The Imidazole-Based Statins
Development work toward an enabling synthesis of preparative scale batches of an imidazole-based HMG-CoA reductase inhibitor is described.
The desired target was synthesized in 16% yield over 7 steps, highlighted by an imidazole-forming condensation reaction in which the yield was improved from 20% to >70% via modification of the solvent, acid, and amine equivalents. The step 2 acylation was improved, and a problematic benzyl ester in step 4 was converted into the corresponding benzyl amide to decrease trans-amidation during the step 5 imidazole formation. A highly effective salt formation and crystallization protocol was also developed.
The desired target was synthesized in 16% yield over 7 steps, highlighted by an imidazole-forming condensation reaction in which the yield was improved from 20% to >70% via modification of the solvent, acid, and amine equivalents. The step 2 acylation was improved, and a problematic benzyl ester in step 4 was converted into the corresponding benzyl amide to decrease trans-amidation during the step 5 imidazole formation. A highly effective salt formation and crystallization protocol was also developed.
Citing Articles
Citation data is made available by participants in CrossRef's Cited-by Linking service. For a more comprehensive list of citations to this article, users are encouraged to perform a search in SciFinder.This article has been cited by 2 ACS Journal articles (2 most recent appear below).
Synthesis of 1,2,4,5-Tetrasubstituted Imidazoles by a Sequential Aza-Wittig/Michael/Isomerization Reaction
Yi-Bo Nie, Long Wang, and Ming-Wu DingThe Journal of Organic Chemistry2012 77 (1), 696-700
Synthesis of 1,2,4,5-Tetrasubstituted Imidazoles by a Sequential Aza-Wittig/Michael/Isomerization Reaction
Yi-BoNie, LongWang, and Ming-WuDing
The Journal of Organic Chemistry2012 77 (1), 696-700Carbodiimides 4, obtained from aza-Wittig reactions of iminophosphorane 3 with aryl isocyanates, reacted with secondary amines in the presence of a catalytic amount of sodium alkoxide to give 1,2,4,5-tetrasubstituted imidazoles 7 in good yields.
Development of an Early Enabling Synthesis for PF-03052334-02: A Novel Hepatoselective HMG-CoA Reductase Inhibitor
Daniel M. Bowles, David C. Boyles, Chulho Choi, Jeffrey A. Pfefferkorn, and Stephanie Schuyler, Edward J. HesslerOrganic Process Research & Development2011 15 (1), 148-157Development of an Early Enabling Synthesis for PF-03052334-02: A Novel Hepatoselective HMG-CoA Reductase Inhibitor
Daniel M.Bowles, David C.Boyles, ChulhoChoi, Jeffrey A.Pfefferkorn, and StephanieSchuyler, Edward J.HesslerOrganic Process Research & Development2011 15 (1), 148-157Early process development work toward a promising pyrazole-based HMG-CoA reductase inhibitor is described. PF-03052334-02 (1) was prepared in 14 synthetic steps with a 21% overall yield, highlighted by a modified three-step hydroxypyrazole formation in ...
Attachment of Statin Side chain at 2-position of imidazole will produce more conjugated hetercyclic statins with Phenylgroup or Benzylgroup at 1-position, which will offer another new statin alignment for a variety of biological activity including EMT modulating effects, that are useful for new cancer chemotherapy.
返信削除N-arylimidazoles are new categoly of compounds for PDE inhibiting activity and kinase modulating activity, as well as aldose reductase inhibitory activity, that are all important factors for new drug develpement.
返信削除And also, Hydroxamic acids will open another door for HDAC inhibitory compounds as a most affordable target in Epigenomic research area.
返信削除http://pubs.acs.org/doi/abs/10.1021/op800092e?journalCode=oprdfk
返信削除