Trifluoromethanesulfonic acid → 5-chloro-pyridine-2-carboxylic acid (rel-(4aS,11bS)-2-amino-11b-methyl-4,4a,5,6,7,11b-hexahydro-3-thia-1-aza-dibenzo[a,c]cyclohepten-10-yl)-amide, 2,2,2-trifluoroacetate salt

Participants

Reaction Steps

To a solution of (E)-5-chloro-N-(8-(chloromethyl)-9-methyl-6,7-dihydro-5H-benzo[7]annulen-2-yl)picolinamide from step 3C (30 mg, 0.083 mmol) in ethanol (0.5 mL) was added thiourea (6.32 mg, 0.083 mmol). The mixture was heated to reflux for 3 h. The solvent was removed to give crude (2-(5-chloropicolinamido)-9-methyl-6,7-dihydro-5H-benzo[7]annulen-8-yl)methyl carbamimidothioate hydrochloride (36.3 mg, 0.083 mmol, 100% yield), which was used directly for the next step without purification. To a solution of the crude (2-(5-chloropicolinamido)-9-methyl-6,7-dihydro-5H-benzo[7]annulen-8-yl)methyl carbamimidothioate hydrochloride (36 mg, 0.082 mmol) in TFA (2 mL) was added trifluoromethanesulfonic acid (0.5 mL). The reaction mixture was stirred at rt for 16 h. The mixture was then concentrated and dried by azetropic distillation with toluene. The residue was then dissolved in 1.5 mL of MeOH, and a precipitate was removed by filtration. The mother liquor was purified via HPLC under standard conditions to give 5-chloro-pyridine-2-carboxylic acid (rel-(4aS,11bS)-2-amino-11b-methyl-4,4a,5,6,7,11b-hexahydro-3-thia-1-aza-dibenzo[a,c]cyclohepten-10-yl)-amide, 2,2,2-trifluoroacetate salt (16 mg, 0.030 mmol, 36% yield). LCMS (M+H)+=401.2. 1H NMR (500 MHz, methanol-d4) δ 8.72 (br. s., 1H), 8.21 (br. s., 1H), 8.08 (dd, J=8.4, 2.0 Hz, 1H), 7.90 (d, J=2.1 Hz, 1H), 7.58 (dd, J=8.1, 2.1 Hz, 1H), 7.28 (d, J=8.1 Hz, 1H), 3.22-3.10 (m, 1H), 2.99-2.80 (m, 3H), 2.57-2.40 (m, 2H), 2.10 (dd, J=14.7, 3.7 Hz, 1H), 1.90 (dd, J=14.5, 3.5 Hz, 1H), 1.87 (s, 3H), 1.64-1.52 (m, 1H)

Provenance & Evidence