合成路线1

3-Methoxypropyl chloride (I) is converted to the corresponding Grignard reagent by means of Mg in THF, followed by reaction with trimethyl borate and quenching with aqueous sulfuric acid to produce 3-methoxypropylboronic acid (II). Subsequent treatment of boronic acid (II) with a toluene or heptane solution of pinacol gives the pinacol boronate (III). One-carbon insertion into (III) is accomplished by treatment with dichloromethane, LDA and zinc chloride to furnish the 1-chloro-4-methoxybutylboronate (IV). Substitution of the chloride (IV) with lithium hexamethyldisilazide in THF, followed by desilylation with HCl in cold n-heptane, leads to the aminoboronate (V), which is then coupled with N-benzyloxycarbonyl-D-phenylalanyl-L-proline (VI) via activation as the mixed anhydride with isobutyl chloroformate to afford the tripeptide analogue (VII). The diastereomeric mixture of pinacol boronates (VII) undergoes transesterification and epimerization with diethanolamine in boiling diethyl ether to provide the diethanolamine adduct (VIII). Subsequent acidic hydrolysis of adduct (VIII) gives the boronic acid flovagatran, which is finally isolated as the corresponding sodium salt by treatment with sodium hydroxide in acetonitrile/water (1-3). Scheme 1.