Process for the production of alpha-tocotrienol and derivatives

Patent metadata

Field	Value
Publication number	US-11312697-B2
Application number	US-201816127102-A
Country	US
Kind code	B2
Filing date	Sep 10, 2018
Priority date	Oct 28, 2008
Publication date	Apr 26, 2022
Grant date	Apr 26, 2022

Abstract

The invention discloses novel processes for production, enrichment and/or isolation of alpha-tocotrienol from source material comprising at least one non-alpha-tocotrienol, such as natural extracts comprising mixed tocotrienols.

First claim

What is claimed is:

1. A composition comprising 2-((6E,10E)-3R-hydroxy-3,7,11,15-tetramethylhexadeca-6,10,14-trienyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione, and a solvent selected from isopropyl acetate, n-heptane, and a mixture thereof, wherein the 2-((6E,10E)-3R-hydroxy-3,7,11,15-tetramethylhexadeca-6,10,14-trienyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione comprises at least about 90% of 2-(3-hydroxy-3,7,11,15-tetramethylhexadeca-6,10,14-trienyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione present in the composition.

2. The composition of claim 1 , wherein the 2-((6E,10E)-3R-hydroxy-3,7,11,15-tetramethylhexadeca-6,10,14-trienyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione has a purity of more than about 94%.

3. The composition of claim 1 , wherein the 2-((6E,10E)-3R-hydroxy-3,7,11,15-tetramethylhexadeca-6,10,14-trienyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione has a purity of more than about 95%.

4. The composition of claim 1 , wherein the 2-((6E,10E)-3R-hydroxy-3,7,11,15-tetramethylhexadeca-6,10,14-trienyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione has a purity of more than about 97%.

5. The composition of claim 1 , wherein the 2-((6E,10E)-3R-hydroxy-3,7,11,15-tetramethylhexadeca-6,10,14-trienyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione comprises at least about 95% of the 2-(3-hydroxy-3,7,11,15-tetramethylhexadeca-6,10,14-trienyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione present in the composition.

6. The composition of claim 1 , wherein the 2-((6E,10E)-3R-hydroxy-3,7,11,15-tetramethylhexadeca-6,10,14-trienyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione comprises at about least 96% of the 2-(3-hydroxy-3,7,11,15-tetramethylhexadeca-6,10,14-trienyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione present in the composition.

7. The composition of claim 1 , wherein the 2-((6E,10E)-3R-hydroxy-3,7,11,15-tetramethylhexadeca-6,10,14-trienyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione comprises at least about 97% of the 2-(3-hydroxy-3,7,11,15-tetramethylhexadeca-6,10,14-trienyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione present in the composition.

8. The composition of claim 1 , wherein the 2-((6E,10E)-3R-hydroxy-3,7,11,15-tetramethylhexadeca-6,10,14-trienyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione comprises at least about 98% of the 2-(3-hydroxy-3,7,11,15-tetramethylhexadeca-6,10,14-trienyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione present in the composition.

9. The composition of claim 1 , wherein the 2-((6E,10E)-3R-hydroxy-3,7,11,15-tetramethylhexadeca-6,10,14-trienyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione comprises at least about 99% of the 2-(3-hydroxy-3,7,11,15-tetramethylhexadeca-6,10,14-trienyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione present in the composition.

10. The composition of claim 1 , wherein the 2-((6E,10E)-3R-hydroxy-3,7,11,15-tetramethylhexadeca-6,10,14-trienyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione comprises at least about 99.5% of the 2-(3-hydroxy-3,7,11,15-tetramethylhexadeca-6,10,14-trienyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione present in the composition.

11. The composition of claim 1 that comprises n-heptane and isopropyl acetate in a ratio of about 100:1, about 100:5, about 100:10, or about 100:15.

12. The composition of claim 1 wherein the wherein the 2-((6E,10E)-3R-hydroxy-3,7,11,15-tetramethylhexadeca-6,10,14-trienyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione has a purity of more than about 90% relative to tocols and tocol derivatives in the composition.

13. The composition of claim 1 , wherein the 2-((6E,10E)-3R-hydroxy-3,7,11,15-tetramethylhexadeca-6,10,14-trienyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione is from a single performance of a production, enrichment, and/or isolation of the alpha-tocotrienol precursor of 2-((6E,10E)-3R-hydroxy-3,7,11,15-tetramethylhexadeca-6,10,14-trienyl)-3,5,6-trim ethylcyclohexa-2,5-diene-1,4-dione.

14. The composition of claim 13 , wherein the composition comprises at least 250 grams of 2-((6E,10E)-3R-hydroxy-3,7,11,15-tetramethylhexadeca-6,10,14-trienyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione.

15. The composition of claim 13 , wherein the composition comprises at least 10 kilograms of 2-((6E,10E)-3R-hydroxy-3,7,11,15-tetramethylhexadeca-6,10,14-tri enyl)-3,5,6-trim ethylcyclohexa-2,5-diene-1,4-dione.

16. The composition of claim 13 , wherein the alpha-tocotrienol precursor of 2-((6E,10E)-3R-hydroxy-3,7,11,15-tetramethylhexadeca-6,10,14-trienyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione is mixed with silica gel, filtered to remove the silica gel, and concentrated.

17. The composition of claim 1 , wherein the composition is made without using chromatography on the alpha-tocotrienol precursor of 2-((6E,10E)-3R-hydroxy-3,7,11,15-tetramethylhexadeca-6,10,14-trienyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione.

18. The composition of claim 17 , wherein the alpha-tocotrienol precursor of 2-((6E,10E)-3R-hydroxy-3,7,11,15-tetramethylhexadeca-6,10,14-trienyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione is mixed with silica gel, filtered to remove the silica gel, and concentrated to provide the alpha-tocotrienol precursor.

19. The composition of claim 17 , wherein the composition comprises at least 10 kilograms of 2-((6E,10E)-3R-hydroxy-3,7,11,15-tetramethylhexadeca-6,10,14-trienyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione and is prepared from an alpha-tocotrienol precursor and wherein the process comprises a single performance of a production, enrichment, and/or isolation of 2-((6E,10E)-3R-hydroxy-3,7,11,15-tetramethylhexadeca-6,10,14-trienyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione.

20. The composition of claim 19 , wherein the alpha-tocotrienol precursor of 2-((6E,10E)-3R-hydroxy-3,7,11,15-tetramethylhexadeca-6,10,14-trienyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione is mixed with silica gel, filtered to remove the silica gel, and concentrated.

21. A composition comprising 2-((6E,10E)-3R-hydroxy-3,7,11,15-tetramethylhexadeca-6,10,14-trienyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione, and a buffer selected from sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, phosphate, and any mixture thereof, wherein the 2-((6E,10E)-3R-hydroxy-3,7,11,15-tetramethylhexadeca-6,10,14-trienyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione has a purity of more than about 90%, and wherein the 2-((6E,10E)-3R-hydroxy-3,7,11,15-tetramethylhexadeca-6,10,14-trienyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione comprises at least about 90% of 2-(3-hydroxy-3,7,11,15-tetramethylhexadeca-6,10,14-trienyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione present in the composition.

22. The composition of claim 21 wherein the 2-((6E,10E)-3R-hydroxy-3,7,11,15-tetramethylhexadeca-6,10,14-trienyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione has a purity of more than about 90% relative to tocols and tocol derivatives in the composition.

Assignees

• Ptc Therapeutics Inc

Inventors

• Wesson Kieron E
• Hinman Andrew W
• Jankowski Orion D

Classifications

• C07C46/02

  by oxidation giving rise to quinoid structures · CPC title

• C07D311/72 Primary

  3,4-Dihydro derivatives having in position 2 at least one methyl radical and in position 6 one oxygen atom, e.g. tocopherols · CPC title

• C07C46/06

  of at least one hydroxy group on a six-membered aromatic ring · CPC title

• C07C50/28

  with monocyclic quinoid structure · CPC title