【结 构 式】 |
【分子编号】28021 【品名】4-phenyl-4-piperidinol; 4-Hydroxy-4-phenylpiperidine; 4-(4-Phenyl)-4-hydroxypiperidine 【CA登记号】40807-61-2 |
【 分 子 式 】C11H15NO 【 分 子 量 】177.24624 【元素组成】C 74.54% H 8.53% N 7.9% O 9.03% |
合成路线1
该中间体在本合成路线中的序号:(III)By condensation of 1-tetralone (I) with formaldehyde (II) and 4-phenyl piperidin-4-ol (III) in refluxing ethanol.
【1】 Muller-Calgan, H.; Jonas, R.; Uhl, J.; Irmscher, K. (Merck Patent GmbH); Tetralone and indanone derivs.. DE 2507782; NL 7601762 . |
【2】 Serradell, M.N.; Castaner, J.; EMD-30533. Drugs Fut 1986, 11, 2, 101. |
合成路线2
该中间体在本合成路线中的序号:(IV)4-Hydroxypropiophenone (I) was protected as the triisopropylsilyl ether (II) and subsequently brominated with elemental bromine in CCl4 . The resultant bromo ketone (III) was subsequently coupled with 4-hydroxy-4-phenylpiperidine (IV) to afford the racemic amino ketone (V). This was stereoselectively reduced with NaBH4 in EtOH yielding the threo-amino alcohol (VI). Then, desilylation of (VI) with tetrabutylammonium fluoride furnished the racemic phenol compound. Resolution into the enantiomers has been reported by formation of the corresponding D-tartaric acid salts
【1】 Chenard, B.L.; et al.; (1S,2S)-1-(4-Hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol: A potent new neuroprotectant which blocks N-methyl-D-aspartate responses. J Med Chem 1995, 38, 16, 3138. |
【2】 Chenard, B.L. (Pfizer Inc.); 2-Piperidino-1-alkanol derivs. as antiischemic agents. US 5272160 . |
【3】 Walinsky, S.W.; Rainville, J.P.; Sinay, T.G. Jr. (Pfizer Products Inc.); Process for the preparation of the mesylate salt trihydrate of 1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanol. EP 1151995 . |
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) | 58982 | 4'-Hydroxypropiophenone; 4-Hydroxypropiophenone; Ethyl 4-Hydroxyphenyl ktone; p-Hydroxypropiophenone; Paroxypropione | 70-70-2 | C9H10O2 | 详情 | 详情 |
(II) | 62505 | 1-{4-[(triisopropylsilyl)oxy]phenyl}-1-propanone | C18H30O2Si | 详情 | 详情 | |
(III) | 62506 | 2-bromo-1-{4-[(triisopropylsilyl)oxy]phenyl}-1-propanone | C18H29BrO2Si | 详情 | 详情 | |
(IV) | 28021 | 4-phenyl-4-piperidinol; 4-Hydroxy-4-phenylpiperidine; 4-(4-Phenyl)-4-hydroxypiperidine | 40807-61-2 | C11H15NO | 详情 | 详情 |
(V) | 62507 | 2-(4-hydroxy-4-phenyl-1-piperidinyl)-1-{4-[(triisopropylsilyl)oxy]phenyl}-1-propanone | C29H43NO3Si | 详情 | 详情 | |
(VI) | 62508 | 1-((1S,2S)-2-hydroxy-1-methyl-2-{4-[(triisopropylsilyl)oxy]phenyl}ethyl)-4-phenyl-4-piperidinol | C29H45NO3Si | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号:(IV)4-Hydroxypropiophenone (I) was protected as the triisopropylsilyl ether (II) and subsequently brominated with elemental bromine in CCl4. The resultant bromo ketone (III) was subsequently coupled with 4-hydroxy-4-phenylpiperidine (IV) to afford the racemic amino ketone (V). This was stereoselectively reduced with NaBH4 in EtOH yielding the threo-amino alcohol (VI). Then, desilylation of (VI) with tetrabutylammonium fluoride furnished the racemic phenol compound. Resolution into the enantiomers has been reported by formation of the corresponding D-tartaric acid salts. Finally, the title product was obtained by dissolving D-(-)-tartaric salt (VII) in water in the presence of methanesulfonic acid
【1】 Chenard, B.L.; et al.; (1S,2S)-1-(4-Hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol: A potent new neuroprotectant which blocks N-methyl-D-aspartate responses. J Med Chem 1995, 38, 16, 3138. |
【2】 Chenard, B.L. (Pfizer Inc.); 2-Piperidino-1-alkanol derivs. as antiischemic agents. US 5272160 . |
【3】 Walinsky, S.W.; Rainville, J.P.; Sinay, T.G. Jr. (Pfizer Products Inc.); Process for the preparation of the mesylate salt trihydrate of 1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanol. EP 1151995 . |
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) | 58982 | 4'-Hydroxypropiophenone; 4-Hydroxypropiophenone; Ethyl 4-Hydroxyphenyl ktone; p-Hydroxypropiophenone; Paroxypropione | 70-70-2 | C9H10O2 | 详情 | 详情 |
(II) | 62505 | 1-{4-[(triisopropylsilyl)oxy]phenyl}-1-propanone | C18H30O2Si | 详情 | 详情 | |
(III) | 62506 | 2-bromo-1-{4-[(triisopropylsilyl)oxy]phenyl}-1-propanone | C18H29BrO2Si | 详情 | 详情 | |
(IV) | 28021 | 4-phenyl-4-piperidinol; 4-Hydroxy-4-phenylpiperidine; 4-(4-Phenyl)-4-hydroxypiperidine | 40807-61-2 | C11H15NO | 详情 | 详情 |
(V) | 62507 | 2-(4-hydroxy-4-phenyl-1-piperidinyl)-1-{4-[(triisopropylsilyl)oxy]phenyl}-1-propanone | C29H43NO3Si | 详情 | 详情 | |
(VI) | 62508 | 1-((1S,2S)-2-hydroxy-1-methyl-2-{4-[(triisopropylsilyl)oxy]phenyl}ethyl)-4-phenyl-4-piperidinol | C29H45NO3Si | 详情 | 详情 | |
(VII) | 62509 | 1-[(1S,2S)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]-4-phenyl-4-piperidinol | C20H25NO3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号:(III)Hydroxy dibenzooxepine (I) was converted to the corresponding chloride (II) by treatment with SOCl2 in CH2Cl2. Condensation of (II) with 4-hydroxy-4-phenylpiperidine (III) produced adduct (IV). The carboxylate group of (IV) was then reduced by means of LiAlH4 in cold THF to furnish the title alcohol.
【1】 Kumazawa, T.; Koshimura, H.; Aono, S.; Ichikawa, S.; Kitamura, S. (Kyowa Hakko Kogyo Co., Ltd.); Phenylpiperidine derivs.. EP 0974583; WO 9710213 . |
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) | 41323 | methyl 11-hydroxy-6,11-dihydrodibenzo[b,e]oxepine-2-carboxylate | C16H14O4 | 详情 | 详情 | |
(II) | 41324 | methyl 11-chloro-6,11-dihydrodibenzo[b,e]oxepine-2-carboxylate | C16H13ClO3 | 详情 | 详情 | |
(III) | 28021 | 4-phenyl-4-piperidinol; 4-Hydroxy-4-phenylpiperidine; 4-(4-Phenyl)-4-hydroxypiperidine | 40807-61-2 | C11H15NO | 详情 | 详情 |
(IV) | 41325 | methyl 11-(4-hydroxy-4-phenyl-1-piperidinyl)-6,11-dihydrodibenzo[b,e]oxepine-2-carboxylate | C27H27NO4 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号:(XV)The protection of 3-bromo-1-propanol (I) with dihydropyran (DHP) and p-toluenesulfonic acid gives the tetrahydropyranyl ether (II), which is condensed with 3,4-dichlorophenylacetonitrile (III) by means of NaH in THF yielding the pentanenitrile (IV). The condensation of (IV) with ethyl 3-bromopropionate (V) by means of potassium hexamethyldisylazide (KHMDS) in THF affords the heptanoate (VI), which is reductocyclized with H2 over RaNi in ethanol/aq. NH4OH affording the piperidone (VII). The reduction of (VII) by means of LiAlH4 in THF gives the piperidine (VIII), which is deprotected with HCl in ethyl ether yielding the racemic propanol (IX). The optical resolution of (IX) by means of (+)-camphorsulfonic acid in isopropanol affords the desired enantiomer (X), which is acylated with benzoyl chloride (XI) and DIEA in dichloromethane providing the benzoylpiperidine (XII). The reaction of (XII) with methanesulfonyl chloride and triethylamine gives the mesylate (XIII), which is treated with KI in refluxing acetone to yield the 3-iodopropyl derivative (XIV). Finally, (XIV) is condensed with 4-hydroxy-4-phenylpiperidine (XV) by means of KHCO3 in hot acetonitrile. The intermediate 4-hydroxy-4-phenylpiperidine (XV) has been obtained as follows: The reaction of 1-benzyl-4-piperidone (XVI) with phenyllithium in THF gives 1-benzyl-4-hydroxy-4-phenylpiperidine (XVII), which is then debenzy-lated by hydrogenation with H2.
【1】 Kuo, B.-S.; Lee, H.T.; Roth, B.D.; Chung, F.-Z.; Atherton, J.; Chen, M.H.; Syntheses and biological activities of chiral piperidines-tachykinin NK3 antagonists. Acta Pharm Sin 1999, 20, 3, 283. |
【2】 Chen, M.H.G.; Lee, H.T.; Chung, F.-Z. (Pfizer Inc.); 3-Alkyl-3-phenyl-piperidines. WO 9811090 . |
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) | 12573 | 3-Bromo-1-propanol; 3-Bromopropanol | 627-18-9 | C3H7BrO | 详情 | 详情 |
(II) | 29460 | 2-(4-bromobutoxy)tetrahydro-2H-pyran; 4-bromobutyl tetrahydro-2H-pyran-2-yl ether | C9H17BrO2 | 详情 | 详情 | |
(III) | 26935 | 2-(3,4-dichlorophenyl)acetonitrile | 3218-49-3 | C8H5Cl2N | 详情 | 详情 |
(IV) | 29461 | 2-(3,4-dichlorophenyl)-6-(tetrahydro-2H-pyran-2-yloxy)hexanenitrile | C17H21Cl2NO2 | 详情 | 详情 | |
(V) | 29132 | ethyl 3-bromopropanoate | 539-74-2 | C5H9BrO2 | 详情 | 详情 |
(VI) | 29462 | ethyl 4-cyano-4-(3,4-dichlorophenyl)-8-(tetrahydro-2H-pyran-2-yloxy)octanoate | C22H29Cl2NO4 | 详情 | 详情 | |
(VII) | 29463 | 5-(3,4-dichlorophenyl)-5-[4-(tetrahydro-2H-pyran-2-yloxy)butyl]-2-piperidinone | C20H27Cl2NO3 | 详情 | 详情 | |
(VIII) | 29464 | 3-(3,4-dichlorophenyl)-3-[4-(tetrahydro-2H-pyran-2-yloxy)butyl]piperidine; 4-[3-(3,4-dichlorophenyl)-3-piperidinyl]butyl tetrahydro-2H-pyran-2-yl ether | C20H29Cl2NO2 | 详情 | 详情 | |
(IX) | 29465 | 3-[3-(3,4-dichlorophenyl)-3-piperidinyl]-1-propanol | C14H19Cl2NO | 详情 | 详情 | |
(X) | 29466 | 3-[(3S)-3-(3,4-dichlorophenyl)piperidinyl]-1-propanol | C14H19Cl2NO | 详情 | 详情 | |
(XI) | 10463 | Benzoyl chloride | 98-88-4 | C7H5ClO | 详情 | 详情 |
(XII) | 29467 | [(3S)-3-(3,4-dichlorophenyl)-3-(3-hydroxypropyl)piperidinyl](phenyl)methanone | C21H23Cl2NO2 | 详情 | 详情 | |
(XIII) | 29468 | 3-[(3S)-1-benzoyl-3-(3,4-dichlorophenyl)piperidinyl]propyl methanesulfonate | C22H25Cl2NO4S | 详情 | 详情 | |
(XIV) | 29469 | [(3S)-3-(3,4-dichlorophenyl)-3-(3-iodopropyl)piperidinyl](phenyl)methanone | C21H22Cl2INO | 详情 | 详情 | |
(XV) | 28021 | 4-phenyl-4-piperidinol; 4-Hydroxy-4-phenylpiperidine; 4-(4-Phenyl)-4-hydroxypiperidine | 40807-61-2 | C11H15NO | 详情 | 详情 |
(XVI) | 15720 | 1-benzyltetrahydro-4(1H)-pyridinone; 1-Benzyl-4-piperidone; N-Benzyl-4-piperidone; 1-(benzyl)-4-piperidinone; 1-benzylpiperidin-4-one; 1-(benzyl)piperidin-4-one | 3612-20-2 | C12H15NO | 详情 | 详情 |
(XVII) | 24014 | Phenyllithium | 591-51-5 | C6H5Li | 详情 | 详情 |
(XVIII) | 29470 | 1-benzyl-4-phenyl-4-piperidinol | C18H21NO | 详情 | 详情 |