(2S)-1-[(2-methylpropan-2-yl)oxycarbonyl]piperazine-2-carboxylic acid

反応条件: temp:15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of lithium aluminium hydride in tetrahydrofuran (1M, 22.0 ml, 22.0 mmol) was added dropwise to a solution of (2S)-1-(tert-butoxycarbonyl)piperazine-2-carboxylic acid (see U.S. Pat. No. 5,348,955, 1.007 g, 4.38 mmol) in tetrahydrofuran (20 ml) cooled to −15° C. The mixture was allowed to warm to 15° C. over 1.5 hours and then heated at reflux for 3 hours. The mixture was cooled in an ice bath and then water (0.4 ml) was added dropwise followed by a dilute solution of sodium hydroxide (1M, 0.4 ml) and a further portion of water (1.2 ml). The mixture was stirred at room temperature for 0.5 hours and then allowed to stand overnight. The resultant precipitate was filtered and the residue was washed with diethyl ether. The filtrate was evaporated and the residue purified by silica gel chromatography eluting with a 10% mixture of methanol (containing 10% 7M ammonia in methanol) in dichloromethane to give [(2S)-1-methylpiperazin-2-yl]methanol (0.3802 g, 67% yield): heated at reflux for 3 hours The mixture was cooled in an ice bath to stand overnight The resultant precipitate was filtered the residue was washed with diethyl ether The filtrate was evaporated the residue purified by silica gel chromatography eluting with a 10% mixture of methanol (containing 10% 7M ammonia in methanol) in dichloromethane

反応条件: temp:15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of lithium aluminium hydride in tetrahydrofuran (1M, 22.0 ml, 22.0 mmol) was added dropwise to a solution of (2S)-1-(tert-butoxycarbonyl)piperazine-2-carboxylic acid (see U.S. Pat. No. 5,348,955, 1.007 g, 4.38 mmol) in tetrahydrofuran (20 ml) cooled to −15° C. The mixture was allowed to warm to 15° C. over 1.5 hours and then heated at reflux for 3 hours. The mixture was cooled in an ice bath and then water (0.4 ml) was added dropwise followed by a dilute solution of sodium hydroxide (1M, 0.4 ml) and a further portion of water (1.2 ml). The mixture was stirred at room temperature for 0.5 hours and then allowed to stand overnight. The resultant precipitate was filtered and the residue was washed with diethyl ether. The filtrate was evaporated and the residue purified by silica gel chromatography eluting with a 10% mixture of methanol (containing 10% 7M ammonia in methanol) in dichloromethane to give [(2S)-1-methylpiperazin-2-yl]methanol (0.3802 g, 67% yield): heated at reflux for 3 hours The mixture was cooled in an ice bath to stand overnight The resultant precipitate was filtered the residue was washed with diethyl ether The filtrate was evaporated the residue purified by silica gel chromatography eluting with a 10% mixture of methanol (containing 10% 7M ammonia in methanol) in dichloromethane

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 270 mg of [1-(5-carbamoyl-4-{(1R)-1-[2-(trifluoromethyl)phenyl]ethoxy}-2-thienyl)-1H-imidazo[4,5-c]pyridin-6-yl]methyl methanesulfonate and 130 mg of (4-methylpiperazin-2-yl)methanol (synthesized starting from commercially available 1-(tert-butoxycarbonyl)piperazine-2-carboxylic acid in one step in analogy to the synthesis of (2S)-1-(tert-butoxycarbonyl)piperazine-2-carboxylic acid described in patent application WO2005/026152) in 10 ml dichloromethane is stirred at room temperature for 16 hours. 505 mg triethylamine is added and the reaction mixture is stirred additional 24 h at room temperature. Water (20 ml) is added to the mixture. After separation of the organic layer, the aqueous layer is extracted with dichloromethane (2×20 ml). The combined organic layers are dried over MgSO4. After filtration the solvent is removed under reduced pressure. The resulting residue is purified by flash chromatography [silica gel, eluent: ethyl acetate/methanol/aqueous solution of ammonia, 20/4/1 (v/v/v) and subsequently by preparative HPLC (ammonium formate buffer/acetonitrile, elution gradient 65/35 to 15/85 (v/v)) to give the title product. synthesized the reaction mixture is stirred additional 24 h at room temperature After separation of the organic layer the aqueous layer is extracted with dichloromethane (2×20 ml) The combined organic layers are dried over MgSO4 After filtration the solvent is removed under reduced pressure The resulting residue is purified by flash chromatography [silica gel, eluent ethyl acetate/methanol/aqueous solution of ammonia, 20/4/1 (v/v/v) and subsequently by preparative HPLC (ammonium formate buffer/acetonitrile, elution gradient 65/35 to 15/85 (v/v))

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 270 mg of [1-(5-carbamoyl-4-{(1R)-1-[2-(trifluoromethyl)phenyl]ethoxy}-2-thienyl)-1H-imidazo[4,5-c]pyridin-6-yl]methyl methanesulfonate and 130 mg of (4-methylpiperazin-2-yl)methanol (synthesized starting from commercially available 1-(tert-butoxycarbonyl)piperazine-2-carboxylic acid in one step in analogy to the synthesis of (2S)-1-(tert-butoxycarbonyl)piperazine-2-carboxylic acid described in patent application WO2005/026152) in 10 ml dichloromethane is stirred at room temperature for 16 hours. 505 mg triethylamine is added and the reaction mixture is stirred additional 24 h at room temperature. Water (20 ml) is added to the mixture. After separation of the organic layer, the aqueous layer is extracted with dichloromethane (2×20 ml). The combined organic layers are dried over MgSO4. After filtration the solvent is removed under reduced pressure. The resulting residue is purified by flash chromatography [silica gel, eluent: ethyl acetate/methanol/aqueous solution of ammonia, 20/4/1 (v/v/v) and subsequently by preparative HPLC (ammonium formate buffer/acetonitrile, elution gradient 65/35 to 15/85 (v/v)) to give the title product. synthesized the reaction mixture is stirred additional 24 h at room temperature After separation of the organic layer the aqueous layer is extracted with dichloromethane (2×20 ml) The combined organic layers are dried over MgSO4 After filtration the solvent is removed under reduced pressure The resulting residue is purified by flash chromatography [silica gel, eluent ethyl acetate/methanol/aqueous solution of ammonia, 20/4/1 (v/v/v) and subsequently by preparative HPLC (ammonium formate buffer/acetonitrile, elution gradient 65/35 to 15/85 (v/v))

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A partial solution of 1.32 g (5.74 mmole) of (S)-1-(tert-butyloxycarbonyl)piperazine-2-carboxylic acid in 25 ml of dried DMF was treated dropwise over 5 min with 1.48 g (11.47 mmole of diisopropylethyl amine at 25° under nitrogen with stirring. The clear solution which resulted was treated dropwise over 15 min with a solution of 1.26 g (5.74 mmole) of dipentylcarbamoyl chloride in 5 ml of DMF and the mixture was stirred under nitrogen at 25° for 16 hr. The solution was concentrated in vacuo and the residue was dissolved in 100 ml of dichloromethane which was extracted with 2×100 ml of 0.5M citric acid and 2×25 ml of water. Without drying, the solution was concentrated in vacuo to 1.85g (78%) of medium yellow oil which was homogeneous by the (silica gel, 1:1:1:1 ethylacetate: n-butanol: acetic acid: water, Rf =0.50). The clear solution which resulted the mixture was stirred under nitrogen at 25° for 16 hr The solution was concentrated in vacuo the residue was dissolved in 100 ml of dichloromethane which was extracted with 2×100 ml of 0.5M citric acid and 2×25 ml of water Without drying the solution was concentrated in vacuo to 1.85g (78%) of medium yellow oil which

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 4.00 g (10.98 mmole) of (S)-4-(benzyloxycarbonyl)-1-(tert-butyloxycarbonyl)-piperazine-2-carboxylic acid in 40 ml of methanol was hydrogenated over 1.0 g of 10% pd/c with rocking at 25° under 40 psi of hydrogen for 16 hr. The mixture was filtered and the cake was washed with a mixture of 100 ml of dichloromethane, 50 ml of methanol and 1.0 g of diisopropylethyl amine. Concentration in vacuo followed by Pumping in vacuo for 2 hr left 2.39 g (95%) of white solid which was homogeneous by tlc (silica gel, 1:1:1:1 ethyl acetate:n-butanol:acetic acid:water, Rf =0.70). The mixture was filtered the cake was washed with a mixture of 100 ml of dichloromethane, 50 ml of methanol and 1.0 g of diisopropylethyl amine Concentration in vacuo left 2.39 g (95%) of white solid which

反応条件: temp:15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of lithium aluminium hydride in tetrahydrofuran (1M, 22.0 ml, 22.0 mmol) was added dropwise to a solution of (2S)-1-(tert-butoxycarbonyl)piperazine-2-carboxylic acid (see U.S. Pat. No. 5,348,955, 1.007 g, 4.38 mmol) in tetrahydrofuran (20 ml) cooled to −15° C. The mixture was allowed to warm to 15° C. over 1.5 hours and then heated at reflux for 3 hours. The mixture was cooled in an ice bath and then water (0.4 ml) was added dropwise followed by a dilute solution of sodium hydroxide (1M, 0.4 ml) and a further portion of water (1.2 ml). The mixture was stirred at room temperature for 0.5 hours and then allowed to stand overnight. The resultant precipitate was filtered and the residue was washed with diethyl ether. The filtrate was evaporated and the residue purified by silica gel chromatography eluting with a 10% mixture of methanol (containing 10% 7M ammonia in methanol) in dichloromethane to give [(2S)-1-methylpiperazin-2-yl]methanol (0.3802 g, 67% yield): heated at reflux for 3 hours The mixture was cooled in an ice bath to stand overnight The resultant precipitate was filtered the residue was washed with diethyl ether The filtrate was evaporated the residue purified by silica gel chromatography eluting with a 10% mixture of methanol (containing 10% 7M ammonia in methanol) in dichloromethane