鹽酸托莫西汀

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, treatm

3、ent of, psychopharmacologic drugs, norepinephrine reuptake inhibitors【研發(fā)狀態(tài)】launched-2003【合成情況】來源tetrahedron lett合成路線標(biāo)題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 reductio

4、n 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

5、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 protec

6、ted final product (viii), which is finally deprotected with dry hcl in methanol.作者dike, s.y.; kumar, a.; ner, d.h.參考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出處tetrahedr

7、on lett1991,32,(16):1901備注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-phenylpropioni

8、c 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-cre

9、sol (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-tolyloxy)propylamine (i) is allowed to react w

10、ith 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 (-)-mande

11、late 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.參考casta馿r, j.; prous, j.; tomoxetine hydrochloride. drugs fut 1986, 11, 2, 134出處drugs fut1986,11,(2):134備注synthesis of 090043: n,n-dimethyl 3-phenyl-3-(o-tolyloxy

12、)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 in wate

13、r 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 - perkins trans i合成路線標(biāo)題chemoenzymatic synthesis of the

14、 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 dichlorometh

15、ane 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-methylphe

16、nol (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.參考anthonsen, t.; ho, b.h.; liu, h.l.; chemoenzymatic synthesis of the non-tricyclic antidepressan

17、ts fluoxetine, tomoxetine and nisoxetine. j chem soc - perkins trans i 2000, 11, 11, 1767出處j chem soc - perkins trans i2000,11,(11):1767備注來源tetrahedron lett合成路線標(biāo)題pd-catalyzed kinetic resolution of benzylic alcohols: a practical synthesis of (r)-tomoxetine and (s)-fluoxetine hydrochlorides合成方法the red

18、uction 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

19、 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 an

20、d dead in ethyl ether to provide the target (r)-tomoxetine.作者ali, i.s.; sudalai, a.參考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出處tetrahedron lett2002,43,(

21、31):5435備注來源j org chem合成路線標(biāo)題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) and t

22、bu-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

23、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.參考gao, y.; sharpless, k.b.; asymmetric synthesis of both enantiomers of tomoxet

24、ine and fluoxetine. selective reduction of 2,3-epoxycinnamyl alcohol with red-al. j org chem 1988, 53, 17, 4081出處j org chem1988,53,(17):4081備注來源j am chem soc合成路線標(biāo)題catalytic asymmetric epoxidation and kinetic resolution: modified procedures including in situ derivatization合成方法the asymmetric epoxidati

25、on 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 regioselectiv

26、e 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)-tom

27、oxetine.作者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):5765備注來源ep 0052492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 with l-mandelic aci