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Preparation method of D-tryptophan lower alcohol ester hydrochloride with high optical purity

A technology of alcohol ester hydrochloride and alcohol ester sulfonate, which is applied in the field of preparation of tadalafil intermediates, can solve the problems of low optical purity and low yield, improve optical purity, stabilize the production process, avoid Effects of decomposition and other side reactions

Inactive Publication Date: 2013-12-11
ZHANGJIAGANG HUACHANG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Because tryptophan is more sensitive to acid, it is easy to decompose and racemize in a strong acidic system. The preparation of D-tryptophan lower alcohol ester hydrochloride by conventional methods not only has low yield and low optical purity of the product

Method used

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  • Preparation method of D-tryptophan lower alcohol ester hydrochloride with high optical purity
  • Preparation method of D-tryptophan lower alcohol ester hydrochloride with high optical purity
  • Preparation method of D-tryptophan lower alcohol ester hydrochloride with high optical purity

Examples

Experimental program
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Effect test

Embodiment 1

[0028] This example provides a kind of preparation method of D-tryptophan methyl ester hydrochloride, specifically as follows:

[0029] Add 1mol D-tryptophan (204g) into 400mL tetrahydrofuran, stir, add 206g 1.2mol methyl benzenesulfonate in batches, heat to 60°C, react for 8 hours, distill off tetrahydrofuran, add 300mL purified water, stir well Finally, adjust the pH to about 9.5 with 10wt% NaOH solution, extract with butyl acetate (250mL*3), combine the butyl acetate extract, wash with purified water (150mL*2), and dehydrate the butyl acetate extract with molecular sieve A3 overnight. Filter out the molecular sieves, pass dry hydrogen chloride gas into the butyl acetate extract, make the pH to about 4.5, evaporate most of the butyl acetate, and precipitate most of the crystals after cooling, and vacuum-dry the crystals after filtration to obtain a white solid 228 gram, which is D-tryptophan methyl ester hydrochloride, with an optical purity of 99.61% (HPLC), and a calculat...

Embodiment 2

[0031] This example provides a kind of preparation method of D-tryptophan ethyl ester hydrochloride, specifically as follows:

[0032] Add 1mol D-tryptophan (204g) into 400mL tetrahydrofuran, stir, add 223g 1.2mol ethyl benzenesulfonate in batches, heat to 60°C, react for 8 hours, distill off tetrahydrofuran, add 300mL purified water, stir well Finally, adjust the pH to about 9.0 with 10wt% NaOH solution, extract with butyl acetate (250mL*3), combine the butyl acetate extract, wash with purified water (150mL*2), and dehydrate the butyl acetate extract with molecular sieve A3 overnight. Filter out the molecular sieves, pass dry hydrogen chloride gas into the butyl acetate extract, make the pH to about 4.5, evaporate most of the butyl acetate, and precipitate most of the crystals after cooling, and vacuum-dry the crystals after filtration to obtain a white solid 236 gram, which is D-tryptophan ethyl ester hydrochloride, with an optical purity of 99.56% (HPLC), and a calculated ...

Embodiment 3

[0034] This example provides a kind of preparation method of D-tryptophan propyl ester hydrochloride, specifically as follows:

[0035] Add 1mol D-tryptophan (204g) into 400mL tetrahydrofuran, stir, add 240g 1.2mol propyl benzenesulfonate in batches, heat to 60°C, react for 8 hours, distill off tetrahydrofuran, add 300mL purified water, stir well Finally, adjust the pH to about 10 with 10wt% NaOH solution, extract with butyl acetate (250mL*3), combine the butyl acetate extract, wash with purified water (150mL*2), and dry the butyl acetate extract with anhydrous sodium sulfate , dehydrated overnight. Filter off anhydrous sodium sulfate, pass dry hydrogen chloride gas into the butyl acetate extract, make the pH to about 4.5, evaporate most of the butyl acetate, precipitate most of the crystals after cooling, and vacuum-dry the crystals after filtration to obtain 245 g of white solid is D-tryptophan propyl ester hydrochloride, the optical purity is 99.53% (HPLC), and the calcula...

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Abstract

The invention relates to a preparation method of a D-tryptophan lower alcohol ester hydrochloride with high optical purity. The preparation method comprises the steps of: (1) reacting D-tryptophan and sulfoacid lower alcohol ester in a solvent at the temperature of 25-100 DEG C to produce D-tryptophan lower alcohol ester sulfonate; (2) dissolving the D-tryptophan lower alcohol ester sulfonate in water, adjusting the pH to alkaline with alkali so as to invert the D-tryptophan lower alcohol ester sulfonate into D-tryptophan low alcohol ester, performing extraction with an organic solvent after reaction is finished, and adding a drying agent for dehydration to obtain an extract liquor containing D-tryptophan low alcohol ester; and (3) introducing dry hydrogen chloride gas into the extract liquor containing D-tryptophan low alcohol ester to react, thereby producing the D-tryptophan lower alcohol ester hydrochloride. The preparation method is stable during production and avoids tryptophan decomposition and other side reactions, so that both the yield and the optical purity of the D-tryptophan lower alcohol ester hydrochloride are enhanced.

Description

technical field [0001] The invention relates to a preparation method of a tadalafil intermediate, in particular to a preparation method of D-tryptophan lower alcohol ester hydrochloride. Background technique [0002] D-Tryptophan lower alcohol (C1~C6) ester hydrochloride is an extremely important intermediate in the synthesis of Tadalafil (also known as Cialis), its purity, especially optical purity, is directly related to the quality of Tadalafil quality. [0003] In the prior art, D-tryptophan lower alcohol ester hydrochloride is usually prepared by conventional synthetic methods of amino acid ester hydrochloride, specifically acid-catalyzed direct esterification method and thionyl chloride method. Because tryptophan is more sensitive to acid, it is easy to decompose and racemize in a strong acidic system. The preparation of D-tryptophan lower alcohol ester hydrochloride by conventional methods not only has low yield but also low optical purity of the product. Contents ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/20
Inventor 庞靖李苑陈绘如庞宝华王平
Owner ZHANGJIAGANG HUACHANG PHARMA
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