Dihydroraloxifene

合成路线:The hydrolysis of 2-(dimethylamino)-6-methoxybenzo[b]thiophene (I) with HCl in refluxing THF gives 6-methoxybenzo[b]thiophen-2(3H)-one (II),which is condensed with 4-methoxybenzaldehyde (III) by means of piperidine in methanol yielding the 3-benzylidene derivative (IV).The rearrangement of (IV) with the same catalyst and solvent affords trans-6-methoxy-2-(4-methoxyphenyl)-2,3-dihydrobenzo[b]thiophene-3-carboxylic acid methyl ester (V),which is hydrolyzed with NaOH in methanol to the corresponding acid (VI).The reaction of (VI) with SOCl2 in dichloromethane gives the acyl chloride (VII),which is condensed with N,O-dimethylhydroxylamine by means of triethylamine in dichloromethane providing the N-methoxy-N-methylamide (VIII).The condensation of (VIII) with the Grignard reagent (IX) in THF affords the dimethyl ether of the target compound (X),which is finally demethylated with AlCl3 and propanethiol in dichloromethane.The intermediate Grignard reagent (IX) has been obtained by condensation of 4-bromophenol (XI) with 1-(2-chloroethyl)piperidine (XII) by means of K2CO3 in hot DMF to give 1-[2-(4-bromophenoxy)ethyl]piperidine (XIII),which is then treated with magnesium in THF to afford (IX).

参考文献标题:Synthesis and biological activity of dihydroraloxifene
文献作者:Glasebrook,A.L.; Schmid,C.R.; Stephenson,G.A.; Misner,J.W.
参考来源:217th ACS Natl Meet (March 21 1999,Anaheim) 1999,Abst MEDI 072


合成路线:The hydrolysis of 2-(dimethylamino)-6-methoxybenzo[b]thiophene (I) with HCl in refluxing THF gives 6-methoxybenzo[b]thiophen-2(3H)-one (II),which is condensed with 4-methoxybenzaldehyde (III) by means of piperidine in methanol yielding the 3-benzylidene derivative (IV).The rearrangement of (IV) with the same catalyst and solvent affords trans-6-methoxy-2-(4-methoxyphenyl)-2,3-dihydrobenzo[b]thiophene-3-carboxylic acid methyl ester (V),which is hydrolyzed with NaOH in methanol to the corresponding acid (VI).The reaction of (VI) with SOCl2 in dichloromethane gives the acyl chloride (VII),which is condensed with N,O-dimethylhydroxylamine by means of triethylamine in dichloromethane providing the N-methoxy-N-methylamide (VIII).The condensation of (VIII) with the Grignard reagent (IX) in THF affords the dimethyl ether of the target compound (X),which is finally demethylated with AlCl3 and propanethiol in dichloromethane.The intermediate Grignard reagent (IX) has been obtained by condensation of 4-bromophenol (XI) with 1-(2-chloroethyl)piperidine (XII) by means of K2CO3 in hot DMF to give 1-[2-(4-bromophenoxy)ethyl]piperidine (XIII),which is then treated with magnesium in THF to afford (IX).
参考文献标题:Synthesis and biological activity of trans-2,3-dihydroraloxifene
文献作者:Schmid,C.R.; Glasebrook,A.L.; Misner,J.W.; Stephenson,G.A.
参考来源:Bioorg Med Chem Lett 1999,9(8),1137