合成路线:In a related synthesis,(3,4-dichlorophenyl)acetonitrile (XI) was alkylated with bromide (XXII) --prepared by protection of 3-bromopropanol (XXI) with dihydropyran-- to afford (XXIII).Subsequent Michael addition of methyl acrylate (XII) to (XXIII) in the presence of Triton B?gave the cyanoacid (XXIV).This was cyclized to the glutarimide (XXV) by refluxing in HOAc in the presence of H2SO4.Reduction of (XXV) using borane-dimethylsulfide complex produced the already reported racemic piperidinoalcohol (XVI).After acylation of the amine group of (XVI) with benzoyl chloride to yield (XXVI),its hydroxyl group was converted into the target mesylate precursor (XXVII) with methanesulfonyl chloride and Et3N.
合成路线:An alternative preparation of the precursor 4-(N-methyl-N-acetyl)amino-4-phenylpiperidine (XXXIX) has been reported.The N-benzyl protecting group of piperidine (III) was replaced with an N-Boc group by catalytic hydrogenolysis to (XXXVI),followed by treatment with Boc2O to yield (XXXVII).Amide (XXXVII) alkylation with iodomethane under phase-transfer conditions gave the N-methyl derivative (XXXVIII).Subsequent N-Boc group cleavage in (XXXVIII) was accomplished by using zinc chloride in CH2Cl2 to afford the piperidine-ZnCl2 complex (XXXIX).This was then alkylated with mesylate (XXVII),and the title compound was finally isolated from the racemic mixture by means of preparative chiral HPLC.
合成路线:In a further method,aminopiperidine (IV) was converted to the formamide (XL) by heating in ethyl formate.Formyl group reduction in (XL) with LiAlH4 provided the N-metyl amine (XLI).The N-benzyl group of (XLI) was then removed by catalytic hydrogenation over Pd/C.Alkylation of the resultant piperidine (XLII) with mesylate (XXVII) gave adduct (XLIII).After acetylation of (XLIII) in neat Ac2O,the racemic mixture was separated by chiral HPLC.
参考文献标题:Process for the preparation of 3,3-disubstd.piperidines
文献作者:Grugni,M.; Rigolio,R.; Erhard,K.F.(GlaxoSmithKline Inc.; GlaxoSmithKline SpA)
参考来源:WO 9805640
合成路线:In a related synthesis,(3,4-dichlorophenyl)acetonitrile (XI) was alkylated with bromide (XXII) --prepared by protection of 3-bromopropanol (XXI) with dihydropyran-- to afford (XXIII).Subsequent Michael addition of methyl acrylate (XII) to (XXIII) in the presence of Triton B?gave the cyanoacid (XXIV).This was cyclized to the glutarimide (XXV) by refluxing in HOAc in the presence of H2SO4.Reduction of (XXV) using borane-dimethylsulfide complex produced the already reported racemic piperidinoalcohol (XVI).After acylation of the amine group of (XVI) with benzoyl chloride to yield (XXVI),its hydroxyl group was converted into the target mesylate precursor (XXVII) with methanesulfonyl chloride and Et3N.
合成路线:An alternative preparation of the precursor 4-(N-methyl-N-acetyl)amino-4-phenylpiperidine (XXXIX) has been reported.The N-benzyl protecting group of piperidine (III) was replaced with an N-Boc group by catalytic hydrogenolysis to (XXXVI),followed by treatment with Boc2O to yield (XXXVII).Amide (XXXVII) alkylation with iodomethane under phase-transfer conditions gave the N-methyl derivative (XXXVIII).Subsequent N-Boc group cleavage in (XXXVIII) was accomplished by using zinc chloride in CH2Cl2 to afford the piperidine-ZnCl2 complex (XXXIX).This was then alkylated with mesylate (XXVII),and the title compound was finally isolated from the racemic mixture by means of preparative chiral HPLC.
合成路线:In a further method,aminopiperidine (IV) was converted to the formamide (XL) by heating in ethyl formate.Formyl group reduction in (XL) with LiAlH4 provided the N-metyl amine (XLI).The N-benzyl group of (XLI) was then removed by catalytic hydrogenation over Pd/C.Alkylation of the resultant piperidine (XLII) with mesylate (XXVII) gave adduct (XLIII).After acetylation of (XLIII) in neat Ac2O,the racemic mixture was separated by chiral HPLC.
参考文献标题:A reliable and efficient synthesis of SR 142801
文献作者:Giardina,G.A.M.; et al.
参考来源:Bioorg Med Chem Lett 1996,6(19),2307
合成路线:In a related synthesis,(3,4-dichlorophenyl)acetonitrile (XI) was alkylated with bromide (XXII) --prepared by protection of 3-bromopropanol (XXI) with dihydropyran-- to afford (XXIII).Subsequent Michael addition of methyl acrylate (XII) to (XXIII) in the presence of Triton B?gave the cyanoacid (XXIV).This was cyclized to the glutarimide (XXV) by refluxing in HOAc in the presence of H2SO4.Reduction of (XXV) using borane-dimethylsulfide complex produced the already reported racemic piperidinoalcohol (XVI).After acylation of the amine group of (XVI) with benzoyl chloride to yield (XXVI),its hydroxyl group was converted into the target mesylate precursor (XXVII) with methanesulfonyl chloride and Et3N.
合成路线:In a further procedure,nitrile (XXIII) was alkylated with ethyl 3-bromopropionate (XXVIII) to give cyano ester (XXIX).Catalytic hydrogenation of the cyano group of (XXIX) gave rise to the piperidinone (XXX),which was further reduced to piperidine (XXXI) with LiAlH4 in THF.Acid deprotection of the tetrahydropyranyl group of (XXXI),followed by resolution with (+)-camphorsulfonic acid,furnished the desired (S)-piperidinoalcohol camphorsulfonate salt (XXXII).Treatment of piperidine (XXXII) with benzoyl chloride in the presence of DIEA yielded benzamide (XXXIII).Conversion of the primary alcohol of (XXXIII) into the desired alkyl iodide (XXXV) was achieved via formation of the mesylate ester (XXXIV),followed by displacement of the mesylate group with KI in refluxing acetone.
合成路线:A new method has been reported.Formamide (XL) was prepared form carbinol (II) by a modified Ritter reaction with cyanotrimethylsilane.Subsequent reduction of (XL) with LiAlH4 gave the N-methyl amine (XLI),which was converted to acetamide (XLIV) by treatment with acetyl chloride.Benzyl group hydrogenolysis in (XLIV) afforded the piperidine (X).Finally,alkylation of piperidine (X) with the chiral alkyl iodide (XXXV) provided the title compound.
参考文献标题:A practical and scalable synthesis of SR 142801,a tachykinin NK3 antagonist
文献作者:Chen,H.G.; et al.
参考来源:Bioorg Med Chem Lett 1997,7(5),555
产品链接: CAS No. 160492-56-8›› 产品链接: CAS No.173050-51-6››