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【结 构 式】 
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【分子编号】17034 【品名】7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylic acid 【CA登记号】100361-18-0 |
【 分 子 式 】C12H8ClFN2O3 【 分 子 量 】282.6583032 【元素组成】C 50.99% H 2.85% Cl 12.54% F 6.72% N 9.91% O 16.98% |
合成路线1
该中间体在本合成路线中的序号：(XIII)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.
| 【1】 Lee, J.M.; Whang, H.S.; Lee, K.H.; Song, S.B.; Yoon, Y.H.; Kim, J.W.; Cho, I.H.; Practical synthesis of CFC-222, a new fluoroquinolone. 35th Intersci Conf Antimicrob Agents Chemother (Sept 17-20, San Francisco) 1995, Abst F198. |
| 【2】 Graul, A.; Castañer, J.; Ecenofloxacin Hydrochloride. Drugs Fut 1998, 23, 4, 370. |
| 【3】 Kim, C.S.; Kim, J.W.; Lee, J.M.; Cho, I.H.; Youn, Y.S.; Shin, Y.J.; Lee, K.H.; Kim, J.H.; Jung, Y.H.; An, S.H. (Cheil Jedang Corporation); Novel pyridone carboxylic acid derivs. JP 1996505384; US 5527910; WO 9415933 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| rac-(VIII) | 17029 | (1R,5S)-1-methyl-3-[(4-methylphenyl)sulfonyl]-3-azabicyclo[3.2.0]heptan-6-one | C14H17NO3S | 详情 | 详情 | |
| rac-(IX) | 17030 | (1R,5S)-1-methyl-3-[(4-methylphenyl)sulfonyl]-3-azabicyclo[3.2.0]heptan-6-one oxime | C14H18N2O3S | 详情 | 详情 | |
| rac-(X) | 17031 | (rac)-(1R*,5S*,6S*)-1-methyl-3-[(4-methylphenyl)sulfonyl]-3-azabicyclo[3.2.0]hept-6-ylamine; (rac)-(1R*,5S*,6S*)-1-methyl-3-[(4-methylphenyl)sulfonyl]-3-azabicyclo[3.2.0]heptan-6-amine | C14H20N2O2S | 详情 | 详情 | |
| rac-(XIV) | 17035 | (1R,5S)-1-methyl-3-[(4-methylphenyl)sulfonyl]-3-azabicyclo[3.2.0]heptan-6-one O-methyloxime | C15H20N2O3S | 详情 | 详情 | |
| (I) | 17022 | beta-Alanine; 3-aminopropionic acid | 107-95-9 | C3H7NO2 | 详情 | 详情 |
| (II) | 17023 | 3-(Toluene-4-sulfonylamino)-propionic acid; 3-[[(4-methylphenyl)sulfonyl]amino]propionic acid | C10H13NO4S | 详情 | 详情 | |
| (III) | 17024 | ethyl 3-[[(4-methylphenyl)sulfonyl]amino]propanoate | C12H17NO4S | 详情 | 详情 | |
| (V) | 17026 | ethyl 3-[[(4-methylphenyl)sulfonyl](2-methyl-2-propenyl)amino]propanoate | C16H23NO4S | 详情 | 详情 | |
| (VI) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (VII) | 17028 | 4-methyl-N-(2-methyl-2-propenyl)-N-[3-oxo-3-(1-pyrrolidinyl)propyl]benzenesulfonamide | C18H26N2O3S | 详情 | 详情 | |
| (XI) | 65065 | (1R,5S,6S)-1-methyl-3-[(4-methylphenyl)sulfonyl]-3-azabicyclo[3.2.0]hept-6-ylamine; (1R,5S,6S)-1-methyl-3-[(4-methylphenyl)sulfonyl]-3-azabicyclo[3.2.0]heptan-6-amine | C14H20N2O2S | 详情 | 详情 | |
| (XII) | 17033 | (1R,5S,6S)-1-methyl-3-azabicyclo[3.2.0]heptan-6-amine; (1R,5S,6S)-1-methyl-3-azabicyclo[3.2.0]hept-6-ylamine | C7H14N2 | 详情 | 详情 | |
| (XIII) | 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：(XI)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3
该中间体在本合成路线中的序号：(XIX)Condensation of the intermediate pyrrolidine (XII) with the fluoronaphthyridine (XIX) provided adduct (XX). Simultaneous cleavage of the ketal and N-Boc groups under acidic conditions gave (XXI). The keto group of (XXI) was finally converted to the title O-methyloxime by treatment with O-methylhydroxylamine in pyridine.
| 【1】 Lee, C.-W.; et al.; Synthesis antibacterial activities of DW286, a new fluoronaphthyridone antibiotic as an enantiomer. 41st Intersci Conf Antimicrob Agents Chemother (Dec 16 2001, Chicago) 2001, Abst F-553. |
| 【2】 Yoon, S.J.; Chung, Y.H.; Lee, C.W.; Choi, D.R.; Lee, J.S.; Yang, W.Y.; Kim, N.D.; Jin, Y.H.; Song, W.J.; Kim, I.H.; Shin, J.H. (Dong-Wha Pharmaceuticals Industry Co. Ltd); Optically active quinoline carboxylic acid derivs. having 7-pyrrolidine substitutes causing optical activity and a process for preparing thereof. WO 0071541 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XII) | 53063 | tert-butyl [(4S)-4,8,8-trimethyl-6,10-dioxa-2-azaspiro[4.5]dec-4-yl]methylcarbamate | n/a | C16H30N2O4 | 详情 | 详情 |
| (XIX) | 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 |
| (XX) | 53070 | 7-((4R)-4-{[(tert-butoxycarbonyl)amino]methyl}-4,8,8-trimethyl-6,10-dioxa-2-azaspiro[4.5]dec-2-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylic acid | n/a | C28H37FN4O7 | 详情 | 详情 |
| (XXI) | 53071 | 7-[(3R)-3-(aminomethyl)-3-methyl-4-oxopyrrolidinyl]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylic acid | n/a | C18H19FN4O4 | 详情 | 详情 |