|
【结 构 式】 
|
【药物名称】Iopentol, Compound-5411, Ivepaque, Imagopaque 【化学名称】N,N'-Bis(2,3-dihydroxypropyl)-5-[N-(2-hydroxy-3-methoxypropyl)acetamido]-2,4,6-triiodoisophthalamide 【CA登记号】89797-00-2 【 分 子 式 】C20H28I3N3O9 【 分 子 量 】835.17406 |
【开发单位】Amersham Health (Originator), Nycomed Pharma (Originator), Daiichi Pharmaceutical (Licensee), Sanofi-synthélabo (Licensee) 【药理作用】Contrast Mediums, DIAGNOSTIC AGENTS |
合成路线1
Acetylation of 5-amino-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide (I) in refluxing acetic anhydride in the presence of p-toluenesulfonic acid affords acetamide (II). The title compound is then obtained by alkylation of acetamide (II) with 1-chloro-3-methoxy-2-propanol (III). The selectivity in the alkylation at the acetamide N has been improved with the addition of several metallic cations, the best results being obtained with calcium ions.
| 【1】 Bjoersvik, H.-R.; et al.; An observation of cationic influence on the N/O alkylation selectivity in the alkylation of a compound containing several nucleophilic sites. Acta Chem Scand 1994, 48, 7, 582. |
| 【2】 Wille, K. (Amersham plc); X-Ray contrast agents. EP 0105752 . |
| 【3】 Cockbain, J.R.M.; Gulbrandsen, T.; Ingvoldstad, O.E.; Holmaas, L.T. (Amersham plc); Process for the preparation of contrast agents. WO 9808805 . |
| 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) | 59316 | 5-amino-N~1~,N~3~-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide | C14H18I3N3O6 | 详情 | 详情 | |
| (II) | 59311 | 5-(acetylamino)-N~1~,N~3~-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide | C16H20I3N3O7 | 详情 | 详情 | |
| (III) | 34214 | 1-chloro-3-methoxy-2-propanol | 4151-97-7 | C4H9ClO2 | 详情 | 详情 |
合成路线2
Alternatively, 5-acetamido-2,4,6-triiodoisophthalic acid (I) is alkylated with 1-chloro-3-methoxy-2-propanol (II) to produce (III). After protection of the alcoholic hydroxyl group as the acetate ester (IV), the carboxyl groups are activated as the corresponding acid chloride (V) with SOCl2. Coupling of (V) with 3-amino-1,2-propanediol (VI) then produces the title amide.
| 【1】 Skjoeld, W.; Berg, A.; Preparative liquid chromatography in the field of X-ray contrast agents. J Chromatogr 1986, 366, 299. |
| 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) | 59317 | 5-(acetylamino)-2,4,6-triiodoisophthalic acid | C10H6I3NO5 | 详情 | 详情 | |
| (II) | 34214 | 1-chloro-3-methoxy-2-propanol | 4151-97-7 | C4H9ClO2 | 详情 | 详情 |
| (III) | 59318 | 5-[acetyl(2-hydroxy-3-methoxypropyl)amino]-2,4,6-triiodoisophthalic acid | C14H14I3NO7 | 详情 | 详情 | |
| (IV) | 59319 | 5-{acetyl[2-(acetyloxy)-3-methoxypropyl]amino}-2,4,6-triiodoisophthalic acid | C16H16I3NO8 | 详情 | 详情 | |
| (V) | 59320 | 2-[acetyl-3,5-bis(chlorocarbonyl)-2,4,6-triiodoanilino]-1-(methoxymethyl)ethyl acetate | C16H14Cl2I3NO6 | 详情 | 详情 | |
| (VI) | 12979 | 3-Amino-1,2-propanediol；3-aminopropane-1,2-diol | 616-30-8 | C3H9NO2 | 详情 | 详情 |
合成路线3
In an improved method, the acetamido isophthalamide (I) is treated with boric acid and KOH to form the cyclic diborate tripotassium salt (II). Subsequent alkylation of (II) with 1-chloro-3-methoxy-2-propanol (III) yields regioselectively the N-alkylated acetamide (IV). The borate groups of (IV) are finally removed upon quenching with diluted HCl.
| 【1】 Bjoersvik, H.-R.; et al.; A selective process for N-alkylation in competition with O-alkylation: Boric acid, borax, and metaborate as a cheap and effective protecting group applicable for industrial-scale synthetic processes. Org Process Res Dev 2001, 5, 5, 472. |
| 【2】 Priebe, H. (Amersham plc); An N-alkylation. GB 2331098 . |