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【结 构 式】 
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【分子编号】19846 【品名】2-(4-methyl-2-sulfanyl-1,3-thiazol-5-yl)acetic acid 【CA登记号】34272-64-5 |
【 分 子 式 】C6H7NO2S2 【 分 子 量 】189.25912 【元素组成】C 38.08% H 3.73% N 7.4% O 16.91% S 33.89% |
合成路线1
该中间体在本合成路线中的序号：(V)The condensation of 2-(methoxyimino)-2-(2-tritylaminothiazol-4-yl)acetic acid (I) with 7-aminocephalosporanic acid (II) by means of dicyclohexylcarbodiimide in CH2Cl2 gives 7-[2-(methoxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]cephalosporanic acid (III), which is deprotected by means of formic acid in water yielding 7-[2-(methoxyimino)-2-(2-aminothiazol-4-yl)acetamido]cephalosporanic acid (IV). Finally, this compound is condensed with 5-(carboxymethyl)-2-mercapto-4-methyl-1,3-thiazole (V) by means of NaHCO3 or NaOH in hot water.
| 【1】 Wolff, S.; et al.; Results of a multicenter phase III trial of magnetic resonance angiography (MRA) with MS-325 for the detection of peripheral vascular disease in the aortolliac region. Circulation 2002, 106, 19, Suppl. 2, Abst 3408. |
| 【2】 Duerckeimer, W.; et al. (Aventis Pharma AG); Cephem derivative. BE 0865632; FR 2385722; GB 1604971; JP 5706887; US 4278793 . |
| 【3】 Serradell, M.N.; Castaner, J.; Cefodizime. Drugs Fut 1984, 9, 3, 177. |
| 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) | 25058 | 2-(methoxyimino)-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetic acid | 64485-90-1 | C25H21N3O3S | 详情 | 详情 |
| (II) | 15672 | 7-Aminocephalosporanic acid; 3-[(acetoxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid; 7-ACA | C10H12N2O5S | 详情 | 详情 | |
| (III) | 30338 | 3-[(acetoxy)methyl]-7-([2-(methoxyimino)-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetyl]amino)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | 66254-46-4 | C35H31N5O7S2 | 详情 | 详情 |
| (IV) | 30339 | 3-[(acetoxy)methyl]-7-[[2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C16H17N5O7S2 | 详情 | 详情 | |
| (V) | 19846 | 2-(4-methyl-2-sulfanyl-1,3-thiazol-5-yl)acetic acid | 34272-64-5 | C6H7NO2S2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)Displacement of the acetate group of 7-aminocephalosporanic acid (I) with the mercapto thiazole (II) yielded thioether (III). This was then acylated with 2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetic acid (IV) in the presence of DCC and HOBt to furnish the corresponding amide.
| 【1】 Wolff, S.; et al.; Results of a multicenter phase III trial of magnetic resonance angiography (MRA) with MS-325 for the detection of peripheral vascular disease in the aortolliac region. Circulation 2002, 106, 19, Suppl. 2, Abst 3408. |
| 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) | 15672 | 7-Aminocephalosporanic acid; 3-[(acetoxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid; 7-ACA | C10H12N2O5S | 详情 | 详情 | |
| (II) | 19846 | 2-(4-methyl-2-sulfanyl-1,3-thiazol-5-yl)acetic acid | 34272-64-5 | C6H7NO2S2 | 详情 | 详情 |
| (III) | 56514 | 7-amino-3-({[5-(carboxymethyl)-4-methyl-1,3-thiazol-2-yl]sulfanyl}methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C14H15N3O5S3 | 详情 | 详情 | |
| (IV) | 24737 | 2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetic acid | 65872-41-5 | C6H7N3O3S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VII)The D-threonine (I) is converted into the azetidinone (II), and into the enol (III) according to (Tsubouchi, H., et al. Tetrahedron Assimetry, 1944, 5: 441). The tosylation of (III) with tosyl chloride and N-methylpyrrolidine yielded the tosylated enol (IV), which was cyclized with H2S and triethylamine to the isocephem derivative (V). The chlorination of (V) with N-bromosuccinimide (NBS) and AIBN affords the bromomethyl derivative (VI), which is treated with 2-(4-methyl-2-sulfanylthiazol-5-yl)acetic acid (VII) and triethylamine or NaHCO3 and then esterified with diphenyldiazomethane to give the expected condensation product (VIII). The reaction of (VIII) with methylhydrazine cleaves the phthalimide group affording (IX), which is then amidated wih the acetic acid derivative (X) by means of dicyclohexylcarbodiimide (DCC) givig the fully protected final product (XI). Finally, this compound is treated with trifluoroacetic acid to eliminate the diphenyl nad triphenyl protecting groups.
| 【1】 Tsuji, K.; et al.; Synthesis and structure-activity relationships of cephalosporins, 2-isocephems, and 2-oxaisocephems with C-3' or C-7 catechol or related aromatics. Bioorg Med Chem 1996, 4, 12, 2135. |
| 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) | 19840 | (2R,3S)-3-hydroxy-2-methylbutyric acid | C5H10O3 | 详情 | 详情 | |
| (II) | 19841 | benzhydryl (2R,3S)-2-[(3S,4R)-3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-2-oxo-4-[(E)-2-phenylethenyl]azetidinyl]-3-hydroxybutanoate | C36H30N2O6 | 详情 | 详情 | |
| (III) | 19842 | benzhydryl (Z)-2-((2R,3S)-3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-2-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-4-oxoazetidinyl)-3-hydroxy-2-butenoate | C31H28N2O7S | 详情 | 详情 | |
| (IV) | 19843 | benzhydryl (Z)-2-((2R,3S)-3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-2-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-4-oxoazetidinyl)-3-[[(4-methylphenyl)sulfonyl]oxy]-2-butenoate | C38H34N2O9S2 | 详情 | 详情 | |
| (V) | 19844 | benzhydryl (6S,7S)-7-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-methyl-8-oxo-4-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C29H22N2O5S | 详情 | 详情 | |
| (VI) | 19845 | benzhydryl (6S,7S)-3-(bromomethyl)-7-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-8-oxo-4-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C29H21BrN2O5S | 详情 | 详情 | |
| (VII) | 19846 | 2-(4-methyl-2-sulfanyl-1,3-thiazol-5-yl)acetic acid | 34272-64-5 | C6H7NO2S2 | 详情 | 详情 |
| (VIII) | 19847 | benzhydryl (6S,7S)-3-[([5-[2-(benzhydryloxy)-2-oxoethyl]-4-methyl-1,3-thiazol-2-yl]sulfanyl)methyl]-7-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-8-oxo-4-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C48H37N3O7S3 | 详情 | 详情 | |
| (IX) | 19848 | benzhydryl (6S,7S)-7-amino-3-[([5-[2-(benzhydryloxy)-2-oxoethyl]-4-methyl-1,3-thiazol-2-yl]sulfanyl)methyl]-8-oxo-4-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C40H35N3O5S3 | 详情 | 详情 | |
| (X) | 19849 | 2-([[1,5-bis(benzhydryloxy)-4-oxo-1,4-dihydro-2-pyridinyl]methoxy]imino)-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetic acid | C56H44N4O6S | 详情 | 详情 | |
| (XI) | 19850 | benzhydryl (6S,7S)-3-[([5-[2-(benzhydryloxy)-2-oxoethyl]-4-methyl-1,3-thiazol-2-yl]sulfanyl)methyl]-7-([2-([[1,5-bis(benzhydryloxy)-4-oxo-1,4-dihydro-2-pyridinyl]methoxy]imino)-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetyl]amino)-8-oxo-4-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C96H77N7O10S4 | 详情 | 详情 |