TW386084B - A process for the preparation of 9-(2-hydroxy)-ethoxymethyl-guanine - Google Patents

Description

The preparation of poison) is described, for example, in Belgian Patent No. 833,006. This method starts with guanine, and first trimethylsilylates at the 3-amino * 6- and 9-positions. The resulting silylated intermediate is then treated with 2-benzylacetoxyethoxymethyl chloride, and K is formed (after the protective group is removed at the N2 and He positions) Ascetic Loufo was recovered from it by ammonia hydrolysis in methanol. This method uses a large excess of alkylating agent, so there are obvious problems of cost and waste. Furthermore, it leads to the formation of quite impure products, and the amount of 7-substituted isomers is unacceptable in terms of pharmaceutical pupae. . British patent 1,567, δ71 discloses another method, in which the protection of the amine group at the 2-position is carried out by hydration; the patent discloses that Methyl, propyl, butyl, and benzyl are used as fluorenyl groups, among which The only example mentioned is the reaction of Ν 2, 9 -diethylfluorenylguanine with 2 -oxa-1, 4 -diethylfluorenyloxybutane to give Ν 2 -ethylfluorenyl-9-(2 -acetamidine (Oxy) ethoxymethylguanine, which is then hydrolyzed to give the final acecrofo, the yield of this reaction is only if the 7-isomer is not formed in significant amounts (up to 13%) Satisfied, but it requires expensive pure paper. Standards are applicable to China National Standards (CNS) Α4 (210 乂 297 mm). Ordered by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs.

The preparation of poison) is described, for example, in Belgian Patent No. 833,006. This method starts with guanine, and first trimethylsilylates at the 3-amino * 6- and 9-positions. The resulting silylated intermediate is then treated with 2-benzylacetoxyethoxymethyl chloride, and K is formed (after the protective group is removed at the N2 and He positions) 9- (2-fluorenyloxy) -ethoxymethylguanine Ascetic Loufo was recovered from it by ammonia hydrolysis in methanol. This method uses a large excess of alkylating agent, so there are obvious problems of cost and waste. Furthermore, it leads to the formation of quite impure products, and the amount of 7-substituted isomers is unacceptable in terms of pharmaceutical pupae. . British patent 1,567, δ71 discloses another method, in which the protection of the amine group at the 2-position is carried out by hydration; the patent discloses that Methyl, propyl, butyl, and benzyl are used as fluorenyl groups, among which The only example mentioned is the reaction of Ν 2, 9 -diethylfluorenylguanine with 2 -oxa-1, 4 -diethylfluorenyloxybutane to give Ν 2 -ethylfluorenyl-9-(2 -acetamidine (Oxy) ethoxymethylguanine, which is then hydrolyzed to give the final acecrofo, the yield of this reaction is only if the 7-isomer is not formed in significant amounts (up to 13%) Satisfactory, but it requires expensive pure paper sizes to apply Chinese National Standards (CNS) Α4 specifications (210 公 297 mm) Ordered by the Central Consumers Bureau of the Ministry of Economic Affairs Printed by the Consumer Cooperatives -3- Amendment page A7 B7 Amendments to supplement this year 丨丨 Month 1 > Said the jade, invention description (7 mixed with 107.4 g (0.502 mol) NaI〇4) printed by the employee's consumer cooperative of the Central Standards Bureau of the Ministry of Economic Affairs and maintained the temperature by the help of a water bath 3 υ , Flail monitors the p p value to make it approximately within the range of 1.8-2.2. The reaction is a mild, constant exothermic reaction, in It was completed in about 2 hours after the addition of the oxidant. After completion, the reaction mixture was cooled to 5 13 and then filtered, washed with water and dried. S 2 g of methyl amidinoguanine (3) (yield: 96%), 1 ^ 1 ^ Analysis shows purity> 98%. 4 c) H2 -Methylmethyl-9- (ethoxy) ethoxymethylguanine (4, R = CH3) 100 g (0.55 9 mol) of formazan Fluorinoguanine (3), 300 g (1.705 mol) of 2-oxo-1,4-diethylfluorenyl-butane and 2 g (0.0105 mol) of p-toluenesulfonic acid on an oil bath In a 500 ml round bottom flask equipped with a thermometer and a distillation device. Depressurize the system (30-40fflflllU) and heat the material to an internal temperature of 1 1 — 1 2 2 ° C in about 1 hour. The temperature was maintained at U S -1 2 2 C for a total of 8 hours, and the acetic acid formed was distilled off. The mixture is cooled to 50-60 ° C, then diluted with 150 ml of acetone (or n-butanol or ethyl acetate), cooled to 0-5 ° C, filtered and dried under vacuum at 60-70 ° C to obtain 148.3 g (4) (R = CH3), yield 90%. Elementary analysis and spectral data confirm the putative structure. Compound_i (R = CH3) 1H HMR (DMSO-d < s. 2iC) H ^ jpm) * 11.5 (1H, broad), 6 MS (m, broad; 80 Os), 8.13 (1H, s), 5.49 (2H, s), 4.09 (2H, m), 3.71 (2H ·, m), (3H, s); 13C NMR (DMS0) δ (ppm) = 170.16, 1 ^ 2.79, 155.5, 148.97, Η7.26 .Ί39.97, 120.4, 72.22, 66.84, 62. <S4,20.58; IR υ (cnrl) Single 3] 0 · 2940. 2920, 2790, Γ740, I'm 1360, i500, J290; MS (e〇 rn / c: 295 〇6). 261 < l〇). 208 (9), 192 (12); i & i (] 'k) t {51. (35), 87 (100)-, elemental analysis (CuUsOs)% experimental value U 诂 counted): c = 44.86 (4 4.75) (Please read the precautions on the back first, then the IP page) Installation · This paper size is applicable to China National Standard (CNS) A4 specifications (2 丨OX297 public splash) 9 amended to buy A6 B6 printed by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (2)-the transformation step, and it is not good for the yield of the desired product. It was surprisingly found that the alkylation of the 9-position of the purine ring on N2-formylguanosine with 2-oxo-1,4-diethyloxobutane gave Asek Loufo in high yield, Denier can substantially prevent unwanted 7-isomer formation. N2-Methanol-based guanine is described in the literature (Shapiro, Biochemistry, 8, 231-245 (1969)). According to the author, N2-formylguanosine can be obtained by treating glyoxal-guanine adducts with sodium periodate and / or periodate; in fact, the high yield of the method is reproducible However, in the method of the present invention, N2-formylguanine can also be obtained in other ways, such as:-oxidizing glyoxal guanine adduct with peracetic acid or hydrogen peroxide or lead tetraacetate; -In the presence or absence of a solvent such as dimethylformamide or dimethylimide, and optionally dicyclohexyl sulfonium diimine, directly formazanate guanine with formic acid; -Direct methylation of guanine with formamidine acetic anhydride, optionally in the presence of a solvent such as dimethylformamide, dimethylmethane, trimethylamine hexamethylphosphate or formic acid. No matter what steps are followed to prepare the hydrazone 2-formaldehyde guanine eyelid, the subsequent reaction of the compound with 2-oxo-1,4-diethoxybutane is in a yield of more than 90% (more importantly , Only the 7-isomer of microscopic examination is formed) to form N2-formyl-9- (2-ethylfluorenyl) ethoxymethylguanosine, which in the end is not a single step using the remaining aqueous solution to remove the fluorenyl group. That is, the methylidene group is first removed in an acid medium, and then the acetaldehyde group is removed by alkali hydrolysis. The following diagram summarizes the process of the present invention. ......... ri: iiri:,: ........... ©: .i: ^ ..... ......... 玎 .............- ii-: 4, ..) {Please read the notes on the back before filling the nest (This page) The paper size is applicable to the national standard (CNS) A4 specification (210x297 mm) λ 5. Description of the invention (3) KM2z / en

Hz > x 0 s

o A6 B6 · CHO Iho y 0

π Shake (please read the precautions on the back before filling out this page).... Order. Φ Printed by the Central Bureau of Standards of the Ministry of Economic Affairs oh o H s TsOH o / >},

O. Line * Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A 6 ___B6 V. Description of the Invention (: t) In the figure, R is argon, Q-C4 alkyl or phenyl. The glycol product (2) can be recovered in high yield by suspending guanine (1) in water, adding an aqueous solution of glyoxal, and heating the mixture to 80 ° F for 4 hours (R. S hapir 〇, 1o c. cit; R. Shapiro and J. Haehraann, Biochemistry 5, 2799 (1966)). The diol (2) is then oxidized with stoichiometric N a I 04 in water maintained at a pH of 1.8-2.2 to form a formamidine derivative (3) in an excellent yield, and then N2-formamylguanine昤 (3) (which can also be obtained by directly formicating the bird's pupa as above) can be alkylated to obtain N-9 alkylated compound (4) in high yield without forming a significant ratio of N. -7 alkylation product; finally, hydrolyzing compound (4) with an aqueous solution of Na 0 得到 to obtain Aseklaufo (I) in excellent yield. In summary, the above synthesis method allows the desired product (I) to be obtained in a highly satisfactory yield, which is higher than that obtained by the acetonitrile synthesis method, and the most important one does not form a significant amount No. 7-alkylation products. In another specific example, the method of the present invention provides a final purification step to obtain Asseq Lou Buddha which is substantially free of guanine. This purification step provides very high purity Assyk Loufo. It has been found that by dissolving the alkaline aqueous solution of Aseklaufo on a strong anion exchange resin, a desired product substantially free of guanine can be obtained. According to the present invention, the purification step comprises: a) dissolving the Assyrian Loufo in an alkaline aqueous solution and diluting the solution so obtained with water; b) loading the dilute solution prepared by a) on a strong anion exchange column, the resin and (谙 Please read the notes on the back before filling this page)-Binding:-Thread-This paper size is applicable to China National Standard (CNS) A4 specifications (210X297 mm) 6 Printed by A6 B6, Consumer Cooperative of Central Standards Bureau, Ministry of Economic Affairs V. Description of the invention (5) The weight ratio of Aseklou Buddha is 2. · 1.5; c) The diluted solution is dissolved at a rate of 20Θ-300ml / hour; d) The volume ratio is as low as 0.8: 1.2 The dissolving agent composed of the master alcohol / alkaline aqueous solution dissolves the azeklofo, and the v / w ratio of the leaching agent and the acelofo is 15: 1 to 20: 1 liter / kg, and the dissolution rate is the same as c) To obtain the dissolve; e) separate the Assyrian Buddha from the dissolve in d). The anion exchange resin is a basic resin, which is composed of a resin having some degree of crosslinking and having a quaternary ammonium group. The resin used in the present invention is a strong concrete resin. Examples of strong base resins are dextrin, agar, cellulose, divinylbenzene, which are appropriately functionalized with a quaternary ammonium group. These resins are usually supplied on the market under the trademarks Araberlite &, Dowex ^, Set & hacelR, SephadexR and the like. Amber 1 iteR IRA- 4 0 0, Re 1 iteR 3A, IMAC ΗP-441 is preferred. Chromatography was performed on a basic resin. Dissolution was performed at room temperature. The alkaline aqueous solution of a) consists of a solution of a rhenium metal hydroxide such as lithium hydroxide, sodium or potassium hydroxide. The alkali concentration is 5 to 15%, and a 10% sodium hydroxide solution is preferred. The w / w ratio of the resin to the Assyrian Buddha is preferably 1.75. The preferred dissolution rate is 250 ml / h. d) The lower alcohols are methanol, ethanol, and propanol. d) The aqueous alkali solution is composed of an alkali metal hydroxide having a concentration of 0.8 to 1.2M. The V / V ratio of methanol / 1M sodium hydride is preferably 1: 1. ...........-........------------ r!-,,: ...: Ί:! Θ ...... ............. Installed ....................: --tri -.............. ......... € ', (Please read the notes on the back before filling in this page) This paper size applies to China National Standard (CNS) A4 specification (210x297 mm) q A6 B6 Central Ministry of Economic Affairs Printed by the Consumer Bureau of the Standards Bureau. V. Description of the invention (6) The dissolving agent / pg of the Seco Loufo V / w fcb is preferably 17.5 liters / kg. The eluate is isolated from the product in e), according to conventional techniques. The leachate is preferably acidified with a suitable acid and precipitated. The bird's wren content of the product thus obtained was less than 0.1. According to the purification step of the present invention, the best product commercially available in Asseq Loufoby thus obtained is 3 to 4 times pure. -The above-mentioned pure form of the Assyrian Buddha is another object of the present invention. The purification step of the present invention can be applied to a variety of other known methods of making Aseki Lou Buddha. For example, the final product obtained by the above methods of BE 833,006 and GB 1,567,671 contains 1 to 3.¾guanine. Since the maximum limit of the US Pharmacopeia is 0.75 ¾, this amount is an unacceptable amount. Therefore, the purification of the Assyrian Lou Buddha constitutes another object of the present invention. The following examples further illustrate the process of the present invention. Example 1 a) Ethylenediguanosine (2) 100 g (0.662 moles) of guanine, 800 ml of H2O and 150 ml of a 40% w / w glyoxal aqueous solution (1.3 2 moles) At room temperature, mix in a 2-liter figure bottom flask equipped with a condenser, thermometer, and magnetic stir bar, and heat the mixture to 80 ° C for 4 hours. After that, gradually cool the contents of the flask to 5¾, then Filtration and washing with water gave 1 3 S of the product (yield: 9 8? ≪). HPLC analysis showed a purity of 798? b) N 2 -formylguanosine (3) suspended in 100 g (0.478 moles) of glyoxal guanosine in 800 ml of water (using 6 ml of Η 3 P 〇 4 to adjust the p Η value to 1.8 To 2.2) in the suspension, mechanical binding (please read the precautions on the back before filling this page) binding.-Elephant 'This paper size is applicable to China National Standard (CNS) T 4 specifications (210 X 297) Love) 8 A7 B7 amended and supplemented this year 丨 丨 January 1> said the jade and invention description printed by the staff consumer cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs (7 mixed with 107.4 g (0.502 Mear) NaI〇4 and With the help of a water bath, the temperature is maintained at 30 υ, and the p Η value is monitored to make it approximately within the range of 1.8-2.2. The reaction is a mild, constant exothermic reaction, about 2 hours after the oxidant is added Completed. After completion, the reaction mixture was cooled to 5 13 and then filtered, washed with water and dried. S 2 g of methyl amidinoguanine (3) was obtained (yield: 96%), 1 ^ 1 ^ analysis showed purity > 98%. 4 c) H2-formyl-9- (ethoxy) ethoxymethylguanine (4, R = CH3) 100 g (0.55 9 moles) formylguanine (3 ), 300 grams (1.705 moles) 2-oxo-1,4-diethoxyl-butane and 2 grams (0.0105 moles) of p-toluenesulfonic acid are placed on an oil bath, equipped with a thermometer and a distillation apparatus. 0 ml round bottom flask. Depressurize the system (30-40fflflllU) and heat the material to an internal temperature of 1 1 — 1 2 2 ° C in about 1 hour. The temperature was maintained at U S -1 2 2 C for a total of 8 hours, and the acetic acid formed was distilled off. The mixture is cooled to 50-60 ° C, then diluted with 150 ml of acetone (or n-butanol or ethyl acetate), cooled to 0-5 ° C, filtered and dried under vacuum at 60-70 ° C to obtain 148.3 g (4) (R = CH3), yield 90%. Elementary analysis and spectral data confirm the putative structure. Compound_i (R = CH3) 1H HMR (DMSO-d < s. 2iC) H ^ jpm) * 11.5 (1H, broad), 6 MS (m, broad; 80 Os), 8.13 (1H, s), 5.49 (2H, s), 4.09 (2H, m), 3.71 (2H ·, m), (3H, s); 13C NMR (DMS0) δ (ppm) = 170.16, 1 ^ 2.79, 155.5, 148.97, Η7.26 .Ί39.97, 120.4, 72.22, 66.84, 62. <S4,20.58; IR υ (cnrl) Single 3] 0 · 2940. 2920, 2790, Γ740, I'm 1360, i500, J290; MS (e〇 rn / c: 295 〇6). 261 < l〇). 208 (9), 192 (12); i & i (] 'k) t {51. (35), 87 (100)-, elemental analysis (CuUsOs)% experimental value U 诂 counted): c = 44.86 (4 4.75) (Please read the precautions on the back first, then the IP page) Installation · This paper size is applicable to China National Standard (CNS) A4 specifications (2 丨OX297 public splash) 9 amendments to buy CS8C84 kl B7 V. Description of the invention (β), H = 4.45 (4.44), H = 22.25 (23.72), 0 = 28. 12 (27.09). D) Asek Loufo (I ) Disperse 65 g (0.220 mol) (4) (R = CH3) in 650 ml of 5¾ NaOH solution and check if the solid is completely dissolved. After stirring for 12 hours, the mixture was neutralized with an aqueous solution of H Cil to a pH of 5-6. The slurry is cooled to 20-25 ° C, the cake is filtered and washed with 400 ml of deionized water. After drying under vacuum at 60-70 ° C *, 46.1 g of Assekloufo (I) was obtained with a yield of 93%. Example 2 a) 9- (2-Ethoxypyridine) ethoxymethylguanine (6) 300 ml of 95% E t 0 Η, 29.5 g (0.1 mole) (4) and 40.4 g (0.4 mol) of Et3f ^ in a 500 ml round-bottomed flask equipped with a thermometer, a stirrer and a spherical condensing agent. The material was refluxed for 5 hours. Adjust the pΗ value to 5-6 with HC1 water, then cool the mixture to 15-20 ° C, filter the cake and wash with 200 ml of deionized water. After drying under vacuum at 60-70 ° C, 22.8 g (6) was obtained (yield: 85 '; 0. b) Asekloufo (I) as in Example 1 d) As described, 26.7 g (0.1 mol) (6) was treated with 5% Na 0Η. Yield of 94% was obtained for Assek Loufo, which is approximately close to the theoretical value. Example 3 'The procedure of Example 1 was followed, but instead of 2-oxo-1,4-diethoxybutane, a corresponding amount of 2-oxo-1, dimethylphenoxybutane was used. Or 2-oxo-1,4-dibenzylacetoxybutane is alkylated with N 2 -formylguanosine. Μ was obtained in the same yield as in Example 1 c). The intermediate (4) in which R == Η or R = phenyl was obtained, respectively. According to Example 1 d), the Asperk paper size was easily obtained from the intermediate. Applicable to China National Standard (CNS) A4 specification (2) 0X297 mm) -10- ~ correction page ~ ---------- install-(#xianwen read the precautions on the back page),- '° Line printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs A7 B7 386084 V. Description of the invention (9) Lou Buddha; where starting from (4) (R = phenyl), Asek Lou Buddha can be obtained. Yield It is 90¾. Compound (R = phenyl) ΪΗ NMR (DMS〇A. 25 0) 6 (pppi) = U.5 (Hi broad), 8, S7 (UI, Uoaxi; 80 C = s), 8.20 (1H, 4 8.15-7.50 (5H, m), 5.51 (2H; c). 4Λ6 (2U, mX; 3.77 (2Iit ra); MS (ci) m / c: 357 (M l-, 28), 236 (35), 151 (37). &Amp; 7 00); elemental analysis (C: i H t 3 N 5 0 5) experimental value (S: estimated value): C = 5 4. 0 1 (5 3. 7 8), H = 4'21 (4.20), N = 22.44 (22.41), 0 = 19'56 (19.6 1). Example 4 δ 7.5 g (125 ml, apparent density = 0.7) strong base Resin (AMBERLITE IRA-400) is suspended in deionized water, and then it is loaded into the layer

Analytical column (diameter = '4cm, = 40cm). After performing general regeneration treatment (using 2M H a 0 Η, 2 MH HC il, 2 MH N a 0 Η and deionized water to dissolve until neutrality), 50 g of Assekloufo was dissolved in 100 ml of 10¾ The solution of HaOH was diluted with water to 200 ml, and the resulting solution was packed into a column, and then the solution was dissolved at a flow rate of M 250 ml / hour (4.2 ml / minute). After dissolving the above solution, the column was dissolved with 900 ml of a 1: lv / v MeOH / 1M NaOH mixture at the same flow rate. The leachate thus obtained was adjusted to p Η with C 1 aqueous solution to 5-6. The precipitated solid was filtered, washed with water and dried. 45 g of acerine-free Buddha was obtained (yield: 90%). Example 5 Preparation of formamylguanine from guanine and formic acid ^ A mixture of guanine (20 g, 0.13 mol) and 9δ fluorene formic acid (200 ml) was refluxed for 48 hours, and then cooled to 0 ~ 5 ° C and filtered with Μ. The resulting solids K water (100 ml X 2) plus K rinse * and draw the paper size at 4 ο υ * the true size of the paper applies the Chinese National Standard (CNS) A4 specification (210 × 297 mm) -11, -corrected consistently- -------- Equipment-(Please read the precautions on the back first and then $ this page) Order-Printed by the Central Consumers Bureau of the Ministry of Economic Affairs, Consumer Cooperatives 386084 A7 B7 V. Description of Invention (10) , And dried to give methyronine guanine (3) (11 g, Η PLC degree 98%, 0.06 mole * yield 46¾) Example 6 Preparation of methyronine from guanine and methenyl acetic anhydride Mix a mixture of guanine (100 g, 0.66 mol) and freshly distilled methyl acetic anhydride (270 ml) at 40 ° C under nitrogen for 12 hours, and then place in It was left under it for an additional 12 hours, the mixture was cooled to room temperature, and then filtered, and the resulting solid was washed with K methanol (100 ml X 2). The solid was then dried under 40¾ * vacuum to obtain formamylguanine (3) (91 g, HPLC purity 97%, 0.49 mole, yield 75¾) ---------- ^ ------ II ----.------ 0 (Please read the notes on the back first and then the page) Printed on the paper by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs. 210X297 mm)

Claims (1)

386084 Α8 Β8 C8 D8 port Scope of patent application 1. A method for preparing 9- (2-hydroxy) ethoxymethylguanine (acyclovir) (1): 〇 Steps containing M: (a) Reaction of guanine with formic acid at a temperature of 0 to 5 ° C or reaction with formamyl acetic anhydride at a temperature of 40 to 80 ° K, and K forms N 2 -formamidine of formula (3) Guanine: Η, (3) (Please read the precautions on the back before filling out this page) ----- "Installation ------ Order --- Printed by the Staff Consumer Cooperative of the Central Echelon Bureau of the Ministry of Economic Affairs (b) 3) Η2-Methylmethylguanine and 2-oxo-1,4-dioxobutane of the following formula in the presence of p-toluenesulfonic acid at a pressure of 20-50 inmHg and a temperature of 11 0- Reaction at 1 3 0 ° C: 0 human R 0 0 (where R is hydrogen, Ci ~ C4 alkyl or phenyl), and M forms N2-methylfluorenyl-9- (2-fluorenyloxy) of formula (4) ) Ethoxymethyl bird. —3 ^ --- • -i-I-I In -B-1—--I i I. I— II 1 ^ 1 _1A paper size applies to the Chinese National Standard (CNS) A4 specification (2iOX297 mm) 386084 Α8 Β8 C8 D8 port Scope of patent application 1. A method for preparing 9- (2-hydroxy) ethoxymethylguanine (acyclovir) (1): 〇 Steps containing M: (a) Reaction of guanine with formic acid at a temperature of 0 to 5 ° C or reaction with formamyl acetic anhydride at a temperature of 40 to 80 ° K, and K forms N 2 -formamidine of formula (3) Guanine: Η, (3) (Please read the precautions on the back before filling out this page) ----- "Installation ------ Order --- Printed by the Staff Consumer Cooperative of the Central Echelon Bureau of the Ministry of Economic Affairs (b) 3) Η2-Methylmethylguanine and 2-oxo-1,4-dioxobutane of the following formula in the presence of p-toluenesulfonic acid at a pressure of 20-50 inmHg and a temperature of 11 0- Reaction at 1 3 0 ° C: 0 human R 0 0 (where R is hydrogen, Ci ~ C4 alkyl or phenyl), and M forms N2-methylfluorenyl-9- (2-fluorenyloxy) of formula (4) ) Ethoxymethyl bird. —3 ^ --- • -i-I-I In -B-1—--I i I. I— II 1 ^ 1 _1A paper size applies to the Chinese National Standard (CNS) A4 specification (2iOX297 mm) AS B8 C8 D8 Ο (4) 386084 t. Scope of patent application Purine: (Wherein R is as defined above); (c) treating N2-methylamidin-9- (2-pentyloxy) ethoxymethylguanine of formula (4) with a dilute aqueous solution of sodium hydroxide at the same time; -Formamylation and 0-demethylation, or firstly treat M with triethylamine in ethanol for de-methylation, and then treat K with a dilute sodium hydroxide solution for 0-demethylation, Borrow KK to get the Assik Lou Buddha of formula (I). (Please read the notes on the reverse side and fill in this page) Printed by the Consumers' Cooperatives of the China Standards Bureau of the Ministry of Economic Affairs — 2 — This paper size applies to China National Standard (CNS) Α4 size (210 X 297 mm)