合成路线1

The esterification of N-(benzyloxycarbonyl)-L-aspartic acid 4-O-benzyl monoester (VII) with 2-(p-toluenesulfonyl)ethanol by means of DCC and pyridine gives the mixed diester (VIII), which is deprotected at the amino group with HCl in dioxane yielding compound (IX). The condensation of (IX) with protected glutamic acid (X) by means of HOBt, DIEA and WSC carbodiimide affords dipeptide (XI), which is deprotected with HCl as before giving (XII). The condensation of (XII) with pyroglutamic acid (XIII) as before yields tripeptide (XIV), which is deprotected at the terminal carboxy group by means of diazabicyclo[4.3.0]non-5-ene (DBN) providing tripeptide (XV).

合成路线2

The reaction of L-phenylalanine (I) with benzyl bromide and K2CO3 in hot EtOH/H2O gives N,N,O-tribenzyl derivative (II), which is condensed with acetonitrile (III) by means of NaNH2 in THF yielding the pentanenitrile (IV). The reaction of nitrile (IV) with benzylmagnesium chloride (V) in THF affords the diphenylhexenone (VI), which is reduced with NaBH4 in THF to give the diphenylhexanol (VII) (slightly impurified (~10%) with other diastereomers that are not eliminated at this stage). The condensation of (VII) with acid chloride (VIII) (obtained by reaction of acid (IX) with SOCl2) in the presence of imidazole yields the amide (X), which is debenzylated with ammonium formate over Pd/C in methanol affording the amine (XI). At this stage the purification (elimination of the diastereomers) has been performed by crystallization of its salt with L-pyroglutamic acid (XII) in EtOH/DMF, pure salt (XIII) being obtained. Finally, this compound is condensed with the acid chloride (XIV) (obtained by reaction of acid (XV) with SOCl2) by means of NaHCO3 in ethyl acetate/water. The intermediates, the acids (IX) and (XV), have been obtained as indicated in schemes 24659001a and 24659001b (intermediates (XIII) and (X) of these schemes, respectively).

合成路线3

The bicyclic carboxamide (V) can be obtained as follows. Esterification of L-pyroglutamic acid (XXIX) with ethanolic H2SO4 followed by protection with Boc2O gives 1-Boc-5-oxoproline ethyl ester (XXXI). After reduction of (XXXI) with LiBHEt3, the obtained hemiaminal (XXXII) is dehydrated to the dehydroproline derivative (XXXIII) employing trifluoroacetic anhydride, DMAP and DIEA. Subsequent hydrolysis of ethyl ester (XXXIII) by means of LiOH leads to the carboxylic acid (XXXIV), which is converted to the corresponding carboxamide (XXXV) via activation with methanesulfonyl chloride, followed by reaction with ammonia. Simmons-Smith cyclopropanation of (XXXV) using diiodomethane and diethylzinc gives the bicyclic derivative (XXXVI), which is then deprotected under acidic conditions to furnish (1S,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carboxamide (V) (2, 3). Scheme 4.

合成路线4