Fluoxetine intermediates

Chaubey A, Parshad R, Koul S et ed. (2006) Enantioselectivity modulation through immobilization of Arthrobacter sp. Upase kinetic resolution of fluoxetine intermediate. J Mol Catal B Enzym 42 39 4... 

Section B shows some Hofmann rearrangements. Entry 9, using basic conditions with bromine, provided an inexpensive route to an intermediate for a commercial synthesis of an herbicide. Entry 10, which uses the Pb(OAc)4 conditions (see p. 949), was utilized in an enantiospecific synthesis of the naturally occurring analagesic (-)-epibatidine. Entry 11 uses phenyliodonium diacetate as the reagent. The product is the result of cyclization of the intermediate isocyanate and was used in an enantioselective synthesis of the antianxiety drug (tf)-fluoxetine. 

The clinical and commercial success of the antidepressant compound fluoxetine (Chapter 2 Prozac) engendered considerable work in other laboratories. A benzo-dioxan based compound that shows similar activity shares only a few stmctural features with the prototype. The benzodioxan nucleus (68-3) is formed by an alkylation reaction between the fluorocatechol (68-1) and the derivative (68-2) from meso, and hence achiral, butanetetrol. The benzyl protecting groups are then removed by hydrogenation over palladium, and the thus-obtained diol is converted to the fiii-toluene-sulfonate (68-4) by reaction with toluenesulfonyl chloride. Treatment of that intermediate with benzylamine leads to fiw-alkylation on the same nitrogen to form a pyrrolidine ring and thus the tricyclic compound (68-5). A second hydrogenolysis step then leads to fluparoxan (68-6) [70]. 

The procedure for getting the polymer-bound ligands is very easy to reproduce. Three jS-functionalized aromatic ketones were successfully reduced to the corresponding alcohols by heterogeneous asymmetric hydrogen transfer reaction with formic acid-triethylamine azeotrope as the hydrogen donor. One of the product alcohols (19c) is an intermediate for the synthesis of optically active fluoxetine. 

Subsequent reduction of the prochiral ketone with diborane in THF and chlorination of the resulting secondary alcohol 9 provided a reactive benzylic chloride that underwent subsequent nucleophilic displacement with 4-trifluoromethylphenoxide to give 10. Von Braun degradation of the V,V-dimethyl amine in 10, via the V-cyano intermediate 11, gave racemic fluoxetine (4). 

It is obvious that the choice between nucleophilic and electrophilic substitution must be mechanistically made but this is generally true of the choice of all disconnections, synthons and reagents. The formation of 31 was easy because the aryl chloride was activated by three groups. In the synthesis of fluoxetine (Prozac), a rather widely taken anti-depressant, aryl ether 34 is an essential intermediate.6 Though disconnection b looks attractive, as a simple Sn2 reaction should work well, disconnection a was preferred because 34 must be a single enantiomer and enantiomerically pure alcohol 36 was available. 

In a randomized, placebo-controlled trial, sudden withdrawal of paroxetine produced significant withdrawal symptoms by as early as the second day, while patients taking fluoxetine remained asymptomatic for the five-day withdrawal period (79). Patients taking sertraline had an intermediate level of abstinence symptoms. Both paroxetine- and sertraline-treated patients reported impaired... 

The antidepressant compound lubazodone (8) illustrates the breadth of the structural requirements for serotonin selective reuptake inhibitors the structure of this agent departs markedly from that of fluoxetine, the first drug in this class. The compound at hand also exemplifies the current trend for preparing drugs in chiral form. Thus reaction of the indanol (6) with the mesylate from chiral glycidic oxide in the presence of base leads to the epoxypropyl ether (7) with retention of chirality. Treatment intermediate 7 with aminoethylsulfonic acid closes the morpholine ring. Product 8 consists of pure (5) enantiomer. ... 

In their role as enantioselective catalysts for the reduction of prochiral ketones, chiral oxazaborolidines have been used for the preparation of prostaglandins, PAF antagonists, a key intermediate of ginkgolide B, bilobalide, a key intermediate of forskolin, (/ )- and (S)-fluoxetine, (R)- and (S)-isopreterenol, vitamin D analogs, the carbonic anhydrase inhibitor the dopamine D1 agonist A-77636, ... 

Problem 20.9 What reagent is needed to reduce A to B, an intermediate in the synthesis of the antidepressant (R)-fluoxetine (trade name Prozac) ... 

Asymmetric reduction of or y-functionalized alkyl aryl ketones provides a wide variety of chiral amino alcohols. Commercial -chloropropiophenone is reduced with borane-tetrahydrofuran adduct catalyzed by oxazaborolidine 45 to provide the chlorohydrin in over 99 % yield with 94 % ee. The resulting alcohol is a key intermediate for synthesis of the R form of fluoxetine (Prozac ), a serotonin-uptake inhibitor [53]. Using hydrogenation processes the functionalized amino ketones are converted directly into the respective products [8, 43e],... 

Finally, the asymmetric arylation of 60 has also been reported, although the yields and ee s are more modest (Scheme 15) [53]. Hydrolysis of the product 61 conveniently gives the 1,3-diol 62, an intermediate in the Sharpless synthesis of fluoxetine [54]. 

The potency of sertraline and its N-demethylated metabolite, desmethylsertraline, and paroxetine for inhibiting P-gp was comparable with that of quinidine (35). Fluoxetine, norfluoxetine, fluvoxamine, reboxetine, and 0-demethylparoxetine showed intermediate inhibition, and citalopram, desmethylcitalopram, venlafaxine, and N-desmethylvenlafaxine showed only weak inhibition. No inhibition was found for 0-desmethylvenlafaxine. 

The asymmetric hydrogenation of several / -amino ketones in toluene-water mixture is catalysed by the chiral complex RuPHOX-Ru (43), stable in air and moisture, in the presence of KOH to corresponding y-amino alcohols with up to 99.9% ee. The key intermediates of fluoxetine, tomoxetine, and nisoxetine were obtained in quantitative yield and in up to 99.9% ee ... 

SCHEME 3439. Structure of fluoxetine 47, tomoxetine 46, and nisoxetine 150 and details of the asymmetric secondary alcohol oxidation kinetic resolution step that provides a common chiral intermediate. 

S)-(+) Dexfenfluramine (Redux ) 21, a serotonin reuptake inhibitor, has been marketed in Europe and the United States as a very effective anti-obesity drug. This isomer, obtained by resolution of racemic fenfluramine using d-camphoric acid, exhibits a greater anorectic effect than die (R)-(-) and racemic forms, since it is more selective on serotonin as a 5-HT agonist (22). As a result of reports of imdesirable side effects, e.g., valvular heart disease, Redux has been wididrawn from the market, while further studies continue. Racemic fluoxetine (Prozac ) (22) is widely used for treatment of major depression and is one of the most commonly prescribed medications. It is also approved for treatment of obsessive compulsive disorder and bulimia. Non-racemic fluoxetine and its intermediates have been prepared by chemical, enzymatic. 

Both enantiomers of fluoxetine and tomoxetine can be obtained from the secondary alcohols 37 and 38 (Scheme 13) obtained by reduction of compounds 35 and 36 and successive manipulations. The reduction of benzoylacetate with baker s yeast, B. bassiana, G. candidum, gave the same S-hydroxy ester with good to high enantiomeric excess [70-72]. A number of methods for the biocatalytic preparation of the same compounds is found in the patent literature [73]. The pharmacologically active enantiomer of denopamine has been obtained. Thus the biomass of Geotrichum sp. was used to reduce the a-keto ester 39 (Scheme 14) intermediate in the synthesis of the above compound [74]. 

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