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【结 构 式】 
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【分子编号】54814 【品名】tert-butyl 3-(1H-imidazo[4,5-b]pyridin-1-yl)propyl(methyl)carbamate 【CA登记号】 |
【 分 子 式 】C15H22N4O2 【 分 子 量 】290.36544 【元素组成】C 62.05% H 7.64% N 19.3% O 11.02% |
合成路线1
该中间体在本合成路线中的序号：(III)The intermediate 1-substituted imidazopyridine (III) was prepared by several procedures. Alkylation of imidazo[4,5-b]pyridine (I) with mesylate (II) in the presence of NaH provided a mixture of the desired compound (III) and its 3-substituted regioisomer (IV), which were separated by column chromatography.
| 【1】 Itani, H.; et al.; S-3578, a new broad spectrum parenteral cephalosporin exhibiting potent activity against both methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa synthesis and structure-activity relationships. 22nd Symp Med Chem (Nov 27 2002, Shizuoka) 2002, Abst 1P-16. |
| 【2】 Miwa, H.; Yoshida, T.; Shimada, J.; Kuwahara, S.; Nishitani, Y.; S-3578, a new broad-spectrum cephalosporin: I. Synthesis and structure-activity relationships. 41st Intersci Conf Antimicrob Agents Chemother (Dec 16 2001, Chicago) 2001, Abst F-370. |
| 【3】 Itani, H.; Nishitani, Y.; Irie, T. (Shionogi & Co. Ltd.); Imidazo[4,5-b]pyridiniummethyl-containing cephem cpds. having broad antibacterial spectrum. EP 1134222; WO 0032606 . |
| 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) | 44867 | 1H-imidazo[4,5-b]pyridine | C6H5N3 | 详情 | 详情 | |
| (II) | 54813 | 3-[(tert-butoxycarbonyl)(methyl)amino]propyl methanesulfonate | C10H21NO5S | 详情 | 详情 | |
| (III) | 54814 | tert-butyl 3-(1H-imidazo[4,5-b]pyridin-1-yl)propyl(methyl)carbamate | C15H22N4O2 | 详情 | 详情 | |
| (IV) | 54815 | tert-butyl 3-(3H-imidazo[4,5-b]pyridin-3-yl)propyl(methyl)carbamate | C15H22N4O2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(III)In a different strategy, reductive alkylation of 2,3-diaminopyridine (V) with aldehyde (VI) using borane-pyridine complex yielded regioselectively the 3-alkylamino pyridine (VII). Subsequent cyclization of (VII) with triethyl orthoformate afforded the desired imidazopyridine (III). In an alternative, more direct procedure, the bicyclic compound (III) was obtained by reductive condensation of the 2-formamido derivative (VIII) with aldehyde (VI) in the presence of borane-pyridine complex.
| 【1】 Itani, H.; et al.; S-3578, a new broad spectrum parenteral cephalosporin exhibiting potent activity against both methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa synthesis and structure-activity relationships. 22nd Symp Med Chem (Nov 27 2002, Shizuoka) 2002, Abst 1P-16. |
| 【2】 Miwa, H.; Yoshida, T.; Shimada, J.; Kuwahara, S.; Nishitani, Y.; S-3578, a new broad-spectrum cephalosporin: I. Synthesis and structure-activity relationships. 41st Intersci Conf Antimicrob Agents Chemother (Dec 16 2001, Chicago) 2001, Abst F-370. |
| 【3】 Itani, H.; Nishitani, Y.; Irie, T. (Shionogi & Co. Ltd.); Imidazo[4,5-b]pyridiniummethyl-containing cephem cpds. having broad antibacterial spectrum. EP 1134222; WO 0032606 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (III) | 54814 | tert-butyl 3-(1H-imidazo[4,5-b]pyridin-1-yl)propyl(methyl)carbamate | C15H22N4O2 | 详情 | 详情 | |
| (V) | 54816 | 2,3-Diaminopyridine | 452-58-4 | C5H7N3 | 详情 | 详情 |
| (VI) | 54817 | tert-butyl methyl(3-oxopropyl)carbamate | C9H17NO3 | 详情 | 详情 | |
| (VII) | 54818 | tert-butyl 3-[(2-amino-3-pyridinyl)amino]propyl(methyl)carbamate | C14H24N4O2 | 详情 | 详情 | |
| (VIII) | 54819 | 3-amino-2-pyridinylformamide | C6H7N3O | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(III)Imidazopyridine (III) was alkylated either with the iodomethyl cephem derivative (IX) or with the chloromethyl analogue (X) in the presence of NaBr to obtain a mixture of the desired 4-alkylated imidazopyridinium salt (XI) and the 3-alkylated isomer (XII). After acidic cleavage of the N-Boc and PMB protecting groups of (XI) and (XII), the corresponding mixture of deprotected compounds was separated by column chromatography. The target 4-alkylated imidazopyridinium derivative was finally converted to the title sulfate salt.
| 【1】 Itani, H.; et al.; S-3578, a new broad spectrum parenteral cephalosporin exhibiting potent activity against both methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa synthesis and structure-activity relationships. 22nd Symp Med Chem (Nov 27 2002, Shizuoka) 2002, Abst 1P-16. |
| 【2】 Miwa, H.; Yoshida, T.; Shimada, J.; Kuwahara, S.; Nishitani, Y.; S-3578, a new broad-spectrum cephalosporin: I. Synthesis and structure-activity relationships. 41st Intersci Conf Antimicrob Agents Chemother (Dec 16 2001, Chicago) 2001, Abst F-370. |
| 【3】 Itani, H.; Nishitani, Y.; Irie, T. (Shionogi & Co. Ltd.); Imidazo[4,5-b]pyridiniummethyl-containing cephem cpds. having broad antibacterial spectrum. EP 1134222; WO 0032606 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (III) | 54814 | tert-butyl 3-(1H-imidazo[4,5-b]pyridin-1-yl)propyl(methyl)carbamate | C15H22N4O2 | 详情 | 详情 | |
| (IX) | 54820 | 4-methoxybenzyl (7R)-7-{[2-{5-[(tert-butoxycarbonyl)amino]-1,2,4-thiadiazol-3-yl}-2-(ethoxyimino)acetyl]amino}-3-(iodomethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C27H31IN6O8S2 | 详情 | 详情 | |
| (X) | 54821 | 4-methoxybenzyl (7R)-7-{[2-{5-[(tert-butoxycarbonyl)amino]-1,2,4-thiadiazol-3-yl}-2-(ethoxyimino)acetyl]amino}-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C27H31ClN6O8S2 | 详情 | 详情 | |
| (XI) | 54822 | 4-[((7R)-7-{[2-{5-[(tert-butoxycarbonyl)amino]-1,2,4-thiadiazol-3-yl}-2-(ethoxyimino)acetyl]amino}-2-{[(4-methoxybenzyl)oxy]carbonyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl)methyl]-1-{3-[(tert-butoxycarbonyl)(methyl)amino]propyl}-1H-imidazo[4,5-b]pyridin-4-ium | C42H53N10O10S2 | 详情 | 详情 | |
| (XII) | 54823 | 3-[((7R)-7-{[2-{5-[(tert-butoxycarbonyl)amino]-1,2,4-thiadiazol-3-yl}-2-(ethoxyimino)acetyl]amino}-2-{[(4-methoxybenzyl)oxy]carbonyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl)methyl]-1-{3-[(tert-butoxycarbonyl)(methyl)amino]propyl}-1H-imidazo[4,5-b]pyridin-3-ium | C42H53N10O10S2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(IV)The condensation of the aminocephem derivative (I) with the ethoxyiminoacetic acid (II) by means of POCl3 and NMM gives the corresponding amide (III), which is condensed with the imidazo pyridine (IV) by means of NaI or NaBr to yield the protected imidazopyridinium salt (V). Finally, this compound is deprotected by means of AlCl3 and anisole, TiCl4 and anisole or sulfuric and formic acids to afford the target cephem-carboxylate derivative.
| 【1】 Itani, H.; Ishikura, K.; Yoshizawa, H.; et al.; S-3578, a new broad spectrum parenteral cephalosporin exhibiting potent activity against both methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa synthesis and structure-activity relationships. J Antibiot 2002, 55, 11, 975. |
| 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) | 21627 | 4-methoxybenzyl (7R)-7-amino-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C16H17ClN2O4S | 详情 | 详情 | |
| (II) | 58660 | tert-butyl 3-(2-amino-2-oxoethanimidoyl)-1,2,4-thiadiazol-5-ylcarbamate | C11H17N5O4S | 详情 | 详情 | |
| (III) | 54821 | 4-methoxybenzyl (7R)-7-{[2-{5-[(tert-butoxycarbonyl)amino]-1,2,4-thiadiazol-3-yl}-2-(ethoxyimino)acetyl]amino}-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C27H31ClN6O8S2 | 详情 | 详情 | |
| (IV) | 54814 | tert-butyl 3-(1H-imidazo[4,5-b]pyridin-1-yl)propyl(methyl)carbamate | C15H22N4O2 | 详情 | 详情 | |
| (V) | 54822 | 4-[((7R)-7-{[2-{5-[(tert-butoxycarbonyl)amino]-1,2,4-thiadiazol-3-yl}-2-(ethoxyimino)acetyl]amino}-2-{[(4-methoxybenzyl)oxy]carbonyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl)methyl]-1-{3-[(tert-butoxycarbonyl)(methyl)amino]propyl}-1H-imidazo[4,5-b]pyridin-4-ium | C42H53N10O10S2 | 详情 | 详情 |