An Improved and Scalable One Pot Process for the Synthesis of Antineoplastic Drug Capecitabine

LUCÍA, GANDOLFI DONADÍO; CINTIA, CHECURA; CYNTHIA L., GARCÍA; MARINA SANTOS; M. JULIETA, COMIN

Buzios

Congreso; 16 the Brazilian Meeting on Organic Synthesis; 2015

Brazilian Meeting on Organic Synthesis Organizing Committee

An Improved and Scalable One Pot Process for the Synthesisof Antineoplastic Drug CapecitabineGandolfi Donadío, L.; Checura, C.; Garcia, C.; Santos, M; Comin, M. J.Centro de Investigación y Desarrollo en Química, Instituto Nacional de Tecnología Industrial, Argentinajcomin@inti.gob.arKeywords: process optimization, scale up, API nucleoside analogueINTRODUCTIONCapecitabine (1) is an orally administeredchemotherapeutic agent used in the treatment ofnumerous cancers.1 It is commercially availableunder the brand name XELODA®. It is a prodrug thatis enzymatically converted to the thymidylatesynthase inhibitor 5-fluorouracil (2). Two mainstrategies have been described for the synthesis of1. Introduction of the carbamate group into theprotected 5-fluorocytidine intermediate and, morerecently, a glycosylation reaction starting from thesugar precursor 6 employing the derivative 4 asnucleophile. In all cases isolation of everyintermediate was neccesary.2We present here a process that starting from thecommercially available 6, yields capecitabine (1) in aone pot procedure without isolation of intermediatesand in high yield and quality.RESULTS AND DISCUSSIONStarting from the conditions found at laboratoryscale (DMF-Pyridine, anhydrous conditions, roomtemperature, 1 equivalent of 3), we studied theprocess variables such as concentration,temperature, reaction time and equivalents of 3.Scheme 1. Structures of antineoplastic drugsCapecitabine (1) and 5-Fluorouracil (2). Synthetic pathwaytowards capecitabine (1). An efficient and scalableprocess.We found that increasing the concentration and theequivalents of 3 and crystallizing the product fromethanol-water yielded the desired intermediate 4 asa white crystalline product in 75% yield and highpurity (HPLC > 98%). The process was simple anddid not require anhydrous conditions.The key glycosylation step joints a protected sugarwith in situ silylated base 5 in the presence ofstoichiometric trimethylsilyl triflate as Lewis acid.3The first assays during optimization showed that 7was unstable. Variable amounts of partiallydeacetylated products were observed. So, wemodified the process in order to avoid its isolation.We were please to find out that, after glycosylationwas completed, addition of base at low temperatureallowed the clean deprotection in the same reactionmedia. Capecitabine (1) could be isolated as a whitecrystalline product in 65% overall yield and with highpurity (>99% HPLC) after only one crystallization.One critical aspect to the successful development ofthe telescoped procedure was to determine thecomplete conversion from 4 to 5. Only after heatingthe reaction mixture for 5 hours at 85°C, fullconversion was observed as measured by 1H NMRin anhydrous d6-DMSO. At this point, thetemperature was set to -10°C when sugar 6 andLewis acid were added. Glycosylation wasimmediately finished and then, an aqueous solutionof NaOH was added dropwise maintaining thetemperature between -5 and 0°C. After 30 min atthis temperature conversion was total and 1 wasisolated by extraction and crystallization.CONCLUSIONBy thoroughly optimizing reactions conditions wewere able to develop an efficient, robust andscalable process that yielded capecitabine in 49%overall yield and high purity at a multigrame scale.ACKNOWLEDGEMENTSThis work was supported by Consejo Nacional deInvestigaciones Científicas y Técnicas (CONICET),Instituto Nacional de Tecnología Industrial (INTI)and by Laboratorios Richmond SACIF .REFERENCES1 Walko, C. M.; Lindley, C. Clin. Ther. 2005, 27, 23.2 Gore, V.G.; Patkar, L. .; Bhalerao, R.; Hublikar, M. G.; Pokharkar, K. S.WO2011/104540.3Vorbruggen, H.; Ruth-Polens, C. Org. React. 2000, 55, 1.