CN112176011B - Method for preparing valaciclovir hydrochloride through enzyme catalysis - Google Patents
Method for preparing valaciclovir hydrochloride through enzyme catalysis Download PDFInfo
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- CN112176011B CN112176011B CN202011160713.6A CN202011160713A CN112176011B CN 112176011 B CN112176011 B CN 112176011B CN 202011160713 A CN202011160713 A CN 202011160713A CN 112176011 B CN112176011 B CN 112176011B
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- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
- C12P17/18—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms containing at least two hetero rings condensed among themselves or condensed with a common carbocyclic ring system, e.g. rifamycin
- C12P17/182—Heterocyclic compounds containing nitrogen atoms as the only ring heteroatoms in the condensed system
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- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/18—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one oxygen and one nitrogen atom, e.g. guanine
Abstract
The invention discloses a method for preparing valacyclovir hydrochloride by enzyme catalysis, which comprises the steps of adding acyclovir, L-valine hydrochloride and purified water into a container, adding papain, stirring and reacting to obtain a valacyclovir hydrochloride crude product, wherein the reaction process comprises the following steps:
Description
Technical Field
The invention relates to the technical field of drug synthesis, in particular to a method for preparing valacyclovir hydrochloride through enzyme catalysis.
Background
Acyclovir (formula I, CAS number: 59277-89-3) is an acyclic guanine nucleoside analogue having a side chain lacking a 3-hydroxy group, which is a natural nucleoside found to have high antiviral activity, has strong antiviral activity against herpes viruses, and is now widely used worldwide as a therapeutic agent for herpes, herpes zoster, and the like. However, acyclovir is poorly water soluble and absorbed orally (only about 20%), and thus must be administered orally in large doses in order to maintain effective antiviral plasma levels, so that side effects of the drug are highlighted.
In order to overcome these drawbacks of acyclovir, amino acid esters of acyclovir were developed, and the GLaxo company first marketed acyclovir-L-valine ester as an acyclovir prodrug, which is available under the trade name of VALTREX, chinese name valacyclovir hydrochloride, chemical name: 1-L-valine-2- [ (6-oxo-2-amino-1, 6-dihydro-9H-purin-9-yl) -methoxy ] ethyl ester hydrochloride, english name: [ (2-Amino-1, 6-dihydro-6-oxo-9H-purin-9-yl) methoxy ] ethyl-L-Valinate hydrochloride, CAS registry number 124832-26-4, having the formula shown in formula II:
the medicine has obvious advantages in the aspects of oral absorbability and the like, is quickly absorbed and quickly converted into acyclovir in vivo, and the antiviral effect of the medicine is exerted by the acyclovir. The antiviral activity of the product in vivo is superior to that of acyclovir, the therapeutic index of the product to herpes simplex virus I and II is respectively 42.91 percent and 30.13 percent higher than that of acyclovir, the product also has very high curative effect to varicella zoster virus, and the product has very low toxicity to host cells of mammals. The product is converted into acyclovir quickly in vivo, and its metabolite has no accumulation in vivo. The product has the same safety as acyclovir in long-term toxicity tests at different stages.
According to literature reports, the synthesis of the compound mainly comprises the following routes:
US4957924 and EP308065 report that acyclovir is used as a starting material and is subjected to Cbz-L-valine in the presence of DCC and DMAP to generate Cbz-valacyclovir, and then palladium carbon and hydrogen are adopted to remove a Cbz protecting group, and the Cbz-valacyclovir and hydrochloric acid are subjected to salt formation to obtain valacyclovir hydrochloride. At present, the route is generally adopted in domestic production, although the process is stable, the consumption of palladium carbon is too large, the cost is relatively high, and in addition, hydrogen is used, so that the danger is high.
WO03041647 reports the formation of N-t-Boc-valacyclovir from acyclovir as starting material and Boc-L-valine in the presence of EDC and DMAP, followed by deprotection and salification under the action of acid to obtain valacyclovir. Although the route avoids using noble metal catalysts such as palladium carbon and the like, EDC hydrochloride in the method is expensive, ester bonds are easy to damage during acid hydrolysis, the post-treatment process is complex, and the product quality is unstable.
WO9803553 reports the formation of an enamine-protected sodium valine salt from L-valine with methyl acetoacetate under the action of sodium hydroxide. And reacting the acyclovir with paratoluensulfonyl chloride to obtain acyclovir phenylmethanesulfonate. Acyclovir mesylate and enamine protect sodium valine salt to generate ester exchange reaction, and deprotection is carried out under acidic condition to generate valacyclovir hydrochloride. The route has the advantages that the raw materials are relatively cheap, and the disadvantages of relatively complex route and low yield.
In addition, the invention patent with the publication number of CN101372487A adopts the valine protected by the fluorenylmethyloxycarbonyl to synthesize the valacyclovir hydrochloride, and similar to the route reported by WO03041647, the cost of the raw materials is too high, no cost advantage exists, and the industrial production is not facilitated.
In conclusion, the existing process for synthesizing valacyclovir hydrochloride generally has the defects of high cost, complex process and the like, and a large amount of organic solvents are used, so that the three wastes are difficult to treat. With the increasing environmental protection requirement and the increasing competitive price of products, the search for a green and environment-friendly synthesis process with low cost is urgent.
Disclosure of Invention
Therefore, the technical problem to be solved by the invention is to overcome the defects of high cost and complex process of valacyclovir hydrochloride preparation in the prior art, so that the method for preparing valacyclovir hydrochloride through enzyme catalysis is provided, and valacyclovir hydrochloride is prepared through one-step reaction of enzyme catalysis.
In order to solve the technical problem, the invention provides a method for preparing valacyclovir hydrochloride through enzyme catalysis, which comprises the following steps:
adding acyclovir, L-valine hydrochloride and purified water into a container, adding papain, and stirring for reaction to obtain a valacyclovir hydrochloride crude product;
the reaction process is as follows:
preferably, the method for preparing valacyclovir hydrochloride through enzyme catalysis further comprises the following steps: after stirring reaction, cooling to 0-10 ℃, stirring for 5-8 h, filtering, adding dilute acid to adjust the pH value to 3.5-5, and then adding an inverse solvent for crystallization to obtain a valacyclovir hydrochloride crude product.
Preferably, the method for preparing valacyclovir hydrochloride through enzyme catalysis further comprises the following steps: and adding the valacyclovir hydrochloride crude product and methanol into a container, heating, stirring and dissolving, then adding acetone, cooling to 0-10 ℃, and stirring for 2-6 h to obtain the required valacyclovir hydrochloride.
By adopting the technical scheme, impurities can be removed easily, and the purity of the obtained valaciclovir hydrochloride is improved.
Preferably, the molar ratio of acyclovir to L-valine hydrochloride is 1; the mass of the papain is 0.1 to 20 percent of that of the acyclovir; the mass of the purified water is 4 to 20 times of that of the acyclovir.
Preferably, the reaction temperature of the stirring reaction is 10-80 ℃, and the reaction time is 5-100 h.
Preferably, the dilute acid is dilute hydrochloric acid.
Preferably, the reverse phase solvent is one of methanol, ethanol, propanol, acetone or butanone, and the mass of the reverse phase solvent is 2-8 times of that of the purified water.
Preferably, the mass ratio of the valacyclovir hydrochloride crude product to the methanol is 1-1.
The technical scheme of the invention has the following advantages:
1. the method for preparing valacyclovir hydrochloride by enzyme catalysis adopts an enzyme catalysis method, and has the advantages that because the enzyme has specificity and mild reaction process, new impurities are hardly generated, and the post-treatment operation is simple;
2. the method for preparing valacyclovir hydrochloride by enzyme catalysis avoids using expensive reagents such as palladium, carbon and the like, has relatively low cost, does not use dangerous chemicals such as hydrogen and the like in the reaction process, and greatly reduces the safe operation risk.
3. The method for preparing valacyclovir hydrochloride through enzyme catalysis provided by the invention has the advantages that the synthetic route is short, valacyclovir hydrochloride can be obtained through one-step chemical synthesis, the operation is simple, the used solvents are conventional low-toxicity reagents, and the three-waste treatment is simple.
Detailed Description
The following examples are provided to better understand the present invention, not to limit the best mode, and not to limit the content and protection scope of the present invention, and any product that is the same or similar to the present invention and is obtained by combining the present invention with other features of the prior art and the present invention falls within the protection scope of the present invention.
The examples do not show the specific experimental steps or conditions, and can be performed according to the conventional experimental steps described in the literature in the field. The reagents or instruments used are not indicated by manufacturers, and are all conventional reagent products which can be obtained commercially.
Example 1
Adding 22.5g of acyclovir (0.1 moL) into a 250mL reaction bottle, adding 23.0g of L-valine hydrochloride (0.15 moL), adding 1.1g of papain, adding 90g of purified water, stirring, heating to 30 ℃, stirring for reaction for 70h, cooling to 0 ℃ after the reaction is finished, stirring for 6h, filtering, transferring the filtrate into a 500mL reaction bottle, adjusting the pH to 4.0 by using dilute hydrochloric acid under stirring, then dropwise adding 270g of ethanol into the system, cooling to 0 ℃, stirring for 2h, carrying out suction filtration, and drying to obtain 21.6g of valacyclovir hydrochloride crude product.
And adding the crude product obtained in the previous step into a 500mL reaction bottle, adding 64.8g of methanol, heating to 35 ℃, stirring until the mixture is clear, then dropwise adding 129.6g of acetone into the system, cooling to 0 ℃ after dropwise adding, stirring for 3 hours, filtering, leaching with acetone, and drying to obtain 10.2g of valacyclovir hydrochloride finished product with the purity of 99.52% and the yield of 28.3%.
Example 2
Adding 22.5g of acyclovir (0.1 moL) into a 250mL reaction bottle, adding 15.4g of L-valine hydrochloride (0.1 moL), adding 0.8g of papain, adding 90g of purified water, stirring, heating to 25 ℃, stirring for reaction for 90h, cooling to 10 ℃ after the reaction is finished, stirring for 6h, filtering, transferring the filtrate into a 500mL reaction bottle, adjusting the pH to 4.0 by using dilute hydrochloric acid under stirring, then dropwise adding 270g of ethanol into the system, cooling to 10 ℃, stirring for 2h, carrying out suction filtration, and drying to obtain 20.2g of valacyclovir hydrochloride crude product.
And adding the crude product obtained in the previous step into a 500mL reaction bottle, adding 80.8g of methanol, heating to 35 ℃, stirring until the mixture is clear, then dropwise adding 161.6g of acetone into the system, cooling to 10 ℃ after dropwise adding, stirring for 3 hours, filtering, leaching with acetone, and drying to obtain 9.6g of valacyclovir hydrochloride finished product with the purity of 99.63% and the yield of 26.6%.
Example 3
Adding 22.5g of acyclovir (0.1 moL) into a 250mL reaction bottle, adding 15.4g of L-valine hydrochloride (0.1 moL), adding 2.2g of papain, adding 100g of purified water, stirring, heating to 40 ℃, stirring for reaction for 80h, cooling to 5 ℃ after the reaction is finished, stirring for 6h, filtering, transferring the filtrate into a 500mL reaction bottle, adjusting the pH to 5.0 by using dilute hydrochloric acid under stirring, then dropwise adding 300g of methanol into the system, cooling to 5 ℃, stirring for 2h, carrying out suction filtration, and drying to obtain 22.0g of valacyclovir hydrochloride crude product.
And adding the crude product obtained in the previous step into a 500mL reaction bottle, adding 88.0g of methanol, heating to 35 ℃, stirring until the mixture is clear, then dropwise adding 264.0g of acetone into the system, cooling to 5 ℃ after dropwise adding, stirring for 3 hours, filtering, leaching with acetone, and drying to obtain 11.3g of valacyclovir hydrochloride finished product with the purity of 99.58% and the yield of 31.3%.
Example 4
Adding 22.5g acyclovir (0.1 moL) into a 250mL reaction bottle, adding 23.0g L-valine hydrochloride (0.15 moL), adding 2.2g papain, adding 100g purified water, stirring, heating to 35 ℃, stirring for 60 hours, cooling to 0-10 ℃ after the reaction is finished, stirring for 6 hours, filtering, transferring the filtrate into a 500mL reaction bottle, adjusting the pH to 3.5 by using dilute hydrochloric acid under stirring, then adding 300g methanol dropwise into the system, cooling to 0-10 ℃ after the dropwise addition is finished, stirring for 2 hours, carrying out suction filtration, and drying to obtain 21.5g valacyclovir hydrochloride crude product.
And adding the crude product obtained in the previous step into a 500mL reaction bottle, adding 107.5g of methanol, heating to 35 ℃, stirring until the mixture is clear, then dropwise adding 215.0g of acetone into the system, cooling to 0-10 ℃ after dropwise adding, stirring for 3 hours, filtering, leaching with acetone, and drying to obtain 10.4g of valacyclovir hydrochloride finished product with the purity of 99.70% and the yield of 28.8%.
Example 5
Adding 22.5g acyclovir (0.1 moL) into a 1000mL reaction bottle, adding 46.0g L-valine hydrochloride (0.3 moL), adding 2.2g papain, adding 450g purified water, stirring, heating to 10 ℃, stirring for 100h, cooling to 10 ℃ after the reaction is finished, stirring for 6h, filtering, transferring the filtrate into a 2000mL reaction bottle, adjusting the pH to 3.5 by using dilute hydrochloric acid under stirring, then dropwise adding 900g methanol into the system, cooling to 10 ℃, stirring for 2h, carrying out suction filtration, and drying to obtain 21.8g valacyclovir hydrochloride crude product.
Adding the crude product obtained in the previous step into a 2000mL reaction bottle, adding 218g of methanol, heating to 35 ℃, stirring until the mixture is clear, then dropwise adding 1000g of acetone into the system, cooling to 10 ℃ after the dropwise adding is finished, stirring for 3 hours, filtering, leaching with acetone, and drying to obtain 10.9g of valacyclovir hydrochloride finished product with the purity of 99.80% and the yield of 30.2%.
Example 6
Adding 22.5g of acyclovir (0.1 moL) into a 500mL reaction bottle, adding 30.7g of L-valine hydrochloride (0.2 moL), adding 2.2g of papain, adding 225g of purified water, stirring, heating to 80 ℃, stirring for 5h, cooling to 10 ℃ after the reaction is finished, stirring for 2h, filtering, transferring the filtrate into a 2000mL reaction bottle, adjusting the pH to 5 with dilute hydrochloric acid under stirring, then dropwise adding 1200g of acetone into the system, cooling to 10 ℃, stirring for 2h, carrying out suction filtration, and drying to obtain 22.5g of valacyclovir hydrochloride crude product.
And adding the crude product obtained in the previous step into a 1000mL reaction bottle, adding 67.5g of methanol, heating to 35 ℃, stirring until the mixture is clear, then dropwise adding 405.0g of acetone into the system, cooling to 10 ℃ after dropwise adding, stirring for 3 hours, filtering, leaching with acetone, and drying to obtain 10.5g of valacyclovir hydrochloride finished product with the purity of 99.70% and the yield of 29.1%.
It should be understood that the above examples are only for clarity of illustration and are not intended to limit the embodiments. Other variations and modifications will be apparent to persons skilled in the art in light of the above description. This need not be, nor should it be exhaustive of all embodiments. And obvious variations or modifications therefrom are within the scope of the invention.
Claims (8)
1. A method for preparing valacyclovir hydrochloride through enzyme catalysis is characterized by comprising the following steps:
adding acyclovir, L-valine hydrochloride and purified water into a container, adding papain, and stirring for reaction to obtain a valacyclovir hydrochloride crude product;
the reaction process is as follows:
2. the enzymatic process of making valacyclovir hydrochloride of claim 1 further comprising: after stirring reaction, cooling to 0 to 10 ℃, stirring for 5 to 8 hours, filtering, adding dilute acid to adjust the pH to 3.5 to 5, and then adding an inverse phase solvent for crystallization to obtain a valaciclovir hydrochloride crude product.
3. The enzymatic process of preparation of valacyclovir hydrochloride of claim 1 or 2 further comprising: and adding the crude valacyclovir hydrochloride and methanol into a container, heating, stirring and dissolving, then adding acetone, cooling to 0-10 ℃, and stirring for 2-6 h to obtain the required valacyclovir hydrochloride.
4. The enzymatic preparation method of valacyclovir hydrochloride according to claim 3, wherein the molar ratio of acyclovir to L-valine hydrochloride is 1; the mass of the papain is 0.1 to 20 percent of that of the acyclovir; the mass of the purified water is 4 to 20 times of that of the acyclovir.
5. The method for preparing valacyclovir hydrochloride through enzyme catalysis according to claim 4, wherein the reaction temperature of the stirring reaction is 10 to 80 ℃, and the reaction time is 5 to 100h.
6. The enzymatic process of making valacyclovir hydrochloride of claim 2 wherein the dilute acid is dilute hydrochloric acid.
7. The method for preparing valacyclovir hydrochloride through enzyme catalysis according to claim 2, wherein the reverse phase solvent is one of methanol, ethanol, propanol, acetone or butanone, and the mass of the reverse phase solvent is 2 to 8 times that of the purified water.
8. The method for preparing valacyclovir hydrochloride through enzyme catalysis according to claim 3, wherein the mass ratio of the valacyclovir hydrochloride crude product to methanol is 1 to 3 to 1, and the mass of acetone is 2 to 6 times of that of methanol.
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003040145A1 (en) * | 2001-11-05 | 2003-05-15 | Glaxo Group Limited | Anhydrous crystal form of valaciclovir hydrochloride |
| CN1903854A (en) * | 2006-08-09 | 2007-01-31 | 丽珠医药集团股份有限公司 | Method of synthesizing valaciclovir hydrochloride |
| CN101837001A (en) * | 2009-03-20 | 2010-09-22 | 帕特里克·T·普伦德加斯特 | Composition for treating infection and method |
| CN102020642A (en) * | 2010-12-30 | 2011-04-20 | 湖北华龙生物制药有限公司 | Preparation method of valaciclovir hydrochloride |
| WO2012068076A2 (en) * | 2010-11-15 | 2012-05-24 | Dr. Reddy's Laboratories Ltd. | Pharmaceutical formulations containing soluble drugs |
| CN102584825A (en) * | 2011-01-17 | 2012-07-18 | 四川科伦药物研究有限公司 | Method for synthesizing valaciclovir hydrochloride |
| CN106632335A (en) * | 2016-12-27 | 2017-05-10 | 河南康达制药有限公司 | Preparation method of valaciclovir hydrochloride |
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- 2020-10-26 CN CN202011160713.6A patent/CN112176011B/en active Active
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003040145A1 (en) * | 2001-11-05 | 2003-05-15 | Glaxo Group Limited | Anhydrous crystal form of valaciclovir hydrochloride |
| CN1903854A (en) * | 2006-08-09 | 2007-01-31 | 丽珠医药集团股份有限公司 | Method of synthesizing valaciclovir hydrochloride |
| CN101837001A (en) * | 2009-03-20 | 2010-09-22 | 帕特里克·T·普伦德加斯特 | Composition for treating infection and method |
| WO2012068076A2 (en) * | 2010-11-15 | 2012-05-24 | Dr. Reddy's Laboratories Ltd. | Pharmaceutical formulations containing soluble drugs |
| CN102020642A (en) * | 2010-12-30 | 2011-04-20 | 湖北华龙生物制药有限公司 | Preparation method of valaciclovir hydrochloride |
| CN102584825A (en) * | 2011-01-17 | 2012-07-18 | 四川科伦药物研究有限公司 | Method for synthesizing valaciclovir hydrochloride |
| CN106632335A (en) * | 2016-12-27 | 2017-05-10 | 河南康达制药有限公司 | Preparation method of valaciclovir hydrochloride |
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