4-Methylmorpholine → N-[(1S)-3-hydroxy-1-phenylpropyl]-1,3-thiazolidine-2-carboxamide

Participants

Reaction Conditions

Reaction Steps

N-methyl morpholine (NMM) (3.24 g, 2.5 eq, 32.15 mmol) was added to a solution of a compound of general formula (VIII) (Intermediate 8, 4.50 g, 1 eq, 12.86 mmol), e.g., 3-([1,1′-biphenyl]-4-ylsulfonyl)-1,3-thiazolidine-2-carboxylic acid, in dry THF (100 ml) and the reaction mixture was cooled down to −25° C. To the reaction mixture was then added drop wise, over a period of 5 minutes, isobutyl chloroformate (1.84 g, 1.05 eq, 13.50 mmol) in solution in dry THF (20 ml). The resulting mixture was stirred at −25° C. for 30 minutes, after which time an amine of general formula (IV) or (IV*) (commercial or Intermediate 2, 2.14 g, 1.1 eq, 14.15 mmol), e.g., (3S)-3-amino-3-phenyl-1-propanol, was added in dry THF (20 ml) over a period of 5 minutes. The mixture was allowed to gradually warm to room temperature and stirred overnight at room temperature. The solvent was removed and the residue re-dissolved in ethyl acetate (200 ml). The organic layer was washed subsequently with a saturated solution of ammonium chloride (100 ml), saturated bicarbonate (100 ml) and brine (100 ml). The combined organic phases were dried with magnesium sulfate and concentrated in vacuo, yielding the crude product of general formula ([), e.g., 3-(1,1′-biphenyl]-4-ylsulfonyl)-N-[(1S)-3-hydroxy-1-phenylpropyl]-1,3-thiazolidine-2-carboxamide, as a white solid (6.21 g, 96%). Silica gel chromatography, eluting in isocratic conditions (50% ethyl acetate in hexanes), which gave the separation of the desired two pure diastereoisomers of general formula (I), e.g., (2S)-3-([1,1′-biphenyl]-4-ylsulfonyl)-N-[(1S)-3-hydroxy-1-phenylpropyl]-1,3-thiazolidine-2-carboxamide (more polar compound, 3.1 g), and (2R)-3-([1,1′-biphenyl]-4-ylsulfonyl)-N-[(1S)-3-hydroxy-1-phenylpropyl]-1,3-thiazolidine-2-carboxamide (less polar compound, 3.0 g).

Provenance & Evidence