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【结 构 式】 
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【药物名称】Lonapalene, RS-43179 【化学名称】1,4-Diacetoxy-6-chloro-2,3-dimethoxynaphthalene 【CA登记号】91431-42-4 【 分 子 式 】C16H15ClO6 【 分 子 量 】338.74735 |
【开发单位】Roche Bioscience (Originator), AstraZeneca (Licensee) 【药理作用】ANTIINFECTIVE THERAPY, Antipsoriatics, Antiviral Drugs, DERMATOLOGIC DRUGS, Lipoxygenase Inhibitors |
合成路线1
The metalation of 4-chlorobromobenzene (I) with lithium gives 4-chlorophenyllithium (II), which is condensed with dimethyl squarate (III) in THF at -78 C giving 4-(4-chlorophenyl)-4-hydroxy-2,3-dimethoxy-2-cyclobuten-1-one (IV). The isomerization of (IV) in refluxing xylene (38 C) affords naphthohydroquinone (VI) through the intermediate ketene (V). Finally, compound (VI) is acetylated with acetic anhydride in pyridine - dimethylaminopyridine.
| 【1】 Perri, S.T.; Moore, H.W.; Synthesis of lonapalene. Tetrahedron Lett 1987, 28, 39, 4507-10. |
| 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) | 14733 | 4-Bromochlorobenzene; 1-bromo-4-chlorobenzene | 106-39-8 | C6H4BrCl | 详情 | 详情 |
| (II) | 19396 | (4-chlorophenyl)lithium | C6H4ClLi | 详情 | 详情 | |
| (III) | 19999 | 3,4-dimethoxy-3-cyclobutene-1,2-dione | 5222-73-1 | C6H6O4 | 详情 | 详情 |
| (IV) | 20000 | 4-(4-chlorophenyl)-4-hydroxy-2,3-dimethoxy-2-cyclobuten-1-one | C12H11ClO4 | 详情 | 详情 | |
| (V) | 20001 | (3Z)-4-(4-chlorophenyl)-4-hydroxy-2,3-dimethoxy-1,3-butadien-1-one | C12H11ClO4 | 详情 | 详情 | |
| (VI) | 20002 | 6-chloro-2,3-dimethoxy-1,4-naphthalenediol | C12H11ClO4 | 详情 | 详情 |
合成路线2
The chlorination of 6-choro-1,4-naphthoquinone (I) with Cl2 in acetic acid gives 2,3,6-trichloro-2,3-dihydro-1,4-naphthoquinone (II), which is treated with sodium acetate and Cl2 in refluxing acetic acid yielding 2,3,6-trichloro-1,4-naphthoquinone (II) The reaction of (III) with sodium methoxide in reftuxing methanol affords 6-chloro-2,3-dimethoxy-1-4-naphthoquinone (IV), which is finally reduced with H2 over Pd/C IP THF, and acetylated with acetic anhydride in pyridine (I).
| 【1】 Jones, G.H.; Venuti, M.C.; Young, J.M. (Syntex (USA), Inc.); 1,4-Acyloxynaphthalene derivs., topical compsns. containing them, methods for their preparation, and intermediates therefor. EP 0107512; US 4466981 . |
| 【2】 Castaner, J.; Prous, J.; RS-43179. Drugs Fut 1986, 11, 1, 34. |