Efficient and scalable synthesis of ketones via nucleophilic Grignard addition to nitriles using continuous flow chemistry

Tetrahedron Letters

Volumn 54, Issue 18, 2013, Pages 2226-2230

  Mateos, Carlos ^a   Rincón, Juan A ^a   Villanueva, José ^a  

^a ELI LILLY AND COMPANY   (Spain)

Author keywords

Continuous process; Flow chemistry; Grignard reagents; Ketones

Indexed keywords

BROMIDE; IMINE; KETONE DERIVATIVE; NITRILE;

ARTICLE; CHEMICAL STRUCTURE; GRIGNARD REACTION; HYDROLYSIS; NUCLEOPHILICITY; SYNTHESIS;

EID: 84875718891     PISSN: 00404039     EISSN: 18733581     Source Type: Journal    
DOI: 10.1016/j.tetlet.2013.02.069     Document Type: Article

References (13)

1. H.G. Frank, and J.W. Stadelhofer Industrial Aromatic Chemistry 1988 Springer Berlin
2. H. Surburg, and J. Panten Common Fragrance and Flavor Materials 5th ed. 2006 Wiley-VCH Weinheim, Germany
3. H.L. Lochte, J. Horeczy, P.L. Pickard, and A.D. Barton J. Am. Chem. Soc. 70 1948 2012 2015
4. P.L. Pickard, and D.J. Vaughan Ibid. 72 1950 876 878
5. P.L. Pickard, and E.F. Engles Ibid. 74 1952 4607 4608
6. H.S. Mosher, and W.T. Mooney J. Am. Chem. Soc. 73 1951 3948 3949
7. For a recent review on flow chemistry inside the Pharmaceutical Industry see: Laia Malet-Sanz, and Flavien Susanne J. Med. Chem. 55 2012 4062 4098
8. E. Riva, S. Gagliardi, M. Martinelli, D. Passarella, D. Vigo, and A. Rencurosi Tetrahedron 66 2010 3242 3247
9. Theoretical total volume is calculated as a function of diameter and length (V = 3.1416 × (D/2) × L). Calculated residence time based on reactor V and flow rate values are accurate when T is not too high (far from the solvent critical point). At very high T, phase and density changes make the actual residence time lower than the calculated value. The calculated length to diameter ratio value (L/D) is 5500. As a rule of thumb, we considered that L/D must be above the standard minimum number of 5000 to ensure efficient diffusion rates that implies good mixing between the two feed lines. See: S.A. May, M.D. Johnson, T.M. Braden, J.R. Calvin, B.D. Haeberle, A.R. Jines, R.D. Miller, E.F. Plocharczyk, G.A. Rener, R.N. Nichey, C.R. Schmid, R.K. Vaid, and H. Yu Org. Process Res. Dev. 16 2012 982 1002
10. T. Gervais, and K.F. Jensen Chem. Eng. Sci. 61 2006 1102 1121
11. Normal pressure Nemesys syringe pumps. Cetoni Automatisierung and Mikrosysteme GmbH, Germany. www.cetoni.de.
12. N. Timothy, J.R. Naber, L. Hartman, J. McMullen, K.F. Jensen, and S.L. Buchwald Chem. Sci. 2 2011 287
13. For a general review of the management of solid in flow see: Ryan L. Hartman Org. Process Res. Dev. 16 2012 870 887