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Preparation of Methyldopa by Hydrolysis of α-Methyl-(3,4-Dimethoxyphenyl)-α-aminopropionitrile by Two-step Hydrolysis

A technology of dimethoxyphenyl and methyldopa, which is used in the preparation of methylpolycarbonate by hydrolyzing α-methyl-(3,4-dimethoxyphenyl)-α-aminopropionitrile by a two-step hydrolysis method In the field of Pakistan, it can solve the problems of high price, increased by-products, and high energy costs, and achieve the effects of reducing energy and economic costs, improving purity and yield, and reducing acid wastewater discharge.

Inactive Publication Date: 2015-09-23
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But the test finds that there are following problems: 1. Need to carry out long-time heating nitrile group hydrolysis and demethylation hydrolysis reaction, energy cost is very high; 2. If adopt hydrobromic acid to carry out nitrile group hydrolysis and demethylation hydrolysis, the price of hydrobromic acid Expensive, the price of hydrobromic acid is 10 times that of concentrated hydrochloric acid; 3. Even if concentrated hydrochloric acid is used, due to the large amount of acid used, after the nitrile hydrolysis and demethylation hydrolysis reactions, a large amount of hydrochloric acid wastewater will be discharged, and more importantly, Unknown changes in the structure of certain compounds of DL-α-methyl-(3,4-dimethoxyphenyl)-α-aminopropionitrile (or hydrochloride) due to nitrile hydrolysis and demethylation hydrolysis, Increase by-products, partially unhydrolyzed or demethylated nitrile-containing wastes, and other nitriles with unknown structures cause certain environmental pollution

Method used

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  • Preparation of Methyldopa by Hydrolysis of α-Methyl-(3,4-Dimethoxyphenyl)-α-aminopropionitrile by Two-step Hydrolysis
  • Preparation of Methyldopa by Hydrolysis of α-Methyl-(3,4-Dimethoxyphenyl)-α-aminopropionitrile by Two-step Hydrolysis

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] In a three-neck flask equipped with a thermometer, a stirrer and a reflux condenser, add 12.3 grams (0.12 mol) of 36% concentrated hydrochloric acid. Cool to 0~5°C with ice water. Slowly add 2.18 grams (0.0085mol) of DL-2-amino-3-(3,4-dimethoxyphenyl)-2-methyl-propionitrile hydrochloride [or L-2-amino-3-( 3,4-Dimethoxyphenyl)-2-methyl-propionitrile hydrochloride, the same for the following examples] was dissolved in ice-cold concentrated hydrochloric acid. Stir vigorously for 2 hours after the addition is complete. After the reaction was completed, the temperature was raised to room temperature, and N was directly introduced into the reaction mixture slowly. 2 , while extracting excess HCl by distillation under reduced pressure. The solid was washed with 3 x 25ml of acetone to obtain a white solid. It was then vacuum dried at 50°C for 3 hours. It was further dried at 70°C for 5 hours. Obtain product DL-2-amino-3-(3,4-dimethoxyphenyl)-2-methyl-propion hydrochloride...

Embodiment 2

[0041] In a three-neck flask equipped with a thermometer, a stirrer and a reflux condenser, add 24.3 grams (0.24 mol) of 36% concentrated hydrochloric acid. Cool with ice to 0~4°C. Slowly add 14.38 grams (0.056mol) of DL--2-amino-3-(3,4-dimethoxyphenyl)-2-methyl-propionitrile hydrochloride dissolved in ice-cold concentrated hydrochloric acid, and add Afterwards, keep stirring vigorously for 2 hours at 0-4°C. After the reaction was completed, the temperature was raised to room temperature, and N was directly introduced into the reaction mixture slowly. 2 , while extracting excess HCl by distillation under reduced pressure. The solid was washed with 4×25ml of acetone to obtain a white solid. It was then vacuum dried at 50°C for 3 hours. It was further dried at 70°C for 5 hours. 14.70 g of the product DL-2-amino-3-(3,4-dimethoxyphenyl)-2-methyl-propion hydrochloride was obtained, with a yield of 95.2%.

Embodiment 3

[0043] In a three-neck flask equipped with a thermometer, a stirrer and a reflux condenser, add 24.3 grams (0.12 mol) of 18% concentrated hydrochloric acid. Cool to 0~5°C with ice water. Slowly added 2.18 g (0.0085 mol) of DL-2-amino-3-(3,4-dimethoxyphenyl)-2-methyl-propionitrile hydrochloride dissolved in ice-cold concentrated hydrochloric acid. Stir vigorously for 2 hours after the addition is complete. After the reaction was completed, the temperature was raised to room temperature, and N was directly introduced into the reaction mixture slowly. 2 , while extracting excess HCl by distillation under reduced pressure. The solid was washed with 3 x 25ml of acetone to obtain a white solid. It was then vacuum dried at 50°C for 3 hours. It was further dried at 70°C for 5 hours. 1.85 g of the product DL-2-amino-3-(3,4-dimethoxyphenyl)-2-methyl-propion hydrochloride was obtained, with a yield of 79.1%.

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Abstract

The invention belongs to the technical field of nitrile group hydrolysis and demethylation hydrolysis reaction which is one of the key steps for chemical synthesis of a methyldopa drug or a chiral drug of L-methyldopa [L-alpha-methyl-(3,4-dimethoxyphenyl)-alpha-aminopropionitrile, the same below], that is, a reaction for preparing alpha-methyl-(3,4-dimethoxyphenyl)-alpha-aminopropionitrile or L-alpha-methyl-(3,4-dimethoxyphenyl)-alpha-aminopropionitrile by nitrile group hydrolysis and demethylation hydrolysis. Under an acidic condition, the preparation of methyldopa by nitrile group hydrolysis and demethylation hydrolysis of alpha-methyl-(3,4-dimethoxyphenyl)-alpha-aminopropionitrile (or hydrochloride) requires a long period, a large material using amount, and heating hydrolysis of high-concentration acids (and the long-time heating of the high-concentration acids allows the acids to volatilize, so continuous acid addition is required during hydrolysis); however, the long-time high-concentration acid heating hydrolysis can cause unknown change of certain compound structures of alpha-methyl-(3,4-dimethoxyphenyl)-alpha-aminopropionitrile (or hydrochloride), and thus by-products are increased, and the purity and yield are decreased. Therefore, improvement of the hydrolysis technology is necessary.

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]: nitrile group hydrolysis and demethylation hydrolysis reaction. That is, α-methyl-(3,4-dimethoxyphenyl)-α-aminopropionitrile or L-α-methyl-(3,4-dimethoxyphenyl)-α-aminopropionitrile A chemical reaction for preparing methyldopa or L-methyldopa by nitrile hydrolysis and demethylation hydrolysis. 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 a...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C229/36C07C227/26
Inventor 徐伟亮徐子河汪静
Owner ZHEJIANG UNIV
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