3-(trifluoroMethyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine hydrochloride synthesis

Yield: 86.7%

Reaction Conditions:

with hydrogen;palladium on activated charcoal in methanol at 20 - 25; under 1125.11 Torr; for 3 - 4 h;

Steps:

4.1
4.1. Synthesis of 3-trifluoromethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-6-ium Chloride An autoclave was charged with a suspension of 6-benzhydryl-3-trifluoromethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine hydrochloride salt (150 g, 383.8 mmol), Pd/C (7.5 g) and methanol (0.5 L). The suspension was stirred at RT. The autoclave was sealed, the hydrogen pressure set at 1.5 bar (absolute) and the hydrogenation was conducted with stirring at 20-25° C. for 3-4 h. The autoclave was vented, the suspension filtered and the black residue was rinsed twice with methanol (0.5 L, total of 1 L). The filtrate was evaporated at 60° C. under reduced pressure to yield 152.3 g of crude 3-trifluoromethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-6-ium chloride as brown residue. The clear yellow solution of 152.3 g crude product 3-trifluoromethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-6-ium chloride in methanol (200 mL) was diluted with 600 mL EtOAc and the solvent was concentrated at 60° C. under reduced pressure (335-250 mbar) to a total volume of 500 mL. Methanol was exchanged at 60° C., keeping the volume constant under reduced pressure by the addition of 3.5 l EtOAc. The resulting suspension was treated at 60° C. with toluene (125 mL), stirred for 15 min and methanol (50 mL) was added. After stirring for 15 min at 60° C. the suspension was cooled over 1 h to RT and stirred for 1 h. The crystals were filtered and rinsed with a mixture of EtOAc (300 mL), toluene (10 mL) and methanol (10 mL) then dried at 60° C. and <10 mbar for 2 h and overnight at RT to afford 74.8 g (86.7%) of 3-trifluoromethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-6-ium chloride as a beige powder: MS (EI): 189 (M+H⁺, 100).

References:

Roche Palo Alto LLC US2009/143589, 2009, A1 Location in patent:Page/Page column 8-9