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【结 构 式】 
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【分子编号】15748 【品名】(6R,7R)-3-[(acetoacetoxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 【CA登记号】 |
【 分 子 式 】C12H14N2O6S 【 分 子 量 】314.31904 【元素组成】C 45.86% H 4.49% N 8.91% O 30.54% S 10.2% |
合成路线1
该中间体在本合成路线中的序号：(III)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：(I)This compound can be prepared by two related ways: 1) The condensation of (6R,7R)-7-amino-3-(3-oxobutyryloxy)-3-cephem-4-carboxylic acid (I) with 2-[5-(tert-butoxycarbonylamino)-1,2,4-thiadiazol-3-yl]-2(Z)-(methoxyimino)acetic acid (II), by means of PCl5 and bis(trimethylsilyl)acetamide (BSA) gives the corresponding amide (III), which is thencondensed with imidazo[1,2-b]pyridazine (IV) by means of KI in hot aqueous acetonitrile. 2) The condensation of 2-[2-(tert-butoxycarbonylamino)thiazol-4-yl]-2(Z)-(methoxyimino)acetic acid (V) with cephem compound (I) by means of PCl5 and triethylamine yields the corresponding amide (VI), which is deprotected with trifluoroacetic acid to afford free amide (III), already obtained.
| 【1】 Miyake, A.; Kondo, M.; Fujino, M. (Takeda Chemical Industries, Ltd.); Antibacterial cpds., their production and use. AU 8541700; AU 8654168; EP 0160252; EP 0203271; ES 8606363; ES 8705892; ES 8706692; ES 8707245; JP 1985231684; JP 1987149682; WO 8504879; WO 8505620; WO 8605183; WO 8605184 . |
| 【2】 Prous, J.; Castaner, J.; Cefozopran Hydrochloride. Drugs Fut 1992, 17, 9, 771. |
| 【3】 Yoshimura, Y.; Hashimoto, N.; Miyake,A.; Nishimura, T.; Yamaoka, M.; Imada, A.; Studies on condensed-heterocyclic azolium cephalosporins. IV. Synthesis and antibacterial activity of 7beta-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)-alkoxyiminoacetamido]-3-(condensed-heterocyclic azolium)methyl cephalosporins including SCE-2787. J Antibiot 1992, 45, 5, 709-20. |
| 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) | 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 | |
| (II) | 11757 | 2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-(methoxyimino)acetic acid | C5H6N4O3S | 详情 | 详情 | |
| (III) | 15750 | (6R,7R)-3-[(acetoacetoxy)methyl]-7-[[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(methoxyimino)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C17H18N6O8S2 | 详情 | 详情 | |
| (IV) | 15751 | imidazo[1,2-b]pyridazine | C6H5N3 | 详情 | 详情 | |
| (V) | 15752 | 2-[5-[(tert-butoxycarbonyl)amino]-1,2,4-thiadiazol-3-yl]-2-(methoxyimino)acetic acid | C10H14N4O5S | 详情 | 详情 | |
| (VI) | 15753 | (6R,7R)-3-[(acetoacetoxy)methyl]-7-[[2-[5-[(tert-butoxycarbonyl)amino]-1,2,4-thiadiazol-3-yl]-2-(methoxyimino)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C22H26N6O10S2 | 详情 | 详情 |