Amide-based atropisomers in tachykinin NK1-receptor antagonists: Synthesis and antagonistic activity of axially chiral N-benzylcarboxamide derivatives of 2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocin-6-one

Tetrahedron

Volumn 60, Issue 20, 2004, Pages 4481-4490

  Ishichi, Yuji ^a   Ikeura, Yoshinori ^a   Natsugari, Hideaki ^b  

^a TAKEDA PHARMACEUTICAL COMPANY LIMITED   (Japan)

^b UNIVERSITY OF TOKYO   (Japan)

Author keywords

Atropisomer; Pyrido 2,3 b 1,5 oxazocin 6 one; Pyrido 3,2 f 1,4 oxazepin 5(2H) one; Stereoselective synthesis; Tachykinin NK1 antagonist

Indexed keywords

4 [3,5 BIS(TRIFLUOROMETHYL)BENZYL] 7 METHYL 6 PHENYL 3,4 DIHYDROPYRIDO[3,2 F][1,4]OXAZEPIN 5(2H) ONE; 4 [3,5 BIS(TRIFLUOROMETHYL)BENZYL] 8 METHYL 6 PHENYL 3,4 DIHYDROPYRIDO[3,2 F][1,4]OXAZEPIN 5(2H) ONE; 5 [3,5 BIS(TRIFLUOROMETHYL)BENZYL] 3 METHYL 7 PHENYL 2,3,4,5 TETRAHYDRO 6H PYRIDO[2,3 B][1,5]OXAZOCIN 6 ONE; 5 [3,5 BIS(TRIFLUOROMETHYL)BENZYL] 3,8 DIMETHYL 7 PHENYL 2,3,4,5 TETRAHYDRO 6H PYRIDO[2,3 B][1,5]OXAZOCIN 6 ONE; 5 [3,5 BIS(TRIFLUOROMETHYL)BENZYL] 7 PHENYL 2,3,4,5 TETRAHYDRO 6H PYRIDO[2,3 B][1,5]OXAZOCIN 6 ONE; 5 [3,5 BIS(TRIFLUOROMETHYL)BENZYL] 8 METHYL 7 PHENYL 2,3,4,5 TETRAHYDRO 6H PYRIDO[2,3 B][1,5]OXAZOCIN 6 ONE; 5 [3,5 BIS(TRIFLUOROMETHYL)BENZYL] 9 METHYL 7 PHENYL 2,3,4,5 TETRAHYDRO 6H PYRIDO[2,3 B][1,5]OXAZOCIN 6 ONE; AMIDE; BENZYL DERIVATIVE; BOLTON HUNTER REAGENT I 125; NICOTINAMIDE DERIVATIVE; OXAZOCINE DERIVATIVE; SUBSTANCE P; TACHYKININ RECEPTOR ANTAGONIST; TAK 637; UNCLASSIFIED DRUG;

ARTICLE; CYCLIZATION; DRUG SYNTHESIS; ENANTIOMER; HUMAN; HUMAN CELL; IC 50; PHYSICAL CHEMISTRY; PRIORITY JOURNAL; STEREOSPECIFICITY;

EID: 1942468807     PISSN: 00404020     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.tet.2004.01.097     Document Type: Article

References (17)

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12. 4 suggesting that the conformation of the 7-membered ring in compounds 4a-c changes more rapidly than that in TAK-637 derivatives.
13. (3) of 6, note that the sequence of priority is different from that of TAK-637; the methyl group exists in β-configuration for both compounds.
14. 5, ca. 97:3.
15. Coexistence of the two conformers (ca. 98:2) in the solid state of (3S)-6b may not be ruled out.
16. For a recent NOESY (EXSY) experiment in atropisomers, see: Gibson K.R., Hitzel L., Mortishire-Smith R.J., Gerhard U., Jelley R.A., Reeve A.J., Rowley M., Nadin A., Owens A.P. J. Org. Chem. 67:2002;9354-9360.
17. (7)-phenyl protons of 5b, (3S)-6b and (3R)-6b were observed as a broad signal (2H at 6.6-7.4 ppm) and a broad singlet (3H at 7.37 ppm), whereas those of 5a, 5c, (3S)-6a and (3R)-6a were observed as multiplets with sharp peaks, suggesting that rotation of the phenyl ring is moderately restricted for 5b, (3S)-6b and (3R)-6b.