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【结 构 式】 
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【分子编号】45490 【品名】2-[([3-[(2-[[(2-aminoethyl)sulfanyl]methyl]-3-pyridinyl)disulfanyl]-2-pyridinyl]methyl)sulfanyl]ethylamine; 2-[([3-[(2-[[(2-aminoethyl)sulfanyl]methyl]-3-pyridinyl)disulfanyl]-2-pyridinyl]methyl)sulfanyl]-1-ethanamine 【CA登记号】 |
【 分 子 式 】C16H22N4S4 【 分 子 量 】398.64164 【元素组成】C 48.21% H 5.56% N 14.05% S 32.18% |
合成路线1
该中间体在本合成路线中的序号：(XV)Borane reduction of 3-tert-butylthiopyridine-2-carboxylic acid (X) provided alcohol (XI), which was chlorinated to (XII) with SOCl2 and subsequently displaced with N-Boc-2-mercaptoethylamine (XIII), yielding thioether (XIV). Acid deprotection of the tert-butyl groups of (XIV), followed by air oxidation in the presence of FeCl3, produced the dimeric disulfide (XV). This was reprotected with Boc2O to afford the biscarbamate (XVI). Disulfide (XVI) was reduced in situ with PPh3 to the corresponding thiol, which was coupled with the cephem mesylate (IX) to produce adduct (XVII). The title compound was finally obtained by cleavage of the protecting groups of (XVII) by means of trifluoroacetic acid.
| 【1】 Griffith, D.; Blais, J.; Hevker, S.; Price, M.; Huie, K.; Halas, S.; Cho, A.; Dudley, M.; Lee, V.; Ludwikow, M.; Chen, S.; Chemberland, S.; Glinka, T.; Discovery of novel anti-MRSA cephalosporin RWJ-333441 (MC-04,546). Relationships between structure, antibacterial activity, serum stability, pharmacokinetics and efficacy in a series of (3-heteroarylthio)cephems. 40th Intersci Conf Antimicrob Agents Chemother (Sept 17 2000, Toronto) 2000, Abst F-1071. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IX) | 45485 | benzhydryl (6R,7R)-7-([2-[5-[(methoxycarbonyl)amino]-1,2,4-thiadiazol-3-yl]-2-[(trityloxy)imino]acetyl]amino)-3-[(methylsulfonyl)oxy]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C46H38N6O10S3 | 详情 | 详情 | |
| (X) | 45486 | 3-(tert-butylsulfanyl)-2-pyridinecarboxylic acid | 178811-41-1 | C10H13NO2S | 详情 | 详情 |
| (XI) | 45487 | [3-(tert-butylsulfanyl)-2-pyridinyl]methanol | C10H15NOS | 详情 | 详情 | |
| (XII) | 45488 | 3-(tert-butylsulfanyl)-2-(chloromethyl)pyridine; tert-butyl 2-(chloromethyl)-3-pyridinyl sulfide | C10H14ClNS | 详情 | 详情 | |
| (XIII) | 33079 | tert-butyl 2-sulfanylethylcarbamate | C7H15NO2S | 详情 | 详情 | |
| (XIV) | 45489 | tert-butyl 2-([[3-(tert-butylsulfanyl)-2-pyridinyl]methyl]sulfanyl)ethylcarbamate | C17H28N2O2S2 | 详情 | 详情 | |
| (XV) | 45490 | 2-[([3-[(2-[[(2-aminoethyl)sulfanyl]methyl]-3-pyridinyl)disulfanyl]-2-pyridinyl]methyl)sulfanyl]ethylamine; 2-[([3-[(2-[[(2-aminoethyl)sulfanyl]methyl]-3-pyridinyl)disulfanyl]-2-pyridinyl]methyl)sulfanyl]-1-ethanamine | C16H22N4S4 | 详情 | 详情 | |
| (XVI) | 45491 | tert-butyl 2-([[3-([2-[([2-[(tert-butoxycarbonyl)amino]ethyl]sulfanyl)methyl]-3-pyridinyl]disulfanyl)-2-pyridinyl]methyl]sulfanyl)ethylcarbamate | C26H38N4O4S4 | 详情 | 详情 | |
| (XVII) | 45492 | benzhydryl (6R,7R)-3-([2-[([2-[(tert-butoxycarbonyl)amino]ethyl]sulfanyl)methyl]-3-pyridinyl]sulfanyl)-7-([2-[5-[(methoxycarbonyl)amino]-1,2,4-thiadiazol-3-yl]-2-[(trityloxy)imino]acetyl]amino)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C58H54N8O9S4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XV)Borane reduction of 3-tert-butylthiopyridine-2-carboxylic acid (X) provided alcohol (XI), which was chlorinated to (XII) with SOCl2 and subsequently displaced with N-Boc-2-mercaptoethylamine (XIII), yielding thioether (XIV). Acid deprotection of the tert-butyl groups of (XIV), followed by air oxidation in the presence of FeCl3, produced the dimeric disulfide (XV). This was acylated with the protected aspartate pentafluorophenyl ester (XVI) to afford the diamide (XVII). Disulfide (XVII) was reduced in situ with PPh3 to the corresponding thiol, which was coupled with the cephem mesylate (IX) to produce adduct (XVIII). The title compound was finally obtained by cleavage of the protecting groups of (XVIII) by means of trifluoroacetic acid.
| 【1】 Hecker, S.J.; et al.; Prodrugs of anti-MRSA cephalosporin RWJ-333441 (MC-04,546) with improved aqueous solubility. 40th Intersci Conf Antimicrob Agents Chemother (Sept 17 2000, Toronto) 2000, Abst F-1076. |
| 【2】 Griffith, D.; Blais, J.; Hevker, S.; Price, M.; Huie, K.; Halas, S.; Cho, A.; Dudley, M.; Lee, V.; Ludwikow, M.; Chen, S.; Chemberland, S.; Glinka, T.; Discovery of novel anti-MRSA cephalosporin RWJ-333441 (MC-04,546). Relationships between structure, antibacterial activity, serum stability, pharmacokinetics and efficacy in a series of (3-heteroarylthio)cephems. 40th Intersci Conf Antimicrob Agents Chemother (Sept 17 2000, Toronto) 2000, Abst F-1071. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IX) | 45485 | benzhydryl (6R,7R)-7-([2-[5-[(methoxycarbonyl)amino]-1,2,4-thiadiazol-3-yl]-2-[(trityloxy)imino]acetyl]amino)-3-[(methylsulfonyl)oxy]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C46H38N6O10S3 | 详情 | 详情 | |
| (X) | 45486 | 3-(tert-butylsulfanyl)-2-pyridinecarboxylic acid | 178811-41-1 | C10H13NO2S | 详情 | 详情 |
| (XI) | 45487 | [3-(tert-butylsulfanyl)-2-pyridinyl]methanol | C10H15NOS | 详情 | 详情 | |
| (XII) | 45488 | 3-(tert-butylsulfanyl)-2-(chloromethyl)pyridine; tert-butyl 2-(chloromethyl)-3-pyridinyl sulfide | C10H14ClNS | 详情 | 详情 | |
| (XIII) | 33079 | tert-butyl 2-sulfanylethylcarbamate | C7H15NO2S | 详情 | 详情 | |
| (XIV) | 45489 | tert-butyl 2-([[3-(tert-butylsulfanyl)-2-pyridinyl]methyl]sulfanyl)ethylcarbamate | C17H28N2O2S2 | 详情 | 详情 | |
| (XV) | 45490 | 2-[([3-[(2-[[(2-aminoethyl)sulfanyl]methyl]-3-pyridinyl)disulfanyl]-2-pyridinyl]methyl)sulfanyl]ethylamine; 2-[([3-[(2-[[(2-aminoethyl)sulfanyl]methyl]-3-pyridinyl)disulfanyl]-2-pyridinyl]methyl)sulfanyl]-1-ethanamine | C16H22N4S4 | 详情 | 详情 | |
| (XVI) | 45493 | 4-(tert-butyl) 1-(2,3,4,5,6-pentafluorophenyl) (2S)-2-[(tert-butoxycarbonyl)amino]butanedioate | C19H22F5NO6 | 详情 | 详情 | |
| (XVII) | 45494 | tert-butyl (3S)-3-[(tert-butoxycarbonyl)amino]-4-([2-[([3-[(2-[(7S)-7-[2-(tert-butoxy)-2-oxoethyl]-11,11-dimethyl-6,9-dioxo-10-oxa-2-thia-5,8-diazadodec-1-yl]-3-pyridinyl)disulfanyl]-2-pyridinyl]methyl)sulfanyl]ethyl]amino)-4-oxobutanoate | C42H64N6O10S4 | 详情 | 详情 | |
| (XVIII) | 45495 | benzhydryl (6R,7R)-3-[(2-[(7S)-7-[2-(tert-butoxy)-2-oxoethyl]-11,11-dimethyl-6,9-dioxo-10-oxa-2-thia-5,8-diazadodec-1-yl]-3-pyridinyl)sulfanyl]-7-([2-[5-[(methoxycarbonyl)amino]-1,2,4-thiadiazol-3-yl]-2-[(trityloxy)imino]acetyl]amino)-8-oxo-5-thia-1 | C66H67N9O12S4 | 详情 | 详情 |