Gemifloxacin mesilate, LB-20304(free base), LB-20304a, SB-265805, Factive
甲磺酸吉米沙星吉米沙星Chemical Name: (?-7-[(Z)-3-(Aminomethyl)-4-(methoxyimino)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid methanesulfonate; (?-7-[3-(Aminomethyl)-4-oxopyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid 7(4)-(Z)-(O-methyloxime) methanesulfonate
CAS No. 210353-53-0, 204519-64-2 (free base), 175463-14-6 (free base, no stereoch.), 210353-56-3 (sesquihydrate), 210353-55-2 (trihydrate)
项目整合开发状态: Launched-2004
项目研究机构: LG Chem (Originator), Oscient Pharmaceuticals (Licensee)
合成路线:1) The condensation of 3-methyl-1-[2-(1-piperidinyl)phenyl)butylamine (I) with 2-[3-ethoxy-4-(ethoxycarbonyl)phenyl]acetic acid (II) by means of triphenylphosphine,triethylamine and CCl4 gives the corresponding amide-ester (III),which is then hydrolyzed with NaOH in ethanol/water to the racemic repaglinide.2) The condensation of amine (I) with 2-[4-(ethoxycarbonyl)-3-hydroxyphenyl]acetic acid (IV) by means of triphenylphosphine as before yields the corresponding amide-ester (V),which is then submitted to ethoxylation with NaH and ethyl bromide in DMF to afford the racemic amide-ester (III),already obtained.
合成路线:The addition of glycine ethyl ester (I) to 2-propenenitrile (II) by means of KOH in water gives N-(2-cyanoethyl)glycine ethyl ester (III),which is cyclized by means of di-tert-butyl dicarbonate yielding the protected pyrrolidinone (IV).The reduction of (IV) with NaBH4 in ethanol affords the pyrrolidinol (V),which is further reduced with LiAlH4 in THF and protected with di-tert-butyl dicarbonate to give the fully N-protected compound (VI).The oxidation of (VI) with pyridine/SO3 complex yields the pyrrolidinone (VII),which is treated with O-methylhydroxylamine (VIII) to afford the correponding oxime (IX).The deprotection of (IX) with acetyl chloride in cool methanol gives 4-(aminomethyl)pyrrolidin-3-one O-methyloxime (X),which is finally condensed with 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (XI) by means of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in acetonitrile.
📌 参考资料/链接：
参考文献标题:Novel quinoline carboxylic acid derivs.having 7-(4-amino-methyl-3-oxime)pyrrolidine substituents and processes for their preparation
文献作者:Kwak,J.H.; Jeong,Y.N.; Oh,J.I.(LG Chem Ltd.)
参考来源:CA 2151890; EP 0688772; JP 1996041050; US 5633262; US 5698570; US 5776944
📄 详细内容
合成路线:The addition of glycine ethyl ester (I) to 2-propenenitrile (II) by means of KOH in water gives N-(2-cyanoethyl)glycine ethyl ester (III),which is cyclized by means of di-tert-butyl dicarbonate yielding the protected pyrrolidinone (IV).The reduction of (IV) with NaBH4 in ethanol affords the pyrrolidinol (V),which is further reduced with LiAlH4 in THF and protected with di-tert-butyl dicarbonate to give the fully N-protected compound (VI).The oxidation of (VI) with pyridine/SO3 complex yields the pyrrolidinone (VII),which is treated with O-methylhydroxylamine (VIII) to afford the correponding oxime (IX).The deprotection of (IX) with acetyl chloride in cool methanol gives 4-(aminomethyl)pyrrolidin-3-one O-methyloxime (X),which is finally condensed with 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (XI) by means of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in acetonitrile.
参考文献标题:Novel fluoroquinolone antibacterial agents containing oxime-substituted (aminomethyl)pyrrolidines: Synthesis and antibacterial activity of LB20304
文献作者:Hong,C.Y.; Kim,Y.K.; Chang,J.H.; Kim,S.H.; Choi,H.; Nam,D.H.; Kim,Y.Z.; Kwak,J.H.
参考来源:J Med Chem 1997,40(22),3584-93
合成路线:The addition of glycine ethyl ester (I) to 2-propenenitrile (II) by means of KOH in water gives N-(2-cyanoethyl)glycine ethyl ester (III),which is cyclized by means of di-tert-butyl dicarbonate yielding the protected pyrrolidinone (IV).The reduction of (IV) with NaBH4 in ethanol affords the pyrrolidinol (V),which is further reduced with LiAlH4 in THF and protected with di-tert-butyl dicarbonate to give the fully N-protected compound (VI).The oxidation of (VI) with pyridine/SO3 complex yields the pyrrolidinone (VII),which is treated with O-methylhydroxylamine (VIII) to afford the correponding oxime (IX).The deprotection of (IX) with acetyl chloride in cool methanol gives 4-(aminomethyl)pyrrolidin-3-one O-methyloxime (X),which is finally condensed with 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (XI) by means of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in acetonitrile.
参考文献标题:SB-265805/LB-20304a
文献作者:Graul,A.; Castar,J.
参考来源:Drugs Fut 1998,23(11),1199-1204