Preparation method and application of green acyclovir

Abstract

The application discloses a green acyclovir green preparation method and application thereof, and belongs to the technical field of medical chemical synthesis. The method is characterized in that guanine and 2-oxa-1,4-butanediol diacetate are used as raw materials, a high-selectivity N-9 alkylation reaction is carried out through pulse microwave irradiation in a mixed solvent composed of a deep eutectic solvent and a low-viscosity polar cosolvent, and acyclovir is synthesized in one step. The deep eutectic solvent is composed of a choline salt and a polyol or an organic acid, and has the functions of a reaction medium and a catalyst; and the low-viscosity cosolvent is DMF, DMSO or acetonitrile. By introducing the low-viscosity cosolvent, the technical problems of poor mass transfer and incompatibility with microwave heating of a high-viscosity DES system are effectively solved, and the reaction efficiency and selectivity are synergistically improved. The method has the advantages of mild reaction conditions, short steps, high yield, good purity, recyclability of the DES, environmental friendliness and the like, and is suitable for industrial production.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical chemical synthesis technology, and more specifically to a method for preparing green acyclovir and its application. Background Technology

[0002] Acyclovir, chemically named 9-[(2-hydroxyethoxy)methyl]guanine, is a broad-spectrum, highly effective nucleoside antiviral drug. It is primarily used to treat infections caused by herpes simplex virus, varicella-zoster virus, and other similar viruses, and is one of the most widely used antiviral drugs in clinical practice.

[0003] Currently, the classic industrial route for synthesizing acyclovir typically uses guanine as the starting material, undergoing an alkylation reaction with 2-oxa-1,4-butanediol diacetate (or other similar bifunctional alkylating agents). Because the guanine molecule contains two nitrogen atoms, N-7 and N-9, that can be alkylated, this reaction produces a mixture of two isomers: N-9 (the target product) and N-7 (a byproduct). Therefore, achieving highly selective generation of the N-9 alkylated product is the core and challenging aspect of the synthetic process.

[0004] To improve selectivity, existing technologies typically employ the following strategies, but all of them have significant drawbacks: Phase transfer catalysis (e.g., CN102120771A): This method involves reaction in an alkaline aqueous solution and requires the use of large amounts of organic solvents (e.g., dichloromethane, toluene) for extraction, which not only generates serious "three wastes" pollution, but also makes post-treatment extremely complicated.

[0005] Organic / inorganic alkaline method (e.g., US4409212): Triethylamine, potassium carbonate, etc., are used as acid-binding agents in polar aprotic solvents such as DMF and DMSO. These solvents are expensive, difficult to recycle, and pose a risk of residual toxicity. At the same time, the strongly alkaline environment can easily trigger side reactions such as guanine ring-opening, affecting product purity.

[0006] Heavy metal catalysis: This method guides selectivity through complexation with copper or silver salts. However, the introduction of heavy metals brings unavoidable drug safety risks and purification challenges, failing to meet Good Manufacturing Practices (GMP) requirements for pharmaceuticals.

[0007] Multi-step protection method: This method indirectly achieves N-9 alkylation by first protecting and then deprotecting specific sites on guanine. This route is lengthy, has poor atom economy, and low overall yield, making it unsuitable for industrial-scale production.

[0008] In summary, existing acyclovir synthesis technologies generally suffer from common technical problems such as being environmentally unfriendly (using large amounts of VOCs), relying on toxic / expensive catalysts, having poor regioselectivity, and having cumbersome process flows.

[0009] Therefore, developing a new green method for preparing acyclovir that is environmentally friendly, simple in procedure, highly selective, has a high yield, and is suitable for industrial production is a technical problem that urgently needs to be solved by those skilled in the art. Summary of the Invention

[0010] In view of this, the present invention overcomes the above-mentioned defects of the prior art and provides a green, efficient and highly selective method for preparing acyclovir.

[0011] To achieve the above objectives, this application adopts the following technical solution: The primary objective of this application is to provide a method for preparing green acyclovir, comprising the following steps: using guanine and 2-oxa-1,4-butanediol diacetate as raw materials, performing an alkylation reaction in a mixed solvent under microwave irradiation conditions, and obtaining acyclovir after post-treatment after the reaction; wherein the mixed solvent is composed of a deep eutectic solvent and a low-viscosity polar co-solvent, and the deep eutectic solvent serves as both a reaction medium and a catalyst.

[0012] As a preferred technical solution, the low-viscosity polar co-solvent is selected from at least one of N,N-dimethylformamide, dimethyl sulfoxide, and acetonitrile; the volume of the low-viscosity polar co-solvent accounts for 10-30% of the total volume of the mixed solvent.

[0013] As a preferred technical solution, the deep eutectic solvent is composed of a hydrogen bond donor and a hydrogen bond acceptor in a molar ratio of 1:1 to 1:3; the hydrogen bond donor is selected from at least one of choline chloride, choline bromide, and acetylcholine; and the hydrogen bond acceptor is selected from at least one of ethylene glycol, glycerol, urea, oxalic acid, and citric acid.

[0014] As a preferred technical solution, the deep eutectic solvent is choline chloride / oxalic acid, choline chloride / glycerol, or choline chloride / urea.

[0015] As a preferred technical solution, the total volume of the mixed solvent, calculated as guanine, is 10 ~ 30 mL / mmol.

[0016] As a preferred technical solution, the molar ratio of guanine to 2-oxa-1,4-butanediol diacetate is 1:1.05 to 1:1.3.

[0017] As a preferred technical solution, the microwave radiation adopts a pulse mode or a gradient power mode; specifically, the microwave radiation procedure is as follows: first, the temperature is raised to 80-120°C with a power of 300-600W, and then the reaction is maintained at a power of 100-300W for 10-45 minutes.

[0018] As a preferred technical solution, the post-processing includes: after the reaction is completed, cooling the reaction solution, adding purified water to precipitate the solid, filtering, washing the filter cake with water and low-carbon alcohol in sequence, and drying to obtain the acyclovir product; the mixed solution of the deep eutectic solvent and the low-viscosity polar co-solvent is recycled after recovery.

[0019] Another object of this application is to provide: an acyclovir prepared by the above method, having a chemical purity of not less than 99.7% and an N-7 alkylated isomer content of less than 0.08%.

[0020] Another object of this application is to provide: the use of the above-mentioned acyclovir in the preparation of a medicament for treating herpes virus infection.

[0021] As can be seen from the above technical solution, compared with the prior art, the present invention has the following beneficial effects: (1) First, this method has achieved a fundamental breakthrough in terms of green environmental protection and atom economy. By pioneering the use of DES composed of natural, inexpensive, and low-toxic components to completely replace traditional volatile organic solvents and toxic catalysts, environmental pollution and safety risks are eliminated at the source. DES has the dual functions of solvent and catalyst, and can be recycled after simple recovery, which greatly reduces the emission of "three wastes" and perfectly conforms to the principles of green chemistry.

[0022] (2) Secondly, this method successfully solves the industry problem of balancing high selectivity and high efficiency in the synthesis of acyclovir. Specific DES systems (such as choline chloride / oxalic acid) can selectively activate the N-9 site of guanine and inhibit the reactivity of the N-7 site through intermolecular interactions, thereby improving the selectivity of the N-9 alkylation product to an unprecedented level, resulting in a product with extremely high purity (N-7 isomer content <0.08%). At the same time, the introduction of microwave radiation technology realizes "internal heating" at the molecular level, shortening the reaction time from several hours in traditional methods to tens of minutes, significantly reducing energy consumption and greatly improving production efficiency.

[0023] (3) Most importantly, this invention creatively solves the inherent technical contradiction between the high viscosity of DES and the requirements of microwave heating. Deep eutectic solvents (DES), as a novel green medium, have brought new hope to the green synthesis of acyclovir due to their designability and the combination of solvent and catalytic functions. However, when DES is directly combined with efficient microwave-assisted synthesis technology, a technical obstacle that has not yet been fully recognized and resolved in the field becomes apparent: there is a fundamental contradiction between the inherent high viscosity of most DES and the rapid mass transfer and uniform heating required by microwave heating. High viscosity will severely limit the diffusion of reactant molecules, resulting in the inefficient conversion of microwave energy into reaction kinetic energy. This not only limits the improvement of reaction efficiency, but may also cause side reactions due to local overheating, thereby damaging its high selectivity advantage. By introducing a specific proportion of low-viscosity co-solvents, a "DES-co-solvent-pulsed microwave" synergistic system is constructed. The main role of these organic co-solvents is to significantly reduce the macroscopic viscosity of the DES system and improve mass transfer, while they themselves are within a framework that can be effectively recycled and recycled. This approach significantly improves mass transfer efficiency without sacrificing the catalytic function of DES, achieving a simultaneous leap in reaction rate and selectivity. The combination of these technical pathways produces unexpected synergistic effects, with yields consistently above 97%, and the process is simplified and cost-effective, demonstrating outstanding substantive features and significant prospects for industrial application. Detailed Implementation

[0024] 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.

[0025] Example 1 (1) Preparation of deep eutectic solvent (DES): Add choline chloride (13.94 g, 0.1 mol) and oxalic acid dihydrate (12.61 g, 0.1 mol) to a flask and stir at 80 °C until clear to obtain choline chloride / oxalic acid DES; (2) Preparation of mixed solvent: Take 9 mL of the above DES, add 3 mL of N,N-dimethylformamide (DMF), mix well, and the total volume is 12 mL; (3) Microwave reaction: Add guanine (1.51 g, 10.0 mmol), 12 mL of the mixed solvent from step (2), and 2-oxa-1,4-butanediol diacetate (2.19 g, 11.2 mmol) to a 50 mL microwave reaction tube. Seal and place in a microwave synthesizer; Microwave program settings: Stage 1: 500W, heat to 100℃ (approximately 3 minutes); Stage 2: 200W, maintain 100℃ for 25 minutes. Stirring speed: 500 rpm.

[0026] (4) Post-processing: After the reaction was complete, cool to room temperature. Add 36 mL of purified water and crystallize in an ice bath for 30 minutes. Filter by suction, and wash the filter cake successively with ice water (10 mL × 2) and ethanol (10 mL × 2). Dry under vacuum at 60 °C for 8 hours to obtain the product.

[0027] The structure of the above product was confirmed by ¹H NMR and compared with that of acyclovir standard.

[0028] Instrument Model: Bruker AVANCE NEO 400 MHz Nuclear Magnetic Resonance Spectrometer Solvent: Deuterated dimethyl sulfoxide (DMSO-*d*6) Internal standard: Tetramethylsilane (TMS) Example 1: ¹H NMR data and analysis of the product: δ (ppm): 10.58 (s, 1H, N1-H), 7.78 (s, 1H, C8-H), 6.51 (br s, 2H, N2-H2), 5.39 (t, J = 5.6 Hz, 1H, CH2-OH), 4.97 (s, 2H, N9-CH2-O), 3.53 (m, 2H, O-CH2-CH2), 3.36 (m, 2H, CH2-CH2-OH).

[0029] Analysis Conclusion: The spectral data were consistent with the acyclovir standard. The characteristic singlet at chemical shift δ 4.97 ppm was attributed to the methylene proton (N9-CH2-O) directly bonded to the N-9 atom of guanine, a key characteristic of N-9 alkylation products. No broad peak was observed near δ ~ 5.5 ppm (this peak belongs to N7-CH2-O in the N-7 alkylation isomer), demonstrating the product's extremely high regioselectivity. 2.20 g of acyclovir product was obtained, with a yield of 97.0%.

[0030] (5) Solvent recovery: The filtrate and washing water were combined, and water and DMF were removed by vacuum distillation. The remaining DES was treated with activated carbon and then vacuum dried. The recovery rate was >92%. Example 2

[0031] The method is basically the same as in Example 1, except that the mixed solvent is choline chloride / glycerol DES (9 mL) and dimethyl sulfoxide (DMSO) (3 mL).

[0032] Microwave program: Heat to 95°C at 450W, then maintain reaction at 150W for 35 minutes to obtain the product.

[0033] The structure of the above product was confirmed by ¹H NMR and compared with that of acyclovir standard.

[0034] Instrument Model: Bruker AVANCE NEO 400 MHz Nuclear Magnetic Resonance Spectrometer Solvent: Deuterated dimethyl sulfoxide (DMSO-*d*6) Internal standard: Tetramethylsilane (TMS) Example 2: ¹H NMR data and analysis of the product: δ (ppm): 10.57 (s, 1H, N1-H), 7.77 (s, 1H, C8-H), 6.50 (br s, 2H, N2-H2), 5.38 (t, J = 5.6 Hz, 1H, CH2-OH), 4.96 (s, 2H, N9-CH2-O), 3.52 (m, 2H, O-CH2-CH2), 3.35 (m, 2H, CH2-CH2-OH).

[0035] Conclusion: The chemical shifts and splitting patterns of each proton signal were completely consistent with those of Example 1 and the standard, confirming the product as acyclovir. The N9-CH2-O characteristic peak was clear, and no obvious N-7 isomer characteristic peak was observed within the NMR detection limit (approximately 1%). 2.18 g of acyclovir was prepared, with a yield of 96.1%. Example 3

[0036] The method is basically the same as in Example 1, except that the mixed solvent is choline chloride / urea DES (10 mL) and acetonitrile (ACN) (2 mL).

[0037] Microwave program: Heat to 105℃ at 400W, then maintain the reaction at 250W for 20 minutes to obtain the product.

[0038] The structure of the above product was confirmed by ¹H NMR and compared with that of acyclovir standard.

[0039] Instrument Model: Bruker AVANCE NEO 400 MHz Nuclear Magnetic Resonance Spectrometer Solvent: Deuterated dimethyl sulfoxide (DMSO-*d*6) Internal standard: Tetramethylsilane (TMS) Example 3: ¹H NMR data and analysis of the product: δ (ppm): 10.59 (s, 1H, N1-H), 7.79 (s, 1H, C8-H), 6.52 (br s, 2H, N2-H2), 5.40 (t, J = 5.6 Hz, 1H, CH2-OH), 4.98 (s, 2H, N9-CH2-O), 3.54 (m, 2H, O-CH2-CH2), 3.37 (m, 2H, CH2-CH2-OH).

[0040] Conclusion: The spectral data further confirmed the successful synthesis of the target product, acyclovir. The characteristic signal of N-9 alkylation was clear, and no obvious N-7 isomer impurity signal was observed within the NMR detection limit (approximately 1%). The yield of acyclovir obtained was 2.17 g, with a yield of 95.7%.

[0041] Comparative Example 1 (pure DES, constant microwave power)

[0042] Pure DES (12 mL) from Example 1 was used, without the use of DMF.

[0043] Microwave conditions: constant power 300W, temperature 100℃, reaction time 30 minutes.

[0044] Results: The reaction system was significantly viscous and difficult to stir. After the reaction was completed, 2.05 g of product was obtained, with a yield of 90.3%. HPLC showed that the N-7 isomer content was 0.25%.

[0045] Comparative Example 2 (pure DES, no microwave)

[0046] Pure DES (12 mL) from Example 1 was reacted at 100°C for 4 hours in a conventional oil bath with stirring.

[0047] Results: Yield 85%, N-7 isomer content 0.35%.

[0048] Comparative Example 3 (Traditional Solvent + Microwave)

[0049] Use 20 mL of DMF as solvent, without adding DES. Add the same amount of raw material as in Example 1.

[0050] The microwave conditions are the same as in Example 1.

[0051] Results: The yield was 93%, but the N-7 isomer content was as high as 1.2%, and a large amount of DMF needed to be removed in the post-processing, resulting in significant environmental pollution.

[0052] Purity and selectivity analysis: The chemical purity and N-7 isomer content of the products of Examples 1-3 and Comparative Examples 1-3 were determined by HPLC.

[0053] Chromatographic conditions: Column: C18 column (4.6 × 250 mm, 5 μm); Mobile phase: methanol-potassium dihydrogen phosphate buffer (pH 3.0) (10:90, v / v); Flow rate: 1.0 mL / min; Detection wavelength: 254 nm; Column temperature: 30℃.

[0054] Table 1. Experimental results for different groups

[0055] Results Analysis: Relationship between viscosity and yield / selectivity: Comparative Example 1 (pure DES) had extremely high viscosity, resulting in the worst yield and selectivity. Examples 1-3 showed significant viscosity reduction and substantial improvement in yield and selectivity through the addition of a co-solvent. Comparative Example 3 (pure DMF) had the lowest viscosity and a acceptable yield, but its selectivity was extremely poor due to the lack of DES-directing catalytic effect. This demonstrates that the mixed solvent achieves the optimal balance between "maintaining DES catalytic function" and "reducing system viscosity".

[0056] Advantages of pulsed microwaves: In the pure DES system of Comparative Example 1, even the use of microwaves was not effective. However, in the low-viscosity mixing system of this invention, the pulsed microwave mode (Example 1) further reduced the by-product content compared to the constant power mode, demonstrating its importance in maintaining high selectivity.

[0057] Synergistic effect: The technical effects of this invention (high yield, high selectivity, short time) are the result of the synergistic effect of the catalytic selectivity of DES, the viscosity-reducing and mass transfer effect of the co-solvent, and the efficient and controllable heating of pulsed microwaves. None of these factors can be omitted. This synergistic effect is unexpected and constitutes the core inventiveness and non-obviousness of this invention. Example 4

[0058] DES recycling and reuse

[0059] The filtrate and wash water from the post-treatment in Example 1 were combined and subjected to vacuum distillation to remove most of the water, yielding a concentrated DES aqueous solution. This solution was passed through a column packed with activated carbon to adsorb any remaining organic impurities. The effluent was then concentrated again under vacuum until almost anhydrous, and subsequently dried under vacuum at 80°C for 4 hours to recover DES.

[0060] The recovered DES was used in a new round of acyclovir synthesis, under the same reaction conditions as in Example 1. This recovery and reuse experiment was repeated four times, and the results are shown in Table 2.

[0061] Table 2. Number of DES cycles, yield, and chemical purity

[0062] Results Analysis: Regarding the greenness and economy, Table 2 of Example 4 shows that the DES used in this invention can be effectively recovered and reused at least four times, with no significant decrease in product yield and purity. This greatly reduces solvent costs and wastewater discharge, demonstrating the green sustainability and economic advantages of the method.

[0063] Furthermore, to verify the difference in effectiveness between the preparation method of this application and the phase transfer catalysis method and the traditional organic base method, comparative examples 4 and 5 were set up to conduct a control experiment with Example 1. The specific comparative examples 4 and 5 are as follows:

[0064] Comparative Example 4 (Traditional Phase Transfer Catalysis)

[0065] A method for preparing acyclovir, the specific steps of which are as follows: In a 250 mL three-necked flask, add guanine (1.51 g, 10.0 mmol), sodium hydroxide granules (0.80 g, 20.0 mmol), purified water (30 mL), and the phase transfer catalyst tetrabutylammonium bromide (0.32 g, 1.0 mmol). Place the reaction flask in a 35 °C water bath and slowly add 20 mL of dichloromethane solution containing 2-oxa-1,4-butanediol diacetate (2.34 g, 12.0 mmol) dropwise with mechanical stirring (600 rpm). After the addition is complete, stir vigorously at 35 °C for 6 hours.

[0066] After the reaction was complete, the reaction mixture was transferred to a separatory funnel and allowed to stand for separation. The aqueous phase was collected, and the organic phase was back-extracted with purified water (15 mL × 2). All aqueous phases were combined, and the pH was carefully adjusted to neutral (approximately pH 7.0) with concentrated hydrochloric acid, at which point a large amount of solid precipitated. The mixture was placed in an ice-water bath and aged for another 1 hour, followed by filtration. The filter cake was washed successively with ice water (10 mL × 2) and ethanol (10 mL × 2), and dried in a vacuum drying oven at 60 °C for 8 hours to obtain an off-white solid.

[0067] HPLC analysis revealed that the solid was a mixture of N-9 acyclovir and the N-7 isomer. Calculations showed an overall yield of 85%, with 88% being the N-9 target product and 12% being the N-7 isomer. Based on this, the actual yield of N-9 acyclovir was approximately 74.8% (85% × 88%).

[0068] Comparative Example 5 (Traditional Organic Alkali Method)

[0069] A method for preparing acyclovir, the specific steps of which are as follows: In a 100 mL dry three-necked round-bottom flask, add guanine (1.51 g, 10.0 mmol), anhydrous potassium carbonate (2.76 g, 20.0 mmol), and dry N,N-dimethylformamide (DMF, 25 mL). Stir at room temperature for 10 minutes under a nitrogen atmosphere. Then, slowly add a 5 mL solution of 2-oxa-1,4-butanediol diacetate (2.34 g, 12.0 mmol) in DMF through a constant-pressure dropping funnel. After the addition is complete, heat the reaction system to 100 °C and reflux in an oil bath with stirring for 8 hours.

[0070] After the reaction solution was cooled to room temperature, it was filtered to remove insoluble inorganic salts and possible byproducts. The filter cake was washed with a small amount of DMF (about 5 mL). The filtrate and washings were combined and transferred to a round-bottom flask. The mixture was then subjected to rotary evaporation under reduced pressure at 60 °C to remove most of the DMF, yielding a viscous oily substance or solid residue. Purified water (20 mL) was added to the residue, and the mixture was ultrasonically dispersed and stirred in an ice-water bath for 2 hours to allow crystallization. The residue was filtered, and the filter cake was washed with water (10 mL × 2) and dried under vacuum at 60 °C for 8 hours to obtain crude acyclovir. HPLC analysis showed a yield of 90%, with N-9 acyclovir purity of 92% and N-7 isomer content of 8%. Based on this, the actual yield of N-9 acyclovir was calculated to be approximately 82.8% (90% × 92%).

[0071] Table 3 Experimental results of different groups

[0072] Results analysis: A Leap Forward in Selectivity and Product Purity: The results of Comparative Examples 4 and 5 clearly demonstrate the limitations of traditional methods. Although they can achieve a certain degree of N-9 selectivity through optimized conditions, the N-7 isomer impurity content (8%-12%) is far higher than the 0.05% in Example 1 of this invention. This indicates that traditional methods have reached their upper limit in solving the core problem of regioselectivity, while this invention achieves a qualitative breakthrough through the specific catalytic effect of DES.

[0073] Comparative Example 4 (phase transfer catalysis) generated a large amount of saline organic wastewater. Subsequent steps such as extraction, separation, and pH adjustment were cumbersome, which not only increased the operation time and cost, but also brought severe environmental pressure.

[0074] Comparative Example 5 (organic base method) used a large amount of DMF that is difficult to recycle and regenerate. Its high boiling point and potential toxicity make solvent recovery costly, and the reaction produces alkali-containing solid waste.

[0075] In contrast, the post-treatment of this invention (Example 1) only requires the addition of water for crystallization, and the DES can be recycled, which greatly reduces waste emissions from the source. The process is simple and efficient. Although a small amount of organic co-solvent is used, it operates in a recyclable closed system, and the overall environmental benefits are far superior to traditional methods, perfectly embodying the principles of green chemistry.

[0076] 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.

[0077] 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 preparing green acyclovir, characterized in that, Includes the following steps: Acyclovir was obtained by alkylation of guanine and 2-oxa-1,4-butanediol diacetate in a mixed solvent under microwave irradiation. After the reaction, the acyclovir was obtained by post-treatment. The mixed solvent consisted of a deep eutectic solvent and a low-viscosity polar co-solvent, with the deep eutectic solvent serving as both the reaction medium and catalyst. The low-viscosity polar co-solvent is selected from at least one of N,N-dimethylformamide, dimethyl sulfoxide, and acetonitrile; the volume of the low-viscosity polar co-solvent accounts for 10% to 30% of the total volume of the mixed solvent; The deep eutectic solvent is composed of a hydrogen bond donor and a hydrogen bond acceptor in a molar ratio of 1:1 to 1:3; the hydrogen bond donor is selected from choline chloride; and the hydrogen bond acceptor is selected from at least one of glycerol, urea, and oxalic acid. The deep eutectic solvent is choline chloride / oxalic acid, choline chloride / glycerol, or choline chloride / urea.

2. The method according to claim 1, characterized in that, The total volume of the mixed solvent, calculated as guanine, is 10 to 30 mL / mmol.

3. The method according to claim 1, characterized in that, The molar ratio of guanine to 2-oxa-1,4-butanediol diacetate is 1:1.05 to 1:1.

3.

4. The method according to claim 1, characterized in that, The microwave radiation adopts a pulse mode or a gradient power mode; the microwave radiation procedure is as follows: first, the temperature is raised to 80-120℃ with a power of 300-600W, and then the reaction is maintained at a power of 100-300W for 10-45 minutes.

5. The method according to claim 1, characterized in that, The post-processing includes: after the reaction is completed, the reaction solution is cooled, purified water is added to precipitate the solid, the solution is filtered, the filter cake is washed with water and low-carbon alcohol in sequence, and dried to obtain the acyclovir product; the mixed solution of the deep eutectic solvent and the low-viscosity polar co-solvent is recycled after recovery.

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