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【结 构 式】 
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【药物名称】(S)-Fluoxetine 【化学名称】(S)-N-Methyl-gamma-[4-(trifluoromethyl)phenoxy]benzenepropanamine 【CA登记号】100568-02-3 【 分 子 式 】C17H18F3NO 【 分 子 量 】309.33431 |
【开发单位】Sepracor (Originator) 【药理作用】ANALGESIC AND ANESTHETIC DRUGS, Antimigraine Drugs, 5-HT Reuptake Inhibitors |
合成路线1
The enantioselective reduction of 2-benzoylacetonitrile (I) with BH3/Me2S complex catalyzed by the chiral catalyst (II) in THF gives 3(S)-hydroxy-3-phenylpropylamine (III), which is protected with tert-butyl dicarbonate and NaOH to yield the carbamate (IV). The condensation of (IV) with 4-(trifluoromethyl)phenol (V) by means of triphenylphosphine and diethyl azodicarboxylate (DEAD) in THF affords N-[3(S)-phenyl-3-[4-(trifluoromethyl) phenoxy]propyl]carbamic acid tert-butyl ester (VI), which is finally reduced with LiAlH4 in refluxing THF to give the target (S)-Fluoxetine.
| 【1】 Jurgens, A.R.; Hilborn, J.W. (Sepracor Inc.); Fluoxetine process from benzoylacetonitrile. WO 0007976 . |
| 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) | 34897 | 3-oxo-3-phenylpropanenitrile | 614-16-4 | C9H7NO | 详情 | 详情 |
| (II) | 34898 | (3aR,8aS)-2-methyl-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d][1,3,2]oxazaborole | C10H12BNO | 详情 | 详情 | |
| (III) | 34899 | (1S)-3-amino-1-phenyl-1-propanol | C9H13NO | 详情 | 详情 | |
| (IV) | 34900 | tert-butyl (3S)-3-hydroxy-3-phenylpropylcarbamate | C14H21NO3 | 详情 | 详情 | |
| (V) | 33607 | 4-(trifluoromethyl)phenol | 402-45-9 | C7H5F3O | 详情 | 详情 |
| (VI) | 34901 | tert-butyl (3S)-3-phenyl-3-[4-(trifluoromethyl)phenoxy]propylcarbamate | C21H24F3NO3 | 详情 | 详情 |
合成路线2
A new enantioselective synthesis of (S)-fluoxetine has been reported: Reduction of 3-furaldehyde (I) under Wolff-Kishner conditions provided the desired 3-methylene-2,3-dihydrofuran (II) along with minor amounts of 3-methylfuran (III), which were used in the next step without previous separation. The asymmetric carbonyl-ene reaction of (II) with benzaldehyde (IV) using (S)-1,1'-binaphthol and titanium isopropoxide furnished the target (S)-2-(3-furyl)-1-phenylethanol (V). Condensation of the sodium alkoxide of (V) with 4-fluorobenzotrifluoride (VI) gave rise to ether (VII). Carboxylic acid (VIII) was then obtained by oxidative cleavage of the furan derivative (VII) with RuCl3/NaIO4. Coupling of acid (VIII) with methylamine gave amide (IX). Finally, amide reduction employing borane in THF yielded the title compound.
| 【1】 Miles, W.H.; et al.; Enantioselective synthesis of (S)- and (R)-fluoxetine hydrochloride. Tetrahedron 2001, 57, 50, 9925. |
| 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) | 47247 | 3-Furaldehyde | 498-60-2 | C5H4O2 | 详情 | 详情 |
| (II) | 55641 | 3-methylene-2,3-dihydrofuran | C5H6O | 详情 | 详情 | |
| (III) | 55642 | 3-Methylfuran | 930-27-8 | C5H6O | 详情 | 详情 |
| (IV) | 10498 | Benzaldehyde;Benzoic aldehyde;Phenylmethanal | 100-52-7 | C7H6O | 详情 | 详情 |
| (V) | 55651 | (1S)-2-(3-furyl)-1-phenyl-1-ethanol | C12H12O2 | 详情 | 详情 | |
| (VI) | 52131 | 4-Fluorobenzotrifluoride; alpha,alpha-4-Tetrafluorotoluene | 402-44-8 | C7H4F4 | 详情 | 详情 |
| (VII) | 55652 | (1S)-2-(3-furyl)-1-phenylethyl 4-(trifluoromethyl)phenyl ether; 3-{(2S)-2-phenyl-2-[4-(trifluoromethyl)phenoxy]ethyl}furan | C19H15F3O2 | 详情 | 详情 | |
| (VIII) | 55653 | (3S)-3-phenyl-3-[4-(trifluoromethyl)phenoxy]propanoic acid | C16H13F3O3 | 详情 | 详情 | |
| (IX) | 55654 | (3S)-N-methyl-3-phenyl-3-[4-(trifluoromethyl)phenoxy]propanamide | C17H16F3NO2 | 详情 | 详情 |
合成路线3
The asymmetric epoxidation of (E)-3-phenyl-2-propen-1-ol (I) by means of titanium tetraisopropoxide, (+)-diethyl tartrate (+)-(DET) and tBu-OOH in dichloromethane gives the chiral epoxide (II) (1), which is opened by means of bis(2-methoxyethoxy)aluminum hydride (Red-Al) in DME to yield the chiral diol (III). The regioselective reaction of (III) with Ms-Cl and TEA in ethyl ether affords the primary mesylate (IV), which is treated with methylamine in hot THF to afford the secondary amine (V). Finally this compound is condensed with 4-(trifluoromethyl)chlorobenzene (VI) by means of NaH in dimethylacetamide to give rise to the target (S)-fluoxetine.
| 【1】 Gao, Y.; et al.; Catalytic asymmetric epoxidation and kinetic resolution: Modified procedures including in situ derivatization. J Am Chem Soc 1987, 109, 19, 5765. |
| 【2】 Gao, Y.; Sharpless, K.B.; Asymmetric synthesis of both enantiomers of tomoxetine and fluoxetine. Selective reduction of 2,3-epoxycinnamyl alcohol with Red-Al. J Org Chem 1988, 53, 17, 4081. |
| 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) | 57231 | Ethyl beta-hydroxyhydrocinnamate | C11H14O3 | 详情 | 详情 | |
| (II) | 57227 | 1-Phenyl-1,3-propanediol | C9H12O2 | 详情 | 详情 | |
| (III) | 57228 | 3-hydroxy-3-phenylpropyl 4-methylbenzenesulfonate | C16H18O4S | 详情 | 详情 | |
| (IV) | 57229 | (3S)-3-hydroxy-3-phenylpropyl 4-methylbenzenesulfonate | C16H18O4S | 详情 | 详情 | |
| (V) | 57230 | 3-oxo-3-phenylpropyl 4-methylbenzenesulfonate | C16H16O4S | 详情 | 详情 | |
| (VI) | 10008 | (1S)-3-(Methylamino)-1-phenyl-1-propanol | 114133-37-8 | C10H15NO | 详情 | 详情 |
| (VII) | 11973 | 1-Chloro-4-(trifluoromethyl)benzene; 4-Chlorobenzotrifluoride | 98-56-6 | C7H4ClF3 | 详情 | 详情 |
合成路线4
The reduction of 3-hydroxy-3-phenylpropionic acid ethyl ester (I) with LiAlH4 in THF gives 1-phenylpropane-1,3-diol (II), which is treated with Ts-Cl and TEA in dichloromethane to yield the monotosylate (III). The optical resolution of (III) by means of (Pd(OAc)2, (-)-sparteine and O2 in hot toluene yields a mixture of the desired (S)-1-phenyl-3-(tosyloxy)-1-propanol (IV) and the propiophenone (V) that is separated by column chromatography. The reaction of (IV) with methylamine in hot THF affords the chiral secondary amine (VI), which is finally condensed with 4-(trifluoromethyl)chlorobenzene (VII) by means of NaH in hot dimethylacetamide to provide the target (S)-fluoxetine.
| 【1】 Ali, I.S.; Sudalai, A.; Pd-catalyzed kinetic resolution of benzylic alcohols: A practical synthesis of (R)-tomoxetine and (S)-fluoxetine hydrochlorides. Tetrahedron Lett 2002, 43, 31, 5435. |
| 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) | 13951 | (E)-3-Phenyl-2-propen-1-ol | 104-54-1 | C9H10O | 详情 | 详情 |
| (II) | 57232 | (2R,3R)-3-Phenyl glycidol | 98819-68-2 | C9H10O2 | 详情 | 详情 |
| (III) | 57233 | (S)-1-Phenyl-1,3-propanediol; (S)-3-Phenyl-1,3-propanediol | 96854-34-1 | C9H12O2 | 详情 | 详情 |
| (IV) | 57234 | (3S)-3-hydroxy-3-phenylpropyl methanesulfonate | C10H14O4S | 详情 | 详情 | |
| (V) | 10008 | (1S)-3-(Methylamino)-1-phenyl-1-propanol | 114133-37-8 | C10H15NO | 详情 | 详情 |
| (VI) | 11973 | 1-Chloro-4-(trifluoromethyl)benzene; 4-Chlorobenzotrifluoride | 98-56-6 | C7H4ClF3 | 详情 | 详情 |