Base-catalyzed ring closure of benzoquinones containing unsaturated side chains.

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 catalytic amount of a base. TIFF2024515469000090.tif72147 The reaction is highly efficient and has been shown 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 is via 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 the formation of chromene by ring-closing in pyridine as reaction medium, i.e. pyridine present in large amount (corresponding to a significant excess relative to the amount of benzoquinone). Pyridine is a compound that is carcinogenic to animals and highly pyrophoric, so its use, especially in large amounts, is highly undesirable. Furthermore, 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 uses 4-(phenylazo)benzoyl chloride, a very expensive and highly toxic chemical, making the process overall highly disadvantageous.

[0005] Also, Doetz KHet al., Chem. Ber. 115, 1278-1285 (1982) and Terashima K. et al., Bioorganic & Medicinal Chemistry 10, 1619-1625 (2002) disclose a cyclization reaction by refluxing the corresponding benzoquinone in a large molar excess of pyridine.

[0006] 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.

[0007] [Summary of the Invention] The problem to be solved by the present invention is therefore to provide a process which leads to chromenes and chromans in a manner which generally avoids the use of large amounts of pyridine or base.

[0008] This problem is solved by the process according to claim 1. In particular, it has been found that a base can be used in catalytic amounts for the ring-closing reaction of the benzoquinone of formula (II) to obtain the chromene of formula (I). In particular, it has been found that strongly basic catalysts are particularly suitable as catalytic bases for said ring-closing reaction. It has been found that the compound of formula (I) can be obtained in very high conversions and yields.

[0009] This process provides a highly advantageous synthetic route to the chromans of formula (III) or (IV) according to claims 8 or 9.

[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 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 that 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 present invention relates to a process for producing a compound of formula (II), [ka] in the presence of a basic catalyst 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; any 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; It is characterized in that the molar ratio of basic catalyst to compound of formula (I) is from 1:1'000 to 1:5, in particular from 1:100 to 1:10.

[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 1~3 An 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] "pKa " 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 a2 Regarding 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 4represents 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 (due to the carbon-carbon double bond present). 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] [Basic catalyst] The process includes the step of ring-closing a compound of formula (I) in the presence of a basic catalyst ("cat") to obtain a compound of formula (I), as represented as step a) in the reaction scheme of FIG.

[0037] The basic catalyst 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 basic catalyst is an organic amine, especially an organic tertiary amine.

[0039] The basic catalyst is a base. Not all bases work equally well in the present invention. The basic catalyst is preferably not pyridine. It has a pK of 8.6 to 15.7, especially 9 to 15.7, measured in water. a It has been shown that the conjugate acid of the basic catalyst having a pK of preferably 5.4 to 0, in particular 5 to 0, is particularly suitable. b It means that

[0040] [Table 1]

[0041] In one embodiment, the basic catalyst is an organic amine selected in particular 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] In another embodiment, the basic catalyst 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 basic catalyst is most preferably NaOH or KOH.

[0043] 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.

[0044] 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).

[0045] In another embodiment, when the basic catalyst is an alkali metal hydroxide, water may be present.

[0046] The ring closure step is preferably carried out in a hydrocarbon solvent, especially toluene.

[0047] When a hydrocarbon solvent is used, the solvent is preferably used in an amount such that the solution containing the compound of formula (II) is 0.05 to 5 mol, more preferably 0.1 to 1 mol, relative to the compound of formula (II).

[0048] When water is present, it is preferred to carry out the ring-closure reaction in a two-phase system, ie an aqueous phase and an organic phase, especially an aqueous and an organic solvent phase.

[0049] It is important to emphasize that the basic substance is present in a catalytic amount, i.e. the basic catalyst is not present in a stoichiometric amount relative to the compound of formula (II), but in a much smaller amount, i.e. the molar ratio of basic catalyst to compound of formula (I) is from 1:1'000 to 1:5, in particular from 1:100 to 1:10.

[0050] 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.

[0051] By the above process, a compound represented by formula (I) [ka] It has been shown that the above compounds can be easily obtained.

[0052] 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).

[0053] 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]

[0054] Highly preferred compounds are those of formula (I-As): [ka] n=3-9, especially n=8

[0055] Highly preferred compounds are those of formula (I-Cis). [ka] n=1-12, especially n=2-5

[0056] The compound of formula (I) obtained as shown above can be hydrogenated with a hydrogenating agent.

[0057] In one embodiment, as shown in FIG. 1, 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 producing a compound of formula (III) upon hydrogenation. [ka]

[0058] 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]

[0059] Highly preferred compounds are those of formula (III-Cis). [ka] n=3-6, especially n=5

[0060] In another embodiment, as shown in FIG. 1, during the hydrogenation, all of the olefin carbon-carbon double bonds are hydrogenated ("full hydrogenation"), thereby producing a compound of formula (IV) upon hydrogenation. [ka]

[0061] 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] n=0~12 [ka]

[0062] Highly preferred compounds are those of formula (IV-Cs): [ka] n=3-12, especially n=3-5

[0063] Thus, in a further aspect, the present invention also provides a compound of 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 said compound of formula (III).

[0064] 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.

[0065] 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).

[0066] 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.

[0067] Preferably, the heterogeneous transition metal catalyst is a heterogeneous supported transition metal catalyst.

[0068] 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.

[0069] 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.

[0070] When the support is Ce, the preferred oxide is CeO2. The preferred oxides of Al are Al2O3 and AlO(OH). Particularly preferred is Al2O3.

[0071] 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.

[0072] Compositions comprising a compound of formula (II) and the basic catalyst itself are also an object of the present invention.

[0073] 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) comprising a basic catalyst; It relates to a composition characterized in that the molar ratio of basic catalyst to compound of formula (I) is between 1:1'000 and 1:5, in particular between 1:100 and 1:10.

[0074] The compound of formula (II) and the basic catalyst, as well as preferred embodiments thereof, have already been described in great detail above for the process.

[0075] In the present invention, it has been found that a catalytic amount of a base can be used for efficient ring closure in the above ring closure step.

[0076] Thus, in a further aspect, the present invention relates to the catalytic use of a base for the ring closure reaction of a compound of formula (II) to give 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.

[0077] The compound of formula (II), the basic catalyst and the ring closure step as well as preferred embodiments thereof have already been described in great detail above for the process.

[0078] 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.

[0079] 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.

[0080] 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.

[0081] 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.

[0082] 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.

[0083] [Example] The invention is further illustrated by the following experiments.

[0084] [Formation of (E)-2-(4,8-dimethylnona-3,7-dien-1-yl)-2,5,7,8-tetramethyl-2H-chromen-6-ol] 4-Hydroxy-2,3,6-trimethyl-5-((6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-yl)phenylacetate (2.0 g, 4.74 mmol) was mixed with 50 mL of diethyl ether and cooled to 5°C. Lithium aluminum hydride (2M in THF) (2.96 ml, 5.92 mmol) was then added and after 3.5 h at 0-24°C the reaction was quenched by adding 40 mL (4N) of HCL. The organic phase was washed once with 40 mL of brine and 0.2 g of sodium dithionite and dried over MgSO4. After filtration and evaporation, 2,3,5-trimethyl-6-((6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-yl)benzene-1,4-diol was isolated in 85% yield.

[0085] 2,3,5-trimethyl-6-((6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-yl)benzene-1,4-diol was dissolved in diethyl ether (7.5 mL), 1.5 equivalents of silver oxide and 46 μL of acetic acid were added, and the mixture was stirred at room temperature for 2 h. After filtration and purification by chromatography (neutral silica), 2,3,5-trimethyl-6-((6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-yl)cyclohexa-2,5-diene-1,4-dione was isolated in 88% yield.

[0086] 2,3,5-trimethyl-6-((6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-yl)cyclohexa-2,5-diene-1,4-dione (1.27 g (3.29 mmol)), 18 ml of toluene, and 0.15 ml (0.988 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene (=DBU) were added, and the mixture was stirred at reflux (110°C) for 20 hours to produce (E)-2-(4,8-dimethylnona-3,7-dien-1-yl)-2,5,7,8-tetramethyl-2H-chromen-6-ol in a yield of 86.5%.

[0087] [Experiment series 1] Geranylgeranyltrimethylbenzoquinone (97% purity) (0.5 g (1.183 mmol)), 6 ml of toluene, and the corresponding amount of basic catalyst provided in Table 1 were added and stirred under 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) with the conversion and yield as shown in Table 1.

[0088] [Table 2]

[0089] The results in Table 1 show that all bases used in catalytic amounts resulted in the formation of the desired product, i.e., 3,4-dehydro-α-tocotrienol. Most examples show that very high conversions and yields of over 94% can be achieved. Furthermore, Examples 7, 8 and 9 in Table 1 show that the conjugate acids have pK values ​​lower than 8.6. a It has been shown that a basic catalyst having a cation group with 1,2-dichlorophenyl ether results in even lower conversions and yields. The experiments also show that pyridine shows particularly low conversions at catalyst concentrations. Comparison of Examples 2 and 3 shows that even at a 10-fold lower concentration, significantly higher conversions and yields can still be achieved.

[0090] [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.

[0091] [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.

[0092] [Experiment series 2] 0.46 g (1.098 mmol) of geranylgeranyltrimethylbenzoquinone (purity 97%), toluene in the amount shown in Table 2, and 5.49 μmol of DBU (1 / 200) were added and stirred at reflux (110° C.) for 24 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) in the conversion and yield shown in Table 2.

[0093] [Table 3]

[0094] [Experiment series 3] In a further 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)) in the presence of 3.5 mg of tetrabutylammonium bromide (1 mol % (relative to geranylgeranyltrimethylbenzoquinone)) were added and stirred at reflux (110° C.) for the reaction times listed in Table 2 to give 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 3.

[0095] [Table 4]

Claims

1. Formula (I) 【Chemistry 1】 A method for preparing a compound of formula (II) 【Chemistry 2】 in the presence of a basic catalyst 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 【Chemistry 3】 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; The molar ratio of the basic catalyst to the compound of formula (I) is from 1:1000 to 1:

5.

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 basic catalyst is either an organic amine or a metal hydroxide or a metal carbonate.

4. The conjugate acid of the base catalyst has a pK of 8.6 to 15.7 as measured in water. ａ 3. The method according to claim 1 or 2, characterized in that it comprises:

5. 3. The method according to claim 1, wherein the basic catalyst is 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.

6. 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). 【Chemistry 4】

7. 3. The process according to claim 1 or 2, characterized in that the ring closure step is carried out in a hydrocarbon solvent.

8. Formula (III) 【Chemistry 5】 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 【Chemistry 6】 (wherein the dotted line 【Chemistry 7】 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).

9. Formula (IV) 【Chemistry 8】 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 【Chemistry 9】 (wherein the dotted line 【Chemistry 10】 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 said compound of formula (IV).

10. 1. A composition comprising: i) a compound represented by formula (II) 【Chemistry 11】 (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 【Chemistry 12】 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) comprises a basic catalyst; The composition, wherein the molar ratio of the basic catalyst to the compound of formula (I) is 1:1000 to 1:

5.

11. The conjugate acid of the base catalyst has a pK of 8.5 to 15.7 as measured in water. ａ The composition of claim 10, characterized in that it has

12. The composition according to claim 10 or 11, characterized in that the compound of formula (II) is a compound of formula (II-BB). 【Chemistry 13】

13. 1. The catalytic use of a base for the ring-closure reaction of a compound of formula (II) to obtain a compound of formula (I), 【Chemistry 14】 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 【Chemistry 15】 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.

14. 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 【Chemistry 16】 In the formula, n=0 to 9; 【Chemistry 17】 In the formula, n=0 to 12; 【Chemistry 18】 In the formula, n=0 to 9; 【Chemistry 19】 In the formula, n=0 to 12; 【Chemistry 20】 In the formula, n=0 to 9; 【Chemistry 21】 n=0 to 12; During the ceremony, R １ represents hydrogen or a methyl group; dotted line 【Chemical 22】 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.

15. A compound of formula (I-As) or (I-Cis) or (III-Cis) or (IV-Cs), 【Chemistry 23】 In the formula, n=3 to 9; 【Chemistry 24】 In the formula, n=1 to 12; 【Chemistry 25】 In the formula, n=3 to 6; 【Chemistry 26】 In the formula, n=3 to 12; And, in the formula: R １ represents hydrogen or a methyl group; dotted line 【Chemical 27】 any bonds in each represent, independently of each other, either a carbon-carbon single bond or a carbon-carbon double bond; A compound wherein any 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.

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