Process for preparation of delta-tocotrienols

Abstract

The present invention relates to a process for the preparation of vitamin E derivatives, in particular a process for the synthesis of delta-tocotrienols of formula (I). # imgabs0 #

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This international PCT application claims priority to and the benefit of PCT application No. PCT / US2022 / 082646, filed on December 30, 2022, the contents of which are incorporated herein by reference in their entirety. Background Art

[0002] Vitamin E, also known as tocopherol, is a fat-soluble vitamin introduced into the body through food. It is stored in the liver and released from the body in small doses when needed.

[0003] It is abundant in foods, especially in oil-bearing fruits such as olives, peanuts, and corn, and in wheat seeds. It can also be found in cereals, nuts, and green vegetables.

[0004] Vitamin E is a major fat-soluble component of the cellular antioxidant defense system. It protects cells from free radical damage and, in certain cases, reduces the production of free radicals. These characteristics make it an important tool for cancer prevention. Additionally, vitamin E has been found to be very effective in preventing and reversing complications of a variety of diseases due to its antioxidant function, its role in anti-inflammatory processes, its inhibition of platelet aggregation, and its immunopotentiating activity.

[0005] This vitamin occurs naturally in eight major isomers: α-, β-, γ-, and δ-tocotrienol, as well as the four corresponding tocopherols. Tocotrienols differ from tocopherols by having a farnesyl moiety (three double bonds) instead of a saturated phytyl side chain. The α-, β-, γ-, and δ-homologues are defined by the methylation pattern of the aromatic ring.

[0006] Tocotrienols have been shown to have positive effects on various aspects of human health: they downregulate cholesterol biosynthesis by increasing the degradation of HMG-CoA reductase and reducing the translation efficiency of HMG-CoA reductase mRNA; they are lipid-soluble antioxidants that protect membranes and cellular components from free radical-mediated oxidative stress and also inhibit the oxidation of low-density lipoproteins, which is associated with cardiovascular disease. Furthermore, tocotrienols possess important neuroprotective and antitumor properties: of the isomers, delta-tocotrienol is perhaps the most studied in the context of tumor pathology. In fact, in vitro and preclinical studies have shown that delta-tocotrienol is most active in preventing the proliferation of human melanoma cells.

[0007] Tocotrienols are particularly abundant in palm oil and cereal seeds. Other cultivated plants rich in tocotrienols include rice, wheat, barley, rye, and oats. Tocotrienols are also found naturally in various other oils, seeds, and fruits at varying levels.

[0008] Given the importance of tocotrienols in health management and due to their presence in various natural sources and foods at varying levels; supplementation of these molecules is often indicated.

[0009] However, isolating delta-tocotrienol from natural sources presents several challenges. First, the supply of raw materials, such as plant oils or seeds, is limited and inadequate. Second, isolation from natural sources requires several preparative-scale reverse-phase chromatography methods or expensive methods involving critical distillation procedures or simulated moving-bed chromatography. These limitations have led to the development of various synthetic routes to delta-tocotrienol and its derivatives.

[0010] Delta-tocotrienol is a compound of formula (I): Chemically known as (2R)-2,8-dimethyl-2-[(3E,7E)-4,8,12-trimethyltrideca-3,7,11-trienyl]-3,4-dihydrochromen-6-ol. It has an absolute (2R) configuration at the chiral carbon of the chroman ring and three double bond sites at the 3', 7' and 11' positions of the 16-carbon chain attached to the chroman ring.

[0011] Various delta-tocotrienol processes are known in the literature, most of which share similar synthetic methods.

[0012] In particular, δ-tocotrienol can be synthesized by 8-methylchroman-2-methanol (MCM) of formula (II) With the 15-carbon farnesyl chain of formula (III) to obtain, Wherein Y represents a leaving group.

[0013] This reaction is carried out in the presence of n-butyllithium and hexamethylphosphoramide, forming a carbanion in the alpha position relative to the leaving group Y, and which subsequently attacks the chroman derivative of formula (II).

[0014] Following the same synthetic method, R. Chenevert et al. disclosed a method for preparing tocotrienol in the form of α-isomer in Bioorg. Med. Chem. 2006, 14, 5389-5396, as reported in the following Scheme 1: Solution 1 E. Couladouros et al. disclosed in J. Org. Chem. 2007, 72, 6735-6741 a method for preparing β-, γ- and δ-tocotrienol according to the synthetic route reported in Scheme 2 below: Option 2

[0015] Similarly, international patent application WO 2019 / 053605 discloses the method reported in Scheme 3: Option 3

[0016] In addition, international patent application WO 2005 / 035490 discloses a process for the synthesis of delta-tocotrienol, wherein a protected chroman sulfonate is reacted with a Grignard reagent prepared from a farnesyl halide according to the synthetic route reported in Scheme 4 below: Option 4 wherein P is a protecting group and Q is a sulfonate derivative. However, the methods disclosed in the prior art are difficult to implement on an industrial scale because they require harsh reaction conditions such as very low temperature (-78°C), hazardous reagents such as metallic lithium and toxic substances such as hexamethylphosphoramide, which do not allow large-scale use.

[0017] We have now discovered a new synthetic method for preparing delta-tocotrienol, which involves reacting a chroman derivative directly with a farnesyl derivative without the use of toxic reagents or low temperatures. This synthetic method allows the desired product to be obtained in high yield and purity and reduces costs due to a more simplified chemical process.

[0018] Therefore, the object of the present invention is a process for preparing delta-tocotrienol of formula (I), The method comprises: c) making a compound of formula (V) and a compound of formula (VII) wherein P represents a protecting group selected from benzoyl, acetyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, p-toluenesulfonate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, benzenesulfonate, methanesulfonate, benzyl ether, methyl ether, 2-tetrahydropyranyl ether, 2-tetrahydrofuranyl ether, methoxymethyl ether, X is a halogen atom selected from bromine, iodine, and chlorine, Z is a halogen atom selected from bromine, iodine, and chlorine, reacting in the presence of magnesium metal, a magnesium activator and optional additives To provide a compound of formula (VIII), as well as d) Deprotecting the obtained compound of formula (VIII) to give the desired delta-tocotrienol of formula (I).

[0019] According to the process of the present invention, the coupling reaction between the chroman derivative of formula (V) and the farnesyl derivative of formula (VII) in step c) is carried out in an inert organic solvent in the presence of metallic magnesium, a magnesium activator and optional additives.

[0020] Examples of inert organic solvents according to the invention are diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, toluene or mixtures thereof.

[0021] Preferably, the coupling reaction is carried out in 2-methyltetrahydrofuran.

[0022] In the process of the present invention, metallic magnesium is introduced into a reaction mixture containing a chroman derivative of the formula (V) and a farnesyl derivative of the formula (VII) dissolved in an inert organic solvent.

[0023] Preferably, metallic magnesium is added in an amount comprised between 1.0 and 10.0 molar equivalents, more preferably between 5.0 and 7.0 molar equivalents relative to the molar amount of the compound of formula (V).

[0024] In fact, the applicants of the present invention surprisingly found that the Grignard reagent formed by the reaction between metallic magnesium and the chroman derivative of formula (V) cannot be obtained under well-known experimental conditions (see comparative examples), and that the coupling reaction only occurs when the two single compounds are reacted in the presence of metallic magnesium.

[0025] Furthermore, contrary to the experimental conditions disclosed in the prior art, in particular in WO 2005 / 035490, the coupling reaction is carried out at a higher temperature, in particular comprised between 20°C and 100°C, preferably at about 80°C.

[0026] Optional additives are lithium, zinc, cobalt, nickel, copper, palladium or iron salts selected from the group consisting of lithium chloride, lithium bromide, lithium iodide, zinc chloride, zinc bromide, zinc iodide, cobalt chloride, cobalt dichloride, nickel chloride, copper (I) chloride, copper (II) chloride, copper (I) bromide, copper (II) dibromide, copper iodide, copper trifluoromethanesulfonate, palladium chloride, iron (III) chloride, preferably lithium chloride; and / or an organic chelate compound selected from the group consisting of tetramethylethylenediamine (TMEDA), 1,2-dimethylethylenediamine (DMEDA), ethanolamine (ETA), triphenylphosphine (PPh3), 1,3-bis(diphenylphosphino)propane (DPPP), 1,3-butadiene, isoprene, preferably TMEDA.

[0027] Said optional additives are preferably used in an amount comprised between 0.1 and 3.0 molar equivalents relative to the molar amount of the compound of formula (V).

[0028] The magnesium activator is chosen from iodine, dichloroethane, dibromoethane, trimethylsilyl chloride and is added to the reaction mixture in an amount comprised between 0.01 and 1.0 molar equivalents relative to the molar amount of the compound of formula (V).

[0029] Once the coupling reaction is complete, the compound of formula (VIII) is obtained and is isolated from the reaction mixture according to techniques well known to the skilled person, such as extraction, filtration, crystallization, precipitation.

[0030] This compound is subsequently subjected to a deprotection which can be carried out under different conditions depending on the protecting group P present on the aromatic moiety to obtain the desired delta-tocotrienol of formula (I).

[0031] As is well known to the skilled person, the deprotection is carried out in the presence of an acid or base chosen from sodium hydroxide, potassium hydroxide, hydrochloric acid, sulfuric acid, acetic acid, formic acid, in a solvent chosen from water, alcohols, ethers, ketones or mixtures thereof at a temperature comprised between 25°C and 80°C.

[0032] According to one embodiment of the present invention, the compound of formula (VII) (wherein Z represents a halogen atom selected from chlorine, bromine, iodine, preferably bromine) is obtained by halogenating a commercially available compound of formula (IX) in the presence of a halogenating agent.

[0033] Typically, examples of halogenating agents that can be used in the process of the present invention are phosphorus tribromide, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, thionyl chloride in an aprotic solvent selected from N,N-dimethylformamide, tetrahydrofuran, dichloromethane.

[0034] In an alternative, iodine and bromine can be used as halogenating agents in the presence of triphenylphosphine and imidazole.

[0035] According to a further embodiment, the present invention also relates to a process for the synthesis of chroman derivatives of formula (V), The method comprises the following steps: a) selectively protecting the aromatic hydroxyl group of 8-methylchroman-2-methanol of formula (II) in the form of a single enantiomer in the presence of a protecting agent To obtain the intermediate of formula (IV), wherein P has the meaning reported above; and b) converting the compound of formula (IV) into the corresponding halide derivative of formula (V), wherein X is a halogen atom selected from bromine, iodine and chlorine, preferably iodine.

[0036] According to the present invention, step a) is performed by dissolving the compound of formula (II) (ie 8-methylchroman-2-methanol) in an aprotic solvent.

[0037] Examples of aprotic solvents that can be used in this reaction are N,N-dimethylformamide, tetrahydrofuran, dichloromethane.

[0038] Preferably, 8-methylchroman-2-methanol is dissolved in dichloromethane.

[0039] In the presence of a base, a protecting agent of the formula PX, wherein P has the meaning mentioned above and X is a halogen atom, is introduced into the reaction mixture.

[0040] The preferred base according to the present invention is selected from triethylamine, tributylamine, N,N-diisopropylethylamine, 4-dimethylaminopyridine, potassium carbonate, sodium carbonate, more preferably triethylamine.

[0041] Examples of protecting agents which can be used to introduce the P group having the above-mentioned meaning are tosyl chloride and benzyl bromide.

[0042] Preferably, the protecting agent is used in an amount comprised between 1.0 and 2.0 molar equivalents, more preferably about 1.1 molar equivalents, relative to the molar amount of the compound of formula (II).

[0043] The compound of formula (IV) thus obtained is subsequently halogenated under experimental conditions familiar to the skilled person in order to obtain the desired chroman derivative of formula (V).

[0044] In an alternative embodiment, the compound of formula (V) can be prepared according to a method comprising the following steps: b1) the compound of formula (IV) Converted into the corresponding compound of formula (VI), wherein P has the meaning mentioned above, and LG represents a sulfonate leaving group selected from the group consisting of tosyl, mesyl, nitrobenzenesulfonyl, triflate, nonafluoromethanesulfonate, preferably tosyl; b2) Halogenation of the compound of formula (VI) thus obtained to provide the desired compound of formula (V).

[0045] Preferably, the chroman derivative of formula (V) is prepared by first converting the compound of formula (IV) into an intermediate compound of formula (VI) and then converting the compound of formula (VI) into the corresponding halide.

[0046] According to the most preferred embodiment, the present invention relates to a process for the preparation of delta-tocotrienol of formula (I), The method comprises the following steps: a) selectively protecting the aromatic hydroxyl group of 8-methylchroman-2-methanol of formula (II) in the form of a single enantiomer in the presence of a protecting agent To obtain the intermediate of formula (IV), wherein P represents a protecting group selected from benzoyl, acetyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, p-toluenesulfonate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, benzenesulfonate, methanesulfonate, benzyl ether, methyl ether, 2-tetrahydropyranyl ether, 2-tetrahydrofuranyl ether, methoxymethyl ether, b1) converting the compound of formula (IV) into the corresponding compound of formula (VI), wherein P and LG have the meanings reported above, b2) halogenating the compound of formula (VI) thus obtained to provide a compound of formula (V), wherein P has the meaning reported above, X is a halogen atom selected from bromine, iodine, chlorine, c) reacting a compound of formula (V) with a compound of formula (VII), Z is a halogen atom selected from bromine, iodine, and chlorine, reacting in the presence of magnesium metal, a magnesium activator and optional additives To provide a compound of formula (VIII), as well as d) Deprotecting the obtained compound of formula (VIII) to give the desired delta-tocotrienol of formula (I).

[0047] The process object of the present invention can be represented schematically as reported in Scheme 5 below. Option 5

[0048] The invention will now be illustrated with the aid of some examples, which should not be considered as limiting the scope of the invention. Example Example 1 . Synthesis of (S)-(6-(Benzyloxy)-2,8-dimethylchroman-2-yl)methanol.

[0049] In a reaction flask, 20.0 g of 8-methylchroman-2-methanol (MCM, 1 eq), 100 mL of dimethylformamide (5 vol), 19.9 g of potassium carbonate (1.5 vol), and 18.1 g of benzyl bromide (1.1 eq) were charged.

[0050] The reaction mixture was stirred at room temperature overnight. At the end of the reaction, 150 mL of water and 150 mL of ethyl acetate were added, and the organic phase was washed with water (3 x 100 mL) and brine (1 x 50 mL). The collected organic phase was filtered over celite and charcoal and then dried over magnesium sulfate. After evaporation of the solvent, 28.42 g of (S)-(6-(benzyloxy)-2,8-dimethylchroman-2-yl)methanol (99.3%) was obtained. 1H-NMR (CDCl3, 400 MHz): δ 7.46-7.34 (m, 5H), δ 6.70-6.69 (d, 1H), δ6.58-6.57 (d, 1H), δ 5.00 (s, 2H), δ 3.69-3.59 (m, 2H) δ 2.89-2.71 (m, 2H), δ2.18 (s, 3H), δ 2.07-1.96 (m, 2H), δ 1.74-1.65 (m, 1H), δ 1.27 (s, 1H). 13 C-NMR (CDCl3, 400 MHz): δ 151.87, δ 145.73, δ 137.59, δ 128.54, δ127.82, δ 127.49, δ 127.19, δ 121.11, δ 115.97, δ 112.32, δ 70.58, δ 69.41, δ27.81, δ 22.29, δ 20.84, δ 16.28. Example 2 . Synthesis of (S)-(6-(benzyloxy)-2,8-dimethylchroman-2-yl)methyl 4-toluenesulfonate.

[0051] In a reaction flask, 25.0 g of (S)-(6-(benzyloxy)-2,8-dimethylchroman-2-yl)methanol (1 equivalent), 250 mL of dichloromethane (10 volumes), and 18.8 g of 4-dimethylaminopyridine (DMAP, 2 equivalents) were charged.

[0052] The reaction mixture was cooled to 10°C and 19.1 g of tosyl chloride (1.2 eq) was added. The reaction was stirred at room temperature overnight.

[0053] At the end of the reaction, 50 mL of water was added. The organic phase was washed with 6 N hydrochloric acid solution (1 x 20 mL) and water (2 x 50 mL) to a pH of 6. The collected organic phases were dried over magnesium sulfate. After evaporation of the solvent, 37.63 g of (S)-(6-(benzyloxy)-2,8-dimethylchroman-2-yl)methyl 4-toluenesulfonate (99.2%) was obtained. 1H-NMR (CDCl3, 400 MHz): δ 7.84-7.82 (d, 2H), δ 7.45-7.35 (m, 7H), δ6.69-6.68 (d, 1H), δ 6.54-6.53 (d, 1H), δ 5.00 (s, 2H), δ 4.07-3.95 (dd, 2H), δ 2.72-2.69 (m, 2H), δ 2.48 (s, 3H), δ 2.11 (s, 3H), δ 1.95-1.93 (m, 1H), δ1.80-1.76 (m, 1H), δ 1.34 (s, 3H). 13 C-NMR (CDCl3, 400 MHz): δ 152.00, δ 145.25, δ 144.95, δ 137.53, δ132.75, δ 129.94, δ 128.56, δ 127.95, δ 127.85, δ 127.48, 127.31, δ 120.55, δ116.10, δ 112.13, δ 73.97, δ 73.51, δ 70.52, δ 28.16, δ 22.38, δ 21.93, δ21.68, δ 16.14. Example 3 . Synthesis of (S)-6-(benzyloxy)-2-(iodomethyl)-2,8-dimethylchroman.

[0054] A reaction flask was charged with 2.9 g of (S)-(6-(benzyloxy)-2,8-dimethylchroman-2-yl)methyl 4-toluenesulfonate (1 equivalent), 29 mL of dimethylformamide (10 volumes), and 5.3 g of potassium iodide (5 equivalents). The temperature was brought to 150°C, and the reaction mixture was stirred under these conditions for approximately 10 hours.

[0055] At the end of the reaction, 30 mL of water and 30 mL of ethyl acetate were added, the phases were separated and the aqueous phase was extracted with 20 mL of ethyl acetate. The organic phases were then combined and washed with water (3 x 50 mL) and brine (1 x 20 mL).

[0056] The collected organic phases were filtered over celite and charcoal and then dried over magnesium sulfate.After evaporation of the solvent, 2.34 g of (S)-6-(benzyloxy)-2-(iodomethyl)-2,8-dimethylchroman were obtained (89.6%). 1H-NMR (CDCl3, 400 MHz): δ 7.46-7.34 (m, 5H), δ 6.71-6.70 (d, 1H), δ6.58-6.57 (d, 1H), δ 5.01 (s, 2H), δ 3.36 (m, 2H), δ 2.76-2.73 (m, 2H), δ2.19 (s, 3H), δ 2.13-2.08 (m, 1H), δ 1.96-1.91 (m, 1H), δ 1.49 (s, 3H). 13 C-NMR (CDCl3, 400 MHz): δ 152.08, δ 145.62, δ 137.63, δ 128.59, δ127.87, δ 127.63, δ 127.53, δ 120.61, δ 116.16, δ 112.20, δ 73.71, δ 70.58, δ30.28, δ 25.60, δ 22.61, δ 16.39, δ 15.24. Example 4 . Synthesis of (S)-6-(benzyloxy)-2-(bromomethyl)-2,8-dimethylchroman.

[0057] A reaction flask was charged with 4.2 g of (S)-(6-(benzyloxy)-2,8-dimethylchroman-2-yl)methyl 4-toluenesulfonate (1 equivalent), 40 mL of dimethylformamide (10 volumes), and 12.0 g of sodium bromide (15 equivalents). The temperature was brought to 150°C, and the reaction mixture was stirred under these conditions for approximately 10 hours.

[0058] At the end of the reaction, 50 mL of water and 50 mL of ethyl acetate were added, the phases were separated, and the aqueous phase was extracted with 20 mL of ethyl acetate. The organic phases were then combined and washed with water (3 x 50 mL) and brine (1 x 20 mL).

[0059] The collected organic phases were filtered over celite and charcoal and then dried over magnesium sulfate.After evaporation of the solvent, 3.40 g of (S)-6-(benzyloxy)-2-(bromomethyl)-2,8-dimethylchroman were obtained (98.0%). Example 5 Synthesis of (S)-2,8-dimethyl-2-((p-toluenesulfonyloxy)methyl)chroman-6-yl 4-toluenesulfonate.

[0060] A reaction flask was charged with 0.5 g of 8-methylchroman-2-methanol (MCM, 1 eq), 5.0 mL of dichloromethane (10 vol), 0.73 g of triethylamine (3 eq), and 0.05 g of 4-dimethylaminopyridine (DMAP, 0.2 eq). 1.09 g of tosyl chloride (2.4 eq) was added, and the reaction mixture was stirred at room temperature overnight. At the end of the reaction, 5 mL of dichloromethane and 10 mL of 1 N hydrochloric acid solution were added. The phases were separated, and the organic phase was washed with water (2 x 10 mL) to a pH of 6. The collected organic phases were dried over magnesium sulfate. After evaporation of the solvent, 1.20 g of (S)-2,8-dimethyl-2-((p-toluenesulfonyloxy)methyl)chroman-6-yl 4-toluenesulfonate was obtained (97%). 1 H-NMR (CDCl3, 400 MHz): δ 7.78-7.76 (d, 2H), δ 7.73-7.70 (d, 2H), δ7.35-7.31 (m, 4H), 6.55-6.52 (d, 2H), δ 4.00-3.90 (dd, 2H), δ 2.63-2.59 (m,2H), δ 2.45 (s, 6H), δ 1.98 (s, 3H), δ 1.89-1.87 (m, 1H), δ 1.73-1.70 (m,1H), δ 1.27 (s, 3H). 13 C-NMR (CDCl3, 400 MHz): δ 149.63, δ 145.19, δ 145.10, δ 141.98, δ132.66, δ 132.58, δ 129.69, δ 129,68, δ 128.47, δ 127.87, δ 127.63, δ 122.27, δ 120.71, δ 120.11, δ 74.60, δ 73.35, δ 27.59, δ 22.21, δ 21.70, δ 21.65, δ21.55, δ 15.91. Example 6 Synthesis of (S)-2-(iodomethyl)-2,8-dimethylchroman-6-yl 4-toluenesulfonate

[0061] A reaction flask was charged with 24.8 g of (S)-2,8-dimethyl-2-((p-toluenesulfonyloxy)methyl)chroman-6-yl 4-toluenesulfonate (1 equivalent), 250 mL of dimethylformamide (10 volumes), and 39.8 g of potassium iodide (5 equivalents). The temperature was brought to 150°C, and the reaction mixture was stirred under these conditions for approximately 10 hours.

[0062] At the end of the reaction, 250 mL of water and 250 mL of ethyl acetate were added, the phases were separated, and the aqueous phase was extracted with 200 mL of ethyl acetate. The organic phases were then combined and washed with water (3 x 250 mL) and brine.

[0063] The collected organic phases were filtered over celite and charcoal and then dried over magnesium sulfate.After evaporation of the solvent, 20.9 g of (S)-2-(iodomethyl)-2,8-dimethylchroman-6-yl 4-toluenesulfonate were obtained (92%). 1 H-NMR (CDCl3, 400 MHz): δ 7.74-7.72 (d, 2H), δ 7.34-7.32 (d, 2H), δ6.59-6.56 (d, 2H), δ 3.32 (m, 2H), δ 2.66 (m, 2H), δ 2.46 (s, 3H), δ 2.10 (s,3H), δ 2.06 (m, 1H), δ 1.89 (m, 1H), δ1.45 (s, 3H). 13 C-NMR (CDCl3, 400 MHz): δ 149.94, δ 145.11, δ 141.98, δ 132.77, δ129.65, δ 128.50, δ 127.85, δ 122.24, δ120.76, δ 120.16, δ 75.22, δ 29.79, δ25.32, δ 21.92, δ 21.72, δ 16.09, δ 14.76 Example 7 . Synthesis of (2E,6E)-1-bromo-3,7,11-trimethyldodeca-2,6,10-triene.

[0064] A reaction flask was charged with 5.0 g of trans,trans-farnesol (1 equivalent) and 25 mL of tetrahydrofuran (5 volumes). The reaction mixture was cooled to 0°C, and 2.8 g of phosphorus tribromide (0.46 equivalents) was added dropwise over approximately 40 minutes. The reaction mixture was stirred under these conditions for approximately 3 hours.

[0065] Once the reaction is complete, 12.5 mL of water is added dropwise, maintaining the temperature at 0°C. After the reaction has reached room temperature, 12.5 mL of methyltetrahydrofuran is added and the phases are separated. The aqueous phase is extracted with 10 mL of methyltetrahydrofuran, and the combined organic phases are washed with a saturated sodium bicarbonate solution (3 x 250 mL) and brine (1 x 5 mL).

[0066] The collected organic phases were dried over magnesium sulfate, and the solvent was evaporated to obtain 6.4 g of (2E,6E)-1-bromo-3,7,11-trimethyldodeca-2,6,10-triene (99.8%). 1 H-NMR (CDCl3, 400 MHz): δ 5.55 (t, 1H), δ 5.12-5.09 (m, 2H), δ 4.05-4.03 (d, 2H), δ 2.13-1.99 (m, 8H), δ 1.75 (s, 3H), δ 1.70 (s, 3H), δ 1.62 (s,6H). 13 C-NMR (CDCl3, 400 MHz): δ 143.55, δ 135.59, δ 131.28, δ 124.34, δ123.40, δ 120.61, δ 39.69, δ 39.53, δ 29.60, δ 26.71, δ 26.11, δ 25.71, δ17.71, δ 16.05, δ 15.97 Example 8 Synthesis of (R)-2,8-dimethyl-2-((3E,7E)-4,8,12-trimethyltrideca-3,7,11-trien-1-yl)chroman-6-yl 4-toluenesulfonate.

[0067] Under a nitrogen atmosphere, a reaction flask was charged with 32.0 g of magnesium turnings (6 equivalents) and 200 mL of methyltetrahydrofuran (2 volumes). The reaction mixture was slowly warmed to 70°C, and a solution of 105.0 g of (S)-6-(benzyloxy)-2-(iodomethyl)-2,8-dimethylchroman (1 equivalent) and (2E,6E)-1-bromo-3,7,11-trimethyldodeca-2,6,10-triene (76.0 g, 1.2 equivalents) in 300 mL of methyltetrahydrofuran (3 volumes) was added dropwise over approximately 1.30 hours. The reaction mixture was stirred at reflux under these conditions for approximately 1 hour.

[0068] Once the reaction was complete, the reaction mixture was allowed to reach room temperature and the solid magnesium turnings were removed. The solvent was evaporated, and the crude (R)-2,8-dimethyl-2-((3E,7E)-4,8,12-trimethyltrideca-3,7,11-trien-1-yl)chroman-6-yl 4-toluenesulfonate was extracted with ethane (2 x 250 mL). The organic phases were combined, and after evaporation of the solvent, the crude product obtained was used as is in the next step. 1 H-NMR (CDCl3, 400 MHz): δ 7.75-7.73 (d, 2H), δ 7.33-7.31 (d, 2H), δ6.56 (s, 2H), δ 5.13 (m, 3H), δ 2.67 (m, 2H), δ 2.46 (s, 3H), δ 2.09 (m, 9H), δ 2.01 (m, 4H), δ1.76 (m, 2H) δ 1.70 (m, 3H), δ 1.62 (m, 9H), δ 1.28 (m, 5H). 13 C-NMR (CDCl3, 400 MHz): δ 150.67, δ 144.96, δ 141.43, δ 135.30, δ134.97, δ 132.89, δ 131.20, δ 129.57, δ 128.53, δ 127.43, δ 124.37, δ 124.16, δ 124.06, δ 121.89, δ 121.09, δ 120.18, δ 76.07, δ 39.81, δ 39.73, δ 39.69, δ30.88, δ 26.77, δ 26.58, δ 25.71, δ 23.99, δ 22.31, δ 22.12, δ 21.67, δ17.69, δ 16.04, δ 16.02, δ 15.88. Example 9 Used in the coupling reaction of (R)-2,8-dimethyl-2-((3E,7E)-4,8,12-trimethyltrideca-3,7,11-trien-1-yl)chroman-6-yl 4-toluenesulfonate (comparative).

[0069] The coupling reaction was carried out according to the experimental conditions disclosed in the prior art WO 2005 / 035490 (Example 1 - Step 2). There was no evidence of the formation of the desired product. Example 10 . Synthesis of δ-tocotrienol

[0070] Under a nitrogen atmosphere, a reaction flask was charged with 15.5 g of crude (R)-2,8-dimethyl-2-((3E,7E)-4,8,12-trimethyltrideca-3,7,11-trien-1-yl)chroman-6-yl 4-toluenesulfonate (1 equivalent), 140 mL of tetrahydrofuran (9 volumes), 15 mL of water (1 volume), and 19.5 g of potassium carbonate (5 equivalents). The reaction mixture was stirred under reflux overnight under these conditions.

[0071] Once the reaction is complete, the reaction is allowed to reach room temperature and the solvent is removed by evaporation. The crude product is dissolved in methyltetrahydrofuran (10 volumes) and water (10 volumes), the phases are separated, and the organic phase is washed with brine and dried over magnesium sulfate. The solvent is evaporated, and 10.8 g of δ-tocotrienol (97%) is obtained. 1 H-NMR (CDCl3, 400 MHz): δ 6.52 - 6.51 (d, 1H), δ 6.43 - 6.42 (d, 1H), δ 5.19 - 5.15 (m, 3H), δ 5.05 (s, 1H), δ 2.74 - 2.71 (t, 2H), δ 2.17 – 2.10(m, 9H), δ 2.02 (m, 4H), δ 1.85 – 1.82 (m, 2H), δ 1.80 (m, 4H) δ 1.78 – 1.73(m, 10H), δ 1.31 (m, 3H). 13 C-NMR (CDCl3, 400 MHz): δ 148.17, δ 147.75, δ 145.97, δ 135.15, δ134.99, δ 131.28, δ 127.35, δ 124.46, δ 124.34, δ 124.24, δ 121.28, δ 115.78, δ112.73, δ 75.37, δ 39.75, δ 39.73, δ 31.42, δ 26.79, δ 26.63, δ 25.73, δ24.04, δ 22.51, δ 22.21, δ 17.72, δ 16.09, δ 16.04, δ 15.91.

Claims

1. A method for preparing delta-tocotrienol of formula (I), The method comprises the following steps: c) making a compound of formula (V) and a compound of formula (VII) wherein P represents a protecting group selected from benzoyl, acetyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, p-toluenesulfonate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, benzenesulfonate, methanesulfonate, benzyl ether, methyl ether, 2-tetrahydropyranyl ether, 2-tetrahydrofuranyl ether, methoxymethyl ether, X is a halogen atom selected from bromine, iodine, and chlorine, Z is a halogen atom selected from bromine, iodine, and chlorine, reacting in the presence of metallic magnesium, a magnesium activator, and optional additives to provide a compound of formula (VIII), as well as d) Deprotecting the obtained compound of formula (VIII) to give the desired delta-tocotrienol of formula (I).

2. The process according to claim 1, wherein metallic magnesium is added in an amount comprised between 1.0 and 10.0 molar equivalents, preferably between 5.0 and 7.0 molar equivalents, relative to the molar amount of the compound of formula (V).

3. The process according to any one of the preceding claims, wherein the magnesium activator is selected from iodine, ethylene dichloride, ethylene dibromide, trimethylsilyl chloride.

4. The process according to claim 3, wherein the magnesium activator is added to the reaction mixture in an amount comprised between 0.01 and 1.0 molar equivalents relative to the molar amount of the compound of formula (V).

5. The process according to claim 1 , wherein the optional additive is a lithium, zinc, cobalt, nickel, copper, palladium or iron salt selected from the group consisting of lithium chloride, lithium bromide, lithium iodide, zinc chloride, zinc bromide, zinc iodide, cobalt chloride, cobalt dichloride, nickel chloride, copper (I) chloride, copper (II) chloride, copper (I) bromide, copper (II) dibromide, copper iodide, copper trifluoromethanesulfonate, palladium chloride, iron (III) chloride, preferably lithium chloride; and / or an organic chelating compound selected from the group consisting of tetramethylethylenediamine (TMEDA), 1,2-dimethylethylenediamine (DMEDA), ethanolamine (ETA), triphenylphosphine (PPh 3 ), 1,3-bis(diphenylphosphino)propane (DPPP), 1,3-butadiene, isoprene.

6. Process according to any one of the preceding claims, wherein the temperature of step c) is comprised between 20°C and 100°C, preferably about 80°C.

7. A process according to any one of the preceding claims, wherein X is iodine and Z is bromine.

8. The process according to any one of the preceding claims, wherein the compound of formula (V) is prepared by the following steps: a) selectively protecting the aromatic hydroxyl group of 8-methylchroman-2-methanol of formula (II) in the form of a single enantiomer in the presence of a protecting agent To obtain the intermediate of formula (IV), wherein P has the meaning reported above, b) converting the compound of formula (IV) into the corresponding halide derivative of formula (V), wherein X is a halogen atom selected from bromine, iodine, and chlorine.

9. The method according to any one of claims 1 to 7, wherein the compound of formula (V) is prepared by the following steps: a) selectively protecting the aromatic hydroxyl group of 8-methylchroman-2-methanol of formula (II) in the form of a single enantiomer in the presence of a protecting agent To obtain the intermediate of formula (IV), wherein P has the meaning reported above, b1) converting the compound of formula (IV) into the corresponding compound of formula (VI), wherein P has the meaning mentioned above, and LG represents a sulfonate leaving group selected from the group consisting of tosyl, mesyl, nitrobenzenesulfonyl, triflate, nonafluoromethanesulfonate, preferably tosyl; b2) Halogenation of the compound of formula (VI) thus obtained to provide the desired compound of formula (V).

10. The method according to any one of the preceding claims, wherein the compound of formula (VII) wherein Z represents a halogen atom selected from chlorine, bromine, and iodine, The compound of formula (IX) is halogenated in the presence of a halogenating agent to obtain 。

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