An improved procedure for the large scale preparation of 2-chloro-4,6-dimethoxy-1,3,5-triazine

Synthetic Communications

Volumn 26, Issue 18, 1996, Pages 3491-3494

  Cronin, Jason S ^a   Ginah, Francis O ^a   Murray, Angela R ^a   Copp, James D ^a  

^a ELI LILLY AND COMPANY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

TRIAZINE DERIVATIVE;

ARTICLE; DRUG SYNTHESIS; REACTION ANALYSIS;

EID: 0029809456     PISSN: 00397911     EISSN: None     Source Type: Journal    
DOI: 10.1080/00397919608003754     Document Type: Article

References (12)

1. Kaminski, Z.J. Tetrahedron Lett. 1985, 26, 2901; Cook, G.K., Hornback, W.J., Jordan, C.L., McDonald III, J.H., Munroe, J.E. J. Org. Chem. 1989, 54, 5828; Taylor, E.C., Gillespie, P. J. Org. Chem. 1992, 57, 5757; Barnett, C.J., Wilson, T.M., Wendel, S.R., Winningham, M.J., Deeter, J.B. J. Org. Chem. 1994, 59, 7038; Hipskind, P.A., Howbert, J.J., Cho, S., Cronin, J.S., Fort, S.L., Ginah, F.O., Hansen, G.J., Huff, B.E., Lobb, K.L., Martinelli, M.J., Murray, A.R., Nixon, J.A., Staszak, M.A., Copp, J.D. J. Org. Chem. 1995, 60, 7033.
2. Kaminski, Z.J. Tetrahedron Lett. 1985, 26, 2901; Cook, G.K., Hornback, W.J., Jordan, C.L., McDonald III, J.H., Munroe, J.E. J. Org. Chem. 1989, 54, 5828; Taylor, E.C., Gillespie, P. J. Org. Chem. 1992, 57, 5757; Barnett, C.J., Wilson, T.M., Wendel, S.R., Winningham, M.J., Deeter, J.B. J. Org. Chem. 1994, 59, 7038; Hipskind, P.A., Howbert, J.J., Cho, S., Cronin, J.S., Fort, S.L., Ginah, F.O., Hansen, G.J., Huff, B.E., Lobb, K.L., Martinelli, M.J., Murray, A.R., Nixon, J.A., Staszak, M.A., Copp, J.D. J. Org. Chem. 1995, 60, 7033.
3. Kaminski, Z.J. Tetrahedron Lett. 1985, 26, 2901; Cook, G.K., Hornback, W.J., Jordan, C.L., McDonald III, J.H., Munroe, J.E. J. Org. Chem. 1989, 54, 5828; Taylor, E.C., Gillespie, P. J. Org. Chem. 1992, 57, 5757; Barnett, C.J., Wilson, T.M., Wendel, S.R., Winningham, M.J., Deeter, J.B. J. Org. Chem. 1994, 59, 7038; Hipskind, P.A., Howbert, J.J., Cho, S., Cronin, J.S., Fort, S.L., Ginah, F.O., Hansen, G.J., Huff, B.E., Lobb, K.L., Martinelli, M.J., Murray, A.R., Nixon, J.A., Staszak, M.A., Copp, J.D. J. Org. Chem. 1995, 60, 7033.
4. Kaminski, Z.J. Tetrahedron Lett. 1985, 26, 2901; Cook, G.K., Hornback, W.J., Jordan, C.L., McDonald III, J.H., Munroe, J.E. J. Org. Chem. 1989, 54, 5828; Taylor, E.C., Gillespie, P. J. Org. Chem. 1992, 57, 5757; Barnett, C.J., Wilson, T.M., Wendel, S.R., Winningham, M.J., Deeter, J.B. J. Org. Chem. 1994, 59, 7038; Hipskind, P.A., Howbert, J.J., Cho, S., Cronin, J.S., Fort, S.L., Ginah, F.O., Hansen, G.J., Huff, B.E., Lobb, K.L., Martinelli, M.J., Murray, A.R., Nixon, J.A., Staszak, M.A., Copp, J.D. J. Org. Chem. 1995, 60, 7033.
5. Kaminski, Z.J. Tetrahedron Lett. 1985, 26, 2901; Cook, G.K., Hornback, W.J., Jordan, C.L., McDonald III, J.H., Munroe, J.E. J. Org. Chem. 1989, 54, 5828; Taylor, E.C., Gillespie, P. J. Org. Chem. 1992, 57, 5757; Barnett, C.J., Wilson, T.M., Wendel, S.R., Winningham, M.J., Deeter, J.B. J. Org. Chem. 1994, 59, 7038; Hipskind, P.A., Howbert, J.J., Cho, S., Cronin, J.S., Fort, S.L., Ginah, F.O., Hansen, G.J., Huff, B.E., Lobb, K.L., Martinelli, M.J., Murray, A.R., Nixon, J.A., Staszak, M.A., Copp, J.D. J. Org. Chem. 1995, 60, 7033.
6. (a) Dudley, J.R., Thuyrston, J.T., Schaefer, F.C., Holm-Hansen, D., Hull, C.J., Adams, P. J. Am. Chem. Soc. 1951, 73, 2986;
7. (b) Weber, A.J.M., Huysmans, W.G.B., Mijs, W.J., Bovee, W.M.M.J., Smidt, J., Vriend, J. Recl. Trav. Chim. Pays-Bas 1978, 97, 107,
8. (c) Menicagli, R., Malanga, C., Peluso, P. Synth. Commun. 1994, 24, 2153.
9. Potassium bicarbonate functioned equally well in the reaction. Other bases such as sodium, potassium, and cesium carbonate gave increased levels of 2 and/or lower yields of 1.
10. The reaction mixture was analysed using a Hewitt Packard 5980 capillary GC with an DB-1 crosslinked methyl-silicon column, 30m × 0.25mm × -.25μm, at a column temperature of 250° C and flow rate of 1.7 mL/min. The retention times are as follows: 2,4-dichloro-6-methoxy-1,3,5-triazine: 2.5 min; 2-chloro-4,6-dimethoxy-1,3,5-triazine: 3.0 min; 2,4,6-trimethoxy-1,3,5-triazine: 3.4 min.
11. The endpoint of this reaction is defined as the time at which >97% conversion of the intermediate 2,4-dichloro-6-methoxy-1,3,5-triazine to CDMT has occurred. There is no residual cyanuric chloride.
12. The conversion of cyanuric chloride to 2,4-dichloro-6-methoxy-1,3,5-triazine is accompanied by an exotherm. This appears to start at around 20° C and facilitates the warm-up to 35° C.