合成路线1

A general synthesis of this entire class of thrombin inhibitors has been published recently. An alternative synthesis for the preparation of napsagatran is outlined in Scheme 21319301a: L-Aspartic acid is sulfonated with naphthalenesulfochloride to give the sulfonamide (I). Reaction of (I) with formaldehyde leads to the oxazolinone (II), which is reacted with N-cyclopropylglycine ethyl ester (III) to afford the aspartate (IV). Condensation of (IV) with the guanidine (IX) and saponification of the ethyl ester group provides napsagatran. For the preparation of the guanidine (IX), picolylamine is hydrogenated to give the racemic 3-aminomethyl-piperidine, from which the desired enantiomer (V) is isolated as dibenzoyltartrate by crystallization. Reaction of piperidine (V) with acetoacetate affords the protected piperidine (VI), which is amidinated with amidinotriazole (VII) to give the protected guanidine (VIII). Deprotection of (VIII) with hydrochloric acid provides the enantiomerically pure guanidine (IX) as dihydrochloride.