Trifluoroacetic acid → (+/-)-trans 2-(2,4-dichlorophenyl)-5,6,8,8a,9,10,11,11a-octahydro-4H-pyrido[3,2,1-ij]pyrrolo[3,4-c]quinoline

Participants

Reaction Steps

A solution of (±)-trans tert-butyl 2-bromo-5,6,8a,9,11,11a-hexahydro-4H-pyrido[3,2,1-ij]pyrrolo[3,4-c]quinoline-10(8H)-carboxylate from EXAMPLE 7, Part A (55 mg, 0.139 mmol), Ba(OH)2-8 H2O (70 mg, 0.222 mmol), and 2,4-dichlorophenyl boronic acid (35 mg, 0.181 mmol) in DME (3 mL) and water (2 mL) were degassed with argon at near reflux temperature. The solution was cooled to rt, and a mixture of solid PPh3 (5.5 mg, 20.9 mmol) and Pd(PPh3)2Cl2 (5 mg, 6.95 μmol) was added in a single portion. The solution was stirred at reflux under a positive pressure of argon for 4 h. After the starting bromide was consumed, the DME was removed under reduced pressure. The residue was diluted with EtOAc and washed with water followed by brine. The organic layer was dried over Na2SO4, and evaporated under reduced pressure to a golden oil (80 mg crude weight). The crude product was purified on a Redipak (5 g) silica column using a gradient elution of 5%-33% EtOAc in hexanes. Evaporation of the fractions containing product as identified by TLC gave N-Boc protected biaryl intermediate as a white foam (44 mg, 69%). The N-Boc protected indoline (44 mg, 95.8 μmol) was dissolved into CH2Cl2 (9.0 mL) and cooled to 0° C. under N2. Neat trifluoroacetic acid (TFA) was added via syringe in a single portion to the stirred, cooled solution. The reaction was stirred at 0° C. for 2 h and followed by TLC analysis. When all of the N-Boc protected material had been consumed, the solution was basified to pH>10 with 3 N NaOH. The product was extracted into CH2Cl2, washed with brine, and dried over Na2SO4. The solvent was evaporated under reduced pressure to give crude free-base. The crude free-base was purified by semi-preparative HPLC (Dynamax 60 Å, C-18) using an isocratic mobile phase of 50:50:0.05 v/v/v water:acetonitrile:TFA. The title compound of EXAMPLE 34 was obtained as a yellow semi-solid (26 mg, 76%). 1H NMR (500 MHz, CDCl3) δ 0.88 (m, 1H), 1. 26 (broad s, 2H), 1.91-1.94 (m, 1H), 2.00-2.06 (m, 1H), 2.28 (m, 1H), 2.72 (broad s, 1H), 2.95 (m, 1H), 3.0-3.5 (m, 4H), 3.59 (m, 2H), 3.83 (broad s, 1H), 6.68 (s, 1H), 6.91 (s, 1H), 7.21 (m, 2H), 7.42 (s, 1H). LRMS (ES)+: 359 (M+H)+.

Provenance & Evidence