benzyl N-[(3R,4S)-3-fluoropiperidin-4-yl]carbamate

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

実験手順: (cis)-tert-Butyl 4-(benzyloxycarbonylamino)-3-fluoropiperidine-1-carboxylate (7.5 g, 21.3 mmol) was weighed into a 500 mL 1 neck round bottom and dissolved in 200 mL of DCM, followed by addition of TFA (16.4 mL, 213 mmol) and stirring at ambient temperature for 1 hour, at which time all bubbling had ceased and the reaction appeared complete by TLC. The crude reaction was concentrated in vacuo, followed by aqueous work-up with 2 N NaOH and DCM. The combined organics were dried over Na2SO4, filtered and concentrated in vacuo to afford benzyl(cis)-3-fluoropiperidin-4-ylcarbamate (4.25 g, 16.8 mmol, 79.2% yield) as a white solid. The crude reaction was concentrated in vacuo The combined organics were dried over Na2SO4 filtered concentrated in vacuo

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

実験手順: (cis)-tert-Butyl 4-(benzyloxycarbonylamino)-3-fluoropiperidine-1-carboxylate (7.5 g, 21.3 mmol) was weighed into a 500 mL 1 neck round bottom and dissolved in 200 mL of DCM, followed by addition of TFA (16.4 mL, 213 mmol) and stirring at ambient temperature for 1 hour, at which time all bubbling had ceased and the reaction appeared complete by TLC. The crude reaction was concentrated in vacuo, followed by aqueous work-up with 2 N NaOH and DCM. The combined organics were dried over Na2SO4, filtered and concentrated in vacuo to afford benzyl (cis)-3-fluoropiperidin-4-ylcarbamate (4.25 g, 16.8 mmol, 79.2% yield) as a white solid. The crude reaction was concentrated in vacuo The combined organics were dried over Na2SO4 filtered concentrated in vacuo

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

実験手順: This was prepared from cis-4-benzyloxycarbonylamino-3-fluoropiperidine Enantiomer 2 (7a) and (R)-2-(6-methoxy-[1,5]-naphthyridin-4-yl)oxirane (20d) (100% ee) by the method of Example (20e).

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

実験手順: This was prepared from cis-4-benzyloxycarbonylamino-3-fluoropiperidine Enantiomer 2 (7a) and (R)-2-(6-methoxy-[1,5]-naphthyridin-4-yl)oxirane (20d) (100% ee) by the method of Example (20e).

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

実験手順: (cis)-tert-Butyl 4-(benzyloxycarbonylamino)-3-fluoropiperidine-1-carboxylate (7.5 g, 21.3 mmol) was weighed into a 500 mL 1 neck round bottom and dissolved in 200 mL of DCM, followed by addition of TFA (16.4 mL, 213 mmol) and stirring at ambient temperature for 1 hour, at which time all bubbling had ceased and the reaction appeared complete by TLC. The crude reaction was concentrated in vacuo, followed by aqueous work-up with 2 N NaOH and DCM. The combined organics were dried over Na2SO4, filtered and concentrated in vacuo to afford benzyl(cis)-3-fluoropiperidin-4-ylcarbamate (4.25 g, 16.8 mmol, 79.2% yield) as a white solid. The crude reaction was concentrated in vacuo The combined organics were dried over Na2SO4 filtered concentrated in vacuo

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

実験手順: (cis)-tert-Butyl 4-(benzyloxycarbonylamino)-3-fluoropiperidine-1-carboxylate (7.5 g, 21.3 mmol) was weighed into a 500 mL 1 neck round bottom and dissolved in 200 mL of DCM, followed by addition of TFA (16.4 mL, 213 mmol) and stirring at ambient temperature for 1 hour, at which time all bubbling had ceased and the reaction appeared complete by TLC. The crude reaction was concentrated in vacuo, followed by aqueous work-up with 2 N NaOH and DCM. The combined organics were dried over Na2SO4, filtered and concentrated in vacuo to afford benzyl(cis)-3-fluoropiperidin-4-ylcarbamate (4.25 g, 16.8 mmol, 79.2% yield) as a white solid. The crude reaction was concentrated in vacuo The combined organics were dried over Na2SO4 filtered concentrated in vacuo

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of methyl 2-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]-2-propenoate (953 mg, 3.63 mmol), cis-phenylmethyl[3-fluoro-4-piperidinyl]carbamate Enantiomer 2 (for a synthesis see WO2004058144, prepared by analogy to Examples 142(b), (c) and (d) from the Enantiomer 2 of Example 142(a)) (1.1 g, 4.35 mmol) and 1,1,3,3-tetramethylguanidine (6 drops) in DMF (3.5 ml) was heated at 80° C. under argon for 3 hours, cooled and evaporated. Chromatography, eluting with 1% methanol/dichloromethane, gave the product in 100% yield. cooled evaporated Chromatography, eluting with 1% methanol/dichloromethane gave the product in 100% yield

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of methyl 2-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]-2-propenoate (953 mg, 3.63 mmol), cis-phenylmethyl[3-fluoro-4-piperidinyl]carbamate Enantiomer 2 (for a synthesis see WO2004058144, prepared by analogy to Examples 142(b), (c) and (d) from the Enantiomer 2 of Example 142(a)) (1.1 g, 4.35 mmol) and 1,1,3,3-tetramethylguanidine (6 drops) in DMF (3.5 ml) was heated at 80° C. under argon for 3 hours, cooled and evaporated. Chromatography, eluting with 1% methanol/dichloromethane, gave the product in 100% yield. cooled evaporated Chromatography, eluting with 1% methanol/dichloromethane gave the product in 100% yield

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

実験手順: (cis)-tert-Butyl 4-(benzyloxycarbonylamino)-3-fluoropiperidine-1-carboxylate (7.5 g, 21.3 mmol) was weighed into a 500 mL 1 neck round bottom and dissolved in 200 mL of DCM, followed by addition of TFA (16.4 mL, 213 mmol) and stirring at ambient temperature for 1 hour, at which time all bubbling had ceased and the reaction appeared complete by TLC. The crude reaction was concentrated in vacuo, followed by aqueous work-up with 2 N NaOH and DCM. The combined organics were dried over Na2SO4, filtered and concentrated in vacuo to afford benzyl (cis)-3-fluoropiperidin-4-ylcarbamate (4.25 g, 16.8 mmol, 79.2% yield) as a white solid. The crude reaction was concentrated in vacuo The combined organics were dried over Na2SO4 filtered concentrated in vacuo

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

実験手順: This was prepared from cis-4-benzyloxycarbonylamino-3-fluoropiperidine Enantiomer 2 (7a) and (R)-2-(6-methoxy-[1,5]-naphthyridin-4-yl)oxirane (20d) (100% ee) by the method of Example (20e).

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

実験手順: (cis)-tert-Butyl 4-(benzyloxycarbonylamino)-3-fluoropiperidine-1-carboxylate (7.5 g, 21.3 mmol) was weighed into a 500 mL 1 neck round bottom and dissolved in 200 mL of DCM, followed by addition of TFA (16.4 mL, 213 mmol) and stirring at ambient temperature for 1 hour, at which time all bubbling had ceased and the reaction appeared complete by TLC. The crude reaction was concentrated in vacuo, followed by aqueous work-up with 2 N NaOH and DCM. The combined organics were dried over Na2SO4, filtered and concentrated in vacuo to afford benzyl(cis)-3-fluoropiperidin-4-ylcarbamate (4.25 g, 16.8 mmol, 79.2% yield) as a white solid. The crude reaction was concentrated in vacuo The combined organics were dried over Na2SO4 filtered concentrated in vacuo

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of methyl 2-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]-2-propenoate (953 mg, 3.63 mmol), cis-phenylmethyl[3-fluoro-4-piperidinyl]carbamate Enantiomer 2 (for a synthesis see WO2004058144, prepared by analogy to Examples 142(b), (c) and (d) from the Enantiomer 2 of Example 142(a)) (1.1 g, 4.35 mmol) and 1,1,3,3-tetramethylguanidine (6 drops) in DMF (3.5 ml) was heated at 80° C. under argon for 3 hours, cooled and evaporated. Chromatography, eluting with 1% methanol/dichloromethane, gave the product in 100% yield. cooled evaporated Chromatography, eluting with 1% methanol/dichloromethane gave the product in 100% yield