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

Abstract

The present invention relates to the formation of compound (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 acidic catalyst.

Description

Technical Field

[0001] This invention relates to the field of synthesis of chromanes and chromenes, particularly to the synthesis of 3,4-dehydrotocotrienols, tocotrienols, and tocopherols. Background Technology

[0002] Synecans containing alkene carbon-carbon double bonds are an important class of chemicals. In particular, α-tocotrienols are very important members of this class.

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

[0004] For example, WO 2004 / 063182 A1 discloses the formation of α-tocopherol acetate from 2,3,6-trimethylhydroquinone-1-acetate and isophyll in the presence of various trifluoromethanesulfonic acid metal salts. Isophyll has only one carbon-carbon double bond for coupling reactions; however, it does not have any additional double bonds that could lead to secondary cyclization (i.e., cyclization in the side chain).

[0005] WO 2004 / 046126 A1 discloses the formation of α-tocopherol acetate from 2,3,6-trimethylhydroquinone-1-acetate and isophyll in the presence of various sulfonic acids, particularly trifluoromethanesulfonic acid or p-toluenesulfonic acid. Due to the use of isophyll, secondary cyclization is not possible.

[0006] EP 949255A1 discloses the use of sulfuric acid or some sulfonic acids, particularly trifluoromethanesulfonic acid or p-toluenesulfonic acid, to couple TMHQ with isophytol.

[0007] However, it has been shown that the use of these acidic catalysts is generally unsuitable for 2,3,6-trimethylhydroquinone (TMHQ) or its protected forms with the corresponding... Unsaturated The reaction of alcohols (such as geraniol or farnesol) results in the formation of undesirable cyclic compounds.

[0008] This finding is entirely consistent with Kabbe and Heitzer, Synthesis 1978, 12, 888-889, which reported that the known route for synthesizing vitamin E (i.e., α-tocopherol) using TMHQ and isophytol is unsuitable for synthesizing tocotrienols (i.e., tocotrienols synthesized from TMHQ and geranylidene linalool) because the isoprene side chain undergoes an acid-catalyzed secondary ring-closing reaction.

[0009] However, the synthesis of tocotrienols and their precursors remains very important. Summary of the Invention

[0010] Therefore, the problem to be solved by the present invention is to find a suitable method for producing compounds of formula (I) from TMHQ or its protected form and unsaturated alcohols of formula (IIIa) or (IIIb).

[0011] It is quite surprising that, despite the teachings of the prior art, some members of trifluoromethanesulfonic acid metal salts and sulfonic acids are suitable catalysts for this reaction and produce compounds of formula (I) in high yield and with selectivity, especially with a low tendency to form cyclic compounds as byproducts from isoprene-like side chains.

[0012] Further aspects of the invention are the subject of the additional independent claims. Particularly preferred embodiments are the subject of the dependent claims. Detailed Implementation

[0013] In a first aspect, the present invention relates to a method for manufacturing a compound of formula (I).

[0014]

[0015] The method includes reacting a compound of formula (II) with a compound of formula (IIIa) or (IIIb).

[0016]

[0017]

[0018] The reaction step in the presence of an acidic catalyst,

[0019] The acid catalyst is

[0020] Gd(OTf)3 or Tm(OTf)3 or Al(OTf)3 or Y(OTf)3 or Fe(OTf)2

[0021] or

[0022] Camphor sulfonic acid;

[0023] or

[0024] BiCl3;

[0025] in

[0026] 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;

[0027] R represents hydrogen or R' as a protecting group for phenol;

[0028] OTf stands for trifluoromethanesulfonate;

[0029] and

[0030] Any key with a dashed line Each can represent a carbon-carbon single bond or a carbon-carbon double bond independently, provided that at least one of the bonds with dashed lines represents a carbon-carbon double bond.

[0031] Any wavy line represents a carbon-carbon bond independently of each other, and is in either the Z-configuration or the E-configuration when connected to a carbon-carbon double bond.

[0032] Preferably, any wavy line is in the E-configuration when connected to a carbon-carbon double bond.

[0033] For clarity, some terms used in this document are defined as follows:

[0034] In this document, "C x-y An alkyl group is an alkyl group containing x to y carbon atoms, for example, C 1-3 An alkyl group is an alkyl group containing 1 to 3 carbon atoms. Alkyl groups can be straight-chain or branched. For example, -CH(CH3)-CH2-CH3 is considered a C4 alkyl group.

[0035] An "aralkyl" group is an alkyl group that has been replaced by an aryl group.

[0036] Therefore, in this document, "C x-y "-Aryl" groups are aryl groups containing x to y carbon atoms, i.e., for example, C 7-16 Aryl groups are aryl groups containing 7 to 16 carbon atoms. Aryl groups can be straight-chain or branched. For example, the benzyl group (-CH2-C6H5) is considered a C7-aryl group.

[0037] In cases where the same notation for a symbol or group exists in several formulas, the definition of the group or symbol made in the context of a particular formula in this document also applies to other formulas containing the same notation.

[0038] The term “independently of each other” in this document means that, in the context of a substituent, part or group, the same designated substituent, part or group may appear simultaneously in the same molecule with different meanings.

[0039] In this document, any dashed line in the formula represents a bond through which a substituent is bonded to the rest of the molecule.

[0040] In this document, any bond in a chemical formula that is outlined with a dashed line is considered a bond. They can represent carbon-carbon single bonds or carbon-carbon double bonds independently of each other.

[0041] Any wavy line in any formula of this document represents a carbon-carbon bond, and when attached to a carbon-carbon double bond, it is in either the Z-configuration or the E-configuration. Preferably, the carbon-carbon double bond is in the E-configuration in all molecules.

[0042] As used in this document, the term "OTf" refers to trifluoromethanesulfonate.

[0043] "pKa" is usually referred to as the negative logarithm of the acid dissociation constant to the base 10 (pKa). a =-log 10 K a When an organic acid has several protons, pKa, as used in this document, relates to the dissociation constant of the last proton. For example, for a base with two basic sites, "pKa" refers to pK. a2 pKa is measured at standard temperature and pressure.

[0044] Compound of formula (II)

[0045] Compound (II) is 2,3,5-trimethylhydroquinone (=2,3,5-trimethylbenzene-1,4-diol, TMHQ) (R=H) or its single protected derivative (R≠H; R=R').

[0046]

[0047] A phenol protecting group is a group that protects the phenol group (OH) in any formula in this document, having R=H, and the protecting group can be readily removed, i.e., removed by state-of-the-art methods, resulting again in the corresponding compound having a free phenol group.

[0048] The phenol protecting group R' is introduced by a chemical reaction of a compound having H as R with a protecting agent.

[0049] The protecting agents that cause the corresponding phenol protecting groups, as well as the chemical methods and conditions used in this reaction, are known to those skilled in the art. For example, if the phenol protecting group forms an ester with the rest of the molecule, suitable protecting agents are, for example, acids, acid anhydrides, or acyl halides.

[0050] The phenol protecting group R' is specifically selected from the group consisting of:

[0051]

[0052] Where R 10 and R 11 C is represented independently of each other. 1-15 -Alkyl or fluorinated C 1-15 -alkyl or C 1-15 -cycloalkyl or C 7-15-Aryl group;

[0053] R 12 Representing C 1-15 Alkylene or C 6-15 Alkylene;

[0054] And among them

[0055] R 13 Representing C 1-15 Alkyl groups, alkoxyalkyl groups, or polyoxyalkylene groups;

[0056] R 14 Represents hydrogen or C 1-15 alkyl groups;

[0057] or

[0058] R 13 and R 14 Together, they represent C forming 5 to 7-membered rings. 3-7 alkylene groups;

[0059] Furthermore, each dashed line represents a bond in which the substituent is bonded to the rest of the molecule.

[0060] If R' equals R 10 The corresponding compound is an ether, which can be formed by reacting a phenolic group (OH) with a suitable protecting agent. In this case, the protecting agent can be, for example, an alkylating agent, such as the corresponding C... 1-15 -Alkyl or fluorinated C 1-15 -alkyl or C 1-15 -cycloalkyl or C 7-15 -Aryl halides, especially iodides.

[0061] In a preferred embodiment, R 10 It is a methyl group.

[0062] In another preferred embodiment, R 10 It is C 7-15 -Aryl group, preferably benzyl group or substituted benzyl group, particularly preferably benzyl group.

[0063] If R' is If indicated, the corresponding compound is an ester of a carboxylic acid or a dicarboxylic acid, which can be formed by reacting a corresponding protecting agent with a phenolic group (OH). In this case, the protecting agent can be, for example, an anhydride or halide of the corresponding carboxylic acid (1) or dicarboxylic acid (2).

[0064] (1)

[0065] (2)

[0066] If the corresponding compound is an ester of a carboxylic acid or dicarboxylic acid, then it is preferred that R' is C. 1-7 Acyl group, preferably acetyl, trifluoroacetyl, propionyl or benzoyl, or substituted benzoyl group.

[0067] If R' is The corresponding compound is an acetal, which can be formed by reacting a phenolic group (OH) with a corresponding protecting agent. In this case, the protecting agent can be, for example, the corresponding aldehyde, alkyl halide (e.g., MeO(CH2)2OCH2Cl), or enol ether (e.g., 3,4-dihydro-2H-pyran).

[0068] In this case, the substituent R' is preferably...

[0069] Where n = 0 or 1.

[0070] In some cases, acetals are also referred to as "ethers," especially in the cases mentioned above: methoxymethyl ether (MOM ether), β-methoxyethoxymethyl ether (MEM ether), or tetrahydropyran ether (THP ether).

[0071] In another preferred embodiment, the corresponding compound is an ester of phosphoric acid, pyrophosphoric acid, phosphorous acid, sulfuric acid, or sulfurous acid.

[0072] Depending on the reaction conditions, esterification can be complete or partial, leaving some residual acid groups of the corresponding acid unesterified.

[0073] The most preferred option is that the protecting group R is benzoyl or C. 1-4 Acyl group, particularly acetyl or trifluoroacetyl, more particularly acetyl. Wherein R' represents an acyl group, and molecules with acetyl groups can be readily prepared from the corresponding unprotected molecules via esterification, and the unprotected phenolic compounds can be obtained from the corresponding esters via ester hydrolysis.

[0074] The protecting group of phenol can be removed by deprotection reaction step b), as discussed later.

[0075] Preferably, R' is a phenolic protecting group of the following formula.

[0076]

[0077] Where R 11 It is C 1-15 -Alkyl or fluorinated C 1-15 -alkyl or C 1-15 -cycloalkyl or C 7-15 -Aryl group, preferably methyl or benzyl group.

[0078] Compounds of formula (IIIa) or (IIIb)

[0079]

[0080] 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.

[0081] Preferably, n = 0, 1, or 2; more preferably, 1 or 2; and most preferably, n = 2.

[0082] Examples of preferred compounds of formula (IIIa) are compounds selected from the group consisting of:

[0083]

[0084]

[0085] Specifically, choose from the following groups:

[0086]

[0087]

[0088] More preferably, all double bonds are in the E-configuration.

[0089] The most preferred compounds of formula (IIIa) are 3,7,11-trimethyldodecyl-2,6,10-trien-1-ol, preferably (6E)-3,7,11-trimethyldodecyl-2,6,10-trien-1-ol, also known as farnesol; and 3,7,11,15-tetramethylhexadecyl-2,6,10,14-tetraen-1-ol, preferably (6E,10E)-3,7,11,15-tetramethylhexadecyl-2,6,10,14-tetraen-1-ol, also known as geraniol. Particularly preferred are (2E,6E)-farnesol and (2E,6E,10E)-geraniol.

[0090] Examples of preferred compounds of formula (IIIb) are compounds selected from the group consisting of:

[0091]

[0092]

[0093] Specifically, choose from the following groups:

[0094]

[0095] The most preferred compound of formula (IIIb) is 3,7,11-trimethyldodecyl-1,6,10-trien-3-ol, preferably (E)-3,7,11-trimethyldodecyl-1,6,10-trien-3-ol, also known as nerolidol; and 3,7,11,15-tetramethylhexadecyl-1,6,10,14-tetraen-3-ol, preferably (6E,10E)-3,7,11,15-tetramethylhexadecyl-1,6,10,14-tetraen-3-ol, also known as geranylide.

[0096] Compounds of formulas (IIIa) and (IIIb), particularly geranyl linalool and geranyl geraniol, can be prepared industrially or commercially available by known methods, for example from Sigma-Aldrich or from natural / bio-based sources, such as those disclosed by John A. Hyatt et al., Organic Process Research and Development 2002, 6, 782-787.

[0097] acid catalyst

[0098] The compound of formula (II) reacts with the compound of formula (IIIa) or (IIIb) in the presence of an acidic catalyst, which is camphor sulfonic acid, BiCl3, Gd(OTf)3, Tm(OTf)3, Al(OTf)3, Y(OTf)3, or Fe(OTf)2.

[0099] It has been found that only very small amounts of Brønsted or Lewis acids are suitable as acidic catalysts for the reactions of this invention.

[0100] In one embodiment, the acidic catalyst is camphor sulfonic acid. Camphor sulfonic acid as used in this document is camphor-10-sulfonic acid.

[0101]

[0102] Preferably, camphor sulfonic acid is in its (+) form.

[0103] In another embodiment, the acid catalyst is BiCl3.

[0104] In another embodiment, the acidic catalyst is a trifluoromethanesulfonate of gadolinium, thulium, aluminum, yttrium, or iron. Preferred trifluoromethanesulfonates are Gd(OTf)3, Al(OTf)3, and Fe(OTf)2.

[0105] Preferably, in the above reaction, the molar ratio of compound (II) to compound (IIIa) or (IIIb) is between 3 and 1, preferably between 2.5 and 1.1, and more preferably between 2.0 and 1.2.

[0106] Furthermore, it is preferred that the molar ratio of the acidic catalyst to the compound of formula (II) is 0.001 mol% to 1 mol%, preferably 0.005 mol% to 1 mol%, and more preferably 0.02 mol% to 1 mol%.

[0107] The reaction is carried out at a temperature between 20°C and 160°C, preferably between 80°C and 120°C.

[0108] Furthermore, the reaction is typically carried out under environmental pressure.

[0109] Preferably, in one embodiment, the reaction is carried out in the presence of a solvent, said solvent being a hydrocarbon, preferably toluene, or C. 5-10 Alkanes, with hexane or heptane being the most preferred.

[0110] Preferably, in another embodiment, the reaction is carried out in the presence of a solvent, which is an organic carbonate, preferably carbonate of formula (X).

[0111]

[0112] Where Y 1 and Y 2 Each can independently represent an H, methyl, or ethyl group.

[0113] Preferably, the organic carbonate is ethylene carbonate or propylene carbonate. Mixtures of different formula (X) carbonates can also be used, particularly as binary or ternary mixtures of ethylene carbonate and / or propylene carbonate and / or butene carbonate, most preferably as a binary mixture of ethylene carbonate and propylene carbonate. Preferably, the ratio of ethylene carbonate to propylene carbonate is between 20:80 and 80:20, particularly between 25:75 and 75:25.

[0114] Preferably, the solvent of the formula is produced by Huntsman under a trademark. Commercially available carbonate solvents, particularly blends of ethylene carbonate and propylene carbonate. EC-75 EC-50 and EC-25.

[0115] In another, or even 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 C24.5-10 The alkane is most preferably hexane or heptane. The organic carbonate is preferably a carbonate of formula (X). Furthermore, in this embodiment, the organic carbonate used can be a mixture of different carbonates of formula (X), particularly as a binary or ternary mixture of ethylene carbonate and / or propylene carbonate and / or butene carbonate, most preferably as a binary mixture of ethylene carbonate and propylene carbonate. If the mixture of ethylene carbonate and propylene carbonate is used with hydrocarbons, it is preferred that the ratio of ethylene carbonate to propylene carbonate is between 20:80 and 80:20, particularly between 25:75 and 75:25.

[0116] 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.

[0117] Preferably, all bonds with dashed lines in formulas (I), (IIIa), and (IIIb) represent carbon-carbon double bonds.

[0118] Compound (I) can be oxidized to compound (V) and cyclized to compound (VI).

[0119] Therefore, in another aspect, the present invention relates to a method for manufacturing a compound of formula (VI).

[0120]

[0121] The method includes the following steps:

[0122] a) Prepare compound (I) by the method described in great detail above.

[0123]

[0124] b) In the case where R in formula (I) is a phenol protecting group, deprotect the compound of formula (I) to the compound of formula (I').

[0125]

[0126] c) The following compound

[0127]

[0128] Oxidation to compound of formula (V)

[0129]

[0130] d) Cycling of compound (V) to compound (VI) in the presence of a basic catalyst.

[0131]

[0132] When the compound of formula (I) has a protected phenolic group, i.e., R = R', the corresponding protecting group needs to be removed by the deprotection reaction in step b) to obtain the corresponding deprotected compound of formula (I').

[0133]

[0134] 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 acids or bases, or acetals can be readily deprotected under the influence of acids.

[0135] Esters, such as acetates, are particularly deprotected by lithium aluminum hydride to produce the corresponding unprotected phenols.

[0136] The oxidation in step c) can be carried out by using a suitable oxidizing agent, preferably silver oxide in the presence of an acid, especially acetic acid, or oxygen or air in methanol.

[0137] In step d), compound (V) is cyclized into compound (VI) in the presence of a basic catalyst.

[0138] The alkaline catalyst is preferably an organic amine, preferably an organic tertiary amine, or a metal hydroxide or carbonate, especially an organic tertiary amine or an alkali metal hydroxide.

[0139] It has been shown that pK measured in water a The conjugate acid of the basic catalyst is particularly suitable between 8.6 and 15.7, especially between 9 and 15.7. This means that the pK of the basic catalyst is... b Preferably between 5.4 and 0, especially between 5 and 0.

[0140] PK of corresponding acids a Some non-restrictive examples:

[0141]

[0142]

[0143] 1 pKa corresponding to conjugate acids

[0144] 2 H. Ripin; DAEvans (2002). pK a 's of Nitrogen Acids"

[0145] https: / / organicchemistrydata.org / hansreich / resources / pka / pka_data / evans_pKa_table.pdf

[0146] 3 https: / / www.aatbio.com / data-sets / pka-and-pkb-reference-table

[0147] 4 Less preferred alkaline catalysts (pk a <8.6)

[0148] In one embodiment, the basic catalyst is an organic amine, particularly 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 (=quinine ring), and cytisine, preferably selected from the group consisting of: 4-dimethylaminopyridine (=DMAP), 1,8-diazabicyclo[5.4.0]undec-7-ene (=DBU) and 1-azabicyclo[2.2.2]octane (=quinine ring).

[0149] In another embodiment, the alkaline catalyst is preferably a hydroxide or carbonate of an alkali metal or alkaline earth metal, preferably a hydroxide, particularly an alkali metal hydroxide. In this embodiment, most preferably, the alkaline catalyst is NaOH or KOH.

[0150] Preferably, the ring-closing step is performed in a hydrocarbon solvent, particularly in toluene.

[0151] When using a hydrocarbon solvent, the solvent is preferably used in an amount such that the solution having the compound of formula (V) is between 0.05 mol and 5 mol, more preferably between 0.1 mol and 1 mol, relative to the compound of formula (V).

[0152] In the presence of water, it is preferred that the closed-loop reaction be carried out in a two-phase system, namely an aqueous phase and an organic phase, particularly an aqueous phase and an organic solvent phase.

[0153] The preferred catalyst is an alkaline catalyst. catalytic The presence of a quantity, i.e., the basic catalyst relative to compound (V) no It exists not in stoichiometric amounts, but in significantly lower amounts, i.e., the molar ratio of the basic catalyst to the compound of formula (V) is preferably 1:1,000 to 1:5, particularly 1:100 to 1:10.

[0154] The closed-loop step is typically performed under stirring, preferably at a temperature between 40°C and 200°C, more preferably between 90°C and 150°C, more preferably at the reflux temperature of the organic solvent when using it, and / or at a pressure between 1 bar and 10 bar. Further preferably, this reaction is performed under an inert atmosphere, preferably under nitrogen.

[0155] Compound (VI) can be hydrogenated by means of a hydrogenating agent that is either a compound of formula (VIII) (partially hydrogenated) or a compound of formula (IX) (fully hydrogenated).

[0156]

[0157] Therefore, in another aspect, the present invention relates to a method for manufacturing a (VIII) compound.

[0158]

[0159] The method includes the following steps:

[0160] i) To manufacture compound (VI) by the method described in detail above

[0161]

[0162] ii) The compound of formula (VI) is partially hydrogenated by means of a hydrogenating agent suitable for partial hydrogenation to obtain the compound of formula (VIII).

[0163] In the partial hydrogenation in step ii), only the carbon-carbon double bonds in the ring are hydrogenated, while the olefinic carbon-carbon double bonds are not hydrogenated (“partial hydrogenation”), so that the hydrogenation produces compound (VIII).

[0164] The hydrogenating agent used in step ii) is one that hydrogenates only the carbon-carbon double bonds of the ring in formula (VIII). Sodium / ethanol is particularly suitable as a hydrogenating agent, for example, as described in Schudel, Mayer, Isler, Helv. Chim. Acta 46, 2517-2526 (1963), especially in the last paragraph on page 2524.

[0165] This process specifically results in α-tocotrienols, which have three double bonds in their side chains. α-Tocotrienols are an important compound found in natural vitamin E.

[0166] Therefore, in another aspect, the present invention relates to a method for manufacturing a compound of formula (IX).

[0167]

[0168] The method includes the following steps:

[0169] i) To manufacture compound (VI) by the method described in detail above

[0170]

[0171] ii') Hydrogenate compound (VI) by means of a hydrogenating agent to obtain compound (IX).

[0172] The hydrogenating agent used in step ii') is a hydrogenating agent that hydrogenates all alkene carbon-carbon double bonds in the ring of formula (VI). Particularly suitable as a hydrogenating agent is hydrogen in the presence of a transition metal from Group 7, Group 8, Group 9, or Group 10, specifically selected from the group consisting of Pd, Pt, Rh, Ru, Mn, Fe, Co, and Ni, more preferably Pd.

[0173] The heterogeneous transition metal catalyst is preferably a heterogeneous supported transition metal catalyst.

[0174] Such hydrogenation is disclosed, for example, by Kabbe and Heitzer, Synthesis 1978, 12, 888-889.

[0175] In this embodiment, a transition metal is loaded onto a support, specifically palladium attached to / or deposited on the support. The support is a solid material.

[0176] 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, particularly oxides of Al or Si. Particularly preferred are silicon dioxide, aluminum oxide, titanium dioxide, and cerium dioxide.

[0177] When the support is Ce, the preferred oxide is CeO2. Preferably, the oxides of Al are Al2O3 and AlO(OH). Al2O3 is particularly preferred.

[0178] Hydrogenation is preferably performed under pressure, particularly at a hydrogen pressure of 2 to 20 bar. More preferably, hydrogenation is performed at a temperature between 0°C and 100°C.

[0179] This process specifically produces α-tocopherol, which has a fully saturated side chain. α-Tocopherol is an important compound in natural vitamin E.

[0180] Compound of formula (IA) is novel. Therefore, in another aspect, the present invention relates to a compound of formula (IA).

[0181]

[0182] As already noted, R' represents a phenol protecting group, and the wavy line represents a carbon-carbon bond connected to a carbon-carbon double bond, in either the Z-configuration or the E-configuration. Protecting groups have been discussed in detail above. In this embodiment, the protecting group R' is preferably an acetyl group.

[0183] It has been shown that the E / Z mixture is produced in the presence of the method discussed in detail above. Prepared.

[0184] If necessary, the E / Z mixture can be separated by chromatography.

[0185] As demonstrated by this invention, compounds of formula (I) are highly suitable reagents for synthesizing compounds of formulas (V'), (VI'), and (VIII') or (IX').

[0186]

[0187] Figure 1 The method discussed in detail above, particularly highlighted by boxes, is illustrated schematically. The method for producing compound (I) includes the step of reacting compound (II) with compound (IIIa) or (IIIb) in the presence of an acidic catalyst (“cat”), which is Gd(OTf)3 or Tm(OTf)3 or Al(OTf)3 or Y(OTf)3 or Fe(OTf)2 or camphorsulfonic acid or BiCl3.

[0188] Example

[0189] The present invention is further illustrated by the following experiments.

[0190] Experiment Series 1

[0191] Geraniyl linalool (12.51 g (43 mmol)), 65 ml of ethylene carbonate / heptane mixture (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 produce 2,3,5-trimethyl-6-((2E,6E,10E)-3,7,11,15-tetramethylhexadecyl-2,6,10,14-tetraen-1-yl)benzene-1,4-diol in the conversions and yields shown in Table 1.

[0192]

[0193] Table 1. Different acidic catalysts used for the condensation of TMHQ and geranylidene linalool.

[0194] 1(+)-camphor sulfonic acid was used in all experiments in this document.

[0195] Experiment Series 2

[0196] Geraniol (3.45 g (12 mmol)), 15 ml of a ethylene carbonate / heptane mixture (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 catalysts shown in Table 2 to produce 2,3,5-trimethyl-6-((2E,6E,10E)-3,7,11,15-tetramethylhexadecyl-2,6,10,14-tetraen-1-yl)benzene-1,4-diol in the conversions and yields shown in Table 2.

[0197]

[0198] Table 2. Different acid catalysts used for the condensation of TMHQ and geraniol.

[0199] *LiN(Tf)2=bis((trifluoromethyl)sulfonyl)amide lithium.

[0200] **Cu / Zn / HCOOH: Cu and Zn in formic acid (M. Kajiwara et al.)

[0201] Heterocyles, Vol. 14, No. 12, 1995-1198 (1980).

[0202] Experiment Series 3

[0203] Geraniol (3.42 g (12 mmol)), 15 ml of a ethylene carbonate / heptane mixture (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 catalysts shown in Table 3 to produce 4-hydroxy-2,3,6-trimethyl-5-((2E,6E,10E)-3,7,11,15-tetramethylhexadecyl-2,6,10,14-tetraen-1-yl)phenyl acetate at the conversions and yields shown in Table 3.

[0204]

[0205] Table 3. Condensation of TMHQ-1 acetate and geraniol.

[0206] Experiment Series 4

[0207] Geraniyl linalool (12.51 g (43 mmol)), 65 ml of a ethylene carbonate / heptane mixture (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 catalysts shown in Table 4 to produce 4-hydroxy-2,3,6-trimethyl-5-((2E,6E,10E)-3,7,11,15-tetramethylhexadecyl-2,6,10,14-tetraen-1-yl)benzoate in the conversions and yields shown in Table 4.

[0208]

[0209] Table 4. Different acids used in the condensation of TMHQ-1 benzoate and geraniol

[0210] Sex catalyst.

[0211] Experiment Series 5

[0212] 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 ratio of 1.17 / 1 g / g) was heated to reflux with stirring. 2.2 g (7.5 mmol) of (all-E)-geranyl linalool 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-tetramethylhexadecyl-2,6,10,14-tetraen-1-yl)phenyl acetate was obtained in the yields shown in Table 5.

[0213]

[0214] Table 5. Different acidic catalysts for the condensation of TMHQ-1 acetate and (all-E)-geranyl linalool.

[0215] 1 Yield of E-isomer 2 The yield of the Z-isomer was determined by GC using an internal standard (E+Z).

[0216] Experiment Series 6

[0217] 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 ratio of 1.17 / 1 g / g) was heated to reflux with 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-trimethyldodecyl-2,6,10-trien-1-yl)phenyl acetate was obtained in the yields shown in Table 6.

[0218]

[0219] Table 6. Different acidic catalysts used for the condensation of TMHQ-1 acetate with E-nerolidol and (all-E)-farnesol. 1 Determined by GC using internal standards.

Claims

1. A method for manufacturing a compound of formula (I) The method includes reacting a compound of formula (II) with a compound of formula (IIIa) or (IIIb). The reaction step in the presence of an acidic catalyst, The acid catalyst is Gd(OTf)3 or Tm(OTf)3 or Al(OTf)3 or Fe(OTf)2 or Camphor sulfonic acid; in 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' as a protecting group for phenol; OTf stands for trifluoromethanesulfonate; and Any key with a dashed line ( Each of the following can represent a carbon-carbon single bond or a carbon-carbon double bond independently, provided that at least one of the bonds with dashed lines represents a carbon-carbon double bond. Any wavy line independently represents a carbon-carbon bond, and when connected to a carbon-carbon double bond, it is in either the Z-configuration or the E-configuration. The molar ratio of the acidic catalyst to the compound of formula (II) is from 0.001 mol% to 1 mol.

2. The method according to claim 1, characterized in that, R' is the phenolic protecting group of the following formula. Where R 11 It is C 1-15 -Alkyl or fluorinated C 1-15 -alkyl or C 1-15 -cycloalkyl or C 7-15 -Aryl group.

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

4. The method according to any one of claims 1 to 2, characterized in that, In equations (I), (IIIa), and (IIIb), all bonds with dashed lines represent carbon-carbon double bonds.

5. The method according to any one of claims 1 to 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 between 3 and 1.

6. The method according to any one of claims 1 to 2, characterized in that, The reaction is carried out in the presence of a solvent, which is a hydrocarbon.

7. The method according to any one of claims 1 to 2, characterized in that, The reaction is carried out in the presence of a solvent, which is an organic carbonate.

8. The method according to any one of claims 1 to 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.

9. The method according to any one of claims 1 to 2, characterized in that, The reaction is carried out at a temperature between 20°C and 160°C.

10. A method for manufacturing a compound of formula (VI). The method includes the following steps: a) To manufacture compound (I) by the method according to any one of claims 1 to 9, b) In the case where R in formula (I) is a phenol protecting group, deprotect the compound of formula (I) to the compound of formula (I'). c) The following compound Oxidation to compound of formula (V) d) Cycling of compound (V) to compound (VI) in the presence of a basic catalyst.

11. The method according to claim 10, characterized in that, The basic catalyst in step d) is present in a molar ratio with the compound of formula (V) between 1:1,000 and 1:

5.

12. A method for manufacturing a compound of formula (VIII) The method includes the following steps: i) To produce compound of formula (VI) by the method according to claim 10 or 11 Any of the keys with dashed lines ( Each of these can independently represent a carbon-carbon single bond or a carbon-carbon double bond; and Any wavy line represents a carbon-carbon bond independently of each other, and is in either the Z-configuration or the E-configuration when connected to a carbon-carbon double bond; ii) The compound of formula (VI) is partially hydrogenated by means of a hydrogenating agent suitable for partial hydrogenation to obtain the compound of formula (VIII).

13. A method for manufacturing compound of formula (IX) The method includes the following steps: i) To produce compound of formula (VI) by the method according to claim 10 or 11 Any of the keys with dashed lines ( Each of these can independently represent a carbon-carbon single bond or a carbon-carbon double bond; and Any wavy line represents a carbon-carbon bond independently of each other, and is in either the Z-configuration or the E-configuration when connected to a carbon-carbon double bond; ii') Hydrogenate compound (VI) by means of a hydrogenating agent to obtain compound (IX).

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