Functionalized 2,5-disubstituted benzazepines: Stereoselective synthesis of 3-methyl-5-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-2-carbonitrile and related derivatives

Synlett

Volumn , Issue 8, 2004, Pages 1394-1398

  Cobb, Jeff E ^a   Nanthakumar, Suganthini S ^a,b   Rutkowske, Randy ^a   Uehling, David E ^a  

^a GLAXOSMITHKLINE   (United States)

^b VERTEX PHARMACEUTICALS   (United States)

Author keywords

2,5 trans disubstituted 2 aminomethyl 3 benzazepine; Cyanide addition; Stereoselective synthesis

Indexed keywords

2 CARBONITRILE 5 PHENYLBENZAZEPINE; 3 METHYL 1 PHENYL 2,3 DIHYDRO 1H 3 BENZAZEPINE; 3 METHYL 5 PHENYL 2,3,4,5 TETRAHYDRO 1H 3 BENZAZEPINE 2 CARBONITRILE; BENZAZEPINE DERIVATIVE; BENZENE DERIVATIVE; CYANIDE; PHENOL DERIVATIVE; UNCLASSIFIED DRUG; [4 HYDROXY 3 (METHYLOXY)PHENYL]ACETIC ACID;

ACYLATION; ARTICLE; DIASTEREOISOMER; DRUG SYNTHESIS; PROTON NUCLEAR MAGNETIC RESONANCE; REDUCTION; STEREOCHEMISTRY; SUBSTITUTION REACTION;

EID: 3142673534     PISSN: 09365214     EISSN: None     Source Type: Journal    
DOI: 10.1055/s-2004-825618     Document Type: Article

References (19)

1. Recent reviews of 3-benzazepines: (a) Bourne, J. A. CNS Drug Reviews 2001, 7, 399. (b) Kawase, M.; Saito, S.; Motohashi, N. Int. J. Antimicrob. Agents 2000, 14, 193.
2. Recent reviews of 3-benzazepines: (a) Bourne, J. A. CNS Drug Reviews 2001, 7, 399. (b) Kawase, M.; Saito, S.; Motohashi, N. Int. J. Antimicrob. Agents 2000, 14, 193.
3. (a) Walter, L. A.; Chang, W. K. U.S. Patent 3393192, 1968.
4. (b) Kasparek, S. Adv. Heterocycl. Chem. 1974, 17, 45.
5. (c) Berger, J. G.; Chang, W. K.; Clader, J. W.; Hou, D.; Chipkin, R. E.; McPhail, A. T. J. Med. Chem. 1989, 32, 1913.
6. (d) Chumpradit, S.; Kung, M. P.; Billings, J. J.; Kung, H. F. J. Med. Chem. 1991, 34, 877.
7. Gerritz, S. W.; Smith, J. S.; Nanthakumar, S. S.; Uehling, D. E.; Cobb, J. E. Org. Lett. 2000, 2, 4099.
8. 3
9. For examples and further references see: (a) Heathcock, C. H.; Norman, M. H.; Dickman, D. A. J. Org. Chem. 1990, 55, 798. (b) Mitch, C. H. Tetrahedron Lett. 1988, 29, 6831. (c) Grierson, D. S.; Harris, M.; Husson, H.-P. J. Am. Chem. Soc. 1980, 102, 1064.
10. For examples and further references see: (a) Heathcock, C. H.; Norman, M. H.; Dickman, D. A. J. Org. Chem. 1990, 55, 798. (b) Mitch, C. H. Tetrahedron Lett. 1988, 29, 6831. (c) Grierson, D. S.; Harris, M.; Husson, H.-P. J. Am. Chem. Soc. 1980, 102, 1064.
11. For examples and further references see: (a) Heathcock, C. H.; Norman, M. H.; Dickman, D. A. J. Org. Chem. 1990, 55, 798. (b) Mitch, C. H. Tetrahedron Lett. 1988, 29, 6831. (c) Grierson, D. S.; Harris, M.; Husson, H.-P. J. Am. Chem. Soc. 1980, 102, 1064.
12. A related reaction with a 1-benzazepine substrate has been reported: Corbel, J. C.; Uriac, P.; Huet, J.; Martin, C. A. E.; Advenier, C. J. Med. Chem. 1995, 30, 3.
13. For an analogous route to a secondary, rather than tertiary lactam, see: Berney, D.; Schuh, K. Helv. Chim. Acta 1981, 64, 373.
14. 3): δ = 2.62 (s, 3 H), 3.43 (s, 3 H), 3.49-3.56 (m, 2 H), 3.85, (s, 3 H), 4.42 (d, 1 H, J = 5.2 Hz), 5.02 (d, 1 H, J = 11.2 Hz), 5.06 (d, 1 H, J = 6.4 Hz), 5.10 (d, 1 H, J = 6.4 Hz), 5.88 (d, 1 H, J = 11.2 Hz), 6.63 (s, 1 H), 6.73 (s, 1 H), 7.08 (d, 2 H, J = 7.6 Hz), 7.16 (t, 1 H, J = 7.2 Hz), 7.25 (d, 2 H, J = 7.6 Hz).
15. 1H NMR NOESY analysis indicated that 5a is the trans diastereomer as assigned.
16. 1H NMR NOESY analysis indicated that 5b is the assigned cis diastereomer.
17. 3): δ = 2.60 (s, 3 H), 2.63-2.81 (m, 4 H), 2.99 (dd, 1 H, J = 14.4, 3.2 Hz), 3.21 (d, 1 H, J = 14.1 Hz), 3.32 (s, 3 H), 3.47 (dd, 1 H, J = 14.4, 10.0 Hz), 3.71-3.74 (m, 2 H), 3.83 (s, 3 H), 4.46 (dd, 1 H, J = 10.0, 2.8 Hz), 4.91 (d, 1 H, J = 6.4 Hz), 4.93 (d, 1 H, J = 6.4 Hz), 6.38 (s, 1 H), 6.62 (s, 1 H), 7.11 (d, 2 H, J = 6.8 Hz), 7.23 (t, 1 H, J = 6.8 Hz), 7.31 (t, 2 H, J = 7.2 Hz).
18. 4 reduction under anhydrous conditions may be the fact that both are under thermodynamic control but involve distinct amine protonation states. At pH 7.2 there may be a strong thermodynamic preference for the protonated form of 5a relative to the protonated form of Sb, while under the conditions of the reduction there may be little thermodynamic bias between free base 5a and 5b. Experiments to further examine this question by attempting the epimerization of 5a or 5b under more basic conditions in the presence of a proton source have not been carried out.
19. 3·HCl: C, 64,64; H, 6.15; N. 7.80. Found: C, 64.70; H, 6.10; N, 7.66.