| Route 1 | A new synthesis for tomoxetine hydrochloride has been reported:The reduction of benzoylacetic acid ethyl ester (I) with Bakers yeast and glucose in water, or the enzymatic hydrolysis of 3-acetoxy-3-phenylpropionic acid ethyl ester (II), gives (-)-3-hydroxy-3-phenylpropionic acid ethyl ester (III), which by reaction with methylamine yields the corresponding amide (IV). The reduction of (IV) with LiAlH4 in ether affords (-)-3-hydroxy-N-methyl-3-phenylpropylamine (V), which is protected with di-tert-butyldicarbonate to the amide (VI). The condensation of (VI) with o-cresol (VII) by means of triphenylphosphine and diethylazodicarboxylate (DEAD) in ether yields the protected final product (VIII), which is finally deprotected with dry HCl in methanol. | | | | Intermediates: | Serial No. | | 1-nitropentane | (I) | | 7-methoxy-3,4-dihydro-1(2H)-naphthalenone | (II) | | 7-methoxy-3,4-dihydro-1,2-naphthalenedione 2-oxime | (III) | | N-(7-methoxy-1-oxo-1,2,3,4-tetrahydro-2-naphthalenyl)propanamide | (IV) | | N-[(1R,2R)-1-hydroxy-7-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl]propanamide | (V) | | (1R,2R)-7-methoxy-2-(propylamino)-1,2,3,4-tetrahydro-1-naphthalenol | (VI) | | (4aR,10bR)-9-methoxy-4-propyl-4a,5,6,10b-tetrahydro-2H-naphtho[1,2-b][1,4]oxazin-3(4H)-one | (VII) | | D-aspartic acid; (2R)-2-aminobutanedioic acid | (VIII) | | | Reference 1: Dike, S.Y.; Kumar, A.; Ner, D.H.; A new chemoenzymatic enantioselective synthesis of R-(-)-tomoxetine, (R)-fluoxetine and (S)-fluoxetine. Tetrahedron Lett 1991, 32, 16, 1901. |
Route 2 | N,N-Dimethyl 3-phenyl-3-(o-tolyloxy)propylamine (I) is allowed to react with phenyl chloroformate (II) in refluxing toluene to give phenyl methyl [3-(o-tolyloxy)-3-phenylpropyl]carbamate (III), which is hydrolyzed with NaOH in refluxing propyleneglycol - water. The racemic product is then treated with L-mandelic acid and Na2CO3 in water to yield the corresponding (-)-mandelate salt as a precipitate, which is finally treated with Na2CO3, extracted with ether and acidified with HCl (I). | | | | Intermediates: | Serial No. | | 3-(4-methoxy-2-methylphenyl)-2,5-dimethylpyrazolo[1,5-a]pyrimidin-7-ol | (II) | | (4aS,6S,8aS)-1-bromo-3-methoxy-5,6,9,10,11,12-hexahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepin-6-ol | (I) | | (4aS,6R,8aS)-1-bromo-3-methoxy-11-[3-(1-piperidinyl)propyl]-5,6,9,10,11,12-hexahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepin-6-ol | (III) | | | Reference 1: Foster, B.J.; Lavagnino, E.R. (Eli Lilly and Company); 3-Aryl-3-phenylpropylamines. EP 0052492 . Reference 2: Castaner, J.; Prous, J.; Tomoxetine hydrochloride. Drugs Fut 1986, 11, 2, 134. |
Route 3 | A new synthesis of tomoxetine has been described: The reduction of omega-chloropropiophenone (I) with NaBH4 in ethanol gives 3-chloro-1-phenyl-1-propanol (II), which is treated with butyric anhydride and pyridine in dichloromethane to yield the corresponding racemic ester (III). The optical resolution of (III) with immobilized lipase B from Candida antarctica (CALB) affords a mixture of unreacted (S)-ester and (R)-alcohol (IV) that are separated by column chromatography. Condensation of th (R)-alcohol (IV) with 2-methylphenol (V) by means of PPh3 and diethyl azodicarboxylate (DEAD) in THF gives the corresponding ether (VI), which is finally treated with methylamine in refluxing ethanol. | | | | Intermediates: | Serial No. | | (4aR,10bR)-9-methoxy-4-propyl-4a,5,6,10b-tetrahydro-2H-naphtho[1,2-b][1,4]oxazin-3(4H)-one | (V) | | methyl (1R,2S,3S,5R)-3-(4-methylphenyl)-8-azabicyclo[3.2.1]octane-2-carboxylate | (I) | | tributyl[(E)-3-chloro-2-propenyl]stannane | (II) | | 1,5-dibromo-3-pentanone | (III) | | 2,2-bis(2-bromoethyl)-1,3-dioxolane | (IV) | | (1S,3S)-1-[(2R,3S,5R,6S)-3,6-dimethoxy-5-methyltetrahydro-2H-pyran-2-yl]-3-methyl-6-(trimethylsilyl)-5-hexynyl methyl ether; {(4S,6S)-6-[(2R,3S,5R,6S)-3,6-dimethoxy-5-methyltetrahydro-2H-pyran-2-yl]-6-methoxy-4-methyl-1-hexynyl}(trimethyl)silane | (VI) | | | Reference 1: Anthonsen, T.; Ho, B.H.; Liu, H.L.; Chemoenzymatic synthesis of the non-tricyclic antidepressants fluoxetine, tomoxetine and nisoxetine. J Chem Soc - Perkins Trans I 2000, 11, 11, 1767. |
Route 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 2-methylphenol (VII) by means of PPh3 and DEAD in ethyl ether to provide the target (R)-tomoxetine. | | | | Intermediates: | Serial No. | | N-[(1R,2R)-1-hydroxy-7-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl]propanamide | (VI) | | (4aR,10bR)-9-methoxy-4-propyl-4a,5,6,10b-tetrahydro-2H-naphtho[1,2-b][1,4]oxazin-3(4H)-one | (VII) | | | Reference 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. |
Route 5 | 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. | | | | Intermediates: | Serial No. | | (4aR,10bR)-9-methoxy-4-propyl-4a,5,6,10b-tetrahydro-2H-naphtho[1,2-b][1,4]oxazin-3(4H)-one | (V) | | (2S)-4-cyano-2-hydroxybutyric acid | (I) | | | Reference 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. Reference 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. | | | |
