Cefpodoxime proxetil, RU-51807, U-76252, CS-807, Otreon, Vantin, Doxef, Orelox, Podomexef, Banan, -Drug Synthesis Database

【结构式】

【药物名称】Cefpodoxime proxetil, RU-51807, U-76252, CS-807, Otreon, Vantin, Doxef, Orelox, Podomexef, Banan

【化学名称】(6R,7R)-7-[2-(2-Amino-4-thiazolyl)-2(Z)-(methoxyimino)acetamido]-3-(methoxymethyl)-3-cephem-4-carboxylic acid 1-(isopropoxycarbonyloxy)ethyl ester
　　　　　　[6R-(6alpha,7beta(Z)]-7-[(2-Amino-4-thiazolyl)(methoxyimino)acetylamino]-3-(methoxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 1-[(1-methylethoxy)carbonyloxy]ethyl ester

【CA登记号】87239-81-4, 62628-58-4 (CS-807)

【分子式】C₂₁H₂₇N₅O₉S₂

【分子量】557.60544

【开发单位】Sankyo (Originator), Aventis Pharma (Not Determined), Pfizer (Not Determined), Hosbon (Licensee), Ranbaxy (Generic)

【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5

合成路线1

1) The methanolysis of 3-(acetoxymethyl)-7-[4-chloro-3-oxo-2(Z)-(methoxyimino)butyrylamidol-3-cephem-4-carboxylic acid (I) with methanol and NaHCO3 gives the corresponding 3-(methoxymethyl) derivative (II), which is esterified with 1-iodoethylisopropyl carbonate (III) by means of dicyclohexylamine in DMA to afford the corresponding ester (IV). Finally, this compound is cyclized with thiourea (V) and methyl iodide in a phosphate buffer.

参考文献中间体

【1】 Fujimoto, K.; Nakayama, E.; Nakao, H. (Sankyo Co., Ltd.); Process for preparing 3-alkoxymethylcephalosporin derivatives. DE 3244457 .
【2】 Fujimoto, K.; Ishihara, S.; Yanagisawa, H.; Ide, J.; Nakayama, E.; Nakao, H.; Sugawara, S.; Iwata, M.; Studies on orally active cephalosporin esters. J Antibiot 1987, 40, 3, 370.
【3】 Castaner, J.; Serradell, M.N.; Cefpodoxime Proxetil. Drugs Fut 1988, 13, 1, 16.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	27347	N,N-dicyclohexylamine	101-83-7	C₁₂H₂₃N	详情	详情
(I)	21554	(6R,7R)-3-[(acetoxy)methyl]-7-[[4-chloro-2-(methoxyimino)-3-oxobutanoyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid		C₁₅H₁₆ClN₃O₈S	详情	详情
(II)	21555	(6R,7R)-7-[[4-chloro-2-(methoxyimino)-3-oxobutanoyl]amino]-3-(methoxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid		C₁₄H₁₆ClN₃O₇S	详情	详情
(III)	15685	1-iodoethyl isopropyl carbonate		C₆H₁₁IO₃	详情	详情
(V)	10180	Thiourea	62-56-6	CH₄N₂S	详情	详情
(VI)	21558	(6R,7R)-7-[[2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino]-3-(methoxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid		C₁₅H₁₇N₅O₆S₂	详情	详情

合成路线2

2) The free acid (II) can be cyclized with thiourea in a similar way as before to give 7-[2 (2-amino-thiazol-4-yl)-2-(Z)-(methoxyimino)acetamido]-3-(methoxymethyl)-3-cephem 4-carboxylic acid (VI), which is finally esterified with the iodoester (III) as before.

参考文献中间体

【1】 Fujimoto, K.; Nakayama, E.; Nakao, H. (Sankyo Co., Ltd.); Process for preparing 3-alkoxymethylcephalosporin derivatives. DE 3244457 .
【2】 Castaner, J.; Serradell, M.N.; Cefpodoxime Proxetil. Drugs Fut 1988, 13, 1, 16.
【3】 Fujimoto, K.; Ishihara, S.; Yanagisawa, H.; Ide, J.; Nakayama, E.; Nakao, H.; Sugawara, S.; Iwata, M.; Studies on orally active cephalosporin esters. J Antibiot 1987, 40, 3, 370.

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)	21554	(6R,7R)-3-[(acetoxy)methyl]-7-[[4-chloro-2-(methoxyimino)-3-oxobutanoyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid		C₁₅H₁₆ClN₃O₈S	详情	详情
(II)	21555	(6R,7R)-7-[[4-chloro-2-(methoxyimino)-3-oxobutanoyl]amino]-3-(methoxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid		C₁₄H₁₆ClN₃O₇S	详情	详情
(III)	15685	1-iodoethyl isopropyl carbonate		C₆H₁₁IO₃	详情	详情
(IV)	21559	1-[(isopropoxycarbonyl)oxy]ethyl (6R,7R)-7-[[4-chloro-2-(methoxyimino)-3-oxobutanoyl]amino]-3-(methoxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate		C₂₀H₂₆ClN₃O₁₀S	详情	详情
(V)	10180	Thiourea	62-56-6	CH₄N₂S	详情	详情

合成路线3

3) The iodoester (III) is obtained as follows: The chlorination of ethyl chloroformate (VII) with SO2Cl2 and benzoyl peroxide gives 1-chloroethyl-chloroformate (VIII), which is esterified with o-propanol in pyridine to afford 1-chloroethyl isopropyl carbonate (IX). Finally, this compound is iodinated with NaI and 18-crown-6 in refluxing benzene.

参考文献中间体

【1】 Fujimoto, K.; Nakayama, E.; Nakao, H. (Sankyo Co., Ltd.); Process for preparing 3-alkoxymethylcephalosporin derivatives. DE 3244457 .
【2】 Castaner, J.; Serradell, M.N.; Cefpodoxime Proxetil. Drugs Fut 1988, 13, 1, 16.
【3】 Fujimoto, K.; Ishihara, S.; Yanagisawa, H.; Ide, J.; Nakayama, E.; Nakao, H.; Sugawara, S.; Iwata, M.; Studies on orally active cephalosporin esters. J Antibiot 1987, 40, 3, 370.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(III)	15685	1-iodoethyl isopropyl carbonate	C₆H₁₁IO₃	详情	详情
(VII)	21560	1-[[(chlorooxy)carbonyl]oxy]ethane	C₃H₅ClO₃	详情	详情
(VIII)	21561	1-chloro-1-[[(chlorooxy)carbonyl]oxy]ethane	C₃H₄Cl₂O₃	详情	详情
(IX)	21562	1-chloroethyl isopropyl carbonate	C₆H₁₁ClO₃	详情	详情

合成路线4

A new process for the preparation of cefpodoxime, which can be converted into cefpodoxime proxetil by known methods, has been described: The condensation of 2-(2-aminothiazol-4-yl)-2(Z)-(methoxyimino)acetic acid 2-benzothiazolyl ester (I) with (6R,7R)-7-amino-3-(methoxymethyl)-3-cephem-4-carboxylic acid (II) by means of an organic base such as Et3N, pyridine, N-methylpiperidine, DBU or DMAP in either THF/water, acetone/water, DMF/water, dimethylacetamide or dichloromethane directly gives cefpodoxime (III).

参考文献中间体

【1】 Nizar, H.; Singh, K.; Khanna, J.M.; Kumar, Y.; De, S.; Arora, R.K. (Ranbaxy Laboratories Ltd.); Process for the preparation of cefpodoxime acid. WO 0068234 .

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)	43810	S-(1,3-benzothiazol-2-yl) 2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)ethanethioate	80756-85-0	C₁₃H₁₀N₄O₂S₃	详情	详情
(II)	43811	(6R,7R)-7-amino-3-(methoxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid		C₉H₁₂N₂O₄S	详情	详情
(III)	21558	(6R,7R)-7-[[2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino]-3-(methoxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid		C₁₅H₁₇N₅O₆S₂	详情	详情

合成路线5

The condensation of 7-amino-3-(methoxymethyl)-3-cephem-4-carboxylic acid (I) with 4-bromo-2-(methoxyimino)-3-oxobutyric acid (II) by means of PCl5 and HMDS in dichloromethane gives the butyramide (III), which is cyclized with thiourea (IV) by means of Na-OAc in water to yield the thiazol derivative (IV). Finally, the carboxy group of (IV) is esterified with 1-iodoethyl isopropyl carbonate (VI) by means of DBU in DMA to afford the target cefpodoxime proxetil.

参考文献中间体

【1】 Kumar, Y.; Nizar, H.; Tewari, N.; Rai, B.P.; Aryan, R.C. (Ranbaxy Laboratories Ltd.); Process for the preparation of cefpodoxime acid. WO 0283634 .

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)	43811	(6R,7R)-7-amino-3-(methoxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid		C₉H₁₂N₂O₄S	详情	详情
(II)	58114	4-bromo-2-(methoxyimino)-3-oxobutanoic acid;(Z)-4-bromo-2-(methoxyimino)-3-oxobutanoic acid		C₅H₆BrNO₄	详情	详情
(III)	58115	(6R,7R)-7-{[4-bromo-2-(methoxyimino)-3-oxobutanoyl]amino}-3-(methoxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid		C₁₄H₁₆BrN₃O₇S	详情	详情
(IV)	10180	Thiourea	62-56-6	CH₄N₂S	详情	详情
(V)	21558	(6R,7R)-7-[[2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino]-3-(methoxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid		C₁₅H₁₇N₅O₆S₂	详情	详情
(VI)	58116	isopropyl 3-iodobutanoate		C₇H₁₃IO₂	详情	详情

Extended Information