A scaled-up preparation method of valganciclovir hydrochloride

Abstract

The invention discloses an enlarged preparation method of valganciclovir hydrochloride, and belongs to the field of pharmaceutical synthesis technology. The core point of the invention is that ganciclovir is used as a raw material, and the 2-amino group of ganciclovir is first protected by reacting with Boc anhydride, and then reacting with Cbz-valine, and then removing Cbz protection to obtain valganciclovir hydrochloride; under the best optimized conditions, the reaction can still be carried out without amino protection. The method greatly shortens the reaction steps, avoids the use of dangerous reagents, reduces the cost of raw materials, has a simple and reliable process, is easy to industrialize, and provides a new reaction path for the synthesis of valganciclovir hydrochloride.

Description

Technical Field

[0001] The invention relates to an enlarged preparation method of valganciclovir hydrochloride, belonging to the technical field of pharmaceutical synthesis. Background Art

[0002] Cytomegalovirus (CMV) belongs to the herpesvirus family. The virus is dormant in individuals with normal immune function, but it can cause severe symptoms when the immune function is impaired (such as AIDS patients, patients receiving immunosuppressants after organ transplantation and bone marrow transplantation, etc.). CMV infection is transmitted through direct contact with infected (vertical infection) tissues or body fluids (such as saliva, blood or urine). The transmission routes are very wide, the most common of which are intrauterine, cervical secretions or breast milk transmission, close contact with infants in intensive care units, and sexual contact. The most common symptom of CMV in AIDS patients is CMV retinitis, an eye infection that can cause blindness.

[0003] Valganciclovir hydrochloride is a herpes virus DNA synthesis inhibitor developed by Roche in Switzerland. It was first marketed as a prescription drug in Sweden and Finland in 2010, approved by the US FDA in March 2001, and first marketed in the United States in May 2001. Valganciclovir hydrochloride is a prodrug of ganciclovir and an active ganciclovir valine ester. After oral administration, it can be rapidly hydrolyzed into ganciclovir by phosphatases in intestinal and liver cells. Its antiviral spectrum and mechanism of action are similar to those of ganciclovir, but its bioavailability is significantly higher than that of ganciclovir. Its oral bioavailability is 62.4%, which is 10 times that of ganciclovir, while its toxicity is greatly reduced. Clinical trials show that after two years of treatment with valganciclovir hydrochloride, 62% of the cases are still alive, while the survival rate of cases not treated with valganciclovir is only 18%. Many studies at home and abroad have shown that Valganciclovir Hydrochloride Tablets have obvious pharmacological effects, novel mechanisms of action, low toxicity, few adverse reactions, significant clinical efficacy, high patient compliance, safe application, and broad market prospects. In my country, Valganciclovir Hydrochloride is an urgently needed drug in clinical practice, but there are no domestically produced varieties on the market, which is completely dependent on imports, expensive, and a heavy economic burden on patients.

[0004] Valganciclovir hydrochloride has a complex structure, and many technical barriers need to be overcome during the research and development process. The synthesis is difficult. The synthesis of valganciclovir hydrochloride in the existing technology is mainly as follows:

[0005] Patent WO9727194 discloses a method for preparing valganciclovir hydrochloride, which uses ganciclovir as a raw material, first reacts with trimethylchlorosilane to generate an N-silane compound, protects the 2-amino group of ganciclovir, then reacts with Cbz-valine, and removes the Cbz protection to obtain valganciclovir hydrochloride. Since the two hydroxyl groups of ganciclovir have the same activity, the esterification process is non-selective, resulting in difficulty in separating ganciclovir, monoester, and diester, and the yield is low. The synthetic route is as follows:

[0006]

[0007] Patent US5700936 discloses a method for preparing valganciclovir hydrochloride, which also uses ganciclovir as a starting material, reacts with an active L-valine derivative under the catalysis of triethylamine, first generates a diester product, then hydrolyzes under alkaline conditions to hydrolyze the L-valine group on one of the hydroxyl groups, and finally removes the Cbz protection to obtain valganciclovir hydrochloride. The difficulty is that a mixture of ganciclovir, monoester and diester will be obtained during the second step of the hydrolysis reaction, which is difficult to separate and has a low yield.

[0008] Its synthetic route is as follows:

[0009]

[0010] Patent US5756736 discloses that ganciclovir is used as a starting material, and triphenylmethane is reacted under the catalysis of 4-dimethylaminopyridine and triethylamine to generate N,O-di(triphenylmethyl)ganciclovir derivatives, and firstly one alcoholic hydroxyl group and the 2-amino group of ganciclovir are protected, and then esterified with Cbz-L-valine, and then the protecting group triphenylmethyl is removed under the action of trifluoroacetic acid to obtain a monoester. The main problem is that the two hydroxyl groups of ganciclovir have the same activity, it is not easy to introduce a single protecting group, the route is long, the yield is difficult to improve, and the product quality is poor.

[0011] Its synthetic route is as follows:

[0012]

[0013] Since the two hydroxyl groups of ganciclovir have the same activity and are non-selective, the above routes cannot achieve highly selective monoesterification of ganciclovir. The mixture of ganciclovir, monoester and diester can only be separated by different purification methods. The final product has poor quality and low yield.

[0014] US5840890 discloses that ganciclovir is used as a starting material, reacted with trimethyl orthoformate under the catalysis of trifluoroacetic acid, and acidified with formic acid to obtain a substituted ganciclovir with a protective group, and then esterified with an active acid anhydride compound under the catalysis of triethylamine to obtain a diester, which is hydrolyzed with hydrochloric acid to remove the formyl group, and finally hydrogenated to obtain the target product. This route introduces an orthoester to construct a monosubstituted ganciclovir, and the monosubstituted ganciclovir is esterified to obtain an asymmetric diester. The asymmetric diester can be highly selectively hydrolyzed to obtain a monoester product under controlled hydrochloric acid concentration and reaction temperature, and the total yield can be greatly increased to more than 30%. However, it does not pay attention to the problems of uncontrollable diastereoisomer ratio, generation of N-methylated impurities, and excessive palladium residue in valganciclovir hydrochloride. Summary of the invention

[0015] In order to overcome the above technical defects, the present invention provides a method for enlarging the preparation of valganciclovir hydrochloride. The core points of the present invention are that ganciclovir is used as a raw material, first reacts with Boc anhydride to protect the 2-amino group of ganciclovir, then reacts with Cbz-valine, and removes Cbz protection to obtain valganciclovir hydrochloride. The method greatly shortens the reaction steps, avoids the use of dangerous reagents, reduces the cost of raw materials, has a simple and reliable process, is easy to industrialize, and provides a new reaction path for the synthesis of valganciclovir hydrochloride.

[0016] The enlarged preparation method of valganciclovir hydrochloride of the present invention comprises the following steps:

[0017] Step 1: react ganciclovir, Boc2O / Me3SiCl / TrCl, and an organic base in an organic solvent to generate intermediate 1.

[0018] Step 2: react intermediate 1, Cbz-valine and phosphine ligand in an organic solvent under the action of azodicarboxylate to generate intermediate 2.

[0019] Step 3: In the presence of hydrogen chloride or hydrochloric acid, intermediate 2 is subjected to palladium-carbon catalytic hydrogenation reaction to obtain valganciclovir hydrochloride.

[0020] The reaction equation is expressed as follows:

[0021]

[0022] Furthermore, in the above technical solution, the organic base in the first step is selected from: pyridine, triethylamine or N,N-diisopropylethylamine.

[0023] Furthermore, in the above technical solution, the molar ratio of ganciclovir, Boc2O / Me3SiCl / TrCl and organic base in the first step is 1:1-3:1-3; and the reaction temperature is 20-45°C.

[0024] Furthermore, in the above technical solution, the organic solvent in the first step is selected from: dichloromethane, tetrahydrofuran, and 2-methyltetrahydrofuran.

[0025] Furthermore, in the above technical solution, the organic solvent in the second step is selected from: dichloromethane, 1,2-dichloroethane, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, etc.

[0026] Furthermore, in the above technical solution, the phosphine ligand in the second step is selected from: triphenylphosphine, tricyclohexylphosphine, tributylphosphine and the like.

[0027] Furthermore, in the above technical solution, the azodicarboxylic acid ester in the second step is selected from: diethyl azodicarboxylate, diisopropyl azodicarboxylate, etc.

[0028] Furthermore, in the above technical solution, the molar ratio of the phosphorus ligand, azodicarboxylate, intermediate 1 and Cbz-valine in the second step is 1.1-1.2:1.1-1.2:1:1-1.05.

[0029] Furthermore, in the above technical scheme, after the reaction in the second step is completed, the temperature is lowered and frozen to -20°C to -40°C, and the by-products form a complex form, which can be removed by filtration by more than 90%; under the optimized conditions, the purification method is to first lower the temperature to below -20°C, filter out most of the by-products, and then adjust the pH to 6-6.5. The remaining by-products precipitate again at this pH value, freeze to -40°C, and after all are precipitated, filter out with diatomaceous earth.

[0030] Furthermore, in the above technical scheme, the hydrogen chloride in the third step is selected from hydrogen chloride, acetyl chloride / methanol in-situ generation, and hydrogen chloride / ethyl acetate solution. Firstly adding an equivalent amount of hydrochloric acid and then catalyzing the hydrogenation reaction is faster, and the efficiency is improved compared with hydrogenation first and then salting with hydrochloric acid. The amount of catalyst palladium carbon (two specifications of 5% and 10%) is reduced to 0.5-2%, and hydrogenation at normal pressure is sufficient.

[0031] Furthermore, in the above technical solution, the reaction solvent in the third step is selected from methanol, ethanol, ethyl acetate, and tetrahydrofuran.

[0032] On the basis of the above, the present application attempts to directly carry out the second step condensation and the third step deprotection without protecting the amino group at the 2-position of ganciclovir. It is unexpectedly found that the reaction can also proceed smoothly, and the reaction operation is further simplified.

[0033]

[0034] Furthermore, in the above technical solution, the organic solvent in the first step is selected from: dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 2-methyltetrahydrofuran, etc.

[0035] Furthermore, in the above technical solution, the phosphine ligand in the first step is selected from: triphenylphosphine, tricyclohexylphosphine, tributylphosphine and the like.

[0036] Furthermore, in the above technical solution, the azodicarboxylic acid ester in the first step is selected from: diethyl azodicarboxylate, diisopropyl azodicarboxylate, etc.

[0037] Furthermore, in the above technical solution, the molar ratio of the phosphorus ligand, azodicarboxylate, intermediate 1 and Cbz-valine in the first step is 1.1-1.2:1.1-1.2:1:1-1.05.

[0038] Furthermore, in the above technical scheme, after the reaction in the first step is completed, the temperature is cooled and frozen to -20°C to -40°C, and the by-products form a complex form, which can be removed by filtration. Under the optimized conditions, the purification method is to first lower the temperature to below -20°C, filter out most of the by-products, and then adjust the pH to 6-6.5. The remaining by-products precipitate again at this pH value, freeze to -40°C, and after all are precipitated, filter out with diatomaceous earth.

[0039] Furthermore, in the above technical solution, the hydrogen chloride in the second step is selected from hydrogen chloride, acetyl chloride / methanol in-situ generation, and hydrogen chloride / ethyl acetate solution.

[0040] Furthermore, in the above technical solution, the second step reaction solvent is selected from methanol, ethanol, ethyl acetate, and tetrahydrofuran.

[0041] Beneficial effects of the present invention

[0042] The present invention reduces the amount of impurities generated, improves the reaction yield, greatly reduces the amount of three wastes, and the entire preparation process is more environmentally friendly; the comprehensive production cost is greatly reduced compared with the production process in existing literature or patents, and the product is more competitive in the market. Compared with the use of 2-amino for protection, the optimization scheme is also successfully completed by using direct reaction. BRIEF DESCRIPTION OF THE DRAWINGS

[0043] Figure 1 The HNMR spectrum of the product valganciclovir hydrochloride of Example 1 is shown in FIG.

[0044] Figure 2 The HPLC-MS spectrogram of the product valganciclovir acid obtained in Example 3 is shown. DETAILED DESCRIPTION

[0045] The present invention will be further described below in conjunction with specific embodiments. These embodiments should be understood to be only used to illustrate the present invention and not to limit the scope of protection of the present invention. After reading the content of the present invention, those skilled in the art may make various changes or modifications to the present invention, and these equivalent changes and modifications also fall within the scope defined by the claims of the present invention.

[0046] Example 1

[0047]

[0048] first step:

[0049] Under the temperature control of 0-10° C., a dichloromethane solution of Boc anhydride (126.58 g, 0.58 mol) was slowly dripped into a dichloromethane (600 ml) solution of ganciclovir (100 g, 0.39 mol) and triethylamine (118.39 g, 1.17 mol). The reaction solution was stirred at 20-25° C. for 15 hours, and the reaction was completed by HPLC detection after sampling and quenching. Water was added to quench the reaction, and dichloromethane was extracted. The organic phase was washed with water, dried and spin-dried to obtain intermediate 1a (130.55 g, yield 93.76%).

[0050] Step 2:

[0051] The intermediate 1a (130.00 g, 365.84 mmolmol) obtained in the previous step, CBZ-L-valine (91.93 g, 365.84 mmol) and triphenylphosphine (105.55 g, 402.42 mol) were added to a tetrahydrofuran (500 ml) solution. Diisopropyl azodicarboxylate (81.37 g, 402.42 mol) was slowly dripped into the reaction solution at a temperature of -20 to -10°C, and the temperature was continued to be controlled and stirred for 30 minutes. After sampling and quenching, the reaction was completed by HPLC detection, and the temperature was cooled to below -20°C. After the by-products were filtered and removed, a saturated aqueous solution of ammonium chloride was added to the filtrate to adjust the pH to 6-6.5, and the organic layer was separated. The filtrate was frozen again to -40°C and stirred for 1.5 hours, filtered through diatomaceous earth, and the organic layer was washed with brine and dried over anhydrous sodium sulfate to obtain intermediate 2a (198.33 g, yield 92.10%).

[0052] Step 3:

[0053] 10 g of palladium on carbon (10%) was added to an intermediate 2a (198.00 g, 336.39 mmol), a hydrochloric acid ethyl acetate solution (168 ml, 2N, 336 mmol) and a methanol (1 L) solution, and the mixture was stirred under 1 atmosphere of hydrogen for 3 hours. After the reaction was completed, the mixture was spin-dried and then pulped and filtered with an isopropanol / n-hexane mixed solvent to obtain a white powder of valganciclovir hydrochloride (121.08 g, yield 92.1%). 1 H NMR(CD3OD,400M Hz)δ0.93-1.15(m,6H,2CH3),2.08-2.11(m,1H,CH),3.60-3.80(3H,m,CH2COO,C H2OH),4.03(s,1H,OCH),4.16-4.19(m,1H,C H NH2),4.34-4.37(dd,1H,C H 2OH),5.57-5.58(s,2H,NC H2 O), 7.89-7.90 (d, 1H, CH).

[0054] Example 2

[0055]

[0056] first step:

[0057] A dichloromethane solution of trimethylsilyl chloride (6.38 g, 58.77 mmol) was slowly dripped into a dichloromethane (50 ml) solution of ganciclovir (10 g, 39.18 mmol) and pyridine (9.30 g, 117.54 mmol) at a temperature of 0-10° C. The reaction solution was stirred at 20-25° C. for 15 hours, and the reaction was completed by HPLC detection after sampling and quenching. Water was added to quench the reaction, and dichloromethane was extracted. The organic phase was washed with water, dried and spin-dried to obtain a mixture of 1b, 1c and 1d (14.5 g).

[0058] Step 2:

[0059] The mixture of the products 1b, 1c and 1d in the previous step (14.5 g), CBZ-L-valine (10.34 g, 41.14 mmol) and triphenylphosphine (12.33 g, 47.02 mmol) were added to a tetrahydrofuran (60 ml) solution. Diisopropyl azodicarboxylate (9.51 g, 47.02 mmol) was slowly added dropwise to the reaction solution at a temperature of -20 to -10°C, and the temperature was continued to be controlled and stirred for 30 minutes. After sampling and quenching, the reaction was completed by HPLC detection, and the temperature was cooled to below -20°C. After the by-products were filtered and removed, a saturated aqueous solution of ammonium chloride was added to the filtrate to adjust the pH to 6-6.5, and the organic layer was separated. The filtrate was frozen again to -40°C and stirred for 1.5 hours, filtered through diatomaceous earth, and the organic layer was washed with brine and dried over anhydrous sodium sulfate to obtain the intermediate 2c (the structure was not identified, and the structure was inferred based on the liquid mass molecular weight, 7.14 g, and the two-step yield was 42.73%).

[0060] Step 3:

[0061] 0.35 g of palladium on carbon (10%) was added to the intermediate 2c (7.14 g, 16.74 mmol) obtained in the previous step, a hydrochloric acid ethyl acetate solution (8.37 ml, 2N, 16.74 mmol) and an ethyl acetate (40 ml) solution, and the mixture was stirred for 3 hours under 1 atmosphere of hydrogen. After the reaction was completed, the mixture was spin-dried and then slurried and filtered with an isopropanol / n-hexane mixed solvent to obtain valganciclovir hydrochloride (5.97 g, yield 91.2%). The structure was correct as detected by nuclear magnetic resonance.

[0062] Example 3

[0063]

[0064] first step:

[0065] Under the temperature control of 0-10° C., a dichloromethane solution of triphenylmethane (24.03 g, 86.20 mmol) was slowly dripped into a dichloromethane (100 ml) solution of ganciclovir (10 g, 39.18 mmol) and triethylamine (11.89 g, 117.54 mmol). The reaction solution was stirred at 20-25° C. for 15 hours, and the reaction was completed by HPLC detection after sampling and quenching. Water was added to quench the reaction, and dichloromethane was extracted. The organic phase was washed with water, dried and spin-dried to obtain a mixture of intermediates 1e and 1f (21.82 g).

[0066] Step 2:

[0067] The mixture of intermediates 1e and 1f obtained in the previous step (21.82 g), CBZ-L-valine (9.84 g, 39.18 mmol) and triphenylphosphine (12.33 g, 47.02 mmol) were added to a tetrahydrofuran (200 ml) solution. Diisopropyl azodicarboxylate (9.51 g, 47.02 mmol) was slowly added dropwise to the reaction solution at a temperature of -20 to -10°C, and the temperature was continued to be controlled and stirred for 30 minutes. After sampling and quenching, the reaction was completed by HPLC detection, and the temperature was cooled to below -20°C. After the by-products were filtered and removed, a saturated aqueous solution of ammonium chloride was added to the filtrate to adjust the pH to 6-6.5, and the organic layer was separated. The filtrate was frozen again to -40°C and stirred for 1.5 hours, filtered through diatomaceous earth, and the organic layer was washed with brine and dried over anhydrous sodium sulfate to obtain intermediate 2d (16.03 g, yield: 55.99%).

[0068] Step 3:

[0069] 0.8 g of palladium on carbon (10%) was added to the intermediate 2d (16 g, 21.89 mmol) obtained in the previous step, a hydrochloric acid ethyl acetate solution (10.95 ml, 2N, 21.89 mmol) and an ethyl acetate (200 ml) solution, and the mixture was stirred under 1 atmosphere of hydrogen for 3 hours. After the reaction was completed, the mixture was spin-dried and then slurried and filtered with an isopropanol / n-hexane mixed solvent to obtain valganciclovir hydrochloride (7.95 g, yield 93.10%). The structure was correct as determined by nuclear magnetic resonance.

[0070] Example 4

[0071]

[0072] first step:

[0073] Under the temperature control of 0-10° C., a tetrahydrofuran solution of Boc anhydride (1.02 kg, 4.67 mol) was slowly dripped into a tetrahydrofuran (5 L) solution of ganciclovir (1 kg, 3.92 mol) and pyridine (0.46 kg, 5.82 mol). The reaction solution was stirred at 25-35° C. for 15 hours, and the reaction was completed by HPLC detection after sampling and quenching. Water was added to quench the reaction, and dichloromethane was extracted. The organic phase was washed with water, dried and spin-dried to obtain intermediate 1a (1.33 kg, yield 95.5%).

[0074] Step 2:

[0075] The intermediate 1a (1.3 kg, 3.66 mol) obtained in the previous step, CBZ-L-valine (0.96 kg, 3.84 mol) and tricyclohexylphosphine (1.23 kg, 4.39 mol) were added to a 2-methyltetrahydrofuran (6 L) solution. Diethyl azodicarboxylate (0.76 kg, 4.36 mol) was slowly dripped into the reaction solution at a temperature of -20 to -10 ° C, and the temperature was continued to be controlled and stirred for 30 minutes. After sampling and quenching, the reaction was completed by HPLC detection, and the temperature was cooled to below -20 ° C. After the by-products were filtered and removed, a saturated aqueous solution of ammonium chloride was added to the filtrate to adjust the pH to 6-6.5, and the organic layer was separated. The filtrate was frozen again at -40 ° C and stirred for 1.5 hours, filtered through diatomaceous earth, and the organic layer was washed with brine and dried over anhydrous sodium sulfate to obtain intermediate 2a (2.0 kg, yield 93.0%).

[0076] Step 3:

[0077] 100g of palladium carbon (10%) and intermediate 2a (2kg, 3.40mol) were added to a solution of acetyl chloride (266.90g, 3.4mol) and methanol (1.4L), and stirred for 3 hours under 1 atmosphere of hydrogen. After the reaction was completed, the mixture was spin-dried and then slurried and filtered with a mixed solvent of isopropanol / n-hexane to obtain valganciclovir hydrochloride in the form of a white powder (1.24kg, yield 93.6%). After testing, MS+1=355.3( Figure 2 ).

[0078] Example 5

[0079]

[0080] first step:

[0081] Ganciclovir (10 g, 39.18 mmol), CBZ-L-valine (9.84 g, 39.18 mmol), and triphenylphosphine (12.33 g, 47.02 mmol) were added to a 2-methyltetrahydrofuran (200 ml) solution. Diisopropyl azodicarboxylate (9.5 g, 47.02 mmol) was slowly dripped into the reaction solution at a temperature of -20 to -10°C, and the temperature was continued to be controlled and stirred for 30 minutes. After sampling and quenching, the reaction was completed by HPLC detection, and a saturated aqueous ammonium chloride solution was added to quench the reaction, and the dichloromethane was extracted. The organic layer was washed with brine and dried over anhydrous sodium sulfate to obtain intermediate 2f (14.55 g, yield 76%).

[0082] Step 2:

[0083] 0.7 g of palladium carbon (10%) was added to a solution of intermediate 2f (14 g, 28.6 mmol), acetyl chloride (2.25 g, 28.6 mol) and methanol (60 ml), and stirred for reaction for 3 hours under 1 atmosphere of hydrogen. After the reaction was completed, the mixture was spin-dried and then slurried and filtered with a mixed solvent of isopropanol / n-hexane to obtain valganciclovir hydrochloride (10.06 g, yield 90%). The structure was found to be correct.

[0084] The above embodiments describe the basic principles, main features and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited by the above embodiments, and the above embodiments and descriptions are only for explaining the principles of the present invention. Without departing from the scope of the principles of the present invention, the present invention may have various changes and improvements, and these changes and improvements all fall within the scope of protection of the present invention.

Claims

1. A method for enlarging the preparation of valganciclovir hydrochloride, characterized in that: The reaction equation is expressed as follows: The steps include: Step 1: react ganciclovir, Boc2O and an organic base in an organic solvent to generate intermediate 1; Step 2: reacting the intermediate 1, Cbz-valine and the phosphine ligand in an organic solvent under the action of azodicarboxylate to generate the intermediate 2; the molar ratio of the phosphine ligand, azodicarboxylate, intermediate 1 and Cbz-valine is 1.1-1.2:1.1-1.2:1:1-1.05; Step 3: In the presence of hydrogen chloride or hydrochloric acid, intermediate 2 is subjected to palladium-carbon catalytic hydrogenation reaction to obtain valganciclovir hydrochloride.

2. The method for preparing valganciclovir hydrochloride according to claim 1, wherein: In the first step, the organic base is selected from pyridine, triethylamine or N,N-diisopropylethylamine; the organic solvent is selected from dichloromethane, tetrahydrofuran, and 2-methyltetrahydrofuran.

3. The method for preparing valganciclovir hydrochloride according to claim 1, wherein: In the first step, the molar ratio of ganciclovir, Boc2O and organic base is 1:1-3:1-3; and the reaction temperature is 20-45°C.

4. The method for preparing valganciclovir hydrochloride according to claim 1, wherein: In the second step, the organic solvent is selected from dichloromethane, 1,2-dichloroethane, toluene, tetrahydrofuran, and 2-methyltetrahydrofuran.

5. The method for preparing valganciclovir hydrochloride according to claim 1, characterized in that: The phosphine ligand is selected from triphenylphosphine, tricyclohexylphosphine and tributylphosphine; the azodicarboxylate is selected from diethyl azodicarboxylate and diisopropyl azodicarboxylate.

6. The method for enlarging the preparation of valganciclovir hydrochloride according to claim 1, characterized in that: In the second step, after the reaction is finished, the temperature is cooled and frozen to -20°C to -40°C, and the by-products form a complex form, which can be removed by filtering for more than 90%.

7. The method for preparing valganciclovir hydrochloride according to claim 6, characterized in that: The second step is the purification method after the reaction is completed. The temperature is firstly lowered to below -20°C to filter out most of the by-products, and then the pH is adjusted to 6-6.

5. The remaining by-products are precipitated again at this pH value, and then frozen to -40°C to be completely precipitated, and then filtered out with diatomaceous earth.

8. The method for enlarging the preparation of valganciclovir hydrochloride according to claim 1, characterized in that: In the third step, hydrogen chloride is generated in situ from acetyl chloride / methanol or using hydrogen chloride / ethyl acetate solution; the reaction solvent is selected from methanol, ethanol, ethyl acetate, tetrahydrofuran.

9. A method for enlarging the preparation of valganciclovir hydrochloride, characterized in that: The reaction equation is as follows: The reaction conditions of the first step and the second step are the same as those of the second step and the third step in claim 1, respectively.

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