【结 构 式】 |
【药物名称】Atomoxetine hydrochloride, Tomoxetine hydrochloride, LY-139602 [(+)-isomer], LY-135252(racemate), LY-139603, Strattera 【化学名称】(R)-(-)-N-Methyl-gamma-(2-methylphenoxy)benzenepropanamine hydrochloride 【CA登记号】82248-59-7, 83015-26-3 (free base) 【 分 子 式 】C17H22ClNO 【 分 子 量 】291.82399 |
【开发单位】Lilly (Originator) 【药理作用】Antidepressants, Attention Deficit Hyperactivity Disorder (ADHD), Treatment of, Autism, Treatment of, Mood Disorders, Treatment of, PSYCHOPHARMACOLOGIC DRUGS, Norepinephrine Reuptake Inhibitors |
合成路线1
【1】 Trost BM, Fraisse PL, Bcrll ZT. 2002.A stereospeafic rutheniunrcatalyzed allylic alkylation, Angew Chem Int Ed, 41:; 1059~1061 |
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) | 66125 | (1S,2R)-2-(methylamino)-1-phenylpropan-1-ol | 321-98-2 | C10H15NO | 详情 | 详情 |
(II) | 66126 | (1S)-phenylprop-2-en-1-ol | C9H10O | 详情 | 详情 | |
(III) | 66127 | (S)-tert-butyl (1-phenylallyl) carbonate | C14H18O3 | 详情 | 详情 | |
(IV) | 66128 | (S)-1-methyl-2-((1-phenylallyl)oxy)benzene | C16H16O | 详情 | 详情 | |
(V) | 66129 | (S)-3-phenyl-3-(o-tolyloxy)propan-1-ol | C16H18O2 | 详情 | 详情 |
合成路线2
【1】 Clark EP, Michael RA, Otto WL 2000.Stereospecific method for preparing tomoxetine and intermeduite,thereof. W0 2000058262 |
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) | 36679 | 2-fluorobenzaldehyde | 446-52-6 | C7H5FO | 详情 | 详情 |
(II) | 66130 | (E)-1-(3,3-dimethylbut-1-en-1-yl)-2-fluorobenzene | C12H15F | 详情 | 详情 | |
(III) | 66131 | (R)-4-methyl-1-phenylpentan-1-ol | C12H18O | 详情 | 详情 | |
(IV) | 66132 | (S,E)-3-(2-(3,3-dimethylbut-1-en-1-yl)phenoxy)-N,N-dimethyl-3-phenylpropan-1-amine | C23H31NO | 详情 | 详情 | |
(V) | 66133 | (S)-2-(3-(dimethylamino)-1-phenylpropoxy)benzaldehyde | C18H21NO2 | 详情 | 详情 | |
(VI) | 66134 | (R)-(2-(3-(dimethylamino)-1-phenylpropoxy)phenyl)methanol | C18H23NO2 | 详情 | 详情 |
合成路线3
【1】 Brown HC 1989. Novel process of producing phenyl or substituted phenylalkylanune pharmaceutical agents and novel chiral intermediatesof high enantiomeric purity useful therein US 4868344 |
合成路线4
【1】 Kumar A, Ner DH, Dike SY. 1991.A new chemoenzjrnutic enantioselective synthesis of R-(?)-tomoxe-One, (R)- and (S)-fluoxetine. Tetnhedron Lett, 32r 1901~1904 |
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) | 10006 | Ethyl (3S)-3-hydroxy-3-phenylpropanoate; (-)-Ethyl (S)-3-hydroxy-3-phenylpropionate | 33401-74-0 | C11H14O3 | 详情 | 详情 |
(II) | 10007 | (3S)-3-Hydroxy-N-methyl-3-phenylpropanamide | C10H13NO2 | 详情 | 详情 | |
(III) | 10008 | (1S)-3-(Methylamino)-1-phenyl-1-propanol | 114133-37-8 | C10H15NO | 详情 | 详情 |
(IV) | 10009 | tert-Butyl N-[(3S)-3-hydroxy-3-phenylpropyl]-N-methylcarbamate | C15H23NO3 | 详情 | 详情 | |
(V) | 10011 | tert-Butyl N-methyl-N-[(3R,4E,6Z)-3-(2-methylphenoxy)-4-vinyl-4,6-octadienyl]carbamate | C22H29NO3 | 详情 | 详情 |
合成路线5
【1】 Srebnik M, Ramachandran PV, Brown HC 1988. Chinl synthesis via organoboranes 18. Selective reductions 43. Diisopinocampheylchloroborane as an excellent chinl reducing reagent for the synthesis of halo alcohols of lugh enantiomeric purity. A highly enantioselective synthesis of both opticaJ isamers of Tomoxetine, Fluoxetine, and Nisoxetine. J O:rg Chem, 53s 2916~2920 |
合成路线6
A new synthesis for tomoxetine hydrochloride has been reported: The reduction of benzoylacetic acid ethyl ester (I) with Baker's 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.
【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. |
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) | 10004 | Ethyl 3-oxo-3-phenylpropanoate; Benzoylacetic acid, ethyl ester | 94-02-0 | C11H12O3 | 详情 | 详情 |
(II) | 10005 | Ethyl 3-(acetoxy)-3-phenylpropanoate | C13H16O4 | 详情 | 详情 | |
(III) | 10006 | Ethyl (3S)-3-hydroxy-3-phenylpropanoate; (-)-Ethyl (S)-3-hydroxy-3-phenylpropionate | 33401-74-0 | C11H14O3 | 详情 | 详情 |
(IV) | 10007 | (3S)-3-Hydroxy-N-methyl-3-phenylpropanamide | C10H13NO2 | 详情 | 详情 | |
(V) | 10008 | (1S)-3-(Methylamino)-1-phenyl-1-propanol | 114133-37-8 | C10H15NO | 详情 | 详情 |
(VI) | 10009 | tert-Butyl N-[(3S)-3-hydroxy-3-phenylpropyl]-N-methylcarbamate | C15H23NO3 | 详情 | 详情 | |
(VII) | 10010 | o-Cresol | 95-48-7 | C7H8O | 详情 | 详情 |
(VIII) | 10011 | tert-Butyl N-methyl-N-[(3R,4E,6Z)-3-(2-methylphenoxy)-4-vinyl-4,6-octadienyl]carbamate | C22H29NO3 | 详情 | 详情 |
合成路线7
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).
【1】 Foster, B.J.; Lavagnino, E.R. (Eli Lilly and Company); 3-Aryl-3-phenylpropylamines. EP 0052492 . |
【2】 Castaner, J.; Prous, J.; Tomoxetine hydrochloride. Drugs Fut 1986, 11, 2, 134. |
合成路线8
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.
【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. |
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) | 28073 | 3-chloro-1-phenyl-1-propanone | 936-59-4 | C9H9ClO | 详情 | 详情 |
(II) | 28074 | 3-chloro-1-phenyl-1-propanol | C9H11ClO | 详情 | 详情 | |
(III) | 37781 | 3-chloro-1-phenylpropyl butyrate | C13H17ClO2 | 详情 | 详情 | |
(IV) | 37782 | (1R)-3-chloro-1-phenyl-1-propanol | C9H11ClO | 详情 | 详情 | |
(V) | 10010 | o-Cresol | 95-48-7 | C7H8O | 详情 | 详情 |
(VI) | 44328 | (1R)-3-chloro-1-phenylpropyl 2-methylphenyl ether; 1-[[(1R)-3-chloro-1-phenylpropyl]oxy]-2-methylbenzene | 114446-47-8 | C16H17ClO | 详情 | 详情 |
合成路线9
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.
【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) | 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) | 10010 | o-Cresol | 95-48-7 | C7H8O | 详情 | 详情 |
合成路线10
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 |