【结 构 式】 |
【分子编号】25404 【品名】D-cysteine; (S)-2-Amino-3-mercaptopropionic acid 【CA登记号】921-01-7 |
【 分 子 式 】C3H7NO2S 【 分 子 量 】121.16012 【元素组成】C 29.74% H 5.82% N 11.56% O 26.41% S 26.47% |
合成路线1
该中间体在本合成路线中的序号:(II)A new method for the synthesis of MT-141 has been reported: By condensation of 7-bromoacetamido-7alpha-methoxy-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (I) with D-cysteine (II) in aqueous NaHCO3.
【1】 Ogino, H.; Omoto, S.; Tsuruoka, T.; Miyauchi, K.; Niida, T.; Inouye, S.; Mizutani, K.; Iwamatsu, K.; Watanabe, T.; Synthesis and biological activity of 7beta-(2-amino-2-carboxy)-ethylthioacetamido-7alpha-methoxycephalosporin derivatives. J Antibiot 1983, 36, 3, 229-241. |
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) | 30738 | (6R,7S)-7-[(2-bromoacetyl)amino]-7-methoxy-3-[[(1-methyl-1H-1,2,3,4-tetraazol-5-yl)sulfanyl]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C13H15BrN6O5S2 | 详情 | 详情 | |
(II) | 25404 | D-cysteine; (S)-2-Amino-3-mercaptopropionic acid | 921-01-7 | C3H7NO2S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号:(II)The reaction of 7-beta-bromoacetamido-7-alphamethoxycephalosporanic acid (I) with D-cysteine (II) in water at pH 7 gives 7-(2-aminocarboxyethylthio)acetamido-7-alpha-methoxycephalosporanic acid (III), which is then condensed with 5-mercapto-1-methyl-1H-tetrazole (IV) in water at pH 6.5-7 and at 60 C.
【1】 Iwamatsu, K.; Inoue, S.; Miyauchi, K.; Kondo, S.; Seki, S.; Yamada, Y. (Meiji Seika Kaisha, Ltd.); 7alpha-Methoxycephalosporin derivatives. JP 55083791 . |
【2】 Blancafort, P.; Castaner, J.; Loren, J.G.; Serradell, M.N.; MT-141. Drugs Fut 1982, 7, 6, 395. |
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) | 31959 | (6R,7S)-3-[(acetoxy)methyl]-7-[(2-bromoacetyl)amino]-7-methoxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid; 7-beta-bromoacetamido-7-alphamethoxycephalosporanic acid | C13H15BrN2O7S | 详情 | 详情 | |
(II) | 25404 | D-cysteine; (S)-2-Amino-3-mercaptopropionic acid | 921-01-7 | C3H7NO2S | 详情 | 详情 |
(III) | 31960 | (6R,7S)-3-[(acetoxy)methyl]-7-[(2-[[(2S)-2-amino-2-carboxyethyl]sulfanyl]acetyl)amino]-7-methoxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid; 7-(2-aminocarboxyethyIthio)acetamido-7-alpha-methoxycephalosporanic acid | C16H21N3O9S2 | 详情 | 详情 | |
(IV) | 28420 | 5-Mercapto-1-methyl-1H-tetrazole; 1-Methyl-1H-1,2,3,4-tetraazol-5-ylhydrosulfide | 13183-79-4 | C2H4N4S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号:(III)Nitrile (II) was prepared by reaction of 2,4-dihydroxybenzaldehyde (I) with nitroethane and NaOAc in boiling AcOH. Subsequent condensation with D-cysteine (III) in the presence of phosphate buffer at pH 5.95 in MeOH provided the title thiazolidine.
【1】 Bergeron, R.J.; Wiegand, J.; Weimar, W.R.; Vinson, J.R.; Bussenius, J.; Yao, G.W.; McManis, J.S.; Desazadesmethyldesferrithiocin analogues as orally effective iron chelators. J Med Chem 1999, 42, 1, 95. |
【2】 Bergeron, R.J. Jr. (University of Florida); Thiazoline acid derivs.. WO 0012493 . |
合成路线4
该中间体在本合成路线中的序号:(XI)The reaction of 1,5-dichloropentane (I) with N-(benzyloxy)carbamic tert-butyl ester (II) by means of NaH in DMF gives N-(benzyloxy)-N-(5-chloropentyl)carbamic acid tert-butyl ester (III), which is treated with TFA in dichloromethane to yield the O-(benzyloxy)hydroxylamine (IV). The acylation of (IV) with AcCl and NaOH in dichloromethane affords the acetamide (V), which is condensed with (II) by means of NaH in DMF giving the acetamidopentyl carbamate (VI), which is debenzylated with H2 over Pd/C in methanol providing the dihydroxy compound (VII). The treatment of (VII) with TFA in dichloromethane gives the free hydroxylamine derivative (VIII), which is finally condensed with the thiazolinecarboxylic acid (IX) by means of BOP and DIEA in DMF to furnish the target compound. Alternatively the condensation of intermediate N-(benzyloxy)-N-(5-chloropentyl) carbamic acid tert-butyl ester (III) with N-(benzyloxy)acetamide (XI) by means of NaH in DMF gives directly the previously described acetamidopentyl carbamate (VI). The intermediate the thiazolinecarboxylic acid (IX) has been obtained by cyclization of D-cysteine (XI) with 3-hydroxypyridine-2-carbonitrile (XII) by means of NaOH in water.
【1】 Bergeron, R.J.; et al.; The desferrithiocin pharmacophore. J Med Chem 1994, 37, 10, 1411. |
【2】 Peter, H.H.; Moerker, T.; Bergeron, R.J. Jr. (Novartis AG; University of Florida); 2-(Pyrid-2'-yl)-2-thiazoline-4(S)-carboxylic acid derivs.. WO 9411367 . |
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) | 38237 | 1,5-dichloropentane | 628-76-2 | C5H10Cl2 | 详情 | 详情 |
(II) | 38238 | tert-butyl benzyloxycarbamate | 79722-21-7 | C12H17NO3 | 详情 | 详情 |
(III) | 38239 | tert-butyl benzyloxy(5-chloropentyl)carbamate | C17H26ClNO3 | 详情 | 详情 | |
(IV) | 38240 | O-benzyl-N-(5-chloropentyl)hydroxylamine; 1-([[(5-chloropentyl)amino]oxy]methyl)benzene | C12H18ClNO | 详情 | 详情 | |
(V) | 38241 | N-(benzyloxy)-N-(5-chloropentyl)acetamide | C14H20ClNO2 | 详情 | 详情 | |
(VI) | 38243 | tert-butyl 5-[acetyl(benzyloxy)amino]pentyl(benzyloxy)carbamate | C26H36N2O5 | 详情 | 详情 | |
(VII) | 38244 | tert-butyl 5-[acetyl(hydroxy)amino]pentyl(hydroxy)carbamate | C12H24N2O5 | 详情 | 详情 | |
(VIII) | 38245 | N-hydroxy-N-[5-(hydroxyamino)pentyl]acetamide | C7H16N2O3 | 详情 | 详情 | |
(IX) | 38246 | (4S)-2-(3-hydroxy-2-pyridinyl)-4,5-dihydro-1,3-thiazole-4-carboxylic acid | C9H8N2O3S | 详情 | 详情 | |
(X) | 38242 | N-(benzyloxy)acetamide | C9H11NO2 | 详情 | 详情 | |
(XI) | 25404 | D-cysteine; (S)-2-Amino-3-mercaptopropionic acid | 921-01-7 | C3H7NO2S | 详情 | 详情 |
(XII) | 38247 | 3-hydroxy-2-pyridinecarbonitrile | C6H4N2O | 详情 | 详情 |