Ammonia → methyl 4-[(1S)-1-[[(3R)-2-(2-phenoxyethyl)-3,4-dihydro-1H-isoquinoline-3-carbonyl]amino]ethyl]benzoate

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Reaction Steps

To a stirring mixture of silica gel (200 g, 3.33 mol) and dichloromethane (1100 mL) at 22° C., add a solution of sodium periodate (56.2 g, 260 mmol) in water (352 mL) in a dropwise fashion. After the end of the addition, stir the mixture for an additional 30 minutes, then add 3-phenoxyl-1,2-propanediol (34.5 g, 195 mmol), resulting in a slight exotherm. Stir the mixture for an additional 30 minutes, then filter to remove the solids, discard the aqueous layer, and dry the organic layer over MgSO4, filter to remove the solids, and treat the filtrate with methyl 4-[(1S)-1-[[(3R)-1,2,3,4-tetrahydroisoquinoline-3-carbonyl]amino]ethyl]benzoate (44 g, 130 mmol). Then, add sodium triacetoxyborohydride (57.4 g, 260 mmol) in small portions. Upon completion of the addition, stir the mixture for one additional hour, then add water (200 mL). Add a 32% aqueous ammonia solution until the pH of the aqueous layer reaches 10. Separate the layers, dry the organic layer over MgSO4, filter to remove the solids, and concentrate the filtrate under reduced pressure. Dissolve the resulting crude oil in TBME (300 mL), then add water (250 mL) and 1 M aqueous hydrochloric acid (200 mL). Stir the resulting slurry for 30 minutes, concentrate under reduced pressure to remove the TBME, and isolate the resulting white precipitate by filtration. Pour this precipitate into a stirring mixture of water (400 mL) and TBME (400 mL), and add a 32% aqueous ammonia solution until the pH of the aqueous layer reaches 10. Remove the aqueous layer, and wash the organic layer with a saturated aqueous sodium chloride solution (200 mL). Isolate the organic layer, dry over MgSO4, filter to remove the solids, and concentrate under reduced pressure. Subject the resulting crude material to flash chromatography on silica gel using a 30% to 70% EtOAc/hexanes gradient. Consolidate the fractions containing the product, and concentrate them under reduced pressure to furnish the title compound as a white solid (44 g, 74% yield). Mass spectrum (m/z): 459 ([M+H]+).

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