tert-butyl N-(3-hydroxypropyl)-N-methylcarbamate

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

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

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

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

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

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

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

Procedure: Dry dichloromethane (40 ml), triphenylphosphine (3.28 g), imidazole (1.05 g) and iodine (3.85 g) were combined in that order. A solution of tert-butyl N-(3-hydroxypropyl)-N-methylcarbamate (1.90 g, J. Org. Chem., 1988, 53(10), 2229) in dichloromethane (10 ml) was added and the resulting reaction mixture stirred at room temperature for 1 hour. An aqueous solution of sodium hydrogen sulphite (6 g in 100 ml of water) was then added and the organic layer separated. The latter was dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with iso-hexane:ether (7:3) to give tert-butyl N-(3-iodopropyl)-N-methylcarbamate (2.54 g) which was used immediately. Caesium carbonate (0.655 g) was added to a suspension of N-(3-hydroxy-2-methylphenyl)-tricyclo[3.3.1.13,7]decane-1-acetamide (0.453 g, Example 26) in acetonitrile (35 ml) and the mixture heated at 100° C. for 10 minutes. After cooling to room temperature a solution of tert-butyl N-(3-iodopropyl)-N-methylcarbamate (0.600 g) in acetonitrile (5 ml) was added and the reaction heated at reflux for 90 minutes. The reaction was concentrated under reduced pressure and the residue partitioned between dichloromethane (100 ml) and water (100 ml). The organic layer was dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with dichloromethane:ethyl acetate (9:1) to give a solid that was dissolved in methanol (10 ml). A solution of hydrogen chloride (generated by slow addition of acetyl chloride (12 ml) to methanol (15 ml) at 0° C. CARE—Very Exothermic) was then added to the latter solution and the reaction stirred at room temperature for 1 hour. The reaction was concentrated under reduced pressure to give a gum that was scratched under ether:hexane (1:1) (20 ml) to give the title compound as a pale yellow powder (0.477 g). the resulting reaction mixture the organic layer separated The latter was dried over anhydrous magnesium sulphate filtered concentrated under reduced pressure The residue was purified by column chromatography over silica eluting with iso-hexane:ether (7:3)

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

Procedure: Diethyl azodicarboxylate (0.50 ml) was added to a solution of N-(5-hydroxy-2-methylphenyl)-tricyclo[3.3.1.13,7]decane-1-acetamide (0.50 g, Example 12), tert-butyl N-(3-hydroxypropyl)-N-methylcarbamate (0.60 g, J. Org. Chem., 1988, 53(10), 2229) and triphenylphosphine (0.88 g) in tetrahydrofuran (5 ml). After stirring for 19 hours at room temperature further triphenylphosphine (0.90 g) and diethyl azodicarboxylate (0.50 ml) were added. After stirring for 4 hours at room temperature further triphenylphosphine (0.90 g) and diethyl azodicarboxylate (0.50 ml) were added and the reaction mixture was stirred for 3 days. The reaction was then concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with dichloromethane:ethyl acetate (9:1) to give material that was further purified by chromatography over a Dynamax® column using a Gilson automated chromatography machine eluting with iso-hexane:ethyl acetate (4:1) to give the Mitsunobu reaction product (0.29 g) which was dissolved in methanol (10 ml). A solution of hydrogen chloride (generated by slow addition of acetyl chloride (12 ml) to methanol (10 ml) at 0° C. CARE—Very Exothermic) was then added to the latter solution and the reaction stirred at room temperature for 1 hour. The reaction was then concentrated under reduced pressure to give the title compound as a yellow solid (0.13 g). were added were added The reaction was then concentrated under reduced pressure the residue was purified by silica gel chromatography eluting with dichloromethane:ethyl acetate (9:1) to give material that was further purified by chromatography over a Dynamax® column eluting with iso-hexane:ethyl acetate (4:1) to give the reaction stirred at room temperature for 1 hour The reaction was then concentrated under reduced pressure

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

Procedure: Diethyl azodicarboxylate (0.50 ml) was added to a solution of N-(5-hydroxy-2-methylphenyl)-tricyclo[3.3.1.13,7]decane-1-acetamide (0.50 g, Example 12), tert-butyl N-(3-hydroxypropyl)-N-methylcarbamate (0.60 g, J. Org. Chem., 1988, 53(10), 2229) and triphenylphosphine (0.88 g) in tetrahydrofuran (5 ml). After stirring for 19 hours at room temperature further triphenylphosphine (0.90 g) and diethyl azodicarboxylate (0.50 ml) were added. After stirring for 4 hours at room temperature further triphenylphosphine (0.90 g) and diethyl azodicarboxylate (0.50 ml) were added and the reaction mixture was stirred for 3 days. The reaction was then concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with dichloromethane:ethyl acetate (9:1) to give material that was further purified by chromatography over a Dynamax® column using a Gilson automated chromatography machine eluting with iso-hexane:ethyl acetate (4:1) to give the Mitsunobu reaction product (0.29 g) which was dissolved in methanol (10 ml). A solution of hydrogen chloride (generated by slow addition of acetyl chloride (12 ml) to methanol (10 ml) at 0° C. CARE—Very Exothermic) was then added to the latter solution and the reaction stirred at room temperature for 1 hour. The reaction was then concentrated under reduced pressure to give the title compound as a yellow solid (0.13 g). were added were added The reaction was then concentrated under reduced pressure the residue was purified by silica gel chromatography eluting with dichloromethane:ethyl acetate (9:1) to give material that was further purified by chromatography over a Dynamax® column eluting with iso-hexane:ethyl acetate (4:1) to give the reaction stirred at room temperature for 1 hour The reaction was then concentrated under reduced pressure

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

Procedure: A solution of 3-(N-t-butoxycarbonyl-N-methylamino)propanol (2.40 g) and triethylamine (2.07 g) in methylene chloride (25 ml) was cooled to 0° C. and treated with methanesulfonyl chloride (1.883 g). After being stirred for 1 hour at 0°-4° C., the solution was evaporated in vacuo. The residue was partitioned between ethyl acetate (25 ml) and water (50 ml). The separated organic layer was washed with 0.5 N hydrochloric acid (50 ml), water (50 ml), aqueous sodium bicarbonate (50 ml), water (50 ml) and brine (50 ml) successively, and dried over magnesium sulfate. The evaporation of the solvent gave 3-(N-t-butoxycarbonyl-N-methylamino)propyl methanesulfonate (3.742 g) as an oil. the solution was evaporated in vacuo The residue was partitioned between ethyl acetate (25 ml) and water (50 ml) The separated organic layer was washed with 0.5 N hydrochloric acid (50 ml), water (50 ml), aqueous sodium bicarbonate (50 ml), water (50 ml) and brine (50 ml) successively dried over magnesium sulfate The evaporation of the solvent

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

Procedure: To a solution of N-t-butoxycarbonyl-N-methyl-β-alanine methyl ester (3.911 g) in methanol (20 ml) and water (20 ml) was added sodium borohydride (6.81 g) portionwise at 4° C. and the mixture was stirred at room temperature for 3 hours. The solution was concentrated in vacuo, and the residue was portioned between ethyl acetate (100 ml) and 0.5 N hydrochloric acid (100 ml). The separated organic layer was washed with 0.5 N hydrochloric acid (100 ml), water (100 ml), aqueous sodium bicarbonate (100 ml), water (100 ml) and brine (100 ml) successively, and dried over magnesium sulfate. Evaporation of the solvent gave 3-(N-t-butoxycarbonyl-N-methylamino)propanol (2.48 g) as an oil. The solution was concentrated in vacuo The separated organic layer was washed with 0.5 N hydrochloric acid (100 ml), water (100 ml), aqueous sodium bicarbonate (100 ml), water (100 ml) and brine (100 ml) successively dried over magnesium sulfate Evaporation of the solvent

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

Procedure: To a solution of N-t-butoxycarbonyl-N-methyl-β-alanine methyl ester (3.911 g) in methanol (20 ml) and water (20 ml) was added sodium borohydride (6.81 g) portionwise at 4° C. and the mixture was stirred at room temperature for 3 hours. The solution was concentrated in vacuo, and the residue was portioned between ethyl acetate (100 ml) and 0.5 N hydrochloric acid (100 ml). The separated organic layer was washed with 0.5 N hydrochloric acid (100 ml), water (100 ml), aqueous sodium bicarbonate (100 ml), water (100 ml) and brine (100 ml) successively, and dried over magnesium sulfate. Evaporation of the solvent gave 3-(N-t-butoxycarbonyl-N-methylamino)propanol (2.48 g) as an oil. The solution was concentrated in vacuo The separated organic layer was washed with 0.5 N hydrochloric acid (100 ml), water (100 ml), aqueous sodium bicarbonate (100 ml), water (100 ml) and brine (100 ml) successively dried over magnesium sulfate Evaporation of the solvent