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【结 构 式】 
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【分子编号】59274 【品名】2-(3,4-dichlorophenyl)-5-(tetrahydro-2H-pyran-2-yloxy)pentanenitrile 【CA登记号】 |
【 分 子 式 】C16H19Cl2NO2 【 分 子 量 】328.2378 【元素组成】C 58.55% H 5.83% Cl 21.6% N 4.27% O 9.75% |
合成路线1
该中间体在本合成路线中的序号：(XXIII)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.
| 【1】 Giardina, G.A.M.; et al.; A reliable and efficient synthesis of SR 142801. Bioorg Med Chem Lett 1996, 6, 19, 2307. |
| 【2】 Chen, H.G.; et al.; A practical and scalable synthesis of SR 142801, a tachykinin NK3 antagonist. Bioorg Med Chem Lett 1997, 7, 5, 555. |
| 【3】 Grugni, M.; Rigolio, R.; Erhard, K.F. (GlaxoSmithKline Inc.; GlaxoSmithKline SpA); Process for the preparation of 3,3-disubstd. piperidines. WO 9805640 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XI) | 26935 | 2-(3,4-dichlorophenyl)acetonitrile | 3218-49-3 | C8H5Cl2N | 详情 | 详情 |
| (XII) | 14156 | methyl acrylate | 96-33-3 | C4H6O2 | 详情 | 详情 |
| (XVI) | 29465 | 3-[3-(3,4-dichlorophenyl)-3-piperidinyl]-1-propanol | C14H19Cl2NO | 详情 | 详情 | |
| (XXI) | 12573 | 3-Bromo-1-propanol; 3-Bromopropanol | 627-18-9 | C3H7BrO | 详情 | 详情 |
| (XXII) | 42252 | 3-bromopropyl tetrahydro-2H-pyran-2-yl ether; 2-(3-bromopropoxy)tetrahydro-2H-pyran | C8H15BrO2 | 详情 | 详情 | |
| (XXIII) | 59274 | 2-(3,4-dichlorophenyl)-5-(tetrahydro-2H-pyran-2-yloxy)pentanenitrile | C16H19Cl2NO2 | 详情 | 详情 | |
| (XXIV) | 59275 | 4-cyano-4-(3,4-dichlorophenyl)-7-(tetrahydro-2H-pyran-2-yloxy)heptanoic acid | C19H23Cl2NO4 | 详情 | 详情 | |
| (XXV) | 59276 | 3-[3-(3,4-dichlorophenyl)-2,6-dioxo-3-piperidinyl]propyl acetate | C16H17Cl2NO4 | 详情 | 详情 | |
| (XXVI) | 59277 | [3-(3,4-dichlorophenyl)-3-(3-hydroxypropyl)-1-piperidinyl](phenyl)methanone | C21H23Cl2NO2 | 详情 | 详情 | |
| (XXVII) | 59278 | 3-[1-benzoyl-3-(3,4-dichlorophenyl)-3-piperidinyl]propyl methanesulfonate | C22H25Cl2NO4S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XXIII)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.
| 【1】 Chen, H.G.; et al.; A practical and scalable synthesis of SR 142801, a tachykinin NK3 antagonist. Bioorg Med Chem Lett 1997, 7, 5, 555. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXIII) | 59274 | 2-(3,4-dichlorophenyl)-5-(tetrahydro-2H-pyran-2-yloxy)pentanenitrile | C16H19Cl2NO2 | 详情 | 详情 | |
| (XXVIII) | 29132 | ethyl 3-bromopropanoate | 539-74-2 | C5H9BrO2 | 详情 | 详情 |
| (XXIX) | 59279 | ethyl 4-cyano-4-(3,4-dichlorophenyl)-7-(tetrahydro-2H-pyran-2-yloxy)heptanoate | C21H27Cl2NO4 | 详情 | 详情 | |
| (XXX) | 59280 | 5-(3,4-dichlorophenyl)-5-[3-(tetrahydro-2H-pyran-2-yloxy)propyl]-2-piperidinone | C19H25Cl2NO3 | 详情 | 详情 | |
| (XXXI) | 59281 | 3-[3-(3,4-dichlorophenyl)-3-piperidinyl]propyl tetrahydro-2H-pyran-2-yl ether; 3-(3,4-dichlorophenyl)-3-[3-(tetrahydro-2H-pyran-2-yloxy)propyl]piperidine | C19H27Cl2NO2 | 详情 | 详情 | |
| (XXXII) | 59282 | C24H35Cl2NO5S | 详情 | 详情 | ||
| (XXXIII) | 29467 | [(3S)-3-(3,4-dichlorophenyl)-3-(3-hydroxypropyl)piperidinyl](phenyl)methanone | C21H23Cl2NO2 | 详情 | 详情 | |
| (XXXIV) | 29468 | 3-[(3S)-1-benzoyl-3-(3,4-dichlorophenyl)piperidinyl]propyl methanesulfonate | C22H25Cl2NO4S | 详情 | 详情 | |
| (XXXV) | 29469 | [(3S)-3-(3,4-dichlorophenyl)-3-(3-iodopropyl)piperidinyl](phenyl)methanone | C21H22Cl2INO | 详情 | 详情 |