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【结 构 式】 
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【药物名称】 【化学名称】(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 【CA登记号】 【 分 子 式 】C31H23N7O9S3 【 分 子 量 】733.76246 |
【开发单位】Aventis Pharma (Originator) 【药理作用】Cephalosporins |
合成路线1
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).
| 【1】 Aszodi, J.; Dini, C.; Fauveau, P. (Aventis Pharma SA); Cephalosporins having in position 7 as substd. axymino radical, intermediates, processes for their preparation and their use as medicaments. CA 2111164; EP 0628562; JP 1994345776 . |
| 【2】 Dini, C.; Aszodi, J.; Synthesis of a dihydroxythiophene analogue of catechosporines. Bioorg Med Chem Lett 2000, 10, 4, 349. |
| 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) | 23995 | ethyl 2-sulfanylacetate | 2713-34-0 | C4H8O2S | 详情 | 详情 |
| (II) | 31883 | 2-bromoacetonitrile | 590-17-0 | C2H2BrN | 详情 | 详情 |
| (III) | 35506 | ethyl 2-[(cyanomethyl)sulfanyl]acetate | C6H9NO2S | 详情 | 详情 | |
| (IV) | 17571 | Diethyl oxalate; Ethyl 2-ethoxy-2-oxoacetate | 95-92-1 | C6H10O4 | 详情 | 详情 |
| (V) | 35507 | ethyl 5-cyano-3,4-dihydroxy-2-thiophenecarboxylate | C8H7NO4S | 详情 | 详情 | |
| (VI) | 35508 | ethyl 5-cyano-3,4-bis[(2-methoxyethoxy)methoxy]-2-thiophenecarboxylate | C16H23NO8S | 详情 | 详情 | |
| (VII) | 35509 | 5-(hydroxymethyl)-3,4-bis[(2-methoxyethoxy)methoxy]-2-thiophenecarbonitrile | C14H21NO7S | 详情 | 详情 | |
| (VIII) | 35510 | 5-formyl-3,4-bis[(2-methoxyethoxy)methoxy]-2-thiophenecarbonitrile | C14H19NO7S | 详情 | 详情 | |
| (X) | 35511 | 2-([5-cyano-3,4-bis[(2-methoxyethoxy)methoxy]-2-thienyl]methylene)malononitrile | C17H19N3O6S | 详情 | 详情 | |
| (XI) | 35512 | 3-[5-cyano-3,4-bis[(2-methoxyethoxy)methoxy]-2-thienyl]-2,2-oxiranedicarbonitrile | C17H19N3O7S | 详情 | 详情 | |
| (XII) | 35513 | 2-chloro-2-[5-cyano-3,4-bis[(2-methoxyethoxy)methoxy]-2-thienyl]acetic acid | C15H20ClNO8S | 详情 | 详情 | |
| (XIII) | 35514 | benzhydryl 2-chloro-2-[5-cyano-3,4-bis[(2-methoxyethoxy)methoxy]-2-thienyl]acetate | C28H30ClNO8S | 详情 | 详情 | |
| (XIV) | 13505 | N-Hydroxyphthalimide; 2-Hydroxy-1H-isoindole-1,3(2H)-dione | 524-38-9 | C8H5NO3 | 详情 | 详情 |
| (XV) | 35515 | benzhydryl 2-[5-cyano-3,4-bis[(2-methoxyethoxy)methoxy]-2-thienyl]-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]acetate | C36H34N2O11S | 详情 | 详情 | |
| (XVI) | 35516 | benzhydryl 2-(aminooxy)-2-[5-cyano-3,4-bis[(2-methoxyethoxy)methoxy]-2-thienyl]acetate | C28H32N2O9S | 详情 | 详情 | |
| (XVII) | 23008 | 2-oxo-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetic acid | C24H18N2O3S | 详情 | 详情 | |
| (XVIII) | 35517 | 2-[(2-(benzhydryloxy)-1-[5-cyano-3,4-bis[(2-methoxyethoxy)methoxy]-2-thienyl]-2-oxoethoxy)imino]-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetic acid | C52H48N4O11S2 | 详情 | 详情 |
合成路线2
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.
| 【1】 Aszodi, J.; Dini, C.; Fauveau, P. (Aventis Pharma SA); Cephalosporins having in position 7 as substd. axymino radical, intermediates, processes for their preparation and their use as medicaments. CA 2111164; EP 0628562; JP 1994345776 . |
| 【2】 Dini, C.; Aszodi, J.; Synthesis of a dihydroxythiophene analogue of catechosporines. Bioorg Med Chem Lett 2000, 10, 4, 349. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVIII) | 35517 | 2-[(2-(benzhydryloxy)-1-[5-cyano-3,4-bis[(2-methoxyethoxy)methoxy]-2-thienyl]-2-oxoethoxy)imino]-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetic acid | C52H48N4O11S2 | 详情 | 详情 | |
| (XIX) | 35518 | benzhydryl (6R,7R)-7-amino-3-[(E)-3-chloro-1-propenyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C23H21ClN2O3S | 详情 | 详情 | |
| (XX) | 35519 | C75H67ClN6O13S3 | 详情 | 详情 | ||
| (XXI) | 35520 | C75H67IN6O13S3 | 详情 | 详情 | ||
| (XXII) | 35521 | quinoline | 91-22-5 | C9H7N | 详情 | 详情 |
| (XXIII) | 35522 | C84H74N7O13S3 | 详情 | 详情 |