Reaction Steps
To a suspension of alpha-methyl-DL-phenylalanine (2.00 g, 11.2 mmol) in conc. HCl (30 mL) was added formaldehyde (37%, 4.0 mL, 4.36 g, 4.81 mmol) and the resulting suspension was stirred at 60° C. for 48 h. The precipitated solid was collected and dried in vacuo to give 1.02 g (40%) of 3-methyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid hydrochloride. 1H NMR (400 MHz, CD3OD): δ 7.33-7.24 (m, 4H), 4.53 (d, J=16.8 Hz, 1H), 4.42 (d, J=16.0 Hz, 1H), 3.43 (d, J=17.6 Hz, 1H), 3.18 (d, J=17.2 Hz, 1H), 1.67 (s, 3H); LC-MS (EI) m/z: 192.0 (M+H+). Using the same method as for VP-2851, 3-methyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid hydrochloride (1.01 g, 4.436 mmol) was converted to yield methyl 7-amino-3-methyl-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate hydrochloride (600 mg, 38% yield, 2 steps) as a grey solid. 1H NMR (400 MHz, CD3OD): δ 7.48 (d, J=7.6 Hz, 1H), 7.38 (s, 1H), 7.37 (dd, J=8.0, 2.4 Hz, 1H), 4.83 (d, J=15.2 Hz, 1H), 4.78 (d, J=15.2 Hz, 1H), 3.63 (s, 3H), 3.27 (d, J=14.8 Hz, 1H), 3.15 (d, J=14.4 Hz, 1H), 1.51 (s, 3H); LC-MS (EI) m/z: 317.0 (M+H+). Using general method M, methyl 7-amino-3-methyl-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate hydrochloride (0.600 g, 1.70 mmol) and pivaloylacetonitrile (0.21 g, 1.7 mmol) were combined to afford methyl 7-(5-amino-3-t-butyl-1H-pyrazol-1-yl)-3-methyl-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (240 mg, 30% yield) as a yellow foam. LC-MS (EI) m/z: 439.0 (M+H+).
