Efficient and scalable synthesis of ethyl 2,6-dichloro-5-fluoronicotinoyl acetate using the blaise reaction as a key step

Organic Process Research and Development

Volumn 9, Issue 3, 2005, Pages 311-313

  Bo, Seung Choi ^a   Jay, Hyok Chang ^a   Choi, Hyeong Wook ^a   Young, Keun Kim ^a   Ki, Kon Lee ^a   Kyu, Woong Lee ^a   Jae, Hoon Lee ^a   Heo, Taeho ^a   Do, Hyun Nam ^a   Shin, Hyunik ^a  

^a LG Chemical Ltd   (South Korea)

Author keywords

[No Author keywords available]

Indexed keywords

ACETIC ACID DERIVATIVE; ETHYL 2,6 DICHLORO 5 FLUORONICOTINOYL ACETATE; PYRIDINE DERIVATIVE; UNCLASSIFIED DRUG;

ADDITION REACTION; ARTICLE; CARBON NUCLEAR MAGNETIC RESONANCE; DRUG SYNTHESIS; HYDROLYSIS; PROTON NUCLEAR MAGNETIC RESONANCE;

EID: 20444442013     PISSN: 10836160     EISSN: None     Source Type: Journal    
DOI: 10.1021/op050012a     Document Type: Article

References (25)

1. The content of the paper has been published as a part of patent. See: Shin, H.; Choi, B. S., Choi, S. C. WO 2003033469, 2003.
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8. The reported yield of 1 from the acid chloride 2 is 74%. See: (a) Bouzard, D.; Di Cesare, P.; Essiz, M.; Jacquet, J. P.; Ledoussal, B.; Remuzon, P.; Kessler, R. E.; Fung-Tomc, J. J. Med. Chem. 1992, 35, 518.
9. (b) Miyamoto, T.; Matsumoto, J.-I. Chem. Pharm. Bull. 1990, 38, 3211.
10. 1H NMR data of the methyl ketone impurity: (300 MHz) δ 7.57 (d, 1H, J = 7.3 Hz), 2.71 (s, 3H).
11. The reported yield of 1 from the acid chloride 2 is 96%. See: (a) Refer to ref 2.
12. (b) O'Neill, B. T.; Busch, F. R.; Lehner, R. S. EP 449445, 1991.
13. (c) Clay, R. J.; Collom, T. A.; Karrick, G. L.; Wemple, J. Synthesis 1993, 290.
14. The reported yield of 1 from the acid chloride 2 is 70%. See: Urban, F. J.; Moore, B. S.; Spargo, P. L. Org. Prep. Proced. Int. 1997, 29, 231.
15. (a) Blaise, E. E. C. R. Acad. Sci. 1901, 132, 478 and 978.
16. (b) Carson, J.; Rinehart, K. L., Jr.; Thornton, S. D., Jr. J. Org. Chem. 1953, 18, 1594.
17. (c) Kagan, H. B.; Suen, Y.-H. Bull. Chim. Soc. Fr. 1966, 1819.
18. (d) Konrad, J.; Jezo, I. Chem. Zvesti. 1980, 34, 125.
19. Hannick, S. M.; Kishi, Y. J. Org. Chem. 1983, 48, 3833.
20. Evolution of hydrogen should be noticed.
21. Isolation of 1 through extractive workup with ethyl acetate and subsequent column chromatography of the residue showed 85-90% yield.
22. Shin, H.; Choi, B. S.; Lee, K. K.; Choi, H.-w.; Chang, J. H.; Lee, K. W.; Nam, D. H.; Kim, N.-S. Synthesis 2004, 2629.
23. Clark, J. D.; Weisenburger, G. A.; Anderson, D. K.; Colson, P.-J.; Edney, A. D.; Gallagher, D. J.; Kleine, H. P.; Knable, C. M.; Lantz, M. K.; Moore, C. M. V.; Murphy, J. B.; Rogers, T. E.; Ruminski, P. G.; Shah, A. S.; Storer, N.; Wise, B. E. Org. Process Res. Dev. 2004, 8, 51.
24. The thermokinetic data of the Blaise reaction of 4 using 5 mol % MsOH (Figure 1d) are as follows: Cp initial [J/kg/K] = 2167, Cp final [J/kg/K] = 2640, total heat [kJ] = 271 (for 0.15 kg of 4), molar heat [kJ/mol] = 266, adiabatic temp rise [°C] = 164.
25. The percentage of atom economy of the process is 66.1% compared to 41.1% of the diethyl malonate route of ref 6. However, the disposal of zinc waste should be accounted for further scale-up.