o 1.5) is 3.63 grams of m...

Embodiment 3

[0036] In a three-necked flask equipped with a thermometer, a stirrer and a reflux condenser, add 4.3g (0.016mol) of 5-methyl-5-(3,4-dimethoxybenzyl)hydantoin, adding 47% 20.7 g (0.12 mol) of hydrobromic acid. Then the oil bath was slowly heated to 65-70°C (40 minutes) and stirred for 6 hours, and then heated to 100-120°C (to achieve vigorous reflux), and stirred for 24 hours. After the reaction was completed, N was directly introduced into the reaction mixture slowly. 2 , while extracting excess hydrobromic acid by distillation under reduced pressure. Adjust the pH of the solution with ammonia water and solids appear, stir until the pH is constant. Then, carefully adjust the pH to 6, let stand for 1 hour, and filter the solid. The solid was washed with 4×25ml of acetone to obtain a white solid. It was then vacuum dried at 50°C for 5 hours. Obtain product DL-2-amino-3-(3,4-dihydroxyphenyl)-2-methyl-propionic acid (C 10 h 13 NO 4 ·H 2 o 1.5 ) namely methyldopa 3.45 gr...

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Abstract

The invention belongs to the technical field of one of key steps of chemical synthesis of medicine methyldopa [alpha-methyl-(3,4-dihydroxyphenyl]-alpha-alanine] or synthesis of chiral medicine L-methyldopa [L-alpha-methyl-(3,4-dihydroxyphenyl]-alpha-alanine]: reaction for preparing methyldopa by hydrolyzing 5-methyl-5-(3,4-dimethoxybenzyl)hydantoin. The invention relates to a method for preparing methyldopa or L-methyldopa by directly hydrolyzing 5-methyl-5-(3,4-dimethoxybenzyl)hydantoin with acid at appropriate temperature. When disacidification is carried out under reduced pressure after the reaction finishes, N2 is introduced to protect the product from easy oxidative stain and accelerate the disacidification. In order to protect the product from deterioration, the vacuum drying temperature of the product is generally carried out at 50 DEG C for 5 hours.

Description

technical field [0001] The technical field of the present invention belongs to chemically synthesized drug methyldopa [Methyldopa, α-methyl-(3,4-dihydroxyphenyl)-α-alanine, the same below] or synthetic chiral drug L-methyldopa One of the key steps in [L-methyldopa, L-α-methyl-(3,4-dihydroxyphenyl)-α-alanine, the same below]: hydrolysis of 5-methyl-5-(3 , 4-dimethoxybenzyl) hydantoin to prepare methyldopa reaction. Background technique [0002] L-Methyldopa is a catecholamine hormone in the body and is a decarboxylase inhibitor [SLETA INGER M,CHEMERDA J M,W BOLL INGER F.Potent decarboxylase inhibitors.analogs of methyldopa[J].J Med Chem,1963,6( 2): 1012103.], has antihypertensive effect, and is clinically used to treat hypertension [XU J M, ZHENG H J. Clinical application and evaluation of methyldopa[J]. Chin J New Drugs Clin Rem (Chinese New Drugs and Clinical Journal ), 1990, 9(6):367-369.]. L-methyldopa is also one of the main drugs for the treatment of Parkinson's dise...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C229/36C07C227/24
Inventor 徐伟亮汪静徐子河黄有明
Owner ZHEJIANG CHIRAL MEDICINE CHEM
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