Highly selective hydrolysis of chloropyrimidines to pyrimidones in 12 N hydrochloric acid

Organic Process Research and Development

Volumn 10, Issue 5, 2006, Pages 921-926

  Padilla, Amphlett G ^a   Pearlman, Bruce A ^a,b  

^a PFIZER INC   (United States)

^b MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

EID: 33750140716     PISSN: 10836160     EISSN: None     Source Type: Journal    
DOI: 10.1021/op060093q     Document Type: Article

References (31)

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11. Delia, T. J.; Nagarajan, A. J. Heterocycl. Chem. 1998, 35, 269.
12. Jacobsen, E. J.; McCall, J. M.; Ayer, D. E.; Van Doornik, F. J.; Palmer, J. R.; Belonga, K. L.; Braughler, J. M.; Hall, E. D.; Houser, D. J.; Krook, M. A.; Runge, T. A. J. Med. Chem. 1990, 33, 1145.
13. The letters u and s denote the unsymmetrical and symmetrical isomer, respectively.
14. Martin, V. S.; Woodard, S. S.; Katsuki, T.; Yamada, Y.; Ikeda, M.; Sharpless, K. B. J. Am. Chem. Soc. 1981, 103, 6237.
15. A preliminary account of this research has been published: Pearlman, B. Specialty Chemicals 1998, 18, 94.
16. Isopar H is a mixture of branched hydrocarbons of approximate boiling point range 177 to 187 °C.
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24. values interpolated from table published in: Akerlof, G.; Teare, J. W. J. Am. Chem. Soc. 1937, 59, 1855.
25. 2D to 3 N HCl to 6 N HCl by approximately the same amount, indicating that roughly similar fractions of 3s and 3u are protonated at each acid concentration, thus contradicting the premise that a higher percentage of 3s than 3u is protonated. See Supporting Information for details.
26. We thank a referee for the suggestion that the high selectivity could be due to a difference in activation entropy, which would be expected to be greater for the transition state requiring the ordering of two extra molecules of water (3u).
27. This process has been patented: Pearlman, B. A.; Padilla, A. G. U.S. Patent 5,225,555, July 6, 1994.
28. f = 0.58. The reaction mixture is spotted directly. The reaction is judged complete when only 3u/3s are present.
29. LC assay: column, DuPont Zorbax C8, 25 cm × 4.6 mm; temperature, ambient; flow rate, 2.9 mL/min; detection, 254 nm; mobile phase, 500 mL of methanol/200 mL of acetonitrile/300 mL of water/0.8 mL of triethylamine/0.4 mL of acetic acid. Retention times: 2,4,6-trichloropyrimidine, 2.03 min; 2,4-dichloro-6-pyrrolidinylpyrimidine (2u), 2.40 min; 2-chloro-4,6-bis- pyrrolidinylpyrimidine (3s), 3.18 min.; 4,6-dichloro-2-pyrrolidinylpyrimidine (2s), 4.76 min; 6-chloro-2,4-bis-pyrrolidinylpyrimidine (3u), 6.52 min; 2,4,6-tripyrrolidinylpyrimidine, 8.94 min.
30. -8.
31. -10.