Synthesis of R -Fluoxetine

To a solution of (R)-3-(methylamino)-l-phenylpropan-l-ol (200 mg, 1.21 mmol) in dry dimethylsulfoxide (5 mL) at room temperature was added sodium hydride 

To the above-formed alkoxide was added 4-chlorobenzotrifluoride (330 mg, 1.82 mmol) in dimethylsulfoxide (3mL) and the resulting mixmre was heated at 95 °C for 1 h. 

The procedure provides a practical and highly enantioselective methodology for the synthesis of an optically active 1,3-amino alcohol. In respect of the efhciency and high enantioselectivity observed, this method represents a very useful alternative to previously reported procedures. Finally, we applied this method to the enantioselective synthesis of the antidepressant drug (f )-fluoxetine. 

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R)-liINAP-RuBr2 can be successfully applied to the enantioselective hydrogenation of /i-kelo esters in the synthesis of (+)-(2R,3 W)-corynomycolic acid 115. ( S )-MeO-BIPHEP-RuBr2 was used in a similar manner in the synthesis of (R)-fluoxetine (116, Prozac ) and (S)-duloxetine (117).648... 

POLYMER-SUPPORTED CHIRAL SULFONAMIDE CATALYZED REDUCTION OF j -KETO NITRILES A PRACTICAL SYNTHESIS OF (R)-FLUOXETINE... 

A short, enantioselective synthesis of (R)-fluoxetine, 24, has been described (Figure 16.8) [47]. The asymmetry was established in the first step, which is key... 

SCHEME 35.28. Using the asyimnetric epoxidation of amide 101 under ShibasaM s conditions for the asymmetric synthesis of (R)-fluoxetine. 

Kakei H, Nemoto T, Ohshima T, Shibasaki M. Efficient synthesis of chiral a- and P-hydroxy amides application to the synthesis of (R)-fluoxetine. Angew. Chem. Lnt. Ed. 2004 ... 

Synthesis of fluoxetine as a racemic mixture is shown in scheme-2. Recently several patents and publications have appeared in the literature describing the synthesis of (S)- and ( R) enantiomers. 

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],... 

Kamal, A., Ramesh Khanna, G.B., and Ramu, R. (2002) Chemoenzymatic synthesis of both enantiomers of fluoxetine, tomoxetine and nisoxetine lipase-catalyzed resolution of 3-aryl-3-hydroxypropanenitriles. Tetrahedron Asymmetry, 13, 2039-2051. 

A range of highly reactive Ru"-BINAP complexes 222 were shown to be effective in significantly expanding the substrate scope in ketone reductions to include aromatic and unsaturated cyclic and acyclic ketones lacking any additional polar functionality as shown in Figure 2.9 [115-118, 141, 142]. An example that demonstrates the powerful use of the mixed Ru-complex 231 is found in Noyori s asymmetric synthesis of the antidepressant (R)-fluoxetine (186, Scheme 2.28) [142]. 

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