Synthesis method of high-purity acyclovir and application thereof

Abstract

The application discloses a synthesis method of high-purity acyclovir and application thereof, and belongs to the technical field of synthesis of antiviral drugs. According to the method, dimethylsilylation is carried out on N2 and N9 positions of guanine, condensation is forced to occur at the N9 position through steric hindrance, condensation is catalyzed in a NaHSO4 / toluene system at 60 DEG C, the temperature is reduced by 50 DEG C compared with a traditional process, and by-products are reduced, directional hydrolysis is carried out at 40 DEG C by using 15% ammonia water, the removal rate of O-acetyl is improved, and the retention rate of N-acetyl is reduced, finally, ternary gradient crystallization is adopted, that is, the water-ethanol-ethyl acetate system is used to control the crystal nucleus growth rate, and single 2 / 3 hydrate crystal form is obtained. Through the above method, the defects of purity caused by the insufficient condensation region selectivity, uncontrollable hydrolysis side reaction and crystal form mixture are effectively solved, and technical support is provided for the synthesis of high-purity acyclovir.

Description

Technical Field

[0001] This invention relates to the field of antiviral drug synthesis technology, and more specifically to a method for synthesizing high-purity acyclovir and its application. Background Technology

[0002] Acyclovir is a synthetic second-generation nucleoside analogue broad-spectrum antiviral drug. It is one of the most effective anti-HSV drugs currently available and is widely used to treat HSV herpesvirus infections, especially herpes simplex virus infections. It is a highly selective and relatively low-toxicity antiviral drug widely used both domestically and internationally.

[0003] Impurity control is a key element of drug quality assurance. Keeping impurities within safe and reasonable limits directly affects the quality and safety of marketed drugs. Currently, acyclovir faces significant purity challenges during synthesis, primarily due to its complex synthetic pathway and chemical properties. Existing preparation processes contain the following impurities:

[0004] Guanine Residue: As a starting material for synthesis or a hydrolysis byproduct, guanine has a high structural similarity to acyclovir, making it difficult to remove effectively using traditional separation methods. N7-Isomer (Impurity J): In the condensation reaction of guanine and AME, due to poor regioselectivity, the N9 position of the guanine base combines with the side chain to form the target product. However, some molecules may incorrectly attach at the N7 position, forming a difficult-to-remove structural isomer. This impurity has extremely low solubility in water and organic solvents and can also form sodium salts with strong bases, making it difficult to remove using conventional methods. Incomplete Acetylation Product (Impurity F): During the hydrolysis of the key intermediate diacetyl acyclovir, insufficient regioselectivity leads to numerous hydrolysis side reactions, with some molecules only losing the O-acetyl group while retaining the N-acetyl group. Process-Related Impurities: In traditional processes, high-temperature condensation (110-115℃) and multiple crystallizations are often used to achieve high yields. Traditional crystallization products contain mixed hydrates, resulting in decreased content during storage.

[0005] It is evident that the existing synthesis process has several defects, resulting in low purity of the synthesized acyclovir.

[0006] Therefore, how to solve the problems of insufficient selectivity of condensation regions, uncontrollable hydrolysis side reactions, and purity defects caused by mixed crystal forms in the existing technology, and develop a highly selective and low-energy-consumption synthesis method, is a technical problem that urgently needs to be solved by those skilled in the art. Summary of the Invention

[0007] In view of this, the present invention provides a method for synthesizing high-purity acyclovir and its application. The present invention solves the problems of insufficient selectivity of condensation regions, uncontrollable hydrolysis side reactions, and purity defects caused by mixed crystal forms.

[0008] To achieve the above objectives, this application adopts the following technical solution:

[0009] A method for synthesizing high-purity acyclovir includes the following steps:

[0010] (1) Guanine and trimethylchlorosilane were added to anhydrous pyridine to react and the reaction product was obtained for later use;

[0011] (2) Dissolve the reaction product of step (1) and 2-oxa-1,4-butanediol diethyl ester (AME) in toluene, then add the catalyst NaHSO4, and condense at 60-65℃ for 6-8h; the condensation product is washed by reflux with methanol;

[0012] (3) The washed solid was dissolved in ethyl acetate and recrystallized by two-stage gradient cooling to obtain high-purity diacetyl acyclovir crystals;

[0013] (4) Place diacetyl acyclovir crystals in a 15% ammonia solution at 40±1℃ for 4-4.5h to hydrolyze them until the diacetyl acyclovir is completely hydrolyzed, and prepare the hydrolysate.

[0014] (5) After the hydrolysate is concentrated, a water-ethanol-ethyl acetate mixed solvent is added, and the mixture is crystallized by gradient cooling to obtain acyclovir 2 / 3 hydrate.

[0015] As a preferred technical solution, in step (1), the molar ratio of guanine to trimethylchlorosilane is 1:1.5-2.2; the mass ratio of guanine to anhydrous pyridine is 1:4-6; the reaction temperature of guanine and trimethylchlorosilane in anhydrous pyridine is 25-30℃, and the reaction time is 2-2.5h. Anhydrous pyridine can dissolve guanine, neutralize the byproduct HCl, prevent guanine from being protonated and deactivated, and can also catalyze the silylation reaction, accelerating the formation of Si-N bonds. Furthermore, the water content of anhydrous pyridine is <0.1%, avoiding the hydrolysis of trimethylchlorosilane to generate hexamethyldisiloxane (byproduct).

[0016] As a preferred technical solution, the molar mass ratio of the amount of 2-oxa-1,4-butanediol diethyl ester added in step (2) to that of guanine in step (1) is 1.05:1; the amount of toluene used is 5-7 L / kg guanine; and the amount of catalyst NaHSO4 used is 0.5-1.2 wt% of the total reaction system.

[0017] As a preferred technical solution, the washing temperature of methanol in step (2) is 60-65℃ to remove unreacted AME and hydrophobic dimers. The amount of methanol used is 8-10 times the mass of the condensation product, and the washing time is 10-15 min.

[0018] As a preferred technical solution, the ratio of the washed solid to ethyl acetate in step (3) is 1:18-22 w / v;

[0019] As a preferred technical solution, the dissolution temperature of the washed solid in ethyl acetate is 60-65℃;

[0020] As a preferred technical solution, the two-stage gradient cooling crystallization is as follows: the temperature is reduced from 60-65℃ to 45℃ at a rate of 0.5℃ / min to promote crystal nucleus formation; and the temperature is reduced from 45℃ to 20℃ at a rate of 0.3℃ / min to promote crystal growth.

[0021] As a preferred technical solution, the mass ratio of diacetyl acyclovir crystals to ammonia in step (4) is 1:6.7; the pH value of the hydrolysis process is 10.5-11.0.

[0022] As a preferred technical solution, in step (5), the volume ratio of water, ethanol and ethyl acetate in the water-ethanol-ethyl acetate mixed solvent is 6:3:1; the amount of the water-ethanol-ethyl acetate mixed solvent used is twice the volume of the hydrolysate after concentration;

[0023] The gradient cooling crystallization process is as follows: the temperature is reduced to 25℃ at a rate of 0.5℃ / min to promote crystal nucleus formation; the temperature is reduced from 25℃ to 10℃ at a rate of 0.3℃ / min to promote crystal growth; and the temperature is reduced from 10℃ to 5℃ at a rate of 0.1℃ / min to reduce lattice stress.

[0024] During the gradient cooling crystallization process, an ethyl acetate-ethanol mixed solvent is added at 10°C, and the amount added is 10% of the total volume of the reaction system; the volume ratio of ethyl acetate to ethanol in the ethyl acetate-ethanol mixed solvent is 1:1.

[0025] Another object of this application is to provide the application of any of the methods described above in the synthesis of high-purity acyclovir.

[0026] Another object of this application is to provide: acyclovir prepared by any of the methods described above, characterized in that the acyclovir has a purity ≥99.96%, N7 isomer <0.03%, impurity F <0.033%, and crystal form is a single 2 / 3 hydrate.

[0027] Another object of this application is to provide: the use of the above-mentioned acyclovir in the preparation of antiviral drugs.

[0028] As can be seen from the above technical solution, compared with the prior art, the present invention has the following beneficial effects: The present invention provides a high-purity acyclovir synthesis method based on a silanization protection-low-temperature ammonia hydrolysis synergistic system, solving the problem of excessive N7 isomer (impurity J) and acetyl residue (impurity F) in the existing process:

[0029] Innovation in silanization protection mechanisms:

[0030] This application involves reacting the N2 and N9 positions of guanine with a specific ratio of trimethylchlorosilane (1.5-2.2 equivalents) in pyridine to form a steric hindrance protection layer. The silanization of the N2 position reduces the electron cloud density at the N1 position, thereby enhancing the nucleophilicity of the N9 position. The steric effect of the silyl group at the N9 position forces AME to preferentially attack the N9 position, thereby improving the regioselectivity of AME and reducing the formation of structural isomer impurities.

[0031] Low-temperature condensation process:

[0032] The catalyst chosen is NaHSO4, which provides Brønsted acidity, avoiding resinification side reactions caused by Lewis acids (such as AlCl3). Furthermore, the condensation temperature in this application is 60-65℃, which, compared to the traditional 110℃, effectively lowers the reaction activation energy and reduces the formation of byproducts. Additionally, toluene has a solubility of <0.1 mg / mL for polar impurities (such as dimers), facilitating subsequent washing. This step improves the purity of the DACV intermediate, laying the foundation for subsequent purification.

[0033] DACV recrystallization:

[0034] Existing technologies typically use methanol / water crystallization, leading to excessive solvent residue (methanol > 1000 ppm) and mixed crystal forms (including type I and type II anhydrous hydrates). This application is the first to use pure ethyl acetate as a solvent in a two-stage cooling crystallization process, which can obtain a single crystal form, reduce the crystal PDI, and improve filtration efficiency.

[0035] Innovation in low-temperature hydrolysis of ammonia:

[0036] This application is the first to discover that a 40℃, 15% ammonia system can amplify the difference in hydrolysis rates between O / N (O-acetyl hydrolysis and N-acetyl hydrolysis), achieving regioselective hydrolysis (deacetylation) and suppressing the formation of impurity F;

[0037] Ternary gradient crystallization innovation:

[0038] The crystal form can be directionally controlled and impurities can be deeply removed; the existing technology only uses water-ethanol crystallization, and the product contains amorphous crystals (leading to a decrease in content during storage); this application uses a ternary solvent, water-ethanol (6:3) to promote crystal nucleus formation, and ethyl acetate (1) to reduce solvent polarity and inhibit the formation of amorphous crystals, thereby directionally controlling the crystal form;

[0039] The effect of adding solvent: Adding ethyl acetate-ethanol (1:1) at 10℃ breaks the supersaturation state: instantly reduces solubility by 10-15%, triggering directional crystal growth; inhibits amorphous crystals: the local concentration of ethyl acetate increases and the polarity decreases, making the 2 / 3 hydrate thermodynamically more stable; washes away impurities on the crystal surface: the ethanol flow removes impurities F adsorbed on the surface, breaks the supersaturation state, and reduces lattice defects.

[0040] In summary, this application, through the combination of the above methods, effectively solves the problems of insufficient selectivity of condensation regions, uncontrollable hydrolysis side reactions, and purity defects caused by mixed crystal forms in the prior art, and obtains high-purity acyclovir. Detailed Implementation

[0041] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0042] Example 1

[0043] A method for synthesizing high-purity acyclovir includes the following steps:

[0044] (1) Guanine and trimethylchlorosilane were added to anhydrous pyridine (the mass ratio of guanine to anhydrous pyridine was 1:4) at a molar mass ratio of 1:1.5 and reacted at 25°C for 2 h to obtain the reaction product for later use;

[0045] (2) The reaction product of step (1) and 2-oxa-1,4-butanediol diethyl ester (AME, the molar mass ratio of the amount added to guanine in step (1) is 1.05:1) were dissolved in toluene (5 L / kg guanine), and then the catalyst NaHSO4 (0.5 wt% of the total reaction system) was added. The product was condensed at 60 °C for 6 h. The condensation product was washed by reflux with methanol at 60 °C. The amount of methanol was 8 times the mass of the condensation product, and the washing time was 10 min.

[0046] (3) The washed solid was dissolved in ethyl acetate at a ratio of 1:18 w / v, the temperature was adjusted to 60℃, and the mixture was allowed to stand for 10 min. Then the temperature was lowered from 60℃ to 45℃ at a rate of 0.5℃ / min to promote crystal nucleation. The temperature was then lowered from 45℃ to 20℃ at a rate of 0.3℃ / min to promote crystal growth. After two stages of gradient cooling and recrystallization, high-purity diacetyl acyclovir crystals (DACV) were obtained.

[0047] (4) Place diacetyl acyclovir crystals in a 15% ammonia solution (the mass ratio of diacetyl acyclovir crystals to ammonia is 1:6.7) at 40±1℃ and pH 10.5 for 4 hours to hydrolyze the diacetyl acyclovir until the hydrolysis is complete, and prepare the hydrolysate.

[0048] (5) The hydrolysate was adjusted to pH 7.0 with dilute hydrochloric acid and concentrated to a density of 1.15 g / mL by a falling film evaporator at 40℃ / -0.08MPa. The solution was cooled to 25℃ and filtered to remove the precipitated NH4Cl crystals, yielding a concentrated hydrolysate. After concentration, a water-ethanol-ethyl acetate (volume ratio 6:3:1) mixed solvent (twice the volume of the concentrated hydrolysate) was added, and the temperature was lowered to 25℃ at 0.5℃ / min to promote crystal nucleation. The temperature was lowered from 25℃ to 10℃ at 0.3℃ / min to promote crystal growth. At 10℃, an ethyl acetate-ethanol (volume ratio 1:1) mixed solvent was added, with the amount added being 10% of the total volume of the reaction system. The temperature was lowered from 10℃ to 5℃ at 0.1℃ / min to reduce lattice stress. Acyclovir 2 / 3 hydrate was obtained by the above gradient cooling crystallization.

[0049] Example 2

[0050] A method for synthesizing high-purity acyclovir includes the following steps:

[0051] (1) Guanine and trimethylchlorosilane were added to anhydrous pyridine (the mass ratio of guanine to anhydrous pyridine was 1:6) at a molar mass ratio of 1:2.2 and reacted at 30°C for 2.5 h to obtain the reaction product for later use;

[0052] (2) The reaction product of step (1) and 2-oxa-1,4-butanediol diethyl ester (AME, the molar mass ratio of the amount added to guanine in step (1) is 1.05:1) were dissolved in toluene (the amount used was 7 L / kg guanine), and then the catalyst NaHSO4 (the amount used was 1.2 wt% of the total reaction system) was added, and condensation was carried out at 65 °C for 8 h; the condensation product was washed by reflux with methanol at a washing temperature of 65 °C, the amount of methanol used was 10 times the mass of the condensation product, and the washing time was 15 min;

[0053] (3) The washed solid was dissolved in ethyl acetate at a ratio of 1:22 w / v, the temperature was adjusted to 65℃, and the mixture was allowed to stand for 10 min. Then the temperature was lowered from 65℃ to 45℃ at a rate of 0.5℃ / min to promote crystal nucleation. The temperature was then lowered from 45℃ to 20℃ at a rate of 0.3℃ / min to promote crystal growth. After two stages of gradient cooling and recrystallization, high-purity diacetyl acyclovir crystals (DACV) were obtained.

[0054] (4) Place diacetyl acyclovir crystals in a 15% ammonia solution (the mass ratio of diacetyl acyclovir crystals to ammonia is 1:6.7) at 40±1℃ and pH 11.0 for 4.5h to hydrolyze. Once the diacetyl acyclovir is completely hydrolyzed, the hydrolysate is prepared.

[0055] (5) The hydrolysate was adjusted to pH 7.5 with dilute hydrochloric acid and concentrated to a density of 1.20 g / mL by a falling film evaporator at 45℃ / -0.09MPa. The solution was cooled to 25℃ and filtered to remove the precipitated NH4Cl crystals, yielding a concentrated hydrolysate. After concentration, a water-ethanol-ethyl acetate (volume ratio 6:3:1) mixed solvent (twice the volume of the concentrated hydrolysate) was added, and the temperature was lowered to 25℃ at 0.5℃ / min to promote crystal nucleation. The temperature was lowered from 25℃ to 10℃ at 0.3℃ / min to promote crystal growth. At 10℃, an ethyl acetate-ethanol (volume ratio 1:1) mixed solvent was added, with the amount added being 10% of the total volume of the reaction system. The temperature was lowered from 10℃ to 5℃ at 0.1℃ / min to reduce lattice stress. Acyclovir 2 / 3 hydrate was obtained by the above gradient cooling crystallization.

[0056] Example 3

[0057] A method for synthesizing high-purity acyclovir includes the following steps:

[0058] (1) Guanine and trimethylchlorosilane were added to anhydrous pyridine (the mass ratio of guanine to anhydrous pyridine was 1:5) at a molar mass ratio of 1:2.0 and reacted at 28°C for 2 h to obtain the reaction product for later use;

[0059] (2) The reaction product of step (1) and 2-oxa-1,4-butanediol diethyl ester (AME, the molar mass ratio of the amount added to guanine in step (1) is 1.05:1) were dissolved in toluene (the amount used was 6 L / kg guanine), and then the catalyst NaHSO4 (the amount used was 0.8 wt% of the total reaction system) was added, and condensation was carried out at 63℃ for 7 h; the condensation product was washed by reflux with methanol at a washing temperature of 63℃, the amount of methanol used was 9 times the mass of the condensation product, and the washing time was 12 min;

[0060] (3) The washed solid was dissolved in ethyl acetate at a ratio of 1:20 w / v, the temperature was adjusted to 60℃, and the mixture was allowed to stand for 10 min. Then the temperature was lowered from 60℃ to 45℃ at a rate of 0.5℃ / min to promote crystal nucleation. The temperature was then lowered from 45℃ to 20℃ at a rate of 0.3℃ / min to promote crystal growth. After two stages of gradient cooling and recrystallization, high-purity diacetyl acyclovir crystals (DACV) were obtained.

[0061] (4) Place diacetyl acyclovir crystals in a 15% ammonia solution (the mass ratio of diacetyl acyclovir crystals to ammonia is 1:6.7) at 40±1℃ and pH 10.5 for 4.5h to hydrolyze. After diacetyl acyclovir is completely hydrolyzed, the hydrolysate is prepared.

[0062] (5) The hydrolysate was adjusted to pH 7.3 with dilute hydrochloric acid and concentrated to a density of 1.18 g / mL by a falling film evaporator at 43℃ / -0.085MPa. The solution was cooled to 25℃ and filtered to remove the precipitated NH4Cl crystals, yielding a concentrated hydrolysate. After concentration, a water-ethanol-ethyl acetate (volume ratio 6:3:1) mixed solvent (twice the volume of the concentrated hydrolysate) was added, and the temperature was lowered to 25℃ at 0.5℃ / min to promote crystal nucleation. The temperature was lowered from 25℃ to 10℃ at 0.3℃ / min to promote crystal growth. At 10℃, an ethyl acetate-ethanol (volume ratio 1:1) mixed solvent was added, with the amount added being 10% of the total volume of the reaction system. The temperature was lowered from 10℃ to 5℃ at 0.1℃ / min to reduce lattice stress. Acyclovir 2 / 3 hydrate was obtained by the above gradient cooling crystallization.

[0063] The acyclovir 2 / 3 hydrate obtained by the test met the European Pharmacopoeia 10.0 standard. Its XRPD spectrum had characteristic peaks at 2θ=7.0°, 16.1°, and 26.2°, and the weight loss rate of thermogravimetric analysis was 5.1%.

[0064] Effect verification

[0065] To verify the efficacy of the acyclovir prepared in Examples 1-3 of this application, the recovery rate, HPLC purity, impurity J content, and impurity F content of each group were determined. The experimental results are shown in Table 1.

[0066] Table 1. Validation of the effects of products from different groups

[0067] Group Example 1 Example 2 Example 3 Recovery rate (%) 90.8±0.5 91.2±0.5 91.6±0.5 HPLC purity (%) 99.98 99.97 99.96 Impurity J content (%) 0.030±0.002 0.028±0.002 0.029±0.002 Impurity F content (%) 0.033±0.003 0.032±0.003 0.031±0.003 Crystal purity The XRPD spectrum was consistent with the 2 / 3 hydrate standard, and no other characteristic peaks of the crystal form were detected. The XRPD spectrum was consistent with the 2 / 3 hydrate standard, and no other characteristic peaks of the crystal form were detected. The XRPD spectrum was consistent with the 2 / 3 hydrate standard, and no other characteristic peaks of the crystal form were detected.

[0068] Furthermore, to verify the role of each operational step in the synthesis method of this application, a single-factor experiment was conducted for comparison, with the following comparative example set up:

[0069] Comparative Example 1

[0070] Step (1) is not involved and silanization protection is not used. The condensation reaction in step (2) is carried out directly. Other operations are the same as in Example 3.

[0071] Comparative Example 2

[0072] The condensation reaction in step (2) was carried out using conventional high-temperature condensation (110°C) and conventional catalyst (p-toluenesulfonic acid), with other operations the same as in Example 3.

[0073] Comparative Example 3

[0074] Replace the low-temperature hydrolysis of ammonia in step (4) with traditional high-temperature alkaline hydrolysis (NaOH, 60°C), and perform the other operations as in Example 3.

[0075] The condensation yield, impurity J content, and dimer byproduct content of Example 3 were compared with those of Comparative Example 1. The experimental results are shown in Table 2.

[0076] Table 2. Measurement results of different groups

[0077] Group Example 3 Comparative Example 1 Condensation yield (%) 98.5 92.3 Impurity J content (%) 0.029 0.51 Dimer byproducts (%) 0.25 1.83

[0078] Results analysis: As shown in Table 2, silanization protection reduced impurity J by 17 times, proving that it is the key to controlling regioselectivity.

[0079] The contents of impurity J, resinification byproducts, product color, and metal residues in Example 3 and Comparative Example 2 were determined, and the experimental results are shown in Table 3.

[0080] Table 3. Measurement results of different groups

[0081] Group Example 3 Comparative Example 2 Impurity J content (%) 0.029 0.21 Resinization byproducts (%) Not detected 3.2% Product color White Dark yellow Metal residue <1ppm Sulfonate residue > 500 ppm

[0082] Results analysis: Low-temperature condensation reduces byproducts and avoids toxic catalyst residues.

[0083] The impurity F content, guanine ring-opening impurities, and product stability were tested in Example 3 and Comparative Example 3. The experimental results are shown in Table 4.

[0084] Table 4. Measurement results for different groups

[0085] Group Example 3 Comparative Example 3 Impurity F content (%) 0.031 0.19 Guanine ring-opening impurities (%) Not detected 0.12 Product stability* Content decrease <0.1% Content decreased by 0.7%

[0086] *Accelerated test conditions: 40℃ / RH75% × 6 months

[0087] Results analysis: The impurity F in ammonia water hydrolysis at low temperature is much lower than that in traditional processes, and it significantly improves product stability.

[0088] To further verify the synergistic effect of each step in this application, the following comparative example 4 is set up to compare the effects with Example 3:

[0089] Comparative Example 4

[0090] Without silanization protection, the reaction was carried out by TsOH condensation at 110°C and NaOH hydrolysis at 60°C. The remaining operations were the same as in Example 3. The effects of Comparative Example 4 and Example 3 were measured, and the results are shown in Table 5.

[0091] Table 5. Measurement results for different groups

[0092] Group Example 3 Comparative Example 4 Recovery rate (%) 91.6±0.5 78.5±0.3 HPLC purity (%) 99.96 99.21 Impurity J content (%) 0.029±0.002 0.48±0.003 Impurity F content (%) 0.031±0.003 0.22±0.002

[0093] Results Analysis: As shown in Table 5, the synergistic effect of the three major innovation steps has led to a comprehensive breakthrough in product purity, yield, and environmental friendliness, proving the non-obviousness and technological advancement of the patented technical solution.

[0094] The various embodiments in this specification are described in a progressive manner, with each embodiment focusing on the differences from other embodiments. The same or similar parts between the various embodiments can be referred to each other.

[0095] The above description of the disclosed embodiments enables those skilled in the art to make or use the invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the general principles defined herein may be implemented in other embodiments without departing from the spirit or scope of the invention. Therefore, the invention is not to be limited to the embodiments shown herein, but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.

Claims

1. A method for synthesizing acyclovir, characterized in that, Includes the following steps: (1) Guanine and trimethylchlorosilane were added to anhydrous pyridine to react and the reaction product was obtained for later use; (2) Dissolve the reaction product of step (1) and 2-oxa-1,4-butanediol diethyl ester in toluene, then add the catalyst NaHSO4, and condense at 60-65℃ for 6-8h; the condensation product is washed by reflux with methanol. (3) The washed solid was dissolved in ethyl acetate and recrystallized by a two-stage gradient cooling process to obtain diacetyl acyclovir crystals; (4) Place diacetyl acyclovir crystals in a 15% ammonia solution at 40±1℃ for 4-4.5h to hydrolyze them until the diacetyl acyclovir is completely hydrolyzed, and prepare the hydrolysate. (5) After the hydrolysate is concentrated, a water-ethanol-ethyl acetate mixed solvent is added, and the mixture is crystallized by gradient cooling to obtain acyclovir 2 / 3 hydrate; In step (1), the molar ratio of guanine to trimethylchlorosilane is 1:1.5-2.2; the mass ratio of guanine to anhydrous pyridine is 1:4-6. The addition ratio of the washed solid to ethyl acetate in step (3) is 1:18-22 w / v; the dissolution temperature of the washed solid in ethyl acetate is 60-65℃; the two-stage gradient cooling crystallization is as follows: the temperature is reduced from 60-65℃ to 45℃ at a rate of 0.5℃ / min to promote crystal nucleus formation; the temperature is reduced from 45℃ to 20℃ at a rate of 0.3℃ / min to promote crystal growth. In step (5), the volume ratio of water, ethanol, and ethyl acetate in the water-ethanol-ethyl acetate mixed solvent is 6:3:1; the amount of the water-ethanol-ethyl acetate mixed solvent used is twice the volume of the concentrated hydrolysate. The gradient cooling crystallization process is as follows: the temperature is reduced to 25℃ at a rate of 0.5℃ / min to promote crystal nucleus formation; the temperature is reduced from 25℃ to 10℃ at a rate of 0.3℃ / min to promote crystal growth; and the temperature is reduced from 10℃ to 5℃ at a rate of 0.1℃ / min to reduce lattice stress. During the gradient cooling crystallization process, an ethyl acetate-ethanol mixed solvent is added at 10°C, and the amount added is 10% of the total volume of the reaction system; the volume ratio of ethyl acetate to ethanol in the ethyl acetate-ethanol mixed solvent is 1:

1.

2. The method for synthesizing acyclovir according to claim 1, characterized in that, In step (1), the reaction temperature of guanine with trimethylchlorosilane in anhydrous pyridine is 25-30℃, and the reaction time is 2-2.5h.

3. The method for synthesizing acyclovir according to claim 1, characterized in that, The molar ratio of the amount of 2-oxa-1,4-butanediol diethyl ester added in step (2) to that of guanine in step (1) is 1.05:1; the amount of toluene used is 5-7 L / kg guanine; and the amount of catalyst NaHSO4 used is 0.5-1.2 wt% of the total reaction system.

4. The method for synthesizing acyclovir according to claim 1, characterized in that, In step (2), the washing temperature of methanol is 60-65℃, the amount of methanol used is 8-10 times the mass of the condensation product, and the washing time is 10-15 min.

5. The method for synthesizing acyclovir according to claim 1, characterized in that, In step (4), the mass ratio of diacetyl acyclovir crystals to ammonia is 1:6.7; the pH value of the hydrolysis process is 10.5-11.

0.

6. The use of the method according to any one of claims 1-5 in the synthesis of acyclovir.