3-hexadecoxypropan-1-ol

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

Procedure: To a mixture of adefovir (1.36 g, 5 mmol) and 3-hexadecyloxy-1-propanol (1.8 g, 6 mmol) in dry pyridine was added DCC (2.06 g, 10 mmol). The mixture was heated to reflux and stirred 18 h then cooled and filtered. The filtrate was concentrated under reduced pressure and the residue was applied to a short column of silica gel. Elution of the column with 9:1 dichloromethane/methanol yielded hexadecyloxypropyl-adefovir (HDP-ADV) as a white powder. The mixture was heated to reflux then cooled filtered The filtrate was concentrated under reduced pressure Elution of the column with 9:1 dichloromethane/methanol

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

Procedure: To a mixture of adefovir (1.36 g, 5 mmol) and 3-hexadecyloxy-1-propanol (1.8 g, 6 mmol) in dry pyridine was added DCC (2.06 g, 10 mmol). The mixture was heated to reflux and stirred 18 h then cooled and filtered. The filtrate was concentrated under reduced pressure and the residue was applied to a short column of silica gel. Elution of the column with 9:1 dichloromethane/methanol yielded hexadecyloxypropyl-adefovir (HDP-ADV) as a white powder. The mixture was heated to reflux then cooled filtered The filtrate was concentrated under reduced pressure Elution of the column with 9:1 dichloromethane/methanol

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

Procedure: To a mixture of adefovir (1.36 g, 5 mmol) and 3-hexadecyloxy-1-propanol (1.8 g, 6 mmol) in dry pyridine was added DCC (2.06 g, 10 mmol). The mixture was heated to reflux and stirred 18 h then cooled and filtered. The filtrate was concentrated under reduced pressure and the residue was applied to a short column of silica gel. Elution of the column with 9:1 dichloromethane/methanol yielded hexadecyloxypropyl-adefovir (HDP-ADV) as a white powder. The mixture was heated to reflux then cooled filtered The filtrate was concentrated under reduced pressure Elution of the column with 9:1 dichloromethane/methanol

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Under an inert atmosphere, e.g., nitrogen, a reactor was charged with 1,3-propanediol (4.07 kg) and NMP (30 L). The reaction was cooled to −5 to 5° C. and kept under a nitrogen atmosphere. Sodium hydride (1.07 kg, 60% in mineral oil) was cautiously added portion-wise. After the addition was complete, the reaction was stirred at room temperature for an additional 2 hours. A solution of hexadecyl methanesulfonate 4 (4.39 kg) dissolved in NMP (10 L) was added slowly to the reaction mixture at 20 to 55° C. The resulting solution was stirred for 12 to 28 hours at 20 to 35° C. The reaction was monitored by GC-MS and was considered complete when the conversion rate was >95%. The reaction mixture was cooled down to −5 to 5° C. and slowly diluted with water (15 L). The reaction was extracted with ethyl acetate (2×25 L). The organic phase was washed with water (20 L), dried over Na2SO4 and concentrated to give a brown oil. The crude product was dissolved in methanol (20 L) and aged at 20 to 30° C. for 12 hours. The resulting solid impurities were filtered and discarded and the filtrate was concentrated. Acetonitrile (40 L) was added to the concentrate and the mixture was aged 5 to 15° C. for 16 hours. The solid was filtered and dried at 25 to 30° C. to afford 5 as a white solid (3.1 kg, 77%). Typical HPLC (AUC) purity was >95%. 1H-NMR was consistent with structure. After the addition was added slowly to the reaction mixture at 20 to 55° C The resulting solution was stirred for 12 to 28 hours at 20 to 35° C The reaction mixture was cooled down to −5 to 5° C. The reaction was extracted with ethyl acetate (2×25 L) The organic phase was washed with water (20 L) dried over Na2SO4 concentrated to give a brown oil aged at 20 to 30° C. for 12 hours The resulting solid impurities were filtered the filtrate was concentrated Acetonitrile (40 L) was added to the concentrate the mixture was aged 5 to 15° C. for 16 hours The solid was filtered dried at 25 to 30° C.

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

Procedure: adding a solution of hexadecyl methanesulfonate dissolved in N-methylpyrrolidinone to form the 3-(hexadecyloxy)propan-1-ol.

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Under an inert atmosphere, e.g., nitrogen, a reactor was charged with 1,3-propanediol (4.07 kg) and NMP (30 L). The reaction was cooled to −5 to 5° C. and kept under a nitrogen atmosphere. Sodium hydride (1.07 kg, 60% in mineral oil) was cautiously added portion-wise. After the addition was complete, the reaction was stirred at room temperature for an additional 2 hours. A solution of hexadecyl methanesulfonate 4 (4.39 kg) dissolved in NMP (10 L) was added slowly to the reaction mixture at 20 to 55° C. The resulting solution was stirred for 12 to 28 hours at 20 to 35° C. The reaction was monitored by GC-MS and was considered complete when the conversion rate was ≧95%. The reaction mixture was cooled down to −5 to 5° C. and slowly diluted with water (15 L). The reaction was extracted with ethyl acetate (2×25 L). The organic phase was washed with water (20 L), dried over Na2SO4 and concentrated to give a brown oil. The crude product was dissolved in methanol (20 L) and aged at 20 to 30° C. for 12 hours. The resulting solid impurities were filtered and discarded and the filtrate was concentrated. Acetonitrile (40 L) was added to the concentrate and the mixture was aged 5 to 15° C. for 16 hours. The solid was filtered and dried at 25 to 30° C. to afford 5 as a white solid (3.1 kg, 77%). Typical HPLC (AUC) purity was >95%. 1H-NMR was consistent with structure. After the addition was added slowly to the reaction mixture at 20 to 55° C The resulting solution was stirred for 12 to 28 hours at 20 to 35° C The reaction mixture was cooled down to −5 to 5° C. The reaction was extracted with ethyl acetate (2×25 L) The organic phase was washed with water (20 L) dried over Na2SO4 concentrated to give a brown oil aged at 20 to 30° C. for 12 hours The resulting solid impurities were filtered the filtrate was concentrated Acetonitrile (40 L) was added to the concentrate the mixture was aged 5 to 15° C. for 16 hours The solid was filtered dried at 25 to 30° C.

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Under an inert atmosphere, e.g., nitrogen, a reactor was charged with 1,3-propanediol (4.07 kg) and NMP (30 L). The reaction was cooled to −5 to 5° C. and kept under a nitrogen atmosphere. Sodium hydride (1.07 kg, 60% in mineral oil) was cautiously added portion-wise. After the addition was complete, the reaction was stirred at room temperature for an additional 2 hours. A solution of hexadecyl methanesulfonate 4 (4.39 kg) dissolved in NMP (10 L) was added slowly to the reaction mixture at 20 to 55° C. The resulting solution was stirred for 12 to 28 hours at 20 to 35° C. The reaction was monitored by GC-MS and was considered complete when the conversion rate was ≧95%. The reaction mixture was cooled down to −5 to 5° C. and slowly diluted with water (15 L). The reaction was extracted with ethyl acetate (2×25 L). The organic phase was washed with water (20 L), dried over Na2SO4 and concentrated to give a brown oil. The crude product was dissolved in methanol (20 L) and aged at 20 to 30° C. for 12 hours. The resulting solid impurities were filtered and discarded and the filtrate was concentrated. Acetonitrile (40 L) was added to the concentrate and the mixture was aged 5 to 15° C. for 16 hours. The solid was filtered and dried at 25 to 30° C. to afford 5 as a white solid (3.1 kg, 77%). Typical HPLC (AUC) purity was >95%. 1H-NMR was consistent with structure. After the addition was added slowly to the reaction mixture at 20 to 55° C The resulting solution was stirred for 12 to 28 hours at 20 to 35° C The reaction mixture was cooled down to −5 to 5° C. The reaction was extracted with ethyl acetate (2×25 L) The organic phase was washed with water (20 L) dried over Na2SO4 concentrated to give a brown oil aged at 20 to 30° C. for 12 hours The resulting solid impurities were filtered the filtrate was concentrated Acetonitrile (40 L) was added to the concentrate the mixture was aged 5 to 15° C. for 16 hours The solid was filtered dried at 25 to 30° C.

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

Procedure: To a mixture of adefovir (1.36 g, 5 mmol) and 3-hexadecyloxy-1-propanol (1.8 g, 6 mmol) in dry pyridine was added DCC (2.06 g, 10 mmol). The mixture was heated to reflux and stirred 18 h then cooled and filtered. The filtrate was concentrated under reduced pressure and the residue was applied to a short column of silica gel. Elution of the column with 9:1 dichloromethane/methanol yielded hexadecyloxypropyl-adefovir (HDP-ADV) as a white powder. The mixture was heated to reflux then cooled filtered The filtrate was concentrated under reduced pressure Elution of the column with 9:1 dichloromethane/methanol

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

Procedure: To a mixture of adefovir (1.36 g, 5 mmol) and 3-hexadecyloxy-1-propanol (1.8 g, 6 mmol) in dry pyridine was added DCC (2.06 g, 10 mmol). The mixture was heated to reflux and stirred 18 h then cooled and filtered. The filtrate was concentrated under reduced pressure and the residue was applied to a short column of silica gel. Elution of the column with 9:1 dichloromethane/methanol yielded hexadecyloxypropyl-adefovir (HDP-ADV) as a white powder. The mixture was heated to reflux then cooled filtered The filtrate was concentrated under reduced pressure Elution of the column with 9:1 dichloromethane/methanol

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

Procedure: To a mixture of adefovir (1.36 g, 5 mmol) and 3-hexadecyloxy-1-propanol (1.8 g, 6 mmol) in dry pyridine was added DCC (2.06 g, 10 mmol). The mixture was heated to reflux and stirred 18 h then cooled and filtered. The filtrate was concentrated under reduced pressure and the residue was applied to a short column of silica gel. Elution of the column with 9:1 dichloromethane/methanol yielded hexadecyloxypropyl-adefovir (HDP-ADV) as a white powder. The mixture was heated to reflux then cooled filtered The filtrate was concentrated under reduced pressure Elution of the column with 9:1 dichloromethane/methanol

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

Procedure: To a mixture of adefovir (1.36 g, 5 mmol) and 3-hexadecyloxy-1-propanol (1.8 g, 6 mmol) in dry pyridine was added DCC (2.06 g, 10 mmol). The mixture was heated to reflux and stirred 18 h then cooled and filtered. The filtrate was concentrated under reduced pressure and the residue was applied to a short column of silica gel. Elution of the column with 9:1 dichloromethane/methanol yielded hexadecyloxypropyl-adefovir (HDP-ADV) as a white powder. The mixture was heated to reflux then cooled filtered The filtrate was concentrated under reduced pressure Elution of the column with 9:1 dichloromethane/methanol

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

Procedure: To a mixture of adefovir (1.36 g, 5 mmol) and 3-hexadecyloxy-1-propanol (1.8 g, 6 mmol) in dry pyridine was added DCC (2.06 g, 10 mmol). The mixture was heated to reflux and stirred 18 h then cooled and filtered. The filtrate was concentrated under reduced pressure and the residue was applied to a short column of silica gel. Elution of the column with 9:1 dichloromethane/methanol yielded hexadecyloxypropyl-adefovir (HDP-ADV) as a white powder. The mixture was heated to reflux then cooled filtered The filtrate was concentrated under reduced pressure Elution of the column with 9:1 dichloromethane/methanol