The chemical development of CI-972 and CI-1000: A continuous nitration, a MgCl2/Et3N-mediated C-alkylation of a chloronitropyrimidine, a catalytic protodediazotizatlon of a diazonium salt, and an air oxidation of an amine

Organic Process Research and Development

Volumn 5, Issue 3, 2001, Pages 216-225

  De Jong, Randall L ^a   Davidson, James G ^a   Dozeman, Gary J ^a   Fiore, Philip J ^a   Giri, Punam ^a   Kelly, Margaret E ^a   Puls, Timothy P ^a   Seamans, Ronald E ^a  

^a PFIZER INC   (United States)

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[No Author keywords available]

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EID: 0035533029     PISSN: 10836160     EISSN: None     Source Type: Journal    
DOI: 10.1021/op000298d     Document Type: Article

References (43)

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9. A manuscript detailing the development of this continuous nitration is under preparation.
10. Over the course of our scale-up work, two batches gave unexpectedly low yields of 45% and 49% (batches 2 and 3). In those runs, 98% rather than 90% nitric acid was used. We postulate that the higher strength acid and possibly higher reaction temperatures resulted in oxidative destruction of the product - no UV absorbing impurities were found by HPLC.
11. Several persons developed skin rashes and became sensitized to this material over the course of this project. One must exercise care to minimize skin contact when handling this compound.
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13. For some recent examples of amine additions to 8a, see: (a) Bailey, S. W.; Chandrasekaran, R. Y.; Ayling, J. E. J. Org. Chem. 1992, 57, 4470.
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23. The salts were generally prepared at 0-5°C in water using 2-3 mol equiv of acid and 1.2-1.4 mol equiv of sodium nitrite. The resulting slurry was then warmed to ambient temperature and the diazonium salt isolated by filtration.
24. On one occasion, removal of some dry diazonium chloride salt from a filter funnel - scraping with a metal spatula-resulted in rapid decomposition, giving a black foam.
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35. Church, R. F. R.; Schaub, R. E.; Weis,. M. J. J. Org. Chem. 1971, 36, 723. Church notes that this reduction is unusual.
36. 2 and HCl.
37. The addition of HCl is not required, but it does appear to increase the rate of reaction. We added excess acid primarily to obtain the full 1:1 HCl salt of the weakly basic 2.
38. A higher percentage of water resulted in a faster reduction rate, but more impurities were formed.
39. ADP carbon was found to be superior to the 15 or more carbons that were evaluated.
40. Elliot and co-workers who were also developing similar PNP inhibitors at the time reported that Raney nickel reduction of 12 gave detectable levels of 2, but due to extensive decomposition products it was not amendable to isolation. Elliott, A. J.; Kotian, P. L.; Montgomery, J. A.; Walsh, D. A. Tetrahedron Lett. 1996, 37, 5829.
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42. 4, and CAN) were evaluated in an attempt at improving the oxidation with respect to rate and purity; however, they were either ineffective or resulted in decomposition of 16 without conversion to 2. The use of Cu(II) salts did increase the rate of air oxidation, but the reaction mixtures became very dark.
43. Presumably due to the formation of hydrogen chloride and nitrogen during the reduction, the batch pressure actually increases as the hydrogen is consumed. During this hydrogenation the pressure was relieved twice from 60 to 50 psig and once from 60 to 5 psig, followed by repressurizing to 50 psig with hydrogen. The hydrogenation was essentially complete after 1 h.