2-(acetyloxymethoxy)ethyl acetate

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Matsumoto in Chem Pharm Bull, 36(3), 1153-1157 and JP 63-107982 teaches a process for the synthesis of acyclovir(Ia) by condensation of diacetyl guanine (DAG Va) with 2-oxa-1,4-butanediol diacetate (OBDDA, VIIa) in DMSO in presence of an acid catalyst to get a mixture of N-9/N-7 isomer (66:26). The former is isolated by column chromatography and deacetylated with methanolic ammonia to give acyclovir. Overall yield of acyclovir from guanine is 42% to get a mixture of N-9/N-7 isomer (66:26) The former is isolated by column chromatography

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixed solution containing 100 mg (0.35 mmol) of N2 -acetyl-7-benzylguanine and 1 ml of DMF was added 64 mg (0.37 mmol) of (2-acetoxyethoxy)methyl acetate [prepared by the method described in M. J. Robins et al., Can. J. Chem., 60, 547 (1982)]. The mixture was heated at 80° C. for 20 h, and then allowed to cool. The reaction solution was concentrated, and purified by silica-gel column chromatography to yield 9-(2-acetoxyethoxy)methyl-7-benzyl-N2 -acetylguaninium acetate. prepared by the method to cool The reaction solution was concentrated purified by silica-gel column chromatography

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Thymine (0.63 g, 5 mmol) was added to 2-acetoxyethyl acetoxymethyl ether (1.32 g, 7.5 mmol) dissolved in CH2Cl2 (15 mL). The reaction mixture was stirred at room temperature and N,O-bis(trimethylsilyl)acetamide (2.96 mL, 12 mmol) was added dropwise. After 3 hours of stirring, the clear solution was cooled to 0° C., and SnCl4 (0.12 mL, 1 mmol) was added. The reaction mixture was allowed to come to room temperature and stirred overnight. A mixture of saturated aqueous NaHCO3 (25 mL) and CHCl3 (50 mL) was prepared and cooled in ice. The reaction mixture was added slowly with vigorous stirring; a white foam formed immediately. After filtration, the aqueous layer was further extracted with ethyl acetate (3×25 mL) and CHCl3 (25 mL), and the combined organic layers were dried over anhydrous Na2SO4. After filtration of drying agent and removal of solvents in vacuo, an oily liquid was obtained. It was purified on a silica gel column using 2:1 CHCl3/CH3COCH3 as the eluent to give the desired product. Yield 36%; Wt. 4.0 g; mp 105°-107° C.; 1H NMR (DMSO-d6) 1.8 (s, CH3 C5 thymine), 2.0 (s, CH3 CO), 3.65 (m, CO O CH2 CH2), 4.1 (m, CO O CH2 CH2), 5.05 (s, O CH2 N), 7.55 (s, H C6 thymine), 11.3 (s, HN thymine ). After 3 hours of stirring the clear solution was cooled to 0° C. to come to room temperature stirred overnight was prepared cooled in ice The reaction mixture was added slowly with vigorous stirring a white foam formed immediately After filtration the aqueous layer was further extracted with ethyl acetate (3×25 mL) and CHCl3 (25 mL) the combined organic layers were dried over anhydrous Na2SO4 After filtration of drying agent and removal of solvents in vacuo an oily liquid was obtained It was purified on a silica gel column

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Thymine (0.63 g, 5 mmol) was added to 2-acetoxyethyl acetoxymethyl ether (1.32 g, 7.5 mmol) dissolved in CH2Cl2 (15 mL). The reaction mixture was stirred at room temperature and N,O-bis(trimethylsilyl)acetamide (2.96 mL, 12 mmol) was added dropwise. After 3 hours of stirring, the clear solution was cooled to 0° C., and SnCl4 (0.12 mL, 1 mmol) was added. The reaction mixture was allowed to come to room temperature and stirred overnight. A mixture of saturated aqueous NaHCO3 (25 mL) and CHCl3 (50 mL) was prepared and cooled in ice. The reaction mixture was added slowly with vigorous stirring; a white foam formed immediately. After filtration, the aqueous layer was further extracted with ethyl acetate (3×25 mL) and CHCl3 (25 mL), and the combined organic layers were dried over anhydrous Na2SO4. After filtration of drying agent and removal of solvents in vacuo, an oily liquid was obtained. It was purified on a silica gel column using 2:1 CHCl3/CH3COCH3 as the eluent to give the desired product. Yield 36%; Wt. 4.0 g; mp 105°-107° C.; 1H NMR (DMSO-d6) 1.8 (s, CH3 C5 thymine), 2.0 (s, CH3 CO), 3.65 (m, CO O CH2 CH2), 4.1 (m, CO O CH2 CH2), 5.05 (s, O CH2 N), 7.55 (s, H C6 thymine), 11.3 (s, HN thymine ). After 3 hours of stirring the clear solution was cooled to 0° C. to come to room temperature stirred overnight was prepared cooled in ice The reaction mixture was added slowly with vigorous stirring a white foam formed immediately After filtration the aqueous layer was further extracted with ethyl acetate (3×25 mL) and CHCl3 (25 mL) the combined organic layers were dried over anhydrous Na2SO4 After filtration of drying agent and removal of solvents in vacuo an oily liquid was obtained It was purified on a silica gel column

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 6-(3,5-dimethylbenzyl)-5-ethyluracil (see the above Example 4-A) (516 mg, 2 mmol) and 1-acetoxy-2-acetoxymethoxyethane [A. Rosowski, S. H. Kim. M. Wick, J. Med. Chem. (1981) 24, 1177-81]) (704 mg, 4 mmol) were suspended, under nitrogen atmosphere, in acetonitrile (20 ml). It was added thereto HMDS (hexamethyldisilazane) (646 mg, 4 mmol) and TMSCl (chlorotrimethyl-silane) (435 mg, 4 mmol) and the mixture was then stirred for 10 mn. Then it was added dropwise thereto, over 10 mn, a solution of tinIV chloride (625 mg, 2.4 mmol) in acetonitrile (5 ml). After 14 h under stirring, it was added thereto dichloromethane (50 ml) and an aqueous saturated sodium hydrogenocarbonate solution (50 ml). The mixture was extracted with dichloromethane (3×50 ml). The organic phases, collected, were washed with a aqueous saturated sodium hydrogenocarbonate solution (25 ml), with water (25 ml), and then with an aqueous saturated sodium chloride solution. The organic phase was dried (sodium sulfate), concentrated, and then subjected to a flash column chromatography (petroleum ether/ethyl acetate 3:2) to give 1-(2-acetoxyethoxymethyl-6-(3,5-dimethylbenzyl)-5-ethyluracil (690 mg, 92%) in the form of a white solid. It was added Then it was added dropwise it was added The mixture was extracted with dichloromethane (3×50 ml) The organic phases, collected were washed with a aqueous saturated sodium hydrogenocarbonate solution (25 ml), with water (25 ml) The organic phase was dried (sodium sulfate) concentrated

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 10 gms (66 mmoles) of guanine, 50 ml of hexamethyldisilazane, and 0.4 gms (3 mmmol) of ammonium sulfate was heated to 115°-118° C. for 18 hours. The ammonia gas was removed as it was formed. After 18 hours of heating, a solution was formed indicating the completion of silylation. To this solution was added 15 gms (85 mmol) of 2-oxa-1,4-butanediol diacetate and 0.1 ml of trimethylsilyl triftriflate. The mixture was heated to 130° C. for a period of 4.5 hours. The solution was cooled to 50° C. and 10 ml of water dissolved in 100 ml of acetone was added. The mixture was heated to reflux and a precipitate was formed immediately. The mixture was cooled and the solid was collected by filtration to yield 10.1 g (58% yield) of 9-(2-acetoxyethoxy)methylguanine, with a 13:1 ratio of N-9 to N-7 isomer. Characteristic analytical data are as follows: 1H NMR (DMSO-d6) δ1.90 (3H, singlet, --OAc) , 3.58 (2H, multiplet, --OCH2 --) , 4.0 (2H, multiplet, --CH2OAc) , 5.25 (2H, singlet, --NCH2O--), 6.5 (2H, br singlet, --NH2), 7.75 (1H, singlet, --N=CH--N--). was heated to 115°-118° C. for 18 hours The ammonia gas was removed as it was formed After 18 hours of heating a solution was formed The solution was cooled to 50° C. was added The mixture was heated to reflux a precipitate was formed immediately The mixture was cooled the solid was collected by filtration

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 10 gms (66 mmoles) of guanine, 50 ml of hexamethyldisilazane, and 0.4 gms (3 mmmol) of ammonium sulfate was heated to 115°-118° C. for 18 hours. The ammonia gas was removed as it was formed. After 18 hours of heating, a solution was formed indicating the completion of silylation. To this solution was added 15 gms (85 mmol) of 2-oxa-1,4-butanediol diacetate and 0.1 ml of trimethylsilyl triftriflate. The mixture was heated to 130° C. for a period of 4.5 hours. The solution was cooled to 50° C. and 10 ml of water dissolved in 100 ml of acetone was added. The mixture was heated to reflux and a precipitate was formed immediately. The mixture was cooled and the solid was collected by filtration to yield 10.1 g (58% yield) of 9-(2-acetoxyethoxy)methylguanine, with a 13:1 ratio of N-9 to N-7 isomer. Characteristic analytical data are as follows: 1H NMR (DMSO-d6) δ1.90 (3H, singlet, --OAc) , 3.58 (2H, multiplet, --OCH2 --) , 4.0 (2H, multiplet, --CH2OAc) , 5.25 (2H, singlet, --NCH2O--), 6.5 (2H, br singlet, --NH2), 7.75 (1H, singlet, --N=CH--N--). was heated to 115°-118° C. for 18 hours The ammonia gas was removed as it was formed After 18 hours of heating a solution was formed The solution was cooled to 50° C. was added The mixture was heated to reflux a precipitate was formed immediately The mixture was cooled the solid was collected by filtration

Conditions: temp:138.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2,6-Dichloropurine 5.5 g and 2-oxa-1,4-butanediol diacetate 513 g were placed in a flask and partially evacuated and then heated to 138° C., initially the mixture was too thick to stir but gradually gave rise to a melt which was stirred, and after 20 minutes was completely melted and the reaction mixture heated for 10 minutes more (total heat time=30 minutes). The mixture was then cooled to room temperature and para-toluenesulphonic acid 150 mg was added, the vacuum reapplied and heating resumed with stirring. After 20 minutes heating vigorous bubbling was noted; the mixture was cooled to room temperature; chloroform was added, and the solution was extracted once with saturated aqueous sodium bicarbonate and once with water. The chloroform phase was dried over anhydrous sodium sulphate and evaporated. The residual oil was dissolved in benzene and applied to a column of 200 g. of silica gel in benzene. Benzene elution removed the acetate by-products. Ether elution gave 2,6-dichloro-9-(2-acetyloxyethoxymethyl)purine (64% yield). Recrystallization from benzene gave lustrous white flakes, m.p. 96°-99° C. partially evacuated gradually gave rise to a melt which was stirred the reaction mixture heated for 10 minutes more (total heat time=30 minutes) The mixture was then cooled to room temperature para-toluenesulphonic acid 150 mg was added heating with stirring After 20 minutes heating vigorous bubbling the mixture was cooled to room temperature chloroform was added the solution was extracted once with saturated aqueous sodium bicarbonate and once with water The chloroform phase was dried over anhydrous sodium sulphate evaporated The residual oil was dissolved in benzene Benzene elution removed the acetate by-products Ether elution

Conditions: temp:138.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2,6-Dichloropurine 5.5 g and 2-oxa-1,4-butanediol diacetate 513 g were placed in a flask and partially evacuated and then heated to 138° C., initially the mixture was too thick to stir but gradually gave rise to a melt which was stirred, and after 20 minutes was completely melted and the reaction mixture heated for 10 minutes more (total heat time=30 minutes). The mixture was then cooled to room temperature and para-toluenesulphonic acid 150 mg was added, the vacuum reapplied and heating resumed with stirring. After 20 minutes heating vigorous bubbling was noted; the mixture was cooled to room temperature; chloroform was added, and the solution was extracted once with saturated aqueous sodium bicarbonate and once with water. The chloroform phase was dried over anhydrous sodium sulphate and evaporated. The residual oil was dissolved in benzene and applied to a column of 200 g. of silica gel in benzene. Benzene elution removed the acetate by-products. Ether elution gave 2,6-dichloro-9-(2-acetyloxyethoxymethyl)purine (64% yield). Recrystallization from benzene gave lustrous white flakes, m.p. 96°-99° C. partially evacuated gradually gave rise to a melt which was stirred the reaction mixture heated for 10 minutes more (total heat time=30 minutes) The mixture was then cooled to room temperature para-toluenesulphonic acid 150 mg was added heating with stirring After 20 minutes heating vigorous bubbling the mixture was cooled to room temperature chloroform was added the solution was extracted once with saturated aqueous sodium bicarbonate and once with water The chloroform phase was dried over anhydrous sodium sulphate evaporated The residual oil was dissolved in benzene Benzene elution removed the acetate by-products Ether elution

Conditions: temp:138.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2,6-Dichloropurine 5.5 g and 2-oxa-1,4-butanediol diacetate 513 g were placed in a flask and partially evacuated and then heated to 138° C., initially the mixture was too thick to stir but gradually gave rise to a melt which was stirred, and after 20 minutes was completely melted and the reaction mixture heated for 10 minutes more (total heat time = 30 minutes). The mixture was then cooled to room temperature and para-toluenesulphonic acid 150 mg was added, the vacuum reapplied and heating resumed with stirring. After 20 minutes heating vigorous bubbling was noted; the mixture was cooled to room temperature; chloroform was added, and the solution was extracted once with saturated aqueous sodium bicarbonate and once with water. The chloroform phase was dried over anhydrous sodium sulphate and evaporated. The residual oil was dissolved in benzene and applied to a column of 200 g. of silica gel in benzene. Benzene elution removed the acetate by-products. Ether elution gave 2,6-dichloro-9-(2-acetyloxyethoxymethyl)purine (64% yield). Recrystallization from benzene gave lustrous white flakes, m.p. 96°-99° C. partially evacuated gradually gave rise to a melt which was stirred the reaction mixture heated for 10 minutes more (total heat time = 30 minutes) The mixture was then cooled to room temperature para-toluenesulphonic acid 150 mg was added heating with stirring After 20 minutes heating vigorous bubbling the mixture was cooled to room temperature chloroform was added the solution was extracted once with saturated aqueous sodium bicarbonate and once with water The chloroform phase was dried over anhydrous sodium sulphate evaporated The residual oil was dissolved in benzene Benzene elution removed the acetate by-products Ether elution

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Matsumoto in Chem Pharm Bull, 36(3), 1153-1157 and JP 63-107982 teaches a process for the synthesis of acyclovir(Ia) by condensation of diacetyl guanine (DAG Va) with 2-oxa-1,4-butanediol diacetate (OBDDA, VIIa) in DMSO in presence of an acid catalyst to get a mixture of N-9/N-7 isomer (66:26). The former is isolated by column chromatography and deacetylated with methanolic ammonia to give acyclovir. Overall yield of acyclovir from guanine is 42% to get a mixture of N-9/N-7 isomer (66:26) The former is isolated by column chromatography