【药物名称】A-319492, ABT-492, WQ-3034
化学结构式(Chemical Structure):
参考文献No.32928
标题:Novel pyridonecarboxylic acid derivs. or their salts and antibacterial agent comprising the same as the active ingredient
作者:Yazaki, A.; Niino, Y.; Ohshita, Y.; Hirao, Y.; Amano, H.; Hayashi, N.; Kuramoto, Y. (Wakunaga Pharmaceutical Co., Ltd.)
来源:EP 0911327; EP 0992501; JP 1999322715; JP 2000136191; US 5998436; US 6133284; WO 9711068
合成路线图解说明:

Reaction of 2,3,5,6-tetrafluoropyridine (I) with benzylamine (II) in refluxing acetonitrile gives 2-(benzyl-amino)-3,5,6-trifluoropyridine (III), which is debenzylated with H2 over Pd/C in methanol to yield 3,5,6-trifluoropyridine-2-amine (IV). Reaction of amine (IV) with 4-methoxybenzylamine (V) in N-methylpyrrolidone at 140 C affords 3,5-difluoro-6-(4-methoxybenzylamino)pyridine-2-amine (VI), which is cyclized with 2-(3-chloro-2,4,5-trifluorobenzoyl)-3-ethoxyacrylic acid ethyl ester (VII) ?obtained by condensation of 2-(3-chloro-2,4,5-trifluorobenzoyl)acetic acid ethyl ester (VIII) with triethyl orthoformate (IX) by means of acetic anhydride ?in hot DMF in the presence of K2CO3 to provide the N-protected aminoquinolone derivative (X). Reaction of quinolone (X) with HCl in refluxing acetic acid gives 4-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (XI), which is finally condensed with 3-hydroxyazetidine (XII) by means of N-methylpyrrolidine in refluxing acetonitrile.

参考文献No.694439
标题:Structure-activity relationships of fluoroquinolones containing various heteroaromatics at N-1; WQ-3034/ABT-492 and its derivatives
作者:Ohshita, Y.; Kuramoto, Y.; Niino, Y.; Yazaki, A.
来源:42nd Intersci Conf Antimicrob Agents Chemother (Sept 27 2002, San Diego) 2002,Abst F-544
合成路线图解说明:

Reaction of 2,3,5,6-tetrafluoropyridine (I) with ammonia in formamide gives the 2-aminopyridine derivative (IV), which is condensed with tert-butylamine (XIII) in N-methylpyrrolidone to yield 6-(tert-butylamino)-3,5-di- fluoropyridine-2-amine (XIV). Condensation of amine (XIV) with 2-(3-chloro-2,4,5-trifluorobenzoyl)-3-ethoxyacrylic acid ethyl ester (VII) gives the adduct (XV), which is cyclized by means of K2CO3 in DMF to afford the quinolone derivative (XVI). Treatment of quinolone (XVI) with HCl in AcOH produces simultaneous ester hydrolysis and tert-butyl group removal, providing 4-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (XI). Finally, this compound is condensed with 3-hydroxyazetidine (XII) by means of N-methylpyrrolidine in DMF.

参考文献No.707859
标题:ABT-492
作者:Mealy, N.E.; Casta馿r, J.
来源:Drugs Fut 2002,27(11),1033
合成路线图解说明:

Reaction of 2,3,5,6-tetrafluoropyridine (I) with benzylamine (II) in refluxing acetonitrile gives 2-(benzyl-amino)-3,5,6-trifluoropyridine (III), which is debenzylated with H2 over Pd/C in methanol to yield 3,5,6-trifluoropyridine-2-amine (IV). Reaction of amine (IV) with 4-methoxybenzylamine (V) in N-methylpyrrolidone at 140 C affords 3,5-difluoro-6-(4-methoxybenzylamino)pyridine-2-amine (VI), which is cyclized with 2-(3-chloro-2,4,5-trifluorobenzoyl)-3-ethoxyacrylic acid ethyl ester (VII) ?obtained by condensation of 2-(3-chloro-2,4,5-trifluorobenzoyl)acetic acid ethyl ester (VIII) with triethyl orthoformate (IX) by means of acetic anhydride ?in hot DMF in the presence of K2CO3 to provide the N-protected aminoquinolone derivative (X). Reaction of quinolone (X) with HCl in refluxing acetic acid gives 4-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (XI), which is finally condensed with 3-hydroxyazetidine (XII) by means of N-methylpyrrolidine in refluxing acetonitrile.

合成路线图解说明:

Reaction of 2,3,5,6-tetrafluoropyridine (I) with ammonia in formamide gives the 2-aminopyridine derivative (IV), which is condensed with tert-butylamine (XIII) in N-methylpyrrolidone to yield 6-(tert-butylamino)-3,5-di- fluoropyridine-2-amine (XIV). Condensation of amine (XIV) with 2-(3-chloro-2,4,5-trifluorobenzoyl)-3-ethoxyacrylic acid ethyl ester (VII) gives the adduct (XV), which is cyclized by means of K2CO3 in DMF to afford the quinolone derivative (XVI). Treatment of quinolone (XVI) with HCl in AcOH produces simultaneous ester hydrolysis and tert-butyl group removal, providing 4-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (XI). Finally, this compound is condensed with 3-hydroxyazetidine (XII) by means of N-methylpyrrolidine in DMF.

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