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【结 构 式】 
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【分子编号】33224 【品名】1-[2-(dimethylamino)ethyl]-1H-1,2,3,4-tetraazole-5-thiol; 1-[2-(dimethylamino)ethyl]-1H-1,2,3,4-tetraazol-5-ylhydrosulfide 【CA登记号】61607-68-9 |
【 分 子 式 】C5H11N5S 【 分 子 量 】173.24204 【元素组成】C 34.67% H 6.4% N 40.43% S 18.51% |
合成路线1
该中间体在本合成路线中的序号：(VI)The reaction of 7-beta-(D-5-phthalimido-5-carboxylvaleramido)-3-hydroxy-methyl-3-cephem-4-carboxylic acid (I) with diketene in CH2Cl2 gives the 3-(3-oxobutyryloxy)methyl derivative (II), which is treated with triethylamine-N,N-dimethylaniline, dimethyldichlososilane and PCl5 to obtain 7-beta-amino-3-(3-oxobutyryloxy)methyl-3-cephem-4-carboxylic acid (III).The acylation of (III) with 4-chloro-3-oxobutyryl chloride (A) and triethylamine in CH2Cl2 affords the amide (IV), which is condensed with thiourea (B) by means of NaHCO3 in acetone yielding the thiazole derivative (V). Finally, this compound is condensed with 5-mercapto-1-[2-(N,N-dimethylamino)ethyl-1H-tetrazole (VI) by means of NaHCO3 in hot water.
| 【1】 Tsushima, S.; et al. (Takeda Chemical Industries, Ltd.); Novel 3-acyloxymethyl-cephem compounds useful as intermediates for preparing cephalosporin antibiotics. DE 2607064; ES 459261; FR 2301528; GB 1544103; US 4245088 . |
| 【2】 Blancafort, P.; Serradell, M.N.; Castaner, J.; Roberts, P.J.; Cefotiam. Drugs Fut 1979, 4, 6, 400. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (B) | 10180 | Thiourea | 62-56-6 | CH4N2S | 详情 | 详情 |
| (A) | 15696 | 4-chloro-3-oxobutanoyl chloride | C4H4Cl2O2 | 详情 | 详情 | |
| (I) | 33220 | (6R,7R)-7-[[5-carboxy-5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)pentanoyl]amino]-3-(hydroxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C22H21N3O9S | 详情 | 详情 | |
| (II) | 33221 | (6R,7R)-3-[(acetoacetoxy)methyl]-7-[[5-carboxy-5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)pentanoyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C26H25N3O11S | 详情 | 详情 | |
| (III) | 15748 | (6R,7R)-3-[(acetoacetoxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C12H14N2O6S | 详情 | 详情 | |
| (IV) | 33222 | (6R,7R)-3-[(acetoacetoxy)methyl]-7-[(4-chloro-3-oxobutanoyl)amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C16H17ClN2O8S | 详情 | 详情 | |
| (V) | 33223 | (6R,7R)-3-[(acetoacetoxy)methyl]-7-[[2-(2-imino-2,3-dihydro-1,3-thiazol-4-yl)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C17H18N4O7S2 | 详情 | 详情 | |
| (VI) | 33224 | 1-[2-(dimethylamino)ethyl]-1H-1,2,3,4-tetraazole-5-thiol; 1-[2-(dimethylamino)ethyl]-1H-1,2,3,4-tetraazol-5-ylhydrosulfide | 61607-68-9 | C5H11N5S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VI)The condensation of 7-acetoacetamido-3-acetoxymethyl-3-cephem-4-carboxylic acid (VII) with the mercaptane (VI) by means of NaHCO3 in hot water gives 7-beta-amino-3-[1-[2-(N,N-dimethylamino)ethyl]-1H-tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid (VIII), which is then condensed with 2-aminothiazol-4-ylacetic acid (IX) by means of N-hydroxysuccinimide and dicyclohexylcarbodiimide in THF. The free amino group of (VIII) is acylated with Cl2 and diketene giving the 4-chloro-3-oxobutyramido derivative (X), which is finally cyclized with thiourea (B) by means of NaHCO3 in acetone.
| 【1】 Numata, M.; et al. (Takeda Chemical Industries, Ltd.); 7-Alpha-(2-aminothiazole)acetamidocephalosporins. DE 2461478; FR 2255077; GB 1491018; NL 7416609; US 4080498; US 4421912; US 4517361 . |
| 【2】 Blancafort, P.; Serradell, M.N.; Castaner, J.; Roberts, P.J.; Cefotiam. Drugs Fut 1979, 4, 6, 400. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (B) | 10180 | Thiourea | 62-56-6 | CH4N2S | 详情 | 详情 |
| (VI) | 33224 | 1-[2-(dimethylamino)ethyl]-1H-1,2,3,4-tetraazole-5-thiol; 1-[2-(dimethylamino)ethyl]-1H-1,2,3,4-tetraazol-5-ylhydrosulfide | 61607-68-9 | C5H11N5S | 详情 | 详情 |
| (VII) | 33225 | (6R,7R)-7-(acetoacetamido)-3-[(acetoxy)methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C14H16N2O7S | 详情 | 详情 | |
| (VIII) | 33226 | (6R,7R)-7-amino-3-[([1-[2-(dimethylamino)ethyl]-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 | C13H19N7O3S2 | 详情 | 详情 | |
| (IX) | 33228 | 2-(2-imino-2,3-dihydro-1,3-thiazol-4-yl)acetic acid | C5H6N2O2S | 详情 | 详情 | |
| (X) | 33227 | (6R,7R)-7-[(4-chloro-3-oxobutanoyl)amino]-3-[([1-[2-(dimethylamino)ethyl]-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 | C17H22ClN7O5S2 | 详情 | 详情 |