The reaction of 4-aminobenzamidine dihydrochloride (I) with succinic anhydride and pyridine in hot DMF gives the succinyl derivative (II), which is activated with isobutyl chloroformate and N-methylmorpholine (NMM) and then coupled to 3(S)-amino-4-pentynoic acid ethyl ester (III) in DMF or DMAc.

The reaction of 4-aminobenzamidine dihydrochloride (I) with succinic anhydride and pyridine in hot DMF gives the succinyl derivative (II), which is activated with isobutyl chloroformate and N-methylmorpholine (NMM) and then coupled to 3(S)-amino-4-pentynoic acid ethyl ester (III) in DMF or DMAc.

The ethyl ester (III), a chiral key intermediate of this synthesis, can be obtained as follows: 2) The treatment of (trimethylsilyl)acetylene (XII) with butyllithium and NMM in methyl tert-butyl ether (MTBE), followed by hydrolysis with aqueous HCl, gives 3-(trimethylsilyl)-2-propynal (XIII). Treatment of (XIII) with lithium bis(trimethylsilyl)amide (LiHMDS) and trimethylsilyl chloride at -20 C gives the imine (XIV), which is reacted in situ with lithium tert-butyl acetate followed by hydrolysis with aqueous NH4Cl to afford racemic tert-butyl ester (XV). Treatment of (XV) with refluxing ethanol in the presence of p-toluenesulfonic acid gives the corresponding ethyl ester (VII) (already obtained in the preceding scheme). Desilylation of (VII) with NaOEt/EtOH affords racemic 3-amino-4-pentynoic acid ethyl ester in situ, which is then resolved using R-(-)-mandelic acid in ethyl acetate/MTBE to give mandelic acid salt (XVI). Recrystallization of (XVI) from acetonitrile/MTBE and treatment with gaseous HCl in MTBE affords ethyl ester (III) as the hydrochloride.

The reaction of 4-aminobenzamidine dihydrochloride (I) with succinic anhydride and pyridine in hot DMF gives the succinyl derivative (II), which is activated with isobutyl chloroformate and N-methylmorpholine (NMM) and then coupled to 3(S)-amino-4-pentynoic acid ethyl ester (III) in DMF or DMAc.

The ethyl ester (III), a chiral key intermediate of this synthesis, can be obtained as follows: 1) The reaction of 4-(benzoyloxy)-2-azetidinone (IV) with 2 equivalents of 1-lithio-2-(trimethylsilyl)acetylene (V) gives azetidinone (VI), which is opened with anhydrous HCl in ethanol, yielding racemic 3-amino-5-(trimethylsilyl)-4-pentynoic acid ethyl ester (VII). Resolution of (VII) by means of diastereomeric amide formation with (R)-O-methyl mandelic acid chloride (VIII) and chromatographic separation of the diastereoisomers (MPLC, ether/hexane) affords the amide (IX), which is then N-protected with Boc2O in acetonitrile to give (X). Treatment of (X) with tetramethylguanidine in methanol gives methyl ester (XI), which is finally treated first with TFA and then with HCl in ethanol to afford ethyl ester (III).

The reaction of 4-aminobenzamidine dihydrochloride (I) with succinic anhydride and pyridine in hot DMF gives the succinyl derivative (II), which is activated with isobutyl chloroformate and N-methylmorpholine (NMM) and then coupled to 3(S)-amino-4-pentynoic acid ethyl ester (III) in DMF or DMAc.

The ethyl ester (III), a chiral key intermediate of this synthesis, can be obtained as follows: 1) The reaction of 4-(benzoyloxy)-2-azetidinone (IV) with 2 equivalents of 1-lithio-2-(trimethylsilyl)acetylene (V) gives azetidinone (VI), which is opened with anhydrous HCl in ethanol, yielding racemic 3-amino-5-(trimethylsilyl)-4-pentynoic acid ethyl ester (VII). Resolution of (VII) by means of diastereomeric amide formation with (R)-O-methyl mandelic acid chloride (VIII) and chromatographic separation of the diastereoisomers (MPLC, ether/hexane) affords the amide (IX), which is then N-protected with Boc2O in acetonitrile to give (X). Treatment of (X) with tetramethylguanidine in methanol gives methyl ester (XI), which is finally treated first with TFA and then with HCl in ethanol to afford ethyl ester (III).

The ethyl ester (III), a chiral key intermediate of this synthesis, can be obtained as follows: 2) The treatment of (trimethylsilyl)acetylene (XII) with butyllithium and NMM in methyl tert-butyl ether (MTBE), followed by hydrolysis with aqueous HCl, gives 3-(trimethylsilyl)-2-propynal (XIII). Treatment of (XIII) with lithium bis(trimethylsilyl)amide (LiHMDS) and trimethylsilyl chloride at -20 C gives the imine (XIV), which is reacted in situ with lithium tert-butyl acetate followed by hydrolysis with aqueous NH4Cl to afford racemic tert-butyl ester (XV). Treatment of (XV) with refluxing ethanol in the presence of p-toluenesulfonic acid gives the corresponding ethyl ester (VII) (already obtained in the preceding scheme). Desilylation of (VII) with NaOEt/EtOH affords racemic 3-amino-4-pentynoic acid ethyl ester in situ, which is then resolved using R-(-)-mandelic acid in ethyl acetate/MTBE to give mandelic acid salt (XVI). Recrystallization of (XVI) from acetonitrile/MTBE and treatment with gaseous HCl in MTBE affords ethyl ester (III) as the hydrochloride.

A short and efficient synthesis of xemilofiban has been achieved as follows: The reaction of ethyl chloroformate (I) with trimethylsilylacetylene (II) by means of butyllithium gives ethyl 3-(trimethylsilyl)propyonate (III), which is condensed with the lithium salt of ethyl acetate (IV) yielding ethyl 5-(trimethylsilyl)-3-oxo-4-pentynoate (V). The selective reduction of (V) with lyophilized baker's yeast (Saccharomyces cerevisiae, Sigma type II) affords ethyl 3(R)-hydroxy-5-(trimethylsilyl)-4-pentynoate (VI), which by reaction with ammonia (VII), diethyl azodicarboxylate (VIII) and triphenylphosphine, followed by hydrolysis with water gives 3(S)-amino-5-(trimethylsilyl)-4-pentynoate (IX). Finally, this compound is condensed with N-(4-amidinophenyl)succinamic acid (XI) by means of isobutyl chloroformate and N-methylmorpholine (NMM). The intermediate succinamic acid (XI) has been obtained by condensation of 4-aminobenzamidine (XII) with succinic anhydride (XIII) in DMF.