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High-purity ganciclovir monoacetate preparation method

A technology of ganciclovir and monoacetyl, which is applied in the field of preparation of high-purity monoacetyl ganciclovir, can solve the problem that the purity of monoacetyl ganciclovir is difficult to achieve ideal quality, affects the quality of valganciclovir, and separates Difficulty in purification and other problems, to achieve the effect of reducing cost and environmental pollution, improving conversion rate and yield, and good reaction selectivity

Inactive Publication Date: 2018-08-17
ANHUI HAIKANG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The main disadvantage of this method is that diacetyl ganciclovir is produced, and the content of diacetyl ganciclovir accounts for 17-21%, and the separation of monoacetyl and diacetyl products is difficult, resulting in the purity of monoacetyl ganciclovir obtained At around 90-95%, it ultimately affects the quality of valganciclovir
[0007] In summary, the common disadvantages of preparing monoacetyl ganciclovir at the present stage are monoacetyl ganciclovir and by-product diacetyl ganciclovir and residual raw material ganciclovir or triacetyl ganciclovir Difficulties in the separation and purification of the product make it difficult for the purity of the product monoacetylganciclovir to reach the ideal quality

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Add 500.0g (1.96mol, 1.0eq) of ganciclovir, 244.0g (0.98mol, 0.5eq) of dibutyltin oxide, and 5.0kg of tetrahydrofuran into the reaction kettle, heat to reflux for 3 hours, and control the reaction of raw materials in TLC. Completely, lowered to room temperature, added iodine 49.7g (0.196mol, 0.1eq), then added dropwise 337.5g (3.92mol, 2.0eq) of vinyl acetate, stirred at room temperature for 5 hours, controlled monoacetylganciclovir and impurities in HPLC The ratio is 95 / 3, lower the temperature to 0-10°C, add 2.0kg of methanol dropwise, stir at room temperature for 2 hours, concentrate the solvent under reduced pressure, add 3.0kg of ethyl acetate, filter out insoluble matter, and wash the filtrate once with 500g of water. The layers were separated, the aqueous layer was extracted with 500 g of ethyl acetate, the organic layers were combined, concentrated under reduced pressure, and recrystallized from ethanol to obtain 434.5 g of colorless crystals, yield 74.6%, purity...

Embodiment 2

[0034] Add 500.0g (1.96mol, 1.0eq) of ganciclovir, 244.4g (2.35mol, 1.2eq) of trimethyl borate, and 7.5kg of toluene into the reaction kettle, heat to reflux for 5 hours, and the reaction of the raw materials in TLC is complete. , lowered to room temperature, added 396.7g (3.93mol, 2.0eq) of triethylamine, then added 323.7g (2.94mol, 1.5eq) of 1-acetylimidazole, stirred at room temperature for 6 hours, and controlled monoacetylganciclovir in HPLC The ratio of N, O-diacetylganciclovir to N,O-diacetylganciclovir is 94 / 4, lower the temperature to 0-10°C, add 2.0kg of methanol dropwise, after dropping, stir at room temperature for 2 hours, concentrate the solvent under reduced pressure, add 3.0kg of ethyl acetate , washed once with 500g water, separated, the aqueous layer was extracted with 500g ethyl acetate, the organic layers were combined, concentrated under reduced pressure, recrystallized from ethanol to obtain 440.9g of colorless crystals, yield 75.7%, purity 99.2%, mp 133.9...

Embodiment 3

[0036]Add 500.0g (1.96mol, 1.0eq) of ganciclovir, 314.7g (2.15mol, 1.1eq) of triethyl borate, and 5.0kg of 2-methyltetrahydrofuran into the reaction kettle, and heat to reflux for 3 hours. Control the raw materials to react completely, lower to room temperature, add 595.0g (5.88mol, 3.0eq) of triethylamine, then add 421.8g (4.9mol, 2.5eq) of vinyl acetate, stir at room temperature for 6 hours, control monoacetylganciclo in HPLC The ratio of Wei and N,O-diacetylganciclovir is 93 / 5, lower the temperature at 0-10°C, add 2.0kg of ethanol dropwise, after dropping, stir at room temperature for 3 hours, concentrate the solvent under reduced pressure, add 3.0kg of ethyl acetate Esters, washed once with 500g water, separated, the aqueous layer was extracted with 500g ethyl acetate, the organic layers were combined, concentrated under reduced pressure, recrystallized from ethanol to obtain 438.0g of colorless crystals, yield 75.2%, purity 99.1%, mp 133.6-134.5 ℃, MS (m / z) 298.2 (M+H) +...

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Abstract

The invention discloses a high-purity ganciclovir monoacetate preparation method which comprises the following steps: utilizing ganciclovir as a raw material and protecting alcoholic hydroxyl by methyl boronic acid; then adding an acetylation reagent to perform selective acetylation to obtain ganciclovir monoacetate. The preparation method disclosed by the invention has the advantages of high rawmaterial conversion rate and good acetylation selectivity; a content of the obtained ganciclovir monoacetate can reach 99% or more, synthesizing quality of follow-up valganciclovir products is improved, production efficiency is high, and the preparation method is suitable for large-scale industrial production.

Description

technical field [0001] The invention belongs to the field of synthesis of pharmaceutical intermediates, in particular to a preparation method of high-purity monoacetylganciclovir. Background technique [0002] Valganciclovir, a prodrug of ganciclovir, is indicated for the treatment of retinitis caused by cytomegalovirus (CMV) in AIDS patients and for the long-term treatment of kidney transplant patients at risk of cytomegalovirus (CMV) disease After oral administration, it can be hydrolyzed into ganciclovir by phosphatase in the intestinal tract and liver to play an antiviral effect, but its bioavailability is significantly higher than that of ganciclovir, which is 10 times that of ganciclovir, and its toxicity is greatly Reduced, and oral administration is convenient, and the market share of valganciclovir has increased year by year in recent years, and the market prospect is broad. [0003] [0004] Monoacetylganciclovir, the chemical name is 9-(1-acetoxy-3-hydroxyl-2-...

Claims

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Application Information

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IPC IPC(8): C07D473/18
CPCC07D473/18
Inventor 张小顺
Owner ANHUI HAIKANG PHARMA
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