Process of preparation of vincamine from tabersonine

Claim 2

EPI-16-VINCAMINE, AND

Claim 3

epi-16-vincamine, and

Claim 4

apo-vincamine, and d. isolating (-)-vincamine from the mixture by crystallization from a member selected from the group of acetone, methanol, ethanol and propanol or by chromatography with aluminum-oxide and crystallization from acetone.

Claim 5

APO-VINCAMINE, AND D. ISOLATING (-)-VINCAMINE FROM THE MIXTURE BY CRYSTALLIZATION FROM A MEMBER SELECTED FROM THE GROUP OF ACETONE, METHANOL, ETHANOL AND PROPANOL OR BY CHROMATOGRAPHY WITH ALUMINUM-OXIDE AND CRYSTALLIZATION FROM ACETONE.

Claim 6

The process of claim 1 wherein the oxidizing step (b) includes treating one molecule of (-) vincadifformine with two molecules of a peroxide to form the (-) 1,2- dehydro-16-carbomethoxy-16-hydroxy-N-oxy-aspidospermidine.

Claim 7

The process of claim 1 wherein the oxidizing step (b) is carried out by first treating the vincadifformine with an equal molecular quantity of a peracid so as to form (-) N-oxy-vincadifformine and then treating the (-) N-oxy-vincadifformine with an equal molecular quantity of a peracid to obtain the (-) dehydro-1,2-carbomethoxy-16-hydroxy-16N-oxyaspidospermidine.

Claim 8

The process of claim 4 wherein the product mixture of step (c) is separated by chromatography into two fractions wherein the more polar fraction consists mainly of (-) vincamine and to a lesser extent of epi-16-vincamine which is separated by crystallization and wherein the less polar fraction is crystallized to give apo-vincamine.

Claim 9

The process of claim 4 wherein the products of step (c) are separated into fractions by repeated crystallization and without chromatography.

Claim 10

The process of claim 1 wherein said solvent is selected from the group of benzene, toluene, ether aliphatic chlorinated hydrocarbons derived from methane or ethane, methylene chloride, carbon tetrachloride, chloroform, trichloroethylene and tetrachloroethane.

Claim 11

The method of claim 1 which comprises oxidizing the (-) vincadifformine by treating with a double quantity of peracid molecules for between 1 and 5 days at room temperature in a water immiscible solvent in order to obtain an approximately 85% yield of (-) 1,2-dehydro-16-carbomethoxy-16-hydroxy-N-oxy-aspidospermidine.

Claim 12

The method of claim 8 wherein said solvent is selected from the group of benzene, toluene, ether, and aliphatic chlorinated hydrocarbon derived from methane or ethane, methylene chloride, carbon tetrachloride, chloroform, trichloroethylene, and tetrachloroethane.

Claim 13

The process of claim 1 which comprises reducing the (-) 1,2-dehydro-16-carbomethoxy-16-hydroxy-N-oxyaspidospermidine by boiling under nitrogen for 1 to 2 hours with an equimolecular quantity of triphenylphosphine, cooling the solution, diluting the solution with an equal quantity of water, washing with a double quantity of benzene or ether so as to remove the triphenylphosphine oxide formed, removing the light organic phase by decantation, rendering the acid aqueous phase alkaline to a pH of 10, and extracting with an organic solvent selected from the group of methylene chloride, chloroform, ether and benzene, decanting the organic phase, washing with water, drying over a dehydrating agent and distilling to eliminate the solvent.

Claim 14

The method of claim 8 wherein said dehydrating agent is sodium sulphate.

Claim 15

The method of claim 1 which comprises reducing the (-) 1,2-dehydro-16-carbomethoxy-16-hydroxy-N-oxyaspidospermidine at room temperature for about 10 hours in an aqueous acetic acid medium with an equimolecular quantity of triphenylphosphine to produce a product of about 85% yield which contains very little apo-vincamine and essentially comprises a mixture of (-) vincamine and epi-16 vincamine in the proportions of three parts to one part by weight of the mixture, isolating the (-) vincamine from the mixture by double crystallization from a member selected from the group of acetone, methanol, ethanol, and propanol.

Claim 16

The method oF claim 1 wherein said alkaline aqueous solution is selected from the group consisting of aqueous solution of sodium carbonate and aqueous solution of sodium bicarbonate.

Claim 17

The process of claim 1 which further comprises dissolving (-)-tabersonine in an alcohol, catalytically hydrogenating the (-)-tabersonine at atmospheric presure in the presence of a catalyst selected from the group of PtO2, Pd/C, and Pt/C until the theoretical volume of hydrogen has been absorbed, and thereafter separating the catalyst from the solution by filtration, distilling the filtrate to remove solvent, and to dry said filtrate and then recrystallizing the filtrate.

Claim 18

The process of claim 4 which comprises oxidizing the vincadifformine with an equal molecular quantity of a peracid at room temperature for about 5 hours in the presence of said water-immiscible solvent, washing the reaction solution with an alkaline aqueous solution to remove most of the peroxidizing agent and the conversion products thereof, and then distilling the reaction solution to remove the solvent and to give an oil comprising (-)-N-oxy-vincadifformine, the yield being apporoximately 90% and then treating the oil with an equal molecular quantity of a peracid selected from the group consisting of peracetic acid, perbenzoic acid, metachloroperbenzoic acid, paranitroperbenzoic acid, performic acid, perphthalic acid, and mixtures thereof, for between 1 and 5 days so as to obtain an approximately 80% yield of (-)-1,2-dehydro-16-carbomethoxy-16-hydroxy-N-oxy-aspidospermidine, and then purifying said aspidospermidine by crystallization from a volatile solvent.