1-(Benzyloxy)-2-bromobenzene → HCID 22622324, compound

Participants

Reaction Steps

2-Benzyloxybromobenzene (242.3 g) was reacted with 1-benzyloxycarbonyl-4-piperidone (214.7 g) according to the method described for Example 2e to afford 4-hydroxy-4-(2-benzyloxyphenyl)-N-Cbz-piperidine (226.75 g) after extraction and chromatography using 10-30% ethyl acetate in hexanes. 1H NMR (300 MHz, CDCl3) δ 7.40-7.21 (m, 12H), 6.98 (m, 2H), 5.12 (s, 4H), 4.11 (br s, 3H), 3.35 (br s, 2H), 2.03 (br s, 4H). A sample of this material (235 g) was reacted with triethylsilane (405 mL) and trifluoroacetic acid (195 mL) according to the method described for Example 2f. Following extraction and chromatography (10-25% ethyl acetate in hexane), residual triethylsilane was removed by distillation (50-60° C., 800-900 millitorr) to afford 4-(2-benzyloxyphenyl)-N-Cbz-piperidine (179.3 g). A solution of this material (4.01 g) in ethanol (60 mL) was shaken for 24 h with palladium hydroxide on carbon [Pearlman's catalyst] (2.2 g) under hydrogen (50 psi). The catalyst was removed by filtration, the filtrate was concentrated and triturated with acetone to afford 4-(2-hydroxyphenyl)-piperidine (0.75 g) as a white powder. 1H NMR (300 MHz, DMSO-d6) δ 8.49 (s, 1H), 7.02 (m, 2H), 6.82 (d, 1H), 6.72 (t, 1H), 3.20 (br d, 2H), 3.02 (m, 1H), 2.85 (tt, 2H), 1.74 (m, 4H). Using standard reductive amination conditions N-[2-(S)-(3,4-dichlorophenyl)]-4-oxobutyl-N-methyl-3-cyano-1-naphthamide (0.213 g) was reacted with 4-(2-hydroxyphenyl)-piperidine to afford N-[(S)-2-(3,4-dichlorophenyl)-4-[4-[2-hydroxyphenyl]-1-piperidinyl]butyl]-N-methyl-3-cyano-1-naphthamide.

Provenance & Evidence