tert-butyl 4-amino-4-benzylpiperidine-1-carboxylate

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:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-benzyl-piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (0.65 mmol) in 1,4-dioxane (2 mL) are added Et3N (0.71 mmol) and DPPA (0.71 mmol) at room temperature. After warming to 100° C. and stirring for 2 h, the reaction mixture is diluted with AcOEt. The organic layer is washed with sat. aq. NaHCO3 and brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue is dissolved in THF (4 mL) and 6N aq. NaOH (0.22 mL) is added at room temperature. After stirring for 4 h, the reaction mixture is diluted with CH2Cl2, washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue is purified by silica gel column chromatography to give the title compound; 1H NMR (CDCl3), δ: 1.18 (2H, bs), 1.28-1.37 (2H, m), 1.46 (9H, s), 1.51-1.64 (2H, m), 2.66 (2H, s), 3.20 (2H, dd), 3.74 (2H, bd), 7.13-7.19 (2H, m), 7.21-7.34 (3H, m). The organic layer is washed with sat. aq. NaHCO3 and brine dried over MgSO4 filtered concentrated in vacuo The residue is dissolved in THF (4 mL) 6N aq. NaOH (0.22 mL) is added at room temperature After stirring for 4 h the reaction mixture is diluted with CH2Cl2 washed with brine dried over MgSO4 filtered concentrated in vacuo The residue is purified by silica gel column chromatography

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

Procedure: To a solution of the 4-amino-4-benzylpiperidine-1-carboxylic acid tert-butyl ester (0.38 mmol, step 66.1) and 2-cyano-4-[(spiro[2.5]oct-6-ylmethyl)amino]pyrimidine-5-carboxylic acid (0.38 mmol) in DMF (1.3 mL) are added HOAt (0.51 mmol) and EDCI-HCl (0.51 mmol) at 0° C. After warming to room temperature and stirring for 15 h, the reaction mixture is diluted with AcOEt and washed with 1N aq. KHSO4, sat. aq. NaHCO3, and brine. The organic layer is dried over MgSO4, filtered, and concentrated in vacuo. The residue is purified by silica gel column chromatography to give 4-benzyl-4-({2-cyano-4-[(spiro[2.5]oct-6-ylmethyl)-amino]-pyrimidine-5-carbonyl}amino)piperidine-1-carboxylic acid tert-butyl ester. washed with 1N aq. KHSO4, sat. aq. NaHCO3, and brine The organic layer is dried over MgSO4 filtered concentrated in vacuo The residue is purified by silica gel column chromatography

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-benzyl-piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (0.65 mmol) in 1,4-dioxane (2 mL) are added Et3N (0.71 mmol) and DPPA (0.71 mmol) at room temperature. After warming to 100° C. and stirring for 2 h, the reaction mixture is diluted with AcOEt. The organic layer is washed with sat. aq. NaHCO3 and brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue is dissolved in THF (4 mL) and 6N aq. NaOH (0.22 mL) is added at room temperature. After stirring for 4 h, the reaction mixture is diluted with CH2Cl2, washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue is purified by silica gel column chromatography to give the title compound; 1H NMR (CDCl3), δ: 1.18 (2H, bs), 1.28-1.37 (2H, m), 1.46 (9H, s), 1.51-1.64 (2H, m), 2.66 (2H, s), 3.20 (2H, dd), 3.74 (2H, bd), 7.13-7.19 (2H, m), 7.21-7.34 (3H, m). The organic layer is washed with sat. aq. NaHCO3 and brine dried over MgSO4 filtered concentrated in vacuo The residue is dissolved in THF (4 mL) 6N aq. NaOH (0.22 mL) is added at room temperature After stirring for 4 h the reaction mixture is diluted with CH2Cl2 washed with brine dried over MgSO4 filtered concentrated in vacuo The residue is purified by silica gel column chromatography

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

Procedure: To a solution of the 4-amino-4-benzylpiperidine-1-carboxylic acid tert-butyl ester (0.38 mmol, step 66.1) and 2-cyano-4-[(spiro[2.5]oct-6-ylmethyl)amino]pyrimidine-5-carboxylic acid (0.38 mmol) in DMF (1.3 mL) are added HOAt (0.51 mmol) and EDCI-HCl (0.51 mmol) at 0° C. After warming to room temperature and stirring for 15 h, the reaction mixture is diluted with AcOEt and washed with 1N aq. KHSO4, sat. aq. NaHCO3, and brine. The organic layer is dried over MgSO4, filtered, and concentrated in vacuo. The residue is purified by silica gel column chromatography to give 4-benzyl-4-({2-cyano-4-[(spiro[2.5]oct-6-ylmethyl)-amino]-pyrimidine-5-carbonyl}amino)piperidine-1-carboxylic acid tert-butyl ester. washed with 1N aq. KHSO4, sat. aq. NaHCO3, and brine The organic layer is dried over MgSO4 filtered concentrated in vacuo The residue is purified by silica gel column chromatography