Triphenylphosphine → Methyl 2-{4-[(tert-butoxycarbonyl)amino]butoxy}-6-hydroxybenzoate

Participants

Reaction Steps

(2RS)-(4-{2-Benzenesulfonylamino-2-[4-(2-methoxycarbonyl-3-hydroxy-phenoxy)butylcarbamoyl]ethyl}-2-bromophenyl)difluoromethylphosphonic acid diethyl ester (Compound 3A) was prepared from the sulfonamide acid obtained in Example 2B following a procedure similar to Example 2C except that 2-(4-amino-butoxy)-6-hydroxybenzoic acid methyl ester was used instead of phenbutylamine. The 2-(4-amino-butoxy)-6-hydroxy-benzoic acid methyl ester was prepared by taking a solution of 2,6-dihydroxymethylbenzoate (1.0 g, 5.95 mmol), 1.5 equivalents N-Boc aminobutanol and 1.5 equivalents of triphenylphosphine (2.34 g, 8.93 mmol) in 40 mL of CH2Cl2 and adding 1.5 equivalents of DIAD (1.80 g, 8.93 mmol). Stirring continued for 1.5 hours at room temperature. Evaporation to dryness followed by column chromatography (30% EtOAc/hexanes) gave 2-(4-tert-butoxycarbonylamino-butoxy)-6-hydroxy-benzoic acid methyl ester. This compound was cooled to 0° C. in an ice/brine bath. HCl gas was bubbled into the solution for 2 minutes and stirring was continued for 1 hour. Evaporation to dryness followed by precipitation with ether and filtration gave 2-(4-aminobutoxy)-6-hydroxybenzoic acid methyl ester as the HCl salt. Compound 3 was prepared from Compound 3A following the procedures in Example 2D. MS (ion spray):m/z 733.4/735.4 (M−H). 1H NMR: (DMSO-d6, 400 MHz) δ 9.91 (br s, 1H), 8.15 (d, 1H, J=9.2 Hz), 7.94 (br s, 1H), 7.55 (d, 2H, J=8.0 Hz), 7.46 (m, 5H), 7.21 (d, 1H, J=8.0 Hz), 7.15 (t, 1H, J=8.0 Hz), 6.47 (m, 2H), 3.95 (m, 1H), 3.85 (m, 2H), 3.72 (s, 3H), 2.85 (m, 3H), 2.65 (m, 1H), 1.49 (m, 2H), 1.35 (m, 2H).

Provenance & Evidence