Advances in the stereoselective synthesis of antifungal agents and ...

Chapter 8 164aqueous phase which was cooled again to 0°C and then acidified with 12NHCl (15.6 ml). KCNS (99 mmol) were added, the mixture was heated to70°C for two hours and was then left to stand in the refrigerator for 48 h.A precipitate was formed during this time , which was filtered off andwashed with cold water, and then dried under high vacuum over P 2 O 5overnight. 55 mmol of 40 were recovered (68 % overall yield).8.10.3 Synthesis of ethyl 4(5)-imidazole carboxylate 37:1.65 ml of conc. HNO 3 were diluted with 4.75 ml of water and theresulting solution was cooled to 0°C. NaNO 2 (100mg) was added after 10min.in a single portion and 4(5)-(2-thiol)-imidazole carboxylate 40 1.5 g(8.7 mmol) was added in small solid portions. During the last addition thetemperature must be kept below 25 °C. After 30 min solid Na 2 CO 3 wasadded to the reaction mixture to neutralize the pH. The product wasextracted in CHCl 3 (200 ml), the organic phase was washed with saturatedNaCl solution (2x 150 ml) and then dried over anhydrous Na 2 SO 4 . 840mg of product 37 were recovered (69% yield).8.11 Synthesis of ethyl 1-[-(4-Biphenylyl)benzyl]imidazole-5-carboxylate 41a and ethyl 1-[-(4-biphenylyl)benzyl]imidazole-4-carboxylate 41b.8.11.1 Synthesis 1:Prepared by Mitsunobu coupling of alcohol 27a and ethyl 4(5)-imidazole carboxylate 37 as the acidic reagent, following the sameprocedure ( synthetic method 7.7.2 b) as described for the synthesis of(±)-33g. After preliminary purification by flash chromatography (nhexane/AcOEt3:1), the isomeric mixture was separated by anotherchromatography using the same eluent affording the less polar compound(Rf 0.66), which was assigned to have the structure (±)-41a. The secondeluted isomer (±)-41b (Rf 0.22) was further purified by flashchromatography using gradient elution with n-hexane/AcOEt 3:1 to 1:1.8.11.2 Synthesis 2: