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A kind of synthetic method of valganciclovir hydrochloride

A technology for valganciclovir hydrochloride and ganciclovir, which is applied in the chemical field, can solve the problems of low purity of valganciclovir hydrochloride and low purity of intermediates, and achieves controllable quality, high product purity and simple operation. Effect

Active Publication Date: 2018-03-30
湖北坦沐生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The purity of each intermediate in this route is not high, and the valganciclovir hydrochloride purity that finally obtains is on the low side

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0018] Example 1 Preparation of monoformyl ganciclovir

[0019] Put 100 grams of ganciclovir, 350 milliliters of DMF, and 75 grams of triethyl orthoformate into the reaction flask, stir, add 1 milliliter of trifluoroacetic acid, heat up to 55-65 ° C for 3 hours, and cool to 0-5 ° C , add water, heat up to 60°C and stir for 15 minutes, then cool to 0-5°C, filter to obtain a wet product. Put the wet product into a reaction bottle, add 130 ml of DMSO, heat up to 65°C, stir to dissolve, add 90 ml of methanol, cool and crystallize, filter at room temperature, and dry at 85°C to obtain 85 grams with a purity of more than 95%.

Embodiment 2

[0020] Example 2 Preparation of Monoacetylganciclovir

[0021] Put 100 grams of ganciclovir, 350 milliliters of DMF, and 70 grams of trimethyl orthoacetate into the reaction flask, stir, add 1 milliliter of trifluoroacetic acid, heat up to 55-65 ° C for 3 hours, and cool to 0-5 ° C , add water, heat up to 60°C and stir for 15 minutes, then cool to 0-5°C, filter to obtain a wet product. Put the wet product into a reaction bottle, add 130 ml of DMSO, heat up to 65°C, stir to dissolve, add 90 ml of methanol, cool and crystallize, filter at room temperature, and dry at 85°C to obtain 82 grams. The purity is above 94%.

Embodiment 3

[0022] The preparation of embodiment 3 N-benzyloxycarbonyl valganciclovir

[0023] Put 96 grams of monoformylganciclovir, 480 milliliters of DMF and 96 grams of DCC into the reaction flask, stir, then add 102 grams of CBZ-L-valine and 6.72 grams of DMAP, and react at a temperature below 10°C for 24 hours , then add 500 milliliters of ethyl acetate and 480 milliliters of water, filter, wash with 300 milliliters of ethyl acetate, combine the filtrate and washings, separate the organic layer, wash with saturated brine, concentrate under reduced pressure, add 288 milliliters of water and 72 ml of hydrochloric acid, stirred at room temperature for 5 hours, added 864 ml of water, adjusted the pH value to 6 with ammonia water, filtered, put the obtained solid into the reaction bottle, added 324 g of acetic acid, stirred to dissolve, added 800 ml of hot water at 50°C, and cooled to room temperature, filtered, and dried at 70°C to obtain 83 grams with a purity of over 98.5%.

[0024] ...

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PUM

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Abstract

The invention discloses a novel valganciclovir hydrochloride synthesis method. The method includes: taking ganciclovir as a raw material, adopting ortho-ester for protecting a hydroxyl radical, then subjecting to condensation with N-carbobenzoxy-L-valine, and performing hydrolysis reaction to obtain N-carbobenzoxy valganciclovir; performing hydrogenation reduction reaction to obtain valganciclovir hydrochloride. The product purity reaches 99.0% or above and accords with United States Pharmacopeia standards.

Description

technical field [0001] The invention belongs to the technical field of chemistry and relates to a novel synthesis method of valganciclovir hydrochloride. Background technique [0002] The synthetic technology of existing valganciclovir hydrochloride generally has long synthetic route, or needs special protective group, or impurity is difficult to control, or has special requirement to production equipment and condition, or final product purity is not high etc., causes The high synthesis cost of this product is unfavorable for industrialized large-scale production. details as follows: [0003] Existing U.S. Patent No. US6083953, the technology uses guanine derivatives as raw materials, and reacts with different propane derivatives through condensation, hydrolysis and hydrogenation to prepare valganciclovir hydrochloride. The total yield is low, and the used propane derivatives are not easy Made, the production cost is very high. [0004] Existing U.S. Patent No. US5756736,...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D473/18
CPCC07D473/18
Inventor 李红英甘斌陈超王雪平王水才
Owner 湖北坦沐生物科技有限公司
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