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【结 构 式】 
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【分子编号】22581 【品名】(2S,4R)-4-hydroxy-1-[[(4-nitrobenzyl)oxy]carbonyl]-2-pyrrolidinecarboxylic acid 【CA登记号】 |
【 分 子 式 】C13H14N2O7 【 分 子 量 】310.26344 【元素组成】C 50.33% H 4.55% N 9.03% O 36.1% |
合成路线1
该中间体在本合成路线中的序号：(XVII)The mercaptopyrrolidine (XIII) is prepared as follows: trans-4-hydroxy-L-proline (XV) is protected with 4-nitrobenzyl chloride (XVI) giving trans 4-hydroxy-N-(4-nitrobenzyloxycarbonyl)-L-proline (XVII), which is esterified with 4-methoxy benzyl chloride (XVIII) to the corresponding ester (XIX). The reaction of (XIX) with thioacetic acid by means of diethyl azodicarboxylate arid triphenyl-phosphine in THF affords the 4-acetylthio derivative (XX), which is partially hydrolyzed with trifluoroacetic acid and anisole to 4beta-(acetylthio)-N-(4-nitrobenzyloxycarbonyl)pyrrolidine-2beta-carboxylic acid (XXI). The condensation of (XXI) with dimethylamine by means of dicyclohexylcarbodiimide (DCC) gives the fully protected dimethylamide (XXII), which is deacetylated with NaOH in water to atford the desired product (XIII).
| 【1】 Fukasawa, M.; Inoue, T.; Kato, M.; Matsumura, H.; Sunagawa, M. (Sumitomo Pharmaceuticals Co., Ltd.); Thiopyrrolidinyl-beta-lactam derivs.. EP 0126587; ES 8600305; JP 1985001186; JP 1985019787; JP 1991041066; US 4933333; US 4943569; US 5122604 . |
| 【2】 Prous, J.; Castaner, J.; SM-7338. Drugs Fut 1988, 13, 6, 534. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 12893 | Ethanethioic S-acid | C2H4OS | 详情 | 详情 | ||
| (XIII) | 22578 | 4-nitrobenzyl (2S,4S)-2-[(dimethylamino)carbonyl]-4-sulfanyl-1-pyrrolidinecarboxylate | C15H19N3O5S | 详情 | 详情 | |
| (XV) | 14489 | (2S,4R)-4-hydroxytetrahydro-1H-pyrrole-2-carboxylic acid; L-Hydroxyproline | 51-35-4 | C5H9NO3 | 详情 | 详情 |
| (XVI) | 22580 | 1-(chloromethyl)-4-nitrobenzene | 100-14-1 | C7H6ClNO2 | 详情 | 详情 |
| (XVII) | 22581 | (2S,4R)-4-hydroxy-1-[[(4-nitrobenzyl)oxy]carbonyl]-2-pyrrolidinecarboxylic acid | C13H14N2O7 | 详情 | 详情 | |
| (XVIII) | 11910 | 4-Methoxybenzyl chloride; 1-(Chloromethyl)-4-methoxybenzene; alpha-Chloro-4-methoxytoluene; 4-(Chloromethyl)phenyl methyl ether | 824-94-2 | C8H9ClO | 详情 | 详情 |
| (XIX) | 22583 | 2-(4-methoxybenzyl) 1-(4-nitrobenzyl) (2S,4R)-4-hydroxy-1,2-pyrrolidinedicarboxylate | C21H22N2O8 | 详情 | 详情 | |
| (XX) | 22584 | 2-(4-methoxybenzyl) 1-(4-nitrobenzyl) (2S,4S)-4-(acetylsulfanyl)-1,2-pyrrolidinedicarboxylate | C23H24N2O8S | 详情 | 详情 | |
| (XXI) | 18241 | (2S,4S)-4-(acetylsulfanyl)-1-[[(4-nitrobenzyl)oxy]carbonyl]-2-pyrrolidinecarboxylic acid | C15H16N2O7S | 详情 | 详情 | |
| (XXII) | 22586 | 4-nitrobenzyl (2S,4S)-4-(acetylsulfanyl)-2-[(dimethylamino)carbonyl]-1-pyrrolidinecarboxylate | C17H21N3O6S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)Treatment of trans-4-hydroxy-L-proline (I) with p-nitrobenzyl chloroformate gave the N-protected 4-hydroxyproline (II), which was esterified to afford the N-protected methyl ester (II). Protection of the hydroxyl group of (III) with t-butyl-dimethylsilyl chloride in the presence of imidazole, followed by reduction of the resulting ester (IV) with lithium borohydride, provided the alcohol (V). This was oxidized using pyridine-sulfur trioxide complex to give the formylpyrrolidine (VI). The vinylpyrrolidine (VII) was obtained by Wittig reaction of aldehyde (VI) with methylene triphenylphosphorane. Dipolar cycloaddition of the nitrile oxide resulting from ethyl chlorooximidoacetate (VIII) and Et3N to vinylpyrrolidine (VII) gave iso-oxazolidine (IX) as a mixture of diastereoisomers. After desilylation of (IX) with tetrabutylammonium fluoride, the resulting alcohol (X) was converted into the diastereomeric mixture of mesylates (XI). Chromatographic separation of the required isomer, followed by reduction with LiBH4, yielded alcohol (XII).
| 【1】 Park, S.W.; Yoo, K.H.; Shin, K.J.; Kang, Y.K.; Hong, C.Y.; Seo, K.J.; Park, S.Y.; Lee, C.-S.; Kim, D.J.; Synthesis and antibacterial activity of new carbapenems containing isoxazole moiety. Bioorg Med Chem Lett 2000, 10, 2, 95. |
| 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) | 14489 | (2S,4R)-4-hydroxytetrahydro-1H-pyrrole-2-carboxylic acid; L-Hydroxyproline | 51-35-4 | C5H9NO3 | 详情 | 详情 |
| (II) | 22581 | (2S,4R)-4-hydroxy-1-[[(4-nitrobenzyl)oxy]carbonyl]-2-pyrrolidinecarboxylic acid | C13H14N2O7 | 详情 | 详情 | |
| (III) | 44922 | 2-methyl 1-(4-nitrobenzyl) (2S,4R)-4-hydroxy-1,2-pyrrolidinedicarboxylate | C14H16N2O7 | 详情 | 详情 | |
| (IV) | 44923 | 2-methyl 1-(4-nitrobenzyl) (2S,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-1,2-pyrrolidinedicarboxylate | C20H30N2O7Si | 详情 | 详情 | |
| (V) | 44924 | 4-nitrobenzyl (2S,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-(hydroxymethyl)-1-pyrrolidinecarboxylate | C19H30N2O6Si | 详情 | 详情 | |
| (VI) | 44925 | 4-nitrobenzyl (2S,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-formyl-1-pyrrolidinecarboxylate | C19H28N2O6Si | 详情 | 详情 | |
| (VII) | 44926 | 4-nitrobenzyl (2S,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-vinyl-1-pyrrolidinecarboxylate | C20H30N2O5Si | 详情 | 详情 | |
| (VIII) | 30424 | 2-ethoxy-N-hydroxy-2-oxoethanimidoyl chloride | 14337-43-0 | C4H6ClNO3 | 详情 | 详情 |
| (IX) | 44927 | ethyl (5R)-5-((2S,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-1-[[(4-nitrobenzyl)oxy]carbonyl]pyrrolidinyl)-4,5-dihydro-3-isoxazolecarboxylate | C24H35N3O8Si | 详情 | 详情 | |
| (X) | 44928 | ethyl (5R)-5-((2S,4R)-4-hydroxy-1-[[(4-nitrobenzyl)oxy]carbonyl]pyrrolidinyl)-4,5-dihydro-3-isoxazolecarboxylate | C18H21N3O8 | 详情 | 详情 | |
| (XI) | 44929 | ethyl (5R)-5-((2S,4R)-4-[(methylsulfonyl)oxy]-1-[[(4-nitrobenzyl)oxy]carbonyl]pyrrolidinyl)-4,5-dihydro-3-isoxazolecarboxylate | C19H23N3O10S | 详情 | 详情 | |
| (XII) | 44930 | 4-nitrobenzyl (2S,4R)-2-[(5R)-3-(hydroxymethyl)-4,5-dihydro-5-isoxazolyl]-4-[(methylsulfonyl)oxy]-1-pyrrolidinecarboxylate | C17H21N3O9S | 详情 | 详情 |