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Preparation method of sodium salt of N-(all trans-retinol)-L-cystathionine methyl ester

A technology of methyl cystylate and all-trans, which is applied in the direction of organic chemistry, can solve the problems of low product yield, long reaction time, and low product purity, and achieve high product yield, improved product purity, and high product purity. high effect

Active Publication Date: 2019-09-10
SHANGHAI MODERN PHARMA ENG INVESTIGATION CENT +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The technical problem to be solved by this invention is in order to overcome the required amount of solvent that exists in the preparation method of the sodium salt of existing N-(all-trans-retinoyl)-L-cystesulfonate methyl ester in the prior art Large, inconvenient operation, easy to emulsify in the subsequent extraction process, difficult to separate, difficult to operate, and incomplete extraction leads to a large number of all-trans retinoic acid residues in the obtained product, low product purity, etc., and synthetic The intermediate all-trans retinoic acid butyric anhydride has poor stability in aqueous solution and is easy to degrade in the solvent system, and the raw material L-methyl cystesulfonate cannot be completely dissolved, resulting in low product yield and long reaction time etc., thus providing a method for preparing the sodium salt of N-(all-trans-retinoyl)-L-cysteinesulfonate methyl ester

Method used

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  • Preparation method of sodium salt of N-(all trans-retinol)-L-cystathionine methyl ester
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  • Preparation method of sodium salt of N-(all trans-retinol)-L-cystathionine methyl ester

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Experimental program
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Effect test

Embodiment 1

[0047] Preparation of all-trans retinoic acid butyric anhydride reaction solution: In a 100mL four-necked flask, add all-trans retinoic acid (2.7g, 9mmol), 18mL tetrahydrofuran, 36mL acetonitrile, and 1.5mL triethylamine in sequence at room temperature , placed in a low-temperature cooling tank, mechanically stirred, and when the reaction system was cooled to -20°C, slowly added butyl chloroformate (1.26mL, 9.9mmol), after the addition was complete, the reaction was continued for 30min to obtain all-trans retinoic acid butyric anhydride The reaction solution.

[0048] Preparation of the sodium salt of N-(all-trans-retinoyl)-L-cysteinesulfonate methyl ester: in a 250mL four-neck flask, add L-cysteinesulfonate methyl ester (2.97g , 13.5mmol), 60mL N,N-dimethylformamide, 2.4mL triethylamine, mechanical stirring, room temperature, after stirring for 30min, began to slowly add the all-trans retinoic acid butyric anhydride reaction solution obtained above. After the dropwise additi...

Embodiment 2

[0054] Preparation of all-trans retinoic acid butyric anhydride reaction solution: In a 100mL four-necked flask, add all-trans retinoic acid (2.7g, 9mmol), 18mL tetrahydrofuran, 36mL acetonitrile, and 1.5mL triethylamine in sequence at room temperature , placed in a low-temperature cooling tank, mechanically stirred, and when the reaction system was cooled to -20°C, butyl chloroformate (1.26mL, 9.9mmol) was slowly added. After the addition was complete, the reaction was continued for 30min. Obtain all-trans retinoic acid butyric anhydride reaction liquid.

[0055] Preparation of the sodium salt of N-(all-trans-retinoyl)-L-cysteinesulfonate methyl ester: in a 250mL four-neck flask, add L-cysteinesulfonate methyl ester (2.97g , 13.5mmol), 90mL N,N-dimethylformamide, 2.4mL triethylamine, mechanical stirring, room temperature, after stirring for 30min, began to slowly add the all-trans retinoic acid butyric anhydride reaction solution obtained above. After the dropwise addition, ...

Embodiment 3

[0057] Preparation of all-trans retinoic acid butyric anhydride reaction solution: In a 100mL four-necked flask, add all-trans retinoic acid (2.7g, 9mmol), 18mL tetrahydrofuran, 36mL acetonitrile, and 1.5mL triethylamine in sequence at room temperature , placed in a low-temperature cooling tank, mechanically stirred, and when the reaction system was cooled to -20°C, butyl chloroformate (1.26mL, 9.9mmol) was slowly added. After the addition was complete, the reaction was continued for 30min. Obtain all-trans retinoic acid butyric anhydride reaction liquid.

[0058] Preparation of the sodium salt of N-(all-trans-retinoyl)-L-cysteinesulfonate methyl ester: in a 250mL four-neck flask, add L-cysteinesulfonate methyl ester (2.97g , 13.5mmol), 60mL N,N-dimethylformamide, 3mL diisopropylethylamine, mechanical stirring, room temperature, after stirring for 30min, began to slowly add the all-trans retinoic acid butyric anhydride reaction solution obtained above. After the dropwise addi...

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Abstract

The invention discloses a preparation method of sodium salt of N-(all trans-retinol)-L-cystathionine methyl ester shown as formula I-Na. The preparation method comprises the following steps: step 1, in a dipolar aprotic solvent, performing acylation reaction on all-trans retinoic acid butyric anhydride shown in formula III and L-cystathionine methyl ester shown in formula II in the presence of organic base to obtain N-(all-trans-retinol)-L-cystathionine methyl ester shown in formula I; and step 2, prepare the n-(all trans-retinol)-l-cystathionine methyl ester shown in formula I obtained in thestep 1 into the sodium salt of n-(all trans-retinol)-l-cystathionine methyl ester shown in the formula I-Na. The preparation method disclosed by the invention has mild reaction conditions, simple operation, high yield and high purity of the obtained product. The production cost is low, the equipment requirement is low, and the method is suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of chemical synthesis, and in particular relates to a preparation method of sodium salt of N-(all-trans-retinoyl)-L-cysteinesulfonate methyl ester. Background technique [0002] The sodium salt of N-(all-trans-retinoyl)-L-cysteine ​​methyl ester has a therapeutic effect by itself, and when it is used in combination with cytotoxic compounds such as docetaxel and doxorubicin, it has synergistic effect. It can be prepared into water-soluble preparations with poorly soluble drugs (such as docetaxel), which can increase the solubility of the drug and enhance pharmacological activity; it can be prepared into water-soluble preparations with water-soluble drugs (such as doxorubicin), The therapeutic window of the drug can be increased, and the therapeutic efficacy can be improved. The structural formula of N-(all-trans-retinoyl)-L-cysteine ​​methyl ester is shown in I: [0003] [0004] The compound and its preparation ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C403/20
CPCC07C403/20C07C2601/16
Inventor 何军成佳佳王哲烽李昌盛王君吉周思维曾馨王笑笑杨亚妮卞玮倪美萍益兵王圣利牛明浩
Owner SHANGHAI MODERN PHARMA ENG INVESTIGATION CENT
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