Process for preparing gemcitabine and associated intermediates

Abstract

Provided is a process for preparing gemcitabine or a salt thereof, which preferably includes removing at least a substantial portion of the a anomer of a N-1-protected-2'-deoxy-2',2'-difluoro-cytidine-3',5'-diester from an anomeric mixture thereof; removing the 3'-ester, the 5'-ester and the N-protecting group; and optionally forming a salt. The 3'-ester and 5'-ester can be the same or different and at least one of the esters preferably is cinnamoyl, benzoyl, 1-naphthoyl, 1-naphthylmethylcarbonyl, 2-methylbenzylcarbonyl, 4-methylbenzylcarbonyl or 9-fluorenylmethyloxycarbonyl ester. Also provided are novel intermediates, including but not limited to 2-deoxy-2,2-difluoro-D-erythro-pentofuranos-1-ulose-3,5-diesters, and methods of producing such intermediates.

Description

Background of the invention Gemcitabine HCl (Gemcitabine HCl), marketed by Eli Lilly under the trade name is a nucleoside analog with antitumor activity, belonging to the large group of chemotherapeutic drugs called antimetabolites. Gemcitabine stops the growth of cancer cells and causes them to die by interfering with the synthesis of nucleic acids, preventing cells from producing DNA and RNA. Gemcitabine is a synthetic glycoside analog of cytosine, which is chemically described as 4-amino-1-(2-deoxy-2,2-difluoro-β-D-ribofuranose)-pyrimidine-2(1H) -keto or 2'-deoxy-2',2'-difluorocytidine (beta isomer). Gemcitabine HCl has the following structure: Gemcitabine HCl 1 Supplied in sterile hydrochloride form in vials for intravenous administration only, containing 200 mg or 1 g of gemcitabine HCl (as the free base) in the form of a sterile lyophilized powder formulated with mannitol ( 200mg or 1g, respectively) and sodium acetate (12.5mg or 62.5mg, respectively). Hydrochlo...

AI Technical Summary

Problems solved by technology

However, this method requires additional steps relative to the method given in Scheme 2, which makes it less attractive in terms of industrial feasibility

The production of gemcitabine is inherently problematic, in particular the method requires the preparation and separation of isomers, which tends to result in lower yields on a commercial scale

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