Cefodizime, THR-221, HR-221, Timecef, Modivid, Diezime, -Drug Synthesis Database

【结构式】

【药物名称】Cefodizime, THR-221, HR-221, Timecef, Modivid, Diezime

【化学名称】[6R-[6alpha,7beta(Z)[[-7-[[(2-Amino-4-thiazolyl)(methoxyimino)acetyl]amino]-3-[[[[5-(carboxymethyl)-4-methyl-2-thiazolyl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid
　　　　　　(6R,7R)-7-[2-(2-Amino-4-thiazolyl)glyoxylamido]-3-[[[5-(carboxymethyl)-4-methyl-2-thiazolyl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 7(2)-(Z)-(O-methyloxime)

【CA登记号】69739-16-8

【分子式】C₂₀H₂₀N₆O₇S₄

【分子量】584.6744

【开发单位】Aventis Pharma (Originator), Lyphomed (Licensee), Taiho (Licensee)

【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 condensation of 2-(methoxyimino)-2-(2-tritylaminothiazol-4-yl)acetic acid (I) with 7-aminocephalosporanic acid (II) by means of dicyclohexylcarbodiimide in CH2Cl2 gives 7-[2-(methoxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]cephalosporanic acid (III), which is deprotected by means of formic acid in water yielding 7-[2-(methoxyimino)-2-(2-aminothiazol-4-yl)acetamido]cephalosporanic acid (IV). Finally, this compound is condensed with 5-(carboxymethyl)-2-mercapto-4-methyl-1,3-thiazole (V) by means of NaHCO3 or NaOH in hot water.

参考文献中间体

【1】 Wolff, S.; et al.; Results of a multicenter phase III trial of magnetic resonance angiography (MRA) with MS-325 for the detection of peripheral vascular disease in the aortolliac region. Circulation 2002, 106, 19, Suppl. 2, Abst 3408.
【2】 Duerckeimer, W.; et al. (Aventis Pharma AG); Cephem derivative. BE 0865632; FR 2385722; GB 1604971; JP 5706887; US 4278793 .
【3】 Serradell, M.N.; Castaner, J.; Cefodizime. Drugs Fut 1984, 9, 3, 177.

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)	25058	2-(methoxyimino)-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetic acid	64485-90-1	C₂₅H₂₁N₃O₃S	详情	详情
(II)	15672	7-Aminocephalosporanic acid; 3-[(acetoxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid; 7-ACA		C₁₀H₁₂N₂O₅S	详情	详情
(III)	30338	3-[(acetoxy)methyl]-7-([2-(methoxyimino)-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetyl]amino)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid	66254-46-4	C₃₅H₃₁N₅O₇S₂	详情	详情
(IV)	30339	3-[(acetoxy)methyl]-7-[[2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid		C₁₆H₁₇N₅O₇S₂	详情	详情
(V)	19846	2-(4-methyl-2-sulfanyl-1,3-thiazol-5-yl)acetic acid	34272-64-5	C₆H₇NO₂S₂	详情	详情

合成路线2

Displacement of the acetate group of 7-aminocephalosporanic acid (I) with the mercapto thiazole (II) yielded thioether (III). This was then acylated with 2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetic acid (IV) in the presence of DCC and HOBt to furnish the corresponding amide.

参考文献中间体

【1】 Wolff, S.; et al.; Results of a multicenter phase III trial of magnetic resonance angiography (MRA) with MS-325 for the detection of peripheral vascular disease in the aortolliac region. Circulation 2002, 106, 19, Suppl. 2, Abst 3408.

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)	15672	7-Aminocephalosporanic acid; 3-[(acetoxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid; 7-ACA		C₁₀H₁₂N₂O₅S	详情	详情
(II)	19846	2-(4-methyl-2-sulfanyl-1,3-thiazol-5-yl)acetic acid	34272-64-5	C₆H₇NO₂S₂	详情	详情
(III)	56514	7-amino-3-({[5-(carboxymethyl)-4-methyl-1,3-thiazol-2-yl]sulfanyl}methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid		C₁₄H₁₅N₃O₅S₃	详情	详情
(IV)	24737	2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetic acid	65872-41-5	C₆H₇N₃O₃S	详情	详情

合成路线3

In a further procedure, 2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetic acid (IV) was activated as the mixed anhydride (V) by treatment with tosyl chloride and triethylamine. After protection of the cephem thioether (III) by silylation with either chlorotrimethylsilane or with bis(trimethylsilyl)acetamide, coupling with the mixed anhydride (V) gave rise to the title compound.

参考文献中间体

【1】 Wagner, H.; Jaenicke, O.; Worm, M. (Aventis Pharma AG); Process for the preparation of cefodizime. EP 0226093 .

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)	56514	7-amino-3-({[5-(carboxymethyl)-4-methyl-1,3-thiazol-2-yl]sulfanyl}methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid		C₁₄H₁₅N₃O₅S₃	详情	详情
(IV)	24737	2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetic acid	65872-41-5	C₆H₇N₃O₃S	详情	详情
(V)	56515	2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl 4-methylbenzenesulfonate		C₁₃H₁₃N₃O₅S₂	详情	详情

合成路线4

Using a different protection strategy, aminoacid (IV) was protected as the N-phenylacetyl derivative (VII) by treatment with acid chloride (VI). Subsequent DCC-mediated coupling with the cephem derivative (III) furnished (VIII). The N-phenylacetyl group was then selectively removed by enzymatic hydrolysis with penicillin G amidase.

参考文献中间体

【1】 Zenoni, M.; Fuganti, C.; A method for the acylation of the 7-amino group of the cephalosporanic ring. EP 0582102 .

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)	56514	7-amino-3-({[5-(carboxymethyl)-4-methyl-1,3-thiazol-2-yl]sulfanyl}methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid		C₁₄H₁₅N₃O₅S₃	详情	详情
(IV)	24737	2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetic acid	65872-41-5	C₆H₇N₃O₃S	详情	详情
(VI)	25890	2-phenylacetyl chloride；Phenylacetyl chloride;Phenacetyl chloride;Benzeneacetyl chloride	103-80-0	C₈H₇ClO	详情	详情
(VII)	56516	2-(methoxyimino)-2-{2-[(2-phenylacetyl)amino]-1,3-thiazol-4-yl}acetic acid		C₁₄H₁₃N₃O₄S	详情	详情
(VIII)	56517	3-({[5-(carboxymethyl)-4-methyl-1,3-thiazol-2-yl]sulfanyl}methyl)-7-[(2-(methoxyimino)-2-{2-[(2-phenylacetyl)amino]-1,3-thiazol-4-yl}acetyl)amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid		C₂₈H₂₆N₆O₈S₄	详情	详情

Extended Information