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【结 构 式】 
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【分子编号】11757 【品名】2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-(methoxyimino)acetic acid 【CA登记号】 |
【 分 子 式 】C5H6N4O3S 【 分 子 量 】202.1938 【元素组成】C 29.7% H 2.99% N 27.71% O 23.74% S 15.86% |
合成路线1
该中间体在本合成路线中的序号：(III)A new synthesis for [14C]-E-1040 has been described: The cyclization of [14C]-labeled potassium thiocyanate (I) with 2-(N-chlorocarboxamidino)-2-(methoxyimino)acetic acid (II) in methanol by means of triethylamine gives 2-(2-aminothiazol-4-yl)-2(Z)-(methoxyimino)acetic acid (III), which is treated with PCl5 in dichloromethane, yielding the corresponding acyl chloride (IV). Finally, this compound is condensed with 7-amino-3-(4-carbamoylquinuclidinio-1-ylmethyl)-3-cephem-4-carboxylate (V) by means of sodium acetate in dichloromethane.
| 【1】 Sugiyama, I.; Nomoto, S.; Mizuo, H.; Yamauchi, H.; Synthesis of (6R,7R)-7-[2-(5-amino-1,2,4-[5-C-14]thiadiazol-3-yl)-(Z)-2-methoxyiminoacetamido]-3-[(4-carbomoyl-1-quinuclidinio)methyl]ceph-3-em-4-carboxylate([C-14]E1040). J Label Compd Radiopharm 1991, 29, 12, 1309. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 11756 | 3-Amino-3-(chloroimino)-2-(methoxyimino)propionic acid | C4H6ClN3O3 | 详情 | 详情 | |
| (III) | 11757 | 2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-(methoxyimino)acetic acid | C5H6N4O3S | 详情 | 详情 | |
| (III) | 45072 | 2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(methoxyimino)acetic acid | C5H6N4O3S | 详情 | 详情 | |
| (IV) | 11758 | 2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-(methoxyimino)acetyl chloride | C5H5ClN4O2S | 详情 | 详情 | |
| (IV) | 45073 | 2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(methoxyimino)acetyl chloride | C5H5ClN4O2S | 详情 | 详情 | |
| (V) | 11759 | (6R,7R)-7-amino-3-[[4-(aminocarbonyl)-1-azoniabicyclo[2.2.2]oct-1-yl]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C16H22N4O4S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)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 |
合成路线3
该中间体在本合成路线中的序号：(VI)The substitution of the triflate group of (I) by the sodium thiolate (II) provided a mixture of 3-cephem (III) and 2-cephem (IV) compounds. Without purification, treatment of the mixture with m-chloroperbenzoic acid gave the corresponding S-oxides, which were reduced with PCl3 to yield the 3-cephem (III). The phenylacetyl group was removed by treatment with PCl5 and pyridine, followed by hydrolysis with MeOH to afford amine (V). Acylation with acid (VI) in the presence of dicyclohexyl carbodiimide (DCC) and 1-hydroxybenzotriazole (HOBT) yielded amide (VII). Then, removal of the benzhydryl protecting group using trifluoroacetic acid and anisole, followed by treatment with aqueous NaHCO3 provided the target cephalosporin.
| 【1】 Tsushima, M.; Iwamatsu, K.; Tamura, A.; Shibahara, S.; Novel cephalosporin derivatives possessing a bicyclic heterocycle at the 3-position. Part I: Synthesis and biological activities of 3-(benzothiazol-2-yl)thiocephalosporin derivatives, CP0467 and related compounds. Bioorg Med Chem 1998, 6, 7, 1009. |
| 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) | 18209 | benzhydryl 8-oxo-7-[(2-phenylacetyl)amino]-3-[[(trifluoromethyl)sulfonyl]oxy]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C29H23F3N2O7S2 | 详情 | 详情 | |
| (II) | 18210 | Benzothiazole-2-thiol sodium salt | C7H4NNaS2 | 详情 | 详情 | |
| (III) | 18211 | benzhydryl 3-(1,3-benzothiazol-2-ylsulfanyl)-8-oxo-7-[(2-phenylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C35H27N3O4S3 | 详情 | 详情 | |
| (IV) | 18212 | benzhydryl 3-(1,3-benzothiazol-2-ylsulfanyl)-8-oxo-7-[(2-phenylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-3-ene-2-carboxylate | C35H27N3O4S3 | 详情 | 详情 | |
| (V) | 18213 | benzhydryl 7-amino-3-(1,3-benzothiazol-2-ylsulfanyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C27H21N3O3S3 | 详情 | 详情 | |
| (VI) | 11757 | 2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-(methoxyimino)acetic acid | C5H6N4O3S | 详情 | 详情 | |
| (VII) | 18215 | benzhydryl 7-[[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(methoxyimino)acetyl]amino]-3-(1,3-benzothiazol-2-ylsulfanyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C32H25N7O5S4 | 详情 | 详情 |