CN115286632A - Preparation process of valganciclovir hydrochloride - Google Patents

Abstract

The invention relates to a preparation process of valganciclovir hydrochloride, which takes ganciclovir as a raw material, reacts with trimethyl orthoacetate in the presence of p-toluenesulfonic acid to obtain monoacetylganciclovir, then reacts with Cbz-L-valine in DMSO, is treated by hydrochloric acid, is adjusted by ammonia water to pH 1.5 to obtain Cbz-L-valganciclovir, and is further prepared by hydrogenation and post-treatment.

Description

Preparation process of valganciclovir hydrochloride

Technical Field

The invention belongs to the technical field of medicine synthesis, and particularly relates to a preparation process of valganciclovir hydrochloride.

Background

Cytomegalovirus (CMV) is a virus of the herpesvirus family, also known as the cellular inclusion body virus, infection of which causes swelling of the cells and the production of large intranuclear inclusions. CMV is a very widespread infection in humans, usually a recessive infection, is present in almost all organs and tissues of the human body, and after infection in healthy humans, it is mostly asymptomatic, but under certain conditions it can invade multiple organs and systems, causing severe infections mainly of diseases of the genitourinary system, the central nervous system and the liver. CMV infection is a common cause of disease in pathologically and physiologically immunocompromised persons (including fetuses and newborns with developmental immunodeficiency) and is one of the most important causes of advanced disease and increased mortality in patients with aids and organ and bone marrow transplants.

Ganciclovir (ganciclovir) is one of the most effective drugs for resisting CMV infection clinically at present, but has poor oral bioavailability and great side effect. Valganciclovir hydrochloride is an oral cell-resistant (CMV) infection drug developed by roche switzerland and approved by FDA in us5 months in 2001 for marketing. Clinically used for treating acute retinitis of patients with acquired immunodeficiency syndrome caused by CMV infection; preventing and treating CMV infection in organ transplant patients. The product is a prodrug of ganciclovir, is rapidly hydrolyzed into ganciclovir by esterase in intestinal tract and liver cells after being taken orally, thereby exerting the drug effect, has the oral absorption bioavailability 10 times that of ganciclovir, greatly reduces the toxicity, and has wide market prospect. In China, valganciclovir hydrochloride belongs to a clinically urgent medicine, but no domestic variety is on the market, the valganciclovir hydrochloride completely depends on import, the price is high, and the economic burden of patients is heavy.

Valganciclovir hydrochloride has a complex structure, needs to overcome multiple technical barriers in the research and development process, and has high synthesis difficulty, and the synthesis of valganciclovir hydrochloride in the prior art is mainly as follows:

patent WO9727194 discloses a preparation method of valganciclovir hydrochloride, which comprises the steps of taking ganciclovir as a raw material, firstly reacting with trimethylchlorosilane to generate an N-silane compound, protecting 2-amino of the ganciclovir, then reacting with Cbz-valine, and obtaining the valganciclovir hydrochloride through Cbz protection removal. The synthetic route is as follows:

the patent US5700936 discloses a preparation method of valganciclovir hydrochloride, which also takes ganciclovir as an initial raw material to react with active L-valine derivatives under the catalysis of triethylamine to generate a diester product, then the diester product is hydrolyzed under an alkaline condition to hydrolyze L-valine groups on one of hydroxyl groups, and finally the valganciclovir hydrochloride is obtained through Cbz removal protection. The difficulty is that the mixture of ganciclovir, monoester and diester can be obtained in the second step hydrolysis reaction process, the separation is difficult, the yield is low, and the synthetic route is as follows:

patent US5756736 discloses that ganciclovir is used as a starting material, and reacts with triphenylchloromethane under the catalysis of 4-dimethylaminopyridine and triethylamine to generate an N, O-bis (triphenylmethyl) ganciclovir derivative, one alcoholic hydroxyl group and 2-amino group of ganciclovir are protected, then esterification is carried out with Cbz-L-valine, and then the protecting group trityl is removed under the action of trifluoroacetic acid to obtain a monoester. The main problems are that the activity of two hydroxyl groups of ganciclovir is consistent, the introduction of a single protecting group is not easy, the route is long, the yield is difficult to improve, the product quality is poor, and the synthetic route is as follows:

because the two hydroxyl groups of the ganciclovir have consistent activity and no selectivity, the route can not realize the high-selectivity mono-esterification of the ganciclovir, and can only separate the mixture of the ganciclovir, the monoester and the diester by different purification methods, and the final product has poor quality and lower yield.

US5840890 discloses a process which also uses ganciclovir as starting material, reacts with trimethyl orthoformate under the catalysis of trifluoroacetic acid, is acidified by formic acid to obtain substituted ganciclovir with introduced protecting group, then is esterified with active anhydride compound under the catalysis of triethylamine to obtain diester, is hydrolyzed by hydrochloric acid to remove formyl group, and finally is hydrogenated and reduced to obtain the target product. According to the method, ortho-acid ester is introduced to construct mono-substituted ganciclovir in a breakthrough manner, asymmetric diester is obtained by esterifying the mono-substituted ganciclovir, the asymmetric diester can be hydrolyzed at high selectivity under the control of hydrochloric acid concentration and reaction temperature to obtain a monoester product, the total yield can be greatly improved to more than 30%, but the problems of uncontrollable diastereoisomer ratio, N-methylated impurities, excessive palladium residue and the like in valganciclovir hydrochloride are not concerned.

Disclosure of Invention

The invention aims to overcome the defects in the prior art and provide a method for preparing valganciclovir hydrochloride with controllable purity and considerable yield.

In order to realize the purpose, the technical scheme adopted by the invention is as follows:

a preparation method of valganciclovir hydrochloride specifically comprises the following steps:

s1: stirring ganciclovir, p-toluenesulfonic acid, trimethyl orthoacetate and DMSO at normal temperature, reacting for 2-4 h, adding purified water, stirring at normal temperature for 0.25-0.5 h, adding ethanol into the reaction solution, separating out white solid, filtering, and drying to obtain monoacetylganciclovir;

s2: adding monoacetylganciclovir into DMSO, heating to 60-70 ℃, stirring for 0.5-1 h, cooling to 20-30 ℃, adding Cbz-L-valine and DMAP, stirring for 0.25-0.5 h, adding DCC, stirring for 3-6 h, adding dichloromethane and purified water after the reaction is finished, stirring for 0.5h, filtering to retain an organic phase, decompressing and evaporating to dryness, adding methanol and dilute hydrochloric acid, stirring for 8-10 h at 20-30 ℃, then adding dichloromethane for extraction, separating to retain a water phase, adjusting the pH to 1.5-3 by using ammonia water, stirring, and filtering to obtain Cbz-L-valganciclovir;

s3: dissolving Cbz-L-valganciclovir in methanol, adjusting pH to be less than 5 by hydrochloric acid, adding 10% palladium carbon, exchanging nitrogen, introducing hydrogen, reacting for 6-12 h at 25-35 ℃, filtering, adding TulsionCH-97 resin into filtrate, stirring for 2.5-3 h at 20-30 ℃, filtering, concentrating the filtrate under reduced pressure to be dry, and carrying out post-treatment to obtain valganciclovir hydrochloride.

As a further improvement of the invention, the mass ratio of ganciclovir to p-toluenesulfonic acid and trimethyl orthoacetate in step S1 is 50-10: 150-400 mL.

As a further improvement of the invention, the adding amount of the pure water in the step S1 is 0.15-0.25 time of the quality of the ganciclovir, and the adding amount of the ethanol is 1-1.5 times of the quality of the dimethyl sulfoxide.

As a further improvement of the invention, the mass ratio of the monoacetylganciclovir, the Cbz-L-valine, the DMAP and the DCC in the step S2 is 45-80.

As a further improvement of the invention, the mass ratio of the monoacetylganciclovir, the Cbz-L-valine, the DMAP and the DCC in the step S2 is 45-55.

As a further improvement of the invention, the addition amount of the dilute hydrochloric acid in the step S2 is 5-8 times of the mass of the monoacetylganciclovir, the concentration is 4mol/L, and the volume ratio of the methanol to the dilute hydrochloric acid is 1-1.5.

As a further improvement of the invention, the 10% palladium on carbon and the Cbz-L-valganciclovir in step S3: the mass ratio of (A) is 1:5-20, and the mass ratio of the TulsionCH-97 resin to the Cbz-L-valganciclovir is 0.5-5.

As a further improvement of the invention, the mass ratio of the 10% palladium carbon to the Cbz-L-valganciclovir in the step S3 is 1:8-15, and the mass ratio of the TulsionCH-97 resin to the Cbz-L-valganciclovir is 0.8-2:1.

As a further improvement of the present invention, the post-processing step in S3 is: adding purified water with the mass of 1-2 times of that of the concentrate, controlling the temperature to be 40-50 ℃, adding isopropanol with the volume of 7-9 times of that of the pure water, cooling to 20-30 ℃, keeping the temperature for reaction for 1 hour, continuously dropwise adding isopropanol with the volume of 8-16 times of that of the pure water, cooling to 0-10 ℃, stirring for 1.5-2 hours, filtering, washing a filter cake with the isopropanol, and drying to obtain the filter cake.

As a further improvement of the present invention, the post-processing step in S3 is: adding purified water with the mass of 1.5 times of that of the concentrate, controlling the temperature to be 40-50 ℃, adding isopropanol with the volume of 8 times of that of the pure water, cooling to 20-30 ℃, keeping the temperature for reaction for 1 hour, continuously dropwise adding isopropanol with the volume of 16 times of that of the pure water, cooling to 0-10 ℃, stirring for 1.5-2 hours, filtering, washing a filter cake with the isopropanol, and drying to obtain the filter cake.

Adopt the produced beneficial effect of above-mentioned technical scheme to lie in:

the method provided by the invention inhibits the generation of byproducts, realizes the removal of the byproducts and impurities, ensures the purity of products, improves the yield of the reaction and ensures that the total yield can reach more than 60 percent by controlling the conditions of each reaction step.

Drawings

In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the embodiments or the prior art descriptions will be briefly described below, and it is obvious that the drawings in the following description are some embodiments of the present invention, and other drawings can be obtained by those skilled in the art without creative efforts.

FIG. 1 is an HPLC profile of monoacetylganciclovir of example 1 of the invention;

FIG. 2 is an HPLC chromatogram of example 1 Cbz-L-valganciclovir of the invention;

FIG. 3 is an HPLC chromatogram of valbixilol hydrochloride of example 1 of the present invention.

Detailed Description

In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention will be described in detail and fully with reference to the following embodiments.

Example 1

S1: 50g of ganciclovir, 200ml of dimethyl sulfoxide, 2.61g of p-toluenesulfonic acid and 45.08g of trimethyl orthoacetate are added into a reaction bottle, and the reaction is stirred at 25 ℃ for 4 hours. Adding 10.58g of purified water into the reaction solution, stirring for 0.5h, adding 240ml of ethanol, separating out a white solid, crystallizing for 14h at 25 ℃, performing suction filtration, washing with ethanol, and performing vacuum drying at 45-55 ℃ to obtain 49.5g of monoacetylganciclovir, wherein the yield is 85.0%, the purity is 99.7%, an HPLC (high performance liquid chromatography) spectrum is shown in figure 1, and peak table data is shown in table 1.

Table 1 monoacetylganciclovir HPLC peak table data

S2: adding 45g of monoacetylganciclovir and 225mL of DMSO into a three-neck bottle, heating to 66 ℃, stirring for 0.5h, cooling to 25 ℃, adding 47.93g of Cbz-L-valine and 3.14g of DMAP, stirring for 15 min, controlling the temperature to be below 20 ℃, adding 44.98g of DCC, controlling the temperature to be 25 ℃ for reaction for 5h, controlling the temperature to be 25 ℃, adding 225mL of DCM, 225mL of purified water, stirring for 30min, filtering, washing a filter cake with dichloromethane, standing, separating the filtrate, concentrating and evaporating an organic phase at 40 ℃ under reduced pressure.

Adding 315mL of methanol into the concentrated residue, stirring, controlling the temperature to be below 30 ℃, adding 315g of 4mol/L dilute hydrochloric acid, controlling the temperature to be 20 ℃ after the addition is finished, reacting for 9h, adding 200mL of DCM for extraction, retaining the water phase, controlling the temperature to be 10 ℃, adjusting the pH to 1.5 by using ammonia water, stirring for 30min, filtering, washing by purified water, and drying in vacuum at 45 ℃ to obtain 63.89g of Cbz-L-valganciclovir, wherein the yield is 86.4%, and the purity is 99.2%, which is shown in figure 2.

S3: adding 500ml of methanol and 50g of Cbz-L-valganciclovir into a reaction bottle, stirring, slowly adding 11g of hydrochloric acid at the temperature of 20 ℃, stirring for dissolving, adding 5g of 10% palladium-carbon, displacing with nitrogen for three times, introducing hydrogen, carrying out hydrogenation reaction at the temperature of 25 ℃ for 8h, controlling the pH of a reaction process system to be less than 5, filtering, washing a filter cake by 32ml of multiplied by 2 methanol, adding 50g of TulsionCH-97 resin into the filtrate, stirring for 3h at the temperature of 20 ℃, filtering, concentrating the filtrate at the temperature of 40 ℃ under reduced pressure to be nearly dry, adding 31.25g of purified water, dropwise adding 250ml of isopropanol at the temperature of 40-50 ℃, cooling to 20-30 ℃, stirring for 1h, continuously dropwise adding 500ml of isopropanol, cooling to 0-10 ℃ for crystallization for 2h, carrying out suction filtration, leaching the filter cake, carrying out vacuum drying at the temperature of 55 ℃ to obtain 35.0g of valganciclovir hydrochloride, obtaining the yield of 87.5%, purity of 99.2%, residual ppm of palladium 4ppm, and the HPLC data are shown in a table 2.

TABLE 2 Peak Table data for valganciclovir hydrochloride

Peak number	Retention time	Area of	Height	Area%	Height%
						1	4.088	75242	12243	0.938	1.162
2	4.875	2802	367	0.035	0.035
						3	5.174	1231	149	0.015	0.014
4	9.935	4261113	526209	53.095	49.938
						5	10.665	3677438	513697	45.823	48.751
6	11.782	1021	143	0.013	0.014
						7	11.898	1104	139	0.014	0.013
8	13.959	5447	768	0.068	0.073
						Total of		8025398	1053715	100.000	100.000

Note: the correction factor of the impurity A ganciclovir is 0.71, the actual content of the impurity A is 0.938% multiplied by 0.71=0.666%, and the purity of the corrected valganciclovir hydrochloride is 99.2%.

Example 2

S1: 50g of ganciclovir, 150ml of dimethyl sulfoxide, 1g of p-toluenesulfonic acid and 40g of trimethyl orthoacetate are added into a reaction bottle, and stirred and reacted for 4 hours at 25 ℃. Adding 12g of purified water into the reaction solution, stirring for 0.5h, adding 200ml of ethanol, separating out a white solid, crystallizing for 14h at 25 ℃, filtering, washing with ethanol, and drying in vacuum at 50 ℃ to obtain 48.4g of monoacetylganciclovir with the yield of 83.1 percent and the purity equivalent to that of example 1.

S2: adding 45g of monoacetylganciclovir and dmso130ml into a three-neck bottle, heating to 60 ℃, stirring for 0.5h, cooling to 30 ℃, adding 40g of Cbz-L-valine and 1g of DMAP, stirring for 15 min, controlling the temperature to be below 20 ℃, adding 40g of DCC, controlling the temperature to be 25 ℃ for reaction for 4h, controlling the temperature to be 25 ℃, adding 225mL of DCM and 225mL of purified water, stirring for 30min, filtering, washing a filter cake by dichloromethane, standing and separating the filtrate, and concentrating and evaporating the organic phase at 40 ℃ under reduced pressure.

Adding 200mL of methanol into the concentrated residue, stirring, controlling the temperature to be below 30 ℃, adding 200g of 4mol/L dilute hydrochloric acid, controlling the temperature to be 20 ℃ after the addition is finished, reacting for 6h, adding 200mL of DCM for extraction, retaining the water phase, controlling the temperature to be 10 ℃, adjusting the pH to 3 by using ammonia water, stirring for 30min, filtering, washing by using purified water, and drying in vacuum at 45 ℃ to obtain 61.40g of Cbz-L-valganciclovir, wherein the yield is 83.0%, and the purity is equivalent to that of the example 1.

S3: adding 500ml of methanol and 50g of Cbz-L-valganciclovir into a reaction bottle, stirring, controlling the temperature to be 20 ℃, slowly adding 11g of hydrochloric acid, stirring for dissolving, adding 10g of 10% palladium-carbon, replacing with nitrogen for three times, introducing hydrogen, carrying out hydrogenation reaction for 6h at 30 ℃, controlling the pH of a reaction process control system to be less than 5, filtering, washing a filter cake by 32ml of multiplied-2 methanol, adding 25g of TulsionCH-97 resin into the filtrate, stirring for 2.5h at 20 ℃, filtering, concentrating the filtrate under reduced pressure at 40 ℃ to be nearly dry, adding 41g of purified water, controlling the temperature to be 40-50 ℃, dropwise adding 328ml of isopropanol, cooling to be 20-30 ℃, stirring for 1h, continuously dropwise adding 328ml of isopropanol, cooling to be 5 ℃ for crystallization for 2h, carrying out suction filtration, carrying out leaching, carrying out vacuum drying on the filter cake at 55 ℃, obtaining 35.5g of valganciclovir hydrochloride, obtaining the yield of 88.8%, the purity of 99.3%, the palladium residue of 4ppm, and the purity is equivalent to that of the embodiment 1.

Example 3

S1: 50g of ganciclovir, 400ml of dimethyl sulfoxide, 10g of p-toluenesulfonic acid and 60g of trimethyl orthoacetate are added into a reaction bottle, and stirred and reacted for 4 hours at 25 ℃. Adding 7.2g of purified water into the reaction solution, stirring for 0.5h, adding 200ml of ethanol, separating out a white solid, crystallizing for 14h at 25 ℃, performing suction filtration, washing with ethanol, and performing vacuum drying at 45 ℃ to obtain 50.4g of monoacetylganciclovir, wherein the yield is 86.5%, and the purity is equivalent to that of example 1.

S2: adding 45g of monoacetylganciclovir and 450mL of DMSO450mL into a three-mouth bottle, heating to 70 ℃, stirring for 0.5h, cooling to 30 ℃, adding 80g of Cbz-L-valine and 10g of DMAP, stirring for 15 min, controlling the temperature to be below 20 ℃, adding 100g of DCC, controlling the temperature to be 25 ℃ for reaction for 4h, controlling the temperature to be 25 ℃, adding 225mL of DCM and 225mL of purified water, stirring for 30min, filtering, washing a filter cake by dichloromethane, standing and separating the filtrate, and concentrating and evaporating the organic phase at 40 ℃ under reduced pressure.

Adding 200mL of methanol into the concentrated residue, stirring, controlling the temperature to be below 30 ℃, adding 500g of 4mol/L dilute hydrochloric acid, controlling the temperature to be 20 ℃ after the addition is finished, reacting for 6h, adding 200mL of DCM for extraction, retaining the water phase, controlling the temperature to be 10 ℃, adjusting the pH to 1.5 by using ammonia water, stirring for 30min, filtering, washing by using purified water, and drying in vacuum at 45 ℃ to obtain 60.26g of Cbz-L-valganciclovir, wherein the yield is 81.5%, and the purity is equivalent to that of example 1.

S3: adding 500ml of methanol and 50g of Cbz-L-valganciclovir into a reaction bottle, stirring, controlling the temperature to be 20 ℃, slowly adding 11g of hydrochloric acid, stirring for dissolving, adding 20g of 10% palladium-carbon, replacing with nitrogen for three times, introducing hydrogen, carrying out hydrogenation reaction at 35 ℃ for 6h, controlling the pH of a reaction process control system to be less than 5, filtering, washing a filter cake by 32ml of multiplied-2 methanol, adding 250g of TulsionCH-97 resin into the filtrate, stirring for 2.5h at 20 ℃, filtering, concentrating the filtrate at 40 ℃ under reduced pressure to be nearly dry, adding 20.8g of purified water, controlling the temperature to be 40-50 ℃, dropwise adding 167ml of isopropanol, cooling to 20-30 ℃, stirring for 1h, continuously dropwise adding 167ml of isopropanol, cooling to 5 ℃ for crystallization for 2h, carrying out suction filtration, leaching the isopropanol, carrying out vacuum drying on the filter cake at 55 ℃, obtaining 34.2g of valganciclovir hydrochloride, obtaining, the yield being 85.5%, purity being 99.2%, and 3ppm of palladium residue, which are equivalent to the purity of the example 1.

Comparative example 1

The reaction conditions of step S1 were examined and the yield and purity were recorded, the results are shown in table 3, and the specific reaction conditions were set as follows:

comparative example 1-1: reference is made to the procedure of example 1, except that DMSO is replaced with DMF;

comparative examples 1 to 2: the procedure of example 1 was followed except that the reaction temperature was 45 ℃;

comparative examples 1 to 3: the procedure of example 1 was followed except that methanol was added after the reaction.

TABLE 3 yield and purity of step S1

	Yield of	Purity of
			Example 1	85.0％	99.7％
Comparative examples 1 to 1	75.3％	91.5％
			Comparative examples 1 to 2	60.5％	70.5％
Comparative examples 1 to 3	10.4％	99.2％

Comparative example 2

The reaction conditions of step S2 were examined and the yield and purity were recorded, the results are shown in table 4, and the specific reaction conditions were set as follows:

comparative example 2-1: reference is made to the procedure of example 1, except that DMSO is replaced with DMF;

comparative examples 2 to 2: the procedure of example 1 was followed except that ammonia was used to adjust the pH to 4;

comparative examples 2 to 3: reference is made to the procedure of example 1, except that the pH is adjusted to 6 with aqueous ammonia.

TABLE 4

Comparative example 3

The reaction conditions of step S3 were examined and the yield and purity were recorded, the results are shown in table 5, and the specific reaction conditions were set as follows:

comparative example 3-1: the procedure of example 1 was followed except that no resin treatment was used;

comparative example 3-2: reference is made to the procedure of example 1, except that the hydrogenation temperature is 40 ℃ and the time is 2h;

comparative examples 3 to 3: the procedure of example 1 was followed, except that 10g of 5% palladium-carbon was used;

comparative examples 3 to 4: the procedure of example 1 was followed, except that the post-treatment steps were: adding 31.25g of purified water, controlling the temperature to be 25 ℃, dropwise adding 250ml of isopropanol, stirring for 1h, cooling to 5 ℃, crystallizing for 2h, performing suction filtration, and leaching with 56ml of isopropanol;

comparative examples 3 to 5: the procedure of example 1 was followed except that the post-treatment steps were: adding 31.25g of purified water, controlling the temperature to be 25 ℃, dropwise adding 750ml of isopropanol, stirring for 1h, cooling to 5 ℃, crystallizing for 2h, filtering, and leaching with 56ml of isopropanol.

TABLE 5

Finally, it should be noted that: the above examples are only intended to illustrate the technical solution of the present invention, but not to limit it; although the present invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some technical features may be equivalently replaced; and such modifications or substitutions do not depart from the spirit and scope of the corresponding technical solutions of the embodiments of the present invention.

Claims (10)

1. A preparation process of valganciclovir hydrochloride is characterized by comprising the following steps:

s1: stirring ganciclovir, p-toluenesulfonic acid, trimethyl orthoacetate and DMSO at normal temperature, reacting for 2-4 h, adding purified water, stirring at normal temperature for 0.25-0.5 h, adding ethanol into the reaction solution, precipitating white solid, filtering, and drying to obtain monoacetylganciclovir;

s2: adding monoacetylganciclovir into DMSO, heating to 60-70 ℃, stirring for 0.5-1h, cooling to 20-30 ℃, adding Cbz-L-valine and DMAP, stirring for 0.25-0.5h, adding DCC, stirring for 3-6 h, adding dichloromethane and purified water after the reaction is finished, stirring for 0.5h, filtering to retain an organic phase, decompressing and evaporating to dryness, adding methanol and diluted hydrochloric acid, stirring for 8-10h at 20-30 ℃, then adding dichloromethane for extraction, separating to retain a water phase, adjusting the pH to 1.5-3 with ammonia water, stirring, and filtering to obtain Cbz-L-valganciclovir;

s3: dissolving Cbz-L-valganciclovir in methanol, adjusting the pH to be less than 5 by hydrochloric acid, adding 10% palladium carbon, replacing with nitrogen, introducing hydrogen, reacting at 25 to 35 ℃ for 6 to 12h, filtering, adding TulsionCH-97 resin into filtrate, stirring at 20 to 30 ℃ for 2.5h to 3h, filtering, concentrating the filtrate under reduced pressure to dryness, and performing post-treatment to obtain valganciclovir hydrochloride.

2. The preparation process of valganciclovir hydrochloride according to claim 1, wherein the mass ratio of ganciclovir to p-toluenesulfonic acid and trimethyl orthoacetate in step S1 is 50 to 10 to 40 to 60, and the mass-volume ratio of ganciclovir to DMSO is 50g:150 to 400mL.

3. The process for preparing valganciclovir hydrochloride according to claim 1, wherein the addition amount of pure water in step S1 is 0.15 to 0.25 times of the mass of ganciclovir, and the addition amount of ethanol is 1 to 1.5 times of dimethyl sulfoxide.

4. The process for preparing valganciclovir hydrochloride according to claim 1, wherein the mass ratio of the monoacetylganciclovir to the Cbz-L-valine to the DMAP to the DCC in the step S2 is 45 to 80 to 40 to 10.

5. The process for preparing valganciclovir hydrochloride according to claim 1, wherein the mass ratio of the monoacetylganciclovir, the Cbz-L-valine, the DMAP and the DCC in the step S2 is 45 to 55.

6. The process for preparing valganciclovir hydrochloride according to claim 1, wherein the amount of dilute hydrochloric acid added in step S2 is 5~8 times the mass of monoacetylganciclovir, the concentration is 4mol/L, and the volume ratio of methanol to dilute hydrochloric acid is 1 to 1.5.

7. The process of claim 1, wherein the ratio of palladium on carbon 10% to the ratio of Cbz-L-valganciclovir hydrochloride in step S3: the mass ratio of the TulsionCH-97 resin to the Cbz-L-valganciclovir is 1 to 5, and the mass ratio of the TulsionCH-97 resin to the Cbz-L-valganciclovir is 0.5 to 5.

8. The process for preparing valganciclovir hydrochloride according to claim 1, wherein the mass ratio of 10% palladium on carbon to the Cbz-L-valganciclovir in the step S3 is 1 to 8 to 15, and the mass ratio of the TulsionCH-97 resin to the Cbz-L-valganciclovir is 0.8 to 2.

9. The process of claim 1, wherein the post-treatment step in S3 comprises: adding purified water which is 1~2 times of the mass of the concentrate, controlling the temperature at 40-50 ℃, adding isopropanol which is 7~9 times of the volume of pure water, cooling to 20-30 ℃, keeping the temperature for reaction for 1h, continuously adding isopropanol which is 8-16 times of the volume of pure water, cooling to 0-10 ℃, stirring for 1.5-2h, filtering, washing a filter cake with isopropanol, and drying to obtain the filter cake.

10. The process of claim 1, wherein the post-treatment step in S3 comprises: adding purified water with the mass being 1.5 times of that of the concentrate, controlling the temperature to be 40-50 ℃, adding isopropanol with the volume being 8 times of that of pure water, cooling to 20-30 ℃, keeping the temperature for reaction for 1h, continuously dropwise adding isopropanol with the volume being 16 times of that of the pure water, cooling to 0-10 ℃, stirring for 1.5-2h, filtering, washing a filter cake with the isopropanol, and drying to obtain the water-soluble glass.

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