新产品编号:1038301
Chemical Name: (6R,7R)-7-[2-(2-Aminothiazol-4-yl)-2(Z)-[1-carboxy-1-(5-cyano-3,4-dihydroxythien-2-yl)methoxyimino]acetamido]-3-[3-quinolinio-1(E)-propenyl]-3-cephem-4-carboxylate
项目整合开发状态: Biological Testing
项目研究机构: Aventis Pharma (Originator)
合成路线:The reaction of ethyl 2-sulfanylacetate (I) with 2-bromoacetonitrile (II) by means of NaOEt in ethanol gives ethyl 2-(cyanomethylsulfanyl)acetate (III),which is cyclized with diethyl oxalate (IV) by means of NaOEt in ethanol yielding 5-cyano-3,4-dihydroxythiophene-2-carboxylic acid ethyl ester (V).The protection of the hydroxyl groups of (V) with 2-methoxyethoxymethyl chloride (Mem-Cl) and DIEA in dichloromethane affords the protected thiophene (VI),which is reduced with (t-BuO)2AlH in THF providing the carbinol (VII).The oxidation of (VII) with MnO2 in dichloromethane yields the carbaldehyde (VIII),which is condensed with malonodinitrile (IX) by means of piperidine in dioxane giving the alkylidenemalonodinitrile (X).The epoxidation of (X) with tert-butyl hydroperoxide and TEA in dioxane yields the epoxide (XI),which is treated with HCl in THF to afford 2-chloro-2-[5-cyano-3,4-bis(2-methoxyethoxymethoxy) thiophen-2-yl]acetic acid (XII).The esterification of (XII) with diphenyldiazomethane affords the corresponding diphenylmethyl ester (XIII),which is condensed with N-hydroxyphthalimide (XIV) and NaHCO3 in dichloromethane providing the adduct (XV).The cleavage of the phthalimido group of (XV) with hydrazine in methanol gives 2-(aminooxy)-2-[5-cyano-3,4-bis(2-methoxyethoxymethoxy)thiophen-2-yl]acetic acid diphenylmethyl ester (XVI),which is condensed with 2-oxo-2-[2-(tritylamino)thiazol-4-yl]acetic acid (XVII) yielding the corresponding alcoxyimino derivative (XVIII).
合成路线:The condensation of (XVIII) with 7-beta-amino-3-(3-chloro-1(E)-propenyl)-3-cephem-4-carboxylic acid diphenylmethyl ester (XIX) affords the expected amide (XX).The halogen exchange in (XX) with I2 and NaI in acetone gives the 3-iodo-1(E)-propenyl derivative (XXI),which is treated with quinoline (XXII) in dichloromethane to provide the quinolinium salt (XXIII).Finally,this compound is fully deprotected by a treatment with TFA and anisole.
📌 参考资料/链接：
参考文献标题:Cephalosporins having in position 7 as substd.axymino radical,intermediates,processes for their preparation and their use as medicaments
文献作者:Aszodi,J.; Dini,C.; Fauveau,P.(Aventis Pharma SA)
参考来源:CA 2111164; EP 0628562; JP 1994345776
📄 详细内容
合成路线:The reaction of ethyl 2-sulfanylacetate (I) with 2-bromoacetonitrile (II) by means of NaOEt in ethanol gives ethyl 2-(cyanomethylsulfanyl)acetate (III),which is cyclized with diethyl oxalate (IV) by means of NaOEt in ethanol yielding 5-cyano-3,4-dihydroxythiophene-2-carboxylic acid ethyl ester (V).The protection of the hydroxyl groups of (V) with 2-methoxyethoxymethyl chloride (Mem-Cl) and DIEA in dichloromethane affords the protected thiophene (VI),which is reduced with (t-BuO)2AlH in THF providing the carbinol (VII).The oxidation of (VII) with MnO2 in dichloromethane yields the carbaldehyde (VIII),which is condensed with malonodinitrile (IX) by means of piperidine in dioxane giving the alkylidenemalonodinitrile (X).The epoxidation of (X) with tert-butyl hydroperoxide and TEA in dioxane yields the epoxide (XI),which is treated with HCl in THF to afford 2-chloro-2-[5-cyano-3,4-bis(2-methoxyethoxymethoxy) thiophen-2-yl]acetic acid (XII).The esterification of (XII) with diphenyldiazomethane affords the corresponding diphenylmethyl ester (XIII),which is condensed with N-hydroxyphthalimide (XIV) and NaHCO3 in dichloromethane providing the adduct (XV).The cleavage of the phthalimido group of (XV) with hydrazine in methanol gives 2-(aminooxy)-2-[5-cyano-3,4-bis(2-methoxyethoxymethoxy)thiophen-2-yl]acetic acid diphenylmethyl ester (XVI),which is condensed with 2-oxo-2-[2-(tritylamino)thiazol-4-yl]acetic acid (XVII) yielding the corresponding alcoxyimino derivative (XVIII).
合成路线:The condensation of (XVIII) with 7-beta-amino-3-(3-chloro-1(E)-propenyl)-3-cephem-4-carboxylic acid diphenylmethyl ester (XIX) affords the expected amide (XX).The halogen exchange in (XX) with I2 and NaI in acetone gives the 3-iodo-1(E)-propenyl derivative (XXI),which is treated with quinoline (XXII) in dichloromethane to provide the quinolinium salt (XXIII).Finally,this compound is fully deprotected by a treatment with TFA and anisole.
参考文献标题:Synthesis of a dihydroxythiophene analogue of catechosporines
文献作者:Dini,C.; Aszodi,J.
参考来源:Bioorg Med Chem Lett 2000,10(4),349