Acetic Acid → Methyl 4-[(2R)-2-({[(2S)-2-hydroxy-3-phenoxypropyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoate

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Reaction Steps

To a solution of anhydrous DMSO (0.839 mmol, 2.5 eq.) in CH2Cl2 (4 mL) at −78° C. was added oxalyl chloride (2M in CH2Cl2, 0.536 mmol, 1.6 eq.) dropwise by syringe. The resulting mixture was stirred at −78° C. for 10 minutes before a solution of methyl 4-[(2R)-2-(hydroxymethyl)-3,4-dihydro-2H-chromen-6-yl]benzoate (Example 62, 0.335 mmol, 1.0 eq.) in CH2Cl2 (4 mL) was added very slowly by syringe. The resulting reaction mixture was stirred at −78° C. for 2 hours, at which time triethylamine (2.01 mmol, 6.0 eq.) was added. The cooling bath was removed and the reaction mixture was allowed to warm to room temperature (about 10 minutes). To the resulting crude aldehyde was added (2S)-1-amino-3-phenoxy-2-propanol (0.67 mmol, 2.0 eq.) in a single portion followed by acetic acid (6.03 mmol, 18.0 eq.). The resulting mixture was stirred for 5 minutes before sodium triacetoxyborohydride (1.005 mmol, 3.0 eq.) was added in a single portion. The reaction mixture was stirred at room temperature for 3 hours. The triacetoxyborohydride was quenched by the addition of 1N NaOH until the pH reached 9-10. The resulting two-phase mixture was extracted with CH2Cl2. The organic extracts were dried over sodium sulfate, concentrated and purified by medium pressure column chromatography (Biotage 40S normal phase silica gel column, CH2Cl2 to CH2Cl2:MeOH=100:3). The product was obtained as a pale yellow solid in 99% yield (two steps). MH+=448.3, retention time (LC-MS)=2.46 min.

Provenance & Evidence