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【结 构 式】 
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【药物名称】GSQ-83698, GBB-83698, BB-83698 【化学名称】N-[1(S)-Acetyl-2,2-dimethylpropyl]-2(R)-(N-formyl-N-hydroxyaminomethyl)hexanamide 【CA登记号】301684-93-5, 428862-38-8 【 分 子 式 】C15H28N2O4 【 分 子 量 】300.40141 |
【开发单位】British Biotech (Originator), GeneSoft (Codevelopment) 【药理作用】Antibacterial Drugs, ANTIINFECTIVE THERAPY, Peptide Deformylase Inhibitors |
合成路线1
The reaction of L-tert-leucine (I) with Boc2O and TEA in methanol gives N-Boc-L-tert-leucine (II), which is condensed with N,O-dimethylhydroxylamine (III) by means of CDI in dichloromethane to yield the corresponding amide (IV) (1). The reaction of (IV) with methyl lithium in THF affords the chiral methylketone (V), which is deprotected by means of TFA in dichloromethane to provide the aminoketone (VI). The condensation of (VI) with 2(R)-(benzyloxyaminomethyl)hexanoic acid (VII) by means of EDC and HOBt in DMF leads to the amide (VIII), which is formylated by means of formylacetic anhydride (IX) in dichloromethane to give the precursor (X). Finally this compound is deprotected by hydrogenation with H2 over Pd/C in ethyl acetate to afford the target compound. Alternatively, the intermediate chiral ketone (V) can also be obtained by reaction of N-Boc-L-tert-leucine pentafluorophenyl ester (XI) with methyl lithium of methylmagnesium bromide
| 【2】 Todd, R.S.; Beckett, R.P.; Brookings, D.C.; Smith, H.K.; Thompson, A.J. (British Biotech Pharmaceuticals Ltd.); Antimicrobial agents. EP 1169031; JP 2002541197; WO 0061134 . |
| 【1】 Ayscough, A.; Beckett, R.P.; Brookings, D.C.; Clements, J.M.; East, S.P.; Keavey, K.; Smith, K.H.; Thomas, W.; Thompson, A.J.; Todd, R.S.; A new series of potent PDF inhibitors displaying broad-spectrum antibacterial activity against respiratory tract infections. 42nd Intersci Conf Antimicrob Agents Chemother (Sept 27 2002, San Diego) 2002, Abst F-1677. |
| 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) | 28445 | (2S)-2-amino-3,3-dimethylbutyric acid | C6H13NO2 | 详情 | 详情 | |
| (II) | 22251 | (2S)-2-[(tert-butoxycarbonyl)amino]-3,3-dimethylbutyric acid;2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoic acid;N-(tert-butoxycarbonyl)-3-methyl-L-valine | 62965-35-9 | C11H21NO4 | 详情 | 详情 |
| (III) | 13361 | (Methoxyamino)methane; N,O-Dimethylhydroxylamine | 1117-97-1 | C2H7NO | 详情 | 详情 |
| (IV) | 60279 | 1,1-dimethylethyl 2,2-dimethyl-1-{[methyl(methyloxy)amino]carbonyl}propylcarbamate | C13H26N2O4 | 详情 | 详情 | |
| (V) | 60280 | 1,1-dimethylethyl 1-acetyl-2,2-dimethylpropylcarbamate | C12H23NO3 | 详情 | 详情 | |
| (VI) | 60281 | 3-amino-4,4-dimethyl-2-pentanone | C7H15NO | 详情 | 详情 | |
| (VII) | 51563 | (2R)-2-[[(benzyloxy)amino]methyl]hexanoic acid | C14H21NO3 | 详情 | 详情 | |
| (VIII) | 60282 | N-(1-acetyl-2,2-dimethylpropyl)-2-({[(phenylmethyl)oxy]amino}methyl)hexanamide | C21H34N2O3 | 详情 | 详情 | |
| (IX) | 29135 | Acetyl formyl mixed anhydride | C3H4O3 | 详情 | 详情 | |
| (X) | 60283 | N-(1-acetyl-2,2-dimethylpropyl)-2-({formyl[(phenylmethyl)oxy]amino}methyl)hexanamide | C22H34N2O4 | 详情 | 详情 | |
| (XI) | 60284 | 2,3,4,5,6-pentafluorophenyl 2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-3,3-dimethylbutanoate | C17H20F5NO4 | 详情 | 详情 |