Gemifloxacin mesilate, LB-20304(free base), LB-20304a, SB-265805, Factive, -Drug Synthesis Database

【结构式】

【药物名称】Gemifloxacin mesilate, LB-20304(free base), LB-20304a, SB-265805, Factive

【化学名称】(±)-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

【CA登记号】210353-53-0, 204519-64-2 (free base), 175463-14-6 (free base, no stereoch.), 210353-56-3 (sesquihydrate), 210353-55-2 (trihydrat

【分子式】C₁₉H₂₄FN₅O₇S

【分子量】485.49483

【开发单位】LG Chem (Originator), GeneSoft (Licensee)

【药理作用】Antibacterial Drugs, ANTIINFECTIVE THERAPY, DNA Gyrase Inhibitors, DNA Topoisomerase IV Inhibitors, Naphthyridines

合成路线1 合成路线2 合成路线3

合成路线1

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.

参考文献中间体

【1】 Kim, Y.K.; Chang, J.H.; Choi, H.; Hong, C.Y.; Nam, D.H.; Kim, Y.Z.; Kim, S.H.; Kwak, J.H.; Novel fluoroquinolone antibacterial agents containing oxime-substituted (aminomethyl)pyrrolidines: Synthesis and antibacterial activity of LB20304. J Med Chem 1997, 40, 22, 3584-93.
【2】 Graul, A.; Castañer, J.; SB-265805/LB-20304a. Drugs Fut 1998, 23, 11, 1199-1204.
【3】 Kwak, J.H.; Jeong, Y.N.; Oh, J.I. (LG Chem Ltd.); Novel quinoline carboxylic acid derivs. having 7-(4-amino-methyl-3-oxime)pyrrolidine substituents and processes for their preparation. CA 2151890; EP 0688772; JP 1996041050; US 5633262; US 5698570; US 5776944 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	10309	ethyl 2-aminoacetate; Glycine ethyl ester	459-73-4	C₄H₉NO₂	详情	详情
(II)	10847	Acrylonitrile	107-13-1	C₃H₃N	详情	详情
(III)	17731	ethyl 2-[(2-cyanoethyl)amino]acetate		C₇H₁₂N₂O₂	详情	详情
(IV)	17732	tert-butyl 3-cyano-4-oxo-1-pyrrolidinecarboxylate		C₁₀H₁₄N₂O₃	详情	详情
(V)	17733	tert-butyl 3-cyano-4-hydroxy-1-pyrrolidinecarboxylate		C₁₀H₁₆N₂O₃	详情	详情
(VI)	17734	tert-butyl 3-[[(tert-butoxycarbonyl)amino]methyl]-4-hydroxy-1-pyrrolidinecarboxylate		C₁₅H₂₈N₂O₅	详情	详情
(VII)	17735	tert-butyl 3-[[(tert-butoxycarbonyl)amino]methyl]-4-oxo-1-pyrrolidinecarboxylate		C₁₅H₂₆N₂O₅	详情	详情
(VIII)	15455	(aminooxy)methane; O-methylhydroxylamine	67-62-9	CH₅NO	详情	详情
(IX)	17737	tert-butyl 3-[[(tert-butoxycarbonyl)amino]methyl]-4-(methoxyimino)-1-pyrrolidinecarboxylate		C₁₆H₂₉N₃O₅	详情	详情
(X)	17738	4-(aminomethyl)-3-pyrrolidinone O-methyloxime		C₆H₁₃N₃O	详情	详情
(XI)	17034	7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylic acid	100361-18-0	C₁₂H₈ClFN₂O₃	详情	详情

合成路线2

参考文献中间体

【1】 Hong CY, Kim YK, Chang JH, et aL 1997. Novel fluoroquinolone antibacterial agents containing oximesubstituted (aminomethyl) pyrrolidines: synthesis ancl antibacterial activity of 7-[4-(aminomethyl)-3-(methox}rimino) pyrrolidin-l-yl]-l-cyclopropyl-6-fluoro-4-axa-l, 4-dihydro[1,8]naphthyridine-3-carboxylic acid (LB20304).J Med Chem, 40 (22): 3584~3593
【2】 Kwak JH. 1997. Novel quinoline carboxylic acid derivatives having 7-(4-anuno-methyl-3-oxime) pyrrolidine substituents and processes for their preparation. US 5698570【本专利为LG Chm Ltd所有）

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(IV)	17735	tert-butyl 3-[[(tert-butoxycarbonyl)amino]methyl]-4-oxo-1-pyrrolidinecarboxylate	C₁₅H₂₆N₂O₅	详情	详情
(I)	17732	tert-butyl 3-cyano-4-oxo-1-pyrrolidinecarboxylate	C₁₀H₁₄N₂O₃	详情	详情
(II)	66451	tert-butyl 3-(aminomethylene)-4-oxopyrrolidine-1-carboxylate	C₁₀H₁₆N₂O₃	详情	详情
(III)	66452	tert-butyl 3-(((tert-butoxycarbonyl)amino)methylene)-4-oxopyrrolidine-1-carboxylate	C₁₅H₂₄N₂O₅	详情	详情
(V)	17737	tert-butyl 3-[[(tert-butoxycarbonyl)amino]methyl]-4-(methoxyimino)-1-pyrrolidinecarboxylate	C₁₆H₂₉N₃O₅	详情	详情
(VI)	17738	4-(aminomethyl)-3-pyrrolidinone O-methyloxime	C₆H₁₃N₃O	详情	详情

合成路线3

参考文献中间体

【1】 Cho SW, Choi HY, Hayler JD 2001. Process for production of naphthyridine-3-carboxylic acid derivatives. W0 2001018002（本专利为Sb Phdmco Puerto Rico Inc, USA; Lg Chmucal Ltd所有）
【2】 Hwang G-H, Kim Y-D, Nam H, et aL 2004. Process for preparing 4-aminomethyl-3-alkoxyinunopyrrolidine methanesulfonates from N-protected 4-cyano-3-moopyrrolidines and (halo) alkoxyamines. WO 2004092129(本专利申请人为LG Life Sciences Ltd,SKorea)
【3】 Noh HK, Lee JS, Kim Y, et 81.2004. Synthesis of the intermediate of gemifloxacin by the chemoselective hydrogenation of 4-cyano-3-metboxyimino-l-(N-tert-butoxycarlxmyl) pyrrolidine. Part 1.Screening of metal catalysts. Org Proc Res Dev,8(5)1 781~787
【4】 Noh HK, Lee JS, Kim Y, et aL 2004. Synthesis of the intermediate ofgemifloxacin by the chemoselective hydrogenationof 4-cyano-3-methoxyimino-l-(N-tert-butoxycarbonyl) pyrrolidine. Part 2.The palladium catalysts in acidic media. Org Proc Res Dev,8(5): 788~795
【5】 Parthasaradhi RB, Rathnakar RK, R.aji RR, et aL 2006. Process for the preparation of amorphous gemifloxacin and its polymorphs for use infusion solutions. W0 2006134608(奉专利申请人为Hetero Drugs Limited, India)

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	17732	tert-butyl 3-cyano-4-oxo-1-pyrrolidinecarboxylate	C₁₀H₁₄N₂O₃	详情	详情
(II)	66453	tert-butyl 3-cyano-4-(methoxyimino)pyrrolidine-1-carboxylate	C₁₁H₁₇N₃O₃	详情	详情
(III)	66454	tert-butyl 3-(aminomethyl)-4-(methoxyimino)pyrrolidine-1-carboxylate	C₁₁H₂₁N₃O₃	详情	详情
(IV)	17738	4-(aminomethyl)-3-pyrrolidinone O-methyloxime	C₆H₁₃N₃O	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)