Stereospecific Synthesis of 2-Deoxy-2,2-difluororibonolactone and Its Use in the Preparation of 2′-Deoxy-2′,2′-difluoro-β-D-ribofuranosyl Pyrimidine Nucleosides: The Key Role of Selective Crystallization

T. S. Chou; P. C. Heath; L. E. Patterson; L. M. Poteet; R. E. Lakin; A. H. Hunt

doi:10.1055/s-1992-26167

Synthesis 1992; 1992(6): 565-570
DOI: 10.1055/s-1992-26167

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Stereospecific Synthesis of 2-Deoxy-2,2-difluororibonolactone and Its Use in the Preparation of 2′-Deoxy-2′,2′-difluoro-β-D-ribofuranosyl Pyrimidine Nucleosides: The Key Role of Selective Crystallization

T. S. Chou^* , P. C. Heath, L. E. Patterson, L. M. Poteet, R. E. Lakin, A. H. Hunt

^*Lilly Research Laboratories, Eli Lilly and Co., Indianapolis, Indiana 46285, USA

Abstract

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A stereospecific synthesis of 2′-deoxy-2′,2′-difluorocytidine (gemcitabine), a potential anticancer agent, is described. The stereoselectivity was accomplished via two diastereoselective crystallizations, i. e. the crystallization of the key intermediate, difluororibonolactone 2a, and the crystallization of the hydrochloride salt of gemcitabine 16b from the anomeric mixture. Because of the availability of 2a in large quantities, other 2′-deoxy-2′,2′-difluoropyrimidine nucleosides such as 2′-deoxy-2′,2′-difluorouridine (19) were synthesized for structure-activity relationship studies.

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