Catalyst, preparation method and application in valaciclovir hydrochloride synthesis

Abstract

The invention provides a catalyst, a preparation method and application in valaciclovir hydrochloride synthesis, and the preparation method comprises the following steps: (1) dissolving a palladium reagent in hydrochloric acid, and diluting with a solvent to obtain a mixture; (2) dropwise adding the mixture into the carrier dispersion liquid, uniformly mixing, further dropwise adding a precipitator, and adjusting the pH value to prepare a precursor solution; (3) dropwise adding the reducing agent solution into the precursor solution, stirring and aging, and then carrying out suction filtration, washing and drying to obtain a catalyst; or filtering and drying the precursor solution, and reducing by using a reducing agent to obtain the catalyst. According to the catalyst, in the practical application that a high-pressure reaction kettle is used as a reactor and a valaciclovir hydrochloride intermediate is used as a raw material for a hydrodebenzylation reaction, the conversion rate of the raw material is greater than 99%, and the selectivity of a target product is greater than 99%.

Description

Technical Field

[0001] This invention relates to the fields of organic catalytic hydrogenation and fine chemical catalytic hydrogenation technology, specifically to a catalyst, its preparation method, and its application in the synthesis of valacyclovir hydrochloride, and more specifically to a catalyst for the debenzylidene hydrochloride, its preparation method, and its application in the synthesis of valacyclovir hydrochloride. Background Technology

[0002] Valacyclovir hydrochloride is a highly effective, broad-spectrum antiviral prodrug that is rapidly converted into acyclovir in the body. Compared to traditional acyclovir, it has significant advantages such as high oral absorption and utilization, and less frequent dosing, making it a first-line drug for the clinical treatment of herpes zoster, herpes simplex (such as genital herpes), and chickenpox. This drug works by inhibiting viral DNA replication, and its effectiveness is best achieved when taken as early as 24-48 hours after the onset of symptoms.

[0003] US4957924 disclosed an earlier method for preparing valacyclovir hydrochloride, which involves condensing CBZ-valine with acyclovir in dimethylformamide (DMF) using 4-dimethylaminopyridine (DMAP) as a catalyst to form protected valacyclovir; subsequently, Pd / C is used for catalytic hydrogenation to remove the CBZ protecting group, thereby converting it into hydrochloride.

[0004] CN1903854A discloses an improved synthetic method in which L-valine-acyclovir with amino-protected groups (such as CBZ, PNZ, or PMZ groups) is reacted in a solvent containing formic acid or formate (such as ammonium formate, sodium formate, etc.) under the action of a Pd / C catalyst. This method can complete the reduction and deprotection at room temperature, avoiding the high-pressure equipment required for conventional hydrogenation reduction, and is suitable for industrial production.

[0005] CN106632335A provides a preparation process in an anhydrous ethanol system, in which CBZ(BOC)-L-valine-acyclovir is reacted with a hydrogen donor under the action of a catalyst (such as palladium-polyethyleneimine) at 65-75℃ for hydrogenation deprotection. After the reaction is completed, the mixture is acidified with hydrochloric acid to pH 3.8-6.2 to obtain the finished product.

[0006] CN109651371A also discloses a preparation route using a Pd / C catalyst. Under nitrogen protection, CBZ-L-valine-acyclovir is dissolved in a mixture of methanol and water. After heating to 20°C, formic acid is added, and the reaction is carried out at 40°C for 2 hours to complete deprotection. Finally, hydrochloric acid alcohol solution is added and acetone is added to crystallize and obtain the product.

[0007] US20070112193A1 mentions an alternative, namely, using Pd / Al2O3 as a catalyst in the presence of hydrogen to reduce the CBZ-protected intermediate to form valacyclovir.

[0008] In addition, the method disclosed in CN1612878A focuses on using tert-butyloxycarbonyl (BOC) as a protecting group, deprotecting it in aqueous solution with concentrated hydrochloric acid, and then adding isopropanol to precipitate valacyclovir hydrochloride. This route does not involve a Pd / C catalytic hydrogenation process.

[0009] None of these existing technologies mention research on catalyst design, but catalysts play a crucial role. Therefore, there is an urgent need for a synthesis method of efficient and long-life Pd / C catalysts to significantly improve the overall synthesis process of valacyclovir hydrochloride. Summary of the Invention

[0010] Based on the above technical objectives, the present invention provides a catalyst and its preparation method and its application in the synthesis of valacyclovir hydrochloride. In practical applications where the catalyst is used as a reactor in a high-pressure reactor and valacyclovir hydrochloride intermediate is used as a raw material for hydrogenation and debenzylation reaction, the raw material conversion rate is greater than 99% and the selectivity of the target product is greater than 99%.

[0011] In a first aspect, a method for preparing a catalyst is provided, comprising the following steps: (1) Dissolve the palladium reagent in hydrochloric acid and dilute it with a solvent to obtain a mixture; (2) Add the mixture dropwise to the carrier dispersion, mix evenly, add precipitant dropwise, adjust pH, and then prepare the precursor solution; (3) Add the reducing agent solution dropwise to the precursor solution, stir and age, filter, wash and dry to obtain the catalyst; or filter the precursor solution, dry it, and reduce it with a reducing agent to obtain the catalyst.

[0012] In some embodiments, the palladium reagent is selected from at least one of palladium chloride, palladium nitrate, palladium sulfate, palladium acetate, palladium chloropalladium, potassium chloropalladium, and palladium acetylacetonate.

[0013] In some embodiments, the solvent is selected from at least one of methanol, ethanol, acetonitrile, acetone, tetrahydrofuran, and ultrapure water.

[0014] In some embodiments, the mass ratio of the carrier to the palladium reagent is 95:(5-10), preferably 95:5, 95:6, 95:7, 95:8, 95:8.33, 95:8.5, 95:9, 95:10, or any two of the above values ​​forming a range.

[0015] In some embodiments, the carrier is selected from alumina, activated carbon, molecular sieve, silica, acid-modified activated carbon, or alkali-modified activated carbon.

[0016] In some embodiments, the solid-liquid mass ratio of the carrier to hydrochloric acid is 95:(1-5), in g / mL, preferably 95:1, 95:2, 95:3, 95:4, 95:5, or any two of the above values ​​forming a range. In this invention, the hydrochloric acid concentration range is 1 M.

[0017] In some embodiments, in step (2), the reaction temperature is room temperature, which is in the range of 10-35°C, preferably 15-30°C.

[0018] In some embodiments, the time for uniform mixing is 1 to 6 hours.

[0019] In some embodiments, the precipitant is one of sodium hydroxide, potassium hydroxide, lithium hydroxide, and sodium carbonate.

[0020] In some embodiments, the precipitant is a sodium hydroxide solution or potassium hydroxide solution with a concentration of 0.1-2 M, preferably 1 M.

[0021] In some embodiments, the precipitant is used to adjust the pH to 8-12, preferably any one of any two values ​​from 8, 9, 10, 11, 12.

[0022] In some embodiments, the reducing agent is at least one selected from hydrazine hydrate, sodium borohydride, formaldehyde, methanol, formic acid, ethanol, ethylene glycol, or hydrogen. In some embodiments, the formaldehyde solution has a mass concentration of 37%. In some embodiments, the hydrazine hydrate solution has a mass concentration of 80%. Through reduction, Pd in ​​the precursor is reduced to Pd. 0 .

[0023] In some embodiments, the volume ratio of the mixture to the carrier dispersion is 1:(1-5), preferably 1:1, 1:2, 1:3, 1:4, 1:5, or any two of the above values ​​forming a range.

[0024] In some embodiments, the reduction temperature for stirring aging is 0-120℃, preferably any one of the following ranges: 0℃, 10℃, 20℃, 30℃, 40℃, 50℃, 60℃, 70℃, 80℃, 90℃, 100℃, 110℃, 120℃, and any two of the above values.

[0025] In some embodiments, the volume ratio of the mixture to the reducing agent solution is 5:(1-5), preferably 5:1, 5:2, 5:3, 5:4, 5:5, or any two of the above values ​​forming a range.

[0026] In some embodiments, the mass ratio of the carrier to the reducing agent is 95:(1-5), preferably 95:1, 95:2, 95:3, 95:3.2, 95:4, 95:5, and any two of the above values ​​forming a range.

[0027] In some embodiments, the mass-to-volume ratio of the carrier to the reducing agent is 95:(10-500), preferably 95:10, 95:20, 95:30, 95:35, 95:40, 95:50, 95:100, 95:150, 95:200, 95:250, 95:300, 95:400, 95:500, or any two of the above values ​​forming any one of the ranges.

[0028] In some embodiments, the reduction time for stirring aging is 12-24 h, preferably 12 h, 14 h, 15 h, 16 h, 18 h, 20 h, 22 h, 24 h, or any two of the above values ​​forming a range.

[0029] In some embodiments, the drying temperature is 40-100°C, preferably 40°C, 50°C, 60°C, 70°C, 80°C, 90°C, 100°C, or any two of the above values ​​forming a range.

[0030] In some embodiments, the drying time is 12-24 h, preferably 12 h, 14 h, 15 h, 16 h, 18 h, 20 h, 22 h, 24 h, or any two of the above values ​​forming a range.

[0031] In some embodiments, when the reducing agent is hydrogen, the temperature is increased to 100°C at 5°C / min, hydrogen is introduced, and the catalyst is obtained by reduction for 2-3 hours.

[0032] Secondly, a catalyst is provided, which is prepared by the method described in this invention.

[0033] Thirdly, the invention provides an application of the catalyst described in the present invention in the synthesis of valacyclovir hydrochloride, the application including: CBZ-L-valine-acyclovir was dissolved in a mixed solution of methanol, water and hydrochloric acid, and the catalyst described in this invention was added. The mixture was heated to 50°C under a nitrogen atmosphere, and hydrogen gas was introduced at a pressure of 0.1-0.5 MPa for 2 h to prepare valacyclovir hydrochloride.

[0034] In some embodiments, the volume ratio of methanol, water and hydrochloric acid is 30:10:1, and the concentration of hydrochloric acid is 1 mol / L.

[0035] In some embodiments, the mass ratio of CBZ-L-valine-acyclovir to the catalyst is (50-200):1, preferably 100:1.

[0036] In some embodiments, the mass-to-volume ratio of CBZ-L-valine-acyclovir to water is 1:5.

[0037] The high-pressure reactor was purged with nitrogen three times. After leak testing to confirm that there were no leaks, the temperature was raised to the reaction temperature, and then hydrogen gas at an appropriate pressure was introduced to start the reaction.

[0038] Compared with the prior art, one of the above technical solutions has the following advantages or beneficial effects: This invention prepares a catalyst metal precursor under acidic conditions, which is then further added dropwise onto an activated carbon support to stabilize Pd adsorption. The pH is then adjusted using a specific precipitant to allow Pd to adsorb. 2+ The Pd / C catalyst is prepared by converting Pd(OH)2 onto a support and reducing it with a specific reducing agent. The resulting Pd / C catalyst has the highest activity and higher dispersion, achieving a synergistic improvement in activity and stability.

[0039] The catalyst of this invention exhibits excellent catalytic performance in the hydrogenolysis of CBZ-L-valine-acyclovir to valacyclovir hydrochloride, significantly improving the yield and purity of the target product while reducing reaction energy consumption and cost. When applied to hydrogenation, the catalyst achieves a feed conversion rate greater than 99% and a target product selectivity greater than 99%.

[0040] The Pd / C catalyst prepared by the method of this invention has the characteristics of high product yield, low cost and low chemical waste, which is conducive to industrial application and promotion. Attached Figure Description

[0041] Figure 1 This is a transmission electron microscope (TEM) image of catalyst 3 prepared in Example 3. From... Figure 1 It is evident that the metal particles are well dispersed.

[0042] Terminology Explanation Certain embodiments of the invention will now be described in detail, examples of which are illustrated by the accompanying structural and chemical formulas. The invention is intended to cover all alternatives, modifications, and equivalents, all of which are included within the scope of the invention as defined in the claims. Those skilled in the art will recognize that many similar or equivalent methods and materials can be used to practice the invention. The invention is by no means limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ from or contradict this application (including, but not limited to, defined terminology, application of terminology, described techniques, etc.), this application shall prevail.

[0043] It should be further appreciated that certain features of the invention, for clarity, have been described in multiple independent embodiments, but may also be provided in combination in a single embodiment. Conversely, various features of the invention, for brevity, have been described in a single embodiment, but may also be provided individually or in any suitable sub-combination.

[0044] Unless otherwise stated, all technical terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art. All patents and publications related to this invention are incorporated herein by reference in their entirety.

[0045] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of the present invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. Moreover, those skilled in the art can combine and integrate the features of the embodiments or examples in this specification without contradiction. Detailed Implementation

[0046] The following provides various embodiments or examples to enable those skilled in the art to implement the invention based on the description. These are merely examples and not intended to limit the invention. The endpoints and values ​​of the ranges disclosed herein are not limited to precise ranges or values; these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, endpoint values ​​of various ranges, endpoint values ​​of various ranges and individual point values, and individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed herein.

[0047] In the description of this specification, references to terms such as "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of the invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples.

[0048] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to embodiments. The specific embodiments described herein are for illustrative purposes only and are not intended to limit the invention in any way. Furthermore, descriptions of well-known structures and techniques are omitted in the following description to avoid unnecessarily obscuring the concepts of this disclosure. Such structures and techniques have also been described in many publications.

[0049] All reagents used in this invention can be purchased commercially or prepared by the methods described in this invention.

[0050] Example 1: 95 g of activated carbon support was uniformly dispersed in 1000 mL of ultrapure water to form a mixed solution. 8.33 g of palladium chloride was weighed and dissolved in 1 mL of 1 M hydrochloric acid, then diluted with water to 500 mL. The diluted solution was added dropwise to the mixed solution with continuous stirring to ensure uniform loading on the support. A 1 M NaOH aqueous solution was prepared. After the addition was complete, the NaOH aqueous solution was added dropwise to the mixed solution to adjust the pH to 10. Then, 3.2 g of NaBH4 was weighed and dissolved in 200 mL of ultrapure water, which was slowly added dropwise to the mixed solution. After the addition was complete, the solution was stirred continuously for 12 h. After stirring, the solution was filtered, washed 5 times, and placed in an oven at 80 °C. After drying for 12 h, catalyst 1 was obtained.

[0051] Example 2: 95 g of activated carbon support was uniformly dispersed in 1000 mL of ultrapure water to form a mixed solution. 8.33 g of palladium chloride was weighed and dissolved in 1 mL of 1 M hydrochloric acid, then diluted with water to 500 mL. The diluted solution was added dropwise to the mixed solution with continuous stirring to ensure uniform loading on the support. A 1 M NaOH aqueous solution was prepared. After the addition was complete, the NaOH aqueous solution was added dropwise to the mixed solution to adjust the pH to 10. Then, 5.87 g of 80% hydrazine hydrate was weighed and dissolved in 200 mL of ultrapure water, and slowly added dropwise to the mixed solution. After the addition was complete, the solution was stirred continuously for 12 h. After stirring, the solution was filtered, washed 5 times, and placed in an oven at 80℃. After drying for 12 h, catalyst 2 was obtained.

[0052] Example 3: 95 g of activated carbon support was uniformly dispersed in 1000 mL of ultrapure water to form a mixed solution. 8.33 g of palladium chloride was weighed and dissolved in 1 mL of 1 M hydrochloric acid, then diluted with water to 500 mL. The diluted solution was added dropwise to the mixed solution with continuous stirring to ensure uniform loading on the support. A 1 M NaOH aqueous solution was prepared. After the addition was complete, the NaOH aqueous solution was added dropwise to the mixed solution to adjust the pH to 10. Then, 40 mL of 37% formaldehyde solution was taken, diluted with ultrapure water to 200 mL, and slowly added dropwise to the mixed solution. After the addition was complete, the solution was stirred continuously for 12 h. After stirring, the solution was filtered, washed 5 times, and placed in an oven at 80℃. After drying for 12 h, catalyst 3 was obtained.

[0053] Example 4: 95 g of activated carbon support was uniformly dispersed in 1000 mL of ultrapure water to form a mixed solution. 8.33 g of palladium chloride was weighed and dissolved in 1 mL of 1 M hydrochloric acid, then diluted with water to 500 mL. The diluted solution was added dropwise to the mixed solution with continuous stirring to ensure uniform loading on the support. A 1 M NaOH aqueous solution was prepared. After the addition was complete, the NaOH aqueous solution was added dropwise to the mixed solution to adjust the pH to 10. Then, 500 mL of ethanol solution was added to the mixed solution, and the mixture was heated to 90 °C and refluxed for 12 h. After cooling to room temperature, the mixture was filtered, washed five times, and placed in an oven at 80 °C. After drying for 12 h, catalyst 4 was obtained.

[0054] Example 5: 95 g of activated carbon support was uniformly dispersed in 1000 mL of ultrapure water to form a mixed solution. 8.33 g of palladium chloride was weighed and dissolved in 1 mL of 1 M hydrochloric acid. The solution was diluted with water to 500 mL, and the diluted solution was added dropwise to the mixed solution with continuous stirring to ensure uniform loading on the support. A 1 M NaOH aqueous solution was prepared. After the addition was complete, the NaOH aqueous solution was added dropwise to the mixed solution to adjust the pH to 10. The solution was then filtered, washed five times, and placed in an oven at 80 °C. After drying for 12 h, the catalyst precursor was obtained. The catalyst precursor was placed in a tube furnace, purged three times with nitrogen, and then heated to 100 °C at a rate of 5 °C / min. Hydrogen was introduced, and the mixture was reduced for 3 h to obtain catalyst 5.

[0055] Example 6: 95 g of activated carbon support was uniformly dispersed in 1000 mL of ultrapure water to form a mixed solution. 8.33 g of palladium chloride was weighed and dissolved in 1 mL of 1 M hydrochloric acid. The solution was diluted with water to 500 mL, and the diluted solution was added dropwise to the mixed solution with continuous stirring to ensure uniform loading on the support. A 1 M NaOH aqueous solution was prepared. After the addition was complete, the NaOH aqueous solution was added dropwise to the mixed solution to adjust the pH to 10. The solution was stirred continuously for 12 h. After stirring, the solution was filtered, washed five times, and placed in an oven at 80 °C. After drying for 12 h, catalyst 6 was obtained.

[0056] Example 7: 95 g of activated carbon support was uniformly dispersed in 1000 mL of ultrapure water to form a mixed solution. 8.33 g of palladium chloride was weighed and dissolved in 1 mL of 1 M hydrochloric acid, then diluted with water to 500 mL. The diluted solution was added dropwise to the mixed solution with continuous stirring to ensure uniform loading on the support. Then, 3.2 g of NaBH4 was weighed and dissolved in 200 mL of ultrapure water, which was slowly added dropwise to the mixed solution. After the addition was complete, the solution was stirred continuously for 12 h. After stirring, the solution was filtered, washed 5 times, and placed in an oven at 80 °C. After drying for 12 h, catalyst 7 was obtained.

[0057] Example 8: 95 g of activated carbon support was uniformly dispersed in 1000 mL of ultrapure water to form a mixed solution. 8.33 g of palladium chloride was weighed and dissolved in 1 mL of 1 M hydrochloric acid, then diluted with water to 500 mL. The diluted solution was added dropwise to the mixed solution with continuous stirring to ensure uniform loading on the support. A 1 M NaOH aqueous solution was prepared. After the addition was complete, the NaOH aqueous solution was added dropwise to the mixed solution to adjust the pH to 10. Then, 1.6 g of NaBH4 was weighed and dissolved in 100 mL of ultrapure water, and slowly added dropwise to the mixed solution. After the addition was complete, the solution was stirred continuously for 12 h. After stirring, the solution was filtered, washed 5 times, and placed in an oven at 80 °C. After drying for 12 h, catalyst 8 was obtained.

[0058] Example 9: 95 g of alumina support was uniformly dispersed in 1000 mL of ultrapure water to form a mixed solution. 8.33 g of palladium chloride was weighed and dissolved in 1 mL of 1 M hydrochloric acid, then diluted with water to 500 mL. The diluted solution was added dropwise to the mixed solution with continuous stirring to ensure uniform loading on the support. A 1 M NaOH aqueous solution was prepared. After the addition was complete, the NaOH aqueous solution was added dropwise to the mixed solution to adjust the pH to 10. Then, 3.2 g of NaBH4 was weighed and dissolved in 200 mL of ultrapure water, which was slowly added dropwise to the mixed solution. After the addition was complete, the solution was stirred continuously for 12 h. After stirring, the solution was filtered, washed 5 times, and placed in an oven at 80 °C. After drying for 12 h, catalyst 9 was obtained.

[0059] Example 10: 95 g of alumina support was uniformly dispersed in 1000 mL of ultrapure water to form a mixed solution. 8.33 g of palladium chloride was weighed and dissolved in 1 mL of 1 M hydrochloric acid, then diluted with water to 500 mL. The diluted solution was added dropwise to the mixed solution with continuous stirring to ensure uniform loading on the support. A 1 M KOH aqueous solution was prepared. After the addition was complete, the KOH aqueous solution was added dropwise to the mixed solution to adjust the pH to 10. Then, 3.2 g of NaBH4 was weighed and dissolved in 200 mL of ultrapure water, which was slowly added dropwise to the mixed solution. After the addition was complete, the solution was stirred continuously for 12 h. After stirring, the solution was filtered, washed 5 times, and placed in an oven at 80 °C. After drying for 12 h, catalyst 10 was obtained.

[0060] Example 11: 100 g of activated carbon support was uniformly dispersed in 1000 mL of ultrapure water and heated to 90 °C for boiling. The catalyst was then treated with 5% nitric acid, washed, and filtered. 95 g of the treated activated carbon support was uniformly dispersed in 1000 mL of ultrapure water to form a mixed solution. 8.33 g of palladium chloride was weighed and dissolved in 1 mL of 1 M hydrochloric acid. The solution was diluted with water to 500 mL and added dropwise to the mixed solution while continuously stirring to ensure uniform loading on the support. A 1 M NaOH aqueous solution was prepared. After the addition was complete, the NaOH aqueous solution was added dropwise to the mixed solution to adjust the pH to 10. Then, 3.2 g of NaBH4 was weighed and dissolved in 200 mL of ultrapure water, which was slowly added dropwise to the mixed solution. After the addition was complete, the solution was stirred continuously for 12 h. After stirring, the solution was filtered, washed 5 times, and placed in an oven at 80 °C. After drying for 12 h, catalyst 11 was obtained.

[0061] Example 12: 95 g of alumina support was uniformly dispersed in 1000 mL of ultrapure water to form a mixed solution. 8.33 g of palladium chloride was weighed and dissolved in 12 mL of ammonia water, then diluted with water to 500 mL. The diluted solution was added dropwise to the mixed solution while continuously stirring to ensure uniform loading on the support. Then, 3.2 g of NaBH4 was weighed and dissolved in 200 mL of ultrapure water, which was slowly added dropwise to the mixed solution. After the addition was complete, the mixture was stirred continuously for 12 h. After stirring, the mixture was filtered, washed five times, and placed in an oven at 80 °C. After drying for 12 h, catalyst 12 was obtained.

[0062] Example 13: 100 g of activated carbon support was uniformly dispersed in 1000 mL of ultrapure water and heated to 90 °C for boiling. The catalyst was then treated with 5% sodium hydroxide, washed, and filtered. 95 g of the treated activated carbon support was uniformly dispersed in 1000 mL of ultrapure water to form a mixed solution. 8.33 g of palladium chloride was weighed and dissolved in 1 mL of 1 M hydrochloric acid. The solution was diluted with water to 500 mL and added dropwise to the mixed solution while continuously stirring to ensure uniform loading on the support. A 1 M NaOH aqueous solution was prepared. After the addition was complete, the NaOH aqueous solution was added dropwise to the mixed solution to adjust the pH to 10. Then, 3.2 g of NaBH4 was weighed and dissolved in 200 mL of ultrapure water, and slowly added dropwise to the mixed solution. After the addition was complete, the solution was stirred continuously for 12 h. After stirring, the solution was filtered, washed 5 times, and placed in an oven at 80 °C. After drying for 12 h, catalyst 13 was obtained.

[0063] Example 14: 95 g of activated carbon support was uniformly dispersed in 1000 mL of ultrapure water to form a mixed solution. 9.16 g of palladium chloride was weighed and dissolved in 1 mL of 1 M hydrochloric acid, then diluted with water to 500 mL. The diluted solution was added dropwise to the mixed solution with continuous stirring to ensure uniform loading on the support. A 1 M NaOH aqueous solution was prepared. After the addition was complete, the NaOH aqueous solution was added dropwise to the mixed solution to adjust the pH to 10. Then, 40 mL of 37% formaldehyde solution was taken, diluted with ultrapure water to 200 mL, and slowly added dropwise to the mixed solution. After the addition was complete, the solution was stirred continuously for 12 h. After stirring, the solution was filtered, washed 5 times, and placed in an oven at 80 °C. After drying for 12 h, catalyst 14 was obtained.

[0064] Example 15: 95 g of activated carbon support was uniformly dispersed in 1000 mL of ultrapure water to form a mixed solution. 7.50 g of palladium chloride was weighed and dissolved in 1 mL of 1 M hydrochloric acid, then diluted with water to 500 mL. The diluted solution was added dropwise to the mixed solution with continuous stirring to ensure uniform loading on the support. A 1 M NaOH aqueous solution was prepared. After the addition was complete, the NaOH aqueous solution was added dropwise to the mixed solution to adjust the pH to 10. Then, 40 mL of 37% formaldehyde solution was taken, diluted with ultrapure water to 200 mL, and slowly added dropwise to the mixed solution. After the addition was complete, the solution was stirred continuously for 12 h. After stirring, the solution was filtered, washed 5 times, and placed in an oven at 80 °C. After drying for 12 h, catalyst 15 was obtained.

[0065] Example 1: The initial activity of the Pd / C catalyst prepared in the embodiments of this application was evaluated using valacyclovir hydrochloride intermediate (CBZ-L-valine-acyclovir) as a raw material.

[0066]

[0067] 10 g of valacyclovir hydrochloride intermediate (CBZ-L-valine-acyclovir) (Formula (I)) was dissolved in a mixed solution of 150 mL methanol, 50 mL water, and 5 mL hydrochloric acid. 0.1 g of catalyst was added, and the mixture was then added to a 500 mL high-pressure reactor. The reactor was purged three times with nitrogen, then heated to 50 °C and purged with hydrogen at 0.2 MPa for 2 h. Subsequent liquid chromatography or TLC analysis showed no residual raw materials. Post-processing yielded valacyclovir hydrochloride (Formula (II)). The product yields are shown in Table 1 below.

[0068] Table 1 Results of the hydrogenation reaction

[0069] The results are shown in Table 1. From catalysts 1-5, it can be concluded that under the same reduction conditions, catalysts prepared with different reducing agents exhibit varying catalytic performance for the hydrodebenzylation reaction of the valacyclovir hydrochloride intermediate. This indicates that the characteristics of the reducing agent affect the reduction efficiency during the catalytic reduction process. For example, NaBH4 is unstable and easily decomposes; adding excessive NaBH4 may lead to boron residue. Hydrazine hydrate has slightly weaker reducing power and is also easily decomposed and corrosive, but its decomposition products are relatively clean and do not easily remain on the catalyst surface. Formaldehyde has weak reducing power; the Pd nanoparticles formed during the reduction process are not easily agglomerated, have small particle size, good dispersibility, and many active sites, resulting in strong catalytic activity. Ethanol also has weak reducing power; it is difficult to reduce Pd without heating.2+ Restore all to Pd 0 .

[0070] Compared with catalyst 1, when catalyst 6 was prepared, the catalyst Pd(OH)2 / C showed poor catalytic effect on the hydrodebenzylation reaction of the valacyclovir hydrochloride intermediate when Pd was not reduced, indicating that the 0-valent Pd nanoparticles mainly played a role in the reaction.

[0071] Compared to catalyst 1, catalyst 7 is prepared by directly loading it onto activated carbon under acidic conditions, and then reducing Pd(Cl)4. 2- Restored to Pd 0 Its catalyst has poor performance in the hydrodebenzylation reaction of valacyclovir hydrochloride intermediate.

[0072] Compared to catalyst 1, catalyst 8 decomposes itself when reduced with a smaller amount of NaBH4 during its preparation, resulting in insufficient catalyst reduction. Therefore, the catalyst's performance in the hydrodebenzylation reaction of the valacyclovir hydrochloride intermediate is reduced.

[0073] Compared to catalyst 1, catalysts 9, 11, and 13 are prepared using different supports, and their overall activity is reduced. Therefore, activated carbon with a larger specific surface area is generally selected as the support. Even after treating the support with acid or alkali, the overall activity of catalysts 11 and 13 for the hydrodebenzylation reaction of the valacyclovir hydrochloride intermediate does not increase but decreases, which may be related to the performance of different carbon supports.

[0074] The comparison of the effects of catalyst 9 and catalyst 10 shows that using KOH as a precipitant results in poorer catalyst activity. Therefore, NaOH is generally chosen as the precipitant and pH adjustment solution during the preparation process.

[0075] The comparison of the effects of catalyst 12 and catalyst 1 shows that the catalyst precursor Pd(NH)4 prepared by modifying palladium chloride with alkali has better performance. 2+ It is further used to synthesize catalyst 12. For the hydrodebenzylation reaction of valacyclovir hydrochloride intermediate, its overall activity decreases instead of increases, which may be related to the different catalyst properties.

[0076] As can be seen from catalysts 3, 14 and 15, different amounts of palladium loading result in different catalytic performances for the hydrodebenzylation reaction of the valacyclovir hydrochloride intermediate, with catalyst 3 showing the best performance.

[0077] In practical applications of the catalyst prepared by this invention, using valacyclovir hydrochloride intermediate as a raw material for the hydrogenation debenzylation reaction, the raw material conversion rate is greater than 99% and the selectivity of the target product is greater than 99%.

[0078] like Figure 1 The transmission electron microscopy (TEM) characterization image of catalyst 3 shown shows that its particles are uniformly dispersed and have an average particle size of 3-5 nm. The data in Table 1 prove that the catalyst has strong catalytic activity.

[0079] The method of this invention has been described through preferred embodiments. Those skilled in the art will readily be able to modify or appropriately alter and combine the methods and applications described herein within the scope, spirit, and context of this invention to implement and apply the technology of this invention. Those skilled in the art can refer to the content herein to appropriately improve process parameters. It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art and are considered to be included within the scope of this invention.

Claims

1. A method for preparing a catalyst, characterized in that, include: (1) Dissolve the palladium reagent in hydrochloric acid and dilute it with a solvent to obtain a mixture; (2) Add the mixture dropwise to the carrier dispersion, mix evenly, add precipitant dropwise, adjust pH, and then prepare the precursor solution; (3) Add the reducing agent solution dropwise to the precursor solution, stir and age, filter, wash and dry to obtain the catalyst; or filter the precursor solution, dry it, and reduce it with a reducing agent to obtain the catalyst.

2. The preparation method according to claim 1, characterized in that, The palladium reagent is selected from at least one of palladium chloride, palladium nitrate, palladium sulfate, palladium acetate, palladium chloroplastate, potassium palladium chloroplastate, and palladium acetylacetone. And / or, the solvent is selected from at least one of methanol, ethanol, acetonitrile, acetone, tetrahydrofuran, and ultrapure water; And / or, the carrier is selected from alumina, activated carbon, molecular sieve, silica, acid-modified activated carbon, or alkali-modified activated carbon.

3. The preparation method according to claim 1, characterized in that, The mass ratio of the carrier to the palladium reagent is 95:(5-10). And / or, the solid-liquid mass ratio of the carrier to hydrochloric acid is 95:(1-5).

4. The preparation method according to claim 1, characterized in that, In step (2), the reaction temperature is room temperature, which ranges from 10 to 35°C; And / or, the time for uniform mixing is 1 to 6 hours; And / or, the precipitant is one of sodium hydroxide, potassium hydroxide, lithium hydroxide, and sodium carbonate; And / or, the precipitant is a sodium hydroxide solution or potassium hydroxide solution with a concentration of 0.1-2 M; And / or, the precipitant is used to adjust the pH to 8-12.

5. The preparation method according to claim 1, characterized in that, The reducing agent is at least one of hydrazine hydrate, sodium borohydride, formaldehyde, methanol, formic acid, ethanol, ethylene glycol, or hydrogen. And / or, the formaldehyde solution has a mass concentration of 37%; And / or, the mass concentration of the hydrazine hydrate solution is 80%.

6. The preparation method according to claim 1, characterized in that, The volume ratio of the mixture to the carrier dispersion is 1:(1-5). And / or, the reduction temperature for the stirring aging is 0-120 °C; And / or, the volume ratio of the mixture to the reducing agent solution is 5:(1-5); And / or, the mass ratio of the carrier to the reducing agent is 95:(1-5); And / or, the mass-to-volume ratio of the carrier to the reducing agent is 95:(10-500); And / or, the reduction time for the stirring aging is 12-24 h.

7. The preparation method according to claim 1, characterized in that, The drying temperature is 40-100 ℃; And / or, the drying time is 12-24 h; And / or, when the reducing agent is hydrogen, the temperature is increased to 100 °C at 5 °C / min, hydrogen is introduced, and the catalyst is obtained by reduction for 2-3 h.

8. A catalyst, characterized in that, Prepared by the method described in any one of claims 1-7.

9. Use of a catalyst prepared by any one of claims 1-7 in the synthesis of valacyclovir hydrochloride, the use comprising: CBZ-L-valine-acyclovir was dissolved in a mixed solution of methanol, water and hydrochloric acid, and the catalyst described in this invention was added. The mixture was heated to 50°C under a nitrogen atmosphere, and hydrogen gas was introduced at a pressure of 0.1-0.5 MPa for 2 h to prepare valacyclovir hydrochloride.

10. The use according to claim 9, characterized in that, The volume ratio of methanol, water and hydrochloric acid is 30:10:1, and the concentration of hydrochloric acid is 1 mol / L. And / or, the mass ratio of CBZ-L-valine-acyclovir to the catalyst is (50-200):1; And / or, the mass-to-volume ratio of CBZ-L-valine-acyclovir to water is 1:5.

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