S-3578, -Drug Synthesis Database

【结构式】

【药物名称】S-3578

【化学名称】7(R)-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2(Z)-(ethoxyimino)acetamido]-3-[1-[3-(methylamino)propyl]-1H-imidazo[4,5-b]pyridin-4-iumylmethyl]-3-cephem- 4-carboxylate sulfate

【CA登记号】

【分子式】C₂₄H₃₀N₁₀O₉S₃

【分子量】698.7603

【开发单位】Shionogi (Originator)

【药理作用】Antibiotics, ANTIINFECTIVE THERAPY, Cephalosporins

合成路线1 合成路线2 合成路线3 合成路线4

合成路线1

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.

参考文献中间体

【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	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

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.

参考文献中间体

【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

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.

参考文献中间体

【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	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

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.

参考文献中间体

【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	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

Extended Information

Drug NewChemical Entity Original Patent(1)