Development of an efficient process for the preparation of Sch 39166: Aziridinium chemistry on scale

Organic Process Research and Development

Volumn 8, Issue 5, 2004, Pages 754-768

  Gala, Dinesh ^a   Dahanukar, Vilas H ^a   Eckert, Jeffery M ^a   Lucas, Brian S ^a   Schumacher, Doris P ^a   Zavialov, Ilia A ^a   Buholzer, Patrik ^b   Kubisch, Peter ^b   Mergelsberg, Ingrid ^b   Scherer, Dominik ^b  

^a MERCK RESEARCH LABORATORIES   (United States)

^b Werthenstein Chemie AG   (Switzerland)

Author keywords

[No Author keywords available]

Indexed keywords

AZIRIDINE; DOPAMINE 1 RECEPTOR BLOCKING AGENT; ECOPIPAM;

ARTICLE; DRUG INDUSTRY; DRUG MANUFACTURE; DRUG STRUCTURE; DRUG SYNTHESIS; GRIGNARD REACTION; REACTION ANALYSIS; RING OPENING; SCALE UP; STEREOCHEMISTRY; STRUCTURE ANALYSIS;

EID: 5144232796     PISSN: 10836160     EISSN: None     Source Type: Journal    
DOI: 10.1021/op0402026     Document Type: Article

References (24)

1. Karlsson, P.; Smith, L.; Farde, L.; Haernryd, C.; Sedvall, G.; Wiesel, F.-A. Psychopharmacology 1995, 121, 309-316.
2. Duffy, R. A.; Hunt, M. A.; Wamsley, J. K.; McQuade, R. D. J. Chem. Neuroanat. 2000, 19, 41-46.
3. Coffin, V.; Glue, P. W. Methods for reducing craving in mammals. WO 9921540-A2, 1999.
4. Romach, M. K.; Glue, P.; Kampman, K.; Kaplan, H. L.; Somer, G. R.; Poole, S.; Clarke, L.; Coffin, V.; Cornish, J. O'Brien, C. P.; Sellers, E. M. Arch. Gen. Psychiatry 1999, 56, 1101-1106.
5. Nann-Vernotica, E.; Donny, E. C.; Bigelow, G. E.; Walsh, S. L. Psychopharmacology 2001, 155, 338-347.
6. (a) Wu, G.; Wong, Y.; Steinman, M.; Tormos, W.; Schumacher, D. P.; Love, G. M.; Shutts, B. P.; Org. Process Res. Dev. 1997, 1, 359-364.
7. (b) Draper, R. W.; Hou, D.; Iyer, R.; Lee, G. M.; Liang, J. T.; Mas, J. L.; Vater, E. J. V. Org. Process Res. Dev. 1998, 2, 186-193.
8. (c) Hou, D.; Schumacher, D. Curr. Opin. Drug Discovery Dev. 2001, 4, 792-799.
9. Draper, R. W.; Hou, D.; Iyer, R.; Lee, G. M.; Liang, J. T.; Mas, J. L.; Tormos, W.; Vater, E. J.; Gunter, F.; Mergelsberg, I.; Scherer, D. Org. Process Res. Dev. 1998, 2, 175-185.
10. Kalkote, U. R.; Choudhary, A. R.; Natu, A. A.; Ayyangar, N. R. Synth. Commun. 1991, 21, 1129-1135.
11. Purchase, C. F.; Goel, O. P. J. Org. Chem. 1991, 56, 457-459.
12. (a) Leonard, N. J.; Paukstelis, J. V. J. Org. Chem. 1965, 30, 821.
13. (b) Olah, G. A.; Szilagyi, P. J. J. Am. Chem. Soc. 1969, 91, 2949-2955.
14. (c) Golding, B. T.; Kebbell, M. J.; Lockhart, I. M. J. Chem. Soc., Perkin Trans. 2 1987, 705-713.
15. (a) Andrews, D. R.; Dahanukar, V. H.; Eckert, J. M.; Gala, D.; Lucas, B. S.; Schumacher, D. P.; Zavialov I. A. Tetrahedron Lett. 2002, 43, 6121-6125.
16. (b) Dahanukar, V. H.; Zavialov, I. A. Curr. Opin. Drug Discovery Dev. 2002, 5, 918-927.
17. Other sulfonyl choride reagents investigated as activating reagents (benzenesulfonyl chloride, 4-chlorobenzenesulfonyl chloride, 4-nitrobenzenesulfonyl chloride, and MsCl) showed no advantage over p-TsCl. Other reagents (methanesulfonic anhydride, p-toluenesulfonyl imidazole, carbonyldimidazole, thionyl chloride, trifluoroacetic anhydride, and oxalyl chloride) also proved to be inferior to p-TsCl.
18. 4 as an external reference standard.
19. Erdik, E. Tetrahedron 1984, 40, 641-657.
20. 2, copper (II) naphthenate, copper (II) acetylacetonate, copper (II) tifluoroacetylacetonate, copper (II) benzoylacetonate, lithium 2-thienylcyanocuprate, and Cu(I) phenylacetylide. Other metal salts (Cr, Fe, Mn, and Ni) failed to show any improvement in the reaction of 16 with 4.
21. In the laboratory, after forming 15b at -20°C, it was mixed with 4 at various temperatures and held for several hours. Aliquots were taken and analyzed periodically by HPLC to quantitate the amount of product 5. This work showed that the reaction of 4 with 16 was sluggish below 0°C and proceeded faster at 25-35°C.
22. This would be a large waste burden for a commercial process: hence, it was to be avoided at any cost.
23. During stress studies, this cyclic acetal was isolated and fully characterized (NMR, MS, IR).
24. Organolithium and organozinc reagents were evaluated in place of Grignard reagents. The former two gave poor yields and/or many byproducts; hence, the decision was made to optimize the Grignard reagent process.