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【结 构 式】 
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【药物名称】BRL-26830A 【化学名称】(R*,R*)-(±)-4-[2-(2-Hydroxy-2-phenylethylamino)propyl]benzoic acid methyl ester hemifumarate 【CA登记号】87857-42-9 【 分 子 式 】C23H27NO7 【 分 子 量 】429.47414 |
【开发单位】GlaxoSmithKline (Originator) 【药理作用】Antiobesity Drugs, METABOLIC DRUGS, Treatment of Nutritional Disorders |
合成路线1
The synthesis of [14C]-labeled BRL-26830A has been described: The reaction of copper sulfate (I) with sodium methabisulfite, followed by treatment with [14C]-labeled potassium cyanide (II) yields cuprous cyanide (III), which is condensed with methyl 4-bromobenzoate (IV) to afford methyl 4-cyanobenzoate (V). The reduction of (V) with Al/Ni and formic acid gives methyl 4-formylbenzoate (VI), which is condensed with nitroethane by means of butylamine and acetic acid in benzene to give methyl 4-(2-nitro-1-propenyl)benzoate (VII). The treatment of (VII) with Fe and HCl in refluxing methanol yields methyl 4-(acetonyl)benzoate (VIII), which is reductocondensed with (R*)-2-amino-1-phenylethanol (IX) by means of NaBH4 in refluxing benzene and crystallized in methanol to fractionate the optical diastereomers. Finally, the (R*,R*)-isomer (X) is treated with fumaric acid.
| 【1】 Freer, R.; Morecombe, D.J.; The synthesis of [14C]BRL 26830A, a novel beta-adrenoceptor agonist. J Label Compd Radiopharm 1992, 31, 9, 697. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 23808 | Fumaric acid; (E)-2-butenedioic acid | 110-17-8 | C4H4O4 | 详情 | 详情 | |
| (IV) | 10168 | 4-Bromobenzoic acid methyl ester; methyl 4-bromobenzoate | 619-42-1 | C8H7BrO2 | 详情 | 详情 |
| (V) | 10169 | methyl 4-cyanobenzoate；4-Cyanobenzoic acid methyl ester | 1129-35-7 | C9H7NO2 | 详情 | 详情 |
| (V) | 44596 | methyl 4-cyanobenzoate | C9H7NO2 | 详情 | 详情 | |
| (VI) | 10170 | methyl 4-formylbenzoate | 1571-08-0 | C9H8O3 | 详情 | 详情 |
| (VI) | 44597 | methyl 4-formylbenzoate | C9H8O3 | 详情 | 详情 | |
| (VII) | 10171 | methyl 4-[(Z)-2-nitro-1-propenyl]benzoate | C11H11NO4 | 详情 | 详情 | |
| (VII) | 44598 | methyl 4-[(Z)-2-nitro-1-propenyl]benzoate | C11H11NO4 | 详情 | 详情 | |
| (VIII) | 10172 | methyl 4-(2-oxopropyl)benzoate | C11H12O3 | 详情 | 详情 | |
| (VIII) | 44599 | methyl 4-(2-oxopropyl)benzoate | C11H12O3 | 详情 | 详情 | |
| (IX) | 10173 | (1R)-2-Amino-1-phenyl-1-ethanol | 2549-14-6 | C8H11NO | 详情 | 详情 |
| (X) | 44595 | methyl 4-((2R)-2-[[(2R)-2-hydroxy-2-phenylethyl]amino]propyl)benzoate | C19H23NO3 | 详情 | 详情 | |
| (X) | 44600 | methyl 4-((2R)-2-[[(2R)-2-hydroxy-2-phenylethyl]amino]propyl)benzoate | C19H23NO3 | 详情 | 详情 |
合成路线2
By condensation of 2-hydroxy-2-phenylethylamine (I) with 1-(4-methoxycarbonylphenyl)-2-propanone (II) in refluxing benzene, followed by reduction with NaBH4 in methanol, and treatment with maleic acid (III).
| 【1】 Ainsworth, A.T.; Smith, D.G. (SmithKline Beecham plc); Secondary amines, their preparation and use in pharmaceutical compositions. DE 2965655; EP 0006735; JP 8009085; US 4478849; US 4654371 . |
| 【2】 Serradell, M.N.; Castaner, J.; BRL-26830A. Drugs Fut 1985, 10, 3, 188. |