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【结 构 式】 
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【药物名称】MC-04, 699, RWJ-333442 【化学名称】(6R,7R)-7-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2(Z)-(hydroxyimino)acetamido]-3-[2-[2-(L-aspartylamino)ethyl]sulfanylmethyl]pyridin-3-ylsulfanyl]-3-cephem-4-carboxylic acid 【CA登记号】 【 分 子 式 】C23H25N9O8S4 【 分 子 量 】683.7672 |
【开发单位】Essential Therapeutics (Originator), R.W. Johnson (Codevelopment) 【药理作用】Antibiotics, ANTIINFECTIVE THERAPY, Cephalosporins |
合成路线1
Thiadiazole (II) was synthesized from 3-aminoisoxazole (I) following a known procedure. Esterification of (II) to give (III) was carried out by treatment with MeOH and SOCl2. Subsequent oxidation of (III) employing I2 in DMSO provided keto ester (IV), which was converted into oxime (V) and then protected as the O-trityl derivative (VI). Basic hydrolysis of the methyl ester group yielded carboxylic acid (VII). Then, coupling of acid (VII) with aminocephalosporin (VIII) by means of POCl3 furnished the corresponding amide (IX).
| 【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 |
|---|---|---|---|---|---|---|
| (I) | 45477 | 3-isoxazolylamine; 3-isoxazolamine | 1750-42-1 | C3H4N2O | 详情 | 详情 |
| (II) | 45478 | 2-[5-[(methoxycarbonyl)amino]-1,2,4-thiadiazol-3-yl]acetic acid | C6H7N3O4S | 详情 | 详情 | |
| (III) | 45479 | methyl 2-[5-[(methoxycarbonyl)amino]-1,2,4-thiadiazol-3-yl]acetate | C7H9N3O4S | 详情 | 详情 | |
| (IV) | 45480 | methyl 2-[5-[(methoxycarbonyl)amino]-1,2,4-thiadiazol-3-yl]-2-oxoacetate | C7H7N3O5S | 详情 | 详情 | |
| (V) | 45481 | methyl 2-(hydroxyimino)-2-[5-[(methoxycarbonyl)amino]-1,2,4-thiadiazol-3-yl]acetate | C7H8N4O5S | 详情 | 详情 | |
| (VI) | 45482 | methyl 2-[5-[(methoxycarbonyl)amino]-1,2,4-thiadiazol-3-yl]-2-[(trityloxy)imino]acetate | C26H22N4O5S | 详情 | 详情 | |
| (VII) | 45483 | 2-[5-[(methoxycarbonyl)amino]-1,2,4-thiadiazol-3-yl]-2-[(trityloxy)imino]acetic acid | C25H20N4O5S | 详情 | 详情 | |
| (VIII) | 45484 | benzhydryl (6R,7R)-7-amino-3-[(methylsulfonyl)oxy]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C21H20N2O6S2 | 详情 | 详情 | |
| (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 |
合成路线2
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 |