Thionyl Chloride → 9-(4-fluorobenzyl)-3-(hydroxymethyl)-2-methyl-4-(p-tolyl)-2,9-dihydro-1H-pyrido[3,4-b]indol-1-one

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Reaction Conditions

Reaction Steps

A mixture of methyl 9-(4-fluorobenzyl)-2-methyl-1-oxo-4-(p-tolyl)-2,9-dihydro-1H-pyrido[3,4-b]indole-3-carboxylate (625 mg, 1.375 mmol) in Methanol (10 mL) and Tetrahydrofuran (THF) (10.00 mL) was treated with 2M LiOH (20 mL, 40.0 mmol) and then refluxed overnight. The mixture was cooled to 0° C., treated with HCl (1M) until pH<2 and then filtered to afford 9-(4-fluorobenzyl)-2-methyl-1-oxo-4-(p-tolyl)-2,9-dihydro-1H-pyrido[3,4-b]indole-3-carboxylic acid as a white solid (595 mg, 1.35 mmol, 98% yield). A suspension of 9-(4-fluorobenzyl)-2-methyl-1-oxo-4-(p-tolyl)-2,9-dihydro-1H-pyrido[3,4-b]indole-3-carboxylic acid (595 mg, 1.35 mmol) in thionyl chloride (10 mL, 137 mmol) was heated at 70° C. for 2 hours and then concentrated. The residue was dissolved in Tetrahydrofuran (THF) (10.00 mL), treated with sodium borohydride (520 mg, 13.75 mmol) and then heated at 70° C. for 2 hours. Additional NaBH4 (15 eq.) was added and then mixture was heated at 70° C. overnight. The mixture was concentrated, treated with NH4Cl (sat. aq) slowly at 0° C. and then extracted with ethyl acetate. The combined extracts were dried over Na2SO4, filtered and concentrated to afford 9-(4-fluorobenzyl)-3-(hydroxymethyl)-2-methyl-4-(p-tolyl)-2,9-dihydro-1H-pyrido[3,4-b]indol-1-one (520 mg, 1.22 mmol, 90% yield) as a white solid which was used in the next step without any further purification. 1H NMR (400 MHz, CHLOROFORM-d) ppm 7.30-7.44 (m, 7H) 7.19-7.27 (m, 3H) 6.95 (s, 4H) 6.62-6.70 (m, 1H) 6.14 (s, 3H) 4.57 (s, 2H) 3.92 (s, 3H) 2.52 (s, 3H); LCMS (m/z) ES+=427 (M+1).

Provenance & Evidence