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【结 构 式】 
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【分子编号】11972 【品名】(1R)-3-(Methylamino)-1-phenyl-1-propanol; (R)-3-Hydroxy-N-methyl-3-phenyl propylamine 【CA登记号】42142-52-9 |
【 分 子 式 】C10H15NO 【 分 子 量 】165.23524 【元素组成】C 72.69% H 9.15% N 8.48% O 9.68% |
合成路线1
该中间体在本合成路线中的序号：(V)The synthesis of (R)-fluoxetine hydrochloride has been described: The condensation of acetophenone (I) with N-benzyl-N-methylamine (II) and formaldehyde by means of concentrated HCl in refluxing methanol gives 3-(N-benzyl-N-methylamino)propiophenone (III), which is asymmetrically reduced with H2 at 30 Atm. over [Rh(1,5-cyclooctadiene)Cl] and the chiral phosphine (2S,4S)-1-(N-methylcarbamoyl)-4-(dicyclohexylphosphino)-2-(diphenylphos phinomethyl)pyrrolidine in methanol yielding (R)-3-(N-benzyl-N-methylamino)-1-phenyl-1-propanol (IV). The debenzylation of (IV) with H2 over Pd/C in ethanol affords (R)-3-(methylamino)-1-phenyl-1-propanol (V), which is finally condensed with 1-chloro-4-(trifluoromethyl)benzene (VI) by means of NaH in dimethylacetamide.
| 【1】 Sakuraba, S.; Achiwa, K.; Efficient asymmetric hydrogenation of beta- and gamma-amino ketone derivatives leading to practical synthesis of fluoxetine and eprozinol. Chem Pharm Bull 1995, 43, 5, 748. |
| 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) | 10317 | Acetophenone | 98-86-2 | C8H8O | 详情 | 详情 |
| (II) | 11969 | N-Methyl(phenyl)methanamine; N-Benzyl-N-methylamine; N-Methylbenzylamine | 103-67-3 | C8H11N | 详情 | 详情 |
| (III) | 11970 | 3-[Benzyl(methyl)amino]-1-phenyl-1-propanone; 3-(N-Benzyl-N-methylamino)propiophenone | 5409-62-1 | C17H19NO | 详情 | 详情 |
| (IV) | 11971 | (1R)-3-[Benzyl(methyl)amino]-1-phenyl-1-propanol | C17H21NO | 详情 | 详情 | |
| (V) | 11972 | (1R)-3-(Methylamino)-1-phenyl-1-propanol; (R)-3-Hydroxy-N-methyl-3-phenyl propylamine | 42142-52-9 | C10H15NO | 详情 | 详情 |
| (VI) | 11973 | 1-Chloro-4-(trifluoromethyl)benzene; 4-Chlorobenzotrifluoride | 98-56-6 | C7H4ClF3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XVI)The chiral precursor (R)-3-(methylamino)-1-phenyl-1-propanol (XVI) has been prepared by an alternative method. Asymmetric reduction of methyl 3-benzoylpropionate (X) to produce the (R)-lactone (XI) was performed either employing commercial (+)-B-chlorodiisopinocampheylborane or generating in situ this reagent from alpha-pinene, NaBH4 and BCl3. Ammonolysis of lactone (XI) in MeOH afforded hydroxy amide (XII). This chiral intermediate (XII) was alternatively obtained by reduction of keto ester (X) with borane in the presence of the oxaazaborolidine chiral auxiliary (XIII) to produce the (R)-hydroxy ester (XIV), which was subsequently treated with ammonium hydroxyde in MeOH. Hofmann rearrangement of amide (XII) using iodobenzene diacetate led to the cyclic carbamate (XV). The key amino alcohol precursor (XVI) was then obtained by reduction of carbamate (XV) with LiAlH4.
| 【1】 Hilborn, J.W.; et al.; A practical asymmetric synthesis of (R)-fluoxetine and its major metabolite (R)-norfluoxetine. Tetrahedron Lett 2001, 42, 51, 8919. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (X) | 43101 | methyl 4-oxo-4-phenylbutanoate | 25333-24-8 | C11H12O3 | 详情 | 详情 |
| (XI) | 55648 | (5R)-5-phenyldihydro-2(3H)-furanone | C10H10O2 | 详情 | 详情 | |
| (XII) | 55649 | (4R)-4-hydroxy-4-phenylbutanamide | C10H13NO2 | 详情 | 详情 | |
| (XIII) | 28292 | (S)-Methyl oxazaborolidine; (3aS)-1-methyl-3,3-diphenyltetrahydro-3H-pyrrolo[1,2-c][1,3,2]oxazaborole | 112022-81-8 | C18H20BNO | 详情 | 详情 |
| (XIV) | 55647 | methyl (4R)-4-hydroxy-4-phenylbutanoate | C11H14O3 | 详情 | 详情 | |
| (XV) | 55650 | (6R)-6-phenyl-1,3-oxazinan-2-one | C10H11NO2 | 详情 | 详情 | |
| (XVI) | 11972 | (1R)-3-(Methylamino)-1-phenyl-1-propanol; (R)-3-Hydroxy-N-methyl-3-phenyl propylamine | 42142-52-9 | C10H15NO | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：（XLVII）
| 【1】 Zhao MM, McNamara JM, Ho GJ, et aL 2002. Practical aaymmetric synthesis of aprepitant,apotmt Human NK-1 receptor anUylonist, viaa stereoselective lewis acid-catalyzed trans aoetalization rraction- J Org Chem, 67 (19)t 6743~6747 |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| （XLIV) | 13188 | ethyl 3-chloro-3-oxopropanoate; 2-Ethoxycarbonylacetyl chloride; Ethyl malonyl chloride | 36239-09-5 | C5H7ClO3 | 详情 | 详情 |
| （XLVI） | 66104 | 2-oxo-2-((1-phenylethyl)amino)acetic acid | C10H11NO3 | 详情 | 详情 | |
| （XLVII） | 11972 | (1R)-3-(Methylamino)-1-phenyl-1-propanol; (R)-3-Hydroxy-N-methyl-3-phenyl propylamine | 42142-52-9 | C10H15NO | 详情 | 详情 |
| （XLVIII） | 66105 | 3-(4-fluorophenyl)-4-((S)-1-phenylethyl)morpholin-2-one hydrochloride | C18H19FClNO2 | 详情 | 详情 | |
| （XLIX） | 66106 | 3-(4-fluorophenyl)-4-((R)-1-phenylethyl)morpholin-2-ol | C18H20FNO2 | 详情 | 详情 | |
| （L） | 66107 | (2S)-3-(4-fluorophenyl)-4-((S)-1-phenylethyl)morpholin-2-yl 2,2,2-trichloroacetimidate | C20H20FCl3N2O2 | 详情 | 详情 | |
| （LI） | 66108 | (R)-1-(3,5-(trifluoromethyl)phenyl)ethanol | C10H8F6O | 详情 | 详情 | |
| （LII） | 66109 | (3R)-2-(1-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(4-fluorophenyl)-4-((R)-1-phenylethyl)morpholine | C28H26F7NO2 | 详情 | 详情 | |
| （XLI） | 66101 | (2R)-2-(1-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(4-fluorophenyl)morpholine | C20H18F7NO2 | 详情 | 详情 | |
| （LIII） | 66110 | 6-(1-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-5-(4-fluorophenyl)-3,6-dihydro-2H-1,4-oxazine | C20H16F7NO2 | 详情 | 详情 | |
| （LIV） | 66111 | 2-(1-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(4-fluorophenyl)morpholine hydrochloride | C20H19ClF7NO2 | 详情 | 详情 | |
| (X) | 18999 | 4-Fluorophenylacetic acid; 2-(4-Fluorophenyl)acetic acid | 405-50-5 | C8H7FO2 | 详情 | 详情 |
| (XXVI) | 44196 | 5-(chloromethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one | C3H4ClN3O | 详情 | 详情 | |
| (XLIII) | 66103 | 1-(4-fluorophenyl)-2,2-dihydroxyethanone | C8H7FO3 | 详情 | 详情 | |
| (XLV) | 10039 | (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine | 3886-69-9 | C8H11N | 详情 | 详情 |