Preparation method and application of green acyclovir

Abstract

The invention discloses a green preparation method and application of green acyclovir. Belongs to the technical field of pharmaceutical chemical synthesis. According to the method, guanine and 2-oxa-1, 4-butanediol diacetate are used as raw materials, in a mixed solvent composed of a deep eutectic solvent and a low-viscosity polar cosolvent, high-selectivity N-9 alkylation reaction is performed through pulse microwave radiation, and acyclovir is synthesized in one step. The deep eutectic solvent is composed of choline salt and polyhydric alcohol or organic acid and has the functions of a reaction medium and a catalyst. The low-viscosity cosolvent is DMF (Dimethyl Formamide), DMSO (Dimethylsulfoxide) or acetonitrile. By introducing the low-viscosity cosolvent, the technical problems that a high-viscosity DES system is poor in mass transfer and incompatible with microwave heating are effectively solved, and synergistic improvement of reaction efficiency and selectivity is realized. And the method has the outstanding advantages of mild reaction conditions, short steps, high yield, good purity, recyclable DES, environmental friendliness and the like, and is suitable for industrial production.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of synthetic medicine chemistry, and more particularly to a preparation method of green acyclovir and application thereof. BACKGROUND

[0002] Acyclovir, with the chemical name of 9-[(2-hydroxyethoxy) methyl] guanine, is a broad-spectrum and highly effective nucleoside antiviral drug. It is mainly used for treating infections caused by herpes simplex virus, varicella-zoster virus, etc., and is one of the most widely used antiviral drugs in clinical use.

[0003] At present, the classical route for synthesizing acyclovir in industry usually uses guanine as a starting material to perform an alkylation reaction with 2-oxa-1,4-butanediol diacetate (or other similar bifunctional alkylating agents). Since there are two nitrogen atoms, N-7 and N-9, in the guanine molecule that can be alkylated, the reaction will generate a mixture of N-9 (the target product) and N-7 (the by-product) isomers. Therefore, how to selectively generate the N-9 alkylation product is the core and difficulty of the synthesis process.

[0004] In order to improve the selectivity, the prior art usually adopts the following strategies, but all have significant defects: Phase transfer catalysis method (such as CN102120771A): This method reacts in an alkaline aqueous solution and needs to use a large amount of organic solvent (such as dichloromethane, toluene) for extraction, which not only produces serious “three wastes” pollution, but also has extremely complex post-treatment.

[0005] Organic / inorganic base method (such as US4409212): In polar aprotic solvents such as DMF and DMSO, triethylamine, potassium carbonate and the like are used as acid binding agents. Such solvents are expensive, difficult to recover and have residual toxicity risks, and the strong alkaline environment easily causes guanine ring opening and other side reactions, affecting product purity.

[0006] Heavy metal catalysis method: The selectivity is guided through complexation of copper salt, silver salt and the like. However, the introduction of heavy metals brings unavoidable drug safety risks and purification problems, which do not meet the pharmaceutical production quality specifications.

[0007] Multi-step protection method: N-9 alkylation is indirectly realized by protecting and then deprotecting specific sites of guanine. This route is long in steps, poor in atom economy and low in total yield, and is not suitable for industrialized production.

[0008] In summary, the existing acyclovir synthesis technology generally has common technical problems such as environmental unfriendliness (use of a large amount of VOCs), dependence on toxic / expensive catalysts, unsatisfactory regioselectivity, and complicated process flow.

[0009] Therefore, developing a new green acyclovir preparation method which is environmentally friendly, simple, highly selective, high yield and suitable for industrial production is an urgent technical problem for those skilled in the art. SUMMARY

[0010] Therefore, the present application overcomes the above-mentioned defects of the prior art and provides a green, efficient and highly selective acyclovir preparation method.

[0011] To achieve the above-mentioned purpose, the present application adopts the following technical solutions: The first object of the present application is to provide a green acyclovir preparation method, which comprises 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, and obtaining acyclovir after post-treatment; the mixed solvent is composed of a deep eutectic solvent and a low-viscosity polar cosolvent, and the deep eutectic solvent simultaneously serves as a reaction medium and a catalyst.

[0012] As a preferred technical solution, the low-viscosity polar cosolvent is selected from at least one of N,N-dimethylformamide, dimethyl sulfoxide and acetonitrile; and the volume of the low-viscosity polar cosolvent 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 1:1-1:3; the hydrogen bond donor is selected from at least one of choline chloride, choline bromide and choline acetate; 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 is 10-30 mL / mmol in terms of guanine.

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

[0017] As a preferred technical solution, the microwave irradiation adopts a pulse mode or a gradient power mode; specifically, the microwave irradiation program is as follows: first, warming up to 80-120℃ at a power of 300-600 W, and then maintaining the reaction at a power of 100-300 W for 10-45 min.

[0018] As a preferred technical scheme, the post-treatment comprises: after the reaction is completed, the reaction solution is cooled, purified water is added to precipitate a solid, the solid is filtered, the filter cake is washed with water and a low-carbon alcohol in sequence, and the acyclovir product is obtained after drying.

[0019] Still another purpose of the present application is to provide acyclovir prepared by the above method, which has a chemical purity of not less than 99.7% and an N-7 alkylated isomer content of less than 0.08%.

[0020] Still another purpose of the present application is to provide the use of the above acyclovir in the preparation of a drug for treating herpes virus infection.

[0021] Via the above technical scheme, the present application has the following beneficial effects compared with the prior art: (1) First, the present method realizes a fundamental breakthrough in green environmental protection and atom economy. The DES composed of natural, cheap and low-toxic components is used to completely replace the traditional volatile organic solvent and toxic catalyst, thereby eliminating environmental pollution and safety risks from the source. The DES has the dual functions of solvent and catalyst, can be recycled after simple recovery after the reaction, greatly reduces the discharge of "three wastes", and perfectly fits the principle of green chemistry.

[0022] (2) Secondly, the present method successfully solves the industry problem that high selectivity and high efficiency are difficult to be considered in the synthesis of acyclovir. The specific DES system (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 interaction, thereby increasing the selectivity of the N-9 alkylation product to an unprecedented level, and the purity of the product is extremely high (N-7 isomer content <0.08%). At the same time, the introduction of microwave radiation technology realizes the "internal heating" at the molecular level, shortens the reaction time from several hours of the traditional method to several tens of minutes, significantly reduces the energy consumption, and greatly improves the production efficiency.

[0023] (3) More importantly, the present application creatively solves the inherent technical contradiction between the high viscosity of DES and the requirement of microwave heating. As a new type of green medium, deep eutectic solvent (DES) brings new hope for the green synthesis of acyclovir due to its designability and the characteristics of both solvent and catalytic function. However, when DES is directly combined with the efficient microwave-assisted synthesis technology, a technical obstacle that has not been fully recognized and solved in the field is highlighted: 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 inability of microwave energy to be efficiently converted into reaction kinetic energy, not only limiting the improvement of reaction efficiency, but also causing side reactions due to local overheating, which may damage its high selectivity advantage. By introducing a specific proportion of low-viscosity cosolvent, a "DES-cosolvent-pulse microwave" synergistic system is constructed. The main role of these organic cosolvents is to significantly reduce the macroscopic viscosity of the DES system and improve mass transfer, and they are also within the framework of being effectively recycled. This scheme significantly improves the mass transfer efficiency without sacrificing the catalytic function of DES, and realizes the simultaneous leap of reaction rate and selectivity. The combination of this technical path produces an unexpected synergistic effect, with a yield of more than 97%, and the process flow is simplified and the cost is low, with outstanding substantial features and significant industrial application prospects. DETAILED DESCRIPTION

[0024] The technical solutions in the embodiments of the present application will be clearly and completely described below in combination with the embodiments of the present application. Obviously, the described embodiments are only part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those of ordinary skill in the art without creative labor fall within the scope of the present application.

[0025] Embodiment 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) in a flask, stir at 80°C until clear, and obtain choline chloride / oxalic acid DES; (2) Preparation of mixed solvent: Take 9 mL of the above DES, add N,N-dimethylformamide (DMF) 3 mL, mix uniformly, and the total volume is 12 mL; (3) Microwave reaction: Add guanine (1.51 g, 10.0 mmol), 12 mL of mixed solvent of step (2), and 2-oxa-1,4-butanediol diacetate (2.19 g, 11.2 mmol) into a 50 mL microwave reaction tube. After sealing, place it in a microwave synthesis instrument; Microwave program was set as follows: 1st stage: 500 W, ramp to 100 °C (about 3 min); 2nd stage: 200 W, maintain 100 °C for 25 min. Stirring speed was 500 rpm.

[0026] (4) Post-treatment: After the reaction was completed, it was cooled to room temperature. 36 mL of purified water was added, and the ice bath was crystallized for 30 minutes. Filtration was performed, and the filter cake was washed with ice water (10 mL x 2) and ethanol (10 mL x 2) in sequence. Vacuum drying at 60 °C for 8 hours was performed to obtain the product.

[0027] The above product was structurally confirmed by nuclear magnetic resonance hydrogen spectrum (1H NMR) and compared with the atlas 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) 1H NMR data of the product of Example 1 and analysis: 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 atlas data is consistent with that of acyclovir standard. Among them, the characteristic single peak at δ 4.97 ppm belongs to the methylene proton (N9-CH2-O) directly connected to the guanine N-9 atom, which is the key marker of N-9 alkylation product. No broad peak (which belongs to N7-CH2-O in N-7 alkylation isomer) is observed near δ ~5.5 ppm in the spectrum, proving that the product has extremely high regioselectivity. It is determined that 2.20 g of acyclovir product is prepared, with a yield of 97.0%.

[0030] (5) Solvent recovery: combine the filtrate and washing water, remove water and DMF by distillation under reduced pressure, and the remaining DES is treated with activated carbon and then vacuum dried, with a recovery rate of >92%. Example 2

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

[0032] Microwave program: 450 W to 95 °C, then 150 W to maintain the reaction for 35 min, to prepare the product.

[0033] The above product was structurally confirmed by nuclear magnetic resonance hydrogen spectrum (1H NMR) and compared with the atlas 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 product 1H NMR data and analysis: 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 of each proton signal are completely consistent with Example 1 and the standard, confirming that the product is acyclovir. The characteristic peak of N9-CH2-O is clear, and no obvious N-7 isomer characteristic peak is observed within the detection limit of nuclear magnetic resonance (about 1%). It was determined that 2.18 g of acyclovir was prepared, with a yield of 96.1%. Example 3

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

[0037] Microwave program: 400 W to 105 °C, then 250 W to maintain the reaction for 20 min, to prepare the product.

[0038] The above product was structurally confirmed by nuclear magnetic resonance hydrogen spectrum (1H NMR) and compared with the atlas 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) Product of Example 3 1H NMR data and assignment: 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 again 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 detection limit of nuclear magnetic resonance (about 1%). It was determined that 2.17 g of acyclovir was prepared, with a yield of 95.7%.

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

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

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

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

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

[0046] Pure DES (12 mL) of Example 1 was used, and the reaction was stirred at 100°C in a traditional oil bath for 4 hours.

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

[0048] Comparative Example 3 (traditional solvent + microwave)

[0049] 20 mL of DMF was used as the solvent without adding DES. The same amount of raw material as Example 1 was added.

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

[0051] Results: Yield 93%, but the content of N-7 isomer was as high as 1.2%, and a large amount of DMF had to be removed in the post-treatment, causing serious environmental pollution.

[0052] Purity and selectivity analysis: HPLC method was used to determine the chemical purity and N-7 isomer content of the products of Examples 1-3 and Comparative Examples 1-3 above.

[0053] Chromatographic conditions: Column: C18 column (4.6 x 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 °C.

[0054] Table 1 Experimental results of different groups

[0055] Result analysis: Relationship between viscosity and yield / selectivity: Comparative Example 1 (pure DES) has very high viscosity, resulting in the worst yield and selectivity. Examples 1-3 have greatly reduced viscosity by adding co-solvents, and the yield and selectivity are significantly improved. Comparative Example 3 (pure DMF) has the lowest viscosity, and the yield is acceptable, but the selectivity is very poor due to the lack of catalytic guidance of DES. This proves that the mixed solvent has achieved the best balance between "maintaining the catalytic function of DES" and "reducing the viscosity of the system".

[0056] Advantages of pulsed microwave: In the pure DES system of Comparative Example 1, even if a microwave is used, the effect is not good. However, in the low-viscosity mixed system of the present application, the pulsed microwave mode (Example 1) can further reduce the content of by-products compared to the constant power mode, which proves its importance in maintaining high selectivity.

[0057] Synergistic effect: The technical effects of the present application (high yield, high selectivity, short time) are the result of the synergistic effect of the catalytic selectivity of DES, the viscosity-reducing mass transfer effect of the co-solvent, and the efficient and controllable heating of the pulsed microwave, which are indispensable. This synergistic effect is unpredictable and constitutes the core creativity and non-obviousness of the present application. Example 4

[0058] Recovery and reuse of DES

[0059] The filtrate and washing water in the post-treatment of Example 1 were combined and subjected to vacuum distillation. After removing most of the water, a concentrated DES aqueous solution was obtained. The solution was passed through a small column packed with activated carbon to adsorb possible residual organic impurities. The effluent was again concentrated under reduced pressure until almost water-free, and then vacuum dried at 80 °C for 4 hours to recover the DES.

[0060] The recovered DES was used for a new round of acyclovir synthesis under the same reaction conditions as Example 1. This recovery and reuse experiment was repeated 4 times, and the experimental results are shown in Table 2.

[0061] Table 2 DES cycle number and yield and chemical purity

[0062] Result analysis: greenness and economy, as indicated by the content of Table 2 of Example 4, the DES used in the present application can effectively recover and at least reuse 4 times, and the product yield and purity do not decrease significantly. This greatly reduces the solvent cost and waste liquid discharge, reflecting the green sustainability and economic advantage of the method.

[0063] Further, in order to verify the difference in effect between the preparation method of the present application and the phase transfer catalysis method and the traditional organic base method, comparative example 4 and comparative example 5 are set up for comparison with example 1, and the specific comparative example 4 and comparative example 5 are as follows:

[0064] Comparative example 4 (traditional phase transfer catalysis method)

[0065] A preparation method of acyclovir, the specific operation is as follows: In a 250 mL three-necked flask, guanine (1.51 g, 10.0 mmol), sodium hydroxide particles (0.80 g, 20.0 mmol), purified water (30 mL) and phase transfer catalyst tetrabutylammonium bromide (0.32 g, 1.0 mmol) were added. The reaction bottle was placed in a 35°C water bath, and a solution of 2-oxa-1,4-butanediol diacetate (2.34 g, 12.0 mmol) in dichloromethane (20 mL) was slowly added under mechanical stirring (600 rpm). After the addition was completed, the reaction was stirred vigorously at 35°C for 6 hours.

[0066] After the reaction was completed, the reaction liquid was transferred to a separatory funnel and allowed to stand to separate into layers. The aqueous phase was collected, and the organic phase was back-extracted with purified water (15 mL x 2). All the aqueous phases were combined and carefully adjusted to neutral pH (about pH 7.0) with concentrated hydrochloric acid, at which time a large amount of solid was precipitated. The mixture was placed in an ice water bath and aged for 1 hour, then filtered. The filter cake was washed with ice water (10 mL x 2) and ethanol (10 mL x 2) in turn, and dried in a vacuum drying oven at 60°C for 8 hours to obtain a white solid.

[0067] HPLC analysis showed that the solid was a mixture of N-9 acyclovir and N-7 isomer. By calculation, the total yield was 85%, of which the content of N-9 target product was 88% and the content of N-7 isomer was 12%. Accordingly, the actual yield of N-9 acyclovir was about 74.8% (85% x 88%).

[0068] Comparative example 5 (traditional organic base method)

[0069] A preparation method of acyclovir, the specific operation is as follows: In a 100 mL dry three-necked round-bottom flask, guanine (1.51 g, 10.0 mmol), anhydrous potassium carbonate (2.76 g, 20.0 mmol) and dry N,N-dimethylformamide (DMF, 25 mL) were added. After stirring for 10 minutes at room temperature under nitrogen atmosphere, 2-oxa-1,4-butanediol diacetate (2.34 g, 12.0 mmol) in DMF (5 mL) was added dropwise through a constant pressure dropping funnel. After the addition was completed, the reaction system was heated to 100 °C and stirred at reflux in an oil bath for 8 hours.

[0070] After the reaction solution was cooled to room temperature, it was filtered to remove insoluble inorganic salts and possible by-products. The filter cake was washed with a small amount of DMF (about 5 mL). The filtrate and washing liquid were combined and transferred to a round-bottom flask, which was rotary evaporated at 60 °C under reduced pressure to remove most of the DMF, obtaining a viscous oily or solid residue. Purified water (20 mL) was added to the residue, which was ultrasonically dispersed and stirred in an ice water bath for 2 hours to crystallize. After filtration, the filter cake was washed with water (10 mL x 2) and dried at 60 °C under vacuum for 8 hours to obtain crude acyclovir. HPLC analysis showed that the yield was 90%, the purity of N-9 acyclovir in the product was 92%, and the content of N-7 isomer was 8%. Accordingly, the actual yield of N-9 acyclovir was about 82.8% (90% x 92%).

[0071] Table 3 Experimental results of different groups

[0072] Result analysis: The results of Comparative Examples 4 and 5 clearly show the limitations of the traditional method. Although they can achieve a certain N-9 selectivity by optimizing the conditions, the content of N-7 isomer impurities (8%-12%) is much higher than 0.05% of Example 1 of the present application. This shows that the traditional method has reached its upper limit in solving the core problem of regioselectivity, while the present application has achieved a qualitative breakthrough through the specific catalytic action of DES.

[0073] Comparative Example 4 (phase transfer catalysis) produces a large amount of salt-containing organic wastewater, and the subsequent extraction, liquid separation, pH adjustment and other steps are complicated, not only increasing the operation time and cost, but also bringing serious environmental pressure.

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

[0075] In comparison, the post-treatment of the present application (Example 1) only needs to add water to crystallize, and the DES can be recycled, which greatly reduces waste emissions from the source, and the process flow is simple and efficient. Although a small amount of organic cosolvent is used, it operates in a recyclable closed system, and the overall environmental benefits are much better than traditional methods, perfectly embodying the principles of green chemistry.

[0076] The various embodiments in the specification are described in a progressive manner, and each embodiment focuses 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 a person skilled in the art to implement or use the present application. Various modifications to these embodiments will be apparent to those skilled in the art, and the general principles defined herein can be implemented in other embodiments without departing from the spirit or scope of the present application. Therefore, the present application will not be limited to these embodiments shown herein, but will conform to the widest scope consistent with the principles and novel features disclosed herein.

Claims

1. A process for the preparation of green acyclovir, characterized in that, The method comprises the following steps: The alkylating reaction is carried out under microwave irradiation in a mixed solvent, which is composed of a deep eutectic solvent and a low-viscosity polar cosolvent, using guanine and 2-oxa-1,4-butanediol diacetate as raw materials, and acyclovir is obtained after the reaction and post-treatment.

2. The method of claim 1, wherein, The low-viscosity polar cosolvent is selected from at least one of N,N-dimethylformamide, dimethyl sulfoxide and acetonitrile; and the volume of the low-viscosity polar cosolvent accounts for 10-30% of the total volume of the mixed solvent.

3. The method according to claim 1 or 2, characterized in that, The deep eutectic solvent is composed of a hydrogen bond donor and a hydrogen bond acceptor in a molar ratio of 1:1-1:3; the hydrogen bond donor is selected from at least one of choline chloride, choline bromide and choline acetate; and the hydrogen bond acceptor is selected from at least one of ethylene glycol, glycerol, urea, oxalic acid and citric acid.

4. The method of claim 3, wherein, The deep eutectic solvent is choline chloride / oxalic acid, choline chloride / glycerol or choline chloride / urea.

5. The method of claim 1, wherein, The total volume of the mixed solvent is 10-30 mL / mmol in terms of guanine.

6. The method of claim 1, wherein, The molar ratio of guanine to 2-oxa-1,4-butanediol diacetate is 1:1.05-1:1.

3.

7. The method of claim 1, wherein, The microwave irradiation is in a pulse mode or a gradient power mode; specifically, the microwave irradiation program is: first, warming up to 80-120℃ at a power of 300-600 W, and then maintaining the reaction at a power of 100-300 W for 10-45 min.

8. The method of claim 1, wherein, The post-treatment comprises: after the reaction, cooling the reaction solution, adding purified water to precipitate solids, filtering, washing the filter cake with water and a low-carbon alcohol in sequence, and drying to obtain the acyclovir product; and the mixed solution of the deep eutectic solvent and the low-viscosity polar cosolvent is recycled after recovery.

9. Aciclovir prepared by the process according to any one of claims 1 to 8, characterized in that, The chemical purity is not less than 99.7%, and the content of N-7 alkylated isomers is less than 0.08%.

10. Use of acyclovir according to claim 9 in the preparation of a medicament for the treatment of herpes virus infections.

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