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【结 构 式】 
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【分子编号】13951 【品名】(E)-3-Phenyl-2-propen-1-ol 【CA登记号】104-54-1 |
【 分 子 式 】C9H10O 【 分 子 量 】134.1778 【元素组成】C 80.56% H 7.51% O 11.92% |
合成路线1
该中间体在本合成路线中的序号：(I)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), 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 condensed with 2-methylphenol (V) by means of PPh3 and DEAD in ethyl ether to provide the adduct (VI). Finally this compound is treated with methylamine in hot aq. THF to give rise to the target (R)-tomoxetine.
| 【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) | 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) | 10010 | o-Cresol | 95-48-7 | C7H8O | 详情 | 详情 |
| (VI) | 57235 | (3R)-3-(2-methylphenoxy)-3-phenylpropyl methanesulfonate | C17H20O4S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(A)Epoxidation of trans-cinnamyl alcohol (A) gives compound (I), which in turn is reacted with sodium 2-ethoxyphenate (B) to give the diol (II). The primary alcoholic group of (II) is reacted with p-nitrobenzoyl chloride to obtain (III), and (IV) is prepared by treatment of (III) with methanesulfonyl chloride. By treatment of (IV) with sodium hydroxide in an aqueous/dioxane solution the epoxide (V) is obtained in high yield, and this reaction causes inversion of configuration at C-2 carbon atom. Treatment of (V) with aqueous methanolic ammonia gives (VI), which in turn is acylated to (VII) with chloroacetyl chloride and cyclized to morpholone (VIII) with potassium tert-butoxide. The reduction to the final compound FCE-20124 is performed with [sodium bis(2-methoxyethoxy)aluminum hydride] (RED-AL) in toluene.
| 【1】 Lazzari, E.; Meroni, M.; Mazzini, G.; Melloni, P.; Della Torre, A.; Configurantional studies on 2[gamma-(2-ethoxyphenoxy)benzyl]morpholine FCE-20124. Tetrahedron 1985, 41, 7, 1393. |
| 【2】 Torre, A.D.; Carniel, G.; Rossi, A.; Melloni, P. (Pharmacia Corp.); Substituted morpholine derivatives and compositions. DE 2901032; FR 2430412; FR 2442839; GB 2014981; JP 54148739; US 4229449 . |
| 【3】 Riva, F.; FCE-20124. Drugs Fut 1985, 10, 11, 905. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (D) | 11296 | 2-Chloroacetyl chloride; Chloroacetic chloride | 79-04-9 | C2H2Cl2O | 详情 | 详情 |
| (A) | 13951 | (E)-3-Phenyl-2-propen-1-ol | 104-54-1 | C9H10O | 详情 | 详情 |
| (B) | 29768 | sodium 2-ethoxybenzenolate | C8H9NaO2 | 详情 | 详情 | |
| (I) | 29767 | [(2R,3S)-3-phenyloxiranyl]methanol | C9H10O2 | 详情 | 详情 | |
| (II) | 29769 | (2S,3S)-3-(2-ethoxyphenoxy)-3-phenyl-1,2-propanediol | C17H20O4 | 详情 | 详情 | |
| (III) | 29770 | (1S,2S)-1-(2-ethoxyphenoxy)-4-(4-nitrophenyl)-1-phenyl-2-butanol | C24H25NO5 | 详情 | 详情 | |
| (IV) | 29771 | 2-ethoxyphenyl (1S,2S)-2-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-4-(4-nitrobenzyloxy)-1-phenylbutyl ether; [[(1S)-1-[(S)-(2-ethoxyphenoxy)(phenyl)methyl]-3-(4-nitrobenzyloxy)propyl]oxy](methyl)dimethylene-lambda(6)-sulfane | C27H31NO6S | 详情 | 详情 | |
| (V) | 29772 | 2-ethoxyphenyl (S)-2-oxiranyl(phenyl)methyl ether; 2-[(S)-(2-ethoxyphenoxy)(phenyl)methyl]oxirane | C17H18O3 | 详情 | 详情 | |
| (VI) | 29773 | (1S,2S)-3-amino-1-(2-ethoxyphenoxy)-1-phenyl-2-propanol | C17H21NO3 | 详情 | 详情 | |
| (VII) | 29774 | 1-[3-[(chlorocarbonyl)amino]-2-hydroxy-1-phenylpropoxy]-2-ethoxybenzene | C18H20ClNO4 | 详情 | 详情 | |
| (VIII) | 29775 | (6R)-6-[(2-ethoxyphenoxy)(phenyl)methyl]-3-morpholinone | C19H21NO4 | 详情 | 详情 | |
| (C) | 18941 | p-nitrobenzoyl chloride; 4-nitrobenzoyl chloride | 122-04-3 | C7H4ClNO3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VIII)This compound can be obtained by three different ways: 1) The reaction of 3-nitrobenzaldehyde (I) with methyl acetoacetate (II) by means of m-toluidine in methanol gives methyl 2-(3-nitrobenzylidene)acetoacetate (III), which is then cyclized with 3-aminocrotonic acid 3-phenyl-2(E)-propenyl ester (IV) in refluxing isopropanol. 2) By cyclization of methyl 3-aminocrotonate (V) with aldehyde (I) and acetoacetic acid 3-phenyl-2(E)-propenyl ester (VI) in refluxing isopropanol. 3) By esterification of 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid monomethyl ester (VII) with 3-phenyl-2(E)-propenyl alcohol (VIII), by means of dicyclohexylcarbodiimide (DCC) in pyridine.
| 【1】 Nishitani, S.; Minamikawa, J.; Kano, M.; Otsubo, J.; Manabe, Y. (Otsuka Pharmaceutical Co., Ltd.); Process for preparing novel dihydropyridine derivs. EP 0173126 . |
| 【2】 Tamada, S.; Ei, K.; Teramoto, S.; Tanaka, T.; Nakagawa, T. (Otsuka Pharmaceutical Co., Ltd.); Dihydropyridine derivs. JP 1986140567 . |
| 【3】 Tamada, S.; Nagami, K.; Teramoto, S.; Tanaka, T.; Nakagawa, K. (Otsuka Pharmaceutical Co., Ltd.); Novel dihydropyridine derivs. and process for preparing the same. EP 0145434; ES 8604516; ES 8701726; ES 8701727; JP 1985120861; JP 1989151557; US 5034395; US 5137889 . |
| 【4】 Prous, J.; Castaner, J.; OPC-13340. Drugs Fut 1991, 16, 2, 119. |
| 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) | 12646 | 3-Nitrobenzaldehyde | 99-61-6 | C7H5NO3 | 详情 | 详情 |
| (II) | 11791 | methyl 3-oxobutanoate; Methyl acetoacetate | 105-45-3 | C5H8O3 | 详情 | 详情 |
| (III) | 12276 | methyl (Z)-2-acetyl-3-(3-nitrophenyl)-2-propenoate | C12H11NO5 | 详情 | 详情 | |
| (IV) | 13947 | (E)-3-phenyl-2-propenyl (E)-3-amino-2-butenoate | C13H15NO2 | 详情 | 详情 | |
| (V) | 11372 | Methyl (E)-3-amino-2-butenoate; Methyl 3-aminocrotonate | C5H9NO2 | 详情 | 详情 | |
| (VI) | 13949 | (E)-3-phenyl-2-propenyl 3-oxobutanoate | C13H14O3 | 详情 | 详情 | |
| (VII) | 13950 | 5-(Methoxycarbonyl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydro-3-pyridinecarboxylic acid | C16H16N2O6 | 详情 | 详情 | |
| (VIII) | 13951 | (E)-3-Phenyl-2-propen-1-ol | 104-54-1 | C9H10O | 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 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5
该中间体在本合成路线中的序号：(XX)Cyclization of the tetracarboxylic acid (XV) gives 4-oxocyclopentane-1,2-dicarboxylic acid (XVI), which is esterified with ethanol and sulfuric acid to yield the diester (XVII). Reaction of diester (XVII) with methyl-(triphenyl)phosphonium bromide and t-BuOK in THF affords 4-methylenecyclopentane-1,2-dicarboxylic acid diethyl ester (XVIII), which is hydrolyzed with KOH in THF/water to provide the corresponding free acid (XIX). The anhydrization of (XIX) by means of propionic anhydride at 135 C gives anhydride (III), which is submitted to an enantioselective quinine-mediated alcoholysis with 3-phenyl-2-propen-1-ol (XX) to yield (1R,2S)-2-amino-4-methylenecyclopentane-1-carboxylic acid 3-phenyl-2-propenyl monoester (XXI). Degradation of the free carboxylic acid group of (XXI) by means of DPPA, TEA and alcohol (XX) in hot toluene affords carbamate (XXII), which is finally fully deprotected with Pd(OAc)2 and PPh3 in ethanol.
| 【1】 Mittendorf, J.; Kunisch, F.; Matzke, M.; Militzer, H.-C.; Schmidt, A.; Schonfeld, W.; Novel antifungal beta-amino acids: Synthesis and activity against Candida albicans. Bioorg Med Chem Lett 2003, 13, 3, 433. |
| 【2】 Sorbera, L.A.; Castañer, J.; Bozzo, J.; PLD-118. Drugs Fut 2002, 27, 11, 1049. |
| 【3】 Schoenfeld, W.; Discovery, synthesis and SAR of beta-amino acid BAY 10-888/PLD-118, a novel antifungal for treatment of yeast infections. 42nd Intersci Conf Antimicrob Agents Chemother (Sept 27 2002, San Diego) 2002, Abst F-811. |
| 【4】 Mittendorf, J. (Bayer AG); Efficient and highly enantioselective process for the preparation of enantiomerically pure cyclopentane-beta-amino acids . EP 0805145 . |
| 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) | 56629 | (3aR,6aS)-5-methylenetetrahydro-1H-cyclopenta[c]furan-1,3(3aH)-dione | C8H8O3 | 详情 | 详情 | |
| (XV) | 56634 | 1,2,3,4-butanetetracarboxylic acid;1,2,3,4-Tetracarboxybutane | 1703-58-8 | C8H10O8 | 详情 | 详情 |
| (XVI) | 56635 | 4-oxo-1,2-cyclopentanedicarboxylic acid | C7H8O5 | 详情 | 详情 | |
| (XVII) | 56636 | diethyl 4-oxo-1,2-cyclopentanedicarboxylate | C11H16O5 | 详情 | 详情 | |
| (XVIII) | 56638 | diethyl 4-methylene-1,2-cyclopentanedicarboxylate | C12H18O4 | 详情 | 详情 | |
| (XIX) | 56639 | 4-methylene-1,2-cyclopentanedicarboxylic acid | C8H10O4 | 详情 | 详情 | |
| (XX) | 13951 | (E)-3-Phenyl-2-propen-1-ol | 104-54-1 | C9H10O | 详情 | 详情 |
| (XXI) | 27283 | (1S,2R)-4-methylene-2-([[(E)-3-phenyl-2-propenyl]oxy]carbonyl)cyclopentanecarboxylic acid | C17H18O4 | 详情 | 详情 | |
| (XXII) | 56637 | (E)-3-phenyl-2-propenyl (1R,2S)-4-methylene-2-{[({[(E)-3-phenyl-2-propenyl]oxy}carbonyl)amino]carbonyl}cyclopentanecarboxylate | C27H27NO5 | 详情 | 详情 |