(S)-tert-Butyl (3-chloro-2-hydroxypropyl)carbamate → (-)-phenylmethyl 7-[(5S)-5-[[[(1,1-dimethylethoxy)carbonyl]amino]methyl]-2-oxo-3-oxazolidinyl]-3,4-dihydro-2(1H)-isoquinolinecarboxylate

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Reaction Steps

A solution of phenylmethyl 3,4-dihydro-7-[[(phenylmethoxy)carbonyl]amino]-2(1H)-isoquinolinecarboxylate (Step 3, 5.12 g, 12.29 mmol) and tert-butyl (2S)-3-chloro-2-hydroxypropylcarbamate (which can be prepared according to U.S. patent application, serial No. 60/241122, 3.22 g, 15.36 mmol) in dry DMF (5.6 mL) at 0° C. under N2 is treated with LiOtBu (1M in THF, 29.5 mL, 29.5 mmol) dropwise over 5 mins. The cooling bath is removed, and the resulting mixture is stirred at ambient temperature for 18 hrs, quenched with saturated aqueous NH4Cl (25 mL), diluted with H2O (25 mL) and extracted with EtOAc (50 mL). The EtOAc phase is then washed with H2O (2×50 mL) and brine (25 mL), dried over MgSO4 and concentrated under reduced pressure, and the residue is chromatographed on a Flash 40M silica gel (90 g, 32-63 μm) cartridge, eluting with a gradient of EtOAc/heptane (25/75-50/50). Those fractions with an Rf=0.20 by TLC (EtOAc/hexane, 50/50) are pooled and concentrated to give 4.69 g (80%) of the title compound as a white solid, mp 135-137° C. [α]25D=−27° (c 1.00, DMSO).

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