Ring closure of benzoquinone containing an unsaturated side chain using a basic catalyst

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 synthesis of chromans and chromenes, and more particularly to the synthesis of 3,4-dehydrotocopherol, 3,4-dehydrotocotrienol, tocopherol, and tocotrienol.

[0002] [Background of the Invention] An important class of chroman compounds is vitamin E and its esters. The synthetic pathway for chroman proceeds via their corresponding chromenes.

[0003] There are various pathways for the formation of chromene.

[0004] Schudel, Mayer, Isler, Helv. Chim. Acta 46, 2517-2526 (1963) discloses that 3,4-dehydrotocotrienol is formed by the cyclization of geranylgeranyltrimethylbenzoquinone in pyridine, which is present in large quantities (corresponding to the significantly excess amount of benzoquinone), to form chromene. Pyridine is a carcinogenic compound to animals and is highly flammable, so its use, especially in large quantities, is highly undesirable. Furthermore, the resulting reaction mixture is complex, and isolation of the desired product requires a complex derivatization procedure to form dehydrotocotrienol-p-phenylazobenzoate for crystallization, separation, and purification. This procedure uses 4-(phenylazo)benzoyl chloride, a very expensive and highly toxic chemical, making the process generally very undesirable.

[0005] Furthermore, Doetz K. Het 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 significantly molar excess of pyridine.

[0006] International Publication No. 2015 / 028643 A1 discloses the formation of chromenes by intramolecular hydroarylation of chiral aryl alkynes using Au(I) or Ag(I) catalysts. Gold and silver catalysts are very expensive.

[0007] [Overview of the prefecture] Therefore, the problem to be solved by the present invention is to provide a process that yields chromene and chroman in a way that generally avoids the use of large amounts of pyridine or base.

[0008] This problem is solved by the process described in claim 1. In particular, it was found that a catalytic amount of a base can be used in the cyclization reaction of benzoquinone of formula (II) to obtain chromene of formula (I). In particular, it was found that a strongly basic catalyst is especially suitable as the catalytic base for the cyclization reaction. It was found that the compound of formula (I) can be obtained with extremely high conversion rates and yields.

[0009] This process provides a highly favorable synthetic route for chroman of formula (III) or (IV) as described in claim 8 or 9.

[0010] Further aspects of the present invention are the subject of further independent claims. Particularly preferred embodiments are the subject of dependent claims. [Brief explanation of the drawing]

[0011] [Figure 1]Only the carbon-carbon double bonds within the ring are hydrogenated, while the carbon-carbon double bonds of the olefin are not hydrogenated ("partial hydrogenation"), thereby producing a compound of formula (III) by hydrogenation, and all the carbon-carbon double bonds of the olefin are hydrogenated ("complete hydrogenation"), thereby producing a compound of formula (IV) by hydrogenation.

[0012] [Detailed Description of the Invention] In a first aspect, the present invention relates to a process for producing a compound of formula (I) [Chemical Formula] which comprises a step of cyclizing a compound of formula (II) [Chemical Formula] in the presence of a basic catalyst to obtain a compound of formula (I), wherein, 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 are each independently of the other, represents hydrogen or a methyl group or a methoxy group, or together represent -CH-CH-CH- to form an aromatic group; the dotted line [Chemical Formula] any bond of which independently of the others, represents either a carbon-carbon single bond or a carbon-carbon double bond; any wavy line independently of the others, represents a carbon-carbon bond which is either in the Z configuration or the E configuration when linked to a carbon-carbon double bond; The molar ratio of the basic catalyst to the compound of formula (I) is characterized in that it is 1:1,000 to 1:5, particularly 1:100 to 1:10.

[0013] For clarity, some terms used in this specification are defined as follows:

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

[0015] In this specification, if the same representation of a symbol or base exists in multiple formulas, the aforementioned definition of the base or symbol made in relation to a particular formula also applies to other formulas that contain the same aforementioned representation.

[0016] In this specification, the term “independent of each other” in the context of substituents, moieties, or groups means that similarly designated substituents, moieties, or groups may coexist in the same molecule while having different meanings.

[0017] In this specification, dotted lines in formulas represent bonds formed when a substituent is attached to the remainder of the molecule.

[0018] In this specification, the dotted line in chemical formulas [ka] Any bond in this sequence independently represents either a carbon-carbon single bond or a carbon-carbon double bond.

[0019] Any tilde in any formula herein represents a carbon-carbon bond that is either in a Z configuration or an E configuration when linked to a carbon-carbon double bond. In all molecules, the carbon-carbon double bond is preferably in an E configuration.

[0020] "pKa " is generally known as the negative logarithm to the base 10 of the acid dissociation constant (pK a =-log 10 K a ). When an organic acid has multiple protons, the pK a used in this specification relates to the dissociation constant of the last proton. For example, in the case of a base having two basic sites, "pka" relates to pK a2 . pK a is measured at standard temperature and standard pressure.

[0021] [Compound of formula (II)] The compounds of formula (II) are substances known to those skilled in the art in a similar manner to their synthesis.

Chemical formula

[0022] In one preferred embodiment, the substituents R 3 and R 4 represent a methoxy group. In this embodiment, the dotted line

Chemical formula

[0023] Ubiquinone is an important representative class in this embodiment. Ubiquinone is represented 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) according to the number of isoprenoid groups in the side chain. Ubiquinone is also known in the old term coenzyme Q. Ubiquinone-10 (n = 8) (= coenzyme Q10) is a particularly preferred species in this embodiment.

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

[0025] R 1 =R 3 =R 4 =CH 3 It is particularly preferable that this be the case.

[0026] It is preferable that n=2. (Dotted line in equation (II)) [ka] It is even more preferable that all bonds are carbon-carbon double bonds, and that they are all in an E configuration.

[0027] In this embodiment, the compound of formula (II) is (II-BB) [ka] = Geranylgeranyltrimethylbenzoquinone It is preferable that it be a compound of the following.

[0028] In another preferred embodiment, substituent R 3 and R 4 Both represent -CH-CH-CH- and form an aromatic group. The compound of this embodiment is [ka] It is represented as follows.

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

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

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

[0032] dotted line [ka] Any bond in the array preferably represents a carbon-carbon double bond and is preferably in an E configuration.

[0033] Menaquinone is denoted 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), according to the number of isoprenoid groups in its side chain.

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

[0035] dotted line [ka] If any of the bonds represent a carbon-carbon double bond, it will be expected by those skilled in the art that secondary ring formation may occur (due to the presence of carbon-carbon double bonds). Since this secondary ring formation has not been observed, it is particularly preferable that at least one of the dotted-line bonds represents a carbon-carbon double bond. Thus, this process in particular yields an α-tocotrienol having three double bonds in its side chain. α-tocotrienols are important compounds in natural vitamin E.

[0036] [Basic catalyst] The process includes a step of cyclizing the compound of formula (I) in the presence of a basic catalyst ("cat") to obtain the compound of formula (I), as shown as step a) in the reaction scheme of Figure 1.

[0037] The basic catalyst is preferably an alkali metal or earth alkali metal hydroxide or carbonate, preferably a hydroxide, and especially an alkali metal hydroxide.

[0038] The basic catalyst is more preferably an organic amine, particularly an organic tertiary amine.

[0039] Basic catalysts are bases. Not all bases act equally and sufficiently in this invention. The basic catalyst is preferably not pyridine. The pK should be 8.6–15.7, particularly 9–15.7, as measured in water. a It has been shown that the conjugate acid of the basic catalyst having the above-mentioned characteristic is particularly suitable. This indicates that the basic catalyst preferably has a pK of 5.4 to 0, particularly 5 to 0. b It means having

[0040] [Table 1]

[0041] In one embodiment, the basic catalyst is an organic amine selected from the group consisting of 4-dimethylaminopyridine (=DMAP), 1,8-diazabicyclo[5.4.0]undeca-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 spartein, and preferably an organic amine selected from the group consisting of 4-dimethylaminopyridine (=DMAP), 1,8-diazabicyclo[5.4.0]undeca-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, and particularly an alkali metal hydroxide. In this embodiment, the basic catalyst is most preferably NaOH or KOH.

[0043] The base is not a hydride like sodium hydride, especially when it comes into contact with the compound of formula (II), as the hydride forms molecular hydrogen. The generation of hydrogen poses a significant safety risk during the ring-closing process and generally during the process.

[0044] When a base is used as a solid, a phase transfer agent is used, especially a quaternary ammonium salt, particularly one of the formulas [NR4]X (wherein R is C). 2~18 Alkyl groups, especially C 3~8 It is preferable to use a quaternary ammonium salt (where X is an alkyl group and X is a halide). Preferably, the phase transfer agent is tetrabutylammonium halide, particularly tetrabutylammonium bromide. The phase transfer agent is preferably used in an amount of 0.1 to 10 mol%, particularly 0.5 to 2 mol%, relative to the compound of formula (II).

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

[0046] The ring-closing process is preferably carried out in a hydrocarbon solvent, particularly in toluene.

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

[0048] When water is present, it is preferable to carry out the ring-closing reaction in a two-phase system, namely an aqueous phase and an organic phase, particularly a water and organic solvent phase.

[0049] It is important to emphasize that the basic substance is present in catalytic amounts; that is, the basic catalyst is not present in stoichiometric amounts relative to the compound of formula (II), but rather in extremely small amounts, i.e., the molar ratio of the basic catalyst to the compound of formula (I) is 1:1,000 to 1:5, and especially 1:100 to 1:10.

[0050] The ring-closing step is typically carried out at a temperature preferably 40 to 200°C, preferably 90 to 150°C, more preferably at the reflux temperature of the organic solvent if an organic solvent is used, and / or with stirring at a pressure of 1 bara to 10 bara. This reaction is even more preferably carried out under an inert atmosphere, preferably under nitrogen.

[0051] The above process results in equation (I) [ka] It has been shown that the compound can be obtained smoothly.

[0052] In particular, the above process makes it possible to isolate the desired compound of formula (I) in a simple manner, that is, without requiring purification by crystallization after any complex derivatization, as in the case of the process disclosed in Schudel, Mayer, Isler, Helv. Chim. Acta 46, 2517-2526 (1963), and ultimately chemically converting the derivative to the desired compound.

[0053] Particularly preferred embodiments of the compound of formula (I) are the compounds of formulas (IA), (IB), and (IC), and preferably the compounds of formulas (I-AA), (I-BB), (I-CC1), and (I-CC2): [ka] n=0 to 9, especially n=8 [ka] n=0 to 9, especially n=8 [ka] n=0 to 9, especially n=2 [ka] [ka] n = 0 to 12 [ka] n=0 to 12, especially n=2 [ka]

[0054] A highly preferred compound is the compound of formula (I-As). [ka] n=3 to 9, especially n=8

[0055] A highly preferred compound is the compound of formula (I-Cis). [ka] n=1 to 12, especially n=2 to 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 Figure 1, during this hydrogenation, only the carbon-carbon double bond within the ring is hydrogenated, while the carbon-carbon double bond of the olefin is not hydrogenated ("partial hydrogenation"), thereby producing the compound of formula (III) by hydrogenation. [ka]

[0058] Particularly preferred embodiments of the compound of formula (III) are the compounds of formulas (III-A), (III-B), and (III-C), and preferably the compounds of formulas (III-AA), (III-BB), (III-CC1), and (III-CC2): [ka] n=0 to 9, especially n=8 [ka] n=0 to 9, especially n=8 [ka] n=0 to 9, especially n=2 [ka] [ka] n = 0 to 12 [ka] n=0 to 12, especially n=2 [ka]

[0059] A highly preferred compound is the compound of formula (III-Cis). [ka] n=3 to 6, especially n=5

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

[0061] Particularly preferred embodiments of the compound of formula (IV) are the compounds of formulas (IV-A), (IV-B), and (IV-C), and preferably the compounds of formulas (IV-A), (IV-BB), and (IV-CC): [ka] n=0 to 9, especially n=8 [ka] n=0 to 9, especially n=2 [ka] n = 0 to 12 [ka]

[0062] A highly preferred compound is the compound of formula (IV-Cs). [ka] n=3 to 12, especially n=3 to 5

[0063] Therefore, in further embodiments, the present invention also relates to formula (III) [ka] Regarding the process for producing the compound, a) Through the process described in great detail above, equation (I) [ka] (In the formula, the dotted line) [ka] Any bond in this sequence independently represents either a carbon-carbon single bond or a carbon-carbon double bond; The process of producing a compound in which any wavy line represents a carbon-carbon bond that is either in a Z configuration or an E configuration when linked to a carbon-carbon double bond independently of each other, b) The process includes the step of partially hydrogenating the compound of formula (I) with a hydrogenating agent suitable for partial hydrogenation to obtain the compound of formula (III).

[0064] The hydrogenating agent used in step b) is one that hydrogenates only the carbon-carbon double bond of the ring of formula (I). Particularly preferred hydrogenating agents are sodium / ethanol, as described in Schudel, Mayer, Isler, Helv. Chim. Acta 46, 2517-2526 (1963), especially in the last paragraph on page 2524.

[0065] Therefore, in a further embodiment, the present invention also relates to formula (IV) [ka] Regarding the process for producing the compound, a) Through the process described in great detail above, equation (I) [ka] (In the formula, the dotted line) [ka] Any bond in this sequence independently represents either a carbon-carbon single bond or a carbon-carbon double bond; The process of producing a compound in which any wavy line represents a carbon-carbon bond that is either in a Z configuration or an E configuration when linked to a carbon-carbon double bond independently of each other, b') The process includes the step of hydrogenating the compound of formula (I) with a hydrogenating agent to obtain the compound of formula (IV).

[0066] The hydrogenating agent used in step b') is a hydrogenating agent that hydrogenates the carbon-carbon double bonds of all olefins in the ring of formula (I). Particularly preferred hydrogenating agents are hydrogen in the presence of a Group 7, Group 8, Group 9, or Group 10 transition metal, selected from the group consisting of Pd, Pt, Rh, Ru, Mn, Fe, Co, and Ni, and more preferably Pd.

[0067] The heterogeneous transition metal catalyst is preferably a heterogeneously supported transition metal catalyst.

[0068] In this embodiment, the transition metal is supported on a carrier, i.e., palladium is attached to / deposited on the carrier. The carrier is a solid material.

[0069] Preferably, the carrier is a carbon or inorganic carrier. Preferred inorganic carriers are oxides or carbonates. Preferred oxides are oxides of Si, Al, Ce, Ti, or Zr, particularly Al or Si. Silicon dioxide, alumina, titanium dioxide, and ceria are particularly preferred.

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

[0071] Hydrogenation is preferably carried out under pressure, particularly under a hydrogen pressure of 2 to 20 bar. It is even more preferable to carry out hydrogenation at a temperature of 0°C to 100°C.

[0072] Compositions containing the compound of formula (II) and the basic catalyst itself are also objects of the present invention.

[0073] Therefore, in further embodiments, the present invention is i) Equation (II) [ka] (In the formula, n = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; R 1 represents a hydrogen or methyl group; R 3 and R 4 teeth, Each of them independently represents either a hydrogen atom, a methyl group, or a methoxy group, Alternatively, both represent -CH-CH-CH- and form an aromatic group; dotted line [ka] Any bond in this sequence independently represents either a carbon-carbon single bond or a carbon-carbon double bond; Any wavy line represents a carbon-carbon bond that is either in a Z configuration or an E configuration when it is independently linked to a carbon-carbon double bond in a compound. and, ii) Containing a basic catalyst, The present invention relates to a composition characterized in that the molar ratio of a basic catalyst to a compound of formula (I) is 1:1,000 to 1:5, particularly 1:100 to 1:10.

[0074] The compounds of formula (II) and basic catalysts, as well as preferred embodiments thereof, have already been described in great detail above with respect to the process.

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

[0076] Accordingly, in a further embodiment, the present invention relates to the catalytic use of a base for the ring-closing reaction of a compound of formula (II) to obtain a compound of formula (I), [ka] During the ceremony, n = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; R 1 represents a hydrogen or methyl group; R 3 and R 4 teeth, Each of them independently represents either a hydrogen atom, a methyl group, or a methoxy group, Alternatively, both represent -CH-CH-CH- and form an aromatic group; dotted line [ka] Any bond in this sequence independently represents either a carbon-carbon single bond or a carbon-carbon double bond; Any wavy lines represent carbon-carbon bonds that are either in a Z configuration or an E configuration when connected to a carbon-carbon double bond, independently of each other.

[0077] As with the compound of formula (II), the basic catalyst, and the ring-closing step, preferred embodiments thereof have already been described in great detail above with respect to the process.

[0078] Furthermore, compounds of formula (IA) or (IC), or (III-A) or (III-C), or (IV-A) or (IV-C) have been found to possess antioxidant properties.

[0079] Accordingly, in a further embodiment, the present invention relates to the use of compounds of formula (IA) or (IC) or (III-A) or (III-C) as antioxidants. [ka] n=0 to 9, especially n=8 [ka] n = 0 to 12 [ka] n=0 to 9, especially n=8 [ka] n = 0 to 12 [ka] n=0 to 9, especially n=8 [ka] n = 0 to 12 In the formula, R 1 represents a hydrogen or methyl group.

[0080] Similar to 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 with respect to the process.

[0081] Some of the compounds disclosed herein are novel. These compounds are not only novel but also inventive, as they are suitable for the disclosed processes and uses.

[0082] Accordingly, in further embodiments, the present invention particularly relates to compounds of formula (I-As), (I-Cis), (III-Cis), or (IV-Cs), [ka] In the formula, n=3 to 9, and in particular n=8, [ka] In the formula, n = 1 to 12, and especially n = 2 to 5. [ka] In the formula, n=3 to 6, and in particular n=5, [ka] In the formula, n = 3 to 12, and especially n = 3 to 5. Furthermore, during the ceremony, R 1 represents a hydrogen or methyl group; dotted line [ka] Any bond in this sequence independently represents either a carbon-carbon single bond or a carbon-carbon double bond; Any wavy lines represent carbon-carbon bonds that are either in a Z configuration or an E configuration when connected to a carbon-carbon double bond, independently of each other.

[0083] [Examples] The present invention will be further explained by the following experiment.

[0084] [Formation of (E)-2-(4,8-dimethylnonal-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. Then, lithium aluminum hydride (2 M in THF) (2.96 ml, 5.92 mmol) was added, and after 3.5 hours at 0-24°C, the reaction was stopped by adding 40 mL (4N) HCl. The organic phase was washed once with 40 mL of brine and 0.2 g of sodium dithionite and dried on 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), and 1.5 equivalents of silver oxide and 46 μL of acetic acid were added. The mixture was stirred at room temperature for 2 hours. After purification by filtration and chromatography (neutral silica), 2,3,5-trimethyl-6-((6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-yl)cyclohexa-2,5-dien-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]undeca-7-ene (=DBU) were added, and the mixture was stirred under reflux (110°C) for 20 hours to produce (E)-2-(4,8-dimethylnonano-3,7-dien-1-yl)-2,5,7,8-tetramethyl-2H-chromen-6-ol in 86.5% yield.

[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 shown 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 rate and yield shown in Table 1.

[0088] [Table 2]

[0089] The results in Table 1 show that the desired product, namely 3,4-dehydro-α-tocotrienol, was formed with all bases used in catalytic amounts. In most examples, very high conversion rates and yields exceeding 94% can be achieved. Furthermore, Examples 7, 8, and 9 in Table 1 show particularly high pK values ​​for conjugate acids lower than 8.6. a It has been shown that using a basic catalyst containing [specific element] results in even lower conversion rates and yields. Furthermore, this experiment revealed that pyridine exhibits particularly low conversion rates at catalyst concentrations. Comparing Examples 2 and 3, it is evident that significantly higher conversion rates and yields can still be achieved despite a tenfold lower concentration.

[0090] [Partial hydrogenation] The 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) prepared above 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)chromen-6-ol, whose identification could be confirmed by NMR.

[0091] [Complete hydrogenation] The 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) prepared above was quantitatively hydrogenated with hydrogen from 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)chromen-6-ol), whose identification could be confirmed by NMR.

[0092] [Experiment Series 2] 0.46 g (1.098 mmol) of geranylgeranyltrimethylbenzoquinone (97% purity), toluene in the amount provided in Table 2, and 5.49 μmol of DBU (1 / 200) were added, and the mixture was stirred under 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) with the conversion rates and yields 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)) were added in the presence of 3.5 mg of tetrabutylammonium bromide (1 mol% (relative to geranylgeranyltrimethylbenzoquinone)), and the mixture was stirred under reflux (110°C) for the reaction times shown in Table 2 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 rates and yields shown in Table 3.

[0095] [Table 4]

Claims

1. Equation (I) 【Chemistry 1】 A method for producing a compound of formula (II) 【Chemistry 2】 The process includes a step of ring-closing the compound in the presence of a basic catalyst to obtain the compound of formula (I), During the ceremony, n = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; R １ represents a hydrogen or methyl group; R ３ and R ４ These independently represent hydrogen, a methyl group, or a methoxy group, or Each of R3 and R4, together with the carbon atom to which they are bonded, forms the following aromatic group: 【Transformation 3】 dotted line 【Chemistry 4】 Any bond in the equation independently represents either a carbon-carbon single bond or a carbon-carbon double bond; Any wavy line represents a carbon-carbon bond that is either in a Z configuration or an E configuration when it is independently linked to a carbon-carbon double bond; The molar ratio of the basic catalyst to the compound of formula (II) is 1:1000 to 1:

5. A method characterized in that the conjugate acid of the basic catalyst has a pKa of 8.6 to 15.7 as measured in water.

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

3. The method according to claim 1 or 2, characterized in that the basic catalyst is an organic amine, or a metal hydroxide or metal carbonate.

4. The method according to claim 1 or 2, characterized in that the basic catalyst is selected from the group consisting of 4-dimethylaminopyridine (=DMAP), 1,8-diazabicyclo[5.4.0]undeca-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 spartein.

5. The method according to claim 1 or 2, characterized in that the compound of formula (I) is the compound of formula (I-BB), and the compound of formula (II) is the compound of formula (II-BB). 【Transformation 5】

6. The method according to claim 1 or 2, characterized in that the ring-closing step is performed in a hydrocarbon solvent.

7. Formula (III) 【Transformation 6】 A method for producing the compound, a) The method according to claim 1 or 2, formula (I) 【Transformation 7】 (In the formula, the dotted line) 【Transformation 8】 Any bond in the equation independently represents either a carbon-carbon single bond or a carbon-carbon double bond; The process of producing a compound in which any wavy line independently of each other, when linked to a carbon-carbon double bond, is either in a Z configuration or an E configuration, b) A method comprising the step of partially hydrogenating a compound of formula (I) with a hydrogenating agent suitable for partial hydrogenation to obtain a compound of formula (III).

8. Formula (IV) 【Chemistry 9】 A method for producing the compound, a) The method according to claim 1 or 2, formula (I) 【Chemistry 10】 (In the formula, the dotted line) 【Chemistry 11】 Any bond in the equation independently represents either a carbon-carbon single bond or a carbon-carbon double bond; The process of producing a compound in which any wavy line independently of each other, when linked to a carbon-carbon double bond, is either in a Z configuration or an E configuration, b') A method comprising the step of hydrogenating the compound of formula (I) with a hydrogenating agent to obtain the compound of formula (IV).

9. A composition, i) Equation (II) 【Chemistry 12】 (In the formula, n = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; R １ represents a hydrogen or methyl group; R ３ and R ４ each independently represents hydrogen, a methyl group or a methoxy group, or Each of R3 and R4, together with the carbon atom to which they are bonded, forms the following aromatic group: 【Chemistry 13】 dotted line 【Chemistry 14】 Any bond in the equation independently represents either a carbon-carbon single bond or a carbon-carbon double bond; Any wavy line represents a carbon-carbon bond that is either in a Z configuration or an E configuration when it is independently linked to a carbon-carbon double bond in a compound. and, ii) Containing a basic catalyst, The molar ratio of the basic catalyst to the compound of formula (II) is 1:1000 to 1:

5. A composition characterized in that the basic catalyst is selected from the group consisting of 4-dimethylaminopyridine (=DMAP), 1,8-diazabicyclo[5.4.0]undeca-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), spartein, and NaOH.

10. The composition according to claim 9, characterized in that the compound of formula (II) is a compound of formula (II-BB). 【Chemistry 15】

11. The catalytic use of a base for the ring-closing reaction of a compound of formula (II) to obtain a compound of formula (I), 【Chemistry 16】 During the ceremony, n = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; R １ represents a hydrogen or methyl group; R ３ and R ４ These independently represent hydrogen, a methyl group, or a methoxy group, or Each of R3 and R4, together with the carbon atom to which they are bonded, forms the following aromatic group: 【Chemistry 17】 dotted line [Chemistry 18] Any bond in the equation independently represents either a carbon-carbon single bond or a carbon-carbon double bond; Any wavy line represents a carbon-carbon bond that is either in a Z configuration or an E configuration when it is independently connected to a carbon-carbon double bond. The molar ratio of the base to the compound of formula (II) is 1:1000 to 1:

5. The use is characterized in that the base is selected from the group consisting of 4-dimethylaminopyridine (=DMAP), 1,8-diazabicyclo[5.4.0]undeca-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), sparteine, and NaOH.

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