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【结 构 式】 
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【分子编号】38648 【品名】methyl 1-methyl-1,2,5,6-tetrahydro-3-pyridinecarboxylate 【CA登记号】 |
【 分 子 式 】C8H13NO2 【 分 子 量 】155.19676 【元素组成】C 61.91% H 8.44% N 9.03% O 20.62% |
合成路线1
该中间体在本合成路线中的序号：(I)The reaction of methyl N-methyl-1,2,5,6-tetrahydropyridine-3-carboxylate (I) with phenylmagnesium bromide (A) gives methyl 1-methyl-4-phenylpiperidine-3-carboxylate (II), which is reduced with LiAlH4 yielding 1-methyl-3-hydroxymethyl-4-phenylpiperidine (III), which, in turn is resolved into its optical isomers. The alcohol (III) is esterified with methanesulfonyl chloride in pyridine affording 3-(methansulfonyloxymethyl)-1-methyl-4-phenylpiperidine (IV), which is finally condensed with p-methoxyphenol (B) by means of sodium methoxide in refluxing methanol.
| 【1】 Christensen, J.A.; Squires, R.F.; 4-Phenylpiperidine compounds. DE 2404113; FR 2215233; GB 1422263; JP 49101385; JP 58174363; US 3912743 . |
| 【2】 Chatterjee, S.S.; Femoxetine. Drugs Fut 1977, 2, 5, 309. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 17616 | bromo(phenyl)magnesium; Phenyl Magnesium Bromide | 100-58-3 | C6H5BrMg | 详情 | 详情 |
| (B) | 32744 | 4-methoxyphenol | 150-76-5 | C7H8O2 | 详情 | 详情 |
| (I) | 38648 | methyl 1-methyl-1,2,5,6-tetrahydro-3-pyridinecarboxylate | C8H13NO2 | 详情 | 详情 | |
| (II) | 40118 | methyl (3R,4S)-1-methyl-4-phenyl-3-piperidinecarboxylate | C14H19NO2 | 详情 | 详情 | |
| (III) | 40119 | [(3R,4S)-1-methyl-4-phenylpiperidinyl]methanol | C13H19NO | 详情 | 详情 | |
| (IV) | 40120 | (3R,4S)-1-methyl-3-([[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]methyl)-4-phenylpiperidine | C16H25NOS | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)The condensation of 1-methyl-1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester (I) with 4-fluorophenylmagnesium bromide (II) in toluene, ether/toluene or ether/dichloromethane gives 1-methyl-4-(4-fluorophenyl)piperidine-3-carboxylic acid methyl ester (III) / (IV), which are an intermediates in the synthesis of paroxetine.(Scheme 10786008a).
| 【1】 Ward, N. (GlaxoSmithKline plc); Process for making paroxetine. US 6172233 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| rac-(III) | 56454 | (rac)-methyl (3R,4R)-4-(4-fluorophenyl)-1-methyl-3-piperidinecarboxylate | C14H18FNO2 | 详情 | 详情 | |
| rac-(IV) | 56455 | (rac)-methyl (3S,4R)-4-(4-fluorophenyl)-1-methyl-3-piperidinecarboxylate | C14H18FNO2 | 详情 | 详情 | |
| (I) | 38648 | methyl 1-methyl-1,2,5,6-tetrahydro-3-pyridinecarboxylate | C8H13NO2 | 详情 | 详情 | |
| (II) | 13643 | 4-fluorophenyl magnesium bromide;Bromo(4-fluorophenyl)magnesium;bromo(p-fluorophenyl)Magnesium;p-Fluorophenylmagnesium bromide | 352-13-6 | C6H4BrFMg | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)The isomerization of arecoline (I) with LDA gives 1-methyl-1,2,3,6-tetrahydropyridine-3-carboxylic acid methyl ester (II), which is reduced with LiAlH4 in THF yielding the carbinol (III). The protection of (III) with trichloroethyl chloroformate (Troc-Cl) and DIEA in toluene affords the demethylated compound (IV), which is treated with K2CO3 in methanol providing 3-(hydroxymethyl)-1,2,3,6-tetrahydropyridine-1-carboxylic acid 2,2,2-trichloroethyl ester (V). The silylation of (V) with TBDPSCl and imidazole in DMF gives the silyl ether (VI), which is epoxidized with MCPBA in dichloromethane yielding the epoxide (VII). Epoxide (VII) opening by means of HClO4 in refluxing water affords a diastereomeric mixture of racemates (VIII) and (IX) that could not be separated. The cleavage of the carbamate group of (VIII) and (IX) by means of HCl in water gives a new mixture that could be separated by flash chromatography to furnish the target compound as a racemate. Alternatively, intermediate (IV) is epoxidized with MCPBA in dichloromethane yielding the epoxide (X), which is treated as before.
| 【1】 Bols, M.; Hansen, S.U.; Synthesis of (±)-isofagomine and its stereoisomers from arecoline. J Chem Soc - Perkins Trans I 2000, 6, 911. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 13664 | 1,1,1-Trichloro-2-[(chlorocarbonyl)oxy]ethane; 2,2,2-Trichloroethyl chloroformate | 17341-93-4 | C3H2Cl4O2 | 详情 | 详情 | |
| (I) | 38648 | methyl 1-methyl-1,2,5,6-tetrahydro-3-pyridinecarboxylate | C8H13NO2 | 详情 | 详情 | |
| (II) | 38649 | methyl 1-methyl-1,2,3,6-tetrahydro-3-pyridinecarboxylate | C8H13NO2 | 详情 | 详情 | |
| (III) | 38650 | (1-methyl-1,2,3,6-tetrahydro-3-pyridinyl)methanol | C7H13NO | 详情 | 详情 | |
| (IV) | 38651 | 2,2,2-trichloroethyl 3-([[(2,2,2-trichloroethoxy)carbonyl]oxy]methyl)-3,6-dihydro-1(2H)-pyridinecarboxylate | C12H13Cl6NO5 | 详情 | 详情 | |
| (V) | 38652 | 2,2,2-trichloroethyl 3-(hydroxymethyl)-3,6-dihydro-1(2H)-pyridinecarboxylate | C9H12Cl3NO3 | 详情 | 详情 | |
| (VI) | 38653 | 2,2,2-trichloroethyl 3-([[tert-butyl(diphenyl)silyl]oxy]methyl)-3,6-dihydro-1(2H)-pyridinecarboxylate | C25H30Cl3NO3Si | 详情 | 详情 | |
| (VII) | 38654 | 2,2,2-trichloroethyl 5-([[tert-butyl(diphenyl)silyl]oxy]methyl)-7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate | C25H30Cl3NO4Si | 详情 | 详情 | |
| (VIII) | 38655 | 2,2,2-trichloroethyl (3R,4R,5R)-3,4-dihydroxy-5-(hydroxymethyl)-1-piperidinecarboxylate | C9H14Cl3NO5 | 详情 | 详情 | |
| (IX) | 38656 | 2,2,2-trichloroethyl (3S,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)-1-piperidinecarboxylate | C9H14Cl3NO5 | 详情 | 详情 | |
| (X) | 38657 | 2,2,2-trichloroethyl 5-([[(2,2,2-trichloroethoxy)carbonyl]oxy]methyl)-7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate | C12H13Cl6NO6 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)The demethylation of 1-methyl-1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester (I) by reaction with 1-chloroethyl chloroformate, followed by reaction with Boc2O gives 1-(tert-butoxycarbonyl) -1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester (II). The isomerization of (II) by means of LDA in THF yields 1-(tert-butoxycarbonyl) -1,2,3,6-tetrahydropyridine-3-carboxylic acid methyl ester (III), which is reduced with LiBHEt3 in THF to afford the hydroxymethyl derivative (IV). The reaction of (IV) with MCPBA in dichloromethane provides the epoxide (V), which is treated with refluxing aq. KOH, resulting in a racemic mixture of the enantiomers (VI) and (VII) as the major products. Finally, the target isofagomine is separated by chiral chromatography.
| 【1】 Kristiansen, M.; Jakobsen, P.; Lundbeck, J.M.; et al.; Iminosugars: Potential inhibitors of liver glycogen phosphorylase. Bioorg Med Chem 2001, 9, 3, 733. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 38648 | methyl 1-methyl-1,2,5,6-tetrahydro-3-pyridinecarboxylate | C8H13NO2 | 详情 | 详情 | |
| (II) | 58297 | 1-(tert-butyl) 3-methyl 5,6-dihydro-1,3(2H)-pyridinedicarboxylate | C12H19NO4 | 详情 | 详情 | |
| (III) | 58298 | 1-(tert-butyl) 3-methyl 3,6-dihydro-1,3(2H)-pyridinedicarboxylate | C12H19NO4 | 详情 | 详情 | |
| (IV) | 58299 | tert-butyl 3-(hydroxymethyl)-3,6-dihydro-1(2H)-pyridinecarboxylate | C11H19NO3 | 详情 | 详情 | |
| (V) | 58300 | tert-butyl 5-(hydroxymethyl)-7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate | C11H19NO4 | 详情 | 详情 | |
| (VI) | 58301 | (3S,4R,5S)-3-(hydroxymethyl)-5-methyl-4-piperidinol | C7H15NO2 | 详情 | 详情 | |
| (VII) | 58302 | (3R,4R,5R)-5-(hydroxymethyl)-3,4-piperidinediol | C6H13NO3 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(I)Addition of 4-chlorophenylmagnesium bromide (II) to arecoline (I) in Et2O at -10 C afforded the corresponding 4-arylpiperidine-3-carboxylate as a mixture of trans (III) and cis (IV) isomers. After chromatographic isolation of the racemic cis isomer (IV), resolution employing dibenzoyl-D-tartaric acid furnished the dextro enantiomer (cis)(+)-(IV). Its epimerization in the presence of NaOMe produced a 1:5.6 mixture of cis/trans isomers, from which the major compound (-)-(trans)(III) was isolated by flash chromatography. Acid hydrolysis of its methyl ester group provided carboxylic acid (V), that was further converted to acid chloride (VI) using oxalyl chloride (1,2). Finally, coupling of (VI) with 1,8-octanediamine (VII) gave the title diamide.
| 【1】 Tamiz, A.P.; Johnson, K.M.; Wang, C.Z.; Kozikowski, A.P.; Zhang, J.; Zhang, M.; Application of the bivalent ligand approach to the design of novel dimeric serotonin reuptake inhibitors. J Am Chem Soc 2000, 122, 22, 5393. |
| 【2】 Tamiz, A.P.; Araldi, G.L.; Kozikowski, A.P. (Georgetown University); Monomeric and dimeric heterocycles, and therapeutic uses thereof. WO 0020390 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (rac)-(III) | 41630 | (rac)-methyl (3S*,4R*)-4-(4-chlorophenyl)-1-methyl-3-piperidinecarboxylate | n/a | C14H18ClNO2 | 详情 | 详情 |
| (rac)-(IV) | 41631 | (rac)-methyl (3R*,4R*)-4-(4-chlorophenyl)-1-methyl-3-piperidinecarboxylate | C14H18ClNO2 | 详情 | 详情 | |
| (+)-(IV) | 41632 | (+)-methyl (3R,4R)-4-(4-chlorophenyl)-1-methyl-3-piperidinecarboxylate | C14H18ClNO2 | 详情 | 详情 | |
| (-)-(III) | 41633 | (-)-methyl (3S,4R)-4-(4-chlorophenyl)-1-methyl-3-piperidinecarboxylate | C14H18ClNO2 | 详情 | 详情 | |
| (I) | 25127 | bromo(4-chlorophenyl)magnesium | 873-77-8 | C6H4BrClMg | 详情 | 详情 |
| (I) | 38648 | methyl 1-methyl-1,2,5,6-tetrahydro-3-pyridinecarboxylate | C8H13NO2 | 详情 | 详情 | |
| (V) | 41634 | (3S,4R)-4-(4-chlorophenyl)-1-methyl-3-piperidinecarboxylic acid | C13H16ClNO2 | 详情 | 详情 | |
| (VI) | 41635 | (3S,4R)-4-(4-chlorophenyl)-1-methyl-3-piperidinecarbonyl chloride | C13H15Cl2NO | 详情 | 详情 | |
| (VII) | 20965 | 1,8-octanediamine; 8-aminooctylamine | 373-44-4 | C8H20N2 | 详情 | 详情 |