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【结 构 式】 
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【药物名称】Bicyclomycin, Bicozamycin, CGP-3543/E, Bacteron 【化学名称】(1S,6R)-6-Hydroxy-5-methylene-1-[(1S,2S)-1,2,3-trihydroxy-2-methylpropyl]-2-oxa-7,9-diazabicyclo[4.2.2]decane-8,10-dione 【CA登记号】38129-37-2 【 分 子 式 】C12H18N2O7 【 分 子 量 】302.28646 |
【开发单位】Fujisawa (Originator), Novartis (Originator) 【药理作用】Antibiotics, ANTIINFECTIVE THERAPY |
合成路线1
Diketopiperazine (I) is protected with benzylating reagents to give N,N'-dibenzyldiketopiperazine (II), which is brominated with Br2 to the dibromo derivative (III). The treatment of (III) with benzyl alcohol affords the dibenzyl ether (IV), which is condensed with the silylated methyl 4-hydroxycrotonate (V) by means of butyllithium, yielding the coupled product (VI). The reduction of the ester group of (VI) first with LiAlH4 and then with NaBH4 yields the primary alcohol (VII), which is protected with dimethyl tert-butylsilyl chloride giving the fully protected compound (VIII). Partial deprotection of (VIII) with H2 over Pd/C in ethanol pyridine eliminates the less shielded benzyl group, affording the secondary alcohol (IX), which is acetylated with acetic anhydride to the acetate (X). Selective deprotection of (X) with acetic acid-water THR at 80 C eliminates the dimethyl tert-butylsilyl group, yielding the alcohol (XI), which is cyclized by heating at 80 C in the presence of pyridinium p-toluenesulfonate, affording the bicyclo compound (XII). The aldol condensation of (XII) with the aldehyde (XIII) by mean of butyllithium yields the alcohol (XIV), which is desilylated with tetrabutylammonium fluoride to the primary alcohol (XV).
| 【1】 Nakatsuka, S. I.; Goto, T.; Total synthesis of bicyclomycin. Heterocycles 1984, 21, 1, 61-73. |
| 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) | 29800 | 2,5-piperazinedione；2,5-diketopiperazine;cycloglycylglycine；2,5-dioxopiperazine;cyclodiglycine;cyclo(glycylglycyl) | 106-57-0 | C4H6N2O2 | 详情 | 详情 |
| (II) | 29801 | 1,4-dibenzyl-2,5-piperazinedione | C18H18N2O2 | 详情 | 详情 | |
| (III) | 29802 | 1,4-dibenzyl-3,6-dibromo-2,5-piperazinedione | C18H16Br2N2O2 | 详情 | 详情 | |
| (IV) | 29803 | 1,4-dibenzyl-3,6-bis(benzyloxy)-2,5-piperazinedione | C32H30N2O4 | 详情 | 详情 | |
| (V) | 29804 | methyl (E)-4-[[tert-butyl(diphenyl)silyl]oxy]-2-butenoate | C21H26O3Si | 详情 | 详情 | |
| (VI) | 29805 | methyl (3R)-4-[[tert-butyl(diphenyl)silyl]oxy]-3-[(2R,5R)-1,4-dibenzyl-2,5-bis(benzyloxy)-3,6-dioxopiperazinyl]butanoate | C53H56N2O7Si | 详情 | 详情 | |
| (VII) | 29806 | (3R,6R)-1,4-dibenzyl-3,6-bis(benzyloxy)-3-[(1R)-1-([[tert-butyl(diphenyl)silyl]oxy]methyl)-3-hydroxypropyl]-2,5-piperazinedione | C52H56N2O6Si | 详情 | 详情 | |
| (VIII) | 29807 | (3R,6R)-1,4-dibenzyl-3,6-bis(benzyloxy)-3-[(1R)-3-[[tert-butyl(dimethyl)silyl]oxy]-1-([[tert-butyl(diphenyl)silyl]oxy]methyl)propyl]-2,5-piperazinedione | C58H70N2O6Si2 | 详情 | 详情 | |
| (IX) | 29808 | (3R,6R)-1,4-dibenzyl-3-(benzyloxy)-3-[(1R)-3-[[tert-butyl(dimethyl)silyl]oxy]-1-([[tert-butyl(diphenyl)silyl]oxy]methyl)propyl]-6-hydroxy-2,5-piperazinedione | C51H64N2O6Si2 | 详情 | 详情 | |
| (X) | 29809 | (2R,5R)-1,4-dibenzyl-5-(benzyloxy)-5-[(1R)-3-[[tert-butyl(dimethyl)silyl]oxy]-1-([[tert-butyl(diphenyl)silyl]oxy]methyl)propyl]-3,6-dioxopiperazinyl acetate | C53H66N2O7Si2 | 详情 | 详情 | |
| (XI) | 29810 | (2R,5R)-1,4-dibenzyl-5-(benzyloxy)-5-[(1R)-1-([[tert-butyl(diphenyl)silyl]oxy]methyl)-3-hydroxypropyl]-3,6-dioxopiperazinyl acetate | C47H52N2O7Si | 详情 | 详情 | |
| (XII) | 29811 | (1S,6R)-7,9-dibenzyl-6-(benzyloxy)-5-([[tert-butyl(diphenyl)silyl]oxy]methyl)-2-oxa-7,9-diazabicyclo[4.2.2]decane-8,10-dione | C45H48N2O5Si | 详情 | 详情 | |
| (XIII) | 29812 | 2,2,4-trimethyl-1,3-dioxolane-4-carbaldehyde | C7H12O3 | 详情 | 详情 | |
| (XIV) | 29813 | (1S,6R)-7,9-dibenzyl-6-(benzyloxy)-5-([[tert-butyl(diphenyl)silyl]oxy]methyl)-1-[(S)-hydroxy[(4S)-2,2,4-trimethyl-1,3-dioxolan-4-yl]methyl]-2-oxa-7,9-diazabicyclo[4.2.2]decane-8,10-dione | C52H60N2O8Si | 详情 | 详情 | |
| (XV) | 29814 | (1S,6R)-7,9-dibenzyl-6-(benzyloxy)-5-(hydroxymethyl)-1-[(S)-hydroxy[(4S)-2,2,4-trimethyl-1,3-dioxolan-4-yl]methyl]-2-oxa-7,9-diazabicyclo[4.2.2]decane-8,10-dione | C36H42N2O8 | 详情 | 详情 |
合成路线2
Elimination of the benzyl groups of (XV) by hydrogenation with H2 over Pd/C in ethanol at 80 C affords the unprotected alcohol (XVI), which is treated successively with methanesulfonyl chloride in pyridine, and then with sodium phenylselenium borohydride in ethanol, giving finally the selenium derivative (XVII). Oxidation of (XVII) with m-chloroperbenzoic acid in dichloromethane affords the selenoxide (XVIII), which by heating at 60 C is converted to the bicyclomycin acetonide (XIX). Finally, this compound is hydrolyzed by a careful treatment with 0.2N H2SO4 at low temperature.
| 【1】 Nakatsuka, S. I.; Goto, T.; Total synthesis of bicyclomycin. Heterocycles 1984, 21, 1, 61-73. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XV) | 29814 | (1S,6R)-7,9-dibenzyl-6-(benzyloxy)-5-(hydroxymethyl)-1-[(S)-hydroxy[(4S)-2,2,4-trimethyl-1,3-dioxolan-4-yl]methyl]-2-oxa-7,9-diazabicyclo[4.2.2]decane-8,10-dione | C36H42N2O8 | 详情 | 详情 | |
| (XVI) | 29815 | (1S,6R)-6-hydroxy-5-(hydroxymethyl)-1-[(S)-hydroxy[(4S)-2,2,4-trimethyl-1,3-dioxolan-4-yl]methyl]-2-oxa-7,9-diazabicyclo[4.2.2]decane-8,10-dione | C15H24N2O8 | 详情 | 详情 | |
| (XVII) | 29816 | (1S,6R)-6-hydroxy-1-[(S)-hydroxy[(4S)-2,2,4-trimethyl-1,3-dioxolan-4-yl]methyl]-5-[(phenylselanyl)methyl]-2-oxa-7,9-diazabicyclo[4.2.2]decane-8,10-dione | C21H28N2O7Se | 详情 | 详情 | |
| (XVIII) | 29817 | (1S,6R)-6-hydroxy-1-[(S)-hydroxy[(4S)-2,2,4-trimethyl-1,3-dioxolan-4-yl]methyl]-5-[(phenylseleninyl)methyl]-2-oxa-7,9-diazabicyclo[4.2.2]decane-8,10-dione | C21H28N2O8Se | 详情 | 详情 | |
| (XIX) | 29818 | (1S,6R)-6-hydroxy-1-[(S)-hydroxy[(4S)-2,2,4-trimethyl-1,3-dioxolan-4-yl]methyl]-5-methylene-2-oxa-7,9-diazabicyclo[4.2.2]decane-8,10-dione | C15H22N2O7 | 详情 | 详情 |