tert-butyl N-[(3aS,7aS)-2,3,3a,4,6,7-hexahydro-1H-pyrano[3,4-c]pyrrol-7a-yl]carbamate

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Triethylamine (0.0737 ml, 0.528 mmol) and 7-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid (49.0 mg, 0.175 mmol) were added to a (1S,6S)-1-tert-butoxycarbonylamino-4-oxa-8-azabicyclo[4.3.0]nonane (42.2 mg, 0.176 mmol) in dimethyl sulfoxide (0.352 mL) in a nitrogen atmosphere, and the mixture was stirred at 75° C. for two days. Dimethyl sulfoxide (0.352 mL) and triethylamine (0.147 mL, 1.06 mmol) were added to the reaction solution, and the mixture was stirred at 75° C. for four days. Dimethyl sulfoxide (0.352 mL) and triethylamine (0.147 ml, 1.06 mmol) were added to the reaction solution, and the mixture was stirred at 75° C. for two days. 7-Fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid (24.6 mg, 0.0881 mmol) and triethylamine (0.147 mL, 1.06 mmol) were added to the reaction solution, and the mixture was stirred for five days. The reaction solution was diluted with ethyl acetate (30 mL) and then washed with a 10% citric acid solution (25 mL), water (25 mL), and a saturated sodium hydroxide solution (25 mL). Further, the organic layer was extracted again from the washing 10% citric acid solution and the washing water with ethyl acetate (40 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and filtered, and then the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=100:0→99:1→98:2). Trifluoroacetic acid (0.402 mL, 3 v/w) was added to a solution of 67.5 mg of the resulting residue in dichloromethane (1.32 mL) with stirring under ice-cooling, and the mixture was stirred at room temperature for one hour. The reaction solution was concentrated under reduced pressure, and trifluoroacetic acid was azeotropically distilled with toluene (×3). 6 mol/L hydrochloric acid was added to the resulting residue under ice-cooling, and the mixture was washed with chloroform (30 mL×5). The aqueous layer was adjusted to pH 12 with a 1 mol/L sodium hydroxide solution under ice-cooling. The basic solution was adjusted to pH 7.4 with 1 mol/L hydrochloric acid, followed by extraction with chloroform (100 mL×2) and chloroform/methanol=10/1 (50 mL). The organic layer was dried over anhydrous sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. The residue was purified by PTLC (lower layer of chloroform/methanol/water=7/3/1) and concentrated under reduced pressure. The resulting residue was dissolved in hot ethanol, and the insoluble material was removed by filtration. The filtrate was concentrated under reduced pressure, dissolved in hot ethanol (1 mL), ultrasonically treated, and cooled with ice water. Then, the slurry was washed with diethyl ether (10 mL). After stirring at room temperature overnight, the precipitated crystals were collected by filtration, washed with ethanol and diethyl ether, and then dried under reduced pressure at 60° C. to give 12.4 mg of the title compound. the mixture was stirred at 75° C. for four days the mixture was stirred at 75° C. for two days the mixture was stirred for five days washed with a 10% citric acid solution (25 mL), water (25 mL) Further, the organic layer was extracted again from the washing 10% citric acid solution dried over anhydrous sodium sulfate filtered the filtrate was concentrated under reduced pressure The resulting residue was purified by silica gel column chromatography (chloroform:methanol=100:0→99:1→98:2) Trifluoroacetic acid (0.402 mL, 3 v/w) was added to a solution of 67.5 mg of the resulting residue in dichloromethane (1.32 mL) with stirring under ice- cooling the mixture was stirred at room temperature for one hour The reaction solution was concentrated under reduced pressure, and trifluoroacetic acid was azeotropically distilled with toluene (×3) 6 mol/L hydrochloric acid was added to the resulting residue under ice- cooling the mixture was washed with chloroform (30 mL×5) cooling followed by extraction with chloroform (100 mL×2) and chloroform/methanol=10/1 (50 mL) The organic layer was dried over anhydrous sodium sulfate filtered the filtrate was concentrated under reduced pressure The residue was purified by PTLC (lower layer of chloroform/methanol/water=7/3/1) concentrated under reduced pressure The resulting residue was dissolved in hot ethanol the insoluble material was removed by filtration The filtrate was concentrated under reduced pressure dissolved in hot ethanol (1 mL) ultrasonically treated cooled with ice water Then, the slurry was washed with diethyl ether (10 mL) After stirring at room temperature overnight the precipitated crystals were collected by filtration washed with ethanol and diethyl ether dried under reduced pressure at 60° C.

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

Procedure: Triethylamine (0.263 mL, 1.88 mmol) and ethyl 8-cyano-6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropan-1-yl]-1,4-dihydro-4-oxoquinoline-3-carboxylate (211 mg, 0.627 mmol) were added to a solution of (1S,6S)-1-tert-butoxycarbonylamino-4-oxa-8-azabicyclo[4.3.0]nonane (151 mg, 0.628 mmol) in acetonitrile (1.25 mL) in a nitrogen atmosphere. The mixture was stirred at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure. Then, the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→90:10→60:40→50:50→34:66→25:75→16:84). A 1 mol/L sodium hydroxide solution (1.94 mL) was added to a solution of the resulting residue in ethanol (2.42 mL) under ice-cooling, and the mixture was stirred at room temperature for one hour. A 10% citric acid solution (30 mL) was added to the reaction solution, followed by extraction with ethyl acetate (40 mL×1, 30 mL×1). The organic layer was washed with brine (45 mL) and then dried over anhydrous sodium sulfate and filtered. The filtrate was then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=100:0→99:1→98:2). Trifluoroacetic acid (1.38 ml, 3 v/w) was added to a solution of 243 mg of the resulting residue in dichloromethane (4.58 mL) with stirring under ice-cooling, and the mixture was stirred at room temperature for 2.5 hours. The reaction solution was concentrated under reduced pressure. Then, hydrochloric acid at pH 1 was added to the resulting residue under ice-cooling, and the mixture was washed with chloroform (40 mL×3). The aqueous layer was adjusted to pH 12 with a 1 mol/L sodium hydroxide solution under ice-cooling. The basic solution was adjusted to pH 7.4 with 1 mol/L hydrochloric acid, followed by extraction with chloroform (100 mL×1, 70 mL×1, 50 mL×1). The organic layer was dried over anhydrous sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. The aqueous layer was concentrated under reduced pressure. The resulting residue was dissolved in chloroform/methanol=10/1, and the insoluble material was removed by filtration (×2). The residues obtained from the organic layer and the aqueous layer were purified by PTLC (lower layer of chloroform/methanol/water=7/3/1), respectively. These were combined and dissolved in dichloromethane (20 mL), and dichloromethane was azeotropically removed with ethanol (three times). Ethanol (5 mL) was added to the resulting residue, and the mixture was ultrasonically treated and then cooled. The precipitated solid was collected by filtration, washed with ethanol and diethyl ether, and dried under reduced pressure at 60° C. to give 122 mg of the title compound. The reaction solution was concentrated under reduced pressure Then, the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→90:10→60:40→50:50→34:66→25:75→16:84) A 1 mol/L sodium hydroxide solution (1.94 mL) was added to a solution of the resulting residue in ethanol (2.42 mL) under ice- cooling the mixture was stirred at room temperature for one hour A 10% citric acid solution (30 mL) was added to the reaction solution followed by extraction with ethyl acetate (40 mL×1, 30 mL×1) The organic layer was washed with brine (45 mL) dried over anhydrous sodium sulfate filtered The filtrate was then concentrated under reduced pressure The resulting residue was purified by silica gel column chromatography (chloroform:methanol=100:0→99:1→98:2) Trifluoroacetic acid (1.38 ml, 3 v/w) was added to a solution of 243 mg of the resulting residue in dichloromethane (4.58 mL) with stirring under ice- cooling the mixture was stirred at room temperature for 2.5 hours The reaction solution was concentrated under reduced pressure Then, hydrochloric acid at pH 1 was added to the resulting residue under ice- cooling the mixture was washed with chloroform (40 mL×3) cooling followed by extraction with chloroform (100 mL×1, 70 mL×1, 50 mL×1) The organic layer was dried over anhydrous sodium sulfate filtered the filtrate was concentrated under reduced pressure The aqueous layer was concentrated under reduced pressure The resulting residue was dissolved in chloroform/methanol=10/1 the insoluble material was removed by filtration (×2) The residues obtained from the organic layer the aqueous layer were purified by PTLC (lower layer of chloroform/methanol/water=7/3/1) dissolved in dichloromethane (20 mL) dichloromethane was azeotropically removed with ethanol (three times) Ethanol (5 mL) was added to the resulting residue the mixture was ultrasonically treated cooled The precipitated solid was collected by filtration washed with ethanol and diethyl ether dried under reduced pressure at 60° C.