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【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
Extended Information