合成路线:The condensation of o-chloronitrobenzene (I) with 2-amino-5-methylthiophene-3-carbonitrile (II) by means of lithium hydroxide in DMSO gives 2-(2-nitroanilino)-5-methylthiophene-3-carbonitrile (III).The reductive cyclization of (III) using stannous chloride in aqueous ethanolic hydrochloric acid gives the primary amidine hydrochloride (IV),which is condensed with N-methylpiperazine (V) in a mixture of 4:1 toluene:DMSO.
参考文献标题:Olanzapine
文献作者:Moore,N.A.; Hotten,T.M.; Tupper,D.E.
参考来源:Drugs Fut 1994,19(2),114
合成路线:The synthesis of some metabolites of olanzapine have been described:1) Synthesis of 4'-N-desmethyl olanzapine: The condensation of 2-fluoronitrobenzene (I) with 5-methylthiophene-2-amine (II) by means of LiOH in DMSO gives the expected secondary amine (III),which is cyclized by means of SnCl2 in ethanol yielding 2-methyl-10H-thieno[2,3-b][1,5]benzodiazepine-4-amine (IV).Finally,this compound is condensed with piperazine (V) in toluene/DMSO affording the metabolite 2-methyl-4-(1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine.
合成路线:2) Synthesis of olanzapine 4'-N-oxide: The condensation of 2-fluoronitrobenzene (I) with 5-methylthiophene-2-amine (II) by means of LiOH in DMSO gives the expected secondary amine (III),which is cyclized by means of SnCl2 in ethanol yielding 2-methyl-10H-thieno[2,3-b][1,5]benzodiazepine-4-amine (IV).The condensation of (IV) with N-methylpiperazine (V) in toluene/DMSO affords 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepin e (olanzapine) (VI),which is finally oxidized with m-chloroperbenzoic acid (m-CPBA) in dichloromethane to give the metabolite 2-methyl-4-(4-methyl-4-oxidopiperazinyl-1-yl)-10H-thieno[2,3-b][1,5]benzodiazepine.
合成路线:3) Synthesis of 2-hydroxymethyl olanzapine:The condensation of 2-fluoronitrobenzene (I) with thiophene-2-amine (II) by means of LiOH in DMSO gives the expected secondary amine (III),which is formylated with DMF by means of POCl3 yielding the aldehyde (IV).The reducticyclization of (IV) with SnCl2 in ethanol affords 4-amino-10H-thieno[2,3-b][1,5]benzodiazepine-2-carbaldehyde (V),which is reduced with NaBH4 in ethanol to the corresponding hydroxymethyl derivative (VI).Finally,this compound is condensed with N-methylpiperazine (VII) in toluene/DMSO to give the metabolite 2-(hydroxymethyl)-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benz odiazepine.
参考文献标题:The synthesis and biological activity of some known and putative metabolites of the atypical antipsychotic agent olanzapine (LY170053)
文献作者:Calligaro,D.O.; Moore,N.A.; Tupper,D.E.; Fairhurst,J.; Hotten,T.M.
参考来源:Bioorg Med Chem Lett 1997,7(1),25
产品链接: CAS No. 132539-06-1››