Preparation of 10-trifluoromethyl artemether and artesunate. Influence of hexafluoropropan-2-ol on substitution reaction.
To prepare 10-trifluoromethyl analogues of important antimalarials such as artemether and artesunate, the substitution reaction of the 10-trifluoromethyl hemiketal 6 and bromide 4 derived from artemisinin was investigated. While 6 appeared to be unreactive under various conditions, bromide 4 could easily undergo substitution with methanol under electrophilic assistance or noncatalyzed conditions. Optimization of the reaction revealed the role of CH(2)Cl(2) as solvent to avoid the competitive elimination process and the crucial influence of hexafluoro-2-propanol (HFIP) in increasing the rate and the stereoselectivity of the substitution reaction (de >98%). The efficiency of this reaction was exemplified with various alcohols and carboxylates (yield up to 89%).
Magueur
Guillaume
G
BIOCIS UPRES A 8076 CNRS, Faculté de Pharmacie, Université Paris-Sud, Rue J. B. Clément, 92296 Châtenay-Malabry, France.
Crousse
Benoit
B
Ourévitch
Michèle
M
Bégué
Jean-Pierre
JP
Bonnet-Delpon
Danièle
D
D000438:Alcohols / Q000737:chemistry; D000962:Antimalarials / Q000138:chemical synthesis*; D000077549:Artemether; D037621:Artemisinins / Q000138:chemical synthesis*; D000077332:Artesunate; D001966:Bromine / Q000737:chemistry; D002264:Carboxylic Acids / Q000737:chemistry; D006845:Hydrocarbons, Fluorinated / Q000737:chemistry*; D008737:Methyl Chloride / Q000737:chemistry; D020005:Propanols / Q000737:chemistry*; D012717:Sesquiterpenes / Q000138:chemical synthesis*
D000438:Alcohols; D000962:Antimalarials; D037621:Artemisinins; D002264:Carboxylic Acids; D006845:Hydrocarbons, Fluorinated; D020005:Propanols; D012717:Sesquiterpenes; C001337:hexafluoroisopropanol; C029999:fluoromethane; D000077332:Artesunate; D008737:Methyl Chloride; D000077549:Artemether; D001966:Bromine