【结 构 式】 |
【药物名称】BRL-35135A 【化学名称】(R*,R*)-(±)-[4-[2-[2-(3-Chlorophenyl)-2-hydroxyethylamino]propyl]phenoxy]acetic acid methyl ester hydrobromide 【CA登记号】86615-41-0, 91097-81-3 (free base, no stereoch.) 【 分 子 式 】C20H25BrClNO4 【 分 子 量 】458.78355 |
【开发单位】GlaxoSmithKline (Originator) 【药理作用】Antidiabetic Drugs, Antiobesity Drugs, ENDOCRINE DRUGS, METABOLIC DRUGS, Treatment of Nutritional Disorders, beta3-Adrenoceptor Agonists |
合成路线1
BRL 35135 may be obtained by the following synthetic procedures: Alkylation of 4-hydroxybenzaldehyde (I) with methyl chloroacetate in boiling acetone in the presence of potassium carbonate and a catalytic quantity of potassium iodide gives methyl 4-formylphenoxyacetate (II), which is condensed with nitroethane in glacial acetic acid in the presence of n-butylamine to give the nitrostyrene (III). Reduction of nitrostyrene (III) with steel wool and glacial acetic acid/methanol leads to methyl 4-(2-oxopropyl)phenoxyacetate (IV). Condensation of (IV) with alpha-(aminomethyl-3-chlorobenzenemethanol (VI) and hydrogenation of the resultant imine with platinum in methyl acetate leads to a mixture of diastereomers (VII). Pure BRL 35135 can be obtained from this mixture of diastereomers by fractional crystallization, and subsequent recrystallization, of the hydrobromide salt from methyl acetate-methanol. The ethanolamine (VI) is prepared by addition of trimethylsilyl cyanide to 3-chlorobenzaldehyde (V) in diethyl ether in the presence of a catalytic amount of zinc iodide and subsequent reduction of the trimethylsilylcyanohydrin with lithium aluminum hydride.
【1】 Ainsworth, A.T.; Smith, D.G. (SmithKline Beecham plc); Ethanamine derivs., their preparation and use in pharmaceutical compsns. EP 0023385 . |
【2】 Cantello, B.C.C.; Smith, S.A.; BRL 35135. Drugs Fut 1991, 16, 9, 797. |
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) | 13433 | 4-Hydroxybenzaldehyde; p-Hydroxybenzaldehyde | 123-08-0 | C7H6O2 | 详情 | 详情 |
(II) | 13657 | methyl 2-(4-formylphenoxy)acetate | C10H10O4 | 详情 | 详情 | |
(III) | 13658 | methyl 2-[4-[(E)-2-nitro-1-propenyl]phenoxy]acetate | C12H13NO5 | 详情 | 详情 | |
(IV) | 13659 | methyl 2-[4-(2-oxopropyl)phenoxy]acetate | C12H14O4 | 详情 | 详情 | |
(V) | 13660 | 3-Chlorobenzaldehyde | 587-04-2 | C7H5ClO | 详情 | 详情 |
(VI) | 13661 | 2-Amino-1-(3-chlorophenyl)-1-ethanol | 121652-86-6 | C8H10ClNO | 详情 | 详情 |
(VII) | 13662 | methyl 2-[4-(2-[[2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl)phenoxy]acetate | C20H24ClNO4 | 详情 | 详情 |