Preparation method of valaciclovir hydrochloride
By using p-toluenesulfonyl chloride instead of DCC for esterification condensation, combined with the reduction reaction of formic acid and 10% palladium on carbon catalyst, the solid waste and safety issues in the preparation of valacyclovir hydrochloride were resolved, achieving high-yield and safe commercial production.
Patent Information
- Application Number
- CN202511958127.9
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-12-23
- Publication Date
- 2026-02-24
AI Technical Summary
Existing methods for preparing valacyclovir hydrochloride generate a large amount of solid waste DCU, which is difficult to completely remove, affecting product purity. Furthermore, the high-pressure hydrogen reduction reaction poses significant safety risks and is not suitable for commercial production.
p-Toluenesulfonyl chloride was used as the esterification condensing agent to replace DCC, and valacyclovir hydrochloride crude product was prepared by a one-pot method. Formic acid was used as the hydrogen source and 10% palladium on carbon catalyst, and methanol was used as the solvent to improve the reaction conversion rate and safety.
It reduces solid waste generation, increases product yield, lowers safety risks, is suitable for commercial production, and has a reaction conversion rate of 98%.
Smart Images
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Abstract
Description
Technical Field
[0001] This invention belongs to the field of drug synthesis technology, specifically relating to a method for preparing valacyclovir hydrochloride. Background Technology
[0002] Valacyclovir hydrochloride is an L-valine ester of acyclovir. It is a prodrug of acyclovir, and its oral bioavailability is significantly improved through esterification modification. It is a first-line drug for treating infections such as herpes simplex virus and varicella-zoster virus, and has important application value in clinical antiviral therapy. At present, valacyclovir hydrochloride has been widely used in the acute phase treatment of herpes zoster, the suppressive therapy of recurrent genital herpes, and the prevention of viral infections in immunocompromised patients. The global annual demand continues to grow, and the market urgently needs efficient, controllable and industrially suitable preparation methods.
[0003] The synthetic route of valacyclovir hydrochloride usually starts with acyclovir as the starting material, and constructs an ester bond through the condensation reaction of acyclovir with an L-valine derivative (such as L-valine methyl ester or L-valine active ester), and then obtains the target product through salt formation (hydrochlorination).
[0004] The traditional condensation agent method uses DCC (dicyclohexylcarbodiimide) as a conventional condensation agent to promote the reaction of acyclovir with L-valine methyl ester in a polar solvent. This method has mild reaction conditions, but it suffers from the following problems: ① A large amount of solid waste DCU (N,N'-dicyclohexylurea) is generated during the reaction, which is difficult to handle and completely remove, affecting the purity of the final product; ② Deprotection is mainly carried out using high-pressure hydrogenation reactions, which poses significant safety risks during hydrogen use and is not conducive to commercial production.
[0005] Existing methods for preparing valacyclovir hydrochloride still have room for improvement in terms of yield, purity, process simplicity, and cost control, especially in achieving the combined requirements of "high yield, low impurities, and suitability for industrial scale-up." Therefore, developing a synthetic route that is high-yield, cost-controllable, and easily industrialized is of great significance for ensuring a stable supply of valacyclovir hydrochloride and reducing drug costs. Summary of the Invention
[0006] This invention eliminates the use of DCC in the condensation reaction, reducing solid waste generation. It uses more environmentally friendly p-toluenesulfonyl chloride for esterification condensation and prepares crude valacyclovir hydrochloride in a one-pot process, improving product yield. Formic acid is used as the hydrogen source in the reduction reaction, 10% palladium on carbon is used as the catalyst, and methanol is used as the solvent. The reaction conversion rate is about 98%. Compared with hydrogen reduction, it increases the safety of the reaction without affecting the reaction conversion rate, making it suitable for commercial production.
[0007] To achieve the above objectives, the present invention provides the following technical solution: A method for preparing valacyclovir hydrochloride includes the following steps: (1) Condensation reaction: CBZ-L-valine is dissolved in a hydrophobic solvent, acid-binding agent and catalyst are added, the temperature is lowered to 5-10℃, p-toluenesulfonyl chloride is added, acyclovir is added at 5-10℃, the temperature is raised to 30±5℃, and the reaction is carried out at 20-30h. After the reaction is completed, drinking water is added, the liquid is separated, the organic phase is collected, and the organic phase is concentrated under reduced pressure at 40±5℃ to a viscous state to obtain CBZ-valacyclovir. (2) Reduction reaction: Add alcohol solvent to CBZ-valacyclovir obtained in step (1), then add 10% palladium on carbon and formic acid, stir and heat to 45±5℃, react for 1-3h, cool to 30±5℃, add hydrochloric acid, adjust pH=1-3, filter, collect filtrate, concentrate under reduced pressure at 45±5℃ to oily substance, add organic solvent, stir to crystallize for 1-3h, filter, dry under vacuum at 45±5℃ to obtain crude valacyclovir hydrochloride; (3) Add the crude valacyclovir hydrochloride obtained in step (2) to an alcohol solvent, stir and heat to 75±5℃, stir until completely dissolved, cool to 10±5℃ to crystallize for 1-3 hours, filter, and dry under vacuum at 45±5℃ to obtain valacyclovir hydrochloride.
[0008] Furthermore, the hydrophobic solvent in step (1) is any one of xylene, toluene, dichloromethane, and ethyl acetate.
[0009] Furthermore, in step (1), the acid-binding agent is any one of triethylamine, pyridine, and N,N-diisopropylethylamine, and the catalyst is DMAP.
[0010] Furthermore, in step (1), the molar ratio of CBZ-L-valine to acyclovir is 1:1.
[0011] Furthermore, in step (1), the molar ratio of CBZ-L-valine to the acid-binding agent is 1:2 to 3, and the molar ratio of CBZ-L-valine to the catalyst is 1:0.1 to 0.3.
[0012] Furthermore, in step (1), the molar ratio of CBZ-L-valine to p-toluenesulfonyl chloride is 1:1 to 2.
[0013] Furthermore, in step (2), the alcohol solvent is any one of methanol, ethanol, and isopropanol, and the organic solvent is any one of acetone, methanol, ethanol, and isopropanol.
[0014] Furthermore, in step (2), the molar ratio of CBZ-L-valine to formic acid is 1:5 to 10.
[0015] Furthermore, in step (3), the alcohol solvent is any one of methanol, ethanol, and isopropanol.
[0016] Furthermore, in step (3), the weight ratio of crude valacyclovir hydrochloride to alcohol solvent is 1:8-15.
[0017] This invention eliminates the use of DCC in the condensation reaction, reducing solid waste generation. It uses more environmentally friendly p-toluenesulfonyl chloride for esterification condensation and prepares crude valacyclovir hydrochloride in a one-pot process, improving product yield. Formic acid is used as the hydrogen source in the reduction reaction, 10% palladium on carbon is used as the catalyst, and methanol is used as the solvent. The reaction conversion rate is about 98%. Compared with hydrogen reduction, it increases the safety of the reaction without affecting the reaction conversion rate, making it suitable for commercial production. Attached Figure Description
[0018] Figure 1 The liquid chromatogram of valacyclovir hydrochloride in Example 1 Detailed Implementation
[0019] The present invention is further illustrated by the following examples, but these are not intended to limit the invention. Example 1
[0020] 1. Condensation reaction Add 20.0g CBZ-L-valine, 100g dichloromethane, 15.9g triethylamine, and 1g DMAP to a three-necked flask. Cool the flask to 5-10℃ and add a solution of p-toluenesulfonyl chloride in dichloromethane (18g p-toluenesulfonyl chloride + 50g dichloromethane). After the addition is complete, add acyclovir in dichloromethane (17.8g acyclovir + 50g dichloromethane) at 5-10℃. After the addition is complete, raise the temperature to 30℃ and react for 24 hours. After the reaction is complete, add 200g drinking water, separate the liquids, collect the organic phase, and concentrate the organic phase under reduced pressure at 40℃ until it becomes viscous to obtain CBZ-valacyclovir.
[0021] 2. Reduction reaction Add 300g methanol, 1.5g 10% palladium on carbon, and 25g formic acid to the above reaction solution. After the addition is complete, stir and heat to 45±5℃, react for 2h, cool to 30±5℃, add hydrochloric acid to adjust pH=2, filter, collect the filtrate, concentrate under reduced pressure at 45±5℃ to an oily substance, add 180g acetone, stir to precipitate crystals for 2h, filter, and dry under vacuum at 45±5℃ to obtain 31.6g crude valacyclovir hydrochloride with a purity of 99.1%, acyclovir 0.3%, and other single impurities <0.1%.
[0022] 3. Refined 20g of crude valacyclovir hydrochloride was added to a reaction flask, followed by 200g of ethanol. The mixture was stirred and heated to 75±5℃ until completely dissolved. The mixture was then cooled to 10±5℃ to allow crystals to precipitate for 2 hours. After filtration, the mixture was dried under vacuum at 45±5℃ to obtain 18.5g of valacyclovir hydrochloride. The total yield was 92%, the purity was 99.7%, acyclovir <0.25%, and other impurities <0.1%.
[0023] H-NMR [DMSO-d6] δ0.90-0.92 (dd, 6H, J=7.0Hz), 2.12 (m, 1H, J=7.0Hz), 3.75 (m, 2H), 3.82 (d, 1H, J=4 .5Hz), 4.20(m, 1H), 4.39(m, 1H), 5.38(s, 2H), 6.73(s, 2H), 7.83(s, 1H), 8.55(s, 3H), 11.01(s, 1H) Synthesis route: Example 2
[0024] 1. Condensation reaction Add 20.0g CBZ-L-valine, 100g xylene, 16.8g triethylamine, and 1g DMAP to a three-necked flask. Cool to 5-10℃ and add a solution of p-toluenesulfonyl chloride and xylene (20g p-toluenesulfonyl chloride + 50g xylene). After the addition is complete, add acyclovir and xylene solution (17.9g acyclovir + 50g xylene) at 5-10℃. After the addition is complete, raise the temperature to 30℃ and react for 24 hours. After the reaction is complete, add 200g drinking water, separate the liquids, collect the organic phase, and concentrate the organic phase under reduced pressure at 40℃ until it becomes viscous to obtain CBZ-valacyclovir.
[0025] 2. Reduction reaction Add 300g of ethanol, 1.5g of 10% palladium on carbon, and 28g of formic acid to the above reaction solution. After the addition is complete, stir and heat to 45±5℃, react for 2h, cool to 30±5℃, add hydrochloric acid to adjust pH=2, filter, collect the filtrate, concentrate under reduced pressure at 45±5℃ to an oily substance, add 180g of ethanol, stir to precipitate crystals for 2h, filter, and dry under vacuum at 45±5℃ to obtain 31.0g of crude valacyclovir hydrochloride with a purity of 99.5%, acyclovir 0.4%, and other single impurities <0.1%.
[0026] 3. Refined 20g of crude valacyclovir hydrochloride was added to a reaction flask, followed by 200g of ethanol. The mixture was stirred and heated to 75±5℃ until completely dissolved. The mixture was then cooled to 10±5℃ to allow crystals to precipitate for 2 hours. After filtration, the mixture was dried under vacuum at 45±5℃ to obtain 19.1g of valacyclovir hydrochloride. The total yield was 95.5%, the purity was 99.7%, acyclovir <0.25%, and other impurities <0.1%. Example 3
[0027] 1. Condensation reaction Add 20.0g CBZ-L-valine, 100g ethyl acetate, 16.5g triethylamine, and 1g DMAP to a three-necked flask. Cool to 5-10℃ and add a solution of ethyl p-toluenesulfonyl chloride (18g p-toluenesulfonyl chloride + 50g ethyl acetate) dropwise. After the addition is complete, add acyclovir ethyl acetate solution (17.8g acyclovir + 50g ethyl acetate) dropwise at 5-10℃. After the addition is complete, raise the temperature to 30℃ and react for 24 hours. After the reaction is complete, add 200g drinking water, separate the liquids, collect the organic phase, and concentrate the organic phase under reduced pressure at 40℃ until it becomes viscous to obtain CBZ-valacyclovir.
[0028] 2. Reduction reaction Add 300g isopropanol, 1.5g 10% palladium on carbon, and 25g formic acid to the above reaction solution. After the addition is complete, stir and heat to 45±5℃, react for 2h, cool to 30±5℃, add hydrochloric acid to adjust pH=2, filter, collect the filtrate, concentrate under reduced pressure at 45±5℃ to an oily substance, add 180g acetone, stir to precipitate crystals for 2h, filter, and dry under vacuum at 45±5℃ to obtain 29.3g crude valacyclovir hydrochloride with a purity of 99.3%, acyclovir 0.6%, and other single impurities <0.1%.
[0029] 3. Refined 20g of crude valacyclovir hydrochloride was added to a reaction flask, followed by 200g of methanol. The mixture was stirred and heated to 75±5℃ until completely dissolved. The mixture was then cooled to 10±5℃ to allow crystals to precipitate for 2 hours. After filtration, the mixture was dried under vacuum at 45±5℃ to obtain 17.2g of valacyclovir hydrochloride. The total yield was 86%, the purity was 99.6%, acyclovir <0.25%, and other impurities <0.1%. Example 4
[0030] 1. Condensation reaction Add 20.0g CBZ-L-valine, 120g dichloromethane, 15.9g triethylamine, and 1g DMAP to a three-necked flask. Cool the flask to 5-10℃ and add a solution of p-toluenesulfonyl chloride in dichloromethane (18g p-toluenesulfonyl chloride + 50g dichloromethane) dropwise. After the addition is complete, add acyclovir in dichloromethane (17.8g acyclovir + 50g dichloromethane) dropwise at 5-10℃. After the addition is complete, raise the temperature to 30℃ and react for 24 hours. After the reaction is complete, add 250g drinking water, separate the liquids, collect the organic phase, and concentrate the organic phase under reduced pressure at 40℃ until it becomes viscous to obtain CBZ-valacyclovir.
[0031] 2. Reduction reaction Add 320g of methanol, 1.5g of 10% palladium on carbon, and 25g of formic acid to the above reaction solution. After the addition is complete, stir and heat to 45±5℃, react for 2h, cool to 30±5℃, add hydrochloric acid to adjust pH=2, filter, collect the filtrate, concentrate under reduced pressure at 45±5℃ to an oily substance, add 200g of acetone, stir to precipitate crystals for 2h, filter, and dry under vacuum at 45±5℃ to obtain 29.7g of crude valacyclovir hydrochloride with a purity of 99.2%, acyclovir 0.5%, and other single impurities <0.1%.
[0032] 3. Refined 20g of crude valacyclovir hydrochloride was added to a reaction flask, followed by 200g of methanol. The mixture was stirred and heated to 75±5℃ until completely dissolved. The mixture was then cooled to 10±5℃ and allowed to crystallize for 2.5 hours. After filtration, the mixture was dried under vacuum at 45±5℃ to obtain 17.6g of valacyclovir hydrochloride, with a total yield of 88% and a purity of 99.5%. Acyclovir content was <0.1%, and other impurities were <0.1%.
[0033] Compared to existing technologies that use DCC (dicyclohexylcarbodiimide) as a conventional condensing agent as a catalyst, there are several problems: The reaction process generates a large amount of solid waste DCU (N,N'-dicyclohexylurea). DCU has very low solubility in almost all common organic solvents (such as ethanol, acetone, ethyl acetate, dichloromethane, etc.) and is almost insoluble in water. The urea bond in the DCU molecule is very stable, resistant to acids and alkalis, and oxidation. Conventional acid-base neutralization and oxidative decomposition methods have little effect on it. Therefore, the generated DCU must be disposed of as hazardous waste, which is a huge and continuous expense, resulting in enormous hazardous waste treatment costs. Post-treatment is also troublesome and difficult to completely remove. High processing costs pose significant environmental, health, and safety risks, impacting the purity of the final product. Existing deprotection technologies primarily utilize high-pressure hydrogenation reactions, which pose significant safety risks during hydrogen use and are unsuitable for commercial production. This invention eliminates the use of DCC in the condensation reaction, reducing solid waste generation. It employs the more environmentally friendly p-toluenesulfonyl chloride for esterification condensation and uses a one-pot method to prepare crude valacyclovir hydrochloride, improving product yield. Simultaneously, formic acid is used as the hydrogen source in the reduction reaction, along with 10% palladium on carbon as the catalyst and methanol as the solvent, achieving a conversion rate of approximately 98%. Compared to hydrogen reduction, this increases reaction safety without affecting the conversion rate, making it suitable for commercial production.
[0034] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.
Claims
1. A method for preparing valacyclovir hydrochloride, characterized in that, Includes the following steps: (1) Condensation reaction: CBZ-L-valine is dissolved in a hydrophobic solvent, acid-binding agent and catalyst are added, the temperature is lowered to 5-10℃, p-toluenesulfonyl chloride is added, acyclovir is added at 5-10℃, the temperature is raised to 30±5℃, and the reaction is carried out at 20-30h. After the reaction is completed, drinking water is added, the liquid is separated, the organic phase is collected, and the organic phase is concentrated under reduced pressure at 40±5℃ to a viscous state to obtain CBZ-valacyclovir. (2) Reduction reaction: Add alcohol solvent to CBZ-valacyclovir obtained in step (1), then add 10% palladium on carbon and formic acid, stir and heat to 45±5℃, react for 1-3h, cool to 30±5℃, add hydrochloric acid, adjust pH=1-3, filter, collect filtrate, concentrate under reduced pressure at 45±5℃ to oily substance, add organic solvent, stir to crystallize for 1-3h, filter, dry under vacuum at 45±5℃ to obtain crude valacyclovir hydrochloride; (3) Add the crude valacyclovir hydrochloride obtained in step (2) to an alcohol solvent, stir and heat to 75±5℃, stir until completely dissolved, cool to 10±5℃ to crystallize for 1-3 hours, filter, and dry under vacuum at 45±5℃ to obtain valacyclovir hydrochloride.
2. The method according to claim 1, characterized in that, The hydrophobic solvent in step (1) is any one of xylene, toluene, dichloromethane, and ethyl acetate.
3. The method according to claim 2, characterized in that, In step (1), the acid-binding agent is any one of triethylamine, pyridine, and N,N-diisopropylethylamine, and the catalyst is DMAP.
4. The method according to claim 3, characterized in that, In step (1), the molar ratio of CBZ-L-valine to acyclovir is 1:
1.
5. The method according to claim 4, characterized in that, In step (1), the molar ratio of CBZ-L-valine to the acid-binding agent is 1:2 to 3, and the molar ratio of CBZ-L-valine to the catalyst is 1:0.1 to 0.
3.
6. The method according to claim 5, characterized in that, In step (1), the molar ratio of CBZ-L-valine to p-toluenesulfonyl chloride is 1:1 to 2.
7. The method according to claim 6, characterized in that, In step (2), the alcohol solvent is any one of methanol, ethanol, and isopropanol, and the organic solvent is any one of acetone, methanol, ethanol, and isopropanol.
8. The method according to claim 7, characterized in that, In step (2), the molar ratio of CBZ-L-valine to formic acid is 1:5 to 10.
9. The method according to claim 8, characterized in that, In step (3), the alcohol solvent is any one of methanol, ethanol, and isopropanol.
10. The method according to claim 9, characterized in that, In step (3), the weight ratio of crude valacyclovir hydrochloride to alcohol solvent is 1:8-15.