3-(Tert-butyldimethylsilyloxy)-2,2-dimethylpropyl methanesulfonate → tert-butyl (2S,4S)-4-{[6-bromo-2-(3-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylpropyl)-1-oxo-1,2-dihydroisoquinolin-4-yl]sulfanyl}-2-({[tert-butyl(diphenyl)silyl]oxy}methyl)piperidine-1-carboxylate

Participants

Reaction Steps

tert-Butyl (2S,4S)-4-[(6-bromo-1-oxo-1,2-dihydroisoquinolin-4-yl)sulfanyl]-2-({[tert-butyl(diphenyl)silyl]oxy}methyl)piperidine-1-carboxylate (Example 67e, 0.68 g) and 3-(tert-butyldimethylsilyloxy)-2,2-dimethylpropyl methanesulfonate (0.315 g) were reacted by the method of Example 58c to afford crude tert-butyl (2S,4S)-4-{[6-bromo-2-(3-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylpropyl)-1-oxo-1,2-dihydroisoquinolin-4-yl]sulfanyl}-2-({[tert-butyl(diphenyl)silyl]oxy}methyl)piperidine-1-carboxylate (0.87 g) as a colourless oil. This was reacted with N-cyclopropyl-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.306 g) by the method of Example 58d to afford tert-butyl (2S,4S)-4-({2-(3-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylpropyl)-6-[5-(cyclo-ropylcarbamoyl)-3-fluoro-2-methylphenyl]-1-oxo-1,2-dihydroisoquinolin-4-yl}sulfanyl)-2-({[tert-butyl(diphenyl)silyl]oxy}methyl)piperidine-1-carboxylate as a colourless oil. This was diluted in ethanol (3 mL) and treated with 4M HCl in dioxane (1 mL) and stirred at room temperature for 20 h. The volatiles were removed in vacuo. The crude material was dissolved in methanol (2 mL) and loaded on to a 10 g SCX cartridge. The impurities were washed through with methanol (50 mL) and discarded. The product was eluted with 1N methanolic ammonia (75 mL) and the solvents evaporated in vacuo. Purification by preparative HPLC (Gemini-NX C18 column using a 95-5% gradient of aqueous 0.1% ammonia in methanol as eluent) afforded the title compound (32 mg) as a white solid.

Provenance & Evidence