An efficient synthesis of the indole acetic acid metabolite of MK-0462

Synthetic Communications

Volumn 26, Issue 10, 1996, Pages 1977-1984

  Chen, Cheng Yi ^a   Lieberman, David R ^a   Street, Leslie J ^b   Guiblin, Alex R ^b   Larsen, Robert D ^a   Verhoeven, Thomas R ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

^b NEUROSCIENCE RESEARCH CENTRE   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

3 (2 DIMETHYLAMINOETHYL) 5 [(1,2,4 TRIAZOL 1 YL)METHYL]INDOLE; 5 [( 1,2,4 TRIAZOL 1 YL)METHYL] 1H INDOLE 3 ACETIC ACID; DRUG METABOLITE; INDOLE DERIVATIVE; L 749335; RIZATRIPTAN; SEROTONIN AGONIST; UNCLASSIFIED DRUG;

ARTICLE; DRUG SYNTHESIS; REACTION ANALYSIS;

EID: 0029994515     PISSN: 00397911     EISSN: None     Source Type: Journal    
DOI: 10.1080/00397919608003552     Document Type: Article

References (13)

1. Street, L. J.; Baker, R.; Davey, W. B.; Guiblin, A. R.; Jelley, R. A.; Reeve, A. J.; Routledge, H.; Sternfeld, F.; Watt, A. P.; Beer, M. S.; Middlemiss, D. N.; Noble, A. J.; Stanton, J. A.; Scholey, K.; Hargreaves, R. J.; Sohal, B.; Graham, M. I.; Matassa, V. G. J. Med. Chem. 1995, 38, 1799.
2. For the isolation and identification of the indole acetic acid 1, see: L. Liu, H. Cheng, C. Chavez, B. K. Matuszewski, A. R. Guiblin, W. J. Polvino, T. S. Chen and J. D. Rogers, Identification of urinary metablites of N-N-dimethyl-2-[5-(1,2,4-triazole-1-ylmethyl)-1H-indol-3-yl] ethylamine benzoate (MK-462) in humans, presented at the American Association of Pharmaceutical Scientists Ninth Annual Meeting, (November 6-11, 1994) in San Diego, CA, USA.
3. For a recent example of the synthesis of an indole acetic acid and references cited therein, see: Guan, X. and Borchardt, R. T. Tetrahedron Lett. 1994, 35, 3013.
4. 4, see: (a) Chen, C.; Senanayake, C. H.; Bill, T. J.; Larsen, R. D.; Verhoeven, T. R.; Reider, P. J. J. Org. Chem. 1994, 59, 3738. (b) The Fisher indole synthesis of 1 from 3-cyanopropionaldehyde dimethyl acetal and the 4-hydrazinobenzyl triazole in polyphosphoric ester followed by KOH hydrolysis gave indole acetic acid 1 in 11% overall yield.
5. 4, see: (a) Chen, C.; Senanayake, C. H.; Bill, T. J.; Larsen, R. D.; Verhoeven, T. R.; Reider, P. J. J. Org. Chem. 1994, 59, 3738. (b) The Fisher indole synthesis of 1 from 3-cyanopropionaldehyde dimethyl acetal and the 4-hydrazinobenzyl triazole in polyphosphoric ester followed by KOH hydrolysis gave indole acetic acid 1 in 11% overall yield.
6. (a) Chen, C.; Lieberman, D. R.; Larsen, R. D.; Reamer, R. A.; Verhoeven, T. R.; Reider, P. J.; Cottrell, I. F.; Houghton, P. G. Tetrahedron Lett. 1994, 35, 6981.
7. (b) Larock, R. C; Yum, E. K. J. Am. Chem. Soc. 1991, 113, 6689.
8. For recent examples of the displacement of indolemetanol with cyanide species, see: (a) Toyota, M.; Fukumoto, K. J. Chem. Soc. Perkin Trans. 1 1992, 547. (b) Runti, C.; Orlando, G. Ann. Chim. (Rome) 1953, 43, 308. (c) Coker, J. N.; Mathre, O. B.; Todd, W. H. J. Org. Chem. 1963, 28, 589. (d) Spande, T. F. in Chemistry of Heterocyclic Compounds, Houlihan, W. J., Ed., Wiley, New York, Vol 25, Part III, Chap. VIII, p. 1. These reactions are believed to proceed via the methylene indolenine i.
9. For recent examples of the displacement of indolemetanol with cyanide species, see: (a) Toyota, M.; Fukumoto, K. J. Chem. Soc. Perkin Trans. 1 1992, 547. (b) Runti, C.; Orlando, G. Ann. Chim. (Rome) 1953, 43, 308. (c) Coker, J. N.; Mathre, O. B.; Todd, W. H. J. Org. Chem. 1963, 28, 589. (d) Spande, T. F. in Chemistry of Heterocyclic Compounds, Houlihan, W. J., Ed., Wiley, New York, Vol 25, Part III, Chap. VIII, p. 1. These reactions are believed to proceed via the methylene indolenine i.
10. For recent examples of the displacement of indolemetanol with cyanide species, see: (a) Toyota, M.; Fukumoto, K. J. Chem. Soc. Perkin Trans. 1 1992, 547. (b) Runti, C.; Orlando, G. Ann. Chim. (Rome) 1953, 43, 308. (c) Coker, J. N.; Mathre, O. B.; Todd, W. H. J. Org. Chem. 1963, 28, 589. (d) Spande, T. F. in Chemistry of Heterocyclic Compounds, Houlihan, W. J., Ed., Wiley, New York, Vol 25, Part III, Chap. VIII, p. 1. These reactions are believed to proceed via the methylene indolenine i.
11. For recent examples of the displacement of indolemetanol with cyanide species, see: (a) Toyota, M.; Fukumoto, K. J. Chem. Soc. Perkin Trans. 1 1992, 547. (b) Runti, C.; Orlando, G. Ann. Chim. (Rome) 1953, 43, 308. (c) Coker, J. N.; Mathre, O. B.; Todd, W. H. J. Org. Chem. 1963, 28, 589. (d) Spande, T. F. in Chemistry of Heterocyclic Compounds, Houlihan, W. J., Ed., Wiley, New York, Vol 25, Part III, Chap. VIII, p. 1. These reactions are believed to proceed via the methylene indolenine i.
12. 4 was used in the reaction to minimize the desilylation of 4a to 4b. This increased the recovery since 4b is lost in the aqueous phase upon partitioning of the reaction mixture between IPAc and water.
13. 2O gives nitrile 5 in 68% yield, which can be purified by silica gel chromatography followed by crystallization. Treatment of 8 with 2 N HCl in methanol affords to nitrile 8 in 80% yield.