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Preparation method for levodopa intermediate derivative

A technology of levodopa intermediates and derivatives is applied in the field of preparation of levodopa intermediate derivatives, and can solve the problems of complicated steps, high cost, unsuitable for industrial production and the like

Active Publication Date: 2015-06-24
SHANGHAI INST OF PHARMA IND CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The problem to be solved by the present invention is that, in order to overcome the existing defects such as relatively cumbersome steps for splitting levodopa intermediates, high cost, and unsuitability for industrialized production, the present invention provides a preparation of levodopa intermediate derivatives method

Method used

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  • Preparation method for levodopa intermediate derivative
  • Preparation method for levodopa intermediate derivative
  • Preparation method for levodopa intermediate derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] Resolution method of (±)-3,4-dimethoxyphenylalanine ethyl ester

[0053] Dissolve 4.96g (±)-3,4-dimethoxyphenylalanine ethyl ester in 30mL ethanol, and add a mixture consisting of 3.56g (+)-dibenzoyltartaric acid and 20mL ethyl acetate under stirring Solution, after standing at room temperature for 24 hours, a large amount of solids precipitated, filtered, washed with a little 3:2 mixed solvent of ethanol and ethyl acetate, and dried to obtain 3.24g [(-)-3,4-dimethoxybenzene ethyl alanine] 2 • (+)-Dibenzoyltartaric acid. The resolution chemical yield was 38.0%, and the optical content by HPLC was 97.2%.

[0054] The salt was placed in an aqueous solution of sodium carbonate (the amount of sodium carbonate used was 0.5 e.q.[(-)-3,4-dimethoxyphenylalanine ethyl ester] 2 ·(+)-dibenzoyl tartaric acid), the temperature is controlled below 5°C, reacted, extracted with ethyl acetate, and evaporated to get (-)-3,4-dimethoxyphenylalanine ethyl acetate.

Embodiment 2

[0056] Resolution method of (±)-3,4-dimethoxyphenylalanine ethyl ester

[0057] Dissolve 4.96g (±)-3,4-dimethoxyphenylalanine ethyl ester in 25mL ethanol, add 3.76g (+)-dibenzoyl tartaric acid monohydrate and 25mL ethyl acetate under stirring After standing at room temperature for 24 hours, a large amount of solids were precipitated, filtered, washed with a little 1:1 mixed solvent of ethanol and ethyl acetate, and dried to obtain 3.1g [(-)-3,4-dimethyl Oxyphenylalanine ethyl ester] 2 • (+)-Dibenzoyltartaric acid. The resolution chemical yield was 36.4%, and the optical content by HPLC was 97.7%.

[0058] The salt was placed in an aqueous solution of sodium carbonate (the amount of sodium carbonate used was 0.5 e.q.[(-)-3,4-dimethoxyphenylalanine ethyl ester] 2 ·(+)-dibenzoyl tartaric acid), the temperature is controlled below 5°C, reacted, extracted with ethyl acetate, and evaporated to get (-)-3,4-dimethoxyphenylalanine ethyl acetate.

Embodiment 3

[0060] Resolution method of (±)-3,4-dimethoxyphenylalanine methyl ester

[0061] Dissolve 4.96g of (±)-3,4-dimethoxyphenylalanine methyl ester in 30mL of methanol, and add a mixture consisting of 3.56g of (+)-dibenzoyltartaric acid and 15mL of ethyl acetate under stirring Solution, after standing at room temperature for 24 hours, a large amount of solids were precipitated, filtered, washed with a little 2:1 mixed solvent of methanol and ethyl acetate, and dried to obtain 3.38g [(-)-3,4-dimethoxybenzene Alanine methyl ester] 2 • (+)-Dibenzoyltartaric acid. The resolution chemical yield was 39.7%, and the optical content by HPLC was 97.4%.

[0062] The salt was placed in an aqueous solution of sodium carbonate (the amount of sodium carbonate used was 0.5 e.q.[(-)-3,4-dimethoxyphenylalanine methyl ester] 2 ·(+)-dibenzoyl tartaric acid), the temperature is controlled below 5°C, reacted, extracted with ethyl acetate, and evaporated to get (-)-3,4-dimethoxyphenylalanine acid met...

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Abstract

The invention relates to a preparation method for a levodopa intermediate derivative. The preparation method comprises: in a solvent, reacting 3, 4-dimethoxybenzene phenylalanine shown as formula I with (+)-tartaric acid derivative to obtain the salt of a [(-)-3, 4-dimethoxybenzene phenylalanine]2.(+)- tartaric acid derivative. The solvent includes an alcohol solvent and an ester solvent. The racemization method includes: in the solvent, under the action of an aldehyde or ketone catalyst, reacting the 3, 4-dimethoxybenzene phenylalanine shown as formula I at 0-90DEG C for 0.5-24 h. The preparation method for the levodopa intermediate derivative provided by the invention has simple steps, and the prepared enantiomer has high purity and is low in cost, thus being applicable to industrial production. (reaction formula).

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a preparation method of a levodopa intermediate derivative. Background technique [0002] L-(-)-3,4-dimethoxyphenylalanine ester or L-(-)-3,4-dimethoxyphenylalanine ester salt is an important pharmaceutical intermediate, which can be used in Prepare levodopa. [0003] Levodopa is an effective drug for the treatment of Parkinson's syndrome and the like. Its structural formula is shown in the following formula (2): [0004] [0005] In the prior art, domestically produced levodopa raw materials are mainly extracted from quinoa seeds, and the price follows the price of agricultural products, with large fluctuations, and it is difficult to effectively control the impurities of the product. [0006] However, there are no industrial reports on the preparation of levodopa by biological fermentation and chemical synthesis; the production of levodopa in foreign countries adopts asymmet...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C229/36C07C227/18C07C227/36C07C69/78C07C67/00
Inventor 翟宁周后元蔡南平王宏博
Owner SHANGHAI INST OF PHARMA IND CO LTD
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