Ring closure of benzoquinones containing unsaturated side chains using bases in two-phase systems.

Abstract

The present invention relates to the formation of a compound of formula (I) by ring closure reaction of a compound of formula (II) in the presence of a base in a biphasic system. TIFF2024515468000090.tif100147 The reaction is highly efficient and has been found to provide an efficient route for the synthesis of, for example, 3,4-dehydro-α-tocotrienol, α-tocotrienol and α-tocopherol, respectively.

Description

Detailed Description of the Invention

[0001] [Technical field] The present invention relates to the field of synthesis of chromanes and chromenes, in particular 3,4-dehydrotocopherol, 3,4-dehydrotocotrienol, tocopherols and tocotrienols.

[0002] [Background of the invention] An important class of chroman compounds is vitamin E and its esters. The synthetic route of chromans goes through their corresponding chromenes.

[0003] There are various pathways for forming the chromenes.

[0004] Schudel, Mayer, Isler, Helv. Chim. Acta 46, 2517-2526 (1963) disclose the formation of 3,4-dehydrotocotrienol by ring-closing reaction of geranylgeranyltrimethylbenzoquinone in forming chromene by ring-closing in pyridine as reaction medium. The resulting reaction mixture is a complex mixture and isolation of the desired product requires a complex derivatization procedure to form dehydrotocotrienol-p-phenylazobenzoate for separation and purification by crystallization. This procedure is highly disadvantageous since it uses 4-(phenylazo)benzoyl chloride, a very expensive and highly toxic chemical.

[0005] WO 2015 / 028643 A1 discloses the Au(I) or Ag(I) catalyzed intramolecular hydroarylation of chiral arylalkynes to form chromenes. Gold and silver catalysts are very expensive.

[0006] Kabbe and Heitzer, Synthesis 1978, 12, 888-889, disclose that the known synthetic route for vitamin E (i.e., α-tocopherol) from TMHQ and isophytol is not suitable for the synthesis of tocotrienols (i.e., from TMHQ and geranilinalool) because the isoprenoid side chain undergoes a secondary acid-catalyzed ring closure reaction.

[0007] [Summary of the invention] The problem to be solved by the present invention is therefore to provide a process leading to chromenes and chromans in a much simpler manner than processes involving complex derivatizations, purifications and chemical transformations to ultimately obtain the desired products.

[0008] This problem is solved by the process according to claim 1. Surprisingly, it has been found that a two-phase system in the presence of a base is very suitable for this purpose, making it possible to easily isolate the desired compound of formula (I). In particular, it has been found that strongly basic catalysts are particularly suitable as bases for the ring-closing reaction.

[0009] This process provides a highly advantageous synthetic route to the chromans of formula (III) or (IV) according to claims 11 or 12.

[0010] Further aspects of the invention are the subject of further independent claims. Particularly preferred embodiments are the subject of the dependent claims. [Brief description of the drawings]

[0011] [Figure 1] It is shown that during hydrogenation, only the endocyclic carbon-carbon double bond is hydrogenated, while the olefinic carbon-carbon double bonds are not hydrogenated ("partial hydrogenation"), thereby resulting in a compound of formula (III), and all olefinic carbon-carbon double bonds are hydrogenated ("complete hydrogenation"), thereby resulting in a compound of formula (IV).

[0012] [Detailed Description of the Invention] In a first aspect, the present invention provides a compound of formula (I) [ka] The process for producing the compound of Formula (II) [ka] in a two-phase system in the presence of a base to obtain a compound of formula (I), During the ceremony, n=0 or 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12; R 1 represents hydrogen or a methyl group; R 3 and R 4 teeth, each independently represents hydrogen, a methyl group, or a methoxy group, or together represent -CH-CH-CH-, forming an aromatic group; dotted line [ka] any bonds in each represent, independently of each other, either a carbon-carbon single bond or a carbon-carbon double bond; The optional wavy lines, independently of each other, when connected to a carbon-carbon double bond, represent carbon-carbon bonds that are in either the Z or E configuration.

[0013] For clarity, some terms used herein are defined as follows:

[0014] In this specification, "C x~y An "alkyl" group is an alkyl group containing x to y carbon atoms, i.e., for example, C 1~3An alkyl group is an alkyl group containing 1 to 3 carbon atoms. An alkyl group may be straight or branched. For example, -CH(CH3)-CH2-CH3 is considered a C4 alkyl group.

[0015] In this specification, when the same designation for a symbol or group occurs in several formulas, the definition of the group or symbol given in relation to a particular formula also applies to other formulas containing the same designation.

[0016] As used herein, the term "independently of each other" in the context of substituents, moieties, or groups means that similarly designated substituents, moieties, or groups can exist simultaneously in the same molecule while having different meanings.

[0017] As used herein, any dotted line in a formula represents the bond by which a substituent is attached to the remainder of the molecule.

[0018] In this specification, the dotted line in the chemical formula [ka] Any bonds in the formula (I) may, independently of each other, represent either a carbon-carbon single bond or a carbon-carbon double bond.

[0019] Any wavy line in any formula herein, when connected to a carbon-carbon double bond, represents a carbon-carbon bond that is in either the Z or E configuration. It is preferred that in all molecules the carbon-carbon double bond is in the E configuration.

[0020] "pK a " is the negative base 10 logarithm of the acid dissociation constant (pK a =-log 10 K a When an organic acid has multiple protons, the pK a refers to the dissociation constant of the last proton. For example, for a base with two base sites, "pka" is the pK a2Regarding pK a is measured at standard temperature and pressure.

[0021] [Compound of formula (II)] The compounds of formula (II) are substances known to those skilled in the art, as is their synthesis. [ka]

[0022] In one preferred embodiment, the substituent R 3 and R 4 represents a methoxy group. [ka] Any bond in preferably represents a carbon-carbon double bond, preferably in the E configuration.

[0023] Ubiquinone is an important representative of this embodiment. Ubiquinone is designated according to the number of isoprenoid groups in the side chain as ubiquinone-2 (n=0), ubiquinone-3 (n=1), ubiquinone-4 (n=2), ubiquinone-5 (n=3), ubiquinone-6 (n=4, ubiquinone-7 (n=5), ubiquinone-8 (n=6), ubiquinone-9 (n=7) and ubiquinone-10 (n=8). Ubiquinone is also known under the old term coenzyme Q. Ubiquinone-10 (n=8) (=coenzyme Q10) is a particularly preferred species of this embodiment.

[0024] In another preferred embodiment, the substituent R 3 and R 4 represents either H or a methyl group. 3 =R 4 It is preferred that =CH3.

[0025] R 1 =R 3 =R 4 =CH 3 It is particularly preferred that:

[0026] It is preferred that n=2. [ka] It is more preferred that all of the bonds in are carbon-carbon double bonds, and more preferably all are in the E configuration.

[0027] In this embodiment, the compound of formula (II) has the formula (II-BB): [ka] = Geranylgeranyltrimethylbenzoquinone It is preferable that the compound is

[0028] In another preferred embodiment, the substituent R 3 and R 4 are together -CH-CH-CH- to form an aromatic group. [ka] It is expressed as:

[0029] In this embodiment, R 1 preferably represents a methyl group.

[0030] Vitamin K1 (phylloquinone) is an example of this embodiment.

[0031] Menaquinone (MK), also known as vitamin K2, is a further important representative of this embodiment.

[0032] dotted line [ka] Any bond in preferably represents a carbon-carbon double bond, preferably in the E configuration.

[0033] Menaquinones are designated according to the number of isoprenoid groups in the side chain as MK-2 (n=0), MK-3 (n=1), MK-4 (n=2), MK-5 (n=3), MK-6 (n=4), MK-7 (n=5), MK-8 (n=6), MK-9 (n=7), MK-10 (n=8), MK-11 (n=9), MK-12 (n=10) and MK-13 (n=11).

[0034] MK-4 (n=2) is a particularly preferred species of this embodiment.

[0035] dotted line [ka] If any of the bonds in the dotted line represent a carbon-carbon double bond, it would be expected by those skilled in the art that secondary ring formation may occur. Since this secondary ring formation has not been observed, it is particularly preferred that at least one of the dotted bonds represents a carbon-carbon double bond. Thus, this process in particular produces α-tocotrienol with three double bonds in the side chain. α-tocotrienol is an important compound in natural vitamin E.

[0036] [base] The process includes the step of ring-closing a compound of formula (I) in the presence of a base ("base") to obtain a compound of formula (I), as depicted as step a) in the reaction scheme of FIG.

[0037] The base is preferably an alkali metal or earth alkali metal hydroxide or carbonate, preferably a hydroxide, in particular an alkali metal hydroxide.

[0038] More preferably, the base is an organic amine, especially an organic tertiary amine.

[0039] Not all bases work equally well in the present invention. The base is preferably not pyridine. It has a pK of 8.6 to 15.7, especially 9 to 15.7, measured in water. aIt has been shown that conjugate acids of said bases having the formula: are particularly suitable, which means that said bases preferably have a pKb of 5.4 to 0, in particular 5 to 0.

[0040] [Table 1]

[0041] In one embodiment, the base is an organic amine, in particular selected from the group consisting of 4-dimethylaminopyridine (=DMAP), 1,8-diazabicyclo[5.4.0]undec-7-ene (=DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (=DBN), 1,4-diazabicyclo[2.2.2]octane (=DABCO), 1-azabicyclo[2.2.2]octane (=quinuclidine) and sparteine, preferably selected from the group consisting of 4-dimethylaminopyridine (=DMAP), 1,8-diazabicyclo[5.4.0]undec-7-ene (=DBU) and 1-azabicyclo[2.2.2]octane (=quinuclidine).

[0042] The base is not a hydride such as sodium hydride, in particular because hydrides form molecular hydrogen when contacted with the compound of formula (II), which would pose a significant safety risk during the ring closure step and the process in general.

[0043] In another embodiment, the base is preferably an alkali metal or earth alkali metal hydroxide or carbonate, preferably a hydroxide, in particular an alkali metal hydroxide. In this embodiment, the base is most preferably NaOH or KOH.

[0044] In yet another embodiment, the base is potassium fluoride on alumina (KF / Al2O3).

[0045] [Two-phase system] The step of ring closure of the compound of formula (II) is carried out in the presence of a base in a two-phase system.

[0046] The biphasic system is a reaction system with two different phases, in particular a liquid phase and a solid or another liquid phase.

[0047] Preferably, one of the two phases comprises a hydrocarbon, preferably toluene.

[0048] The compound of formula (II) is in particular dissolved in said hydrocarbon, preferably toluene.

[0049] The base is preferably in a different phase to the compound of formula (II).

[0050] In one embodiment, the two-phase system comprises two liquid phases, preferably an aqueous phase and an organic phase that is immiscible with the aqueous phase, the organic phase in particular comprising a hydrocarbon, preferably toluene.

[0051] The aqueous phase preferably contains a base.

[0052] In another embodiment, the two-phase system consists of a liquid phase and a solid phase.

[0053] The base is preferably in solid form. Thus, the solid phase is in particular a base or comprises a base. The base may be supported by a solid support. The base may be absorbed or adsorbed or chemically bound to a solid support such as, for example, alumina, silica, carbon, carbonates or silicates, or other minerals.

[0054] The liquid phase in this embodiment is either a liquid organic phase comprising a compound of formula (II) or an organic solvent, in particular a hydrocarbon, preferably toluene.

[0055] Thus, as solid phase, a solid hydroxide or carbonate of an alkali metal or earth alkali metal can be used, preferably a hydroxide, in particular an alkali metal hydroxide. The solid hydroxide or carbonate is preferably used as a solid having a high surface area, in particular obtained by mechanical processes such as grinding, milling or pulverization, or by physicochemical processes such as suitable precipitation or crystallization. The surface area of ​​the solid base (e.g. m 2 It has been found that the higher the molecular weight (defined as 1 / g) of the solid base, the more suitable it is for the purposes of the present invention.

[0056] In certain preferred embodiments, the solid base is potassium fluoride on alumina (KF / Al2O3), a well-known base that is widely used in organic synthesis, as disclosed in BEBlass in Tetrahedron 58 (2002), 9301-9320.

[0057] When the base is used as a solid, the phase transfer agent is preferably a quaternary ammonium salt, in particular a salt of the formula [NR4]X, where R is C 2~18 Alkyl groups, especially C 3~8 It is preferred to use a quaternary ammonium salt of the formula (II) (X is an alkyl group and X is a halide). Preferably, the phase transfer agent is a tetrabutylammonium halide, in particular tetrabutylammonium bromide. The phase transfer agent is preferably used in an amount of 0.1 to 10 mol %, in particular 0.5 to 2 mol %, based on the compound of formula (II).

[0058] In particular, it has been observed that a two-phase system consisting of a liquid phase and a solid phase exhibits very high yields at high conversion rates, and therefore a two-phase system consisting of a liquid phase and a solid phase is preferred.

[0059] The use of a two-phase system for the ring-closing reaction is highly advantageous since the phases can be easily separated from one another, resulting in a better separation of the starting materials as well as the reaction products. The use of such a two-phase system for the reaction in question is therefore advantageous for the work-up of isolating the reaction products one from the other. Moreover, this simplifies the recycling of the starting materials and is advantageous in the continuous reaction mode, which is the preferred method for producing compounds of formula (I) on an industrial scale. If the base is provided as a solid phase, it can be easily provided in the form of larger bodies, typically in the form of ordered packing elements, which can be part of the reactor in which the reduction takes place or elements inserted into said reactor. The ordered packing elements can be random packings, meshes, open-cell structures, preferably made of plastics, such as polyurethane or melamine resins, or ceramics, or ordered packing elements originating from distillation and extraction techniques, i.e. as already known in principle by their geometry. The solid base can also be configured in a vessel with porous walls, such as for example meshes or meshes, with a suitable hole or mesh diameter to allow the passage of the reaction medium but to avoid the passage of the solid base. Useful packed elements are in particular woven metal packings and wire mesh packings, for example of the Montz A3, Sulzer BX, DX and EX designs. Instead of woven metal packings, it is also possible to use packed packings made of other woven, mesh or non-woven materials. Further useful packed packings are preferably flat or corrugated sheets without perforations or other relatively large orifices, for example corresponding to the Montz BI or Sulzer Mellapak designs. Packings made of expanded metal, for example of the Montz BSH type, are also advantageous. In such cases, it is possible to easily remove the base from the reactor and replace it with fresh base, especially when the reaction is carried out in a reactor used in a continuous reaction mode.

[0060] It is indicated that the base can be used in the ring-closing step in particular in an amount such that the molar ratio of base / compound of formula (II) is greater than 1, in particular in an amount of from 2 to 1.1.

[0061] However, it has surprisingly been found that the base can also be used in catalytic amounts, i.e. the base is not present in a stoichiometric amount relative to the compound of formula (II), but in very small amounts, i.e. in a molar ratio of basic catalyst to compound of formula (I) of 1:1'000 to 1:5, in particular 1:1'000 to 1:8, more in particular 1:100 to 1:10.

[0062] The ring closure step is typically carried out with stirring at a temperature of preferably 40-200° C., preferably 90-150° C., more preferably at the reflux temperature of the organic solvent if an organic solvent is used, and / or at a pressure of 1 bara-10 bara. It is further preferred that the reaction is carried out under an inert atmosphere, preferably under nitrogen.

[0063] By the above process, a compound represented by the formula (I) [ka] It has been shown that the above compounds can be obtained smoothly.

[0064] In particular, said process makes it possible to isolate the desired compound of formula (I) in a simple manner, i.e. without the need for any complicated derivatization followed by purification by crystallization and finally chemical conversion of the derivative into the desired compound, as is the case in the process as disclosed in Schudel, Mayer, Isler, Helv. Chim. Acta 46, 2517-2526 (1963).

[0065] Particularly preferred embodiments of the compounds of formula (I) are the compounds of formulae (IA), (IB) and (IC), preferably the compounds of formulae (I-AA), (I-BB), (I-CC1) and (I-CC2): [ka] n=0-9, especially n=8 [ka] n=0-9, especially n=8 [ka] n=0~9, especially n=2 [ka] [ka] n=0~12 [ka] n=0-12, especially n=2 [ka]

[0066] Highly preferred compounds are those of formula (I-As): [ka] n=3-9, especially n=8

[0067] Highly preferred compounds are those of formula (I-Cis). [ka] n=1-12, especially n=2-5

[0068] The compound of formula (I) obtained as shown above can be hydrogenated with a hydrogenating agent.

[0069] In one embodiment, during this hydrogenation, only the endocyclic carbon-carbon double bond is hydrogenated while the olefinic carbon-carbon double bond is not hydrogenated ("partial hydrogenation"), thereby hydrogenating to yield a compound of formula (III), as shown in FIG. 1. [ka]

[0070] Particularly preferred embodiments of the compounds of formula (III) are the compounds of formulae (III-A), (III-B) and (III-C), preferably the compounds of formulae (III-AA), (III-BB), (III-CC1) and (III-CC2): [ka] n=0-9, especially n=8 [ka] n=0-9, especially n=8 [ka] n=0~9, especially n=2 [ka] [ka] n=0~12 [ka] n=0-12, especially n=2 [ka]

[0071] Highly preferred compounds are those of formula (III-Cis). [ka] n=3-6, especially n=5

[0072] In another embodiment, during the hydrogenation, all of the olefin carbon-carbon double bonds are hydrogenated ("full hydrogenation"), whereby the hydrogenation produces a compound of formula (IV), as shown in FIG. [ka]

[0073] Particularly preferred embodiments of the compounds of formula (IV) are the compounds of formulae (IV-A), (IV-B) and (IV-C), preferably the compounds of formulae (IV-A), (IV-BB) and (IV-CC): [ka] n=0-9, especially n=8 [ka] n=0~9, especially n=2 [ka] [ka] n=0~12 [ka]

[0074] Highly preferred compounds are those of formula (IV-Cs): [ka] n=3-12, especially n=3-5

[0075] Thus, in a further aspect, the present invention also provides a method for producing a method for treating a pulmonary arthritis, comprising: Formula (III) [ka] The process for producing the compound of a) by the process as described in great detail above, [ka] (In the formula, the dotted line [ka] any bonds in each represent, independently of each other, either a carbon-carbon single bond or a carbon-carbon double bond; any wavy lines, independently of each other, when connected to a carbon-carbon double bond, represent carbon-carbon bonds that are in either the Z or E configuration; b) partially hydrogenating the compound of formula (I) with a hydrogenating agent suitable for partial hydrogenation to obtain a compound of formula (III).

[0076] The hydrogenating agent used in step b) is a hydrogenating agent which hydrogenates only the carbon-carbon double bond of the ring of formula (I). Particularly suitable as hydrogenating agent is sodium / ethanol as described in Schudel, Mayer, Isler, Helv. Chim. Acta 46, 2517-2526 (1963), especially on page 2524, last paragraph.

[0077] Thus, in a further aspect, the present invention also provides a compound of formula (IV) [ka] The process for producing the compound of a) by the process as described in great detail above, [ka] (In the formula, the dotted line [ka] any bonds in each represent, independently of each other, either a carbon-carbon single bond or a carbon-carbon double bond; any wavy lines, independently of each other, when connected to a carbon-carbon double bond, represent carbon-carbon bonds that are in either the Z or E configuration; b') hydrogenating the compound of formula (I) with a hydrogenating agent to obtain a compound of formula (IV).

[0078] The hydrogenating agent used in step b') is a hydrogenating agent which hydrogenates all olefinic carbon-carbon double bonds in the ring of formula (I). Particularly suitable as hydrogenating agent is hydrogen in the presence of a group 7, 8, 9 or 10 transition metal, in particular selected from the group consisting of Pd, Pt, Rh, Ru, Mn, Fe, Co and Ni, more preferably Pd.

[0079] Preferably, the heterogeneous transition metal catalyst is a heterogeneous supported transition metal catalyst.

[0080] In this embodiment, the transition metal is supported on a support, i.e., the palladium is attached and / or deposited on a support. The support is a solid material.

[0081] Preferably, the support is carbon or an inorganic support. Preferred inorganic supports are oxides or carbonates. Preferred oxides are oxides of Si, Al, Ce, Ti or Zr, in particular of Al or Si. Silicon dioxide, alumina and titanium dioxide and ceria are particularly preferred.

[0082] When the support is Ce, the preferred oxide is CeO2. The preferred oxides of Al are Al2O3 and AlO(OH). Particularly preferred is Al2O3.

[0083] It is preferable to carry out the hydrogenation under pressure, particularly under a hydrogen pressure of 2 to 20 bar, and more preferably at a temperature of 0°C to 100°C.

[0084] A biphasic composition comprising a compound of formula (II) and the base itself is also an object of the present invention.

[0085] Thus, in a further aspect, the present invention provides a method for producing a method for treating a pulmonary arthritis, comprising: i) Formula (II) [ka] (In the formula, n=0 or 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12; R 1 represents hydrogen or a methyl group; R 3 and R 4 teeth, each independently represents hydrogen, a methyl group, or a methoxy group, or together represent -CH-CH-CH-, forming an aromatic group; dotted line [ka] any bonds in each represent, independently of each other, either a carbon-carbon single bond or a carbon-carbon double bond; any wavy lines, independently of each other, when connected to a carbon-carbon double bond, represent carbon-carbon bonds that are in either the Z or E configuration; and, ii) Biphasic compositions, which comprise a base in a separate phase from the compound of formula (II).

[0086] The compounds of formula (II) and the base as well as preferred embodiments thereof have already been described in great detail above for the process.

[0087] In the present invention, it has been found that for efficient ring closure in the above ring closure step, a two-phase based reaction system can be used.

[0088] Thus, in a further aspect, the present invention relates to the use of a base in a different phase to the compound of formula (II) for the ring-closure reaction of the compound of formula (II) to obtain a compound of formula (I), [ka] During the ceremony, n=0 or 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12; R 1 represents hydrogen or a methyl group; R 3 and R 4 teeth, each independently represents hydrogen, a methyl group, or a methoxy group, or together represent -CH-CH-CH-, forming an aromatic group; dotted line [ka] any bonds in each represent, independently of each other, either a carbon-carbon single bond or a carbon-carbon double bond; The optional wavy lines, independently of each other, when connected to a carbon-carbon double bond, represent carbon-carbon bonds that are in either the Z or E configuration.

[0089] The compound of formula (II), the base, the two phases and the ring closure step as well as preferred embodiments thereof have already been described in great detail above for the process.

[0090] Furthermore, the compounds of formula (IA) or (IC) or (III-A) or (III-C) or (IV-A) or (IV-C) have been found to have antioxidant properties.

[0091] Thus, in a further aspect, the present invention relates to the use of a compound of formula (IA) or (IC) or (III-A) or (III-C) or (IV-A) or (IV-C) as an antioxidant. [ka] n=0-9, especially n=8 [ka] n=0~12 [ka] n=0-9, especially n=8 [ka] n=0~12 [ka] n=0-9, especially n=8 [ka] n=0~12 In the formula, R 1 represents hydrogen or a methyl group.

[0092] As well as the compounds of formula (IA) or (IC) or (III-A) or (III-C) or (IV-A) or (IV-C), preferred embodiments thereof have already been described in great detail above for the processes.

[0093] Some of the compounds disclosed herein are novel. The compounds are not only novel but also inventive because of their suitability for the disclosed processes and uses.

[0094] Thus, in a further aspect, the present invention relates in particular to compounds of formula (I-As) or (I-Cis) or (III-Cis) or (IV-Cs), [ka] In the formula, n=3 to 9, particularly n=8; [ka] In the formula, n=1 to 12, particularly n=2 to 5; [ka] In the formula, n=3 to 6, particularly n=5; [ka] In the formula, n=3 to 12, particularly n=3 to 5; And, in the formula: R 1 represents hydrogen or a methyl group; dotted line [ka] any bonds in each represent, independently of each other, either a carbon-carbon single bond or a carbon-carbon double bond; The optional wavy lines, independently of each other, when connected to a carbon-carbon double bond, represent carbon-carbon bonds that are in either the Z or E configuration.

[0095] [Example] The invention is further illustrated by the following experiments.

[0096] [Experimental series 1: Liquid / solid: Toluene / solid NaOH two-phase system] In the first series, 0.46 g (1.098 mmol) of geranylgeranyltrimethylbenzoquinone (97% purity), 6 ml of toluene, and 4.7 mg of solid NaOH (0.1098 mmol, 10 mol % (relative to geranylgeranyltrimethylbenzoquinone)) were added in the presence of 3.5 mg of tetrabutylammonium bromide (1 mol % (relative to geranylgeranyltrimethylbenzoquinone)) and stirred at reflux (110° C.) for the reaction time presented in Table 1 to obtain 2,5,7,8-tetramethyl-2-(4,8,12-trimethyltrideca-3,7,11-trien-1-yl)-2H-chromen-6-ol (3,4-dehydro-α-tocotrienol) in the conversion and yield as shown in Table 1.

[0097] [Table 2]

[0098] [Experimental series 2: Liquid / solid: Toluene / potassium fluoride on alumina (KF / Al2O3) two-phase system] In the second series, 0.46 g (1.098 mmol) of geranylgeranyltrimethylbenzoquinone (purity 97%), 6 ml of toluene, 46 mg of a base of potassium fluoride on alumina (KF: 40 wt %), and tetrabutylammonium bromide (1 mol % (relative to geranylgeranyltrimethylbenzoquinone)) were added and stirred at reflux (110° C.) for 48 hours to obtain 2,5,7,8-tetramethyl-2-(4,8,12-trimethyltrideca-3,7,11-trien-1-yl)-2H-chromen-6-ol (3,4-dehydro-α-tocotrienol) with the conversion and yield as shown in Table 2.

[0099] [Table 3]

[0100] [Experimental series 3: Liquid / liquid: Toluene / aqueous base two-phase system] In the third series, 0.46 g (1.098 mmol) of geranylgeranyltrimethylbenzoquinone (97% purity), 6 ml of toluene, and 6 ml of an aqueous solution of each base at the concentration as shown in Table 3 were added in the presence of 3.5 mg of tetrabutylammonium bromide (1 mol % (relative to geranylgeranyltrimethylbenzoquinone)), and stirred at reflux (110° C.) for the time as shown in Table 3 to obtain 2,5,7,8-tetramethyl-2-(4,8,12-trimethyltrideca-3,7,11-trien-1-yl)-2H-chromen-6-ol (3,4-dehydro-α-tocotrienol) with the conversion and yield as shown in Table 3.

[0101] [Table 4]

[0102] [Partial hydrogenation] The above prepared 3,4-dehydro-α-tocotrienol (=2,5,7,8-tetramethyl-2-(4,8,12-trimethyltrideca-3,7,11-trien-1-yl)-2H-chromen-6-ol) was quantitatively hydrogenated according to the procedure disclosed in the last paragraph on page 2524 of Schudel, Mayer, Isler, Helv. Chim. Acta 46, 2517-2526 (1963) to obtain α-tocotrienol (=2,5,7,8-tetramethyl-2-(4,8,12-trimethyltrideca-3,7,11-trien-1-yl)chroman-6-ol, the identity of which could be confirmed by NMR.

[0103] [Fully hydrogenated] The above prepared 3,4-dehydro-α-tocotrienol (=2,5,7,8-tetramethyl-2-(4,8,12-trimethyltrideca-3,7,11-trien-1-yl)-2H-chromen-6-ol) was quantitatively hydrogenated with hydrogen on Pd / C according to the last paragraph on page 888 of Kabbe and Heitzer, Synthesis 1978;12,888-889 to obtain α-tocotrienol (=2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)chroman-6-ol, the identity of which could be confirmed by NMR.

Claims

1. Formula (I) [Case 1] A method for preparing a compound of formula (II) [Case 2] in a two-phase system in the presence of a base to obtain a compound of formula (I), During the ceremony, n=0 or 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12; R １ represents hydrogen or a methyl group; R ３ and R ４ teeth, each independently represents hydrogen, a methyl group, or a methoxy group, or together represent -CH-CH-CH-, forming an aromatic group; dotted line [C3] any bonds in each represent, independently of each other, either a carbon-carbon single bond or a carbon-carbon double bond; The optional wavy lines, independently of each other, when connected to a carbon-carbon double bond, represent a carbon-carbon bond that is in either the Z or E configuration.

2. R １ = R ３ = R ４ =CH ３ The method according to claim 1, characterized in that

3. 3. The method according to claim 1 or 2, characterized in that the compound of formula (I) is a compound of formula (I-BB) and the compound of formula (ii) is a compound of formula (II-BB). [C4]

4. 3. The process according to claim 1 or 2, characterized in that the base is in a different phase from the compound of formula (II).

5. 3. The method of claim 1 or 2, characterized in that one of the two phases comprises a hydrocarbon.

6. 3. The process according to claim 1 or 2, characterized in that the base is present in the aqueous phase.

7. 3. The process according to claim 1 or 2, characterized in that the base is in solid form.

8. 3. The process according to claim 1 or 2, characterized in that the base is either an organic amine or a metal hydroxide or a metal carbonate.

9. 3. The process according to claim 1 or 2, characterized in that the base is present in a molar ratio of from 1:1000 to 1:5 with respect to the compound of formula (I).

10. 3. The process according to claim 1 or 2, wherein the ring closure reaction is carried out in the presence of a phase transfer agent.

11. Formula (III) [C5] A method for producing a compound of the formula: a) obtaining a compound of formula (I) by the method according to claim 1 or 2 [C6] (wherein the dotted line [C7] any bonds in each represent, independently of each other, either a carbon-carbon single bond or a carbon-carbon double bond; any wavy lines, independently of each other, when connected to a carbon-carbon double bond, represent carbon-carbon bonds that are in either the Z or E configuration; b) partially hydrogenating the compound of formula (I) with a hydrogenating agent suitable for partial hydrogenation to obtain said compound of formula (III).

12. Formula (IV) [C8] A method for producing a compound of the formula: a) obtaining a compound of formula (I) by the method according to claim 1 or 2 [C9] (wherein the dotted line [C10] any bonds in each represent, independently of each other, either a carbon-carbon single bond or a carbon-carbon double bond; any wavy lines, independently of each other, when connected to a carbon-carbon double bond, represent carbon-carbon bonds that are in either the Z or E configuration; b') hydrogenating the compound of formula (I) with a hydrogenating agent to obtain the compound of formula (IV).

13. 1. A biphasic composition comprising: i) a compound represented by formula (II) [C11] (In the formula, n=0 or 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12; R １ represents hydrogen or a methyl group; R ３ and R ４ teeth, each independently represents hydrogen, a methyl group, or a methoxy group, or together represent -CH-CH-CH-, forming an aromatic group; dotted line [C12] any bonds in each represent, independently of each other, either a carbon-carbon single bond or a carbon-carbon double bond; any wavy lines, independently of each other, when connected to a carbon-carbon double bond, represent carbon-carbon bonds that are in either the Z or E configuration; and, ii) A biphasic composition comprising a base in a separate phase from the compound of formula (II).

14. The composition according to claim 13, characterized in that the compound of formula (II) is a compound of formula (II-BB). [C13]

15. Use of a base in a different phase to the compound of formula (II) for the ring-closure reaction of the compound of formula (II) to obtain the compound of formula (I), [C14] During the ceremony, n=0 or 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12; R １ represents hydrogen or a methyl group; R ３ and R ４ teeth, each independently represents hydrogen, a methyl group, or a methoxy group, or together represent -CH-CH-CH-, forming an aromatic group; dotted line [C15] any bonds in each represent, independently of each other, either a carbon-carbon single bond or a carbon-carbon double bond; The optional wavy lines, independently of each other, when connected to a carbon-carbon double bond, represent carbon-carbon bonds that are in either the Z or E configuration.

16. Use of a compound of formula (IA) or (IC) or (III-A) or (III-C) or (IV-A) or (IV-C) as an antioxidant, comprising [C16] In the formula, n=0 to 9; [C17] In the formula, n=0 to 12; [C18] In the formula, n=0 to 9; [C19] In the formula, n=0 to 12; [C20] In the formula, n=0 to 9; [C21] n=0 to 12; During the ceremony, R １ represents hydrogen or a methyl group; dotted line [C22] any bonds in each represent, independently of each other, either a carbon-carbon single bond or a carbon-carbon double bond; The optional wavy lines, independently of each other, when connected to a carbon-carbon double bond, represent carbon-carbon bonds that are in either the Z or E configuration.

17. A compound of formula (I-As) or (I-Cis) or (III-Cis) or (IV-Cs), [C23] In the formula, n=3 to 9; [C24] In the formula, n=1 to 12; [C25] In the formula, n=3 to 6; [C26] A compound of the formula:

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