Stereoselective synthesis of both enantiomers of ketoconazole from (R)- and (S)-epichlorohydrin

Camps, Pelayo; Farrés, Xavier; García, María Hernández; Ginesta, Joan; Pascual, Jordi Alberich; Mauleón, David; Carganico, Germano

doi:10.1016/0957-4166(95)00161-h

Cited by 18 publications

(5 citation statements)

References 11 publications

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“…Access to the enantiomerically pure dioxolanes was key in the synthesis of these novel azoles. Literature precedent , for the stereoselective synthesis of ketoconazole by transketalisation with optically pure solketal tosylates assisted us in the synthesis of 2,4-difluorophenyl dioxolane intermediates 5 and 6 . Recently, the same method was further optimized and used in the stereoselective synthesis of hydroxyitraconazole .…”

Section: Chemistrymentioning

confidence: 99%

Synthesis and in Vitro and in Vivo Structure−Activity Relationships of Novel Antifungal Triazoles for Dermatology

et al. 2005

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In search for new compounds with potential for clinical use as antifungal agents in dermatology, a series of 12 azole compounds were synthesized stereospecifically and investigated specifically for their activity against dermatophyte fungal infections in animal models. This panel of azoles was studied in vitro and compared with itraconazole and terbinafine for their antifungal activity using a panel of 24 Candida spp. and 182 dermatophyte isolates. Three azoles (1c, 2c, and 4c) showed in vitro antifungal potency equivalent to itraconazole, but superior to terbinafine, against a panel of 24 Candida spp. with comparable or lower activity than that of itraconazole and terbinafine against 182 dermatophyte isolates and only rare activity against other pathogenic fungi. However, in vivo 1c and 4c, both given orally, demonstrated antifungal activity at least three times greater than itraconazole and were superior compared to terbinafine in M. canis infected guinea pigs. In a mouse model infected by T. mentagrophytes, again 4c, but not 1c, showed 5-fold superior activity over itraconazole and terbinafine. Compound 2c was effective in both models but less effective than itraconazole in these models. On the basis of these promising results, 4c is currently being clinically investigated for its potential as a novel antifungal agent against dermatophytosis.

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Section: Chemistrymentioning

confidence: 99%

Synthesis and in Vitro and in Vivo Structure−Activity Relationships of Novel Antifungal Triazoles for Dermatology

et al. 2005

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“…As a final example, the stereoselective synthesis of both enantiomers of ketoconazole, a potent orally active broad-spectrum antifungal agent, from commercially available ( R )-epichlorohydrin ( 8 ) and ( S )-epichlorohydrin ( 11 ) has been investigated by García and co-workers . Treatment of ( S )-epichlorohydrin ( 11 ) with acetone in the presence of BF 3 ·Et 2 O led to the selective formation of ( R )-4-chloromethyl-2,2-dimethyl-1,3-dioxolane ( 220 ) (Scheme ), which subsequently underwent selective substitution at the chlorinated carbon atom by sodium benzoate in DMSO to yield acetal ester 221 .…”

Section: Applications Of Epichlorohydrin and Epibromohydrin In The Sy...mentioning

confidence: 99%

“…Treatment of ( S )-epichlorohydrin ( 11 ) with acetone in the presence of BF 3 ·Et 2 O led to the selective formation of ( R )-4-chloromethyl-2,2-dimethyl-1,3-dioxolane ( 220 ) (Scheme ), which subsequently underwent selective substitution at the chlorinated carbon atom by sodium benzoate in DMSO to yield acetal ester 221 . Both ( R )- and ( S )-enantiomers of epichlorohydrin ( 5 ) were used to synthesize isomeric ketoconazoles …”

Section: Applications Of Epichlorohydrin and Epibromohydrin In The Sy...mentioning

confidence: 99%

Epihalohydrins in Organic Synthesis

et al. 2012

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“…This is because hydrogen atom and 2,4-dichlorophenyl in the two chiral centers must share one side as a result of space steric effect. It has been found that R-ketoconazole ((-)-2S,4R-ketoconazole) shows some times of pharmacological activity than that of S-ketoconazole ((+)-2R,4S-ketoconazole) [24,25]. Currently, ketoconazole is prescribed in its racemate form, which links to liver damage and other complications.…”

Section: Introductionmentioning

confidence: 99%

Modeling and optimization of two phase system for recycling high-speed counter-current chromatographic separation of ketoconazole enantiomers

Zhang

Xie

Tang

et al. 2016

Separation and Purification Technology

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An efficient method using recycling high speed counter-current chromatography (HSCCC) with hydroxypropyl-β-cyclodextrin (HP-β-CD) as chiral selector (CS) is developed for the separation of ketoconazole enantiomers. The separation process was performed with a two-phase solvent system composed of n-hexane/acetic acid isobutyl ester/0.1 mol L-1 phosphate buffer solution with pH = 8.5 containing 0.1 mol L-1 HP-β-CD (2:3:5, v/v/v). Important factors that influence the separation efficiency, including organic solvent system, temperature, the pH value of the aqueous phase as well as type and concentration of chiral selector were investigated experimentally. Influence of the pH value and concentration of chiral selector was modeled and the conditions were further optimized by the model. Pure enantiomers with a purity > 99% were obtained by separating 20 mg racemate via HSCCC. The recovery rates ranged from 85% to 89%.

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Stereoselective synthesis of both enantiomers of ketoconazole from (R)- and (S)-epichlorohydrin

Cited by 18 publications

References 11 publications

Synthesis and in Vitro and in Vivo Structure−Activity Relationships of Novel Antifungal Triazoles for Dermatology

Synthesis and in Vitro and in Vivo Structure−Activity Relationships of Novel Antifungal Triazoles for Dermatology

Epihalohydrins in Organic Synthesis

Modeling and optimization of two phase system for recycling high-speed counter-current chromatographic separation of ketoconazole enantiomers

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