Methods for oxidation of alpha tocotrienol in the presence of non-alpha tocotrienols
View Patent ↗A method of producing alpha-tocotrienol quinone or a stereoisomer thereof, the method comprising selective opening of alpha-tocotrienol chroman to alpha-tocotrienol quinone in the presence of non-alpha tocotrienol chromans by oxidizing alpha-to-cotrienol with a metal salt oxidizing agent, wherein the stoichiometric ratio of metal salt oxidizing agent/alpha-tocotrienol is at least 4:1 and wherein said metal oxidizing agent is added in sequential additions, in order to reduce oxidation of any amounts of non-alpha tocotrienol chromans that might have been present in the starting alpha-tocotrienol chroman material. This process uses conditions favoring oxidation rates of the alpha tocotrienol chroman vs. the non-alpha tocotrienol chromans.
1. A method of producing alpha-tocotrienol quinone of Formula I:
or a stereoisomer thereof, the method comprising opening of alpha-tocotrienol to alpha-tocotrienol quinone of Formula I in the presence of non-alpha-tocotrienols by oxidizing alpha-tocotrienol with a metal salt oxidizing agent wherein the metal salt oxidizing agent is iron(III) nitrate (Fe(III)NO 3 ), wherein the stoichiometric ratio of metal salt oxidizing agent/alpha-tocotrienol is at least about 4:1 and wherein said metal salt oxidizing agent is optionally added in sequential additions.
2. The method according to claim 1 comprising oxidizing the alpha-tocotrienol with the metal salt oxidizing agent in a biphasic solution, wherein a first solution comprises the alpha-tocotrienol dissolved in a non-polar solvent; a second solution comprises the metal salt oxidizing agent dissolved in a polar solvent; and the separate first and second solutions are mixed to permit the oxidation.
3. The method according to claim 1 , wherein the metal salt oxidizing agent is sufficient to oxidize at least about 98% of the alpha-tocotrienol into the alpha-tocotrienol quinone.
4. The method according to claim 3 , wherein the composition resulting from the oxidation has less than about 1% of one or more non-alpha-tocotrienol quinone compounds selected from alpha-tocotrienol, beta-tocotrienol, beta-tocotrienol quinone, gamma-tocotrienol, gamma-tocotrienol quinone, delta-tocotrienol, delta-tocotrienol quinone, or combinations thereof.
5. The method according to claim 3 , wherein the composition resulting from the oxidation has less than about 0.7% of one or more non-alpha-tocotrienol quinone compounds, selected from alpha-tocotrienol, beta-tocotrienol, beta-tocotrienol quinone, gamma-tocotrienol, gamma-tocotrienol quinone, delta-tocotrienol, delta-tocotrienol quinone, and combinations thereof.
6. The method according to claim 3 , wherein the composition resulting from the oxidation has less than about 0.2% of one or more non-alpha-tocotrienol quinone compounds, selected from alpha-tocotrienol, beta-tocotrienol, beta-tocotrienol quinone, gamma-tocotrienol, gamma-tocotrienol quinone, delta-tocotrienol, delta-tocotrienol quinone, and combinations thereof.
7. The method according to claim 2 , wherein the non-polar solvent is alcohol, ether, or a mixture of alcohol and ether, and the polar solvent is water or a mixture of water and alcohol.
8. The method according to claim 1 , wherein the non-polar solvent is an approximately 1:2 mixture of ethanol and methyl tert-butyl ether (MTBE), and the polar solvent is an approximately 2:1 mixture of water and ethanol.
9. The method according to claim 2 , where the metal salt oxidizing agent is serially added in multiple portions, wherein (1) a first portion of the second solution is added to the first solution to react with the alpha-tocotrienol, followed by (2) removal of the polar phase of the first portion, and repeating steps (1) and (2) for the remaining portions of the second solution.
10. The method according to claim 8 , where the iron (III) nitrate is serially added in three or four portions, wherein (1) a first portion of iron(III) nitrate is added to the alpha-tocotrienol, followed by (2) removal of the polar phase of the first portion, and repeating steps (1) and (2) for the remaining portions of iron(III) nitrate.
11. The method according to claim 9 , where the oxidation reaction is allowed to proceed while measuring the formation of one or more undesired side-products and is interrupted when one or more of the undesired side-products are detected.
12. The method according to claim 11 , where the oxidation reaction is allowed to proceed while the formation of the one or more undesired side-products is measured and the oxidation is interrupted when the level of a single side-product is about 1%.
13. The method according to claim 11 , where the oxidation reaction is allowed to proceed while the formation of the one or more undesired side-products is measured and the oxidation is interrupted when the level of a single side-product is about 0.5%.
14. The method of claim 1 , where the metal salt oxidizing agent is not added in sequential additions.