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【结 构 式】 
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【分子编号】23008 【品名】2-oxo-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetic acid 【CA登记号】 |
【 分 子 式 】C24H18N2O3S 【 分 子 量 】414.4846 【元素组成】C 69.55% H 4.38% N 6.76% O 11.58% S 7.74% |
合成路线1
该中间体在本合成路线中的序号：(VIII)The bromination of 3,4-diacetoxyphenylacetic acid with N-bromosuccinimide (NBS) and SOCl2 gives the corresponding bromoacetic acid (II), which is esterified with diphenyldiazomethane (III) in acetone affording the diphenylmethyl ester (IV). The reaction of (IV) with N-hydroxyphthalimide (V) by means of triethylamine in acetonitrile yields diphenylmethyl-2-phthalimidooxy-2-(3,4-diacetoxy phenyl)acetate (VI), which is treated witb methyl hydrazine in dichloromethane to give diphenylmethyl-2-aminooxy-2-(3,4-diacetoxyphenyl)acetate (VII). The condensation of (VII) with (2-triphenylmethylamino-4-thiazolyl)glyoxylic acid (VIII) in methanol affords 2-(2-triphenylmethylamino-4-thiazolyl)-2-[(Z)-(diphenyl)methoxyimino]acetic acid (IX), which is condensed with 7beta-amino-3-[2-(diphenylmethoxycarbonyl)-5-methyl-s-triazolo[1,5-a]pyrimidin-7-ylthiomethyl]-3-cephem-4-carboxylic acid diphenylmethyl ester (X) by means of dicyclohexylcarbodiimide (DCC) in dichloromethane giving the protected final product (XI). Finally, this compound is deprotected by treatment first with trifluoroacetic acid and then with NaHCO3 in water.
| 【1】 Ohnishi, H.; Kosuzume, H.; Mizota, M.; Suzuki, Y.; Mochida, E. (Mochida Pharmaceutical Co., Ltd.); Cephalosporin derivs.. AU 8654876; AU 8655860; EP 0197409; EP 0359291; JP 1987077392; JP 1987161793; JP 1987167784; US 4840945; US 5001121; WO 8605786 . |
| 【2】 Prous, J.; Castaner, J.; M-14659. Drugs Fut 1988, 13, 12, 1047. |
| 【3】 Kusakabe, S.; Kosuzume, H.; Kato, K.; Shiihara, T.; Murakami, K.; Yamada, H.; Ishigura, J.; Oikawa, Y.; Mochizuki, H.; Antibacterial and pharmacokinetic properties of M1. J Antibiot 1988, 41, 3, 377. |
| 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) | 23001 | 2-[3,4-bis(acetoxy)phenyl]acetic acid | C12H12O6 | 详情 | 详情 | |
| (II) | 23002 | 2-[3,4-bis(acetoxy)phenyl]-2-bromoacetic acid | C12H11BrO6 | 详情 | 详情 | |
| (III) | 23003 | Diphenyldiazomethane | C13H10N2 | 详情 | 详情 | |
| (IV) | 23004 | benzhydryl 2-[3,4-bis(acetoxy)phenyl]-2-bromoacetate | C25H21BrO6 | 详情 | 详情 | |
| (V) | 13505 | N-Hydroxyphthalimide; 2-Hydroxy-1H-isoindole-1,3(2H)-dione | 524-38-9 | C8H5NO3 | 详情 | 详情 |
| (VI) | 23006 | benzhydryl 2-[3,4-bis(acetoxy)phenyl]-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]acetate | C33H25NO9 | 详情 | 详情 | |
| (VII) | 23007 | benzhydryl 2-(aminooxy)-2-[3,4-bis(acetoxy)phenyl]acetate | C25H23NO7 | 详情 | 详情 | |
| (VIII) | 23008 | 2-oxo-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetic acid | C24H18N2O3S | 详情 | 详情 | |
| (IX) | 23009 | 2-([2-(benzhydryloxy)-1-[3,4-bis(acetoxy)phenyl]-2-oxoethoxy]imino)-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetic acid | C49H39N3O9S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XVII)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 |