Methods of producing molindone and its salts
The present invention is directed towards novel methods of synthesis of molindone, synthesis of the intermediates of molindone, and high-purity compositions of molindone. In particular, the invention relates to the methods of synthesis of molindone through the Mannich reaction.
1. A process for preparing molindone (SUMO-3), comprising:
(a) forming formyl SUMO-2 by reacting 2-methyl-3-ethyl-4-oxo-4,5,6,7-tetrahydroindole (SUMO-2) with a base and ethyl formate;
(b) reacting formyl SUMO-2 with morpholine to form an enamine of formyl SUMO-2; and
(c) reducing the enamine to form molindone
2. A process for preparing molindone (SUMO-3), comprising reacting SUMO-2 with bismorpholinomethane to form molindone:
3. The process of claim 2 , further comprising synthesizing bismorpholinomethane in situ by reacting morpholine with formaldehyde:
4. The process of claim 2 , wherein one to four equivalents of bismorpholinomethane are used in the reaction.
5. The process of claim 2 , wherein the reaction comprises an organic or inorganic acid selected from the group consisting of hydrochloric acid, sulfuric acid, nitric acid, formic acid, acetic acid, trifluoroacetic acid, and combinations thereof.
6. The process of claim 2 , wherein the reaction comprises a solvent selected from the group consisting of methanol, ethanol, propanol, isopropanol, butanol, pentanol, ethylene glycol, ethoxyethanol, methoxyethanol, 1,4-dioxane, toluene, xylene, tetrahydrofuran, dichloromethane, benzene, and combinations thereof.
7. The process of claim 2 , wherein the reaction is carried out at a temperature of from 40° C. to 110° C.
8. The process of claim 7 , wherein the reaction is carried out at a constant temperature of 60° C. to 110° C.
9. The process of claim 7 , wherein the reaction is initiated at a lower temperature and the temperature is raised to 65° C. to 100° C. during the reaction.
10. The process of claim 2 , wherein the entire amount of the bismorpholinomethane is added at the start of the reaction.
11. The process of claim 2 , wherein the bismorpholinomethane is added to the reaction in a step-wise manner.
12. The process of claim 2 , further comprising treating the reaction with water and optionally adding acid.
13. The process of claim 12 , wherein acid is added to the reaction to form an acidic solution, and wherein the acid is selected from the group consisting of hydrogen chloride, sulfuric acid, nitric acid and phosphoric acid.
14. The process of claim 13 , further comprising treating the acidic solution with a base to obtain a basic solution having a pH of more than 7, and precipitating molindone base from the basic solution.
15. The process of claim 14 , wherein the base is selected form the group consisting of ammonia, carbonate, bicarbonates, hydroxides, and combinations thereof.
16. The process of claim 15 , further comprising filtering the molindone base from the basic solution.
17. The process of claim 14 , further comprising adding an adsorbent to the basic solution, wherein the adsorbent is selected from the group consisting of charcoal, zeolite, silicates, and celite.
18. The process of claim 16 , further comprising dissolving and recrystallizing the molindone base in a solvent selected from the group consisting of ethanol, methanol, isopropanol, butanol, acetone, ether, methyl t-butyl ether, nitromethane, ethyl acetate, toluene, and combinations thereof.