Fluoxetine epoxidation

Scheme 3. Sharpless asymmetric epoxidation route to the fluoxetine enantiomers.

Carbamazepine is metabolized to an active 10,11-epoxide metabolite, thus medications that inhibit 3A4 isoenzymes may result in carbamazepine toxicity (e.g., cimetidine, dUtiazem, erythromycin, fluoxetine, fluvoxamine, isoniazid, itraconazole, ketoconazole, nefa-zodone, propoxyphene, and verapamil). " When carbamazepine is combined with valproate, the carbamazepine dose should be reduced because valproate displaces carbamazepine from protein binding sites, thus increasing free levels." Combining clozapine and carbamazepine is not recommended because of the possibdity of bone marrow suppression with both agents. ... 

Two patients developed carbamazepine toxicity (diplopia, blurred vision, tremor, vertigo, nausea, tinnitus etc.) within 7 and 10 days of starting to take fluoxetine 20 mg daily. Their serum carbamazepine levels were found to have risen by about 33% and 60%, respectively. The problem was resolved in one of them by reducing the carbamazepine dosage from 1 g to 800 mg daily, and in the other by stopping the fluoxetine. The effects seen in these cases are supported by a study in 6 healthy patients, where adding fluoxetine 20 mg daily to steady-state carbamazepine caused a rise in the AUC of carbamazepine and carbamazepine-10,11-epoxide (its active metabolite) of about 25 to 50%. ... 

As an application of the modified conditions, the asymmetric synthesis of (7 )-fiuoxetine was demonstrated (Scheme 35.28). Fluoxetine is an antidepressant drug and currently marketed as a racemate. Asymmetric epoxidation of amide 101 under Shibasaki s conditions provided epoxide 102 in 91% yield and 99% ee. Subsequent regionselec-tive reduction with Red-Al in the presence of a crown ether afforded the (3-hydoxyl amide 103, which was converted into (/ )-fluoxetine 104 in two steps. °... 

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

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