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Method for preparing valganciclovir hydrochloride

A technology of valganciclovir hydrochloride and ganciclovir, applied in the field of medicine, can solve the problems of difficult separation of monoester and diester, unfavorable for industrialized production, unfavorable for industrialized production, etc., and achieves reduced post-processing difficulty and less impurities , the effect of less side effects

Inactive Publication Date: 2011-01-26
STAR LAKE BIOSCI CO INC ZHAOQING GUANGDONG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The method 1 reaction process has diester to produce, and the separation of monoester and diester is more difficult, is unfavorable for industrialized production
The orthoesters used in Method 2 are expensive and difficult to remove the protecting group
Method 3 has cumbersome process and high cost, which is not conducive to industrial production

Method used

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  • Method for preparing valganciclovir hydrochloride
  • Method for preparing valganciclovir hydrochloride
  • Method for preparing valganciclovir hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Preparation of tert-butoxyphosphoryl dichloride

[0026] Add 30.7g of phosphorus oxychloride and 30ml of dichloromethane into a 100ml reaction flask, cool to below 0°C, add 22.2g of tert-butanol dropwise, then naturally warm up to room temperature and react for 3 hours, first evaporate the solvent under reduced pressure, and then 36.4 g of tert-butoxyphosphoryl dichloride were evaporated under reduced pressure with an oil pump, with a yield of 95.1%.

Embodiment 2

[0028] Synthesis of Ganciclovir Phosphate Monoester Ⅲ

[0029] Add 40.0g of tert-butoxyphosphoryl dichloride and 400ml of dichloromethane into a 1000ml reaction flask in Example 1, cool to below 0°C, and add 76.3g of ganciclovir under nitrogen protection, and then add 12ml of triethylamine , and then heated up to react at 20-50°C for 5 hours. The reaction was poured into ice water, the organic layer was separated, the aqueous layer was extracted once more with 200ml of dichloromethane, the combined organic layers were washed with water, the organic layer was dried with anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. Vacuum dried to obtain ganciclovir monoester III 73.86g, yield 96.8%.

Embodiment 3

[0031] Synthesis of ganciclovir diester Ⅳ

[0032] Add 49g of ganciclovir monoester and 392mL of DMF in Example 2 into a 1000ml reaction flask, stir and cool down to 0-5°C, then add 53.9g of CBZ-L-Val, 2.1g of DMAP, 51.1g of DCC in sequence, and react at room temperature for 6 Hours later, cool down to 0°C for suction filtration, wash with 10mL of DMF, and dry the filtrate under reduced pressure at 110°C to a white solid, then add 490mL of methanol and stir to dissolve, slowly cool down to 10°C for suction filtration, and dry the filter cake at 80°C Cyclovir diester IV crude product: 74g, add 1295mL ethanol to the crude product, stir and heat up to 75°C to dissolve, slowly cool down to 0°C and filter with suction, and dry the filter cake at 80°C: 96.42g, yield: 88%, purity: 99.1 %.

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PUM

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Abstract

The invention discloses a method for preparing valganciclovir hydrochloride I. The method comprises the following steps of: 1, dissolving phosphorus oxychloride into an inert solvent, and performing a reaction of the mixture and the alcoholic liquor to obtain phosphoryl halide II; 2, performing a reaction of ganciclovir and the phosphoryl halide II obtained in the step to obtain ganciclovir monoester III; 3, esterfying the ganciclovir monoester III in the step 2 and N-carbobenzoxy-L-valine to obtain ganciclovir diester IV; 4, acidizing the ganciclovir diester IV in the step 3 for dephosphorylation to obtain N-carbobenzoxy-L-valine ganciclovir monoester V; and 5, performing a hydrogenation reaction on the product in the step 4 to prepare the valganciclovir hydrochloride I. By the method, the ganciclovir monoester with high purity and yield can be produced, the post-processing is easy, and the post-processing difficulty is reduced.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a new preparation method of valganciclovir hydrochloride. Background technique [0002] Valganciclovir hydrochloride is a new type of antiviral drug, the prodrug of ganciclovir, mainly used for the treatment of acute retinitis caused by cytomegalovirus (CMV) in HIV-infected patients (AIDS patients), and Prevention of CMV infection in high-risk solid organ transplant patients. The oral bioavailability of valganciclovir is much higher than that of ganciclovir, and the toxicity is greatly reduced. At present, there is no such drug on the market in China, and it has a broad market prospect. [0003] Valganciclovir hydrochloride main preparation generation method has at present: 1. take ganciclovir as raw material, directly with N-benzyloxycarbonyl-L-valine-N-acyl anhydride (or N-benzyloxycarbonyl- L--valine) condensation, obtain ganciclovir monoester by controlling the reaction co...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D473/18
Inventor 欧仁树任洪发林晓王海波王晓明
Owner STAR LAKE BIOSCI CO INC ZHAOQING GUANGDONG
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