Fluoxetine hydrochloride synthesis

An extensive study was undertaken to optimize the carbonyl-ene reaction between benzaldehyde (143, Scheme 30) and 3-methylene-2,3-dihydrofuran 144, which was utilized in the enantioselective synthesis of fluoxetine hydrochloride, a selective seratonin reuptake inhibitor.89 The degree of hydration of the molecular sieves proved important in the stereoselectivity of the reaction, with lower enantioselectivities reported both with highly active... 

Synthesis of fluoxetine hydrochloride 10.3 Synthesis of sertraline hydrochloride 10.4 Synthesis of paroxetine hydrochloride 10.5 References... 

Brown et al. achieved a highly enantioselective synthesis of (.S )-fluoxetine hydrochloride (61) (Prozac), an antidepressant medicine26 (Scheme 4.3v). Reduction of (3-chloropropiophenone (62) with (+)-Ipc2BCl provided the secondary alcohol 63 in 97% ee and greater than 99% ee after single recrystallization. Mit-sunobu reaction of the alcohol with p-trifluoromethylphenol afforded the ether 64, which was then converted to (S)-(+)-fluoxetine hydrochloride (61) after subsequent treatment with excess methylamine and a solution of hydrogen chloride in ether. 

Corey s enantioselective synthesis of (7 )- and (S)-fluoxetine hydrochloride via CBS reduction makes a useful comparison with the earlier work of Brown et aZ., who had demonstrated the use of stoichiometric DIP-Cl reagent for the synthesis of the same pharmaceutically relevant target/ In this instance, the DIP-Cl reaction gave similar enantioselectivities for reduction, but with lower yields (<85%) and with the associated drawbacks arising from use of DIP-Cl (stoichiometric reagent, difficult work-up, silica chromatography necessary) (Scheme 14.32). 

Fig. 3. Synthesis of fluoxetine (31). 3-ChIoro-I-phenyl-I-propanol reacts with sodium iodide to afford the corresponding iodo derivative, followed by reaction with methylamine, to form 3-(methyl amin o)-1-phenyl-1-propan 0I. To the alkoxide of this product, generated using sodium hydride, 4-fluorobenzotrifluoride is added to yield after work-up the free base of the racemic fluoxetine (31), thence transformed to the hydrochloride (51)...

An application of this was described by Sudalai et al. [50] for a five-step synthesis of (i )-tomoxetin hydrochloride 141 and (S)-fluoxetine hy-... 

The (2S,4S)-MCCPM-Rh(I) complex was found previously by Achiwa and colleagues to be an efficient catalyst for the enantioselective hydrogenation of /9-amino ketone derivatives, leading to a practical enantioselective synthesis of (F)-fluoxetine [N-methyl-3-(4-trifluoromethylphenoxy)-3-phenylpropylamine] hydrochloride [22 b]. Moreover, the use of AMPP ligands again proved to be efficient for these substrates, as exemplified in Table 33.6 [15 i],... 

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