Sodium Carbonate → (E)-tert-butyl 4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-(2-cyclohexylvinyl)thiazol-5-ylcarbamate

Participants

Reaction Conditions

Reaction Steps

A mixture of tert-butyl 4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-bromothiazol-5-ylcarbamate (0.203 g, 0.33 mmol), Na2CO3 (70 mg, 0.66 mmol) and trans-(2-cyclohexylvinyl)boronic acid (0.102 g, 0.66 mmol) in DME (1.5 mL) and water (0.5 mL) was degassed by gently bubbling nitrogen through the mixture for 15 min. [1,1′-Bis(diphenylphosphino)ferrocene]dichloro-palladium(II) (27 mg, 0.033 mmol) was then added and the mixture degassed for a further 10 min before being heated in a microwave at 130° C. for 45 min. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic extracts were passed through a phase separator cartridge and concentrated under reduced pressure. The residue was purified via silica gel column chromatography (0-100% EtOAc/isohexane) to afford (E)-tert-butyl 4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-(2-cyclohexylvinyl)thiazol-5-ylcarbamate as a brown gum (0.144 g, 68%). A solution of this gum (0.142 g, 0.22 mmol) in MeOH (5 mL) and acetic acid (0.5 mL) was passed through the H-Cube® (70 bar, 70° C., flow rate: 1 mL/min, 30 mm 10% Pd/C cartridge). The solvent was removed under reduced pressure to afford crude tert-butyl 4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-(2-cyclohexylethyl)thiazol-5-ylcarbamate as a clear gum (0.122 g, 99%). This gum (0.122 g, 0.188 mmol) was stirred in HCl in 1,4-dioxane (4.0 M, 2 mL) at room temperature for 18 hr. The solvents were removed under reduced pressure and the crude residue was re-dissolved in MeOH and loaded onto an SCX column. The column was washed with MeOH and 7N ammonia in MeOH to yield 281 as a pink solid (39 mg, 63%). 1H NMR (400 MHz, d4-MeOD) δ 7.43 (s, 1H), 3.71 (s, 3H), 3.21-3.06 (m, 4H), 2.86 (t, J=7.8 Hz, 2H), 2.62 (d, J=6.6 Hz, 2H), 1.87-1.59 (m, 9H), 1.58-1.45 (m, 1H), 1.43-1.15 (m, 6H), 0.99 (q, J=11.9 Hz, 2H). LCMS (ES+) m/z 446 (M+1)

Provenance & Evidence