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【结 构 式】 
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【分子编号】11973 【品名】1-Chloro-4-(trifluoromethyl)benzene; 4-Chlorobenzotrifluoride 【CA登记号】98-56-6 |
【 分 子 式 】C7H4ClF3 【 分 子 量 】180.5566696 【元素组成】C 46.57% H 2.23% Cl 19.64% F 31.57% |
合成路线1
该中间体在本合成路线中的序号：(VII)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2
该中间体在本合成路线中的序号：(VI)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 |
合成路线3
该中间体在本合成路线中的序号：(VI)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4
该中间体在本合成路线中的序号：(VIII)The esterification of 3-benzoylpropionic acid (I) with methanol and sulfuric acid gives the corresponding methyl ester (II), which is regioselectively reduced with (-)-B-chlorodiisopinocampheylborane [(-)-DIP-Cl] in THF, yielding the chiral lactone (III). Ring opening of (III) with ammonia in methanol affords the chiral butyramide (IV), which is treated with iodobenzene diacetate (IBA) in acetonitrile to provide the cyclic carbamate (V). The methylation of (V) with NaH and methyl iodide in DMF gives the expected N-methyl derivative (VI), which is hydrolyzed with NaOH in refluxing ethanol to yield the chiral 3-(methylamino)-1(S)-phenyl-1-propanol (VII). Finally, this compound is condensed with 4-(trifluoromethyl)chlorobenzene (VIII) by means of NaH in DMSO. The intermediate propanol (VII) can also be obtained directly from (V), by reductive cleavage of the carbamate ring with borane/dimethyl sulfide complex in THF.
| 【1】 Senanayake, C.H.; Hilborn, J.W.; Jurgens, A.R. (Sepracor Inc.); Fluoxetine process from benzoylpropionic acid. WO 9967196 . |
| 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) | 43100 | 4-oxo-4-phenylbutyric acid; gamma-oxobenzenebutyric acid; 4-oxo-4-phenylbutyric acid; 3-Benzoylpropionic acid | 2051-95-8 | C10H10O3 | 详情 | 详情 |
| (II) | 43101 | methyl 4-oxo-4-phenylbutanoate | 25333-24-8 | C11H12O3 | 详情 | 详情 |
| (III) | 43102 | (5S)-5-phenyldihydro-2(3H)-furanone | 1008-76-0 | C10H10O2 | 详情 | 详情 |
| (IV) | 43103 | (4S)-4-hydroxy-4-phenylbutanamide | C10H13NO2 | 详情 | 详情 | |
| (V) | 43104 | (6S)-6-phenyl-1,3-oxazinan-2-one | C10H11NO2 | 详情 | 详情 | |
| (VI) | 43105 | (6S)-3-methyl-6-phenyl-1,3-oxazinan-2-one | C11H13NO2 | 详情 | 详情 | |
| (VII) | 10008 | (1S)-3-(Methylamino)-1-phenyl-1-propanol | 114133-37-8 | C10H15NO | 详情 | 详情 |
| (VIII) | 11973 | 1-Chloro-4-(trifluoromethyl)benzene; 4-Chlorobenzotrifluoride | 98-56-6 | C7H4ClF3 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(VI)The asymmetric dihydroxylation of styrene (I) by means of K3Fe(CN)6 and OsO4, catalyzed by 1,4-bis(dihydroquinin-9-O-yl)phthalazine ((DHQ)2PHAL)in tert-butanol/water gives the 1(R)-phenylethane-1,2-diol (II), which is treated with Ts-Cl and pyridine in dichloromethane to yield the monotosylate (III). The reaction of (III) with NaCN in Et-OH/water affords 3(R)-hydroxy-3-phenylpropionitrile (IV), which is reduced by means of BH3/Me2S in refluxing THF to provide the corresponding amine (V). The O-alkylation of (V) with 4-(trifluoromethyl)chlorobenzene (VI) by means of NaH in hot DMSO gives 3(R)-phenyl-3-[4(trifluoromethyl)phenoxy]propylamine (VII), which is treated with methyl chloroformate (VIII) and K2CO3 in dichloromethane to yield the carbamate (IX) Finally, this compound is reduced by means of LiAlH4 in THF to provide the target (R)-fluoxetine.
| 【1】 Pandey, R.K.; et al.; An asymmetric dihydroxylation route to enantiomerically pure norfluoxetine and fluoxetine. Tetrahedron Lett 2002, 43, 25, 4425. |
| 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) | 19649 | 1-vinylbenzene | 100-42-5 | C8H8 | 详情 | 详情 |
| (II) | 57175 | R(-)-1-Phenyl-1,2-ethanediol R(-)-Phenylethylene glycol | C8H10O2 | 详情 | 详情 | |
| (III) | 57176 | (2S)-2-hydroxy-2-phenylethyl 4-methylbenzenesulfonate | C15H16O4S | 详情 | 详情 | |
| (IV) | 57177 | (3R)-3-hydroxy-3-phenylpropanenitrile | C9H9NO | 详情 | 详情 | |
| (V) | 57178 | (1R)-3-amino-1-phenyl-1-propanol | C9H13NO | 详情 | 详情 | |
| (VI) | 11973 | 1-Chloro-4-(trifluoromethyl)benzene; 4-Chlorobenzotrifluoride | 98-56-6 | C7H4ClF3 | 详情 | 详情 |
| (VII) | 57179 | (3R)-3-phenyl-3-[4-(trifluoromethyl)phenoxy]propylamine; (3R)-3-phenyl-3-[4-(trifluoromethyl)phenoxy]-1-propanamine | C16H16F3NO | 详情 | 详情 | |
| (VIII) | 16993 | methyl chlorocarbonate;Carbonochloridic acid methyl ester；[(chlorocarbonyl)oxy]methane；methyl chloroformate | 79-22-1 | C2H3ClO2 | 详情 | 详情 |
| (IX) | 57180 | methyl (3R)-3-phenyl-3-[4-(trifluoromethyl)phenoxy]propylcarbamate | C18H18F3NO3 | 详情 | 详情 |