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Method of synthesizing valaciclovir hydrochloride

A technology of valacyclovir hydrochloride and hydrochloric acid, which is applied in the field of drug synthesis, can solve the problems of high anti-corrosion requirements, low solubility, and large amount of precious metal palladium carbon in reaction kettles, etc., so as to avoid high-pressure reaction equipment, mild reaction conditions, Apply promising effects

Active Publication Date: 2007-01-31
LIVZON PHARM GRP INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] There are following problems in this synthetic method industrialized production: because the condensate of acyclovir and CBZ-L-valine has low solubility in common solvents, in order to make the reaction complete, generally use DMF or methanol, tetrahydrofuran mixed solvent to do solvent
First of all, DMF has better solubility to condensates, but it is not a good carrier of hydrogen, and because it contains an amide structure, it has a poisonous effect on the catalyst, making the amount of precious metal palladium carbon larger and difficult to recycle, resulting in uneconomical industrial production; secondly, methanol 1. Although tetrahydrofuran mixed solvent is a good carrier of hydrogen, its solubility to condensates is not good, and it needs to be mixed to a concentration of 2%, and hydrochloric acid needs to be added to the reaction, and hydrochloric acid is added to the autoclave, which requires the corrosion resistance of the reaction kettle High, so special equipment is required, and even this is very dangerous in production and cannot be mass-produced

Method used

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  • Method of synthesizing valaciclovir hydrochloride
  • Method of synthesizing valaciclovir hydrochloride
  • Method of synthesizing valaciclovir hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Embodiment 1, preparation valacyclovir hydrochloride

[0029] a, the preparation of CBZ-L-valine-acyclovir

[0030] CBZ-L-valine (3.1g, 0.012mol), 4-(dimethylamino)pyridine (DMAP) (0.2g, 0.0016mol) were dissolved in 20ml N, N-dimethylformamide (DMF), Acyclovir (2.0 g, 0.009 mol) was added, and a solution of 1,3-dicyclohexylcarbodiimide (DCC) (5 g, 0.024 mol) dissolved in DMF (10 ml) was added dropwise to the reaction at room temperature React for 12 hours, add 1ml of water to terminate the reaction, filter, concentrate the filtrate to a small volume, add methanol and heat to dissolve, stir and cool down to -10°C, stir overnight, and vacuum dry to obtain 3.7g of pure product

[0031] B, prepare valacyclovir hydrochloride

[0032] CBZ-L-valine-acyclovir (5g, 0.011mol) was added to a mixed solvent containing 15ml of formic acid and 15ml of water, and 1g of 5% palladium carbon was added, stirred at room temperature, and gas was continuously emitted during the reaction. T...

Embodiment 2

[0034] a, the preparation of PMZ-L-valine

[0035]

[0036] Put L-valine (25g, 0.21mol) in a 500ml three-neck flask, dissolve it with 110ml of 2N NaOH, stir at -5 to 0°C and slowly add 120ml of PMZ-Cl (50g, 0.25mol) di Chloromethane solution, while continuously adding 2N NaOH (130ml) dropwise to maintain the reaction at about pH 9, after the addition, continue to stir and react at room temperature for 1h. Then wash twice with diethyl ether, discard the ether layer, add 150ml ethyl acetate to the water layer, slowly add 6N hydrochloric acid dropwise to PH1 under constant stirring, separate the ethyl acetate layer, extract the water layer twice with ethyl acetate, About 50ml each time, combine ethyl acetate, wash with 5% sodium chloride until neutral, dry with anhydrous magnesium sulfate, then concentrate ethyl acetate under reduced pressure to obtain a viscous substance, add a small amount of petroleum ether to stir, and then add a large amount of Petroleum ether was filter...

Embodiment 3

[0042] a, the preparation of PNZ-L-valine

[0043]

[0044] Put L-valine (10g, 0.085mol) in a 250ml three-neck flask, dissolve it with 50ml 2N NaOH, stir at -5 to 0 degrees and slowly add 50ml of PNZ-Cl (22g, 0.1mol) Dichloromethane solution, while continuously adding 2N NaOH (50ml) dropwise to maintain the reaction at about pH 9, after the addition, continue to stir and react at room temperature for 1h. Then wash twice with diethyl ether, discard the ether layer, add 60ml ethyl acetate to the water layer, slowly add 6N hydrochloric acid dropwise to pH 1 under constant stirring, separate the ethyl acetate layer, promote the water layer twice with ethyl acetate, About 20ml each time, combined ethyl acetate, washed with 5% sodium chloride until neutral, dried with anhydrous magnesium sulfate, then concentrated ethyl acetate under reduced pressure to obtain a viscous substance, added a small amount of petroleum ether to stir, and then added a large amount of Petroleum ether w...

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Abstract

The present invention discloses a method for synthesizing valacyclovir hydrochloride. Said method is characterized by that said method includes the following steps: making the aminoprotected L-valine-acyclovir implement reaction in the solvent containing formic acid or form ate under the action of Pd / C catalyst, after the reaction is completed, using hydrochloric acid to make acidification so as to obtain the invented product.

Description

technical field [0001] The invention relates to a method for synthesizing medicine, in particular to a method for synthesizing valacyclovir hydrochloride. Background technique [0002] Acyclovir is the acyclic analogue of natural nucleoside, and its chemical name is 9-(2-hydroxyethoxymethyl) guanine (CAS Registry No. 59277-89-3), US4199574 first discloses the use of acyclovir Wei treats virus infection, and its structural formula is shown in formula I. Acyclovir has strong antiviral activity against herpes viruses, and is now widely used in the world as a therapeutic drug for herpes, herpes zoster, and the like. However, acyclovir has poor water solubility and oral absorbability (about 20%), so there is a problem that a large amount of aciclovir must be administered in order to maintain an effective antiviral concentration in plasma. [0003] (Formula I) [0004] In order to improve these properties, esters formed by acyclovir and amino acids have been developed, especi...

Claims

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Application Information

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IPC IPC(8): C07D473/30
Inventor 冯军汪华白俊杰毛文金张晶
Owner LIVZON PHARM GRP INC
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