A kind of preparation method of valganciclovir hydrochloride

A technology of valganciclovir hydrochloride and ganciclovir, which is applied in the field of medicine, can solve the problems of difficult separation of monoester and diester, unfavorable industrial production, and high price of orthoester, so as to reduce the difficulty of post-processing, The effect of less impurities and easy purification

Inactive Publication Date: 2016-04-20
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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  • A kind of preparation method of valganciclovir hydrochloride
  • A kind of preparation method of valganciclovir hydrochloride
  • A kind of preparation method of 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, and then naturally warm to room temperature to react for 3 hours. First, the solvent is evaporated under reduced pressure, and then 36.4 g of tert-butoxyphosphoryl dichloride was distilled out 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 tert-butoxyphosphoryl dichloride and 400ml dichloromethane of Example 1 into a 1000ml reaction flask, cool to below 0°C, under the protection of nitrogen, add 76.3g ganciclovir, and then add 12ml triethylamine , And then heated at 20-50 ℃ for 5 hours. The reaction was poured into ice water, the organic layer was separated, the aqueous layer was extracted once more with 200 ml of dichloromethane, the organic layers were combined, washed with water, the organic layer was dried with anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. After drying in vacuum, 73.86 g of ganciclovir monoester III was obtained with a yield of 96.8%.

Embodiment 3

[0031] Synthesis of Ganciclovir Diacetate Ⅳ

[0032] Add 49g of ganciclovir monoester and 392mL of DMF of Example 2 into a 1000ml reaction flask, stir and cool to 0~5℃, add 53.9g of CBZ-L-Val, 2.1g of DMAP, 51.1g of DCC, and react at room temperature for 6 hours. After that, the temperature was lowered to 0°C and suction filtered, 10mL DMF was soaked, the filtrate was concentrated and dried at 110°C under reduced pressure to a white solid, then 490mL of methanol was added to stir to dissolve, slowly cooled to 10°C and suction filtered, the filter cake was dried at 80°C to obtain ganciclo The crude product of Wei Dixide IV: 74 g, add 1295 mL of ethanol to the crude product, stir and raise the temperature to 75°C to dissolve, slowly lower the temperature to 0°C and suction filtration. The filter cake is dried at 80°C: 96.42g, yield: 88%, purity: 99.1%.

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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 and a prodrug of ganciclovir. It is mainly used to treat HIV-infected persons (AIDS patients) with acute retinitis caused by cytomegalovirus (CMV) infection, and Prevent 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, which has a broad market prospect. [0003] At present, the main preparation methods of valganciclovir hydrochloride are: 1. Using ganciclovir as a raw material, it is directly combined with N-benzyloxycarbonyl-L-valine-N-acyl anhydride (or N-benzyloxycarbonyl- L-valine) condensation, by controlling the reaction conditions to obtain gan...

Claims

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Application Information

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Patent Type & Authority Patents(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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