Cyclosporin H → Cyclosporin A

Participants

Reaction Steps

510 kg cyclosporin A-containing fermentation broth was extracted twice with 510 L methyl-tert.-butyl ether (MTBE) each, 2.6 kg of the Clariant MD07/049 polyacrylate being added. The ether phases were separated in a 300 L separator in throughfeed and combined. The cyclosporin A-containing ether phase was washed once with 700 L pure water having a pH of about 7, the phases were separated again in a separator and the ether phase was concentrated by azeotropic distillation in a 1000 L thin-layer evaporator at a temperature of about 53° C. so as to achieve a cyclosporin concentration of 100 g/kg. The temperature was then lowered to a value just below the boiling point and this temperature was kept for 2 hours, with MTBE escaping via the distillation head being replaced by fresh one. Thereafter, the solution was concentrated at normal pressure at 53° C. so as to achieve a cyclosporin concentration of 300 g/kg. The residual water content which had been about 1.4% by weight prior to the azeotropic distillation was then 0.1% by weight. Thereafter, the solution was carefully cooled from 53° C. to 45° C. in 120 minutes, to 40° C. in another 60 minutes, to 30° C. in another 60 minutes and to 0° C. in another 60 minutes. 8.55 kg white, crystalline cyclosporin A-MTBE solvate was obtained in a theoretical total yield of about 87%. The isocyclosporin A content was 0.008% by weight, the total content of cyclosporin H and cyclosporin T was 0.28% by weight, which was a highly significant reduction in the content of these contaminations as compared to an extraction method using butyl acetate.

Provenance & Evidence