合成路线1

1) By condensation of benzhydryl (6R,7R)-7-amino-7-methoxy-3-[[(1-methyl-1H-1,2,3,4-tetraazol-5-yl)sulfanyl]methyl]-8-oxo-5-oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (XXIV) with alpha-diphenylmethoxycarbonyl-alpha-(p-hydroxyphenyl)acetic acid (XXVa) by means of Et3N and oxalyl chloride in methylene chloride gives the 7-[alpha-diphenylmethoxycarbonyl-alpha-(p-hydroxyphenyl)acetamido]-7alpha-methoxy compound (XXVIa). Finally, all the protecting groups of (XXVIa) are eliminated by treatment with trifluoroacetic acid in anisole. 2) Compound (XXIV) can also be condensed with alpha-(p-benzyloxyphenyl)malonic acid monobenzyl ester (XXVb) by means of Et3N and oxalyl chloride in methylene chloride yielding the 7beta-[alpha-(p-benzyloxyphenyl)-alpha-benzyloxycarbonylacetamido]-7alpha-methoxy compound (XXVIb), which is hydrolyzed with trifluoroacetic acid in anisole. 3) Compound (XXIV) can also be condensed with alpha-(p-methoxybenzyl)oxycarbonyl-alpha-[p-(p-methoxybenzyl)oxyphenylacetic acid (XXVc) by means of Et3N and oxalyl chloride in methylene chloride giving the corresponding derivative (XXVIc), which can be hydrolyzed with trifluoroacetic acid in anisole. 4) Finally, compound (XXIV) can also be condensed with p-(p-methoxybenzyloxy)phenylmalonic acid (XXVd) by means of Et3N and oxalyl chloride in methylene chloride affording compound (XXVId), which is hydrolyzed with trifluoroacetic in anisole. 5) Compound (XXIV) can also be condensed with alpha-diphenylmethoxycarbonyl-p-(p-methoxybenzyl)oxyphenylacetic acid (XXVe) by means of Et3N and oxalyl chloride in methylene chloride affording the corresponding derivative (XXVIe), which is hydrolyzed with trifluoroacetic acid in anisole.

合成路线2

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.

合成路线3

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, yielding 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), which are separated by column chromatography. The condensation of alcohol (IV) with 4-(trifluoromethyl)phenol (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.

合成路线4

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 yielding 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. The condensation of alcohol (IV) with 2-methoxyphenol (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.

合成路线5

In a different route, hydrogenation of (R)-3-chloro-1-phenyl-1-propanol (XV) over Rh/Al2O3 gave the cyclohexyl carbinol (XVI), which was protected as the ethoxyethyl ether (XVII) by treatment with ethyl vinyl ether in the presence of pyridinium tosylate. Lithiation of chloride (XVII), followed by exchange with lithium (2-thienyl)cyanocuprate, generated the organocuprate reagent (XVIII), which produced a conjugate addition to enone (XIX) to afford the methylene ketone (XX). Protecting group exchange in (XX) was effected by acidic cleavage of the ethoxyethyl group, followed by silylation with t-butyldimethylsilyl triflate, yielding the bis-silylated compound (XXI). The Z-vinylstannane reagent (XXII) was subjected to a stereospecific transmetalation with Me2Cu(CN)Li2 and the resulting cuprate underwent conjugate addition to enone (XXI) yielding adduct (XXIII). Reduction of ketone (XXIII) with L-Selectride®, followed by acidic cleavage of the ethoxyethyl group, provided diol (XXIV). Alkylation of (XXIV) with tert-butyl bromoacetate (X), followed by transterification as above, furnished the isopropyl ester (XXV). The remaining hydroxyl group of (XXV) was subsequently exchanged by a chloride (XXVI) via the corresponding mesylate. Finally, desilylation of (XXVI) with HF in THF gave rise to the title compound.

合成路线6

合成路线7