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【结 构 式】 
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【分子编号】24255 【品名】3-piperidinol 【CA登记号】6859-99-0 |
【 分 子 式 】C5H11NO 【 分 子 量 】101.14848 【元素组成】C 59.37% H 10.96% N 13.85% O 15.82% |
合成路线1
该中间体在本合成路线中的序号：(VIII)5) The esterification of (VI) with 3-hydroxypipendine (VIII) as before gives the corresponding ester (IX), which is then benzylated with benzyl chloride (X) by means of triethylamine in refluxing THF.
| 【1】 Muto, K.; Kuroda, T.; Karasawa, A.; Yamada, K.; Nakamizo, N. (Kyowa Hakko Kogyo Co., Ltd.); 1,4-Dihydropyridine derivatives. CA 1246078; EP 0106275; ES 526441 . |
| 【2】 Prous, J.; Castaner, J.; KW-3049. Drugs Fut 1986, 11, 11, 936. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 13950 | 5-(Methoxycarbonyl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydro-3-pyridinecarboxylic acid | C16H16N2O6 | 详情 | 详情 | |
| (VIII) | 24255 | 3-piperidinol | 6859-99-0 | C5H11NO | 详情 | 详情 |
| (IX) | 24256 | 3-methyl 5-(3-piperidinyl) 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydro-3,5-pyridinedicarboxylate | C21H25N3O6 | 详情 | 详情 | |
| (X) | 19171 | 1-(Chloromethyl)benzene; Benzyl chloride | 100-44-7 | C7H7Cl | 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 acylation of 3-hydroxypiperidine with tosyl chloride followed by oxidation of the OH group with CrO3 and H2SO4 gives 1-tosylpiperidine-3-one (II), which is converted into the enol triflate (III) by reaction with LHMDS and PhN(SO2CF3)2 in THF. The condensation of (III) with 1-(tert-butoxycarbonyl)-2-vinylpiperidine (IV) by means of Pd(OAc)2 affords the diene (V), which is selectively deprotected with NaOH in methanol to afford the piperidine (VI). The condensation of (VI) with silylated methyl propenoate (VII) by means of triethylamine in dichloromethane gives the nonisolated intermediate (VIII) that cyclizes to the tetracyclic compound (IX) (as major isomer). The reaction of (IX) with HF and pyridine in refluxing dichloromethane affords the silylated tetracyclic ketone (X) (as major isomer), which is desilylated with KF, KHCO3 and H2O2 in refluxing methanol/THF providing the tetracyclic hydroxyketone (XI) (as major isomer), separated by column chromatography. Elimination of the OH group of (XI) with C6F5OC(S)-Cl, Bu3SnH and AIBN in refluxing benzdene yields the tetracyclic ketone (XII), which is finally reduced with LiAlH4 in THF.
| 【1】 Brosius, A.D.; et al.; Total synthesis of (+)-aloperine. Use of a nitrogen-bound silicon tether in a intramolecular diels - Alder reaction. J Am Chem Soc 1999, 121, 4, 700. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 17573 | N-Phenyltrifluoromethanesulfonimide; Trifluoro-N-phenyl-N-[(trifluoromethyl)sulfonyl]methanesulfonamide | 37595-74-7 | C8H5F6NO4S2 | 详情 | 详情 | |
| (I) | 24255 | 3-piperidinol | 6859-99-0 | C5H11NO | 详情 | 详情 |
| (II) | 26735 | 1-(methylsulfonyl)-3-piperidinone | C6H11NO3S | 详情 | 详情 | |
| (III) | 26736 | 1-(methylsulfonyl)-1,4,5,6-tetrahydro-3-pyridinyl trifluoromethanesulfonate | C7H10F3NO5S2 | 详情 | 详情 | |
| (IV) | 26737 | tert-butyl (2R)-2-vinyl-1-piperidinecarboxylate | C12H21NO2 | 详情 | 详情 | |
| (V) | 26738 | tert-butyl (2R)-2-[(E)-2-[1-(methylsulfonyl)-1,4,5,6-tetrahydro-3-pyridinyl]ethenyl]-1-piperidinecarboxylate | C18H30N2O4S | 详情 | 详情 | |
| (VI) | 26739 | 1-(methylsulfonyl)-5-[(E)-2-[(2R)piperidinyl]ethenyl]-1,2,3,4-tetrahydropyridine | C13H22N2O2S | 详情 | 详情 | |
| (VII) | 26750 | methyl (E)-3-(dimethyl[[(trifluoromethyl)sulfonyl]oxy]silyl)-2-propenoate | C7H11F3O5SSi | 详情 | 详情 | |
| (VIII) | 26741 | methyl (E)-3-[dimethyl((2R)-2-[(E)-2-[1-(methylsulfonyl)-1,4,5,6-tetrahydro-3-pyridinyl]ethenyl]piperidinyl)silyl]-2-propenoate | C19H32N2O4SSi | 详情 | 详情 | |
| (IX) | 26742 | methyl (5aR,5bR,11aR,12S,12aS)-11,11-dimethyl-1-(methylsulfonyl)-1,2,3,4,5a,5b,6,7,8,9,11,11a,12,12a-tetradecahydropyrido[2',1':5,1][1,2]azasilolo[4,3-g]quinoline-12-carboxylate | C19H32N2O4SSi | 详情 | 详情 | |
| (X) | 26743 | (1R,2S,9S,10R,17R)-17-[fluoro(dimethyl)silyl]-3-(methylsulfonyl)-3,15-diazatetracyclo[7.7.1.0(2,7).0(10,15)]heptadec-7-en-16-one | C18H29FN2O3SSi | 详情 | 详情 | |
| (XI) | 26744 | (1R,2S,9R,10R,17R)-17-hydroxy-3-(methylsulfonyl)-3,15-diazatetracyclo[7.7.1.0(2,7).0(10,15)]heptadec-7-en-16-one | C16H24N2O4S | 详情 | 详情 | |
| (XII) | 26745 | (1S,2S,9S,10R)-3-(methylsulfonyl)-3,15-diazatetracyclo[7.7.1.0(2,7).0(10,15)]heptadec-7-en-16-one | C16H24N2O3S | 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 protection of 3-piperidinol (I) with tert-butoxycarbonyl anhydride or benzyloxycarbonyl chloride gives the corresponding protected piperidine (II), which is oxidized with CrO3 and acetic anhydride in pyridine yielding the piperidinone (III). The condensation of (III) with phosphinate (IV) and triethylamine at 100 C affords the alpha-hydroxyphosphinate (V), which is acylated with methoxalyl chloride (VI) and DMAP giving the methoxalyl ester (VII). The reduction of (VII) with tributyl in hydride and AIBN yields the protected phophinate (VIII), which is finally deprotected and hydrolyzed with 6M HCl.
| 【1】 Stensbol, T.B.; Kehler, J.; Krogsgaard-Larsen, P.; Piperidinyl-3-phosphinic acids as novel uptake inhibitors of the neurotransmitter gamma-aminobutyric acid (GABA). Bioorg Med Chem Lett 1999, 9, 6, 811. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10101 | Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene | 501-53-1 | C8H7ClO2 | 详情 | 详情 | |
| (IIa) | 26964 | benzyl 3-hydroxy-1-piperidinecarboxylate | C13H17NO3 | 详情 | 详情 | |
| (IIb) | 26965 | tert-butyl 3-hydroxy-1-piperidinecarboxylate | C10H19NO3 | 详情 | 详情 | |
| (IIIa) | 26966 | benzyl 3-oxo-1-piperidinecarboxylate | C13H15NO3 | 详情 | 详情 | |
| (IIIb) | 26967 | 1-N-Boc-3-piperodone; tert-butyl 3-oxo-1-piperidinecarboxylate | 98977-36-7 | C10H17NO3 | 详情 | 详情 |
| (Va) | 26969 | benzyl 3-[(diethoxymethyl)(ethoxy)phosphoryl]-3-hydroxy-1-piperidinecarboxylate | C20H32NO7P | 详情 | 详情 | |
| (Vb) | 26970 | tert-butyl 3-[(diethoxymethyl)(ethoxy)phosphoryl]-3-hydroxy-1-piperidinecarboxylate | C17H34NO7P | 详情 | 详情 | |
| (VIIa) | 26972 | benzyl 3-[(diethoxymethyl)(ethoxy)phosphoryl]-3-[(2-methoxy-2-oxoacetyl)oxy]-1-piperidinecarboxylate | C23H34NO10P | 详情 | 详情 | |
| (VIIb) | 26973 | tert-butyl 3-[(diethoxymethyl)(ethoxy)phosphoryl]-3-[(2-methoxy-2-oxoacetyl)oxy]-1-piperidinecarboxylate | C20H36NO10P | 详情 | 详情 | |
| (VIIIa) | 26974 | benzyl 3-[(diethoxymethyl)(ethoxy)phosphoryl]-1-piperidinecarboxylate | C20H32NO6P | 详情 | 详情 | |
| (VIIIb) | 26975 | tert-butyl 3-[(diethoxymethyl)(ethoxy)phosphoryl]-1-piperidinecarboxylate | C17H34NO6P | 详情 | 详情 | |
| (I) | 24255 | 3-piperidinol | 6859-99-0 | C5H11NO | 详情 | 详情 |
| (IV) | 26968 | ethyl diethoxymethylphosphinate | C7H17O4P | 详情 | 详情 | |
| (VI) | 26971 | 2-methoxy-2-oxoacetyl chloride | 5781-53-3 | C3H3ClO3 | 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 protection of 3-piperidinol (I) with tert-butoxycarbonyl anhydride or benzyloxycarbonyl chloride gives the corresponding protected piperidine (II), which is oxidized with CrO3 and acetic anhydride in pyridine yielding the piperidinone (III). The condensation of (III) with phosphinate (IV) and triethylamine at 100 C affords the alpha-hydroxyphosphinate (V), which is acylated with methoxalyl chloride (VI) and DMAP giving the methoxalyl ester (VII). The reduction of (VII) with tributyl in hydride and AIBN yields the protected phophinate (VIII), which is deprotected with trifluoroacetic acid affording (IX) with its free NH group. The alkylation of (IX) with 4,4-diphenyl-3-butenyl bromide (X) provides the alkylated piperidinephosphinate (XI), which is finally hydrolyzed with refluxing 6M HCl.
| 【1】 Stensbol, T.B.; Kehler, J.; Krogsgaard-Larsen, P.; Piperidinyl-3-phosphinic acids as novel uptake inhibitors of the neurotransmitter gamma-aminobutyric acid (GABA). Bioorg Med Chem Lett 1999, 9, 6, 811. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10101 | Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene | 501-53-1 | C8H7ClO2 | 详情 | 详情 | |
| (IIa) | 26964 | benzyl 3-hydroxy-1-piperidinecarboxylate | C13H17NO3 | 详情 | 详情 | |
| (IIb) | 26965 | tert-butyl 3-hydroxy-1-piperidinecarboxylate | C10H19NO3 | 详情 | 详情 | |
| (IIIa) | 26966 | benzyl 3-oxo-1-piperidinecarboxylate | C13H15NO3 | 详情 | 详情 | |
| (IIIb) | 26967 | 1-N-Boc-3-piperodone; tert-butyl 3-oxo-1-piperidinecarboxylate | 98977-36-7 | C10H17NO3 | 详情 | 详情 |
| (Va) | 26969 | benzyl 3-[(diethoxymethyl)(ethoxy)phosphoryl]-3-hydroxy-1-piperidinecarboxylate | C20H32NO7P | 详情 | 详情 | |
| (Vb) | 26970 | tert-butyl 3-[(diethoxymethyl)(ethoxy)phosphoryl]-3-hydroxy-1-piperidinecarboxylate | C17H34NO7P | 详情 | 详情 | |
| (VIIa) | 26972 | benzyl 3-[(diethoxymethyl)(ethoxy)phosphoryl]-3-[(2-methoxy-2-oxoacetyl)oxy]-1-piperidinecarboxylate | C23H34NO10P | 详情 | 详情 | |
| (VIIb) | 26973 | tert-butyl 3-[(diethoxymethyl)(ethoxy)phosphoryl]-3-[(2-methoxy-2-oxoacetyl)oxy]-1-piperidinecarboxylate | C20H36NO10P | 详情 | 详情 | |
| (VIIIa) | 26974 | benzyl 3-[(diethoxymethyl)(ethoxy)phosphoryl]-1-piperidinecarboxylate | C20H32NO6P | 详情 | 详情 | |
| (VIIIb) | 26975 | tert-butyl 3-[(diethoxymethyl)(ethoxy)phosphoryl]-1-piperidinecarboxylate | C17H34NO6P | 详情 | 详情 | |
| (I) | 24255 | 3-piperidinol | 6859-99-0 | C5H11NO | 详情 | 详情 |
| (IV) | 26968 | ethyl diethoxymethylphosphinate | C7H17O4P | 详情 | 详情 | |
| (VI) | 26971 | 2-methoxy-2-oxoacetyl chloride | 5781-53-3 | C3H3ClO3 | 详情 | 详情 |
| (IX) | 27066 | 1-(4,4-diphenyl-3-butenyl)-3-piperidinylphosphinic acid | C21H26NO2P | 详情 | 详情 | |
| (X) | 24116 | 1-(4-bromo-1-phenyl-1-butenyl)benzene | C16H15Br | 详情 | 详情 | |
| (XI) | 27067 | ethyl 1-(4,4-diphenyl-3-butenyl)-3-piperidinylphosphinate | C23H30NO2P | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(VIII)Suzuki coupling between 2-bromo-4-formylbenzonitrile (I) and 2-(trifluoromethyl)phenylboronic acid (II) affords the biphenyl aldehyde (III). The lithiated derivative of imidazole (IV) is then added to aldehyde (III), producing carbinol (V). Alkylation of (V) with the bromomethylpyridine (VI) by using Ag2O yields ether (VII). The chlorine atom of (VII) is finally displaced with 3-hydroxypiperidine (VIII) to provide the title compound.
| 【1】 Wang, G.T.; et al.; Lead optimization of imidazole-containing inhibitors of farnesyl transferase. 224th ACS Natl Meet (Aug 18 2002, Boston) 2002, Abst MEDI 130. |
| 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) | 58990 | 2-bromo-4-formylbenzonitrile | C8H4BrNO | 详情 | 详情 | |
| (II) | 53180 | 2-Trifluoromethylbenzeneboronic acid; 2-Trifluoromethylphenylboronic acid; o-Trifluoromethylphenylboronic acid | 1423-27-4 | C7H6BF3O2 | 详情 | 详情 |
| (III) | 58991 | 5-formyl-2'-(trifluoromethyl)[1,1'-biphenyl]-2-carbonitrile | C15H8F3NO | 详情 | 详情 | |
| (IV) | 58992 | 1-methyl-2-(triethylsilyl)-1H-imidazole | C10H20N2Si | 详情 | 详情 | |
| (V) | 58993 | 5-[hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-2'-(trifluoromethyl)[1,1'-biphenyl]-2-carbonitrile | C19H14F3N3O | 详情 | 详情 | |
| (VI) | 58994 | 6-(bromomethyl)-2-chloronicotinonitrile | C7H4BrClN2 | 详情 | 详情 | |
| (VII) | 58995 | 2-chloro-6-{[[6-cyano-2'-(trifluoromethyl)[1,1'-biphenyl]-3-yl](1-methyl-1H-imidazol-5-yl)methoxy]methyl}nicotinonitrile | C26H17ClF3N5O | 详情 | 详情 | |
| (VIII) | 24255 | 3-piperidinol | 6859-99-0 | C5H11NO | 详情 | 详情 |