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【结 构 式】 
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【分子编号】12184 【品名】4-nitrobenzyl 3-oxo-5-[(2R,3S)-4-oxo-3-[(2-phenoxyacetyl)amino]azetanyl]pentanoate 【CA登记号】 |
【 分 子 式 】C23H23N3O8 【 分 子 量 】469.45104 【元素组成】C 58.85% H 4.94% N 8.95% O 27.26% |
合成路线1
该中间体在本合成路线中的序号：(XVI)A new synthesis of loracarbef has been described: The reaction of L-(+)-phenylglycine (I) with ethyl chloroformate (II) and NaOH in dichloromethane gives L-N-(ethoxycarbonyl)phenylglycine (III), which is reduced with BH3 in THF to the alcohol (IV). The cyclization of (IV) by means of NaH in THF affords oxazolidinone (V), which by alkylation with ethyl bromoacetate and hydrolysis with NaOH is converted into the oxazolidinone-3-acetic acid (VI), and the corresponding acyl chloride (VII). The cyclization of (VII) with 2-[3-(benzylimino)-1-propenyl]furan (VIII) by means of triethylamine in dichloromethane yields the azetidinone (IX), which is purified from its enantiomer by crystallization. The reduction of (IX) with H2 over Pd/C in dichloromethane gives 1-benzyl-2-[2-(2-furyl)ethyl]-3-(2-oxo-4-phenyloxazolidin-3-yl)azetidin-4-one (X) with a 100% optical purity. The cleavage of (X) with Li/NH3 in tert-butanol - THF yields 3(S)-amino-2(R)-[2-(2-furyl)ethyl]azetidin-4-one (XI), which is acylated with phenoxyacetyl chloride (XII) and NaHCO3 to the amide (XIII). Ozonolysis of (XIII) with O3, H2O2 in dichloromethane-methanol affords 3-[4-oxo-3(S)-phenoxyacetamido)azetidin-2(R)-yl]propanoic acid (XIV), which is then condensed with the magnesium salt of the malonic derivative (XV) in THF to yield the ketoester (XVI).
| 【1】 Boyer, B.D.; Bodurow, C.C.; Brennan, J.; et al.; An enantioselective synthesis of loracarbef (LY163892/KT3777). Tetrahedron Lett 1989, 30, 18, 2321. |
| 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) | 10716 | (2S)-2-Amino-2-phenylethanoic acid; L-(+)-alpha-Phenylglycine | 2935-35-5 | C8H9NO2 | 详情 | 详情 |
| (II) | 11229 | 1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate | 541-41-3 | C3H5ClO2 | 详情 | 详情 |
| (III) | 12171 | (2S)-2-[(Ethoxycarbonyl)amino]-2-phenylethanoic acid | C11H13NO4 | 详情 | 详情 | |
| (IV) | 12172 | ethyl N-[(1S)-2-hydroxy-1-phenylethyl]carbamate | C11H15NO3 | 详情 | 详情 | |
| (V) | 12173 | (4S)-4-Phenyl-1,3-oxazolan-2-one; (4S)-4-Phenyl-2-oxazolidinone; (S)-(+)-4-Phenyl-2-oxazolidinone | 99395-88-7 | C9H9NO2 | 详情 | 详情 |
| (VI) | 12174 | 2-[(4S)-2-Oxo-4-phenyl-1,3-oxazolan-3-yl]acetic acid | C11H11NO4 | 详情 | 详情 | |
| (VII) | 12175 | 2-[(4S)-2-Oxo-4-phenyl-1,3-oxazolan-3-yl]acetyl chloride | C11H10ClNO3 | 详情 | 详情 | |
| (VIII) | 12176 | N-Benzyl-N-[(E,2E)-3-(2-furyl)-2-propenylidene]amine; N-[(E,2E)-3-(2-Furyl)-2-propenylidene](phenyl)methanamine | C14H13NO | 详情 | 详情 | |
| (IX) | 12177 | (4S)-3-[(2R,3S)-1-Benzyl-2-[(E)-2-(2-furyl)ethenyl]-4-oxoazetanyl]-4-phenyl-1,3-oxazolan-2-one | C25H22N2O4 | 详情 | 详情 | |
| (X) | 12178 | (4S)-3-[(2R,3S)-1-Benzyl-2-[2-(2-furyl)ethyl]-4-oxoazetanyl]-4-phenyl-1,3-oxazolan-2-one | C25H24N2O4 | 详情 | 详情 | |
| (XI) | 12179 | (3S,4R)-3-Amino-4-[2-(2-furyl)ethyl]-2-azetanone | C9H12N2O2 | 详情 | 详情 | |
| (XII) | 12180 | Phenoxyacetyl chloride; 2-Phenoxyacetyl chloride | 701-99-5 | C8H7ClO2 | 详情 | 详情 |
| (XIII) | 12181 | N-[(2R,3S)-2-[2-(2-Furyl)ethyl]-4-oxoazetanyl]-2-phenoxyacetamide | C17H18N2O4 | 详情 | 详情 | |
| (XIV) | 12182 | 3-[(2R,3S)-4-Oxo-3-[(2-phenoxyacetyl)amino]azetanyl]propionic acid | C14H16N2O5 | 详情 | 详情 | |
| (XV) | 12183 | magnesium di[3-[(4-nitrobenzyl)oxy]-3-oxopropanoate] | 75321-09-4 | C20H16MgN2O12 | 详情 | 详情 |
| (XVI) | 12184 | 4-nitrobenzyl 3-oxo-5-[(2R,3S)-4-oxo-3-[(2-phenoxyacetyl)amino]azetanyl]pentanoate | C23H23N3O8 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XVI)Diazotization of (XVI) with dodecylsulfonyl azide and triethylamine in acetonitrile gives the diazo derivative (XVII), which is cyclized by means of rhodium octanoate in dichloromethane to afford the carbacephem derivative (XVIII). The reaction of (XVIII) with dichlorotriphenoxyphosphine - pyridine in dichloromethane, followed by hydrolysis in acidic medium gives (6R,7S)-7-amino-3-chloro-1-dethia-1-carba-3-cephem-4-carboxylic acid 4-nitrobenzyl ester (XIX). The acylation of (XIX) with the isobutyl anhydride of enamine-protected D-phenylglycine (XX) by means of triethylamine in DMF affords the fully protected compound (XXI), which is finally deprotected by a treatment with Zn and HCl.
| 【1】 Boyer, B.D.; Bodurow, C.C.; Brennan, J.; et al.; An enantioselective synthesis of loracarbef (LY163892/KT3777). Tetrahedron Lett 1989, 30, 18, 2321. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVI) | 12184 | 4-nitrobenzyl 3-oxo-5-[(2R,3S)-4-oxo-3-[(2-phenoxyacetyl)amino]azetanyl]pentanoate | C23H23N3O8 | 详情 | 详情 | |
| (XVII) | 12185 | 2-Diazo-3-oxo-5-[4-oxo-3-(2-phenoxy-acetamido)-azetidin-2-yl]-pentanoic acid 4-nitro-benzyl ester | C23H21N5O8 | 详情 | 详情 | |
| (XVIII) | 12186 | 4-nitrobenzyl (6R,7S)-3-hydroxy-8-oxo-7-[(2-phenoxyacetyl)amino]-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C23H21N3O8 | 详情 | 详情 | |
| (XIX) | 12187 | 4-nitrobenzyl (6R,7S)-7-amino-3-chloro-8-oxo-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C15H14ClN3O5 | 详情 | 详情 | |
| (XX) | 12188 | (2R)-[[(E)-3-Methoxy-1-methyl-3-oxo-1-propenyl]amino](phenyl)ethanoic 2-methylbutyric anhydride | C18H23NO5 | 详情 | 详情 | |
| (XXI) | 12189 | 4-nitrobenzyl (6R,7S)-3-chloro-7-[((2R)-2-[[(E)-3-methoxy-1-methyl-3-oxo-1-propenyl]amino]-2-phenylethanoyl)amino]-8-oxo-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C28H27ClN4O8 | 详情 | 详情 |