Cesium carbonate → HCID 86760987, compound

Participants

Reaction Conditions

Reaction Steps

To methyl 3-{[(1R)-1-(2-chloro-3-hydroxyphenyl)ethyl]oxy}-5-{6-[(methylsulfonyl)methyl]-1H-benzimidazol-1-yl}-2-thiophenecarboxylate (Intermediate 23, 0.050 g, 0.095 mmol) in dimethylformamide (5 mL) was added 1,1-dimethylethyl (2S)-2-({[(4-methylphenyl)sulfonyl]oxy}methyl)-1-pyrrolidinecarboxylate (which may be prepared using literature reference: Tetrahedron Lett, 1991, 47, 7179-7184) (0.053 g, 0.14 mmol), and Cs2CO3 (0.046 g, 0.14 mmol). The mixture was heated in a sealed tube to 60° C. for 24 h and then cooled to rt. The DMF was evaporated under reduced pressure and the residue was purified by flash column chromatography (0 to 50% EtOAc:DCM) to afford 0.050 g (0.071 mmol) of 1,1-dimethylethyl (2S)-2-{[(2-chloro-3-{(1R)-1-[(2-[(methyloxy)carbonyl]-5-{6-[(methylsulfonyl)methyl]-1H-benzimidazol-1-yl}-3-thienyl)oxy]ethyl}phenyl)oxy]methyl}-1-pyrrolidinecarboxylate which was then dissolved in DCM (5 mL) and TFA (1.0 mL, 5.9 mmol) was added. After 1 h the volatiles were evaporated under reduced pressure and the residue was dissolved in 10 mL of DCM and 1 g of MP-Carbonate resin was added to remove excess TFA. After 30 min the resin was removed by filtration and the volatiles were evaporated under reduced pressure to afford 0.040 g (0.068 mmol) of methyl 3-{[(1R)-1-(2-chloro-3-{[(2S)-2-pyrrolidinylmethyl]oxy}phenyl)ethyl]oxy}-5-{6-[(methylsulfonyl)methyl]-1H-benzimidazol-1-yl}-2-thiophenecarboxylate which was then dissolved in DCM/MeOH (3:2) (5 mL). Formaldehyde was added (0.037 g, 1.23 mmol), followed by sodium triacetoxy borohydride (0.025 g, 0.122 mmol) and the mixture stirred at rt for 30 min. The volatiles were evaporated under reduced pressure and the residue was dissolved in 7 N ammonia In MeOH (10 mL). The mixture was heated in a sealed tube to 80° C. for 40 h and then cooled to rt. Silica (1 g) was added, the volatiles were evaporated under reduced pressure and the residue was purified by flash column chromatography (0 to 100% 80/20/1 DCM/MeOH/ammonium hydroxide:DCM) to give 0.024 g (0.04 mmol) of the title compound as a yellow solid. 1H NMR (400 MHz, DMSO): δ 8.60 (s, 1H), 7.84 (s, 1H), 7.78 (d, J=8.23 Hz, 1H), 7.73 (s, 1H), 7.36 (m, 2H), 7.20 (t, J=3.93 Hz, 2H), 7.10 (m, 2H), 5.95 (q, J=6.22 Hz, 1H), 4.61 (m, 2H), 4.00-3.85 (m, 2H), 2.87 (br s, 4H), 2.58 (m, 1H), 2.34 (s, 3H), 2.15 (m, 1H), 1.92 (m, 1H), 1.71 (d, 3H) 1.67-1.52 (m, 3H); MS (ESI): 603 [M+H]+.

Provenance & Evidence