Ecenofloxacin hydrochloride, CFC-222

合成路线: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.

参考文献标题:Practical synthesis of CFC-222,a new fluoroquinolone
文献作者:Lee,J.M.; Whang,H.S.; Lee,K.H.; Song,S.B.; Yoon,Y.H.; Kim,J.W.; Cho,I.H.
参考来源:35th Intersci Conf Antimicrob Agents Chemother (Sept 17-20,San Francisco) 1995,Abst F198


合成路线: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.
参考文献标题:Ecenofloxacin Hydrochloride
文献作者:Graul,A.; Castar,J.
参考来源:Drugs Fut 1998,23(4),370


产品链接: CAS No. 162424-67-1››