Process for the production of alpha-tocotrienol and derivatives

Inventors: Kieron E. Wesson (Burlingame, CA); Andrew W. Hinman (San Francisco, CA); Orion D. Jankowski (Burlingame, CA)

Assignee: PTC THERAPEUTICS, INC.

C07D311/72 C07C46/02

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Quick Facts

Patent No.: US 11,312,697
App. No.: 16/127,102
Granted: Apr 26, 2022
Kind: B2

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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.

Claims (22)

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.

Assignments (5)

TERMINATION AND RELEASE OF PATENT SECURITY AGREEMENT @ REEL 061803 AND FRAME 0878 Recorded Oct 20, 2023

From: WILMINGTON TRUST, NATIONAL ASSOCIATION, AS ADMINISTRATIVE AGENT

To: PTC THERAPEUTICS, INC.

Reel/Frame 065303/0163 →

SECURITY INTEREST Recorded Oct 28, 2022

From: PTC THERAPEUTICS, INC.

To: WILMINGTON TRUST, NATIONAL ASSOCIATION

Reel/Frame 061803/0878 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 15, 2019

From: BIOELECTRON TECHNOLOGY CORPORATION

To: PTC THERAPEUTICS, INC.