A comparative study on the acylative kinetic resolution of racemic fluorinated and non-fluorinated 2-methyl-1,2,3,4-tetrahydroquinolines and 3,4-dihydro-3-methyl-2H-[1,4]benzoxazines

The acylative kinetic resolution of racemic 6-fluoro-2-methyl-1,2,3,4-tetrahydroquinoline, 7,8-difluoro-3,4-dihydro-3-methyl-2H-[1,4]benzoxazine, and their non-fluorinated analogues with (S)-naproxen and N-phthaloyl-(S)-amino acyl chlorides has been carried out. It has been shown that the presence of fluorine atoms in the aromatic fragment of a heterocyclic amine results in the increasing stereoselectivity of acylation with (S)-naproxen acyl chloride and in a decrease in the efficiency of acylative kinetic resolution using N-phthaloyl-(S)-amino acyl chlorides. A method for the preparation of enantiopure (S)-6-fluoro-2-methyl-1,2,3,4-tetrahydroquinoline (ee >99%) was developed.

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(2R)-6-Fluoro-2-methyl-N-[N′-phthaloyl-(S)-phenylalanyl]-1,2,3,4-tetrahydroquinolineC27H23FN2O3[α]D20=-311 (c 0.5, CHCl3)Source of chirality: N-Phthaloyl-(S)-phenylalanineAbsolute configuration: (2R,2′S)

(2S)-6-Fluoro-2-methyl-N-[N′-phthaloyl-(S)-phenylalanyl]-1,2,3,4-tetrahydroquinolineC27H23FN2O3[α]D20=+346 (c 1.0, CHCl3)Source of chirality: N-Phthaloyl-(S)-phenylalanineAbsolute configuration: (2S,2′S)

(2S)-6-Fluoro-N-[(2S)-2-(6-methoxynaphth-2-yl)-propanoyl]-2-methyl-1,2,3,4-tetrahydroquinolineC24H24FNO2[α]D20=+58.0 (c 1.0, CHCl3)Source of chirality: (S)-NaproxenAbsolute configuration: (2S,2′S)

(3S)-7,8-Difluoro-3,4-dihydro-3-methyl-N-(N′-phthaloyl-(S)-phenylalanyl)-2H-[1,4]benzoxazineC26H20F2N2O4[α]D20=+280 (c 1.0, CHCl3)Source of chirality: N-Phthaloyl-(S)-phenylalanineAbsolute configuration: (3S,2′S)

(3R)-7,8-Difluoro-3,4-dihydro-3-methyl-N-(N′-phthaloyl-(S)-phenylalanyl)-2H-[1,4]benzoxazineC26H20F2N2O4[α]D20=-391 (c 1.0, CHCl3)Source of chirality: N-Phthaloyl-(S)-phenylalanineAbsolute configuration: (3R,2′S)

(2S)-6-Fluoro-2-methyl-N-[N′-phthaloyl-(S)-leucyl]-1,2,3,4-tetrahydroquinolineC24H25FN2O3[α]D20=+387 (c 1.0, CHCl3)Source of chirality: N-Phthaloyl-(S)-leucineAbsolute configuration: (2S,2′S)

(2R)-6-Fluoro-2-methyl-N-[N′-phthaloyl-(S)-leucyl]-1,2,3,4-tetrahydroquinolineC24H25FN2O3[α]D20=-176 (c 1.0, CHCl3)Source of chirality: N-Phthaloyl-(S)-leucineAbsolute configuration: (2R,2′S)

(3S)-7,8-Difluoro-3,4-dihydro-3-methyl-N-(N′-phthaloyl-(S)-leucyl)-2H-[1,4]benzoxazineC23H22F2N2O4[α]D20=+279 (c 1.0, CHCl3)Source of chirality: N-Phthaloyl-(S)-leucineAbsolute configuration: (3S,2′S)

(3R)-7,8-Difluoro-3,4-dihydro-3-methyl-N-(N′-phthaloyl-(S)-leucyl)-2H-[1,4]benzoxazineC23H22F2N2O4[α]D20=-217 (c 1.0, CHCl3)Source of chirality: N-Phthaloyl-(S)-leucineAbsolute configuration: (3R,2′S)

(2S)-6-Fluoro-2-methyl-1,2,3,4-tetrahydroquinolineC10H12FN[α]D20=-74.2 (c 0.7, CHCl3)Source of chirality: (2S)-6-Fluoro-N-[(2S)-2-(6-methoxynaphth-2-yl)-propanoyl]-2-methyl-1,2,3,4-tetrahydroquinolineAbsolute configuration: (2S)