Ximelagatran

Description

Ximelagatran (XII), a prodrug of a direct thrombin inhibitor, melagatrin, was approved in the European Union in December, 2003, for the prevention of venous thromboembolic events in patients undergoing major elective orthopedic surgery, that is, hip or knee replacement. The FDA, however, did not approve the drug in the US based on the recommendation of the advisory panel.

Uses

Antithrombotic agent.

brand name

Exanta (proposed) (AstraZeneca).

Synthesis

Synthesis of melagatran and ximelagatran has been published in several patents and is shown in the Scheme. The synthesis is based on coupling of key fragment 86 with acid 91 followed by elaboration to provide ximelagatran. The synthesis of the key intermediate, shown in Scheme 12, was reported to be scalable in high yields. Reaction of benzyl bromide 81 with ditertbutylimino dicarboxylate in the presence of sodium hydride gave 82, which was reacted with hydroxyl amine in aqueous ethanol to give hydroxyl amidine 83 in 80% yield. Immediate hydrogenation removed the hydroxyl group and gave 84, which was protected with benzyl chloroformate to provide 85. Deprotection of 85 with acid furnished amidine intermediate 86. Synthesis of fragment 91 was done by hydrogenation of N-BOC phenyl glycine (87) in the presence of rhodium in alumina to provide cyclohexyl amino acid 88 in 83% yield. Coupling of the acid 88 with azetidine 2-methyl ester (89) using EDC provided 90 in 92% yield. Hydrolysis of the ester followed by coupling to a key intermediate benzyl carbamate protected aminino benzyl amine 86 under EDC coupling conditions provided 92 in 86%. Subsequent hydrogenolysis removed the benzyl carbamate and provided intermediate 93. To complete the synthesis, the intermediate 93 was reacted with activated double ester 94 to furnish simultaneously protected and activated amidine 95. Removal of the BOC group (TFA) followed by reaction with ethyl (Otrifluoromethanesulfonyl)- glycolate in the presence of base provided esterified intermediate 97. Reaction of 97 with hydroxyl amine hydrochloride in the presence of base deprotected and installed hydroxyl amidine product, ximelagatrin (XII).

Raw materials

Preparation Products