Orlistat Alcohol

B. Potassium allyl- and crotyltrifluoroborates undergo addition to aldehydes in biphasic media as well as water to provide homoallylic alcohol in high yields (>94%) and excellent diastereoselectivity (dr >98 2). The presence of a phase-transfer catalyst (e.g., B114NI) significantly accelerates the rate of reaction, whereas adding fluoride ion retards the reaction (Eq. 8.70).165 The method was applied to the asymmetric total synthesis of the antiobesity agent tetrahydrolipstatin (orlistat).166... 

One of the early syntheses of orlistat (1) by Hoffmann-La Roche utilized the Mukaiyama aldol reaction as the key convergent step. Therefore, in the presence of TiCU, aldehyde 7 was condensed with ketene silyl acetal 8 containing a chiral auxiliary to assemble ester 9 as the major diastereomer in a 3 1 ratio. After removal of the amino alcohol chiral auxiliary via hydrolysis, the a-hydroxyl acid 10 was converted to P-lactone 11 through the intermediacy of the mixed anhydride. The benzyl ether on 11 was unmasked via hydrogenation and the (5)-7V-formylleucine side-chain was installed using the Mitsunobu conditions to fashion orlistat (1). 

A study in healthy subjects found that orlistat 120 mg three times daily for 6 days had no significant effect on the pharmacokinetics of alcohol. There is nothing to surest that alcohol should be avoided while taking orlistat. 

Ketoconazole doubled the AUC of rimonabant, and other potent CYP3A4 inhibitors are also expected to raise rimonabant levels. Potent CYP3A4 inducers are expected to lower rimonabant levels. Due to a lack of information the manufacturers suggest that rimonabant should not be taken with antidepressants. Rimonabant does not appear to affect the levels of oral contraceptives, di-goxin, midazolam or warfarin, and alcohol, lorazepam, and orlistat do not appear to alter rimonabant levels. 

Nishimata et al. prepared intermediate 48 during their synthetic work on the amaryllidacae alkaloids crinanine and pretazettine. The preparation of Orlistat (49), the active pharmaceutical ingredient in Xenical , involves a Mitstmobu reaction between a hydroxy- 3-lactone and A -formyl-(Z/)-leucine. A larger scale inversion involving para-nitrobenzoic acid was used in the synthesis of BILN 2061 (50), a potent HCV protease inhibitor. The alcohol... 

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