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 field of synthesis of chromanes and chromenes, in particular 3,4-dehydrotocotrienol, tocotrienol and tocopherol.

[0002] [Background of the invention] Chroman compounds containing olefinic carbon-carbon double bonds are an important class of chemicals, with α-tocotrienol being a particularly important member of this class.

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

[0004] For example, WO 2004 / 063182 A1 discloses the formation of α-tocopheryl acetate from 2,3,6-trimethylhydroquinone-1-acetate and isophytol in the presence of a variety of metal triflates. Isophytol has only one carbon-carbon double bond that can be used in the coupling reaction, but no further double bonds that can lead to secondary ring formation, i.e. ring formation at the side chain.

[0005] WO 2004 / 046126 A1 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 triflic acid or p-toluenesulfonic acid. Due to the use of isophytol, secondary ring formation is not possible.

[0006] EP 949255 A1 discloses the coupling of TMHQ with isophytol using sulfuric acid or several sulfonic acids, in particular triflic acid or p-toluenesulfonic acid.

[0007] However, the use of these acidic catalysts has been shown to be generally unsuitable for the reaction of 2,3,6-trimethylhydroquinone (TMHQ) or its protected form with the respective unsaturated alcohols, such as geranylgeraniol or farnesol, due to the formation of undesired cyclic compounds.

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

[0009] However, the synthesis of tocotrienols and their precursors remains of great importance.

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

[0011] Despite the teachings of the prior art, it was quite surprising to find that several metal triflates and sulfonic acids are suitable catalysts for this reaction, affording compounds of formula (I) in high yield and selectivity, especially with a low tendency to form cyclic compounds as by-products due to the isoprenoid side chain.

[0012] Further aspects of the invention are 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 present invention provides a compound of formula (I) [ka] A method for preparing a compound of formula (II) comprising the steps of: [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 Camphorsulfonic acid; or BiCl3 reacting in the presence of an acid catalyst which is 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 represents hydrogen or R', a phenol protecting group; OTf represents trifluoromethanesulfonate; and Any bond with a dotted line [ka] represent, independently of each other, either a carbon-carbon single bond or a carbon-carbon double bond, provided that at least one of the bonds with a dashed line represents a carbon-carbon double bond; The optional wavy lines, independently of each other, represent carbon-carbon bonds, and when attached to a carbon-carbon double bond, are in either the Z- or E-configuration.

[0014] Any wavy line attached to a carbon-carbon double bond is preferably in the E-configuration.

[0015] For clarity, some terms used herein are defined as follows.

[0016] In this specification, "C x~yA "-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. The alkyl group may be linear or branched. For example, -CH(CH3)-CH2-CH3 is considered to be 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 An "aralkyl" group is an aralkyl group containing x to y carbon atoms, i.e., for example, C 7~16 An aralkyl group is an aralkyl group containing 7 to 16 carbon atoms. The aralkyl group may be linear or branched. For example, a benzyl group (-CH2-C6H5) is considered to be a C7-aralkyl group.

[0019] Where the same label for a symbol or group occurs in several formulas, the definition of said group or symbol made herein for a particular formula also applies to the other formulas containing the same said label.

[0020] The term "independently of each other" in this specification, with reference to substituents, moieties or groups, means that identically designated substituents, moieties or groups can exist simultaneously in the same molecule with different meanings.

[0021] As used herein, a dotted line in a formula represents the bond by which a substituent is attached to the remainder of the molecule.

[0022] In this specification, any bond in a chemical formula having a dotted line [ka] represent, independently of each other, 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 attached to a carbon-carbon double bond, 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.

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

[0025] "pK a " is commonly 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 is related to the dissociation constant of the last proton. For example, for a base with two basic sites, "pka" is the pK a2 It is related to 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 its mono-protected derivative (R≠H; R=R'). [ka]

[0027] A phenol protecting group is a group that protects the phenol group (OH) in any of the formulae herein having R=H, which protecting group can be easily removed, i.e. by state-of-the-art methods, so as to obtain again the respective compound having a free phenol group.

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

[0029] Protecting agents leading 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 in particular selected from the group consisting of: [ka] (In the formula, R 10 , R 11 are independent of each other, C 1~15 -Alkyl group or fluorinated C 1~15 -Alkyl group or C 1~15 -Cycloalkyl group or C 7~15 -represents an aralkyl group; R 12 is C 1~15 -Alkylene or C 6~15 - represents an alkylene group; And one of the following: R 13 is C 1~15 - represents an alkyl group, an alkyleneoxyalkyl group, or a polyoxyalkylene group; R 14 is hydrogen or C 1~15 - represents an alkyl group; or R 13 and R 14 C which combine to form a 5- to 7-membered ring 3~7 - represents an alkylene group; and a single dotted line represents the bond attaching said substituent to the remainder of the molecule).

[0031] R' is R 10 When the protecting agent is equal to each of the C's, the respective compounds are ethers, which can be formed by reaction of the respective protecting agent with a phenolic group (OH). In this case, the protecting agent can be, for example, each of the C's 1~15 -Alkyl or fluorinated C 1~15 -Alkyl or C 1~15-Cycloalkyl or C 7~15 -Alkylating agents such as aralkyl halides, especially iodides.

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

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

[0034] R' is [ka] where the respective compound is an ester of a carboxylic acid or dicarboxylic acid, which may be formed by reaction of the respective protecting agent with a phenolic group (OH), in which case the protecting agent may be, for example, an anhydride or halide of the respective carboxylic acid (1) or dicarboxylic acid (2). [ka]

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

[0036] R' is [ka] where the respective compound is an acetal, which can be formed by reaction of a phenolic group (OH) with a respective protecting agent, such as a respective aldehyde, an alkyl halide, such as MeO(CH2)2OCH2Cl, or an enol ether, such as 3,4-dihydro-2H-pyran.

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

[0038] In some cases, acetals are also called "ethers", particularly as mentioned above, as methoxymethyl ethers (MOM-ethers), β-methoxyethoxymethyl ethers (MEM-ethers), or tetrahydropyranyl ethers (THP-ethers).

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

[0040] Depending on the reaction conditions, the esterification may be complete or partial, with the remaining acid groups of each acid remaining unesterified.

[0041] The protecting group R' is a benzoyl group or 1~4 -acyl group, especially acetyl or trifluoroacetyl group, more especially acetyl group, is most preferred. Molecules in which R' represents an acyl group, especially acetyl group, can be readily prepared from the corresponding unprotected molecule by esterification, and unprotected phenolic compounds can be obtained from the corresponding esters by ester hydrolysis.

[0042] The phenol protecting group can be cleaved off by a deprotection reaction step b) as described below.

[0043] R' is of the formula [ka] (In the formula, R 11 is C 1~15 -Alkyl or fluorinated C 1~15 -Alkyl or C 1~15 -Cycloalkyl or C 7~15 -aralkyl group, preferably methyl or benzyl).

[0044] [Compound of formula (IIIa) or (IIIb)] [ka] where 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.

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

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

[0047] More preferably, all double bonds are in the E-configuration.

[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] and in particular a compound selected from the group consisting of [ka] The compound is selected from the group consisting of:

[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] Compounds of formula (IIIa) and (IIIb), in particular geranilinalool and geranylgeraniol, can be prepared in industrial quantities by known methods or are commercially available, for example from Sigma-Aldrich, or 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 a compound of formula (IIIa) or (IIIIb) in the presence of an acid catalyst which is either camphorsulfonic acid or BiCl3 or Gd(OTf)3 or Tm(OTf)3 or Al(OTf)3 or Y(OTf)3 or Fe(OTf)2.

[0053] It has been found that only a few Bronsted or Lewis acids are suitable as acid catalysts for the reaction of the present invention.

[0054] In one embodiment, the acid catalyst is camphorsulfonic acid. Camphorsulfonic acid as used herein is camphor-10-sulfonic acid. [ka]

[0055] Preferably, camphorsulfonic acid is in its (+) form.

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

[0057] In another embodiment, the acid catalyst is a triflate of gadolinium or thulium or aluminum or yttrium or iron. Preferred triflates are Gd(OTf)3 and 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 even more preferably in the range of 2.0 to 1.2.

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

[0062] The reaction is carried out in one embodiment with a hydrocarbon, preferably toluene, or 5~10 It is preferably carried out in the presence of a solvent which is an alkane, most preferably hexane or heptane.

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

[0064] Preferably, the organic carbonate is ethylene carbonate or propylene carbonate. It is also possible to use mixtures of different carbonates of formula (X), in particular as binary or ternary mixtures of ethylene carbonate and / or propylene carbonate and / or butylene carbonate, most preferably as binary mixtures of ethylene carbonate and propylene carbonate. The ratio of ethylene carbonate to propylene carbonate is preferably 20:80 to 80:20, in particular 25:75 to 75:25.

[0065] Preferably, the solvent of the formula is a carbonate solvent sold by 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 an even more preferred embodiment, the reaction is carried out in the presence of a biphasic solvent mixture comprising at least one hydrocarbon and at least one organic carbonate. The hydrocarbon is preferably toluene or C 5~10 It 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 also be a mixture of different carbonates of formula (X), in particular as a binary or ternary mixture of ethylene carbonate and / or propylene carbonate and / or butylene carbonate, most preferably as a binary mixture of ethylene carbonate and propylene carbonate. When a mixture of ethylene carbonate and propylene carbonate is used with a hydrocarbon, it is preferred that the ratio of ethylene carbonate to propylene carbonate is 20:80 to 80:20, in particular 25:75 to 75:25.

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

[0068] It is preferred that all bonds having dotted lines in formulae (I) and (IIIa) and (IIIb) represent carbon-carbon double bonds.

[0069] A compound of formula (I) can be oxidized to a compound of formula (V) and cyclized to a compound of formula (VI).

[0070] Thus, in a further aspect, the present invention relates to a compound of formula (VI) [ka] A process for producing a compound of the formula: a) obtaining a compound of formula (I) by the process described in detail above; [ka] and preparing a compound of formula (I) b) When R in formula (I) is a phenol protecting group, the formulae (I) to (I') [ka] deprotecting the compound of formula (I); c) The following formula [ka] to oxidize a compound of formula (V) [ka] and forming a compound of the formula: d) cyclizing the compound of formula (V) in the presence of a basic catalyst to give a compound of formula (VI) [ka] and forming a compound of formula (I).

[0071] When the compound of formula (I) has a phenol group in protected form, i.e. R=R′, the compound of formula (I′) [ka] To obtain the respective deprotected compounds of formula (I), the respective protecting group must be removed 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 easily deprotected under the influence of acid or base, or acetals can be easily deprotected under the influence of acid.

[0073] Esters such as acetates can be cleaved, inter alia, with lithium aluminum hydride, to give the respective unprotected phenols.

[0074] The oxidation in step c) can be carried out by using a suitable oxidizing agent, preferably silver oxide in the presence of an acid, in particular 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 either an organic amine, preferably an organic tertiary amine, or a metal hydroxide or carbonate, in particular an organic tertiary amine or an alkali metal hydroxide.

[0077] pK of 8.6-15.7, especially 9-15.7, when 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

[0078] Some non-limiting pk's of the corresponding acidsa Examples include:

[0079] [Table 1]

[0080] 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 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, especially an alkali metal hydroxide. In this embodiment, most preferably, the basic catalyst is NaOH or KOH.

[0082] The ring closure step is preferably carried out in a hydrocarbon solvent, especially toluene.

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

[0084] When water is present, the ring-closure reaction is preferably carried out in a two-phase system, ie an aqueous phase and an organic phase, especially an aqueous phase and an organic solvent phase.

[0085] It is preferred that the basic catalyst is present in a catalytic amount, i.e., the basic catalyst is not present in a stoichiometric amount relative to the compound of formula (V), but in a significantly lower amount, i.e., the molar ratio of the basic catalyst to the compound of formula (V) is preferably 1:1,000 to 1:5, in particular 1:100 to 1:10.

[0086] The ring-closing step is typically carried out under 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 atm to 10 atm. It is further preferred that the reaction is carried out under an inert atmosphere, preferably under nitrogen.

[0087] Compounds of formula (VI) can be hydrogenated using hydrogenating agents, either compounds of formula (VIIII) (partial hydrogenation) or compounds of formula (IX) (full hydrogenation). [ka]

[0088] Thus, in a further aspect, the present invention relates to a compound of formula (VIII) [ka] A process for producing a compound of the formula: i) obtaining a compound of formula (VI) by the process described in detail above; [ka] and preparing a compound of formula (I) ii) partially hydrogenating the compound of formula (VI) using a suitable hydrogenating agent for partial hydrogenation to obtain a compound of formula (VIII).

[0089] In the partial hydrogenation of step ii), only the ring carbon-carbon double bonds are hydrogenated, but not the olefinic carbon-carbon double bonds ("partial hydrogenation"), so that hydrogenation affords a compound of formula (VIII).

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

[0091] This process results in, among other things, α-tocotrienol, which has three double bonds in its side chain and is the key compound found in natural vitamin E.

[0092] Thus, in a further aspect, the present invention relates to a compound of formula (IX) [ka] A process for producing a compound of the formula: i) obtaining a compound of formula (VI) by the process described in detail above; [ka] and preparing a compound of formula (I) ii') hydrogenating the 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 which hydrogenates all olefinic carbon-carbon double bonds of the ring of formula (VI). Particularly suitable as hydrogenating agent is hydrogen in the presence of a transition metal from group 7, 8, 9 or 10, in particular selected from the group consisting of Pd, Pt, Rh, Ru, Mn, Fe, Co and Ni, more preferably Pd.

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

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

[0096] In this embodiment, the transition metal is supported on a support, i.e., the palladium is deposited / vapor-deposited on a support, the support being a solid material.

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

[0098] When the support is Ce, the preferred oxide is CeO2. The preferred oxide of Al is Al2O3, AlO(OH). Particularly preferred is Al2O3.

[0099] The hydrogenation is preferably carried out under pressure, in particular under a hydrogen pressure of 2 to 20 bar. More preferably, the hydrogenation is carried out at a temperature of 0°C to 100°C.

[0100] This process produces, among other things, α-tocopherol, the key compound in natural vitamin E, whose side chain is fully saturated.

[0101] The compounds of formula (IA) are novel. Thus, in a further aspect, the present invention relates to compounds of formula (IA) [ka] The present invention relates to a compound of the formula:

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

[0103] The E / Z mixture is prepared according to the process detailed above in the presence of [ka] and [ka] It is shown to be prepared from

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

[0105] As the present invention shows, the compound of formula (I) is a very suitable agent for the synthesis of the compounds of formulae (V'), (VI') and (VIII'), (IX'), respectively. [ka] [Brief description of the drawings]

[0106] [Figure 1] FIG. 1 shows the above process in schematic detail, with particular emphasis on the box, and shows a process for producing a compound of formula (I), comprising the step of reacting a compound of formula (II) with a compound of formula (IIIa) or (IIIb) in the presence of an acid catalyst ("cat") which is either Gd(OTf)3 or Tm(OTf)3 or Al(OTf)3 or Y(OTf)3 or Fe(OTf)2 or camphorsulfonic acid or BiCl3.

[0107] [Example] 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 / 1 g / g) and 9.91 g (65 mmol) of 2,3,6-trimethylhydroquinone (TMHQ) were added under stirring in the presence of the catalysts 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 and yield 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 / 1 g / g) and 2.29 g (15 mmol) of 2,3,6-trimethylhydroquinone (TMHQ) were added under stirring in the presence of the catalyst 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 and yield 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 / 1 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)phenylacetate with the conversion and yield 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 / 1 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 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 to reflux under stirring. 2.2 g (7.5 mmol) of (all-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 / 1 g / g) was heated to reflux under stirring. 1.69 g (7.5 mmol) of (all-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. Formula (I) 【Chemistry 1】 The method for preparing a compound of formula (II) comprises reacting a compound of formula (IIIa) or (IIIb) 【Chemistry 2】 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 Camphorsulfonic acid; or BiCl ３ reacting in the presence of an acid catalyst which is 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 represents hydrogen or R', a phenol protecting group; OTf represents trifluoromethanesulfonate; and Any bond with a dotted line 【Chemistry 3】 represent, independently of each other, either a carbon-carbon single bond or a carbon-carbon double bond, provided that at least one of the bonds having a dotted line represents a carbon-carbon double bond; The optional wavy lines, independently of each other, represent carbon-carbon bonds, and when attached to said carbon-carbon double bond, are in either the Z- or E-configuration.

2. R' is of the following formula: 【Chemistry 4】 (In the formula, R １１ is C １～１５ -Alkyl or fluorinated C １～１５ -Alkyl or C １～１５ -Cycloalkyl or C ７～１５ 2. The method of claim 1, wherein the phenol protecting group is a -aralkyl group.

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

4. 3. The process according to claim 1 or 2, characterized in that all bonds with dotted lines in formulae (I) and (IIIa) and (IIIb) represent carbon-carbon double bonds.

5. 3. The process 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) ranges from 3 to 1.

6. 3. The process according to claim 1 or 2, characterized in that the molar ratio of the compound of formula (II) to the acid catalyst is between 0.001 mol % and 1 mol %.

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

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

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

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

11. Formula (VI) 【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】 and preparing a compound of formula (I) b) When R in formula (I) is a phenol protecting group, the compound represented by the formulas (I) to (I′) 【Chemistry 7】 deprotecting the compound of formula (I); c) The following formula 【Chemistry 8】 to obtain a compound of formula (V) 【Chemistry 9】 and forming a compound of the formula: d) cyclizing the compound of formula (V) in the presence of a basic catalyst to give a compound of formula (VI): 【Chemistry 10】 and forming a compound of the formula: A method comprising:

12. 12. The process 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 a compound of the formula i) obtaining a compound represented by the formula (VI) by the method according to claim 11 ; 【Chemistry 12】 (wherein any bond with a dotted line 【Chemistry 13】 represent, independently of each other, either a carbon-carbon single bond or a carbon-carbon double bond; and any wavy lines, independently of each other, represent carbon-carbon bonds, and when attached to said carbon-carbon double bond, are in either the Z- or E-configuration; ii) partially hydrogenating the compound of formula (VI) using a hydrogenating agent suitable for partial hydrogenation to obtain a compound of formula (VIII); A method comprising:

14. Formula (IX) 【Chemistry 14】 A method for producing a compound of the formula i) obtaining a compound represented by the formula (VI) by the method according to claim 11 ; 【Chemistry 15】 (wherein any bond with a dotted line 【Chemistry 16】 represent, independently of each other, either a carbon-carbon single bond or a carbon-carbon double bond; and any wavy lines, independently of each other, represent carbon-carbon bonds, and when attached to said carbon-carbon double bond, are in either the Z- or E-configuration; ii') hydrogenating the compound of formula (VI) using a hydrogenating agent to obtain a compound of formula (IX); A method comprising:

15. Formula (IA) 【Chemistry 17】 (wherein R′ represents a phenol protecting group; the wavy line represents a carbon-carbon bond attached to a carbon-carbon double bond that is in the Z or E-configuration.

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