Methanol → Vinblastine

Beteiligte Stoffe

Reaktionsbedingungen

Reaktionsschritte

To a solution of catharanthine (500 mg, 1.5 mmol) in dry dichloromethane (4.5 ml) at −15 C. under a positive atmosphere (greater than 760 mm Hg) of argon there was added m-chloroperbenzoic acid (330 mg, 1.9 mmol) in one portion, and the mixture was stirred at 10° to −15° C. for 5 minutes. After this time, the reaction mixture was cooled to −40° C. and a solution of vindoline (IV, 450 mg, 1 mmol) in dry dichloromethane (1 ml) was added, followed immediately by trifluoroacetic anhydride (1 ml, 7.1 mmol). After 2 hours at −60° C. volatiles were removed in vacuo (high vacuum pump) and dry, degassed methanol (12 mol) was added after flushing the system with argon. The resulting orange solution was cooled to −40° C. and a solution of 1,4-dihydro-1-(sodium-isobutyl-1-carboxylate)-nicotinamide (Formula IX-J) (1.5 g. 6 mmol) in dry degassed methanol (12 ml) was added under a positive atmosphere of argon. After reduction was complete (by reverse-phase HPLC monitoring), cold methanol (about 300 ml) was added, keeping the temperature of the solution between about −5° to about 0° C. Ferric chloride (330 mg, 2 mmol) was then added and dry air was bubbled through the solution at a rate of about 60 ml/min for a period of 20 min. Sodium borohydride (1 g) was added and the solution concentrated in vacuo (water aspirator) before adding water (100 ml) and extracting with ethyl acetate (3×150 ml). The combined organic extract was dried over Na2SO4 and the solvent was evaporated in vacuo to give the crude product which was purified by chromatography as previously described to give 3′,4′-dehydrovinblastine (VII, 95 mg, 12%), vinblastine (315 mg, 39%) and leurosidine (130 mg, 16%).

Herkunft & Nachweise