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【结 构 式】 
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【药物名称】Oxibendazole, SK&F-30310, Filaribits Plus, Anthelcide EQ 【化学名称】N-(5-Propoxy-1H-benzimidazol-2-yl)carbamic acid methyl ester 【CA登记号】20559-55-1 【 分 子 式 】C12H15N3O3 【 分 子 量 】249.27165 |
【开发单位】GlaxoSmithKline (Originator) 【药理作用】ANTIINFECTIVE THERAPY, Treatment of Helminthic Diseases, DNA Polymerase Inhibitors |
合成路线1
Alkylation of 4-hydroxyacetanilide (I) with n-propyl bromide provided 4-propoxyacetanilide (II). Aromatic nitration of (II) with fuming nitric acid in the presence of acetic anhydride afforded the nitro acetanilide (III), which was further hydrolyzed to the nitro aniline (IV) under basic conditions. Subsequent catalytic hydrogenation of the nitro group of (IV) furnished the phenylenediamine (V). Cyanocarbamate (VI), generated from cyanamide and methyl chloroformate, was then condensed with 4-propoxy-1,2-phenylenediamine (V) in hot pyridine to provide the title benzimidazolyl carbamate.
| 【1】 Castaner, J.; Bogan, J.A.; Oxibendazole. Drugs Fut 1976, 1, 5, 255. |
| 【2】 Actor, P.P.; Pagano, J.F. (GlaxoSmithKline Inc.); Anthelmintic compsns. and methods employing esters of benzimidazolyl carbamic acids and their thio analogs. BE 0666795; BE 0691611; CH 479590; DE 1620439; DE 1795799; FR 1510235; GB 1096190; GB 1114069; GB 1123317; US 3574845 . |
| 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) | 21611 | 4'-Hydroxyacetanilide;4-Acetamidophenol;N-Acetyl-4-aminophenol;Paracetamol;Acetaminophen;p-Hydroxyacetanilide; Paracetamol; N-(4-hydroxyphenyl)acetamide | 103-90-2 | C8H9NO2 | 详情 | 详情 |
| (II) | 59302 | N-(4-propoxyphenyl)acetamide | C11H15NO2 | 详情 | 详情 | |
| (III) | 59303 | N-(2-nitro-4-propoxyphenyl)acetamide | C11H14N2O4 | 详情 | 详情 | |
| (IV) | 59304 | 2-nitro-4-propoxyaniline; 2-nitro-4-propoxyphenylamine | C9H12N2O3 | 详情 | 详情 | |
| (V) | 59305 | 2-amino-4-propoxyphenylamine; 4-propoxy-1,2-benzenediamine | C9H14N2O | 详情 | 详情 | |
| (VI) | 33600 | methyl cyanocarbamate | C3H4N2O2 | 详情 | 详情 |
合成路线2
An new process for the preparation of the precursor phenylenediamine (V) has been reported. The previously reported 5-chlorobenzimidazole-2-spirocyclohexane (VII) was treated with sodium propoxide to yield the propoxy derivative (VIII). Sodium dithionite reduction of (VIII) gave rise to the target phenylenediamine (V) via intermediate (IX). Then, condensation of diamine (V) with cyanamide and methyl chloroformate produced the target benzimidazole derivative.
| 【1】 Hazelton, J.C.; et al.; 2H-Benzimidazoles (isobenzimidazoles). Part 10. Synthesis of polysubstituted o-phenylenediamines and their conversion into heterocycles, particularly 2-substituted benzimidazoles with known or potential anthelmintic activity. Tetrahedron 1995, 51, 39, 10771. |