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【结 构 式】 
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【药物名称】Alatrofloxacin mesilate, CP-116517-27, CP-99219(L-Ala-L-Ala), L-Ala-L-Ala-CP-99219, CP-116517, Turvel, Trovan 【化学名称】(alpha,alpha,alpha)-7-[6-(L-Alanyl-L-alanylamino)-3-azabicyclo[3.1.0]hex-3-yl]-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid methanesulfonate 【CA登记号】157605-25-9, 157182-32-6 (free base) 【 分 子 式 】C27H29F3N6O8S 【 分 子 量 】654.62678 |
【开发单位】Pfizer (Originator), Roerig Farmaceutici (Not Determined) 【药理作用】Antibacterial Drugs, ANTIINFECTIVE THERAPY, Naphthyridines |
合成路线1
Addition of ethyl diazoacetate to N-benzylmaleimide (I) generated the bicyclic compound (II). Subsequent reduction of ester and imide groups of (II) with LiAlH4 gave 3-benzyl-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane (III). After hydrogenolytic removal of the N-benzyl group of (III), the resulting amine (IV) was protected as the corresponding benzyl carbamate (V) by treatment with benzyl chloroformate. Jones oxidation of the primary alcohol of (V) provided carboxylic acid (VI). This was subjected to a Curtius rearrangement using diphenylphosphoryl azide in the presence of tert-butanol to afford the Boc-protected amine (VII). The benzyl carbamate group of (VII) was then selectively removed by transfer hydrogenolysis with ammonium formate and Pd/C, yielding amine (VIII). Condensation of amine (VIII) with the ethyl ester of 7-chloro-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (IX) gave rise to adduct (X). Further hydrolysis of the ethyl ester and N-Boc groups of (X) yielded amino acid (XI).
| 【1】 Brighty, K.E. (Pfizer Inc.); Anti-bacterial azabicyclo quinolone carboxylic acids. US 5229396 . |
| 【2】 Brighty, K.E. (Pfizer Inc.); Azabicyclo quinolone and naphthyridone carboxylic acids. US 5164402 . |
| 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) | 15912 | N-Benzylmaleimide; 1-benzyl-1H-pyrrole-2,5-dione | 1631-26-1 | C11H9NO2 | 详情 | 详情 |
| (II) | 43087 | ethyl (1R,5S)-3-benzyl-2,4-dioxo-3-azabicyclo[3.1.0]hexane-6-carboxylate | C15H15NO4 | 详情 | 详情 | |
| (III) | 15915 | [(1R,5S)-3-benzyl-3-azabicyclo[3.1.0]hex-6-yl]methanol | C13H17NO | 详情 | 详情 | |
| (IV) | 15916 | (1R,5S)-3-azabicyclo[3.1.0]hex-6-ylmethanol | C6H11NO | 详情 | 详情 | |
| (V) | 15917 | benzyl (1R,5S)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate | C14H17NO3 | 详情 | 详情 | |
| (VI) | 15918 | (1R,5S)-3-[(benzyloxy)carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxylic acid | C14H15NO4 | 详情 | 详情 | |
| (VII) | 15919 | benzyl (1R,5S)-6-[(tert-butoxycarbonyl)amino]-3-azabicyclo[3.1.0]hexane-3-carboxylate | C18H24N2O4 | 详情 | 详情 | |
| (VIII) | 15920 | tert-butyl (1R,5S)-3-azabicyclo[3.1.0]hex-6-ylcarbamate | C10H18N2O2 | 详情 | 详情 | |
| (IX) | 43088 | ethyl 6-chloro-1-(2,4-difluorophenyl)-7-fluoro-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylate | C17H10ClF3N2O3 | 详情 | 详情 | |
| (X) | 15922 | ethyl 7-[(1R,5S)-6-[(tert-butoxycarbonyl)amino]-3-azabicyclo[3.1.0]hex-3-yl]-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylate | C27H27F3N4O5 | 详情 | 详情 | |
| (XI) | 43089 | 7-[(1R,5S)-6-amino-3-azabicyclo[3.1.0]hex-3-yl]-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylic acid | C20H15F3N4O3 | 详情 | 详情 |
合成路线2
Amino acid (XI) was then coupled with N-Boc-L-alanine (XII) using EDC and HOBt to furnish amide (XIII), and its Boc group was subsequently cleaved with HCl in dioxan, yielding (XIV). A second coupling with N-Boc-L-alanine (XII), followed by acid deprotection gave (XV) as the hydrochloride salt. Conversion to the title methanesulfonate salt was carried out by liberation of the base with NaHCO3 and subsequent treatment with MsOH acetone.
| 【1】 Brighty, K.E. (Pfizer Inc.); Anti-bacterial azabicyclo quinolone carboxylic acids. US 5229396 . |
| 【2】 Brighty, K.E. (Pfizer Inc.); Azabicyclo quinolone and naphthyridone carboxylic acids. US 5164402 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XI) | 43089 | 7-[(1R,5S)-6-amino-3-azabicyclo[3.1.0]hex-3-yl]-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylic acid | C20H15F3N4O3 | 详情 | 详情 | |
| (XII) | 26450 | Boc-L-Alanine;(S)-2-((tert-butoxycarbonyl)amino)propanoic acid;N-Boc-L-alanine; (2S)-2-[(tert-butoxycarbonyl)amino]propionic acid | 15761-38-3 | C8H15NO4 | 详情 | 详情 |
| (XIII) | 43090 | 7-[(1R,5S)-6-([(2S)-2-[(tert-butoxycarbonyl)amino]propanoyl]amino)-3-azabicyclo[3.1.0]hex-3-yl]-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylic acid | C28H28F3N5O6 | 详情 | 详情 | |
| (XIV) | 43091 | 7-((1R,5S)-6-[[(2S)-2-aminopropanoyl]amino]-3-azabicyclo[3.1.0]hex-3-yl)-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylic acid | C23H20F3N5O4 | 详情 | 详情 | |
| (XV) | 43092 | 7-[(1R,5S)-6-[((2S)-2-[[(2S)-2-aminopropanoyl]amino]propanoyl)amino]-3-azabicyclo[3.1.0]hex-3-yl]-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylic acid | C26H25F3N6O5 | 详情 | 详情 |