BRL-35135A

Chemical Name: (R*,R*)-(?-[4-[2-[2-(3-Chlorophenyl)-2-hydroxyethylamino]propyl]phenoxy]acetic acid methyl ester hydrobromide
CAS No. 86615-41-0, 91097-81-3 (free base, no stereoch.)
项目整合开发状态: Phase II
项目研究机构: GlaxoSmithKline (Originator)
合成路线:1) The acylation of 2,6-dimethylaniline (II) with chloroacetyl chloride by means of triethylamine in dichloromethane gives N-(2,6-dimethylphenyl) chloroacetamide (III),which is condensed with piperidine (IV) in refluxing ethanol to yield N-(2,6-dimethylphenyl)-2-piperazinoacetamide IV).Finally,this compound is condensed with 3-(2-methoxyphenoxy)-12-epoxypropane (VI) in refluxing methanol toluene.

合成路线:2) The condensation of epoxide (VI) with piperazine (IV) in refluxing isopropanol gives 1-[3-(2-methoxyphenoxy)-2-hydroxypropyl]piperazine (VII),which is then condensed with chloroacetamide (III) in refluxing ethanol.

合成路线: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.