盐酸托莫西汀.docx

1、盐酸托莫西汀 Atomoxetine hydrochloride, Tomoxetine hydrochloride, LY-1396-药物合成数据库 发布时间：2004-10-25 来源：本站整理 【药物名称】Atomoxetine hydrochloride, Tomoxetine hydrochloride, LY-139602 (+)-isomer, LY-135252(racemate), LY-139603, Strattera【化学名】(R)-(-)-N-Methyl-gamma-(2-methylphenoxy)benzenepropanamine hydrochloride;

2、 (R)-(-)-N-Methyl-3-phenyl-3-(2-methylphenoxy)propylamine hydrochloride【CAS登记号】82248-59-7, 83015-26-3 (free base)【结构式】【分子式】C17-H21-N-O.Cl-H【分子量】291.8198【原研厂家】Lilly (Originator)【作用类别】Antidepressants, Attention Deficit Hyperactivity Disorder (ADHD), Treatment of, Autism, Treatment of, Mood Disorders,

3、Treatment of, PSYCHOPHARMACOLOGIC DRUGS, Norepinephrine Reuptake Inhibitors【研发状态】Launched-2003【合成情况】来源Tetrahedron Lett合成路线标题A new chemoenzymatic enantioselective synthesis of R-(-)-tomoxetine, (R)-fluoxetine and (S)-fluoxetine合成方法A new synthesis for tomoxetine hydrochloride has been reported: The re

4、duction 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)

5、. 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

6、protected final product (VIII), which is finally deprotected with dry HCl in methanol.作者Dike, S.Y.; Kumar, A.; Ner, D.H.参考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出处Tet

7、rahedron Lett1991,32,(16):1901备注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-phenylpr

8、opionic 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

9、 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.来源Drugs Fut合成路线标题Tomoxetine hydrochloride合成方法N,N-Dimethyl 3-phenyl-3-(o-tolyloxy)propylamine (I) is allowed to r

10、eact 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 with L-mandelic acid and Na2CO3 in water to yield the corresponding (-)

11、-mandelate salt as a precipitate, which is finally treated with Na2CO3, extracted with ether and acidified with HCl (I).作者Casta馿r, J.; Prous, J.参考Casta馿r, J.; Prous, J.; Tomoxetine hydrochloride. Drugs Fut 1986, 11, 2, 134出处Drugs Fut1986,11,(2):134备注Synthesis of 090043: N,N-Dimethyl 3-phenyl-3-(o-to

12、lyloxy)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 with L- mandelic acid and Na2CO3 i

13、n 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?来源J Chem Soc - Perkins Trans I合成路线标题Chemoenzymatic synthesis

14、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 (II), which is treated with butyric anhydride and pyridine in dichlo

15、romethane 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-met

16、hylphenol (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.作者Anthonsen, T.; Ho, B.H.; Liu, H.L.参考Anthonsen, T.; Ho, B.H.; Liu, H.L.; Chemoenzymatic synthesis of the non-tricyclic antidep

17、ressants fluoxetine, tomoxetine and nisoxetine. J Chem Soc - Perkins Trans I 2000, 11, 11, 1767出处J Chem Soc - Perkins Trans I2000,11,(11):1767备注来源Tetrahedron Lett合成路线标题Pd-catalyzed kinetic resolution of benzylic alcohols: A practical synthesis of (R)-tomoxetine and (S)-fluoxetine hydrochlorides合成方法T

18、he 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

19、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 P

20、Ph3 and DEAD in ethyl ether to provide the target (R)-tomoxetine.作者Ali, I.S.; Sudalai, A.参考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出处Tetrahedron Lett200

21、2,43,(31):5435备注来源J Org Chem合成路线标题Asymmetric synthesis of both enantiomers of tomoxetine and fluoxetine. Selective reduction of 2,3-epoxycinnamyl alcohol with Red-Al合成方法The asymmetric epoxidation of (E)-3-phenyl-2-propen-1-ol (I) by means of titanium tetraisopropoxide, (+)-diethyl tartrate (+)-(DET)

22、 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

23、 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.作者Gao, Y.; Sharpless, K.B.参考Gao, Y.; Sharpless, K.B.; Asymmetric synthesis of both enantiomers of t

24、omoxetine and fluoxetine. Selective reduction of 2,3-epoxycinnamyl alcohol with Red-Al. J Org Chem 1988, 53, 17, 4081出处J Org Chem1988,53,(17):4081备注来源J Am Chem Soc合成路线标题Catalytic asymmetric epoxidation and kinetic resolution: Modified procedures including in situ derivatization合成方法The asymmetric epo

25、xidation 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 regiose

26、lective 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 (

27、R)-tomoxetine.作者Gao, Y.; et al.参考Gao, Y.; et al.; Catalytic asymmetric epoxidation and kinetic resolution: Modified procedures including in situ derivatization. J Am Chem Soc 1987, 109, 19, 5765出处J Am Chem Soc1987,109,(19):5765备注来源EP 0052492合成路线标题3-Aryl-3-phenylpropylamines合成方法N,N-Dimethyl 3-phenyl-

28、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 with L-mandelic acid and N

29、a2CO3 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).作者Foster, B.J.; Lavagnino, E.R. (Eli Lilly and Company)参考Foster, B.J.; Lavagnino, E.R. (Eli Lilly and Company); 3-Aryl-3-phenylpropylam

30、ines. EP 0052492 出处EP 0052492,():备注Synthesis 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 propylene

31、glycol- 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). (Scheme 09004302a) Description Mp. 166-8? alpha20,D= -37.6? alpha25,365= -181.3?