1、? Atomoxetine hydrochloride, Tomoxetine hydrochloride,LY-1396-藥物合成數(shù)據(jù)庫(kù)? 發(fā)布時(shí)間：2004-10-25 來源：本站整理【藥物名稱】Atomoxetine hydrochloride, Tomoxetine hydrochloride, LY-139602 (+)-isomer,LY-135252(racemate), LY-139603, Strattera【化學(xué)名】(R)-(-)-N-Methyl-gamma-(2-methylphenoxy)benzenepropanamine hydrochloride;(R)-(-)

2、-N-Methyl-3-phenyl-3-(2-methylphenoxy)propylamine hydrochloride【CAS登記號(hào)】82248-59-7, 83015-26-3 (free base)【結(jié)構(gòu)式】【分子式】C17-H21-N-O.Cl-H【分子量】291.8198【原研廠家】Lilly (Originator)【作用類別】Antidepressants, Attention Deficit Hyperactivity Disorder (ADHD), Treatment of, Autism, Treatment of,Mood Disorders, Treatment

3、 of, PSYCHOPHARMACOLOGIC DRUGS, Norepinephrine Reuptake Inhibitors【研發(fā)狀態(tài)】Launched-2003【合成情況】Tetrahedron Lett合成路線Sifthesis of TomoMeiine hordroehlorideBuOCCDp噸 OLAD沁丿 Mil)標(biāo)題A new chemoenzymatic enantioselective synthesis of R-(-)-tomoxetine, (R)-fluoxetine and(S)-fluoxetine合成方法A new synthesis for tomo

4、xetine hydrochloride has been reported: The reduction of benzoylacetic acid ethyl ester (I) with Baker's yeast and glucose in water, or the enzymatic hydrolysis of3-acetoxy-3-phenylpropionic acid ethyl ester (II), gives (-)-3-hydroxy-3-phenylpropionic acid ethyl ester (III), which by reaction wi

5、th methylamine yields the corresponding amide (IV). The reduction of(IV) with LiAIH4 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 di

6、ethylazodicarboxylate (DEAD) in ether yields the protected final product(VIII), which is finally deprotected with dry HCl in methanol.Dike, S.Y.; Kumar, A.; Ner, D.H.Dike, S.Y.; Kumar, A.; Ner, D.H.; A new chemoenzymatic enantioselective synthesis ofR-(-)-tomoxetine, (R)-fluoxetine and (S)-fluoxetin

7、e. Tetrahedron Lett 1991, 32, 16, 1901Tetrahedron Lett1991,32,(16):1901A 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 of3-acetoxy-3-phenylpropionic acid ethyl

8、 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

9、 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.來源Drugs Fut合成路線標(biāo)題Tomoxetine hydrochloride合成方法N,N-Dimethyl 3-phenyl-3-(o

10、-tolyloxy)propylamine (I) is allowed to react with phenyl chloroformate (II) in refluxing toluene to give phenyl methyl 3-(o-tolyloxy)-3-phenylpropylcarbamate (III), which is hydrolyzed with NaOH in refluxing propyleneglycol - water. The racemic product is then treated withL-mandelic acid and Na2CO3

11、 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).Casta 馿 r, J.; Prous, J.Casta 馿 r, J.; Prous, J.; Tomoxetine hydrochloride. Drugs Fut 1986, 11, 2, 134出處Drugs Fut1986,11,(2):134備注Synthesis

12、of 090043: 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-phenylpropylcarbamate (III), which is hydrolyzed with NaOH in refluxing propyleneglycol- water. The racemic product is then tr

13、eated 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). (Scheme 09004302a) Description Mp. 166-8? alpha20,D= -37.6? alpha25,365= -181.3?來源J Chem Soc - Perkin

14、s Trans I合成路線Synttieeifi of lomouetineCALB標(biāo)題Chemoenzymatic synthesis of the non-tricyclic antidepressants fluoxetine, tomoxetine and nisoxetine合成方法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

15、 (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 c

16、olumn chromatography. Condensation of th(R)-alcohol (IV) with 2-methylphenol (V) by means of PPh3 and diethyl azodicarboxylate (DEAD) inTHF gives the corresponding ether (VI), which is finally treated with methylamine in refluxing ethanol.Anthonsen, T.; Ho, B.H.; Liu, H.L.參考Anthonsen, T.; Ho, B.H.;

17、Liu, H.L.; Chemoenzymatic synthesis of the non-tricyclic antidepressants fluoxetine, tomoxetine and nisoxetine. J Chem Soc - Perkins Trans I 2000, 11, 11, 1767J Chem Soc - Perkins Trans 12000,11,(11):1767Tetrahedron Lett合成路線OM OOH標(biāo)題Pd-catalyzed kinetic resolution of benzylic alcohols: A practical sy

18、nthesis of (R)-tomoxetine and(S)-fluoxetine hydrochlorides合成方法The reduction of 3-hydroxy-3-phenylpropionic acid ethyl ester (I) with LiAlH4 in THF gives1- phenylpropane-1,3-diol (II), which is treated with Ts-Cl and TEA in dichloromethane to yield the monotosylate (III). The optical resolution of (I

19、II) by means of (Pd(OAc)2, (-)-sparteine and 02 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), whi

20、ch is finally condensed with2- methylphenol (VII) by means of PPh3 and DEAD in ethyl ether to provide the target (R)-tomoxetine.Ali, I.S.; Sudalai, A.Ali, I.S.; Sudalai, A.; Pd-catalyzed kinetic resolution of benzylic alcohols: A practical synthesis of(R)-tomoxetine and (S)-fluoxetine hydrochlorides

21、. Tetrahedron Lett 2002, 43, 31, 5435Tetrahedron Lett2002,43,(31):5435來源J Org Chem合成路線(W)標(biāo)題Asymmetric synthesis of both enantiomers of tomoxetine and fluoxetine. Selective reduction of2,3-epoxycinnamyl alcohol with Red-AI合成方法The asymmetric epoxidation of (E)-3-phenyl-2-propen-1-ol (I) by means of ti

22、tanium 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

23、 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.Gao, Y.; Sharpless, K.B.Gao, Y.; Sharpless, K.

24、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, 4081J Org Chem1988,53,(17):4081J Am Chem Soc合成路線Ti(ipg)+(D(+>DETRed-AI(W)OH標(biāo)題Catalytic asymmetric epoxidation and kinetic resolution: Mo

25、dified procedures including in situ derivatization合成方法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)alumi

26、num 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

27、 treated with methylamine in hot aq. THF to give rise to the target (R)-tomoxetine.Gao, Y.; et al.參考Gao, Y.; et al.; Catalytic asymmetric epoxidation and kinetic resolution: Modified procedures including in situ derivatization. J Am Chem Soc 1987, 109, 19, 5765出處J Am Chem Soc1987,109,(19):5765EP 005

28、2492合成路線標(biāo)題3- Aryl-3-phenylpropylamines合成方法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-phenylpropylcarbamate (III), which is hydrolyzed with NaOH in refluxing propyleneglycol - water. The racemic product is then treated