Methods of producing molindone and its salts
View Patent ↗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) having the following structure:
comprising reacting 2-methyl-3-ethyl-4-oxo-4,5,6,7-tetrahydroindole (SUMO-2) having the following structure:
with bismorpholinomethane.
2. The process of claim 1 , further comprising at least one of the following steps:
(a) removing
(methylene SUMO-2) by filtration under acidic conditions;
(b) adsorbing oligomeric compounds on charcoal;
(c) filtering and crystallizing SUMO-3 free base from a solvent.
3. The process of claim 1 , further comprising forming and crystallizing a salt of SUMO-3.
4. The process of claim 3 , wherein said salt is selected from the group consisting of molindone hydrochloride, molindone sulfate, molindone phosphate, molindone monohydrogenphosphate, molindone dihydrogenphosphate, molindone bromide, molindone iodide, molindone acetate, molindone propionate, molindone decanoate, molindone caprylate, molindone formate, molindone oxalate, molindone malonate, molindone succinate, molindone fumarate, molindone maleate, molindone citrate, molindone lactate, molindone tartrate, molindone methanesulfonate, and molindone mandelate.
5. The process of claim 1 , wherein the compound SUMO-2 is prepared by reacting 2,3-pentanedione-2-oxime (SUMO-1) having the following structure:
with 1,3-cyclohexanedione.
6. The process of claim 5 , wherein the compound SUMO-2 is prepared by reacting SUMO-1 with 1,3-cyclohexanedione in the presence of a hydrogenation catalyst.
7. The process of claim 5 , wherein the compound SUMO-2 is prepared by reacting SUMO-1 with 1,3-cyclohexanedione in the presence of Zn in acetic acid.
8. The process of claim 6 , wherein said catalyst comprises Pd/C.
9. The process of claim 6 , wherein said catalyst comprises Raney nickel.
10. The process of claim 5 , wherein SUMO-1 is subjected to the hydrogenation conditions prior to the addition of 1,3-cyclohexanedione.
11. The process of claim 10 , wherein SUMO-1 is hydrogenated in the presence of Zn and an acid.
12. The process of claim 11 , wherein Zn is removed prior to the addition of 1,3-cyclohexanedione.
13. The process of claim 10 , wherein SUMO-1 is hydrogenated in the presence of a catalyst.
14. The process of claim 13 , wherein the catalyst is removed prior to the addition of 1,3-cyclohexanedione.
15. The process of claim 13 , wherein said catalyst comprises Pd/C.
16. The process of claim 13 , wherein said catalyst comprises Raney nickel.
17. The process of claim 5 , wherein the process is initiated at a first temperature of from 15° C. to 40° C.
18. The process of claim 17 , wherein the temperature is raised during the process to a second temperature of from 80° C. to 110° C.
19. The process of claim 5 , wherein the compound SUMO-1 is prepared by reacting 2,3-pentanedione with hydroxylamine hydrochloride in the presence of a base.
20. The process of claim 19 , wherein said base is selected from the group consisting of LiOH, NaOH, KOH, Li 2 CO 3 , K 2 CO 3 , Na 2 CO 3 , NaHCO 3 and combinations thereof.
21. The process of claim 19 , wherein the preparation of SUMO-1 is carried out at a pH of from 8 to 9 to optimize regioselectivity.
22. The process of claim 21 , wherein the ratio of SUMO-1/SUMO-1 isomer
is at least 5:1.
23. The process of claim 1 , wherein the amount of the residual isomer SUMO-3
is less than 0.2%.
24. The process of claim 2 , where the solvent is selected from the group consisting of ethanol, methanol, isopropanol, butanol, acetone, ether, methyl t-butyl ether, nitromethane, ethyl acetate, and toluene.
25. The process of claim 1 , wherein the reaction is conducted in the presence of an acid.
26. The process of claim 25 , wherein said acid is selected from the group consisting of HC1, acetic acid, formic acid, sulfuric acid, nitric acid, phosphoric acid, and trifluoroacetic acid.
27. The process of claim 1 , wherein the reaction is conducted in the presence of a solvent.
28. The process of claim 7 , wherein the Zn is present in the form of a powder with a particle size of from 2μ to 50μ.