RU2111967C1 - Method of synthesis of aciclovir - Google Patents

Abstract

FIELD: chemical technology, antiviral preparations. SUBSTANCE: invention relates to synthesis of acyclic guanosine analogues showing antiviral activity, in part, to the preparation aciclovir, [9-(2'-hydroxyethoxymethyl)-guanine] . Method involves combined processes of acetylguanines synthesis in a single reactor and their alkylation with 2-oxa-1,4-butandiol diacetate or dioxolan under conditions of acid catalysis followed by deacetylation of an intermediate substituted guanine with alkaline agent excess and regioselective formation of the end product and its isolation by crystallization. High yield of pure product (80-95%) is provided by precise control of narrow temperature intervals, barometric and time parameters of process and catalysts used. Guanine, guanosine and their acetates can be used as the parent raw. Important aspect of process - simultaneous synthesis of ribofuranose tetraacetates. Invention describes principle scheme of aciclovir synthesis and its derivatives and six typical examples. Synthesized preparation is used in medicine as an effective antiherpes agent. EFFECT: improved method of synthesis. 20 cl, 1 dwg

Description

 The invention relates to the field of chemistry and chemical technology for producing abnormal nucleosides, and more particularly, to methods for producing acyclic guanosine analogues having high antiviral activity and, in particular, to Acyclovir (Aciclovir, Acycloguanosin, Virolex, Zovirax, [9- (2'-hydroxyethoxymethyl) ) guanine]), which has found application in medicine as an effective antiherpetic agent [1 - 3].

 There are various methods for producing acyclovir and its derivatives [4–23], but all of them are quite complex and low-tech, despite the variety of synthetic approaches and differences in the raw materials used. The development of technology in the direction of increasing the yield of the target product occurred mainly by increasing the regioselectivity of the alkylation of the purine cycle at position 9, as well as introducing new methods for the separation of the resulting isomers of substances and purification of the target product.

For the first time Schaeffer H. et.al. [4 - 8] in 1977 - 78 developed and patented a method for producing acyclovir and its derivatives, based on the alkylation of 2,6-dichloropurine 2 with benzoyloxychloromethyl ether in aprotic solvents (dimethylformamide) under the conditions of basic catalysis [(C ₂ H ₅ ) ₃ N] with the subsequent substitution of chlorine atoms in the purine cycle in positions 6 and 2 by hydroxy and amino groups and alkaline removal of benzoyl protection. The yield of acyclovir was about 13% based on the starting 2,6-dichloropurine. Later it was possible to increase the yield of acyclovir to 60% by reacting at low temperature the sodium salt of 2-chloro-6-iodopurine with iodomethyl (trimethylsilyloxy) ethyl ether, prepared in situ from 1,3-dioxolane and trimethyl iodosilane at -78 ^o C. At the final stage, hydrolysis and amination of N-substituted 2-chloro-6-iodopurine to acyclovir [9]. With the development of this method, 2-amino-6-chloropurine was used as the starting material, which was reacted with 2-acetoxyethoxymethyl bromide in the presence of mercury cyanide as a silyl derivative [10]. After alkaline hydrolysis of intermediate N ₉ -substituted purine, the yield of acyclovir reached 70% based on the starting halogenopurine.

The advantage of the described direction is the first laboratory development of production. Unfortunately, these methods are unsuitable for industrial production because of the multi-stage, labor-intensive process, the inaccessibility of halogen-purines, their high cost. The fact is that 2,6-dichloropurine is obtained from expensive xanthine by reacting with POCl ₃ in the presence of tertiary amines (110 ^o C, 20 h) with a yield of 30 - 40%, toxic reagents are used and waste disposal problems arise. 2-Chloro-6-iodopurine is obtained from 2,6-dichloropurin under the influence of hydroiodic acid (corrosion) with a yield of about 50% (for xanthine - 20%). Further, after alkylation of halogenopurines, it is necessary to carry out hydrolysis reactions, amination of the purine cycle.

The direct alkylation of guanine and its acetyl derivatives by the silyl method with the use of 2-acyl ethoxymethyl halides (acyl: acetyl, benzoyl) or 2-trimethylsilyloxyethyl iodomethyl ether in benzene, toluene, dichloroethane and methylene chloride allowed us to reduce the number of necessary stages of acyclovir production and reduce the consumption of raw materials. 6, 8, 17]. However, these methods are characterized by a long guanine silylation process, high moisture sensitivity of trimethylsilyl purines and, most importantly, a low yield of acyclovir (from 10 to 40%), as well as the need for chromatographic purification of the target product from inactive 7-side isomer to the stage of deprotection (ratio N ₉ / N ₇ - isomers ranges from 2/3 to 1/4).

 The alkylation of guanine sodium salts in dimethylformamide with 2-acetoxyethoxymethyl halides leads to the same results. In this method, it is also not possible to avoid the need for chromatographic separation of isomeric substances, which makes it unsuitable for implementation on an industrial scale.

In other versions of the condensation of N ₂ , N _{7 (9)} -diacetylguanine with 2-oxa-1,4-butanediol diacetate in various solvents — toluene, dimethylformamide, dimethyl sulfoxide or sulfolane (110 - 116 ^° C, 15-20 hours) in the presence of substituted arylsulfonic acids, bis (p-nitrophenyl) phosphoric acid or inorganic Lewis acids [21] the total yield of a mixture of isomeric 7- and 9- (2'-acetoxyethoxymethyl) -N ₂ -acetylguanines ranges from 60 - 90% and, at best case, the ratio of 9- and 7-isomers reaches 3.3: 1.3. In all of the above methods, the initial mono- and diacetylguanine are preliminarily obtained by prolonged acetylation of guanine with a large (15-30-fold) excess of acetic anhydride or its mixture with acetic acid (130-140 ^° C, 16-20 hours) with a yield of 75-82 %

Closest to the proposed technical essence is the method of obtaining acyclovir described in [17, p. 1371 - 1374], by heating N ₂ , N _{7 (9)} -diacetylguanine with an excess of 2-oxa-1,4-butanediol diacetate at 150 ^° C. for 45 minutes in the presence of 2% p-toluenesulfonic acid. The mixture was cooled and extracted with boiling ethyl acetate. An insoluble precipitate of diacetylguanine was separated, the extract was evaporated in vacuo to give a white crystalline product consisting of a mixture of 9- and 7- (2'-acetoxyethoxymethyl) -N ₂ -acetylguanines. The obtained isomeric substances are chromatographically separated on a column of silica gel, eluting with a mixture of CHCl ₃ -MeOH (gradient). Recrystallization from methanol gave 27% 9- (2'-acetoxyethoxymethyl) -N ₂ -acetylguanine and 22% 7- (2'-acetoxyethoxymethyl) -N ₂ -acetylguanine. The conversion depth to 9 (7) - (2'-acetoxyethoxymethyl) -N ₂ -acetylguanine was 56% (with the return of part of the feedstock), and the ratio of the isomeric 9- and 7-substituted guanines was 2.7: 2.2 . [17, p. 1374]. The method gives a relatively satisfactory yield and is relatively simple when performed in the laboratory.

 In general, the prototype, as well as the analogue methods, are too expensive to be used on a large industrial scale. This stems from the low technological effectiveness of the methods, their low productivity, the low yield of the target product due to the low regioselectivity of alkylation of guanine diacetate in position 9. In addition, it is necessary to introduce a separate stage for the production of guanine diacetate, and its incomplete conversion during alkylation leads to a laborious operation purification of the side 7-isomer and, as a result, to the high cost of acyclovir.

 The objective of the invention is the development of a simpler, more productive and economical way to obtain acyclovir and its derivatives, i.e. a method that eliminates the disadvantages of the prototype.

The problem is solved in that in a known method for the preparation of acyclovir, including the preparation of acetylguanines, their alkylation with 2-oxa-1,4-butanediol diacetate, followed by isolation of the intermediate 9- (2'-acetoxyethoxymethyl) -N ₂ -acetylguanine, its deacetylation and isolation pure product by crystallization, significant changes and additions have been made, namely: to simplify the process, increase the yield of the target product, guanine acetylation is carried out in the presence of catalytic amounts (1 - 10%) of mineral and organic islot, e.g., CH ₃ COOH, H ₂ SO _4, H ₃ PO _4, HClO _4, n-CH ₃ C ₆ H ₄ SO ₃ H, BF ₃ at 120 - 140 ^o C for 1 - 5 hours, followed by alkylation the resulting N ₂ -acetyl and N ₂ , N _{7 (9)} -diacetylguanines in the presence of the same acid catalysts using a 1 - 2 molar excess of 2-oxa-1,4-butanediol diacetate at 90 - 110 ^o C, and at a reduced pressure, preferably 15 to 25 mm Hg, for 5 to 15 hours

 In addition, to further reduce the cost and simplify the method, the process of alkylation of acetylguanines is carried out in the same reactor as acetylation and immediately after acetylation.

 In addition, to further simplify and reduce the cost of the process, diacetate-2-oxa-1,4-butanediol is obtained directly in an acetylating mixture (in situ) to obtain acetylguanines, an equivalent amount of 1,3-dioxolane is introduced.

 In addition, to expand the raw material base and increase efficiency by simultaneously obtaining a valuable by-product of ribofuranose tetraacetates, the synthesis of acetylguanines can be carried out by catalytic acetolysis of guanosine with the release of 1,2,3,5-tetraacetate β-D-ribofuranose and its α-anomer by concentration stock solution after separation of guanine acetates and crystallization from water and alcohol.

In addition, to further simplify and reduce the cost of the process, the isolation of the intermediate product [9- (2 '- (acetoxyethoxymethyl) -N ₂ -acetylguanine can be carried out by adding an organic solvent (benzene, toluene, ethyl acetate, chloroform, dioxane, acetone, etc.) or mixtures thereof with water, with simultaneous extraction and regeneration of an excess of diacetate-2-oxa-1,4-butanediol.

In addition, to improve the purification efficiency of the target product, purification of 9- (2 '- (acetoxyethoxymethyl) -N ₂ -acetylguanine from impurities of guanine and 7-isomer can be carried out by extraction, for example, with methanol, dimethylformamide, monomethylamine, etc., with followed by selective deacetylation with various alkaline agents, for example, hydroxide, sodium methylate, triethylamine, the target product is acyclovir or its monoacetate derivatives: 9- (2 '- (hydroxyethoxymethyl) -N ₂ -acetylguanine and 9- (2' - (acetoxyethoxymethyl) guanine.

 The invention is illustrated by the scheme for obtaining acyclovir (see the end of the text) and six examples of its implementation.

Example 1. Obtaining acyclovir from guanosine dihydrate with separate stages for the preparation of guanine diacetate, isolation of 1,2,3,5-tetraacetyl-β] -D-ribofuranose from the acetic acid mother liquor, alkylation of N ₂ , N _{7 (9)} -diacetylguanine with diacetate 2- oxa-1,4-butanediol in the presence of p-toluenesulfonic acid when heated in vacuo with distillation of acetic anhydride and acetic acid, isolation of intermediate 9- (2'-acetoxyethoxymethyl) N ₂ -acetylguanine by treatment with methylene chloride, and its purification from guanine impurities by extraction of dimethylform and deacetyliro up to acyclovir directly in the environment of dimethylformamide with a solution of dimethylamine.

Example 2. Obtaining acyclovir from guanine, which is acetylated to N ₂ -acetylguanine in the presence of p-toluenesulfonic acid, then, without isolating the product in situ, 2-oxa-1,4-butanediol diacetate is obtained, followed by heating the reaction mass under reduced pressure and deacetylation of the intermediate product as described in example 1.

 Example 3. Obtaining acyclovir from anhydrous guanosine by analogy with example 1, but in the presence of phosphoric acid.

Example 4. Obtaining acyclovir by in situ synthesis from dioxolane of diacetate of 2-oxa-1,4-butanediol and condensing it with N ₂ , N _{7 (9)} -diacetylguanine, followed by crystallization of 9- (2'-acetoxyethoxymethyl) N ₂ -acetylguanine from chloroform and alkaline deacetylation.

Example 5. Obtaining acyclovir from guanine by acetylation with acetic anhydride catalyzed by phosphoric acid and condensation of the resulting N ₂ -acetylguanine (without isolation) with 2-oxa-1,4-butanediol diacetate followed by crystallization of 9- (2'-acetoxyethoxymethyl) -N _2- acetylguanine from dioxane and its deacetylation.

Example 6. Obtaining derivatives of acyclovir by selective deacetylation of N ₂ -acetyl-9- (2'-acetoxyethoxymethyl) guanine:
a) triethylamine with the formation of 9- (2'-acetoxyethoxymethyl) guanine,
b) sodium methylate with the formation of N ₂ -acetyl-9- (2'-hydroxyethoxymethyl) guanine.

 The proposed method eliminates the above-mentioned disadvantages of the known methods for producing acyclovir and its derivatives.

The essence of the invention lies in the combined catalytic process of guanine acetylation (go guanosine acetolysis) at 120-140 ^° C for 1-5 hours and alkylation of the resulting N ₂ -acetyl and N ₂ , N _{7 (9)} combined in one reactor (or separate ₎ diacetylguanines at 90-110 ^o C and reduced pressure for 5-15 hours in the presence of 1-10% acids (CH ₃ COOH, H ₂ SO ₄ , H ₃ PO ₄ , HClO ₄ , p-CH ₃ C ₆ H ₄ SO ₃ H, etc.) using 1 -. 2 molar excess diacetate 2-oxa-1,4-butanediol as such or prepared in situ from a dioxolane, followed by treatment of the intermediate 9- (2'-atsetoksietoksime yl) -N ₂ -atsetilguanina organic solvent, excess alkali deacetylation agent regioselective formation of the desired product 7-isomer rearrangement of 9-isomer by crystallization and isolation. The yield of pure acyclovir after recrystallization from water is 70-80% based on guanine (or guanosine) and 90-95% based on N ₂ -acetyl-9- (2'-acetoxyethoxymethyl) guanine — a scheme for producing acyclovir.

The basis of this highly regioselective method is the thermal and alkaline isomerization of the N ₇ isomer into the N ₉ isomer of substituted guanines with almost quantitative conversion or strictly defined process parameters. The method does not require the use of chromatography for the separation of isomers, technological and cost-effective. It uses available raw materials - guanine, guanosine, as well as dioxolane (or ethylene glycol and paraform), dimethylformamide and other common solvents. The method allows for the implementation of a continuous process for the preparation of acyclovir and its derivatives by combining successive stages: acetylation of guanine (or acetolysis of guanosine), preparation of 2-oxa-1,4-butanediol diacetate, alkylation of guanine acetates and deacetylation of intermediate 9- (2'-acetoxyethoxymethyl) ) N ₂ -atsetilguanina with simultaneous cleaning of the expected product, which generally simplifies the process, reduces its length and increases performance while reducing the expenditure coefficient for raw materials and a regeneration waste.

A distinctive feature of the method according to the invention is the use of not only N ₂ , N _{7 (9)} -diacetylguanine, but also N ₂ -monoacetylguanine, obtained both from guanine and from guanosine, as a starting material. Catalytic acetylation of guanine and guanosine acetolysis with 10-15-fold quantities of a mixture of acetic anhydride and acetic acid in the presence of catalytic amounts of acids (H ₂ SO ₄ , HClO ₄ , H ₃ PO ₄ , p-CH ₃ C ₆ H ₄ SO ₃ H and t .p.) proceeds in comparison with the known methods [16, 17, 21] faster - in 1-4 hours at 120-140 ^o C and 1.5-2-fold reduction of the module for acetylating mixture with 90-95% yield N _2- monoacetyl- or N ₂ , N _{7 (9)} -diacetylguanine, which crystallize directly from the reaction mass. Moreover, after concentrating the mother liquors of the guanosine acetolysis stage (with regeneration of acetic anhydride and acetic acid), 1,2,3,5-tetra-0-acetyl-β-D-ribofuranose and its α-anomer are obtained (yield 80-90%) widely used in the synthesis of practically important nucleosides [22]. Ribofuranose tetraacetates cost more than synthetic guanine.

The invention allows the use of N ₂ , N _{7 (9)} -diacetylguanine and N ₂ -acetylguanine as such or after they are formed by briefly boiling guanine (or guanosine) in an acetylating mixture and reacting them with 2-oxa-1,4- diacetate butanediol (DOBD) or dioxolane, which is converted in almost quantitative yield to 2-oxa-1,4-butanediol diacetate when reacted with acetic anhydride contained in an acetylating mixture [22 and 23]. It is also important to note that the same acid catalyst - preferably p-toluenesulfonic acid, sulfuric acid, phosphoric acid - ensures smooth reactions of guanine acetylation, formation of 2-oxa-1,4-butanediol diacetate from dioxolane, alkylation of guanine acetates and transformation N ₇ -isomers into the 9-isomer of (2'-acetoxyethoxymethyl) -N ₂ -acetylguanine at 90-110 ^° C and a relatively short process time of 5-15 hours. Isomerization proceeds under mild conditions without gumming; about developing acetic acid and acetic anhydride, the amount of which can determine the degree of conversion of the starting materials. According to HPLC (high performance liquid chromatography), the upper temperature limit is limited by a shift in the thermodynamic equilibrium towards the formation of the N ₉ -isomer, instability of the starting and final substances at elevated temperatures and the boiling point of 2-oxa-1,4-butanediol diacetate, and the lower limit is the rate the passage of the alkylation reaction with the established process parameters. The influence of process parameters is characterized by the following experimental data on the composition of the resulting products established by HPLC. So, with the same molar ratio of N ₂ -acetylguanine: DOBD, 1: 1.5 and p-toluenesulfonic acid in an amount of 4% at 125-135 ^o C the yield of raw 9- (2'acetoxyethoxymethyl) -N ₂ -acetylguanine decreases up to 65-70% with the formation of 5-10% impurities of the 7-isomer, and the reaction is accompanied by partial decomposition of the product. With a decrease in the duration of the alkylation of N ₂ -acetylguanine to 3-4 hours at 105 ^° C and the above reagent ratio, the yield of 9- (2'-acetoxyethoxymethyl) -N ₂ -acetylguanine drops to 45-55% due to the incomplete degree of conversion of acetylguanine. On the contrary, an increase in the reaction time, for example, to 18–20 h under the same conditions, leads to a partial resinification of the reaction mixture, loss of DBPD due to distillation in vacuum, and, as a result, a decrease in the yield of 9- (2'-acetoxyethoxymethyl) -N ₂ -acetylguanine up to 60-70%. Similar results are caused by an increase in the amounts of acid catalyst (more than 10%), which cause deacetylation of the starting and final substances and partial decomposition of the reaction mass. If the amount of catalyst is less than 1%, for example, 0.5% H ₂ SO ₄ , H ₃ PO ₄ , p-CH ₃ C ₆ SO ₃ H, then the yield of 9- (2'-acetoxyethoxymethyl) -guanine is reduced to 40- 55% under the indicated optimal alkylation conditions for N ₂ -acetylguanine due to the low conversion of the starting materials. Similar results are obtained when using N ₂ , N _{7 (9)} -diacetylguanine as the starting material, moreover, H ₂ SO ₄ , H ₃ PO ₄ , and HClO were used as a catalyst, along with p-CH ₃ C ₆ H ₄ SO ₃ H ₄ , BF ₃ . Most preferably, in the reactions of guanine acetylation and guanosine acetolysis, the use of 1-2% HClO ₄ , BF ₃ , and in the combined process for the preparation of acetylguanines and their alkylation, p-CH ₃ C ₆ H ₄ SO ₃ H, H ₂ SO ₄ and H ₃ PO ₄ in the above ranges, which provide greater regioselectivity of the formation of the target 9-isomer (more than 90-95%) compared with HClO ₄ and BF ₃ (80-85%). The ratio of mono- and diacetylguanine to DOBD is determined by practical expediency, and a minimal excess of DOBD is necessary for homogenization of the reaction mixture, since 2-oxa-1,4-butanediol diacetate is both an alkylating agent and a high boiling solvent, the excess of which is easily regenerated by distillation. Intermediate N ₉ - (2'-acetoxyethoxymethyl) -N ₂ -acetylguanine can be isolated by adding an organic solvent (benzene, toluene, ethyl acetate, chloroform, dioxane, acetone, etc.) or mixtures thereof with water in which the product is practically insoluble, and DOBD and acid catalyst, on the contrary, are easily extracted by them.

The method includes original technical solutions both for the large-scale process of alkylation of guanine acetates, and for the purification of intermediate and final target products after deacetylation of guanine impurities and side 7-isomer by combining the indicated technological operations using various organic solvents and alkaline agents (for example, N- methylamides of formic and acetic acids, alcohols, mono- and dimethylamine), ensuring the return of reagents to the production cycle. Alcohates, alkali metal hydroxides, ammonia, aliphatic amines in aqueous-organic media can be used as bases for deacetylation of acyclovir diacetate to acyclovir, and it is also possible to selectively remove one acetyl group to form mainly N ₉ - (2'-acetoxyethoxymethyl) guanine or N ₂ -acetyl-9- (2'-hydroxyethoxymethyl) guanine. According to HPLC, upon processing of N ₉ - (2'-acetoxyethoxymethyl) -N ₂ -acetylguanine, excess of the base and heating simultaneously with the deacetylation reaction completely transforms the impurities of the 7-isomer into the 9-isomer, therefore, the isolation of the latter reduces to a simple crystallization operation from an aqueous reaction solution. The yield of analytically pure acyclovir after crystallization from water is 95% based on N ₂ -acetyl-9- (2'-acetoxyethoxymethyl) guanine or 75-80% based on guanine (or guanosine). The structure of acyclovir and its derivatives is proved by a combination of physicochemical data (UV, IR and NMR spectra).

Example 1. 1225 ml of acetic anhydride are added to 319.3 g (1 mol) of guanosine dihydrate, then a solution of 0.6 ml of 57% perchloric acid in 110 ml of glacial acetic acid is added with stirring. The mixture is heated with stirring to 130-135 ^o C, while the mass first thickens, then after 15-20 minutes there is complete dissolution, and after 1 h the precipitate N ₂ , N _{7 (9)} -diacetylguanine. After brief boiling until guanosine tetraacetate disappears completely (TLC control), the mass is cooled, kept at 0-5 ^o C, the precipitate of diacetylguanine is filtered off, squeezed from the acetic acid mother liquor containing 1,2,3,5-tetraacetyl-D-ribose (see further note), then washed with methylene chloride (3x200 ml) and dried to constant weight. 211.7 g (0.9 mol) of N ₂ , N _{7 (9)} -diacetylguanine are obtained in the form of light yellow crystals. The product is suitable for subsequent operation without further purification.

Analysis for C ₉ H ₉ N ₅ O ₃ (235.20):
Calculated,%: C 45.95; H 3.83; N, 29.78;
Found,%: C 45.86; H 3.72; N, 29.67.

1 H-NMR spectrum (DMCO d ₆ ), δ, ppm: 2.2 (3H, s, CH ₃ CO), 2.8 (3H, s, CH ₃ CO), 8.4 (1H, s, H8), 11.7 (1H , s, N ₁ -H).

UV spectrum, nm (0.1 n NaOH): λ _max 279.
To 211.7 g (0.9 mol) of N ₂ N _{7 (9)} -diacetylguanine, 396.2 g (2.25 mol) of 2-oxa-1,4-butanediol diacetate and 8 g of p-toluenesulfonic acid monohydrate are added. The mixture is heated with stirring on a rotary evaporator at 105-110 ^o C in vacuum 20-25 mm RT.article within 6-6.5 hours with distillation of the by-produced acetic anhydride and acetic acid. At the end of the reaction (TLC control), 300 ml of methylene chloride are added to the mixture, stirred, the crystalline precipitate is filtered off, washed with methylene chloride and dried to constant weight. Obtain 272.2 g (0.88 mol) of the crude 9- (2'-acetoxyethoxymethyl) -N ₂ -acetylguanine in the form of light yellow crystals with so pl. 196-200 ^o C. The yield is 88% for guanosine or 97.7% for diacetylguanine. According to HPLC, the content of impurities of the corresponding 7-isomer and diacetylguanine does not exceed 3%.

Analysis for C ₁₂ H ₁₅ N ₅ O ₅ (309.28):
Calculated,%: C 46.60; H 4.88; N, 22.64;
Found,%: C 46.78; H 4.91; N, 22.57.

1 H-NMR spectrum (DMCO d ₆ ), δ, ppm: 1.96 (3H, s, CH ₃ CO), 2.2 (3H, s, CH ₃ CO), 3.68 (2H, m, H-3 '), 4.07 (2H, m, H-4 '), 5.45 (2H, s, H-1', N-CH ₂ ), 8.10 (1H, s, H-8).

UV spectrum, nm (0.1 n NaOH): λ _max 262.

272.2 g of crude 9- (2'-acetoxyethoxymethyl) -N ₂ -acetylguanine is dissolved in 1350 ml of dimethylformamide with stirring and a temperature of 105-110 ^o C, treated with clarifying charcoal BAU, filtered and the dimethylformamide solution is concentrated in vacuo until the pure product crystallizes intensively. After cooling, 700 ml of a 40% solution of dimethylamine are added to the mass, the resulting solution is left overnight at room temperature and the next day heated to 70-80 ^o C, kept at this temperature for about 1 hour. The solution is evaporated at 70 ^o C in vacuum to half the original volume, in the hot state they are neutralized with acetic acid and then slowly cooled to 0-5 ^o C. The white crystalline precipitate is filtered off, washed with water, alcohol. After drying in air, the product is recrystallized from 5.5 L of boiling water and dried at 60 ^° C. 179 g of 9- (2'-hydroxyethoxymethyl) guanine [acyclovir] are obtained, which is 79% based on the starting guanosine without taking into account additional quantities obtained by evaporation of mother liquors (about 4%). Acyclovir is a white crystalline substance with mp 252-258 ^o C with decomp. TLC on silofole UV 254 Rf 0.41 in the chloroform-methanol-water system, 20: 14: 1.

Calculated in%
Analysis for C ₈ H ₁₁ N ₅ O ₃ (225.21):
Calculated,%: C 42.46; H 4.92; N 31.09;
Found,%: C 42.71; H 4.91; N, 30.98.

1 H-NMR spectrum (DMCO d ₆ , δ, ppm: 7.80 (1H, s, H-8), 6.49 (2H, s, NH ₂ ), 5.33 (2H, s, NCH ₂ ).

UV spectrum, nm (0.1 n NaOH): λ _max 258-268 (area), λ _min 230.

Note
Isolation of 1,2,3,5-tetraacetyl-D-ribofuranose.

The acetic acid mother liquor from guanosine acetolysis was completely evaporated in vacuo (20 mm) at a temperature not exceeding 70 ^o C. The syrupy residue was dissolved in 600 ml of methylene chloride from washing diacetylguanine (see above). The insoluble portion of diacetylguanine is filtered off (about 9 g), the solution is treated with clarifying charcoal and evaporated at 50 ^° C. The residue is re-evaporated with ethanol (2x75 ml) in vacuo and then treated with a solution of 30 g of sodium acetate in 800 ml of ice water. When grinding a syrupy product, crystallization of 1,2,3,5-tetraacetyl-β-D-ribofuranose (β-TARPH) occurs, which is filtered off after washing for 12 hours, washed with water and recrystallized from alcohol. Obtain 222.8-238.7 g of β-TARPH in the form of colorless crystals with so pl. 79-81 ^o C; [α] _D = -14.5 ^° (5.3, methanol); Rf 0.85 on silufol UV-254 in the chloroform-methanol system, 25: 1 (manifestation by heating). A mixture of α- and β-anomers of TARP is isolated from the alcohol mother liquor.

Example 2. A mixture of 60.45 g (0.4 mol of guanine, 306.0 g (3 mol) of acetic anhydride and 0.6 g of p-toluenesulfonic acid is heated with stirring at 135-140 ^o C for 1-1.5 hours. The resulting thick mass of N ₂ -acetylguanine is cooled with ice with water, 0.9 g of p-toluenesulfonic acid are added and then 74 g (1 mol) of dioxolane are added dropwise with stirring.The mixture is kept at 20 ^° C for 2 hours and gradually heated with stirring to 85 ^° C. After complete conversion of dioxolane to diacetate 2- oxa-1,4-butanediol (GLC) is distilled off at 85 ^o C and a vacuum of 20 mm acetic acid and acetic anhydride, the residue was stirred at 100-105 ^° C. for 6.5-7 hours, acetic anhydride was distilled off under vacuum, 200 ml of toluene were added to the hot mixture, stirred, cooled, the crystalline precipitate was filtered off, washed with a small amount of chloroform and dried to constant weight 117.5 g (0.38 mol) of the crude 9- (2'-acetoxyethoxymethyl) -N ₂ -acetylguanine (95% guanine) are obtained in the form of light yellow crystals. According to HPLC, the content of impurities of the corresponding 7-isomer and guanine acetates does not exceed 3%. Toluene mother liquors are distilled to regenerate an excess of 2-oxa-1,4-butanediol diacetate and solvent.

580 ml of dimethylformamide are added to 117.5 g of 9- (2'-acetoxyethoxymethyl) -N ₂ -acetylguanine, heated to 105-110 ^° C with stirring. Brightening charcoal BAU is added to the solution, stirred and filtered while hot. The dimethylformamide solution is evaporated halfway in vacuo and 320 ml of a 40% aqueous solution of dimethylamine are added to the thick crystal mass, and the precipitate dissolves. The solution is left overnight at room temperature, then gradually heated to 70-80 ^o C and maintained at this temperature for 1-1.5 hours until complete conversion of the starting and intermediate products into acyclovir (TLC control). The solution was concentrated in vacuo at 70-75 ^o C until the product crystallized vigorously, neutralized in the hot state with acetic acid and cooled to 0-5 ^o C for 5 hours. The white crystalline precipitate was filtered off, washed with water and alcohol and, after drying in air, was recrystallized from 2.4 liters of boiling water. 67.5 g (0.3 mol) of 9- (2'-hydroxyethoxymethyl) guanine (75% guanine) are obtained; colorless crystals with mp 252-257 ^o C with decomp. TLC on silofole UV-254 R _f 0.41 in the chloroform-methanol-water system, 20: 14: 1.

Analysis for C ₈ H ₁₁ N ₅ O ₃ (225.21):
Calculated,%: C 42.46; H 4.92; N 31.09;
Found,%: C 42.37; H 4.86; N 31.12.

 According to the physico-chemical characteristics of the product is identical to the sample obtained from guanosine (example 1). When concentrating aqueous and dimethylformamide stock solutions, about 5% of technical acyclovir is additionally obtained.

Example 3. To 283.3 g (1 mol) of anhydrous guanosine, 1100 ml of acetic anhydride and 200 ml of acetic acid containing 5.6 g of anhydrous phosphoric acid are added. Guanosine acetolysis (1-1.5 h, 140 ^° C.) was carried out as described in Example 1, 214 g (0.91 mol) of N ₂ , N _{7 (9)} -diacetylguanine and 280 g (0.88 mol) of a mixture of α - and β-anomers were isolated 1,2,3,5-tetraacetyl-D-ribofuranose. To 214 g (0.91 mol) of N ₂ , N _{7 (9)} -diacetyl-guanine, 369.8 g (2.1 mol) of 2-oxa-1,4-butanediol diacetate and 7 g of anhydrous phosphoric acid are added. The mixture is heated in vacuo (20-25 mm) at 95-100 ^o C and stirring for 8.5-9 hours with distillation of the by-product of acetic anhydride and acetic acid. At the end of the reaction, 300 ml of ethyl acetate was added to the mass, cooled for 0.5 h, and the crystalline precipitate was filtered off. 269 g (0.87 mol) of crude 9- (2'-acetoxyethoxymethyl) -N ₂ -acetylguanine are obtained with a basic substance content> 96%. To obtain acyclovir, 269 g (0.87 mol) of this product is suspended in 1.5 L of an aqueous solution of sodium hydroxide (104 g), stirred until complete dissolution and incubated overnight at room temperature. The next day, the solution is treated with heating with clarifying charcoal, filtered and neutralized with 20% hydrochloric acid. After cooling, the precipitate is filtered off, washed with water until the filtrate reacts negatively with chlorine ions and with alcohol. After drying at 60 ^° C., 184.5 (0.82 mol) of 9- (2'-hydroxyethoxymethyl) guanine is obtained with a basic substance content of at least 98%.

Example 4. To a solution of 9 g of p-toluenesulfonic acid monohydrate in 208 ml (2.2 mol) of acetic anhydride was added dropwise with cooling to 0-5 ^° C. 147 ml (2.1 mol) of 1,3-dioxolane. The mixture was stirred at 60 ^° C. until dioxolane (GLC) completely disappeared. To the resulting diacetate of 2-oxa-1,4-butanediol, 211.7 g (0.9 mol) of N ₂ , N _{7 (9)} -diacetylguanine are added and the thick mass is heated at 105-110 ^° C with stirring on a rotary evaporator for 1 hour at atmospheric pressure, then 9 h in vacuum (20 mm) with distillation of acetic anhydride and acetic acid. At the end of the reaction (disappearance of diacetylguanine by TLC), 400 ml of chloroform was added to extract an excess of 2-oxa-1,4-butanediol diacetate, the crystalline precipitate was filtered off and dried. 238.2 g (86%) of 9- (2'-acetoxyethoxymethyl) -N ₂ -acetylguanine are obtained, which are deacetylated with a 40% aqueous solution of dimethylamine in a 1: 7 molar ratio at 70-75 ^° C for 3 hours. Yield of pure acyclovir after recrystallization from water, 160 g (0.71 mol), which is 79% based on diacetylguanine.

Example 5. A mixture of 30.2 g (0.2 mol) of guanine, 188.6 g (1.84 mol) of acetic anhydride and 1.2 g of phosphoric acid is boiled with stirring for 1 hour. 70.4 g (0.4 mol) of 2-oxa diacetate are added to the resulting thick mass. -1,4-butanediol. The reaction mass is heated with stirring at 100-105 ^o C for 1-1.5 hours, then a vacuum (20 mm) is connected, the excess of acetic anhydride is distilled off and the residue is kept at the same temperature for 8 hours. 120 ml of dioxane are added to the obtained viscous product, heated with stirring for 15 minutes and after cooling, the precipitate is filtered off, washed with a small amount of ether and dried. 54.4 g (88%) of 9- (2'-acetoxyethoxymethyl) -N ₂ -acetylguanine are obtained; colorless crystals with mp 199-200 ^o C, physico-chemical characteristics identical to the sample substance described in example 1. The conversion of acyclovir diacetate into acyclovir is carried out as described in example 4.

Example 6. Receive 9- (2'-acetoxyethoxymethyl) -N ₂ -acetylguanine (acyclovir diacetate) from guanosine or guanine as described in examples 1 and 2 and turn it into the corresponding acyclovir monoacetates:
a) A mixture of 30.9 g (0.1 mol) of acyclovir diacetate and 400 ml of a 1 M solution of triethylamine in 95% ethanol is boiled for 10 hours, cooled, the precipitate is filtered off, washed with alcohol and dried at 40 ^° C. 26 g (97%) are obtained. ) 9- (2'-acetoxyethoxymethyl) guanine; colorless crystals with mp 242-246 ^o C (DMF).

Analysis for C ₁₀ H ₁₃ N ₅ O ₄ (267.3):
Calculated,%: C 44.94; H 4.87; N, 26.22;
Found,%: C 45.03; H 4.91; N 26.17.

TLC on silofole UV-254 in the methanol-chloroform-ammonia system, 10: 40: 1 R _f 0.27 (the starting acyclovir diacetate has R _f 0.46.

1 H-NMR spectrum (DMSO d ₆ ), δ, ppm: 1.93 (3H, s, CH ₃ CO), 3.67 (2H, m, H3 '), 4.08 (2H, m, H4'), 5.35 (2H , s, H1 '), 6.41 (2H, s, NH ₂ ), 7.76 (1H, s, H8), 10.59 (1H, s, NH).

UV spectrum in 0.1 n NaOH, nm: λ _max 264 and 257.

b) 12.4 g (0.04 mol) of acyclovir diacetate are added to a solution of 1.84 g of sodium metal in 100 ml of anhydrous methanol. The mixture was stirred for 15-20 minutes until the starting diacetate disappeared (TLC control) and neutralized with 50 ml of 1.5 N HCl. After stirring for 15 hours, the precipitate was filtered off, washed with ice water, cold alcohol and dried. 8.4 g (79%) of N ₂ -acetyl-9- (2'-hydroxyethoxymethyl) guanine are obtained; colorless crystals with mp 217-218 ^o C (aqueous methanol).

Analysis for C ₁₀ H ₁₃ N ₅ O ₄ (267.3):
Calculated,%: C 44.94; H 4.87; N 26.22;
Found,%: C 44.98; H 4.94; N 26.19.

TLC on silofole UV-254 in the methanol-chloroform-ammonia system, 10: 40: 1 R _f 0.15 (the starting acyclovir diacetate has R _f 0.46).

1 H-NMR spectrum (DMCO d ₆ ), δ, ppm: 2.19 (3H, s, CH ₃ CO), 5.47 (2H, s, H1 '), 8.13 (1H, s, H8), 11.75 (1H, s, NH), 12.05 (1H, s, NHCOCH ₃ ).

UV spectra 0.1 n NaOH, nm: λ _max 264.

 The above theoretical provisions and examples of specific performance of the method convincingly prove its feasibility by means known in the industry and on available raw materials. Experimental batches obtained by the claimed method of acyclovir purity meet the requirements of the pharmacopeia and are used in the manufacture of medicines. At the same time, no non-standard equipment was required either in the production of acyclovir or in the manufacture of finished dosage forms.

Technical and economic characteristics of the invention:
simplification of the technology of obtaining acyclovir by introducing new parameters of the process of obtaining and purifying intermediate and final substances, increasing their yield;
increase in productivity due to the combination of the processes of obtaining acetylguanines and their regioselective alkylation with 2-oxa-1,4-butanediol diacetate or dioxolane;
expansion of the raw material base - the use of guanine, guanosine and their acetylated derivatives as starting materials;
profitability - reducing the duration, reducing energy costs and expenditure ratios of expensive guanine derivatives; the simultaneous production of a valuable intermediate - 1,2,3,5-tetra-0-acetyl-β-D-ribofuranose; waste recovery with return to the production cycle.

 The achieved technical and economic advantages allow us to adapt the method for industrial production and use it for the synthesis of related antiviral drugs (ganciclovir, butyclovir, etc.).

 The proposed method meets all the requirements for inventions: it is new, has an inventive step (not obvious) and is industrially applicable.

Sources of information
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 7. USSR patent N 751325, cl. C 07 D 473/18, A 61 K 31/505. A method of obtaining derivatives of purine or its salts. / X.D. Shaffer (Great Britain); application N 2169001/2492435 / 23-04; stated on 01.24.77; publ. 07/23/80. Bull. inventions N 27, 1980.

 8. US patent N 4146715 from 23.03.79 A 61 L 31/52. 2-Amido-9- (2'-acyloxyethoxymethyl) hypoxanthine. / Schaffer H.

 9. A Direct Method for the Preparation of 2-Hydroxyethoxymethyl Derivatives of Guanine, Adenine, Cytosine./ Barro J.R., Bryant J.D., Keyser G.E. // J. Med. Chem. - 1980. - V. 23, N. 5. - P. 572.

 10. Nucleic Acid Relatrd Compounds. 37. Convenient. High Yied Synthesis of N-2 (2'-hydroxyethoxy) methyl] -heterocycles as "Acyclic Nucleoside" Analogues / Robins M.J., Hotfield P.W. // Can. J. Chem. - 1982. - V. 60. - P. 547.

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 14. US patent N 4649140 from 01/28/85, CL. C 07 D 413/18, A 61 K 31/52 / X. D. Schaffer, Burroughs Wellcome Co &.

 15. USSR patent N 1454253, cl. C 07 D 473/18. The method of obtaining 9- (2'-hydroxyethoxymethyl) guanine. / Kobe I., Zupet P. (Yugoslavia). application N 3990801 / 23-04; declared 12/19/85; publ. 01/23/89. Bulletin of inventions N 3, 1989.

 16. Switzerland patent N 634843, cl. C 07 D 473/16, C 07 D 473/18. The method of obtaining substituted derivatives of purine. Verfahren zur Herstellung Substituierter Purinderivate / Schaeffer H. J. The Wellcome Foundation Ltd. N 10466/77, declared. 08/26/77; publ. 02/28/83.

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Claims (5)

1. A method for producing acyclovir, including the synthesis of acetylguanines, alkylation of the obtained guanine acetates with 2-oxa-1,4-butanediol diacetate in the presence of acid, isolation of the intermediate 9- (2'-acetoxyethoxymethyl) -N ₂ -acetylguanine, its subsequent deacetylation and purification of the target crystallization of the product, characterized in that the guanine acetylation is carried out in the presence of catalytic amounts of 1-10% mineral or organic acid, for example CH ₃ COOH, H ₃ PO ₄ , HClO ₄ , n-CH ₃ C ₆ H ₄ SO ₃ H at 120 - 140 ^o C for 1 to 5 hours followed by alkyl the formation of N ₂ -acetyl or N ₂ N _{7 (9)} diacetylguanines formed in the presence of the indicated acid using a 1 to 2 molar excess of 2-oxa-1,4-butanediol diacetate at 90-110 ^° C and under reduced pressure, preferably 15 - 25 mm Hg for 5 to 15 hours  2. The method according to claim 1, characterized in that the alkylation of guanine acetates is carried out in the same reactor as acetylation, immediately after acetylation.  3. The method according to p. 1 or 2, characterized in that the synthesis of acetylguanines is carried out by guanosine acetolysis and 1, 2, 3, 5-tetraacetate-β-D-ribofuranose and its α-anomer are isolated by concentration of the mother liquor after removal of guanine acetates. 4. The method according to claims 1 to 3, characterized in that the isolation of the intermediate 9- (2'-acetoxyethoxymethyl) -N ₂ -acetylguanine is carried out by adding an organic solvent, for example dioxane, with simultaneous extraction and regeneration of an excess of 2-oxa-1 diacetate, 4-butanediol. 5. The method according to claims 1 to 4, characterized in that the purification of 9- (2'-acetoxyethoxymethyl) -N ₂ -acetylguanine from impurities of guanine and 7-isomer is carried out by extraction using, for example, dimethyl fluoramide, followed by selective deacetylation with alkaline agents, for example sodium methylate or triethylamine, in acyclovir or its monoacetate derivatives.