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【结 构 式】 
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【分子编号】18792 【品名】3-methoxyacetophenone; 1-(3-methoxyphenyl)-1-ethanone 【CA登记号】586-37-8 |
【 分 子 式 】C9H10O2 【 分 子 量 】150.1772 【元素组成】C 71.98% H 6.71% O 21.31% |
合成路线1
该中间体在本合成路线中的序号：(I)The required (R)-3-methoxy-alpha-methylbenzylamine (III) was prepared from 3’-methoxyacetophenone (I) via Leuckart reaction, upon heating at 180 C with ammonium formate. The resultant formamide (II) was hydrolyzed with concentrated HCl to the racemic amine, which was then resolved using (R)-mandelic acid.
| 【1】 D'Ambra, T.E.; Vanwagenen, B.C.; Duff, S.R.; Nelson, W.A. (NPS Pharmaceuticals, Inc.); Method of making a benzylpropanamine. WO 9602492 . |
| 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) | 18792 | 3-methoxyacetophenone; 1-(3-methoxyphenyl)-1-ethanone | 586-37-8 | C9H10O2 | 详情 | 详情 |
| (II) | 56139 | 1-(3-methoxyphenyl)ethylformamide | C10H13NO2 | 详情 | 详情 | |
| (III) | 56140 | (R)-1-(3-Methoxyphenyl)ethylamine; (R)-3-Methoxy-alpha-methylbenzylamine; (R)-m-Methoxy-alpha-methylbenzylamine | 88196-70-7 | C9H13NO | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)In a different method, the primary amine (XVIII) was prepared by reduction of nitrile (XI) with either borane-dimethyl sulfide complex or with LiAlH4. Condensation of amine (XVIII) with acetophenone (I) generated imine (XIX). The asymmetric reduction of (XIX) to furnish the title (R)-amine was accomplished by using LiAlH4 in the presence of several chiral auxiliaries, such as 1,1’-binaphthol, (-)-N-methylephedrine, or (-)-N-methylpseudoephedrine, with different degrees of enantioselectivity. Alternatively, imine (XIX) was reduced utilizing a titanium-catalyzed asymmetric hydrosilylation method.
| 【1】 Buchwald, S.L.; Hansen, M.C.; Synthesis of NPS R-568 utilizing titanium-catalyzed asymmetric hydrosilylation. Tetrahedron Lett 1999, 40, 11, 2033. |
| 【2】 Van Wagenen, B.C.; Barmore, R.M. (NPS Pharmaceuticals, Inc.); Chiral reductions of imines leading to the syntheses of optically active amines. WO 9711934 . |
| 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) | 18792 | 3-methoxyacetophenone; 1-(3-methoxyphenyl)-1-ethanone | 586-37-8 | C9H10O2 | 详情 | 详情 |
| (XI) | 56146 | 3-(2-Chlorophenyl)propionitrile; 2-Chlorohydrocinnamonitrile | C9H8ClN | 详情 | 详情 | |
| (XVIII) | 56152 | 3-(2-chlorophenyl)-1-propanamine; 3-(2-chlorophenyl)propylamine | C9H12ClN | 详情 | 详情 | |
| (XIX) | 56153 | 3-(2-chlorophenyl)-N-[(E)-1-(3-methoxyphenyl)ethylidene]-1-propanamine; N-[3-(2-chlorophenyl)propyl]-N-[(E)-1-(3-methoxyphenyl)ethylidene]amine | C18H20ClNO | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)Title compound was prepared by reductive alkylation of 3-phenylpropylamine (I) with 3'-methoxyacetophenone (II) using NaCNBH3 in the presence of titanium isopropoxide in EtOH. Subsequent chiral resolution of the resulting secondary amine (III) by chromatography on ChiralCel OD provided the desired R-enantiomer.
| 【1】 Nemeth, E.F.; Van Wagenen, B.C.; Balandrin, M.F. (NPS Pharmaceuticals, Inc.); Calcium receptor active molecules. WO 9304373 . |
| 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) | 18791 | 3-phenylpropylamine; 3-phenyl-1-propanamine | 2038-57-5 | C9H13N | 详情 | 详情 |
| (II) | 18792 | 3-methoxyacetophenone; 1-(3-methoxyphenyl)-1-ethanone | 586-37-8 | C9H10O2 | 详情 | 详情 |
| (III) | 18793 | N-[1-(3-methoxyphenyl)ethyl]-N-(3-phenylpropyl)amine; N-[1-(3-methoxyphenyl)ethyl]-3-phenyl-1-propanamine | C18H23NO | 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 condensation of 3-methoxyacetophenone (I) with benzaldehyde (II) by means of NaOH in ethanol - water gives 3'-methoxychalcone (III), which by addition of HCN (KCN) in ethanol-acetic acid is transformed into 2-phenyl-4-(3-methoxyphenyl)-4-oxobutyronitrile (IV). The hydrolysis of (IV) with aqueous H2SO4 at 100 C affords the corresponding ketoacid (V), which is reduced with amalgamated zinc and 2N HCl yielding 2-phenyl-4-(3-methoxyphenyl)butyric acid (VI). The cyclization of (VI) by means of liquid HF yields 2-phenyl-6-methoxy-1,2,3,4-tetrahydro-1-naphthalenone (VII), which is finally condensed with 4-(2-pyrrolidinoethoxy)phenylmagnesium bromide in refluxing THF.
| 【1】 Thorpe, P.; Castañer, J.; Nafoxidine. Drugs Fut 1978, 3, 3, 211. |
| 【2】 Duncan, G.W.; Lednicer, D.; US 3483293 . |
| 【3】 Lednicer, D.; US 3274213 . |
| 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) | 18792 | 3-methoxyacetophenone; 1-(3-methoxyphenyl)-1-ethanone | 586-37-8 | C9H10O2 | 详情 | 详情 |
| (II) | 10498 | Benzaldehyde;Benzoic aldehyde;Phenylmethanal | 100-52-7 | C7H6O | 详情 | 详情 |
| (III) | 39791 | (E)-1-(3-methoxyphenyl)-3-phenyl-2-propen-1-one | C16H14O2 | 详情 | 详情 | |
| (IV) | 39792 | 4-(3-methoxyphenyl)-4-oxo-2-phenylbutanenitrile | C17H15NO2 | 详情 | 详情 | |
| (V) | 39793 | 4-(3-methoxyphenyl)-4-oxo-2-phenylbutyric acid | C17H16O4 | 详情 | 详情 | |
| (VI) | 39794 | 4-(3-methoxyphenyl)-2-phenylbutyric acid | C17H18O3 | 详情 | 详情 | |
| (VII) | 39795 | 6-methoxy-2-phenyl-3,4-dihydro-1(2H)-naphthalenone | C17H16O2 | 详情 | 详情 | |
| (VIII) | 29184 | bromo[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]magnesium | C12H16BrMgNO | 详情 | 详情 |