Coupling of 2,3,5-trimethylhydroquinone and unsaturated alcohols

Abstract

The present invention relates to the formation of a compound of formula (I) by reacting 2,3,6-trimethylhydroquinone or a protected derivative thereof with an unsaturated alcohol of formula (IIIa) or (IIIb) in the presence of Gd(OTf)3, or Tm(OTf)3, or Al(OTf)3, or Y(OTf)3, or Fe(OTf)2, or camphorsulfonic acid or BiCl3 as an acid catalyst. TIFF2024517559000061.tif103147

Description

Detailed description of the invention

[0001] [Technical field] The present invention relates to the synthesis of chroman and chromene, particularly 3,4-dehydrotocotrienol, tocotrienol and tocopherol.

[0002] [Background of the Invention] Chroman compounds containing olefinic carbon-carbon double bonds are an important class of chemical substances. In particular, α-tocotrienols are very important members of this class.

[0003] The corresponding compound having a saturated side chain, namely α-tocopherol, is known to be prepared from 2,3,6-trimethylhydroquinone and isophytol in the presence of a Lewis acid and / or a Brønsted acid.

[0004] For example, International Publication No. 2004 / 063182A1 discloses the formation of α-tocopheryl acetate from 2,3,6-trimethylhydroquinone-1-acetate and isophytol in the presence of a wide variety of metal triflates. Isophytol has only one carbon-carbon double bond used in the coupling reaction, but it does not have any further double bonds that could lead to secondary ring formation, i.e., ring formation in the side chain.

[0005] International Publication No. 2004 / 046126A1 discloses the formation of α-tocopheryl acetate from 2,3,6-trimethylhydroquinone-1-acetate and isophytol in the presence of a wide variety of sulfonic acids, particularly triflurelic acid or p-toluenesulfonic acid. Because isophytol is used, secondary ring formation is not possible.

[0006] European Patent Application Publication No. 949255A1 discloses the coupling of TMHQ with isophytol using sulfuric acid or several sulfonic acids, particularly trifluic acid or p-toluenesulfonic acid.

[0007] However, the use of these acidic catalysts has generally been shown to be unsuitable for the reaction of 2,3,6-trimethylhydroquinone (TMHQ) or its protected form with each unsaturated alcohol such as geranylgeraniol or farnesol, since undesirable cyclic compounds are formed.

[0008] This finding is in full agreement with Kabbe and Heitzer, Synthesis 1978, 12, 888 - 889, which reports that the known synthetic route of vitamin E (i.e., α-tocopherol) from TMHQ and isophytol is not suitable for the synthesis of tocotrienols (i.e., from TMHQ and geranyllinalool), since the isoprenoid side chain causes a secondary ring closure reaction with the acid catalyst.

[0009] However, the synthesis of tocotrienols and their precursors remains highly important.

[0010] [Summary of the Invention] Therefore, the problem to be solved by the present invention is to find a suitable process for producing a compound of formula (I) from an unsaturated alcohol of formula (IIIa) or (IIIb) and TMHQ or its protected form.

[0011] Despite the teachings of the prior art, it has been very surprising that several metal triflates and sulfonic acids are suitable catalysts for this reaction, giving high yields and high selectivities, and particularly low tendency to form cyclic compounds by the isoprenoid side chain as by-products, and thus a compound of formula (I) can be obtained.

[0012] A further aspect of the invention is the subject of further independent claims. Particularly preferred embodiments are the subject of the dependent claims.

[0013] [Detailed Description of the Invention] In a first aspect, the invention relates to formula (I) [Chemical formula] A method for producing a compound of formula (II) and a compound of formula (IIIa) or (IIIb) [ka] and One of the following Gd(OTf)3 or Tm(OTf)3 or Al(OTf)3 or Y(OTf)3 or Fe(OTf)2 or Camphor sulfonic acid; or BiCl3 The step includes carrying out the reaction in the presence of an acidic catalyst; During the ceremony, n = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; R represents hydrogen or R', which is a phenol protecting group; OTf stands for trifluoromethanesulfonate; and Any combination separated by a dotted line [ka] Each of the bonds with a dotted line represents either a carbon-carbon single bond or a carbon-carbon double bond, provided that at least one of the bonds represents a carbon-carbon double bond; This invention relates to a method in which any wavy lines independently represent carbon-carbon bonds, and when these bonds are attached to a carbon-carbon double bond, they represent either a Z- or E- conformation.

[0014] It is preferable that any wavy line bonded to the carbon-carbon double bond is in the E conformation.

[0015] For clarity, some terms used in this specification are defined as follows:

[0016] In this specification, "C x~yThe "-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.

[0017] An "aralkyl" group is an alkyl group substituted with an aryl group.

[0018] Therefore, in this specification, "C x~y - The aralkyl group is an aralkyl group containing x to y carbon atoms, that is, for example, C 7~16 - An aralkyl group is an aralkyl group containing 7 to 16 carbon atoms. Aralkyl groups may be linear or branched. For example, the benzyl group (-CH2-C6H5) is considered a C7-aralkyl group.

[0019] If the same symbol or base exists in several formulas, the definition of the base or symbol made in this specification for a particular formula also applies to other formulas that contain the same symbol.

[0020] In this specification, the term "independently of each other" means that identically designated substituents, parts, or groups can coexist in the same molecule with different meanings.

[0021] In this specification, dotted lines in formulas represent bonds through which a substituent is attached to the rest of the molecule.

[0022] In this specification, any bond having a dotted line in a chemical formula is permitted. [ka] These elements independently represent either a carbon-carbon single bond or a carbon-carbon double bond.

[0023] Any wavy line in the formulas herein represents a carbon-carbon bond, and when this is bonded to a carbon-carbon double bond, it is either in the Z or E conformation. In all molecules, it is preferred that the carbon-carbon double bond is in the E conformation.

[0024] As used herein, the term "OTf" means trifluoromethanesulfonate.

[0025] “pK a ” is generally known as the negative decimal logarithm of the acid dissociation constant (pK a = -log 10 K a ). When an organic acid has multiple protons, the pK a used herein 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 pressure.

[0026] [Compound of formula (II)] The compound of formula (II) is 2,3,5-trimethylhydroquinone (= 2,3,5-trimethylbenzene-1,4-diol, TMHQ) (R = H) or a mono-protected derivative thereof (R ≠ H; R = R').

Chemical formula

[0027] A phenol protecting group is a group that protects the phenol group (OH) in any of the formulas herein having R = H, and the protecting group can be removed easily, i.e., by state-of-the-art methods, such that each compound having a free phenol group can be obtained again.

[0028] The phenol protecting group R' is introduced by the chemical reaction of a compound of each formula having H as R with a protecting agent.

[0029] Protecting agents that lead to the corresponding phenol protecting group are known to those skilled in the art, as are the chemical processes and conditions for this reaction. For example, when the phenol protecting group forms an ester with the rest of the molecule, suitable protecting agents are, for example, acids, anhydrides, or acyl halides.

[0030] The phenol protecting group R' is selected from the group consisting of the following: [ka] (In the formula, R 10 , R 11 They are independent of each other, C 1~15 - Alkyl alkyl or fluorinated C 1~15 - Alkyl alkyl group or C 1~15 -Cycloalkyl group or C 7~15 - Represents an aralkyl group; R 12 C 1~15 - Alkylene or C 6~15 - Represents an alkylene group; And any of the following R 13 C 1~15 - Represents an alkyl group, alkylene oxyalkyl group, or polyoxyalkylene group; R 14 is hydrogen or C 1~15 - Does it represent an alkyl group? Or R 13 and R 14 These combine to form a 5-7 membered ring. 3~7 - Represents an alkylene group; (A single dotted line represents a bond in which the substituent is attached to the rest of the molecule.)

[0031] R' is R 10 If equal, then each compound is an ether, which can be formed by the reaction of each protective agent with a phenol group (OH). In this case, the protective agent is, for example, each C 1~15 -Alkyl or fluorinated C 1~15 -Alkyl or C 1~15-Cycloalkyl or C 7~15 - Aralkyl halides, especially alkylating agents such as iodide, may also be used.

[0032] In one preferred embodiment, R 10 It is a methyl group.

[0033] In another preferred embodiment, R 10 C 7~15 - An aralkyl group, preferably a benzyl group or a substituted benzyl group, and particularly preferably a benzyl group.

[0034] R' [ka] When represented by this notation, each compound is an ester of a carboxylic acid or dicarboxylic acid, which can be formed by the reaction of the respective protecting agent with a phenol group (OH). In this case, the protecting agent may be, for example, an anhydride or halogen of each carboxylic acid (1) or dicarboxylic acid (2). [ka]

[0035] If the compound in each formula is an ester of a carboxylic acid or dicarboxylic acid, then R' is C 1~7 - The acyl group is preferably an acetyl, trifluoroacetyl, propionyl, or benzoyl group, or a substituted benzoyl group.

[0036] R' [ka] In this case, each compound is an acetal, which can be formed by the reaction of the respective protective agent with a phenol group (OH). In this case, the protective agent is, for example, the respective aldehyde, alkyl halide, e.g., MeO(CH2)2OCH2Cl, or enol ether, e.g., 3,4-dihydro-2H-pyran.

[0037] In this case, substituent R' is preferably, [ka] (In the formula, n = 0 or 1).

[0038] In some cases, acetals are also called "ethers," and in the above-mentioned cases in particular, they are called methoxymethyl ether (MOM-ether), β-methoxyethoxymethyl ether (MEM-ether), or tetrahydropyranyl ether (THP-ether).

[0039] In another preferred embodiment, each compound is an ester of phosphoric acid, pyrophosphate, phosphorous acid, sulfuric acid, or sulfite.

[0040] Depending on the reaction conditions, esterification may occur completely or partially, leaving the remaining acidic groups of each acid unesterified.

[0041] Protecting group R' is a benzoyl group or C 1~4 - An acyl group, particularly an acetyl group or a trifluoroacetyl group, most preferably an acetyl group. Molecules in which R' represents an acyl group, particularly an acetyl group, can be readily prepared from the corresponding unprotected molecule by esterification, and unprotected phenol compounds can be obtained from the corresponding ester by ester hydrolysis.

[0042] The phenol protecting group can be cleaved by the deprotection reaction step b), as described later.

[0043] R' is an expression [ka] (In the formula, R 11 C 1~15 -Alkyl or fluorinated C 1~15 -Alkyl or C 1~15 -Cycloalkyl or C 7~15 - Preferably, it is a phenol protecting group of an aralkyl group, preferably a methyl group or a benzyl group.

[0044] [Compounds of formula (IIIa) or (IIIb)] [ka] (wherein n = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12).

[0045] It is preferable that n = 0, 1, or 2, most preferably 1 or 2, and most preferably n = 2.

[0046] Examples of preferred compounds of formula (IIIa) are: [ka] A compound selected from the group consisting of, in particular [ka] It is a compound selected from the group consisting of the following:

[0047] It is more preferable that all double bonds are in an E conformation.

[0048] The most preferred compounds of formula (IIIa) are 3,7,11-trimethyldodeca-2,6,10-trien-1-ol, preferably (6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-ol (also known as farnesol); and 3,7,11,15-tetramethylhexadeca-2,6,10,14-tetraen-1-ol, preferably (6E,10E)-3,7,11,15-tetramethylhexadeca-2,6,10,14-tetraen-1-ol (also known as geranylgeraniol). Particularly preferred are (2E,6E)-farnesol and (2E,6E,10E)-geranylgeraniol.

[0049] Examples of preferred compounds of formula (IIIb) are: [ka] A compound selected from the group consisting of, in particular [ka] It is a compound selected from the group consisting of the following:

[0050] The most preferred compounds of formula (IIIb) are 3,7,11-trimethyldodeca-1,6,10-trien-3-ol, preferably (E)-3,7,11-trimethyldodeca-1,6,10-trien-3-ol (also known as nerolidol); and 3,7,11,15-tetramethylhexadeca-1,6,10,14-tetraen-3-ol, preferably (6E,10E)-3,7,11,15-tetramethylhexadeca-1,6,10,14-tetraen-3-ol (also known as geranilinalool).

[0051] The compounds of formulas (IIIa) and (IIIb), particularly geranilinalool and geranylgeraniol, can be prepared in industrial quantities by known methods, or are commercially available, for example, from Sigma-Aldrich, or commercially available from natural / bio-based sources as disclosed in John A. Hyatt et al., Organic Process Research and Development 2002, 6, 782-787.

[0052] [Acidic catalyst] The compound of formula (II) is reacted with the compound of formula (IIIa) or (IIIIb) in the presence of an acidic catalyst, which is either camphor sulfonic acid or BiCl3, Gd(OTf)3, Tm(OTf)3, Al(OTf)3, Y(OTf)3, or Fe(OTf)2.

[0053] It has been found that only a very small number of Brønsted acids or Lewis acids are suitable as acidic catalysts for the reaction of the present invention.

[0054] In one embodiment, the acidic catalyst is camphor sulfonic acid. The camphor sulfonic acid used herein is camphor-10-sulfonic acid. [ka]

[0055] Preferably, camphor sulfonic acid is of the (+) type.

[0056] In another embodiment, the acid catalyst is BiCl3.

[0057] In another embodiment, the acidic catalyst is a triflate of gadolinium, thulium, aluminum, yttrium, or iron. Preferred triflates are Gd(OTf)3, Al(OTf)3, and Fe(OTf)2.

[0058] In the above reaction, the molar ratio of the compound of formula (II) to the compound of formula (IIIa) or (IIIb) is preferably in the range of 3 to 1, more preferably in the range of 2.5 to 1.1, and more preferably in the range of 2.0 to 1.2.

[0059] Furthermore, the molar ratio of the compound of formula (II) to the acidic catalyst is preferably 0.001 mol% to 1 mol%, more preferably 0.005 mol% to 1 mol%, and more preferably 0.02 mol% to 1 mol%.

[0060] The reaction is carried out at a temperature of 20°C to 160°C, preferably 80°C to 120°C.

[0061] Furthermore, the reaction is usually carried out at atmospheric pressure.

[0062] In one embodiment, the reaction involves a hydrocarbon, preferably toluene, or C 5~10 This process is preferably carried out in the presence of a solvent, most preferably an alkane, hexane, or heptane.

[0063] In another embodiment, the reaction is preferably carried out in the presence of a solvent which is an organic carbonate, preferably a carbonate of formula (X): [ka] (In the formula, Y 1 and Y 2 (Each of these independently represents either H, or a methyl group or an ethyl group.)

[0064] Preferably, the organic carbonate is ethylene carbonate or propylene carbonate. Mixtures of different carbonates of formula (X) can also be used, particularly as a binary or ternary mixture of ethylene carbonate and / or propylene carbonate and / or butylene carbonate, and most preferably as a binary mixture of ethylene carbonate and propylene carbonate. The ratio of ethylene carbonate to propylene carbonate is preferably 20:80 to 80:20, and particularly preferably 25:75 to 75:25.

[0065] Preferably, the solvent in the formula is a carbonate solvent commercially available from Huntsman under the trademark Jeffsol®, particularly Jeffsol® EC-75, Jeffsol® EC-50, and Jeffsol® EC-25, which are blends of ethylene carbonate and propylene carbonate.

[0066] In a more preferred embodiment, the reaction is carried out in the presence of a two-phase solvent mixture comprising at least one hydrocarbon and at least one organic carbonate. The hydrocarbon is preferably toluene or C 5~10 The organic carbonate is preferably an alkane, most preferably hexane or heptane. The organic carbonate is preferably a carbonate of formula (X). In this embodiment, the organic carbonate used can be a mixture of different carbonates of formula (X), most preferably a binary or ternary mixture of ethylene carbonate and / or propylene carbonate and / or butylene carbonate. When a mixture of ethylene carbonate and propylene carbonate is used with a hydrocarbon, the ratio of ethylene carbonate to propylene carbonate is preferably 20:80 to 80:20, particularly 25:75 to 75:25.

[0067] Most preferably, the reaction is carried out in a two-phase mixed solvent of hexane and / or heptane and ethylene carbonate and / or propylene carbonate.

[0068] It is preferable that all the dotted bonds in formulas (I), (IIIa), and (IIIb) represent carbon-carbon double bonds.

[0069] The compound of formula (I) can be oxidized to the compound of formula (V), and then cyclized to the compound of formula (VI).

[0070] Therefore, in a further embodiment, the present invention relates to formula (VI) [ka] A process for producing the compound, a) Formula (I) is obtained by the process described in detail above. [ka] The steps for producing the compound, b) When R in formula (I) is a phenol protecting group, then formulas (I) to (I') [ka] The steps include deprotecting the compound and c) The following formula [ka] The compound is oxidized to form formula (V) [ka] The step of making it a compound, d) Cyclizing the compound of formula (V) in the presence of a basic catalyst to form formula (VI) [ka] The present invention relates to a process comprising the step of forming a compound.

[0071] If the compound of formula (I) has a protected form of the phenol group, i.e., R=R', then formula (I') [ka] To obtain each of the deprotected compounds, it is necessary to remove the respective protecting group by a deprotection reaction in step b).

[0072] The conditions for the deprotection reaction in step b) depend on the type of phenol protecting group and are known to those skilled in the art. For example, esters can be readily deprotected under the influence of an acid or a base, or acetals can be readily deprotected under the influence of an acid.

[0073] Esters, such as acetate esters, are cleaved, particularly by lithium aluminum hydride, to obtain their respective unprotected phenols.

[0074] The oxidation in step c) can be carried out by using a suitable oxidizing agent, preferably an acid, particularly silver oxide in the presence of acetic acid, or oxygen or air in methanol.

[0075] In step d), the compound of formula (V) is cyclized to the compound of formula (VI) in the presence of a basic catalyst.

[0076] The basic catalyst is preferably an organic amine, preferably an organic tertiary amine, or a metal hydroxide or carbonate, particularly an organic tertiary amine or an alkali metal hydroxide.

[0077] When measured in water, the pK range was 8.6–15.7, especially 9–15.7. a It has been shown that the conjugate acid of the basic catalyst having the above-mentioned property is particularly suitable. This is because the basic catalyst preferably has a pK of 5.4 to 0, particularly 5 to 0. b It means having

[0078] Some non-restrictive pk of the corresponding acida Examples include the following:

[0079] [Table 1]

[0080] 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]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 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).

[0081] In another embodiment, the basic catalyst is preferably an alkali metal or earth alkali metal hydroxide or carbonate, preferably a hydroxide, particularly an alkali metal hydroxide. In this embodiment, the basic catalyst is most preferably NaOH or KOH.

[0082] The ring-closing step is preferably carried out in a hydrocarbon solvent, particularly toluene.

[0083] When using a hydrocarbon solvent, the solvent is preferably used in such an amount that the solution with the compound of formula (V) is 0.05 to 5 moles, more preferably 0.1 to 1 mole, relative to the compound of formula (V).

[0084] When water is present, the ring-closing reaction is preferably carried out in a two-phase system, i.e., an aqueous phase and an organic phase, particularly an aqueous phase and an organic solvent phase.

[0085] The basic catalyst is present in a catalytic amount, that is, it is present in a significantly lower amount relative to the compound of formula (V) rather than in a stoichiometric amount, and it is preferable that the molar ratio of the basic catalyst to the compound of formula (V) is preferably 1:1,000 to 1:5, and particularly preferably 1:100 to 1:10.

[0086] The ring-closing step is typically carried out under stirring, preferably at a temperature of 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 at a pressure of 1 to 10 atmospheres. This reaction is even more preferably carried out under an inert atmosphere, preferably under nitrogen.

[0087] The compound of formula (VI) can be hydrogenated using either the compound of formula (VIIII) (partial hydrogenation) or the compound of formula (IX) (complete hydrogenation) as a hydrogenating agent. [ka]

[0088] Therefore, in a further embodiment, the present invention relates to formula (VIII) [ka] A process for producing the compound, i) Formula (VI) is obtained by the process described in detail above. [ka] The steps for producing the compound, ii) The present invention relates to a process comprising the step of partially hydrogenating a compound of formula (VI) using a hydrogenating agent suitable for partial hydrogenation to obtain a compound of formula (VIII).

[0089] In step ii) partial hydrogenation, only the carbon-carbon double bond of the ring is hydrogenated, but the olefinic carbon-carbon double bond is not hydrogenated ("partial hydrogenation"), so the compound of formula (VIII) is obtained by hydrogenation.

[0090] The hydrogenating agent used in step ii) is one that hydrogenates only the carbon-carbon double bond of the ring of formula (VIII). Particularly suitable hydrogenating agents are sodium / ethanol, such as those described in Schudel, Mayer, Isler, Helv. Chim. Acta 46, 2517-2526 (1963), especially in the last paragraph on page 2524.

[0091] This process yields α-tocotrienols, in particular, which have three double bonds in their side chains. α-tocotrienols are important compounds found in natural vitamin E.

[0092] Therefore, in a further embodiment, the present invention relates to formula (IX) [ka] A process for producing the compound, i) Formula (VI) is obtained by the process described in detail above. [ka] The steps for producing the compound, ii') The present invention relates to a process comprising the step of hydrogenating a compound of formula (VI) using a hydrogenating agent to obtain a compound of formula (IX).

[0093] The hydrogenating agent used in step ii') is a hydrogenating agent that hydrogenates all olefinic carbon-carbon double bonds in the ring of formula (VI). Particularly suitable hydrogenating agents are transition metals from groups 7, 8, 9, or 10, selected from the group consisting of Pd, Pt, Rh, Ru, Mn, Fe, Co, and Ni, more preferably hydrogen in the presence of Pd.

[0094] The heterogeneous transition metal catalyst is preferably a heterogeneous supported transition metal catalyst.

[0095] Such hydrogenation is disclosed, for example, in Kabbe and Heitzer, Synthesis 1978, 12, 888-889.

[0096] In this embodiment, the transition metal is supported on a carrier. That is, palladium is attached / deposited onto the carrier. The carrier is a solid material.

[0097] 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 oxides of Al or Si. Silicon dioxide, alumina, titanium dioxide, and ceria are particularly preferred.

[0098] When the support material is Ce, the preferred oxide is CeO2. Preferably, the oxides of Al are Al2O3 and AlO(OH). Particularly preferred is Al2O3.

[0099] Hydrogenation is preferably carried out under pressure, particularly under a hydrogen pressure of 2 to 20 bar. Hydrogenation is even more preferably carried out at a temperature of 0°C to 100°C.

[0100] This process, in particular, produces α-tocopherol with fully saturated side chains. α-tocopherol is an important compound in natural vitamin E.

[0101] The compound of formula (IA) is novel. Therefore, in a further embodiment, the present invention relates to formula (IA) [ka] Regarding the compounds.

[0102] As already noted, R' represents a phenol protecting group, and the tilde represents a carbon-carbon bond attached to a carbon-carbon double bond in either a Z- or E- conformation. Protecting groups are described in detail above. In this embodiment, the protecting group R' is preferably an acetyl group.

[0103] The E / Z mixture, in the presence of the process detailed above, [ka] and [ka] It has been shown that it is prepared from.

[0104] The E / Z mixture can be separated by chromatography if necessary.

[0105] As the present invention demonstrates, the compound of formula (I) is a very suitable agent for the synthesis of the compounds of formulas (V'), (VI'), (VIII'), and (IX'). [ka] [Brief explanation of the drawing]

[0106] [Figure 1] Figure 1 schematically illustrates the above process in detail, particularly highlighted by a box, and shows a process for producing the compound of formula (I), which includes the step of reacting the compound of formula (II) with the compound of formula (IIIa) or (IIIb) in the presence of an acidic catalyst ("cat") which is one of the following: Gd(OTf)3, Tm(OTf)3, Al(OTf)3, Y(OTf)3, Fe(OTf)2, camphor sulfonic acid, or BiCl3.

[0107] [Examples] The present invention is further illustrated by the following experiments.

[0108] [Experiment Series 1] Geranilinalool (12.51 g (43 mmol)), 65 ml of a mixture of ethylene carbonate / heptane (1.17 g / g) and 9.91 g (65 mmol) of 2,3,6-trimethylhydroquinone (TMHQ) were added under stirring in the presence of the catalyst shown in Table 1 to obtain 2,3,5-trimethyl-6-((2E,6E,10E)-3,7,11,15-tetramethylhexadeca-2,6,10,14-tetraen-1-yl)benzene-1,4-diol with the conversion rates and yields shown in Table 1.

[0109] [Table 2]

[0110] [Experiment Series 2] Geranylgeraniol (3.45 g (12 mmol)), 15 ml of a mixture of ethylene carbonate / heptane (1.17 g / g) and 2.29 g (15 mmol) of 2,3,6-trimethylhydroquinone (TMHQ) were added under stirring in the presence of the catalysts shown in Table 2 to obtain 2,3,5-trimethyl-6-((2E,6E,10E)-3,7,11,15-tetramethylhexadeca-2,6,10,14-tetraen-1-yl)benzene-1,4-diol with the conversion rates and yields shown in Table 2.

[0111] [Table 3]

[0112] [Experiment Series 3] Geranylgeraniol (3.42 g (12 mmol)), 15 ml of a mixture of ethylene carbonate / heptane (1.17 g / g) and 2.91 g (15 mmol) of 2,3,6-trimethylhydroquinone-1-acetate were added under stirring in the presence of the catalyst shown in Table 3 to obtain 4-hydroxy-2,3,6-trimethyl-5-((2E,6E,10E)-3,7,11,15-tetramethylhexadeca-2,6,10,14-tetraen-1-yl)phenyl acetate with the conversion rates and yields shown in Table 3.

[0113] [Table 4]

[0114] [Experiment Series 4] Geranilinalool (12.51 g (43 mmol)), 65 ml of a mixture of ethylene carbonate / heptane (1.17 g / g) and 16.54 g (65 mmol) of 2,3,6-trimethylhydroquinone-1-benzoate were added under stirring in the presence of the catalyst shown in Table 4 to obtain 4-hydroxy-2,3,6-trimethyl-5-((2E,6E,10E)-3,7,11,15-tetramethylhexadeca-2,6,10,14-tetraen-1-yl)phenylbenzoate with the conversion rate and yield shown in Table 4.

[0115] [Table 5]

[0116] [Experiment Series 5] A solution of 2.19 g (11.3 mmol) of 2,3,6-trimethylhydroquinone-1-acetate and the amount of catalyst shown in Table 5 in a mixture of 5.95 g of ethylene carbonate and 7.5 ml of n-heptane (ethylene carbonate / n-heptane 1.17 / 1 g / g) was heated under stirring until reflux. 2.2 g (7.5 mmol) of (total E)-geranilinalool was added. After removing the ethylene carbonate phase by extraction with heptane, 4-hydroxy-2,3,6-trimethyl-5-((6E,10E)-3,7,11,15-tetramethylhexadeca-2,6,10,14-tetraen-1-yl)phenyl acetate was obtained in the yields shown in Table 5.

[0117] [Table 6]

[0118] [Experiment Series 6] A solution of 2.19 g (11.3 mmol) of 2,3,6-trimethylhydroquinone-1-acetate and the amount of catalyst shown in Table 6 in a mixture of 5.95 g of ethylene carbonate and 7.5 ml of n-heptane (ethylene carbonate / n-heptane 1.17 g / 1 g / g) was heated under stirring until reflux. 1.69 g (7.5 mmol) of (total E)-farnesol or E-nerolidol was added. After removing the ethylene carbonate phase by extraction with heptane, 4-hydroxy-2,3,6-trimethyl-5-((6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-yl)phenyl acetate was obtained in the yields shown in Table 6.

[0119] [Table 7]

Claims

1. Equation (I) 【Chemistry 1】 A method for producing a compound of formula (II) and a compound of formula (IIIa) or (IIIb) 【Chemistry 2】 and Gd(OTf) ３ , Tm(OTf) ３ Al(OTf) ３ , Y(OTf) ３ Fe(OTf) ２ The step includes reacting in the presence of an acidic catalyst, which is camphor sulfonic acid or BiCl3; During the ceremony, n = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; R represents hydrogen or R', which is a phenol protecting group; OTf represents trifluoromethanesulfonate; and Any combination separated by a dotted line 【Transformation 3】 Each of the bonds having the dotted line represents either a carbon-carbon single bond or a carbon-carbon double bond independently of the others, provided that at least one of the bonds represents a carbon-carbon double bond; A method in which any wavy lines independently represent a carbon-carbon bond, and when bonded to the carbon-carbon double bond, the conformation is either Z- or E-.

2. R' is given by the following equation 【Chemistry 4】 (wherein R １１ is a C １～１５ -alkyl or fluorinated C １～１５ -alkyl or C １～１５ -cycloalkyl or C ７～１５ -aralkyl group), the method according to claim 1, characterized in that it is a phenolic protecting group.

3. The method according to claim 1 or 2, characterized in that n = 0, 1, or 2.

4. The method according to claim 1 or 2, characterized in that all bonds having dotted lines in formulas (I), (IIIa), and (IIIb) represent carbon-carbon double bonds.

5. The method according to claim 1 or 2, characterized in that the molar ratio of the compound of formula (II) to the compound of formula (IIIa) or (IIIb) is in the range of 3 to 1.

6. The method according to claim 1 or 2, characterized in that the molar ratio of the compound of formula (II) to the acidic catalyst is 0.001 mol% to 1 mol%.

7. The method according to claim 1 or 2, characterized in that the reaction is carried out in the presence of a hydrocarbon solvent.

8. The method according to claim 1 or 2, characterized in that the reaction is carried out in the presence of a solvent that is an organic carbonate.

9. The method according to claim 1 or 2, characterized in that the reaction is carried out in the presence of a two-phase solvent mixture comprising at least one hydrocarbon and at least one organic carbonate.

10. The method according to claim 1 or 2, characterized in that the reaction is carried out at a temperature of 20°C to 160°C.

11. Equation (VI) 【Transformation 5】 A method for producing the compound, a) Formula (I) obtained by the method described in claim 1 or 2 【Transformation 6】 The steps for producing the compound, b) When R in formula (I) is a phenol protecting group, formulas (I) to (I') 【Transformation 7】 The steps include deprotecting the compound and c) The following formula 【Transformation 8】 The compound is oxidized to form formula (V) 【Chemistry 9】 The step of making it a compound, d) Cycloforming the compound of formula (V) in the presence of a basic catalyst to form formula (VI) 【Chemistry 10】 The step of making it a compound and Methods that include...

12. The method according to claim 11, characterized in that the basic catalyst in step d) is present in a molar ratio of 1:1000 to 1:5 with respect to the compound of formula (V).

13. Formula (VIII) 【Chemistry 11】 A method for producing the compound, i) Formula (VI) obtained by the method of claim 11 【Chemistry 12】 (Any combination with a dotted line in the formula) 【Chemistry 13】 Each represents either a carbon-carbon single bond or a carbon-carbon double bond, independently of the other; and The steps include: producing a compound in which any wavy line independently represents a carbon-carbon bond, and which, when bonded to the carbon-carbon double bond, is in either a Z- or E- conformation; ii) The step of partially hydrogenating the compound of formula (VI) using a hydrogenating agent suitable for partial hydrogenation to obtain the compound of formula (VIII), and Methods that include...

14. Formula (IX) 【Chemistry 14】 A method for producing the compound, i) Formula (VI) obtained by the method of claim 11 【Chemistry 15】 (Any combination with a dotted line in the formula) 【Chemistry 16】 Each represents either a carbon-carbon single bond or a carbon-carbon double bond, independently of the other; and The steps include: producing a compound in which any wavy line independently represents a carbon-carbon bond, and which, when bonded to the carbon-carbon double bond, is in either a Z- or E- conformation; ii') A step of hydrogenating the compound of formula (VI) using a hydrogenating agent to obtain the compound of formula (IX) Methods that include...

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