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【结 构 式】 
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【分子编号】59278 【品名】3-[1-benzoyl-3-(3,4-dichlorophenyl)-3-piperidinyl]propyl methanesulfonate 【CA登记号】 |
【 分 子 式 】C22H25Cl2NO4S 【 分 子 量 】470.41624 【元素组成】C 56.17% H 5.36% Cl 15.07% N 2.98% O 13.6% S 6.82% |
合成路线1
该中间体在本合成路线中的序号：(XXVII)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：(XXVII)An alternative preparation of the precursor 4-(N-methyl-N-acetyl)amino-4-phenylpiperidine (XXXIX) has been reported. The N-benzyl protecting group of piperidine (III) was replaced with an N-Boc group by catalytic hydrogenolysis to (XXXVI), followed by treatment with Boc2O to yield (XXXVII). Amide (XXXVII) alkylation with iodomethane under phase-transfer conditions gave the N-methyl derivative (XXXVIII). Subsequent N-Boc group cleavage in (XXXVIII) was accomplished by using zinc chloride in CH2Cl2 to afford the piperidine-ZnCl2 complex (XXXIX). This was then alkylated with mesylate (XXVII), and the title compound was finally isolated from the racemic mixture by means of preparative chiral HPLC.
| 【1】 Giardina, G.A.M.; et al.; A reliable and efficient synthesis of SR 142801. Bioorg Med Chem Lett 1996, 6, 19, 2307. |
| 【2】 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 |
|---|---|---|---|---|---|---|
| (III) | 54993 | N-(1-benzyl-4-phenyl-4-piperidinyl)acetamide | C20H24N2O | 详情 | 详情 | |
| (XXVII) | 59278 | 3-[1-benzoyl-3-(3,4-dichlorophenyl)-3-piperidinyl]propyl methanesulfonate | C22H25Cl2NO4S | 详情 | 详情 | |
| (XXXVI) | 59283 | N-(4-phenyl-4-piperidinyl)acetamide | C13H18N2O | 详情 | 详情 | |
| (XXXVII) | 59284 | tert-butyl 4-(acetylamino)-4-phenyl-1-piperidinecarboxylate | C18H26N2O3 | 详情 | 详情 | |
| (XXXVIII) | 59285 | tert-butyl 4-[acetyl(methyl)amino]-4-phenyl-1-piperidinecarboxylate | C19H28N2O3 | 详情 | 详情 | |
| (XXXIX) | 59267 | N-methyl-N-(4-phenyl-4-piperidinyl)acetamide | C14H20N2O | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XXVII)In a further method, aminopiperidine (IV) was converted to the formamide (XL) by heating in ethyl formate. Formyl group reduction in (XL) with LiAlH4 provided the N-metyl amine (XLI). The N-benzyl group of (XLI) was then removed by catalytic hydrogenation over Pd/C. Alkylation of the resultant piperidine (XLII) with mesylate (XXVII) gave adduct (XLIII). After acetylation of (XLIII) in neat Ac2O, the racemic mixture was separated by chiral HPLC.
| 【1】 Giardina, G.A.M.; et al.; A reliable and efficient synthesis of SR 142801. Bioorg Med Chem Lett 1996, 6, 19, 2307. |
| 【2】 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 |
|---|---|---|---|---|---|---|
| (IV) | 54994 | 1-benzyl-4-phenyl-4-piperidinylamine; 1-benzyl-4-phenyl-4-piperidinamine | C18H22N2 | 详情 | 详情 | |
| (XXVII) | 59278 | 3-[1-benzoyl-3-(3,4-dichlorophenyl)-3-piperidinyl]propyl methanesulfonate | C22H25Cl2NO4S | 详情 | 详情 | |
| (XL) | 59286 | 1-benzyl-4-phenyl-4-piperidinylformamide | C19H22N2O | 详情 | 详情 | |
| (XLI) | 59287 | 1-benzyl-N-methyl-4-phenyl-4-piperidinamine; N-(1-benzyl-4-phenyl-4-piperidinyl)-N-methylamine | C19H24N2 | 详情 | 详情 | |
| (XLII) | 59288 | N-methyl-4-phenyl-4-piperidinamine; N-methyl-N-(4-phenyl-4-piperidinyl)amine | C12H18N2 | 详情 | 详情 | |
| (XLIII) | 59289 | (3-(3,4-dichlorophenyl)-3-{3-[4-(methylamino)-4-phenyl-1-piperidinyl]propyl}-1-piperidinyl)(phenyl)methanone | C33H39Cl2N3O | 详情 | 详情 |