合成路线:The reaction of 4-(4-fluorophenyl)-1-methyl-1,2,3,6-tetrahydropyridine (I) with formaldehyde and H2SO4 gives racemic 4-(4-fluorophenyl)-3-(hydroxymethyl)-1-methyl-1,2,3,6-tetrahydropyridine (II),which is submitted to optical resolution with (-)-dibenzoyltartaric acid,yielding the 3(S)-enantiomer (III).The reduction of (III) with H2 over Pd/C in ethanol affords trans-(3S,4R)-4-(4-fluorophenyl)-3-(hydroxymethyl)-1-methylpiperidine (IV),which is treated with SOCl2 to provide the corresponding chloromethyl derivative (V).The condensation of (V) with 1,3-benzodioxol-5-ol (VI) by means of NaOMe in methanol furnishes trans-(3S,4R)-3-(1,3-benzodioxol-5-yloxymethyl)-4-(4-fluorophenyl)-1-methylpiperidine (VII) ,which is condensed with phenyl chloroformate (VIII) in dichloromethane to afford the phenyl carbamate (IX).Finally,the phenoxycarbonyl group of (IX) is removed by treatment with KOH in refluxing methylcellosolve or in refluxing toluene.Alternatively,the reaction of methylpiperidine (VII) with ethyl chloroformate (X) in toluene gives the ethyl carbamate (XI),which is finally treated with KOH in refluxing ethanol/water in order to eliminate its ethoxycarbonyl group.Alternatively,the reaction of methylpiperidine (VII) with vinyl chloroformate (XII) in dichloromethane gives the vinyl carbamate (XIII),which is finally treated with dry HCl gas in refluxing dichloromethane/methanol in order to eliminate its vinyloxycarbonyl group.
参考文献标题:Prostaglandin derivs.
文献作者:Sato,F.; Amano,T.; Kameo,K.; Tanami,T.; Muto,K.; Ono,N.; Goto,J.(Taisho Pharmaceutical Co.,Ltd.)
参考来源:JP 1997286775
合成路线:The cyclization of 4-fluoro-alpha-methylstyrene (I) with ethylamine and refluxing aqueous formaldehyde gives (rac)-1-ethyl-3-(hydroxymethyl)-4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine (II),which is submitted to optical resolution by means of (-)-di-O-toluoyltartaric acid to yield (S)-isomer (III) and (R)-isomer (IV).The reduction of (S)-isomer (III) by means of LiAlH4 in THF yields (3S)-trans-1-ethyl-3-(hydroxymethyl)-4-(4-fluorophenyl)piperidine (V),which is condensed with 1,3-benzodioxol-5-ol (VI) by means of benzenesulfonyl chloride and TEA in dichloroethane to afford the aryl ether (VII).Finally,the ethyl group of (VII) is cleaved by means of 1-chloroethyl chloroformate and NaOH in toluene/water,followed by a treatment in refluxing methanol to provide the target paroxetine.The (R)-isomer (IV) can be profited by its reduction with H2 over Pd/C in methanol/AcOH/water to give (3R)-cis-1-ethyl-3-(hydroxymethyl)-4-(4-fluorophenyl)piperidine) (VIII),which is isomerized by means of NaOH in toluene/water and condensed with 1,3-benzodioxol-5-ol (VI) and NaOH in toluene/water to yield the already described aryl ether (VII).
参考文献标题:Chemical process for the reduction of 1-substd.-3-hydroxymethyl-4-(4-fluorophenyl)tetrahydropyridines
文献作者:Brennan,J.P.(Abbott GmbH & Co.KG)
参考来源:US 6326496; WO 9852920
合成路线:By condensation of 4-(4-fluorophenyl)-3-(hydroxymethyl)piperidine (I) with 3,4-methylenedioxyphenol (II) with dicyclohexylcarbodiimide (DCC) at 180 C.
合成路线:The reaction of 4-(4-fluorophenyl)-1-methyl-1,2,3,6-tetrahydropyridine (I) with formaldehyde and H2SO4 gives racemic 4-(4-fluorophenyl)-3-(hydroxymethyl)-1-methyl-1,2,3,6-tetrahydropyridine (II),which is submitted to optical resolution with (-)-dibenzoyltartaric acid,yielding the 3(S)-enantiomer (III).The reduction of (III) with H2 over Pd/C in ethanol affords trans-(3S,4R)-4-(4-fluorophenyl)-3-(hydroxymethyl)-1-methylpiperidine (IV),which is treated with SOCl2 to provide the corresponding chloromethyl derivative (V).The condensation of (V) with 1,3-benzodioxol-5-ol (VI) by means of NaOMe in methanol furnishes trans-(3S,4R)-3-(1,3-benzodioxol-5-yloxymethyl)-4-(4-fluorophenyl)-1-methylpiperidine (VII) ,which is condensed with phenyl chloroformate (VIII) in dichloromethane to afford the phenyl carbamate (IX).Finally,the phenoxycarbonyl group of (IX) is removed by treatment with KOH in refluxing methylcellosolve or in refluxing toluene.Alternatively,the reaction of methylpiperidine (VII) with ethyl chloroformate (X) in toluene gives the ethyl carbamate (XI),which is finally treated with KOH in refluxing ethanol/water in order to eliminate its ethoxycarbonyl group.Alternatively,the reaction of methylpiperidine (VII) with vinyl chloroformate (XII) in dichloromethane gives the vinyl carbamate (XIII),which is finally treated with dry HCl gas in refluxing dichloromethane/methanol in order to eliminate its vinyloxycarbonyl group.
参考文献标题:4-Phenylpiperidine compounds
文献作者:Christensen,J.A.; Squires,R.F.(Ferrosan A/S)
参考来源:DE 2404113; ES 422734; FR 2215233; GB 1422263; JP 58174363; US 3912743
合成路线:The reaction of 4-(4-fluorophenyl)-1-methyl-1,2,3,6-tetrahydropyridine (I) with formaldehyde and H2SO4 gives racemic 4-(4-fluorophenyl)-3-(hydroxymethyl)-1-methyl-1,2,3,6-tetrahydropyridine (II),which is submitted to optical resolution with (-)-dibenzoyltartaric acid,yielding the 3(S)-enantiomer (III).The reduction of (III) with H2 over Pd/C in ethanol affords trans-(3S,4R)-4-(4-fluorophenyl)-3-(hydroxymethyl)-1-methylpiperidine (IV),which is treated with SOCl2 to provide the corresponding chloromethyl derivative (V).The condensation of (V) with 1,3-benzodioxol-5-ol (VI) by means of NaOMe in methanol furnishes trans-(3S,4R)-3-(1,3-benzodioxol-5-yloxymethyl)-4-(4-fluorophenyl)-1-methylpiperidine (VII) ,which is condensed with phenyl chloroformate (VIII) in dichloromethane to afford the phenyl carbamate (IX).Finally,the phenoxycarbonyl group of (IX) is removed by treatment with KOH in refluxing methylcellosolve or in refluxing toluene.Alternatively,the reaction of methylpiperidine (VII) with ethyl chloroformate (X) in toluene gives the ethyl carbamate (XI),which is finally treated with KOH in refluxing ethanol/water in order to eliminate its ethoxycarbonyl group.Alternatively,the reaction of methylpiperidine (VII) with vinyl chloroformate (XII) in dichloromethane gives the vinyl carbamate (XIII),which is finally treated with dry HCl gas in refluxing dichloromethane/methanol in order to eliminate its vinyloxycarbonyl group.
参考文献标题:Process for the preparation of paroxetine and structurally related cpds.
文献作者:Lucas,E.(SmithKline Beecham plc)
参考来源:WO 0078753
合成路线:The hydrogenation of 4-(4-fluorophenyl)-3-(ethoxycarbonyl)-1-methylpyridinium bromide (I) with H2 over PtO2 in toluene/ethanol gives racemic (cis)-4-(4-fluorophenyl)-1-methylpiperidine-3-carboxylic acid methyl ester (rac)-(II),which is isomerized with NaOMe in refluxing toluene to yield the trans-isomer (rac)-(III).The reduction of (rac)-(III) with LiAlH4 in toluene/THF affords the hydroxymethyl compound (rac)-(IV),which is submitted to optical resolution with L-(-)-di-p-toluoyltartaric acid to provide the chiral (3S,4R)-(V).Alternatively,the optical resolution of (cis)-(rac)-(II) with D-(+)-di-p-toluoyltartaric acid gives the ester (cis)-(3R,4R)-(VI),which is isomerized with NaOMe in refluxing toluene to yield ester (trans)-(3S,4R)-(VII).Finally,this compound is reduced with LiAlH4 in toluene/THF to afford the previously reported intermediate (3S,4R)-(V).The reaction of (3S,4R)-(V) with benzenesulfonyl chloride (VIII) and dimethylethylamine in toluene gives the corresponding sulfonate (3S,4R)-(IX),which is condensed with 5-hydroxy-1,3-benzodioxole (X) by means of NaOMe in hot DMF to yield the adduct (3S,4R)-(XI).Finally,this compound is demethylated by reaction with phenyl chloroformate (XII) to afford the cyclic carbamate (3S,4R)-(XIII),which is hydrolyzed with KOH in refluxing toluene.
参考文献标题:Process for the preparation of paroxetine
文献作者:Borrett,G.T.; Ward,N.; Crowe,D.; Wells,A.S.(GlaxoSmithKline plc)
参考来源:WO 0129031
合成路线:By condensation of 4-(4-fluorophenyl)-3-(hydroxymethyl)piperidine (I) with 3,4-methylenedioxyphenol (II) with dicyclohexylcarbodiimide (DCC) at 180 C.
合成路线:Treatment of 1,2-bis-(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (I) with acetic anhydride and pyridine provided the cyclic anhydride (II).Ethylene glycol octyl ether (V) was prepared by Williamson's synthesis from the sodium alkoxide of ethylene glycol (III) and n-octyl bromide (IV).Finally,the title diester was obtained by heating anhydride (II) with the octyl ether of ethyleneglycol (V).
合成路线:Treatment of bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (I) with acetic anhydride in hot pyridine produced the cyclic anhydride (II).Ethyleneglycol mono-ether (V) was prepared by Williamson's synthesis from the sodium alkoxide of ethylene glycol (IV) and octadecyl bromide (III).Then,heating the bis-anhydride (II) with ethyleneglycol monoether (V) produced the title diester
参考文献标题:Lipophilic diesters of chelating agents
文献作者:Kozak,A.; Shapiro,I.(D-Pharm Ltd.)
参考来源:JP 2001518458; WO 9916741
产品链接: CAS No. 61869-08-7››