合成路线1

合成路线2

By reaction of beta-alanine (I) with the phosphorous acid and PCl3 in chlorobenzene at 100 C.

合成路线3

CFC-222 has been obtained by four closely related ways: 1) The acylation of beta-alanine (I) with tosyl chloride and NaOH in water gives the corresponding tosylate (II), which is esterified with SOCl2 and ethanol as usual yielding the ethyl ester (III). The alkylation of the amido group of (III) with 2-methylallyl chloride (IV) by means of KI, K2CO3 and tetrabutylammonium iodide in acetonitrile affords the alkylated sulfonamide (V), which is condensed with pyrrolidine (VI) by means of SOCl2 in dichloromethane to give the acylated pyrrolidine (VII). The cyclization of (VII) by means of trifluoromethanesulfonic anhydride and collidine in dichloromethane yields racemic cis-1-methyl-3-(p-toluenesulfonyl)-3-azabicyclo[3.2.0]heptan-6-one (VIII), which is converted to the corresponding oxime (IX) with hydroxylamine in pyridine. The reduction of (IX) with NaBH4 and NiCl2 affords racemic cis-1-methyl-3-(p-toluenesulfonyl)-3-azabicyclo[3.2.0]heptan-6-amine (X), which is submitted to optical resolution with L-tartaric acid to give pure (1R,5S,6S)-isomer (XI). Elimination of the tosyl group of (XI) with concentrated HBr yields (1R,5S,6S)-3-azabicyclo[3.2.0]heptan-6-amine (XII), which is finally condensed with 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (XIII) by means of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and HCl in acetonitrile. 2) The cyclization of the alkylated sulfonamide (V) to the racemic bicyclic ketone (VIII) can also be performed (with better yields) by direct cyclization with SOCl2 and triethylamine. 3) The conversion of the racemic ketone (VIII) to the racemic amine (X) can also be performed by treatment of (VIII) with O-methylhydroxylamine in methanol to obtain the O-methyloxime (XIV), which is then reduced to amine (X) with NaBH4 and trifluoroacetic acid (with poorer yields). 4) The optical resolution of racemic amine (X) can also be performed with N-tosyl-L-phenylalanine.

合成路线4

Salicylaldehyde (I) was alkylated with 1,3-dibromopropane (II) to provide bromopropyl ether (III). Furter displacement of the bromine of (III) with the potassium salt of 2-mercaptoimidazole (IV) gave thioether (V). Condensation of methyl cyanoacetate (VI) with 3-chlorobenzylamine (VII) at 120 C afforded cyanoacetamide (VIII). Finally, Knoevenagel reaction of (VIII) with benzaldehyde (V) in the presence of beta-alanine furnished the title compound.

合成路线5

Derivative (VIII) is obtained as follows: Activation of protected aminoacid (IX) with DCC/HOSu and coupling with H-Arg(Pmc)-OH (A) yields carboxylic acid derivative (X) which is converted to methyl ester (XI). Catalytic hydrogenation of (XI) and coupling with the protected caproic acid (XII) in presence of DCC and HOSu provides derivative (XIII) which is finally catalytically hydrogenated yielding intermediate (VIII).

合成路线6

Treatment of beta-alanine (I) with phthalic anhydride (II) in refluxing toluene provides phthalimidopropionic acid (III), which upon cyclocondensation with 2-aminophenol (IV) in hot polyphosphoric acid provides the benzoxazole derivative (V). Hydrazinolysis of phthalimide (V) affords the primary amine (VI), which is finally condensed with pyrazole-1-carboxamidine hydrochloride (VII) in DMF to produce the target guanidine compound.