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【结 构 式】 
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【分子编号】17732 【品名】tert-butyl 3-cyano-4-oxo-1-pyrrolidinecarboxylate 【CA登记号】 |
【 分 子 式 】C10H14N2O3 【 分 子 量 】210.23284 【元素组成】C 57.13% H 6.71% N 13.32% O 22.83% |
与该中间体有关的原料药合成路线共 3 条
合成路线1
该中间体在本合成路线中的序号：(IV)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.
| 【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
该中间体在本合成路线中的序号：(I)
| 【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 | CAS号 | 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
该中间体在本合成路线中的序号：(I)
| 【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 | CAS号 | 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