4-Amino-1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid → 3-[({4-[(3-Chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)amino]piperidine-3-carboxylic acid

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)

ORD record

ord-d19e0422f9e8461daaa0be2711045de6

Source dataset

uspto-grants-2009_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07632840B2