tert-butyl N-(4-methylpiperidin-3-yl)carbamate

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: To a solution of 2-(3,5-dichlorophenylamino)acetic acid (153 mg, 0.69 mmol) in DMF (5 mL) was added HOBt (141 mg, 1.0 mmol), EDCI (201 mg, 1.0 mmol), tert-butyl 4-methylpiperidin-3-ylcarbamate (150 mg, 0.69 mmol), and DIEA (0.18 mL, 1.3 mmol) at 0° C. Then the reaction mixture was stirred at rt for 5 h, partitioned between EtOAc and water. The organic phase was separated and washed with brine, and concentrated in vacuo to yield the crude product, which was purified by column chromatography using 0-2% MeOH: DCM solvent mixture to yield the titled intermediate (160 mg, 54%) as a thick liquid. 1H NMR (400 MHz, CDCl3): δ 6.92 (s, 1H), 6.49 (s, 1H), 6.38 (s, 1H), 6.29 (s, 1H), 5.22-5.15 (m, 1H), 4.65-4.56 (m, 1H), 4.35-4.16 (m, 2H), 3.25-2.89 (m, 2H), 2.85-2.69 (m, 2H), 1.82-1.75 (m, 2H), 1.69-1.45 (m, 1H), 1.22 and 1.14 (2s, 9H), 1.05 and 0.95 (2d, J=6.8 Hz, 3H). LC-MS: m/z [M+1]=416. partitioned between EtOAc and water The organic phase was separated washed with brine concentrated in vacuo to yield the crude product, which was purified by column chromatography

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

Procedure: To a solution of 2-(3,5-dichlorophenylamino)acetic acid (153 mg, 0.69 mmol) in DMF (5 mL) was added HOBt (141 mg, 1.0 mmol), EDCI (201 mg, 1.0 mmol), tert-butyl 4-methylpiperidin-3-ylcarbamate (150 mg, 0.69 mmol), and DIEA (0.18 mL, 1.3 mmol) at 0° C. Then the reaction mixture was stirred at rt for 5 h, partitioned between EtOAc and water. The organic phase was separated and washed with brine, and concentrated in vacuo to yield the crude product, which was purified by column chromatography using 0-2% MeOH: DCM solvent mixture to yield the titled intermediate (160 mg, 54%) as a thick liquid. 1H NMR (400 MHz, CDCl3): δ 6.92 (s, 1H), 6.49 (s, 1H), 6.38 (s, 1H), 6.29 (s, 1H), 5.22-5.15 (m, 1H), 4.65-4.56 (m, 1H), 4.35-4.16 (m, 2H), 3.25-2.89 (m, 2H), 2.85-2.69 (m, 2H), 1.82-1.75 (m, 2H), 1.69-1.45 (m, 1H), 1.22 and 1.14 (2s, 9H), 1.05 and 0.95 (2d, J=6.8 Hz, 3H). LC-MS: m/z [M+1]=416. partitioned between EtOAc and water The organic phase was separated washed with brine concentrated in vacuo to yield the crude product, which was purified by column chromatography

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

Procedure: Tert-butyl 4-methylpyridin-3-ylcarbamate (200 mg, 0.96 mmol) was dissolved in glacial acetic acid (5 mL) and treated with PtO2 (200 mg, 1:1 w/w) under an atmosphere of hydrogen. The reaction mixture was stirred at rt for 15 h. The reaction mixture was then filtered through a pad of Celite. The filtrate was neutralized with solid NaHCO3, and extracted with EtOAc (5×50 mL). The organic layer was dried over Na2SO4, concentrated in vacuo to yield the titled compound (160 mg, 77%), which was used for next step without further purification. 1H NMR (400 MHz, CDCl3): δ 4.38-4.21 (m, 1H), 3.32-2.81 (m, 3H), 2.63-2.49 (m, 2H), 2.41-2.32 (m, 1H), 1.78-1.56 (m, 3H), 1.59 (s, 9H), 1.05 and 0.98 (2d, J=6.8 Hz, 3H). ES-MS: m/z [M+1]=215. The reaction mixture was then filtered through a pad of Celite extracted with EtOAc (5×50 mL) The organic layer was dried over Na2SO4 concentrated in vacuo

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

Procedure: To a solution of 2-(3,5-dichlorophenylamino)acetic acid (153 mg, 0.69 mmol) in DMF (5 mL) was added HOBt (141 mg, 1.0 mmol), EDCI (201 mg, 1.0 mmol), tert-butyl 4-methylpiperidin-3-ylcarbamate (150 mg, 0.69 mmol), and DIEA (0.18 mL, 1.3 mmol) at 0° C. Then the reaction mixture was stirred at rt for 5 h, partitioned between EtOAc and water. The organic phase was separated and washed with brine, and concentrated in vacuo to yield the crude product, which was purified by column chromatography using 0-2% MeOH: DCM solvent mixture to yield the titled intermediate (160 mg, 54%) as a thick liquid. 1H NMR (400 MHz, CDCl3): δ 6.92 (s, 1H), 6.49 (s, 1H), 6.38 (s, 1H), 6.29 (s, 1H), 5.22-5.15 (m, 1H), 4.65-4.56 (m, 1H), 4.35-4.16 (m, 2H), 3.25-2.89 (m, 2H), 2.85-2.69 (m, 2H), 1.82-1.75 (m, 2H), 1.69-1.45 (m, 1H), 1.22 and 1.14 (2s, 9H), 1.05 and 0.95 (2d, J=6.8 Hz, 3H). LC-MS: m/z [M+1]=416. partitioned between EtOAc and water The organic phase was separated washed with brine concentrated in vacuo to yield the crude product, which was purified by column chromatography

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

Procedure: Tert-butyl 4-methylpyridin-3-ylcarbamate (200 mg, 0.96 mmol) was dissolved in glacial acetic acid (5 mL) and treated with PtO2 (200 mg, 1:1 w/w) under an atmosphere of hydrogen. The reaction mixture was stirred at rt for 15 h. The reaction mixture was then filtered through a pad of Celite. The filtrate was neutralized with solid NaHCO3, and extracted with EtOAc (5×50 mL). The organic layer was dried over Na2SO4, concentrated in vacuo to yield the titled compound (160 mg, 77%), which was used for next step without further purification. 1H NMR (400 MHz, CDCl3): δ 4.38-4.21 (m, 1H), 3.32-2.81 (m, 3H), 2.63-2.49 (m, 2H), 2.41-2.32 (m, 1H), 1.78-1.56 (m, 3H), 1.59 (s, 9H), 1.05 and 0.98 (2d, J=6.8 Hz, 3H). ES-MS: m/z [M+1]=215. The reaction mixture was then filtered through a pad of Celite extracted with EtOAc (5×50 mL) The organic layer was dried over Na2SO4 concentrated in vacuo