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US20050124687A1 - Process for synthesizing d-tocotrienols - Google Patents

Process for synthesizing d-tocotrienols Download PDF

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US20050124687A1
US20050124687A1 US10/962,389 US96238904A US2005124687A1 US 20050124687 A1 US20050124687 A1 US 20050124687A1 US 96238904 A US96238904 A US 96238904A US 2005124687 A1 US2005124687 A1 US 2005124687A1
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ether
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Elias Couladouros
Andreas Papas
Vassilios Moutsos
Maria Lampropoulou
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • C07D311/70—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with two hydrocarbon radicals attached in position 2 and elements other than carbon and hydrogen in position 6
    • C07D311/72—3,4-Dihydro derivatives having in position 2 at least one methyl radical and in position 6 one oxygen atom, e.g. tocopherols

Definitions

  • This invention relates generally to processes for producing certain compounds in the Vitamin E family, also known generally as tocols.
  • the invention relates to processes for producing tocotrienols having the structure and absolute configuration the same as found in nature.
  • the four naturally occurring tocotrienols have the (R) absolute configuration at the C-2 chroman ring position, and the chemical structures wherein R 1 (at C-5 chroman ring position), R 2 (at C-7 chroman ring position), and R 3 (at C-8 chroman ring position) are methyl in the d-alpha-homologue, R 1 and R 3 are methyl in the d-beta-homologue, R 2 and R 3 are methyl in the d-gamma-homologue, and R 3 is methyl in the d-delta homologue, with the non-methyl R groups being hydrogen atoms.
  • each of the four naturally occurring d-tocotrienols has an (R) absolute configuration at the chiral 2-position carbon of the chroman ring.
  • the tocotrienols have a trans double bond site at each of the 3′ and 7′ chain positions in the 16-carbon side chain attached to the chroman ring.
  • the geometry of each of these double bond sites is trans (also referred to as E) in all four natural tocotrienols.
  • d-Tocotrienols are present in the oils, seeds, and other parts of many plants used as foods (see pp. 99-165 in L. Machlin, ed., “Vitamin E: A Comprehensive Treatise” for a discussion of the occurrence of tocotrienols in foods).
  • Tocotrienol-containing concentrates can be prepared from certain plant oils and plant oil by-products such as rice bran oil or palm oil deodorizer distillate. For examples of such isolation processes, see for instance A. G. Top et al., U.S. Pat.
  • Scott et al. prepared a chiral C 15 chroman and added 5-carbon chains to it three times to make the final product tocotrienol. Sato used a C 9 hydroquinone and a C 20 chain derived from geranylgeraniol. Sato used an intermediate C 18 chroman section and a Clo geranyl section.
  • Chenevert and Courchesne Tetrahedron Letters 43, 7971-7973 (2002) formed unnatural (S) or (i)-alpha-tocotrienol in a process-starting with the achiral triol, dl-chromantriol.
  • Chenevert and Courchesne first converted the achiral triol to a (S) monoester via enzymatic desymmetrization and acetylation. Then, the (S) monoester was further treated with two equivalents of mesyl chloride to provide a (R) dimesylated monoester chroman.
  • the triflated chroman was thereafter coupled with phenyl farnesyl sulfone, i.e., a 15-carbon branched carbon chain having three methylated trans double bond sites corresponding to the 16-carbon side chain of a tocopherol, less the methyl carbon attached to the 2-position carbon of the chroman ring.
  • phenyl farnesyl sulfone i.e., a 15-carbon branched carbon chain having three methylated trans double bond sites corresponding to the 16-carbon side chain of a tocopherol, less the methyl carbon attached to the 2-position carbon of the chroman ring.
  • the present invention is a process of forming a natural form d-tocotrienol from a (2S) 2-hydroxymethyl-6-hydroxy-alklychroman compound having the formula shown by (I), in single enantiomer form, wherein R 1 is —H or —CH 3 , R 2 is —H or —CH 3 , and R 3 is —CH 3 .
  • Compound (I) is converted to a (2S) protected chroman sulfonate having the formula as shown by (II), wherein P is a protecting group and Q is a sulfone leaving group.
  • P is replaced with a hydrogen atom via hydrolysis to form the respective beta-, gamma-, or delta-d-tocotrienol product.
  • a natural form d-tocotrienol is made from converting the (2S) 2-hydroxymethyl-6-hydroxy-alklychroman compound of formula (I) to a protected chroman sulfonate having the structure and absolute configuration of (S) as shown by formula (XIII). Thereafter, compound (XIII) is reacted with a farnesyl carbanion to form a protected sulfonyl-substituted tocotrienol. Thereafter, the aryl sulfonyl group and protecting group are replaced with a hydrogen atom via reduction to form a d-tocotrienol product of formula (IV),
  • the invention further includes several methods for providing the chroman diol compound of formula (I).
  • the present invention in one aspect, is a novel process for preparing d-beta-, d-gamma-, and d-delta-tocotrienol.
  • the present process is improved over existing processes in that it is a highly convergent synthesis using more readily available starting materials.
  • the process is hereinafter described with specific reference to formation of d-beta-tocotrienol, but is equally applicable to formation of the d-gamma-, and d-delta-tocotrienol, unless stated otherwise.
  • the present invention provides a process for preparing tocotrienol compounds, which are in all respects identical to the tocotrienols obtained from natural sources, through attachment of a suitably substituted 15-carbon farnesyl chain to a single-enantiomer chroman derivative suitably substituted for carbon-carbon bond formation with the aforementioned farnesyl derivative.
  • a single enantiomer (2S)-chromanol (diol) is coupled with a substituted farnesyl group, a 15-carbon chain having three methylated trans double bond sites corresponding to the side chain of the tocotrienol compound.
  • a tocotrienol product containing greater than 90% of either the R or S enantiomer, and preferably greater than 95% of the particular enantiomer is considered to be in the “single enantiomer” form.
  • the present invention includes a process of forming d-beta-tocotrienol from a (2S) chromanol comprising providing a single enantiomer (2S) 2-hydroxymethyl-6-hydroxy-2,5,8-trimethylchroman (the “(2S) chromanol”), as shown below in structure (1).
  • the process further continues by protecting the C-6 chroman position via selectively converting the C-6 hydroxyl group to an ester or ether. Thereafter, the chroman derivative is sulfonated at the intended farnesyl chain attachment site via substituting the hydroxyl portion of the C-2 hydroxymethyl group with a sulfonate anion (OSO 2 R), represented below in structure (2) by Q.
  • OSO 2 R sulfonate anion
  • the protected chroman sulfonate is then reacted with a Grignard reagent prepared from a farnesyl halide, said Grignard reagent having the structure (3) below wherein X is iodine, bromine, or chlorine:
  • the Grignard reaction is conducted under the influence of a lithium cuprate catalyst such as Li 2 CuCl 4 to produce a protected d-beta-tocotrienol, from which natural-equivalent d-beta-tocotrienol is obtained after deprotection.
  • a suitable protecting group is one which resists reaction during the subsequent steps of sulfonation and Grignard reaction.
  • protecting groups include p-toluenesulfonate ester, benzenesulfonate ester, methanesulfonate ester, benzyl ether, methyl ether, 2-tetrahydropyranyl ether, and 2-tetrahydrofuranyl ether, methoxymethyl ether, methoxyethoxymethyl ether, and silyl ethers such as trimethylsilyl, tert-butyldimethylsilyl, and tert-butyldiphenylsilyl ethers.
  • the most preferred protecting group in the present invention is p-toluenesulfonate.
  • a suitable sulfonate anion is one that performs as a very good leaving group in the subsequent copper-catalysed reaction with the Grignard reagent.
  • particularly suitable sulfonate anions for use in this step include the phenyl sulfonate, p-tolyl sulfonate, p-alkylphenyl sulfonate, and perfluoroalkyl sulfonate, with p-tolyl sulfonate (commonly known as tosylate), being preferred.
  • the protected sulfonate chroman is reacted with the magnesium farnesyl halide under the influence of a lithium cuprate catalyst chosen from the group comprising preferably Li 2 CuCl 4 , or alternatively Li 2 CuBr 4 , and Li 2 CuI 4 .
  • a lithium cuprate catalyst chosen from the group comprising preferably Li 2 CuCl 4 , or alternatively Li 2 CuBr 4 , and Li 2 CuI 4 .
  • Suitable solvents to be used as the medium for this reaction include those ether solvents which are practical for the preparation of Grignard reagents, such as diethyl ether, symmetrical and unsymmetrical dialkyl ethers bearing C 1 -C 5 alkyl groups, and cyclic ethers such as tetrahydrofuran or 1,4-dioxane.
  • the reaction may be run at temperatures ranging from about ⁇ 78° C. to about 100° C. It is preferred that the reaction be run in tetrahydrofuran solvent between about ⁇ 50° C. and about 0° C.
  • the product of the Grignard reaction is the protected d-beta-tocotrienol derivative shown below as structure (4).
  • An enantiomerically pure d-beta-tocotrienol product is obtained from the protected tocotrienol derivative by a step of removing of the protecting group by methods well known in the literature.
  • the group may be removed via hydrolysis by treatment with 1 to 5 equivalents of potassium or sodium hydroxide in a solvent mixture comprising water and a C 1 -C 5 alcohol in a ratio of between about 1:10 to about 10:1, at a temperature ranging from about 0° C. to about 150° C.
  • KOH in ethanol/water at reflux temperature is preferred to hydrolyze the protecting group P—O bond and leave a 6-position hydroxyl group.
  • d-beta-tocotrienol is formed from the (2S) chromanol, (2S) 2-hydroxymethyl-6-hydroxy-2,5,8-trimethylchroman.
  • the (2S) chromanol is converted through the chemical operations of phenolic benzylation (or application of a protecting group other than the benzyl ether to the phenolic hydroxyl group) and triflation (i.e., formation of the triflate or trifluoromethanesulfonate ester), to a chroman triflate having the following structure:
  • the chroman triflate is thereafter reacted with the following farnesyl aryl sulfone carbanion, thus forming the protected d-beta-tocotrienol substituted with an aryl sulfone at the 2′ sidechain position as shown below as structure (7):
  • the present route B process proceeds further by reductively removing the phenylsulfone group and the protecting group from the molecule using methods well known in the literature, to provide a d-beta-tocotrienol product.
  • the aryl sulfone group is replaced by a hydrogen atom using known reducing reagents and conditions.
  • An exemplary reducing method employs lithium metal dissolved in liquid ammonia or in methylamine or ethylamine at about ⁇ 50° C. to about 25° C., or as taught by D. Eren and E. Keinan ( J. Am. Chem. Soc.
  • the farnesyl aryl sulfone carbanion used in route B is prepared through methods known in the art such as reacting farnesyl bromide or chloride with the sodium salt of p-toluenesulfinic acid in a solvent such as dimethylformamide or dimethylsulfoxide, or in a biphasic water-organic solvent mixture using a phase transfer catalyst.
  • the aryl group attached to the sulfur in the molecule can be phenyl, (preferably) p-tolyl, or other p-alkylphenyl.
  • Deprotenation of the farnesyl aryl sulfone to a carbanion is conducted using a strong, non-nucleophillic base such as n-butyllithium (preferably), phenyllithium, or a secondary or tertiary alkyllithium compound in a solvent such as tetrahydrofuran or a C 1 -C 5 symmetrical or unsymmetrical dialkyl ether, either singly or admixed with hexamethylphosphoramide, at a temperature between ⁇ 70° C. and +25° C.
  • the carbanion which is not isolated, is negatively charged at the carbon atom attached to the sulfur atom and thus reacts with the protected chroman sulfonate.
  • the (2S) chromanol of structure (1) for use as starting material in producing d-tocotrienol via the above two syntheses is not presently commercially available.
  • the present invention further includes three new methods for providing the single enantiomer chroman derivatives represented generally as formula (I) and shown specifically below as, (2S) 2-hydroxymethyl-6-hydroxy-2,5,8-trimethylchroman (beta-series), (2S) 2-hydroxymethyl-6-hydroxy-2,7,8-trimethylchroman (gamma-series), and (2S) 2-hydroxymethyl-6-hydroxy-2,8-dimethylchroman (delta-series).
  • the preferred catalyst is boron trifluoride.
  • the preferred solvent is tetrahydrofuran or a symmetrical or unsymmetrical dialkyl ether having no more than 8 carbon atoms.
  • Other Lewis acids such as aluminum trichloride, ferric chloride, stannic chloride, and the like may be used instead of boron trifluoride.
  • This reaction can also be conducted in a hydrocarbon solvent such as benzene, toluene, xylenes, and the like. It is also possible to carry out this reaction using a monoprotected version of the dimethylhydroquinone such as 2,5-dimethylhydroquinone monobenzoate, monotosylate, or methyl or benzyl ether.
  • the ester-substituted hydroquinone is then treated with a strong acid such as HCl, sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, or trifluoromethanesulfonic acid in a solvent such as a dialkyl ether or tetrahydrofuran, hydrocarbon such as toluene, benzene, or an ester solvent such as methyl, ethyl, or butyl acetate to provide a racemic chroman-2-carboxylic estser.
  • This reaction is preferably carried out at a temperature of between 0 and 100 deg C.
  • the racemic chroman-2-carboxylic ester product of this reaction is then isolated by conventional means and subjected to reduction of the ester group to the hydroxyl oxidation state.
  • the preferred reagent for carrying out this reduction is a hydride reagent such as lithium aluminum hydride, diisobutyl aluminum hydride, or sodium bis(2-methoxyethoxy)aluminum hydride.
  • a hydride reagent such as lithium aluminum hydride, diisobutyl aluminum hydride, or sodium bis(2-methoxyethoxy)aluminum hydride.
  • Other preferred reagents include diborane or the technique of catalytic hydrogenation using a catalyst such as rhodium on alumina, platinum on carbon, platinum on alumina, and the like, under a pressure of between about 20 to about 2000 psi of hydrogen. It is most preferred to use sodium bis(2-methoxyethoxy)aluminum hydride in toluene, tetrahydrofuran, or dialkyl ether solvents at temperatures between about ⁇ 20 and about +50 deg C.
  • the resulting racemic chromanol compound is then subjected to kinetic resolution by reaction with succinic anhydride in the presence of a suitable lipase enzyme catalyst such as the preferred Amano PS-30 lipase, either in the powdered form provided by the manufacturer or supported on a suitable inert support such as Celite filter-aid, using an inert solvent such as tert-butyl methyl ether at temperatures between 0 and +40 deg C.
  • a suitable lipase enzyme catalyst such as the preferred Amano PS-30 lipase
  • the protecting group may be chosen from those phenolic hydroxylprotection groups known and discussed by Greene and Wuts as referenced above. Suitable examples include p-toluenesulfonate ester, benzenesulfonate ester, methanesulfonate ester, benzyl ether, methyl ether, 2-tetrahydropyranyl ether, and 2-tetrahydrofuranyl ether, methoxymethyl ether, methoxyethoxymethyl ether, and silyl ethers such as trimethylsilyl, tert-butyldimethylsilyl, and tert-butyldiphenylsilyl ethers, acetate, benzoate, p-toluenesulfonate, methanesulfonate, and benzenesulfonate. It is most preferred that the protecting group is acetate or benzoate.
  • the acid catalyst for the condensation reaction may be a Lewis acid such as zinc chloride, boron trifluoride, or aluminum trichloride, or a Bronsted acid such as a mineral acid or trifluoroacetic acid, as taught by F. Ismail et al., Tetrahedron Letters 33, 3795-3796 (1992). It is preferred that the catalyst be trifluoroacetic acid, and the solvent be water.
  • the reaction may be run between about ⁇ 20 deg C. and +40 deg C.; it is preferred that it be done at about 20 deg C.
  • the oxidative cleavage of the vinyl group may be carried out using techniques well known in the art, such as the use of ozone, sodium dichromate, chromium trioxide, ruthenium tetrachloride and oxygen, or periodic acid/manganese dioxide.
  • techniques well known in the art such as the use of ozone, sodium dichromate, chromium trioxide, ruthenium tetrachloride and oxygen, or periodic acid/manganese dioxide.
  • the oxidation is accomplished by treatment with ozone, followed by zinc in acetic acid or by sodium borohydride, or by hydrogen gas at a pressure of between 15 and 50 PSI in the presence of a palladium or platinum or nickel catalyst such as 5% Pd on charcoal (preferred).
  • a palladium or platinum or nickel catalyst such as 5% Pd on charcoal (preferred).
  • the illustrated intermediate aldehyde is not produced, but the initially formed ozonide is reduced directly to the desired racemic chroman alcohol.
  • the remaining protecting group my then be removed by treatment with appropriate reagents as taught by Greene and Wuts, such as sodium or potassium hydroxide, potassium carbonate, and the like, to produce an unprotected chroman alcohol which may be converted to the necessary single-enantiomer alcohol by the process technology of Hyatt and Skelton, as discussed in a previous embodiment.
  • appropriate reagents such as sodium or potassium hydroxide, potassium carbonate, and the like
  • (2S) 2-hydroxymethyl-6-hydroxy-2,5,8-trimethylchroman for use as starting material in the present tocotrienol syntheses 2,5-dimethylhydroquinone is suitably protected using one of the above listed protecting group, preferably chosen from benzyl ether, acetate, benzoate, p-toluenesulfonate, and tetrahydropyranyl ether, and then brominated in a position ortho to the remaining phenolic hydroxyl group to form a protected bromodimethylhydroquinone. It is most preferred that the protecting group is acetate or benzoate.
  • the protecting step may be conducted either before or after the bromination step.
  • the protecting group is the benzyl ether
  • the bromination is accomplished using N-bromosuccinimide and a catalytic amount of a C 1 -C 10 trialkylamine, preferably a highly sterically hindered amine such as diisopropylethylamine.
  • a suitable palladium catalyst such as Pd(Ph 3 P) 4 , Pd 2 (dba) 3 /R 3 P (where d
  • the catalyst is tetrakis(triphenylphosphine)palladium
  • the solvent is an ether such as diethyl ether or tetrahydrofuran, an ester such as ethyl acetate, or an inert aliphatic or aromatic hydrocarbon solvent having from 5 to 18 carbon atoms.
  • the solvent is tetrahydrofuran and the temperature is about 10 to about 30 deg C.
  • the resulting compound with or without the addition of an additional protecting group to the primary alcohol functional group (if it is desired to use a protecting group, the most preferred group is the benzyl ether), is subjected to a palladium-catalysed cyclization reaction (Heck reaction) using as catalyst Pd(OAc) 2 in the presence of a C 1 -C 8 phosphine such as triphenylphosphine, tri(o-tolyl)phosphine, tributylphosphine, and the like.
  • the solvent is chosen from the group comprising dimethylformamide, dimethyl acetamide, N-methylpyrollidone, and acetonitrile.
  • the phosphine is triphenylphosphine and the solvent is dimethylformamide.
  • the reaction is carried out at a temperature between 0 deg C. and 150 deg C. The preferred range is between 30 and 100 deg C. and most preferably between 50 and 85 deg C.
  • the product of this reaction is a protected chromene as shown in the above scheme.
  • the unwanted 3,4-olefinic linkage of the protected chromene is next reduced using catalytic hydrogenation, a well-known process in the art.
  • the reaction is carried out in an inert solvent such as a C 1 -C 8 alcohol, and ester such as methyl acetate or ethyl acetate, or an ether solvent having from 2 to 8 carbon atoms.
  • the catalyst is chosen from the group comprising palladium on an inert support and platinum on an inert support.
  • the solvent is ethyl alcohol and the catalyst is 5% Pd on charcoal.
  • Hydrogen is supplied to the reaction at a pressure of between 15 and 250 psi, preferably between 30 and 60 psi, and at a temperature about 0 deg C.
  • Fukumoto et al disclose a process for producing chromans which comprises reacting a phenol, a formaldehyde and an unsaturated compound having carbon-carbon double bond in the presence of a secondary amine and an acid at a temperature between about 100° C. to about 200° C. to produce a chroman, as shown below:
  • Step 1) Preparation of the ditoluenesulfonate of (S)-2,5,8-trimethyl-6-hydroxychroman-2-methanol.
  • a solution of 0.005 mole of (S)-2,5,8-trimethyl-6-hydroxychroman-2-methanol in 20 ml of anhydrous pyridine was cooled to 0-5 deg C. under nitrogen and treated with 0.011 mole ofp-toluenesulfonyl chloride. The mixture was allowed to warm to room temperature overnight, and poured into 150 mL of ice water. The resulting mixture was extracted with ethyl acetate (3 ⁇ 50 ml) and the combined organic phase was washed with 5% aq. HCl, water and NaCl brine.
  • Step 2 Preparation of d-beta-Tocotrienol.
  • a solution of farnesyl bromide (0.005 mole) in anhydrous tetrahydrofuran was stirred at zero degrees under a nitrogen atmosphere.
  • An amount of 0.005 mole of magnesium turnings and a small crystal of iodine was added thereto.
  • the mixture was allowed to warm to room temperature to initiate the reaction. Completion of the reaction was evidenced by consumption of the magnesium metal.
  • Step 1) Preparation of racemic 2,5,8-trimethyl-6-hydroxychroman-2-methanol.
  • Methyl-2,5,8-trimethyl-6-benzoyloxychroman-2-carboxylate was prepared (80% yield) from 2,3-dimethylhydroquinone monobenzoate, methyl methacrylate, and paraformaldehyde in the presence of acetic acid and dibutylamine, following the protocol of E. Fukumoto, M. Torihara, and Y. Tamai, U.S. Pat. No. 5,495,026.
  • This ester was reduced using lithium aluminum hydride in tetrahydrofuran to provide racemic 2,5,8-triemthyl-6-hydroxychroman-2-methanol in 90-95% yield.
  • Step 2 Resolution of racemic 2,5,8-trimethyl-6-hydroxychroman-2-methanol.
  • reaction of the above alcohol with succinic anhydride in the presence of Amano PS-30 lipase supported on filter-aid gave an equimolar mixture of (2R)-2,5,8-trimethyl-6-hydroxychroman-2-methanol and the hemisuccinate ester of (2S)-2,5,8-trimethyl-6-hydroxychroman-2-methanol.
  • Step 3 Preparation of (2S)-2,5,8-trimethyl-6-benzyloxychroman-2methanol trifluoromethanesulfonate:
  • the above (2S)-alcohol was allowed to react with benzyl bromide in dimethylformamide in the presence of potassium carbonate at room temperature overnight to provide an 86% yield of the 6-benzyloxy derivative.
  • This substance was allowed to react with trifluoromethanesulfonic anhydride in dichloromethane/triethylamine at low temperature to provide the title compound in 85% yield.
  • Step 4) Preparation of d-beta-Tocotriene.
  • Phenyl 3,7,11-trimethyldodeca-2,6,10-trienyl sulfone was prepared by known methods from trans-farnesol, via farnesyl bromide which was reacted with sodium benzenesulfinate in dimethylformamide.
  • a solution of this sulfone in anhydrous tetrahydrofuran was cooled to below ⁇ 20 deg C. and treated with a solution of 1.1 molar equivalent of n-butyllithium in tetrahydrofuran. This was followed by addition of a solution of the trifluoromethanesulfonate from Step 3 in tetrahydrofuran.

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US10745371B2 (en) 2015-12-16 2020-08-18 Ptc Therapeutics, Inc. Methods for enriching alpha-tocotrienol from mixed tocol compositions

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EA201200054A1 (ru) 2009-06-25 2012-05-30 Эмпэр Лайф Сайнсиз, Инк. Лечение токотриенолами или экстрактами, богатыми токотриенолами, первазивных расстройств развития
JP2014520894A (ja) 2011-07-19 2014-08-25 エジソン ファーマシューティカルズ， インコーポレイテッド 非アルファトコトリエノールの存在下でのアルファトコトリエノールの選択的酸化のための方法
US8816071B2 (en) * 2011-12-02 2014-08-26 First Tech International Limited Tocotrienol derivatives and associated methods
US9512098B1 (en) 2014-02-03 2016-12-06 Board Of Trustees Of The University Of Arkansas Process of producing purified gamma- and delta-tocotrienols from tocol-rich oils or distillates
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US7038067B2 (en) 2006-05-02
WO2005035490A2 (fr) 2005-04-21

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