Methods for making tocoflexols and analogues thereof

Patent metadata

Field	Value
Publication number	US-9309547-B2
Application number	US-201314402792-A
Country	US
Kind code	B2
Filing date	Mar 13, 2013
Priority date	May 22, 2012
Publication date	Apr 12, 2016
Grant date	Apr 12, 2016

Abstract

Methods for the synthesis of tocoflexols of Formula (I) and (II) and a number of related tocol analogs are provided herein. The methods are economical and amenable to large scale production and can be performed using either pure of partially purified tocotrienols as the starting material.

First claim

What is claimed is:

1. A method of making tocoflexols of Formula (I) or (II) comprising the steps of:
(a) introducing a protective group to the phenolic hydroxyl group of a pure or partially purified tocotrienol of formula (X) to form the product of formula (XI); wherein the solvent used is an aprotic solvent, the reaction temperature is between −20° C. to 120° C. and the reaction time can range from 5 minutes in 24 hours:

wherein R 1 , R 2 , and R 3 , are the same or different and are each selected from hydrogen and methyl and P is hydroxyl protective group; and
(b) cleaving by oxidation the double bonds in products from step (a) in the formula (XI) to afford an aldehyde intermediate in the formula (XII); wherein the oxidation is performed using OsO 4 /NaIO 4 or ozonolysis:

wherein R 1 , R 2 , R 3 , and P are the same as described in step (a);
(c) reacting the aldehyde of the formula (XII) from step (b) with trialkyl 2-phosphonopionate (XIII); wherein the reaction is a Homer-Wadsworth-Emmons reaction; wherein the phosphonopionate (XIII) is initially treated with a base selected from the group consisting of sodium hydride, potassium hydride, lithium hydride, potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, butyl lithium, lithium diisopropylamide, lithium diethylamide, sodium amide, potassium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, and lithium bis(trimethylsilyl)amide:

wherein R 4 is independently methyl, ethyl, propyl, isopropyl, or benzyl to afford products of the formula (XIV):

(d) reducing the compounds obtained from step (c) to form compounds of formula (XV) using diisobutylaluminum hydride, lithium borohydride, lithium triethyl borohydride, borate, lithium aluminium hydride, lithium trimethoxide aluminium hydride, aluminium hydride, lithium aluminium hydride mixed with aluminium chloride, and sodium borohydride mixed with lithium chloride or calcium chloride:

(e) converting the hydroxyl group in the compounds from step (d) to a leaving group to form compounds of the formula (XVI):

wherein Z is OTs, OMs, OTf, Cl, or Br;
(f) performing a coupling reaction between the compounds obtained in step (e) and a Grignard reagent or an organozinc reagent in the formula (XVII), wherein the reaction is catalyzed by a transition metal with or without a ligand:

wherein X′ is chloro, bromo, or iodo; and M is Mg or Zn, to form compound (XVIII) or (XIX);

(g) removing the protective group in compounds in the formula (XVIII) and (XIX) from step (f) to afford the final product in the formula (I) and (II):

2. The method of claim 1 , wherein the protective group of step (a) is selected from methyl, methoxymethyl, benzyloxymethyl, 2-(trimethylsilyl)ethoxymethyl, methylthiomethyl, phenylthiomethyl, tetrahydropyranyl, 1-ethoxyethyl, propargyl, t-butyl, benzyl, 4-methoxybenzyl, o-nitrobenzyl, 9-anthrylmethyl, 4-methoxyphenyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, t-butyldimethylsilyl, t-butyldiphenyisilyl, formyl, acetyl, benzoyl, methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethylcarbonyl, benzoxycarbonyl, methanesulfonyl, and toluenesulfonyl.

3. The method of claim 1 , wherein the tocotrienols of formula (I) are from bran oil, palm oil, and annatto oil.

4. The method of claim 1 , wherein the oxidation in step (b) is performed using OsO 4 /NaIO 4 .

5. The method of claim 4 , wherein the reaction solvent used in step (b) for OsO 4 /NaIO 4 reaction is a mixture of tetrahydrofuran, diethyl ethyl, methyl tert-butyl ether, diisopropyl ether, or 1,4-dioxane with water.

6. The method of claim 1 , wherein the oxidation in step (b) is performed by ozonolysis.

7. The method claim 1 , wherein the reaction temperature in step (b) is below 40° C.

8. The method of claim 1 , wherein the reaction is maintained between −78 to 30° C. during step (c) and/or during step (d) for between 1-12 hours.

9. The method of claim 1 , wherein the solvent used in step (c) and/or in step (d) is selected from tetrahydrofuran, diethyl ether, diisopropyl ether, methyl tert-butyl ether, dimethylformide, and dimethylacetamide.

10. The method of claim 2 , wherein P is t-butyldimethylsilyl; and wherein the reaction temperature for step (a) is between −5° C. and 25° C. and the reaction time for step (a) is between 30 min and 3 hours.

11. The method of claim 10 , wherein the oxidation in step (b) is performed using OsO 4 /NaIO 4 in a solvent comprising tetrahydrofuran and water at a reaction temperature below 40° C.

12. The method of claim 11 , wherein the base of step (c) is sodium hydride.

13. The method of claim 12 , wherein step (d) is performed using diisohutylaluminium hydride; and wherein the reaction temperature of step (d) is between −78° C. and 30° C. and the reaction time of step (d) is between 1 and 12 hours.

Assignees

• Univ Arkansas
• Us Dept Veterans Affairs
• Us Of America As Represented By The Dept Of Veterans Affairs

Inventors

• Zheng Guangrong
• Compadre Cesar
• Hauer-Jensen Martin
• Crooks Peter
• Breen Philip

Classifications

• C07D311/58 Primary

  other than with oxygen or sulphur atoms in position 2 or 4 · CPC title

• C12P17/06 Primary

  containing a six-membered hetero ring, e.g. fluorescein · CPC title

• Y02P20/55

  Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups · CPC title