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【结 构 式】 
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【药物名称】LB-10827 【化学名称】7-[2-(2-Amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-(2,6-diaminopyrimidin-4-ylsulfanylmethylsulfanyl)-3-cephem-4-carboxylic acid 【CA登记号】 【 分 子 式 】C17H16ClN9O5S4 【 分 子 量 】590.08337 |
【开发单位】LG Chem (Originator) 【药理作用】Antibiotics, ANTIINFECTIVE THERAPY, Cephalosporins |
合成路线1
Bicyclic enol compound (I) was phosphorylated by means of diphenyl phosphorochloridate and diisopropylethylamine, and the resulting enol phosphate was displaced with thioacetic acid yielding thioacetate ester (II). Cleavage of the phenylacetamido group of (II) to afford amine (III) was then effected by treatment with PCl5 and pyridine, followed by quenching with isobutyl alcohol. On the other side, thiazole (IV) was chlorinated with N-chlorosuccinimide to provide the 5-chlorothiazole (V). Protection of the amino group of (V) with di-tert-butyl dicarbonate, followed by ester hydrolysis gave (VI). The oximino group of (VI) was then protected as the O-trityl derivative (VII) by treatment with triphenylmethyl chloride. Coupling of carboxylic acid (VII) with amine (III) employing POCl3 and pyridine provided amide (VIII). Optionally, hydrolysis of the thioacetate ester using morpholine and pyridine, followed by S-alkylation with chloroiodomethane furnished the chloromethylsulfanyl derivative (IX).
| 【1】 Oh, S.H.; Lee, C.-S.; Ryu, E.-J.; Paek, K.-S.; Kim, M.Y.; Youn, H.; Synthesis and antibacterial activities of novel C(3)-aminopyrimidinyl substituted cephalosporins including against respiratory tract pathogens. Bioorg Med Chem Lett 2000, 10, 18, 2123. |
| 【2】 Paek, K.S.; Ryu, E.J.; Oh, S.H.; Lee, C.S.; Lee, S.H.; Kim, M.Y.; Synthesis and antibacterial activities of LB10827, a new oral cephalosporin antibiotic. 39th Intersci Conf Antimicrob Agents Chemother (Sept 26 1999, San Francisco) 1999, Abst F397. |
| 【3】 Kim, M.Y.; Oh, S.H.; Kim, Y.Z.; Moon, K.Y.; Lee, C.S.; Ryu, E.J.; Paek, K.S.; Lee, S.H. (LG Chem Ltd.); Novel cephalosporin cpds., processes for preparation thereof and antimicrobial compsns. containing the same. WO 9958535 . |
| 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) | 38210 | benzhydryl 3-hydroxy-8-oxo-7-[(2-phenylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C28H24N2O5S | 详情 | 详情 | |
| (II) | 38199 | benzhydryl 3-(acetylsulfanyl)-8-oxo-7-[(2-phenylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C30H26N2O5S2 | 详情 | 详情 | |
| (III) | 38200 | benzhydryl 3-(acetylsulfanyl)-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C22H20N2O4S2 | 详情 | 详情 | |
| (IV) | 15889 | Ethyl 2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetate;(Z)-ethyl 2-(2-aminothiazol-4-yl)-2-(hydroxyimino)acetate； ethyl 2-(2-amino-1,3-thiazol-4-yl)-2-(hydroxyimino)acetate | 60845-81-0 | C7H9N3O3S | 详情 | 详情 |
| (V) | 38201 | ethyl 2-(2-amino-5-chloro-1,3-thiazol-4-yl)-2-(hydroxyimino)acetate | C7H8ClN3O3S | 详情 | 详情 | |
| (VI) | 38202 | 2-[2-[(tert-butoxycarbonyl)amino]-5-chloro-1,3-thiazol-4-yl]-2-(hydroxyimino)acetic acid | C10H12ClN3O5S | 详情 | 详情 | |
| (VII) | 38203 | 2-[2-[(tert-butoxycarbonyl)amino]-5-chloro-1,3-thiazol-4-yl]-2-[(trityloxy)imino]acetic acid | C29H26ClN3O5S | 详情 | 详情 | |
| (VIII) | 38204 | benzhydryl 3-(acetylsulfanyl)-7-([2-[2-[(tert-butoxycarbonyl)amino]-5-chloro-1,3-thiazol-4-yl]-2-[(trityloxy)imino]acetyl]amino)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C51H44ClN5O8S3 | 详情 | 详情 | |
| (IX) | 38205 | benzhydryl 7-([2-[2-[(tert-butoxycarbonyl)amino]-5-chloro-1,3-thiazol-4-yl]-2-[(trityloxy)imino]acetyl]amino)-3-[(chloromethyl)sulfanyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C50H43Cl2N5O7S3 | 详情 | 详情 |
合成路线2
In a related procedure, chloromethylsulfanyl derivative (IX) was condensed with 2,4-diamino-6-mercaptopyrimidine (XI) to give thioacetal (XIII), which was then deprotected with trifluoroacetic acid-promoted cleavage of Boc, trityl and benzhydryl protecting groups of (XIII) yielded the title compound.
| 【1】 Oh, S.H.; Lee, C.-S.; Ryu, E.-J.; Paek, K.-S.; Kim, M.Y.; Youn, H.; Synthesis and antibacterial activities of novel C(3)-aminopyrimidinyl substituted cephalosporins including against respiratory tract pathogens. Bioorg Med Chem Lett 2000, 10, 18, 2123. |
| 【2】 Paek, K.S.; Ryu, E.J.; Oh, S.H.; Lee, C.S.; Lee, S.H.; Kim, M.Y.; Synthesis and antibacterial activities of LB10827, a new oral cephalosporin antibiotic. 39th Intersci Conf Antimicrob Agents Chemother (Sept 26 1999, San Francisco) 1999, Abst F397. |
| 【3】 Kim, M.Y.; Oh, S.H.; Kim, Y.Z.; Moon, K.Y.; Lee, C.S.; Ryu, E.J.; Paek, K.S.; Lee, S.H. (LG Chem Ltd.); Novel cephalosporin cpds., processes for preparation thereof and antimicrobial compsns. containing the same. WO 9958535 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IX) | 38205 | benzhydryl 7-([2-[2-[(tert-butoxycarbonyl)amino]-5-chloro-1,3-thiazol-4-yl]-2-[(trityloxy)imino]acetyl]amino)-3-[(chloromethyl)sulfanyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C50H43Cl2N5O7S3 | 详情 | 详情 | |
| (XI) | 38206 | 2,6-diamino-4-pyrimidinethiol; 2,6-diamino-4-pyrimidinylhydrosulfide | 81012-96-6 | C4H6N4S | 详情 | 详情 |
| (XIII) | 38207 | benzhydryl 7-([2-[2-[(tert-butoxycarbonyl)amino]-5-chloro-1,3-thiazol-4-yl]-2-[(trityloxy)imino]acetyl]amino)-3-([[(2,6-diamino-4-pyrimidinyl)sulfanyl]methyl]sulfanyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C54H48ClN9O7S4 | 详情 | 详情 |
合成路线3
Thioacetate ester (VIII) was hydrolyzed to thiol (X) by treatment with morpholine and triethylamine. The iodomethylsulfanyl pyrimidine (XII) was prepared by alkylation of 2,4-diamino-6-mercaptopyrimidine (XI) with bromochloromethane, followed by displacement of the chlorine with NaI in acetone. Alkylation of thiol (X) with iodide (XII) gave rise to thioacetal (XIII). Finally, trifluoroacetic acid-promoted cleavage of Boc, trityl and benzhydryl protecting groups of (XIII) yielded the title compound.
| 【1】 Oh, S.H.; Lee, C.-S.; Ryu, E.-J.; Paek, K.-S.; Kim, M.Y.; Youn, H.; Synthesis and antibacterial activities of novel C(3)-aminopyrimidinyl substituted cephalosporins including against respiratory tract pathogens. Bioorg Med Chem Lett 2000, 10, 18, 2123. |
| 【2】 Kim, M.Y.; Oh, S.H.; Kim, Y.Z.; Moon, K.Y.; Lee, C.S.; Ryu, E.J.; Paek, K.S.; Lee, S.H. (LG Chem Ltd.); Novel cephalosporin cpds., processes for preparation thereof and antimicrobial compsns. containing the same. WO 9958535 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIII) | 38204 | benzhydryl 3-(acetylsulfanyl)-7-([2-[2-[(tert-butoxycarbonyl)amino]-5-chloro-1,3-thiazol-4-yl]-2-[(trityloxy)imino]acetyl]amino)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C51H44ClN5O8S3 | 详情 | 详情 | |
| (X) | 38208 | benzhydryl 7-([2-[2-[(tert-butoxycarbonyl)amino]-5-chloro-1,3-thiazol-4-yl]-2-[(trityloxy)imino]acetyl]amino)-8-oxo-3-sulfanyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C49H42ClN5O7S3 | 详情 | 详情 | |
| (XI) | 38206 | 2,6-diamino-4-pyrimidinethiol; 2,6-diamino-4-pyrimidinylhydrosulfide | 81012-96-6 | C4H6N4S | 详情 | 详情 |
| (XII) | 38209 | 2-amino-6-[(iodomethyl)sulfanyl]-4-pyrimidinylamine; 6-[(iodomethyl)sulfanyl]-2,4-pyrimidinediamine | C5H7IN4S | 详情 | 详情 | |
| (XIII) | 38207 | benzhydryl 7-([2-[2-[(tert-butoxycarbonyl)amino]-5-chloro-1,3-thiazol-4-yl]-2-[(trityloxy)imino]acetyl]amino)-3-([[(2,6-diamino-4-pyrimidinyl)sulfanyl]methyl]sulfanyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C54H48ClN9O7S4 | 详情 | 详情 |