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【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%

与该中间体有关的原料药合成路线共 4 条

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 .
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) 20094 2,4-dihydroxybenzaldehyde 95-01-2 C7H6O3 详情 详情
(II) 25403 2,4-dihydroxybenzonitrile C7H5NO2 详情 详情
(III) 25404 D-cysteine; (S)-2-Amino-3-mercaptopropionic acid 921-01-7 C3H7NO2S 详情 详情

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
Extended Information