反应详情

3-Amino-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (Pharmacore, or may be prepared using analogous methodology described for the preparation of 4-Amino-1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid in J. Org. Chem. 1996, 61, 7650-7651, 0.221 g, 0.906 mmol) and molecular sieves 4 Å (ca. 200 mg) were added to a rapidly stirred suspension of 4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazoline-6-carbaldehyde (0.20 g, 0.604 mmol) in a mixture of 5% v/v acetic acid in dichloromethane (2 ml). Sodium triacetoxyborohydride (0.192 g, 0.906 mmol) was added over a period of 3 hours. The reaction mixture was concentrated, dissolved in dichloromethane (1 ml) and treated with trifluoroacetic acid (1 ml). The reaction mixture was stirred for 1 hour at room temperature, concentrated and purified by preparative LCMS (acidic hydrophilic system) to afford the intermediate 3-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)amino]piperidine-3-carboxylic acid as a white foam; Mass Spectrum: (M+H)+ 560. The foam was dissolved in aqueous formaldehyde (1 ml) and acetic acid (0.1 ml) was added followed by sodium cyanoborohydride (100 mg) at 0° C. The reaction mixture was purified directly by preparative LCMS (acidic system) to give 3-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]-1-methylpiperidine-3-carboxylic acid (0.03 g, 10.2%) as a white foam; Mass Spectrum: (M+H)+ 488.

1. concentrationThe reaction mixture was concentrated
2. dissolutiondissolved in dichloromethane (1 ml)
3. additiontreated with trifluoroacetic acid (1 ml)
4. concentrationconcentrated
5. custompurified by preparative LCMS (acidic hydrophilic system)