合成路线1

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2

Treatment of ethyl N-Boc-(S)-pyroglutamate (I) with lithium hexamethyldisilazide in THF at -78 C, followed by aldol condensation of the resulting lithium enolate with cyclopentanone (II) in the presence of boron trifluoride etherate, furnished adduct (III). Dehydration of the alcohol group of (III) to produce olefin (IV) was achieved by treatment of (III) with methanesulfonyl chloride and triethylamine. Hydrolysis of the ester and lactam groups of (IV) by means of LiOH afforded diacid (V). The N-Boc group of (V) was finally cleaved with HCl in EtOH.

合成路线3

Treatment of ethyl N-Boc-(S)-pyroglutamate (I) with lithium hexamethyldisilazide in THF at -78 C, followed by aldol condensation of the resulting lithium enolate with 3-pentanone (II) in the presence of boron trifluoride etherate, furnished adduct (III). Dehydration of the alcohol group of (III) to produce olefin (IV) was achieved by treatment of (III) with methanesulfonyl chloride and triethylamine. Hydrolysis of the ester and lactam groups of (IV) by means of LiOH afforded diacid (V). The N-Boc group of (V) was finally cleaved with HCl in EtOH.

合成路线4

D-Glutamic acid (I) is treated with SOCl2 in EtOH to produce ethyl D-pyroglutamate (II). Further protection of (II) with di-tert-butyl dicarbonate yields the N-Boc pyroglutamate (III) (1). The lithiated derivative of (III) is alkylated with 2-(bromomethyl)benzothiophene (IV) to afford the trans alkylated isomer (V). Basic hydrolysis of (V) produces the N-Boc amino diacid (VI). Then, acidic Boc group cleavage in (VI), followed by treatment of the resultant hydrochloride salt with propylene oxide in MeOH leads to the free aminoacid (1,2).

合成路线5