Preparation of alpha, beta, gamma, delta- or beta, gamma, delta- diunsaturated ketones with terminal carboxyl groups

Abstract

This invention relates to the synthesis of carboxyl-terminated diunsaturated ketones with C=C double bonds at the α,β and γ,δ positions relative to the carbonyl carbon atom, or the β,γ and γ,δ positions. These ketones can be readily obtained from corresponding alkynyl alcohols with terminal carboxyl groups in a few steps. These ketones are important key building blocks for the synthesis of isoprene-like derivatives, especially vitamin E derivatives.

Description

Technical Field

[0001] The present invention relates to diunsaturated ketones having C=C at the α, β and γ, δ positions or β, γ and γ, δ positions relative to the carbonyl carbon atom, and particularly to isoprene-like derivatives, especially vitamin E derivatives. Background Technology

[0002] Zhao et al., in "Analysis of Multiple Metabolites of Tocopherols and Tocotrienols in Mice and Humans", J. Agr. Food Chem, vol. 58, no. 8, 28 April 2010 (2010-04-28), pp. 4844-4852, described the metabolic pathways of tocopherols and tocotrienols, and also described terminal carboxyl tocotrienols. However, they did not disclose the synthetic routes of these compounds.

[0003] The synthesis of 14-hydroxy-2,6,10,14-tetramethylhexadec-15-enoic acid is disclosed in Weichet J., Bláha L., Collect. Czech. Chem. Commun. 1966, Vol. 31, 2424 – 2433, which corresponds to isophytol (3,7,11,15-tetramethylhexadec-1-en-3-ol) with a terminal carboxyl group.

[0004] The compound is prepared from 2-methyl-6-oxoheptanoic acid via a complex reaction process. The described route involves the formation of 2,6-dimethyl-10-oxoundec-6-enoic acid, a monounsaturated ketone with a C=C double bond at the γ,δ position relative to the carbonyl carbon atom of the ketone group, and a terminal carboxyl group. This synthetic route requires multiple chemical steps (see [link to original text]). Figure 1 and Figure 2 (Left side diagram) This includes a multi-step chlorination reaction using highly toxic and corrosive hydrogen chloride gas or high concentrations of hydrochloric acid.

[0005] In the synthesis of isoprene morphologies, especially isophytol, the molecule is typically constructed via a series of C2 / C3 extension reactions. One known synthetic method utilizes the formation of allenones to carry out these C2 / C3 extensions. However, a strong acid is necessary as a catalyst for the formation of allenones.

[0006] US3,029,287 and G. Saucy et al. disclosed in Helv. Chim. Acta 1967, 50(4), 1158-1167 that tert-propargyl alcohols react with ketals or alkenyl ethers in strong acids, especially sulfuric acid, phosphoric acid, or p-phosphoric acid. p A condensation reaction occurs in the presence of benzenesulfonic acid to form β-allenyl ketone.

[0007] However, using strong acids in the preparation of allenones is disadvantageous because these chemicals are extremely hazardous during handling. The production process also requires specialized corrosion-resistant materials and equipment.

[0008] EP2621879 discloses different methods for preparing unsaturated polyisoprene ketones by reacting dehydro-nerolidol with vinyl ether.

[0009] Furthermore, due to the presence of the carboxyl group, it is difficult to determine whether a person skilled in the art would use reaction steps known for isophytol to synthesize 14-hydroxy-2,6,10,14-tetramethylhexadec-15-enoic acid. Summary of the Invention

[0010] Therefore, the technical problem to be solved by the present invention is to provide a method for preparing an intermediate that can be used to synthesize 4-hydroxy-2,6,10,14-tetramethylhexadec-15-enoic acid, wherein the method does not use highly corrosive substances and requires far fewer reaction steps than the methods of the prior art.

[0011] Surprisingly, it has now been found that the method of claim 1 provides a solution to the above-mentioned technical problems.

[0012] What is particularly surprising is that the method successfully generates the desired intermediate product, namely the unsaturated ketone of formula (I), especially since the method is carried out in the absence of strong acids.

[0013] Compared to existing technologies, it has been shown that the number of reaction steps required to form the compound of formula (I) is significantly reduced, offering significant advantages in terms of time, cost, and the impurity profiles of subsequent reaction products and the compound of formula (I).

[0014] Other aspects of the invention are the subject of the other independent claims. Particularly preferred embodiments are the subject of the dependent claims. Detailed Implementation

[0015] In a first aspect, the present invention relates to a method for preparing an unsaturated ketone of formula (I). The method is carried out by reacting a compound of formula (II) with a compound of formula (IIIa) or (IIIb). in, R 3 Indicates methyl or ethyl; R 4 Indicates H, methyl, or ethyl; R 5 Represents linear or branched C 1-10 -alkyl groups, especially methyl or ethyl groups; R 5' and R 5'' express: Linear or branched C 1-10 -alkyl groups, especially methyl or ethyl groups; Or R 5' and R 5'' Together they form linear or branched C 1-10 -alkylene compounds, especially ethylene or propylene; and Where n represents a value from 1 to 2, and m represents a value from 0 to 2, provided that the sum of n and m is 1 or 2; And in formula (I) or formula (II), the formula is derived from... s1 and s2 The substructures can be represented in any order; R represents a group of formula (IVa) or (IVb). Furthermore, each wavy line independently represents a wavy line relative to the C=C double bond. Z - Configuration or presentation E - A carbon-carbon bond of configuration (IVb), or representing the corresponding axial R enantiomer or axial S enantiomer (IVa) or a mixture thereof; Furthermore, any dashed line indicates that the substituents of formula (IVa) or formula (IVb) are bonded to the bonds of the remainder of formula (I).

[0016] For clarity, some of the terms used in this article are defined as follows: In this article, "C" x-y "Alkyl" refers to an alkyl group containing x to y carbon atoms, such as C 1-3 The alkyl group is an alkyl group containing 1 to 3 carbon atoms. The alkyl group may be linear or branched, such as -CH(CH3)-CH2-CH3, which is considered a C4-alkyl group.

[0017] In this article, strong acids are those with pK values ​​measured in water at room temperature. a Any acid with a pKa less than 4, especially less than 2, and preferably less than 1. "pKa" is known to be the negative logarithmic value of the acid dissociation constant (pK). a = -log10 K a) .

[0018] In this document, where the same notation for a symbol or group appears in multiple formulas, the definition of the group or symbol in the context of a particular formula also applies to other formulas containing the same notation.

[0019] In this article, the term “each independently” in the context of a substituent, part or group means that substituents, parts or groups with the same name within the same molecule can have different meanings at the same time.

[0020] In this article, any dashed line in any formula represents a bond that a substituent is bonded to another part of the molecule.

[0021] In this paper, each wavy line in any equation independently represents a wavy line relative to an isolated C=C double bond or a conjugate C=C double bond. Z - Configuration or presentation E - Carbon-carbon bonds in configuration. Preferably, the configuration is as follows: E - The configuration, i.e., the (E)- stereoisomer, is preferred. If multiple such wavy lines exist in a particular formula, then it is preferred that all double bonds are in the - configuration. E - Configuration. If the carbon-carbon bond is a cumulative C = C = C double bond, then the wavy line in either formula represents the corresponding axial R enantiomer or axial S enantiomer or a mixture thereof.

[0022] Compound of formula (I) The compound of formula (I) is a ketone with a terminal carboxyl group and two C=C double bonds.

[0023] Preferably, m = 0, that is, the unsaturated ketone of formula (I) is the unsaturated ketone of formula (Ia). .

[0024] In one embodiment of a compound of formula (I) or (Ia), the double bond is located at the β,γ and γ,δ positions of the carbonyl group relative to the ketone group, thus constituting a compound of formula (Iaa), preferably a compound of formula (Iaaa). .

[0025] In this embodiment, the two C=C double bonds are cumulative. Therefore, the ketone of formula (Iaa) or formula (Iaaa) represents an allene ketone.

[0026] In another embodiment of the compound of formula (I) or (Ia), the double bond is located at the α,β and γ,δ positions of the carbonyl group relative to the ketone group; therefore, the compound corresponds to the compound of formula (Ibb), preferably the compound of formula (Ibbb). .

[0027] In this embodiment, the two C=C double bonds are conjugated. Therefore, the ketones of formulas (Ibb) and (Ibbb) are α,β,γ,δ-unsaturated ketones.

[0028] In another embodiment, the method produces a mixture of allenone of formula (Iaa) and α,β,γ,δ-unsaturated ketone of formula (Ibb). , .

[0029] Preferably, the mixture yields an allenone of formula (Iaaa) and an α,β,γ,δ-unsaturated ketone of formula (Ibbb). , .

[0030] The allenone of the most preferred formula (Iaa) is the allenone of formula (IA). Each wavy line independently represents the C=C double bond relative to equation (Ibb) or equation (Ibbb). Z - Configuration or presentation E - A carbon-carbon bond of configuration, or the corresponding axial R enantiomer or axial S enantiomer or mixture thereof representing formula (Iaa), formula (Iaaa), or formula (IA).

[0031] Further, the allenone of formula (Iaa) is preferably an allenone of formula (I-AA) or an allenone of formula (I-AAA), with the (I-AA) allenone being the most preferred. Each wavy line independently represents a carbon-carbon bond of the axis R enantiomer or axis S enantiomer or a mixture thereof corresponding to formula (I-AA) or formula (I-AAA).

[0032] The highly preferred α,β,γ,δ-unsaturated ketone of formula (Ibb) is the α,β,γ,δ-unsaturated ketone of formula (IB). In this context, each wavy line independently represents a double bond relative to C = C in equation (IB). Z - Configuration or presentation E - Carbon-carbon bond configuration.

[0033] The most preferred α,β,γ,δ-unsaturated ketone of formula (Ibb) is the α,β,γ,δ-unsaturated ketone of formula (I-BB) or (I-BBB), with the α,β,γ,δ-unsaturated ketone of formula (I-BB) being more preferred. Each wavy line independently represents a wavy line relative to the C=C double bond. Z - Configuration or presentation E - Carbon-carbon bond configuration.

[0034] Compound of formula (II) Of the compounds of formula (II), the three embodiments of formula (II-1), formula (II-2), and formula (II-2a) are preferred, especially the embodiments of formula (II-1) and formula (II-2), which are the preferred embodiments. , , The first embodiment is 6-hydroxy-2,6-dimethyloctyl-7-ynetic acid (II-1) (m = 0, n = 1). ; The second embodiment is 10-hydroxy-2,6,10-trimethyldodec-11-acetylic acid (II-2) (m = 0, n = 2). ; The third embodiment is 10-hydroxy-2,6,10-trimethyldodec-6-ene-11-alkynic acid (II-2a) (m = 1, n = 1). .

[0035] Preferably, m = 0, that is, preferably, the compound of formula (II) is the same as the compound of formula (IIa). .

[0036] The compound of formula (II-1) can be obtained by acetylation of 2-methyl-6-oxoheptanoic acid: .

[0037] 2-Methyl-6-oxoheptanoic acid can be obtained from 2,6-dimethylcyclohexane-1-one via oxidation, as described above. For example, it can be obtained by oxidation with potassium permanganate as disclosed in Blahá L. et al. Collect. Czech. Chem. Commun. 1965, Vol. 30, 1214-1220, page 1216.

[0038] The compound of formula (II-2) can be obtained by acetylation of 2,6-dimethyl-10-oxoundecanoic acid (V-1a): .

[0039] 2,6-Dimethyl-10-oxoundecanoic acid can be obtained from the compound of formula (II-1) via the synthetic route detailed below.

[0040] The compound of formula (II-2a) can be obtained by acetylation of 2,6-dimethyl-10-oxoundec-6-enoic acid (V-1b): .

[0041] The acetylation of 2-methyl-6-oxoheptanoic acid, 2,6-dimethyl-10-oxoundecanoic acid, or 2,6-dimethyl-10-oxoundec-6-enoic acid can be carried out by reaction with acetylene in the presence of ammonia and alkali metal hydroxide, as disclosed in WO2004 / 018400A1 for the acetylation of 6,10-dimethyl-2-undecanoic acid, US 4,320,236, or H. Wiederkehr, Chimia, 40(9), 1986, 323–330.

[0042] The compounds of formula (II-1) and formula (II-2) are the most preferred embodiments of the compound of formula (II).

[0043] Compounds of formula (IIIa) The compounds of formula (IIIa) are substances known to those skilled in the art.

[0044] In equation (IIIa), R 3 Indicates methyl or ethyl, and R 4 Indicates H or methyl or ethyl, and R 5 Represents linear or branched C 1-10 -alkyl, especially methyl or ethyl.

[0045] Preferably, the group R 3 It indicates a methyl group.

[0046] Preferably, the group R 4 H represents H.

[0047] Preferably, the group R 5 It indicates a methyl group.

[0048] The most preferred compound of formula (IIIa) is isopropenyl methyl ether ( "IPM" ) or isopropyl ethyl ether ( "IPE" ), especially isopropenyl ethyl ether ( "IPE" 2-Methoxypropyl-1-ene).

[0049] Due to the synthesis of compounds of formula (IIIa), mixtures of compounds of formula (IIIa) are often reacted with compounds of formula (II). For example, for butenyl methyl ethers, 2-methoxybut-1-ene prepared from methanol and methyl ethyl ketone is commonly used. E )-2-methoxybut-2-ene and ( Z A mixture of 2-methoxybut-2-ene.

[0050] Compounds of formula (IIIb) The compounds of formula (IIIb) are substances known to those skilled in the art.

[0051] In equation (IIIb), R 3 Indicates methyl or ethyl, and R 4 It represents H, methyl, or ethyl.

[0052] In one implementation, R 5’ and R 5’’ Represents linear or branched C 1-10 -alkyl, particularly methyl or ethyl. In another embodiment, R 5’ With R 5’ Together they form linear or branched C 1-10 -alkylene, especially ethylene or propyleneene.

[0053] Preferably, the group R 3 It indicates a methyl group.

[0054] Preferably, the group R 4 H represents H.

[0055] In one implementation, R 5’ = R 5’’ And especially R 5’ = R 5’’ = Methyl or ethyl, more preferably, R 5’ = R 5’’ = CH3.

[0056] In another preferred embodiment, R 5’ and R 5’’Together they form ethylidene (CH2CH2) or propylidene (CH2CH2CH2 or CH(CH3)CH2).

[0057] The most preferred compounds of formula (IIIb) are 2,2-dimethoxypropane, 2,2-diethoxypropane, 2,2-dimethyl-1,3-dioxolane, 2,2,4-trimethyl-1,3-dioxolane, or 2,2-dimethyl-1,3-dioxane.

[0058] The most preferred compound of formula (IIIb) is 2,2-dimethoxypropane or 2,2-diethoxypropane, especially 2,2-dimethoxypropane.

[0059] Compounds of formula (IIIa) are preferred over compounds of formula (IIIb).

[0060] In the method for preparing unsaturated ketones of formula (I), preferably formula (Ia), the compound of formula (II), preferably formula (IIa), reacts with the compound of formula (IIIa) or formula (IIIb).

[0061] G. Saucy et al. disclosed in US 3,029,287 and Helv. Chim. Acta 1967, 50(4), 1158-1167 that the reaction of tertiary propargyl alcohol with ketals or alkenyl ethers requires... strong acid catalyst It takes place in the presence of [something].

[0062] In particular, in a preferred embodiment of the invention, the reaction of tertiary propargyl alcohol of formula (II), especially formula (IIa), with an alkenyl ether of formula (IIIa) or a ketal of formula (IIIb) is... In the absence of any strong acid, .

[0063] A catalytically active catalytic agent may be added to the reaction of a compound of formula (II), preferably a compound of formula (IIa), with a compound of formula (IIIa) or (IIIb). However, it has now been surprisingly shown that the reaction can occur even in the complete absence of catalytic activity. Any addition Added It proceeded smoothly even in acidic conditions.

[0064] Furthermore, it was discovered that the reaction can proceed smoothly even in the absence of any ammonium compound as a catalyst, especially in the absence of any strong acid or ammonium catalyst.

[0065] Finally, and quite surprisingly, the reaction even occurred when it was not entirely absent. Any addition of catalystEven under these circumstances, it can proceed smoothly.

[0066] The reaction can be carried out in the absence of solvent or in the presence of an organic solvent.

[0067] Even if the reaction is carried out in the absence of an organic solvent, the starting material, a compound of formula (II), (IIIa), or (IIIb), can still be provided in an organic solvent. Therefore, based on the total weight of the reaction mixture, an amount of up to 10% by weight of organic solvent may be present, preferably up to 5% by weight, and more preferably up to 3% by weight.

[0068] If the reaction is carried out in an organic solvent, aprotic organic solvents are preferred, such as aliphatic ketone solvents like acetone, or hydrocarbon solvents like hexane.

[0069] It has now been found that the above reaction can provide compounds of formula (I) with high conversion, high yield and high selectivity.

[0070] It has now been found that the reaction is preferably carried out in a reaction mixture of the compound of formula (II), preferably the compound of formula (IIa), and the compound of formula (IIIa) or (IIIb) in a molar ratio of 1:15 to 1:2.5, preferably 1:10 to 1:3.5, and more preferably 1:5 to 1:3.5.

[0071] The reaction is preferably carried out in a temperature range of 70°C to 170°C. In one embodiment, the temperature is preferably 110°C to 160°C, and most preferably 115°C to 150°C. This temperature range is particularly suitable for isopropenyl methyl ethers as compounds of formula (IIIa).

[0072] In another embodiment, the temperature is preferably 75°C to 100°C, and most preferably 80°C to 95°C. This temperature range is particularly suitable for butenyl methyl ethers as compounds of formula (IIIa).

[0073] The reaction is preferably carried out at a pressure of 5 to 20 bar (0.5 to 2 MPa), and more preferably at a pressure of 6 to 15 bar (0.6 to 1.5 MPa).

[0074] In one embodiment, the reaction is preferably carried out at a pressure of 5 to 20 bar (0.5 to 2 MPa), more preferably at a pressure of 6 to 15 bar (0.6 to 1.5 MPa). This pressure range is particularly suitable for isopropenyl methyl ethers as compounds of formula (IIIa).

[0075] In another embodiment, the reaction is preferably carried out at atmospheric pressure, which is particularly suitable for butenyl methyl ethers as compounds of formula (IIIa).

[0076] The reaction typically produces a mixture of two isomers of formula (I) or preferred formula (Ia), namely, allenones of formula (Ia) or preferred formula (Iaa) and α,β,γ,δ-unsaturated ketones of formula (Ib) or preferred formula (Ibb).

[0077] , , , .

[0078] Depending on the reaction conditions, the ratios of the resulting formulas (Ia) / (Ib) and (Iaa) / (Ibb) can vary, and even pure or nearly pure products can be obtained. In the case of a mixture, in one embodiment, the two isomers can be separated. In one embodiment, the allenones of formula (Ia) and their corresponding formula (Iaa) can be isomerized to α,β,γ,δ-unsaturated ketones of formulas (Ib) and their corresponding formula (Ibb).

[0079] The isomerization of allenones of formula (Ia) and preferred formula (Iaa) can be carried out by a base or acid, preferably a base, to produce α,β,γ,δ-unsaturated ketones of formula (Ib) and preferred formula (Ibb).

[0080] However, it is preferable that no additional isomerization step is performed before subsequent reaction steps.

[0081] In another aspect, the present invention relates to a method for preparing a saturated ketone of formula (V).

[0082] The method includes the following steps: a) As detailed above, prepare an unsaturated ketone of formula (I), preferably an unsaturated ketone of formula (Ia); then proceed directly to: b) Hydrogenation yields an unsaturated ketone of formula (I) from step a), preferably an unsaturated ketone of formula (Ia); The characteristic is that there is no additional isomerization by other bases or acids between step a) and step b).

[0083] Surprisingly, it has now been discovered that hydrogenation step b) can be carried out smoothly not only from the unsaturated ketone of formula (Ib), preferably the unsaturated ketone of formula (Ibb), but also directly from allenone of formula (Ia), preferably the allenone of formula (Iaa), or from a mixture of allenone of formula (Iaa), preferably the allenone of formula (Iaa), and unsaturated ketone of formula (Ib), preferably the unsaturated ketone of formula (Ibb).

[0084] Therefore, this is highly advantageous because any isomerization of allenones of formula (Ia), preferably allenones of formula (Iaa), to unsaturated ketones of formula (Ib), preferably unsaturated ketones of formula (Ibb), incurs additional costs and time. Thus, the method offers a significant cost advantage.

[0085] Typically, the hydrogenation step b) of the hydrogenation of compounds of formula (I), preferably formula (Ia), to saturated ketones of formula (V) can be carried out by molecular hydrogen in the presence of a noble metal catalyst. Preferably, this hydrogenation is carried out by molecular hydrogen in the presence of palladium supported on a solid support. Particularly preferred noble metal catalysts are selected from palladium supported on carbon, palladium supported on silicon dioxide (SiO2), palladium supported on TiO2, and palladium supported on alumina (Al2O3).

[0086] The molecular hydrogen described herein can be provided as a hydrogen-containing gas, which preferably has a hydrogen content of greater than 99.9%, more preferably greater than 99.99%.

[0087] The hydrogenation in step b) is preferably carried out under pressure conditions, particularly at an absolute pressure of 1 bar to 21 bar (0.1 MPa to 2.1 MPa), and more preferably at an absolute pressure of 1 bar to 6 bar (0.1 MPa to 0.6 MPa).

[0088] The hydrogenation step can be carried out in the absence of an organic solvent. If the hydrogenation reaction is carried out in an organic solvent, aprotic organic solvents, such as hydrocarbons, especially aromatic hydrocarbons, are preferred.

[0089] In another aspect, the present invention relates to a method for preparing propargyl alcohol of formula (II'), .

[0090] This method includes the following steps: a) As described in great detail above, prepare an unsaturated ketone of formula (I), preferably an unsaturated ketone of formula (Ia); then proceed directly to: b) Hydrogenation yields the unsaturated ketone of formula (I) from step a), preferably the unsaturated ketone of formula (Ia); then proceed directly: c) Acetylating compounds of formula (V) to produce compounds of formula (II'); The condition is that n = 1 or 2, and R 4 = hydrogen, and R 3 = Methyl.

[0091] The compound of formula (II') when n = 1 (the compound of formula (II-2)) is 10-hydroxy-2,6,10-trimethyldodec-11-acetylic acid; The compound of formula (II') when n = 2 (the compound of formula (II-3)) is 14-hydroxy-2,6,10,14-tetramethylhexadec-15-acetylic acid.

[0092] The conditions for the acetylation step c) of 2,6,10-trimethyl-14-oxopentadecanoic acid (n = 2) (V-2a) or 2,6-dimethyl-10-oxoundecanoic acid (n = 1) (V-1a) are consistent with the conditions for the acetylation of 2-methyl-6-oxoheptanoic acid as described above.

[0093] Compounds of formula (II-3) of 14-hydroxy-2,6,10,14-tetramethylhexadec-15-alkynic acid can be selectively hydrogenated in the presence of a Lindra catalyst to compounds of formula (VI) of 14-hydroxy-2,6,10,14-tetramethylhexadec-15-alkynic acid.

[0094] The appropriate methods and conditions for this transformation are disclosed in A. Ofner et al. Helv. Chim. Acta 1959,42, 2577-2584 or WO 2020 / 239720 A1 or WO 2020 / 239721 A1.

[0095] Therefore, in a further aspect, the present invention relates to the use of allenones of formula (IA), (I-AA), or (I-AAA) or α,β,γ,δ-unsaturated ketones of formula (IB), (I-BB), or (I-BBB) as intermediates for the synthesis of compounds of formula (VI). .

[0096] 14-Hydroxy-2,6,10,14-Tetramethylhexadec-15-enoic acid (VI) can then react with a compound of formula (VIII) to produce a compound of formula (VII). in, R 20 R' represents a hydrogen or phenolic hydroxyl protecting group; and R 21 Independent of R 20 , indicating a hydrogen or phenolic hydroxyl protecting group R'; and R 10 R 11 and R 12 Each can be used independently to represent hydrogen or methyl.

[0097] R is preferred. 10 R 11 R1 2 The following combinations: R 12 = R 11 = R 10 = CH3; or R 12 = R 10 = CH3, R 11 = H; or R 12 = H, R 11 = R 10 = CH3; or R 12 = R 11 = H, R 10 = CH3.

[0098] More preferably, R 12 = R 11 = R 10 = CH3.

[0099] A phenolic hydroxyl protecting group is a group that protects a phenolic hydroxyl group (OH in any of the formulas herein, wherein R in the formula is R). 20 =H), and the protecting group can be easily removed by existing methods, and the corresponding compound with free phenolic hydroxyl groups can be obtained again.

[0100] The phenolic hydroxyl protecting group R' is introduced by the chemical reaction of a compound with H as the corresponding form of R and a protecting agent.

[0101] Protecting agents that generate the corresponding phenolic hydroxyl protecting group are known to those skilled in the art, as are the chemical processes and conditions of the reaction. For example, if the phenolic hydroxyl protecting group forms an ester with the rest of the molecule, suitable protecting agents are, for example, acids, acid anhydrides, or acyl halides.

[0102] The phenolic hydroxyl protecting group R' is specifically selected from the following groups: , , , and ; Where R30 and R 31 Each can be represented independently as C 1-15 -alkyl, fluorinated C 1-15 -alkyl, C 1-15 -cycloalkyl, C 6-15 -Aryl or C 7-15 -Aryl group; R 32 C represents 1-15 -alkylene or C 6-15 -Aspartic; And among them, R 33 C represents 1-15 -alkyl, alkyleneoxyalkyl, or polyoxyalkylene R 34 C represents 1-15 -alkyl; or, R 33 and R 34 Together, they represent C forming 5-7 member rings. 3-7 -alkylene; or, R 35 R 36 and R 37 Each represents C independently. 1-15 -alkyl, fluorinated C 1-15 -alkyl or C 6-15 -Aryl; And among them, Y 1 Groups representing hydrogen or the following formula: ; Furthermore, the single-dot dashed line represents the bond where the substituent is bonded to the rest of the molecule.

[0103] If R' is R 30 The corresponding compound is an ether, which can be formed by reacting a corresponding protecting agent with a phenolic hydroxyl group (OH). In this case, the protecting agent can be, for example, an alkylating agent, such as the corresponding C... 1-15 -alkyl, fluorinated C 1-15 -alkyl, C 1-15 -cycloalkyl, C 7-15 - Halogenated aralkyl groups.

[0104] In a preferred embodiment, R 30 It is a methyl group.

[0105] In another preferred embodiment, R 30 C 6-10 -Aryl or C 7-15 -Aryl group, preferably benzyl or substituted benzyl, especially benzyl.

[0106] If R' is or If indicated, the corresponding compound is an ester of a carboxylic acid or a dicarboxylic acid, which can be formed by the reaction of the corresponding protecting reagent with the phenolic hydroxyl group (OH).

[0107] If the corresponding compound is an ester of a carboxylic acid or an ester of a dicarboxylic acid, then R' is preferably C. 1-7 -Acyl group, preferably acetyl, trifluoroacetyl, propionyl, benzoyl or substituted benzoyl group.

[0108] Esters can be easily deprotected under the influence of acids or bases.

[0109] If R' is The corresponding compound is an acetal, which can be formed by reacting a corresponding protecting reagent with a phenolic hydroxyl group (OH). In this case, the protecting reagent can be, for example, the corresponding aldehyde, a haloalkane such as MeO(CH2)2OCH2Cl, or an enol ether such as 3,4-dihydro- 2H -Pyran.

[0110] In this case, the substituent R' is preferred. or , where nn = 0 or 1.

[0111] In some instances, acetals are also referred to as "ethers," particularly in the cases mentioned above: methoxymethyl ether (MOM-ether), β-methoxyethoxymethyl ether (MEM-ether), or tetrahydropyran ether (THP-ether).

[0112] Acetals can be easily deprotected under the influence of acids.

[0113] In another preferred embodiment, the corresponding compound is an ester of phosphoric acid, pyrophosphoric acid, phosphorous acid, sulfuric acid, or sulfurous acid.

[0114] Depending on the reaction conditions, esterification can be either complete or partial, leaving some residual acid groups of the corresponding acid un-esterified.

[0115] Most preferably, the protecting group R' is benzoyl or C 1-4 -Acyl group, especially acetyl or trifluoroacetyl, more particularly acetyl. R' indicates that molecules with acyl groups, especially acetyl groups, can be readily prepared from the corresponding deprotected molecules by esterification, and the deprotected phenolic hydroxyl compounds can be prepared from the corresponding esters by ester hydrolysis.

[0116] The most preferred option is that the protecting group R' is an acetyl group.

[0117] The most preferred compound of formula (VIII) is 2,3,6-trimethylhydroquinone (TMHQ) (VIII-A). Correspondingly, the most preferred compound of formula (VII) is the compound of formula (VII-A) or its monoacetate or diacetate.

[0118] It has now been found that the reaction in which a compound of formula (VI) condenses with a compound of formula (VIII) to produce a compound of formula (VII) can be carried out as disclosed in Weichet J., Bláha L. et al., Collect. Czech. Chem. Commun. 1966, Vol. 31, 2434–2443.

[0119] On the other hand, the present invention relates to the use of allenones of formula (IA), (I-AA), and (I-AAA) or α,β,γ,δ-unsaturated ketones of formula (IB), (I-BB), and (I-BBB) as intermediates in the synthesis of compounds of formula (VII). in: R 20 R' represents a hydrogen or phenolic hydroxyl protecting group; R 10 R 11 and R 12 Each can be used independently to represent hydrogen or methyl.

[0120] In another aspect, the present invention relates to a method for preparing compounds of formula (VI), The method is characterized by comprising the following steps: i) Preparation of an unsaturated ketone of formula (I), preferably an unsaturated ketone of formula (Ia), wherein the unsaturated ketone is prepared according to the detailed disclosure above. , .

[0121] Finally, another aspect of the present invention relates to compounds of formula (VII) and methods for their preparation. The characteristic feature is that the synthesis of the compound of formula (VII) includes the following step a): a) Preparation of unsaturated ketones of formula (I) and preferred formula (Ia), wherein the unsaturated ketones of formula (I) and preferred formula (Ia) are prepared according to the method for preparing unsaturated ketones of formula (I) and preferred formula (Ia) disclosed in detail above.

[0122] Reaction route Using the above series of reactions, in particular, compounds of formula (VII) can be synthesized from 2,6-dimethylcyclohexane-1-one or 6-hydroxy-2,6-dimethyloctyl-7-ynetic acid, with a significantly reduced number of steps compared to the synthesis disclosed in Weichert J., Bláha L., Collect. Czech.Chem. Commun.1966, Vol. 31, 2424–2433.

[0123] This advantage is particularly attributed to the method of preparing unsaturated ketones of formula (I) and formula (Ia) according to the present invention.

[0124] The above reaction route is shown in Figure 1 , Figure 2 , Figure 3 and Figure 4 .

[0125] exist Figure 1 and Figure 2 The left side of the diagram schematically illustrates the multi-step reaction of the prior art (labeled as...). REF ), using the compound numbers from that document (shown in italics and neo-Roman font).

[0126] The right-hand section shows the reaction based on the present invention (labeled as...). INV ).

[0127] Figure 1 This represents the reaction route from 2-methyl-6-oxoheptanoic acid to 2,6-dimethyl-10-oxoundecanoic acid (V-1a).

[0128] Figure 2 This indicates a further reaction route, from 2,6-dimethyl-10-oxoundecanoic acid (V-1a) to 2,6,10-trimethyl-14-oxopentadecanoic acid (V-2a).

[0129] Figure 3 The reaction routes from 2,6-dimethyl-10-oxoundec-6-enoic acid (V-1b) to 10-hydroxy-2,6,10-trimethyldodec-6-ene-11-alkynic acid (II-2a) and further to 2,6,10-trimethyl-14-oxopentadecanonicic acid (V-2a) are shown.

[0130] These three figures illustrate compounds of formula (IA), formula (I-AA), and formula (I-AAA). It is evident from the above disclosure that, in this step, compounds of formula (IB), formula (I-BB), formula (I-BBB), or mixtures of compounds of formula (IA) and (IB), formula (I-AA) and (I-BB), or formula (I-AAA) and (I-BBB) may be present.

[0131] .

[0132] In the above formula, each wavy line independently represents a wavy line relative to the C=C double bond. Z- configuration or E - Carbon-carbon bonds of configuration (Formula (IB), (I-BB), (I-BBB)), or representing the corresponding axial R enantiomers, axial S enantiomers (Formula (IA), (I-AA), (I-AAA)) or mixtures thereof.

[0133] Preferably, there is a mixture of formula (IA) and formula (IB), a mixture of formula (I-AA) and formula (I-BB), or a mixture of formula (I-AAA) and formula (I-BBB).

[0134] from Figure 1 It is evident that the reaction from the compound of formula (II-1) to the compound of formula (V-1a) requires at least 7 reaction steps on the left side, while only 2 reaction steps are required on the right side.

[0135] Figure 2 The subsequent reaction pathway of the compound starting with the compound of formula (V-1a) is shown.

[0136] Figure 3 In another embodiment, the reaction route is shown to begin with the compound of formula (V-1b). Hydrogenation of the compound of formula (I-AAA) can be carried out directly to obtain the compound of formula (V-2a).

[0137] It is evident that, on the left side, the reaction from a compound of formula (II-2) to a compound of formula (V-2a), or from a compound of formula (II-2a) to a compound of formula (V-2a), requires at least 7 reaction steps, while on the right side, only 2 reaction steps are required.

[0138] Figure 4 Finally, it indicates a further reaction route for preparing compounds of formula (VII), especially compounds of formula (VII-A), from 2,6,10-trimethyl-14-oxopentadecanoic acid (V-2a).

[0139] Depend on Figures 1 to 4 It can be seen that, starting from methyl-6-oxoheptanoic acid, compounds of formula (II), especially compounds of formula (II-1), to prepare compounds of formula (VII), especially compounds of formula (VII-A), the reaction pathway of the present invention omits at least 10 reaction steps.

[0140] Example The present invention is further illustrated by the following embodiments.

[0141] The numbers following the compounds in the following text refer to the compounds in the figure.

[0142] 2-Methyl-6-oxoheptanoic acid ( 1 Synthesis of 2,6-Dimethylcyclohexane-1-one (109 mL, 784 mmol) was emulsified in a mixture of water (1140 mL) and acetone (360 mL). The colorless mixture was heated to 50°C (internal temperature, using a preheated oil bath at 60°C), the oil bath was removed, and potassium permanganate (351 g, 2197 mmol) was added in nine portions at 30-minute intervals, maintaining the internal temperature at 51°C to 55°C, at which point the reaction mixture turned purple. The reaction mixture was stirred at 50°C for 16 hours (oil bath).

[0143] After cooling to room temperature, the brownish-black suspension was filtered, and the filter cake was washed with water (320 mL) and acetone (110 mL). The acetone was removed under reduced pressure, and solid NaCl (350 g) was added to the aqueous solution. The solution was then precipitated with ethyl acetate (EtOAc) and tert-butyl methyl ether (TME). tert.- butyl methyl ether, tWash with BME and tetrahydrofuran (THF) (250 mL each), add tetrahydrofuran (500 mL), and acidify to pH 1 with concentrated HCl aqueous solution (130 mL). Separate the phases, and extract the aqueous phase again with tetrahydrofuran (250 mL). The combined organic phases are stirred with solid MgCl2 (4 g) for 30 min, then dried (MgSO4), filtered, and the solvent is removed under reduced pressure.

[0144] The crude product was dissolved in 500 ml t BME, cooled to 0°C (water / ice bath), and 2.5 N NaOH (500 mL) was added to adjust the pH to 14. The phases were separated, and the aqueous phase was used... t Wash with BME (2 x 250 mL), then cool again to 0°C and acidify to pH 1 with concentrated HCl aqueous solution (112 mL). t Following BME (500 mL) extraction, the combined organic phases were dried (MgSO4), filtered, and the solvent was removed under reduced pressure to obtain 98.0 g of a yellow oil (77% purity, 61% purity as determined by q-NMR). This oil was further purified to 91% purity by vacuum distillation (q-NMR). The resulting 2-methyl-6-oxoheptanoic acid... ( 1 ) The following analysis and characterization confirmed this: Characterization of 2-methyl-6-oxoheptanoic acid: 1 H NMR (300 MHz, CDCl3) δ [ppm] = 1.19 (d, J = 6.97 Hz, 3 H), 1.39–1.52 (m, 1 H), 1.55–1.74 (m, 3 H), 2.14 (s, 3 H), 2.40–2.53 (m, 3 H).

[0145] 13 C NMR (75 MHz, CDCl3) δ [ppm] = 16.8 (CH3), 21.3 (CH2), 29.9 (CH3), 32.8 (CH2), 39.2 (CH), 43.4 (CH2), 182.6 (C quat ), 208.7 (C quat ).

[0146] HRMS (ESI) (C8H 13 O3 + ): 157.0871; Calculated value: 157.0870.

[0147] Synthesis of 6-hydroxy-2,6-dimethyloctyl-7-ynetic acid (II-1) Before contact with acetylene, all equipment was evacuated and purged with nitrogen (4 cycles). In a 1-liter autoclave at 15°C, ammonia (150 g, 8.81 mol) was added to an aqueous solution of KOH (40 g) (299 mmol, 42%) and 2-methyl-6-oxoheptanoic acid. ( 1 ) In a mixture of 20 g (120 mmol), the reaction was initiated by bubbling acetylene over 1 hour (9.4 bar (0.94 MPa), 1200 rpm). The solvent (ammonia) was evaporated. The autoclave was opened, and the residue was removed with water and ethyl acetate. The reaction mixture was acidified to pH 5 with an aqueous HCl solution (25%) at 0 °C. After phase separation, the organic layer was washed with water (3 x 100 mL). The combined aqueous phases were extracted with ethyl acetate (2 x 100 mL). The combined ethyl acetate phases were dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The separated crude product was a brown, viscous oil (22.2 g, 93.1% purity (GC-ESTD, calibrated), 94% yield). The resulting 6-hydroxy-2,6-dimethyloctyl-7-ynylic acid Confirmation of (II-1) This was confirmed by the following analytical characterization: Characterization of 6-hydroxy-2,6-dimethyloct-7-ynetic acid: 1 H NMR (300 MHz, CDCl3) δ [ppm] = 1.20 (d, J = 6.97 Hz, 3 H), 1.40–1.79 (m, 9 H), 1.40–1.62 (m, 6 H), 2.43–2.56 (m, 2 H), 2.43–2.46 (m, 1 H).

[0148] 13 C NMR (75 MHz, CDCl3) δ [ppm] = 16.8 (CH3), 22.2 (CH2), 29.8 (CH), 33.3 (CH2), 39.2 (CH3), 43.1 (CH2), 67.9 (CH quat ), 71.5 (CH), 87.4 (C quat ), 182.7(C quat ).

[0149] HRMS (ESI) (C 10 H 17 O3 + ): 185.1175; Calculated value: 185.1172.

[0150] 2,6-Dimethyl-10-oxoundec-6,7-dienoic acid (IA) and 2,6-dimethyl-10-oxoundec-6, Synthesis of 8-dienoic acid (IB) 6-Hydroxy-2,6-dimethyloctyl-7-ynetic acid (II-1) (8.22 g, 97.2 wt%, 43.4 mmol) and 2-methoxyprop-1-ene (IPM) (12.8 g, 17 mL, 98 wt%, 173 mmol) were added to a 100 mL stainless steel autoclave. The autoclave was closed, and the solution was heated at 110 °C for 300 min. After cooling to room temperature, the solution was transferred to a round-bottom flask and concentrated under reduced pressure to give a mixture of the desired products of 2,6-dimethyl-10-oxoundec-6,7-dienoic acid (IA) and 2,6-dimethyl-10-oxoundec-6,8-dienoic acid (IB) as an orange oil (70% yield of all isomers, GC, RSTD).

[0151] For comparison, the above reaction was repeated using sulfuric acid as a catalyst, in an amount of 1 mol% relative to the amount of 6-hydroxy-2,6-dimethyloctyl-7-acetylic acid (5.46 g, 97.2 wt%, 28.8 mmol). A mixture of 2,6-dimethyl-10-oxoundec-6,7-dienoic acid (IA) and 2,6-dimethyl-10-oxoundec-6,8-dienoic acid (IB) as an orange oil (70% yield of all isomers, GC, RSTD) was obtained and characterized as follows.

[0152] It can be observed that the reaction can surprisingly produce the desired product in high yield and high purity even in the absence of strong acid.

[0153] Characterization: 1 H NMR (300 MHz, CDCl3) δ [ppm] = 1.14–1.19 (m, 3 H), 1.35–1.73 (m, 4H), 1.84–1.90 (m, 3 H), 2.11–2.34 (m, 5 H), 2.39–2.53 (m, 1 H), 5.94–6.14 (m,2 H), 7.30–7.52 (m, 1 H), 10.87 (s, 1 H).

[0154] 13C NMR (75 MHz, CDCl3) δ [ppm] = 17.0 / 17.1 (CH3), 17.5 (CH3), 24.5(CH3), 25.2 / 25.9 (CH2), 27.56 / 27.60 (CH3), 32.7 / 40.2 (CH2), 33.1 / 33.2 (CH2),39.28 / 39.32 (CH3), 124.0 / 124.9 (CH), 128.56 / 128.61 (CH), 139.3 / 139.8 (CH),150.9 / 151.2 (C quat ), 182.5 / 182.7 (C quat ), 199.28 / 199.33 (C quat ).

[0155] HRMS (EI, after silanization) (C 16 H 28 O3Si1 - ): 296.1794; Calculated value: 296.1808.

[0156] FT-IR: ν̃ [cm 1 = 734, 889, 971, 1164, 1369, 1463, 1582, 1621, 1664,1703, 1732, 2938.

[0157] Synthesis of 2,6-dimethyl-10-oxoundecanoic acid (V-1a) In a 1-liter steel autoclave, a mixture (56.0 g, 250 mmol) of 2,6-dimethyl-10-oxoundec-6,7-dienoic acid (IA) and 2,6-dimethyl-10-oxoundec-6,8-dienoic acid (IB) was dissolved in EtOAc (450 mL). 5% Pd / C (560 mg) was added, and the mixture was purged three times with nitrogen (pressurized to 5 bar (0.5 MPa) and then depressurized) and three times with hydrogen (pressurized to 5 bar (0.5 MPa) and then depressurized). The reaction mixture was heated to 60 °C, pressurized with 5 bar (0.5 MPa) H2, and stirred for 3.5 h. After cooling to room temperature, the mixture was filtered through a 0.45 μm filter, washed with EtOAc, and the solvent was removed under reduced pressure. The crude product was purified to yield 2,6-dimethyl-10-oxoundecanoic acid. (V-1a) And it is characterized as follows.

[0158] Characterization: 1H NMR (600 MHz, CDCl3) δ [ppm] = 0.84 (d, J = 6.6, 3 H), 1.04–1.13(m, 2 H), 1.22–1.44 (m, 6 H), 1.48–1.69 (m, 3 H), 2.13 (s, 3 H), 2.39 (ddd, J = 7.9, 6.7, 2.8, 2 H), 2.41–2.48 (m, 1 H).

[0159] 13 C NMR (151 MHz, CDCl3) δ = 16.9 / 17.0 (CH3), 19.55 / 19.57 (CH3), 21.4 / 21.5 (CH3), 24.7 (CH2), 30.0 (CH3), 32.59 / 32.61 (CH), 33.85 / 33.90 (CH2),36.50 / 36.54 (CH2), 36.75 / 36.76 (CH2), 39.50 / 39.54 (CH), 44.19 (CH2), 183.1(C quat ), 209.70 / 209.71 (C quat ) HRMS (EI, after silanization) (C 16 H 32 O3Si1 + ): 200.2126; Calculated value: 300.2121.

[0160] FT-IR: ν̃ [cm 1 = 735, 808, 942, 1165, 1235, 1291, 1361, 1377, 1414,1463, 1703, 1737, 2564, 2656, 2865, 2933.

[0161] Synthesis of 10-hydroxy-2,6,10-trimethyldodec-11-acetylic acid (II-2) Before contact with acetylene, all equipment was evacuated and purged with nitrogen (4 cycles). In a 1-liter autoclave at 15°C, ammonia (150 g, 8.81 mol) was added to an aqueous solution of KOH (29.3 g) (219 mmol, 42%) and 2,6-dimethyl-10-oxoundecanoic acid. (V-1a)The mixture (18.8 g, 56.6 mmol) was reacted by adding acetylene over 1 hour (9.4 bar (0.94 MPa), 1200 rpm). The solvent (ammonia) was evaporated. The autoclave was opened, and the residue was removed with water and toluene. The reaction mixture was acidified to pH 1 with an aqueous solution of H₂SO₄ (30%) at 0 °C. After phase separation, the organic layer was washed with water (3 x 100 mL). The combined aqueous phases were extracted with toluene (2 x 100 mL). The combined toluene phases were dried (Na₂SO₄), filtered, and concentrated under reduced pressure.

[0162] The crude product was separated into a brown, viscous oil (21.1 g, yield 87%).

[0163] The obtained 10-hydroxy-2,6,10-trimethyldodec-11-acetylic acid Confirmation of (II-2) This was confirmed by the following analytical characterization: Characterization of 10-hydroxy-2,6,10-trimethyldodec-11-acetylic acid: 1 H NMR (300 MHz, CDCl3) δ [ppm] = 0.88 (d, J = 6.59 Hz, 3 H), 1.09–1.21 (m, 5 H), 1.26–1.55 (m, 12 H), 1.59–1.75 (m, 3 H), 2.39–2.56 (m, 2 H).

[0164] 13 C NMR (75 MHz, CDCl3) δ [ppm] = 16.9 (CH / CH3), 19.6 (CH / CH3), 22.0(CH2), 24.5 (CH2), 29.7 (CH / CH3), 32.5 (CH / CH3), 33.8 (CH2), 36.7 (CH2), 36.9(CH2), 39.3 (CH / CH3), 43.7 (CH2), 68.1 (C quat ), 71.3 (CH), 87.7 (C quat ), 182.7(C quat ).

[0165] After HRMS (EI) silanization (C 21 H 41 O3Si2 + ): 397.2578; Calculated value: 397.2594.

[0166] 2,6,10-Trimethyl-14-oxopentadecano-10,11-dienoic acid (I-AA) and 2,6,10-trimethyl-14-oxopentadecano-10,11-dienoic acid Synthesis of pentadecanoic acid (I-BB) 10-hydroxy-2,6,10-trimethyldodec-11-ynynic acid (II-2) (5.10 g, 87.8 wt%, 18.0 mmol) and 2-methoxypropyl-1-ene (5.00 g, 7.0 mL, 98 wt%, 70 mmol) were added to a 100 mL stainless steel reactor. The reactor was closed, and the solution was heated at 115 °C for 300 min. After cooling to room temperature, the solution was transferred to a round-bottom flask and concentrated under reduced pressure to give a mixture of the desired products of 2,6,10-trimethyl-14-oxopentedecano-10,11-dienoic acid (I-AA) and 2,6,10-trimethyl-14-oxopentedecano-10,12-dienoic acid (I-BB), as an orange oil, which was purified (5.51 g, 39% (GC, ISTD), 41%) and characterized as follows.

[0167] For comparison, the above reaction was repeated using sulfuric acid as a catalyst, in an amount of 1 mol% relative to the amount of 10-hydroxy-2,6,10-trimethyldodecano-11-acetylic acid (12.62 g, 89.8 wt%, 44.5 mmol). A mixture of 2,6,10-trimethyl-14-oxopentedecano-10,11-dienoic acid (I-AA) and 2,6,10-trimethyl-14-oxopentedecano-10,12-dienoic acid (I-BB) as an orange oil was obtained, purified (17.1 g, 72% (GC, RSTD), 92%) and characterized as follows.

[0168] It can be observed that the reaction can surprisingly produce the desired product in high yield and high purity even in the absence of strong acid.

[0169] Characterization of mixtures reflecting diastereomers of diene (I-AA) and alladiene (I-BB): 1 H NMR (600 MHz, CDCl3) δ [ppm] = 0.84–0.87 (m, 3 H), 1.07–1.15 (m, 2H), 1.17–1.20 (m, 3 H), 1.24–1.45 (m, 8 H), 1.62–1.70 (m, 1 H), 2.08–2.17 (m, 2 H), 2.26–2.30 (m, 3 H), 2.44–2.50 (m, 1 H), 5.98–6.02 (m, 1 H), 6.06–6.10 (m, 1 H), 7.39–7.47 (m, 1 H).

[0170] 13C NMR (150 MHz, CDCl3) δ [ppm] = 17.0, 17.0, 17.0, 17.0, 17.0, 17.1,17.6, 19.6, 19.6, 19.7, 19.7, 19.7, 21.5, 21.5, 24.5, 24.7, 24.7, 24.7, 24.8,25.2, 25.9, 25.9, 27.6, 27.9, 27.9, 30.0, 32.5, 32.6, 32.6, 32.6, 32.6, 33.3,33.9, 33.9, 33.9, 34.0, 36.5, 36.6, 36.6, 36.6, 36.7, 36.7, 36.8, 36.8, 36.8, 36.8, 36.8, 36.9, 36.9, 39.4, 39.5, 39.5, 40.8, 44.2, 123.8, 124.5, 128.2, 128.2, 128.4, 139.5, 139.5, 140.0, 151.9, 151.9, 152.3, 152.4, 182.6, 182.6, 182.8, 182.8, 182.9, 199.3, 199.3, 209.6, 209.6.

[0171] Synthesis of 2,6,10-trimethyl-14-oxopentadecanoic acid (V-2a) In a 1-liter steel autoclave, the purified 2,6,10-trimethyl-14-oxopentadec-10,11-dienoic acid obtained above was mixed with 2,6,10-trimethyl-14-oxopentadec-10,12-dienoic acid. (I-BB) The mixture (28.5 g) was dissolved in EtOAc (625 mL). 5.5 g of Pd / C was added, and the mixture was purged three times with nitrogen (pressurized to 5 barg (understood as a "bar gauge"), which is a pressure relative to (or above) ambient / atmospheric pressure; therefore, 5 barg corresponds to a relative pressure of 0.5 MPa) and then depressurized, purging three times with hydrogen (pressurized to 5 barg and then depressurized). The reaction mixture and the reaction mixture were heated to 40 °C, pressurized with 5 barg (0.5 MPa) of H2, and stirred for 55 min. After cooling to room temperature, the reaction mixture was filtered through a 0.45 μm filter membrane, the solvent was evaporated, and the product was purified by column chromatography on silica gel to give purified 2,6,10-trimethyl-14-oxopentadecanoic acid. (V-2a) The yield was 99%. Further purification on silica gel column yielded the desired product with a purity of 92% (q-NMR).

[0172] Characterization of 2,6,10-trimethyl-14-oxopentadecanoic acid: 1 H NMR (300 MHz, CDCl3) δ [ppm] = 0.81–0.86 (m, 6H), 1.00–1.12 (m,4H), 1.15–1.19 (m, 3H), 1.19–1.45 (m, 11H), 1.46–1.71 (m, 3H), 2.37–2.42 (m,2H), 2.41–2.49 (m, 1H).

[0173] 13 C NMR (75 MHz, CDCl3) δ [ppm] = 17.0 (CH3), 19.7 (CH3), 19.8 (CH3), 21.6 (CH2), 24.5 (CH2), 24.7 (CH2), 30.0 (CH3), 32.7 (CH), 32.8 (CH), 34.0(CH2), 36.6 (CH2), 36.9 (CH2), 37.0 (CH2), 37.4 (CH2), 39.5 (CH), 44.3 (CH2),183.0 (C quat ), 209.8 (C quat ).

[0174] After HRMS (EI) silanization (C 21 H 42 O3Si + ): 370.2897; Calculated value: 370.2903 Synthesis of 14-hydroxy-2,6,10,14-tetramethylhexadec-15-acetylic acid (II-3) Before contact with acetylene, all equipment was evacuated and purged with nitrogen (4 cycles). In a 1-liter autoclave at 15°C, ammonia (8807 mmol) was added to 18.07 g of a 42% KOH aqueous solution (135 mmol) and 10.81 g of 2,6,10-trimethyl-14-oxopentadecanoic acid. (V-2a) In a mixture of (33.21 mmol), the reaction was initiated by adding acetylene over 1 hour (9.4 bar (0.94 MPa), 1200 rpm). The solvent (ammonia) was evaporated. The autoclave was opened, and the residue was removed with water and MTBE. The reaction mixture was acidified to pH 1 with HCl (25%) at 0 °C.

[0175] After phase separation, the organic layer was washed three times with 100 mL of water. The combined aqueous phases were extracted twice with 100 mL of MTBE. The combined organic phases were dried (Na₂SO₄), filtered, and concentrated under reduced pressure to give 14-hydroxy-2,6,10,14-tetramethylhexadec-15-acetylic acid. (II-3) (80% yield). The product was purified by column chromatography on silica gel to a purity of 97%.

[0176] Characterization of 14-hydroxy-2,6,10,14-tetramethylhexadec-15-alkynic acid: 1 H NMR (600 MHz, CDCl3) δ [ppm] = 0.8–0.8 (m, 3 H), 0.8–0.9 (m, 3 H), 1.0–1.7 (m, 27 H), 2.4 – 2.5 (m, 2 H).

[0177] 13 C NMR (150 MHz, CDCl3) δ [ppm] = 17.0 (CH3), 19.7 (CH3), 19.8 (CH3), 22.2 (CH2), 24.4 (CH2), 24.7 (CH2), 29.9 (CH3), 32.7 (CH), 32.8 (CH), 34.0(CH2), 36.9 (CH2), 37.0 (CH2), 37.3 (CH2), 37.4 (CH2), 39.5 (CH), 43.8 (CH2),68.2 (CH), 71.4 (C quat ), 87.8 (C quat ), 138.1 (C quat ).

[0178] HRMS (ESI) (C 20 H 37 O3 + ): 325.2736, Calculated value: 325.2737.

[0179] Synthesis of 14-hydroxy-2,6,10,14-tetramethylhexadec-15-enoic acid (VI) In a 50 mL autoclave with a glass liner, 14-hydroxy-2,6,10,14-tetramethylhexadecane-15-acetylic acid was... (II-3)(5.0 g) was dissolved in toluene (30 mL). Lindra catalyst (5% Pd / CaCO3 containing 3.5% lead, 1.5 g) and 3,6-dithia-1,8-octanediol (50 mg) were added. The mixture was placed in an autoclave and purged three times with nitrogen (pressurized to 5 bar and then depressurized), and three times with hydrogen (pressurized to 5 bar and then depressurized). The mixture was heated to 80°C, pressurized with 10 bar (1 MPa) H2, and stirred for 3 hours. After cooling to room temperature, the reaction mixture was filtered through a 0.45 μm membrane, washed with toluene, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography on silica gel for two rounds to give 1.17 g (87% purity by q-NMR, 3.12 mmol) of a pale yellow oil. A portion of the sample was further purified by preparative HPLC to give a colorless oil (>99% purity by q-NMR).

[0180] Characterization of 14-hydroxy-2,6,10,14-tetramethylhexadec-15-enoic acid: 1 H NMR (300 MHz, CDCl3) δ [ppm] = 0.85 (d, J = 6.59 Hz, 6 H), 1.01–1.44 (m, 21 H), 1.45–1.57 (m, 2 H), 1.61–1.73 (m, 1 H), 2.36–2.58 (m, 1 H), 5.05 (dd, J = 10.83, 1.22 Hz, 1 H), 5.21 (dd, J = 17.42, 1.22 Hz, 1 H), 5.93(dd, J = 17.33, 10.74 Hz, 1 H).

[0181] 13 C NMR (75 MHz, CDCl3) δ [ppm] = 17.1 (CH3), 19.9 (2 CH3), 21.4 (CH2), 24.4 (CH2), 24.7 (CH2), 27.8 (CH3), 32.6 (CH), 32.7 (CH), 34.0 (CH2), 36. 8(CH2), 37.0 (CH2), 37.3 (CH2), 37.5 (CH2), 39.5 (CH), 42.8 (CH2), 73.7 (C quat ),111.7 (CH2), 145.3 (CH), 182.4 (C quat ).

[0182] HRMS (EI, after silanization) (C 26 H 54 O3Si + ): 470.3631; Calculated value: 470.3612.

[0183] 13-(6-hydroxy-2,5,7,8-tetramethylbenzodihydropyran-2-yl)-2,6,10-trimethyltridecanoic acid Synthesis of (VII-A) According to the process disclosed by Weichet J., Bláha L. et al. Collect. Czech. Chem. Commun. 1966, Vol. 31, 2434–2443 on page 2439, 13-(6-hydroxy-2,5,7,8-tetramethylbenzodihydropyran-2-yl)-2,6,10-trimethyltetrazanoic acid (VII-A) has been synthesized from 14-hydroxy-2,6,10,14-tetramethylhexadecanoic acid (IB) and 2,3,6-trimethylhydroquinone (VIII-A).

[0184] Table of 13-(6-hydroxy-2,5,7,8-tetramethylbenzodihydropyran-2-yl)-2,6,10-trimethyltridecanoic acid Conquest: 1 H NMR (300 MHz, CDCl3) δ [ppm] = 0.84 (dd, J =6.4, 1.9, 6H), 1.00–1.15(m, 4H), 1.18 (d, J =7.0, 4H), 1.21–1.69 (m, 20H), 1.72–1.87 (m, 2H), 2.11 (s, 6H), 2.16 (s, 3H), 2.48 (q, J =6.8, 1H), 2.60 (t, J =6.9, 2H).

[0185] 13 C NMR (75 MHz, CDCl3) δ [ppm] = 11.4 (CH3), 11.9 (CH3), 12.4 (CH3), 17.0 (CH3), 19.7 (CH3), 19.8 (CH3), 20.9 (CH2), 21.2 (CH2), 23.9 (CH3), 24.6(CH2), 24.8 (CH2), 31.7 (CH3), 32.8 (2 CH), 34.0 (CH2), 37.0 (CH2), 37.45–37.71(4 CH2), 39.5 (CH), 40.0 (CH2), 117.4 (C quat), 118.7 (C quat ), 121.2 (C quat ), 122.7(C quat ), 144.6 (C quat ), 145.7 (C quat ), 183.4 (C quat ).

[0186] HRMS (ESI) (C 29 H 48 O4 + ): 460.3527; Calculated value: 460.3547.

Claims

1. A method for preparing an unsaturated ketone of formula (I). The method is carried out by reacting a compound of formula (II) with a compound of formula (IIIa) or (IIIb). in, R 3 Indicates methyl or ethyl; R 4 Indicates H, methyl, or ethyl; R 5 Represents linear or branched C 1-10 -alkyl groups, especially methyl or ethyl groups; R 5' and R 5'' express: Linear or branched C 1-10 -alkyl groups, especially methyl or ethyl groups; Or R 5' and R 5'' Together they form linear or branched C 1-10 -alkylene compounds, especially ethylene or propylene; and Where n represents a value from 1 to 2, and m represents a value from 0 to 2, provided that the sum of n and m is 1 or 2; And in which, in equation (I) or equation (II) by s1 and s2 The substructures can be represented in any order; R represents a group of formula (IVa) or (IVb). Furthermore, each wavy line independently represents a wavy line relative to the C=C double bond. Z - Configuration or presentation E - A carbon-carbon bond of configuration (IVb), or representing the axial R enantiomer or axial S enantiomer corresponding to (IVa), or a mixture thereof; Furthermore, any dashed line indicates that the substituents of formula (IVa) or formula (IVb) are bonded to the bonds of the remainder of formula (I).

2. The method according to claim 1, characterized in that, The compound of formula (I) is an allenone of formula (Iaa), preferably an allenone of formula (Iaaa). ， 。 3. The method according to claim 1, characterized in that, The compound of formula (I) is an α,β,γ,δ-unsaturated ketone of formula (Ibb), preferably an α,β,γ,δ-unsaturated ketone of formula (Ibbb). ， 。 4. The method according to claim 1, characterized in that, The method produces a mixture of allenone of formula (Iaa) and α,β,γ,δ-unsaturated ketones of formula (Ibb), preferably a mixture of allenone of formula (Iaaa) and α,β,γ,δ-unsaturated ketones of formula (Ibbb). 。 5. The method according to any one of the preceding claims, characterized in that, The method is carried out in the absence of any strong acid catalyst, wherein the strong acid is measured in water at room temperature using pK. a Less than 4, especially less than 2, preferably less than 1.

6. The method according to any one of claims 1 to 5, characterized in that, R 3 Represents methyl.

7. The method according to any one of claims 1 to 5, characterized in that, R 4 Represents H.

8. The method according to any one of claims 1 to 7, characterized in that, The molar ratio of the compound of formula (II) to the compound of formula (IIIa) or (IIIb) is 1:15 to 1:2.5, preferably 1:10 to 1:3.5, and more preferably 1:5 to 1:3.

5.

9. A method for preparing a saturated ketone of formula (V) The method includes the following steps: a) Prepare an unsaturated ketone of formula (I) by the method according to any one of claims 1 to 8, preferably an unsaturated ketone of formula (Ia); then proceed directly to the following steps: b) Hydrogenation yields an unsaturated ketone of formula (I) from step a); The characteristic is that there is no additional isomerization by other bases or acids between step a) and step b).

10. An allenone of formula (IA) in, Each wavy line independently represents the corresponding axis R enantiomer or axis S enantiomer or a mixture thereof.

11. An allenone of formula (I-AA) or formula (I-AAA), in, Any wavy line represents the corresponding axis R enantiomer or axis S enantiomer or a mixture thereof.

12. An α,β,γ,δ-unsaturated ketone of formula (IB), in, Each wavy line independently represents a position relative to the C=C double bond. Z - Configuration or presentation E - Carbon-carbon bond configuration.

13. An α,β,γ,δ-unsaturated ketone of the formula (I-BB), in, Each wavy line independently represents a position relative to the C=C double bond. Z - Configuration or presentation E - Carbon-carbon bond configuration.

14. Use of the allenone according to claim 10 or 11 or the α,β,γ,δ-unsaturated ketone according to claim 12 or 13 as an intermediate in the synthesis of compounds of formula (VI), 。 15. Use of the allenone according to claim 10 or 11 or the α,β,γ,δ-unsaturated ketone according to claim 12 or 13 as an intermediate in the synthesis of compounds of formula (VII), in, R 20 R' represents a hydrogen or phenolic hydroxyl protecting group; R 10 R 11 and R 12 Each can be independently represented by hydrogen or methyl; and The phenolic hydroxyl protecting group is selected from the group consisting of: , , , and ; Among them, R 30 and R 31 Each can be represented independently as C 1-15 -alkyl, fluorinated C 1-15 -alkyl, C 1-15 -cycloalkyl, C 6-15 -Aryl or C 7-15 -Aryl group; R 32 C represents 1-15 -alkylene or C 6-15 -alkylene; And among them, R 33 C represents 1-15 -alkyl, alkyleneoxyalkyl, or polyoxyalkylene R 34 C represents 1-15 alkyl; or R 33 With R 34 Together, they represent C forming 5 to 7-membered rings. 3-7 -alkylene; R 35 R 36 and R 37 Each can be represented independently as C 1-15 -alkyl, fluorinated C 1-15 -alkyl or C 6-15 -Aryl; And among them, Y 1 Groups representing hydrogen or the following formula: Furthermore, the single-dot dashed line represents the bond where the substituent is bonded to the rest of the molecule.

16. A method for preparing a compound of formula (VI). Its features are, The method includes the steps of preparing an unsaturated ketone of formula (I), preferably an unsaturated ketone of formula (Ia), by any one of claims 1 to 8 to obtain an unsaturated ketone of formula (I) or preferably an unsaturated ketone of formula (Ia). in, R 3 Indicates methyl or ethyl; R represents a group of formula (IVa) or (IVb). R 4 Indicates H, methyl, or ethyl; n represents a value from 1 to 2, and m represents a value from 0 to 2, provided that the sum of n and m is 1 or 2. And in which, in equation (I) or equation (Ia) by s1 and s2 The substructures can be represented in any order; Furthermore, each wavy line independently represents a wavy line relative to the C=C double bond. Z - Configuration or presentation E - A carbon-carbon bond of configuration (IVb), or representing the axial R enantiomer or axial S enantiomer or mixture thereof corresponding to (IVa); Furthermore, any dotted line indicates that the substituents of formula (IVa) or formula (IVb) are bonded to the remaining parts of formula (I), preferably formula (Ia).

17. A method for preparing a compound of formula (VII). Its features are, The synthesis of the compound of formula (VII) includes the steps of preparing an unsaturated ketone of formula (I), preferably an unsaturated ketone of formula (Ia), according to any one of claims 1 to 8. in, R 3 Indicates methyl or ethyl; R represents a group of formula (IVa) or (IVb). R 4 Indicates H, methyl, or ethyl; n represents a value from 1 to 2, and m represents a value from 0 to 2, provided that the sum of n and m is 1 or 2. And in which, in equation (I) or equation (Ia) by s1 and s2 The substructures can be represented in any order; Furthermore, each wavy line independently represents a wavy line relative to the C=C double bond. Z - Configuration or presentation E - A carbon-carbon bond of configuration (IVb), or representing the axial R enantiomer or axial S enantiomer or mixture thereof corresponding to (IVa); Furthermore, any dashed line indicates that the substituents of formula (IVa) or (IVb) are bonded to the rest of formula (I) or (Ia); and, R 20 R' represents a hydrogen or phenolic hydroxyl protecting group; R 10 R 11 and R 12 Each can be independently represented by hydrogen or methyl; and The phenolic hydroxyl protecting group is selected from the group consisting of: , , , and ; Among them, R 30 and R 31 Each can be represented independently as C 1-15 -alkyl, fluorinated C 1-15 -alkyl, C 1-15 -cycloalkyl, C 6-15 -Aryl or C 7-15 -Aryl group; R 32 C represents 1-15 -alkylene or C 6-15 -alkylene; And among them, R 33 C represents 1-15 -alkyl, alkyleneoxyalkyl, or polyoxyalkylene R 34 C represents 1-15 alkyl; or R 33 With R 34 Together, they represent C forming 5 to 7-membered rings. 3-7 -alkylene; R 35 R 36 and R 37 Each can be represented independently as C 1-15 -alkyl, fluorinated C 1-15 -alkyl or C 6-15 -Aryl; And among them, Y 1 Groups representing hydrogen or the following formula: Furthermore, the single-dot dashed line represents the bond where the substituent is bonded to the rest of the molecule.

18. A compound of formula (VII), Its features are, The synthesis of the compound of formula (VII) includes step a): a) The unsaturated ketone of formula (I), preferably the unsaturated ketone of formula (Ia), is prepared according to any one of claims 1 to 8; in, R 3 Indicates methyl or ethyl; R represents a group of formula (IVa) or (IVb). R 4 Indicates H, methyl, or ethyl; n represents a value from 1 to 2, and m represents a value from 0 to 2, provided that the sum of n and m is 1 or 2. And in which, in equation (I) or equation (Ia) by s1 and s2 The substructures can be represented in any order; Furthermore, each wavy line independently represents a wavy line relative to the C=C double bond. Z - Configuration or presentation E - Carbon-carbon bond configuration, or (IVa) corresponding to the axial R enantiomer or axial S enantiomer or mixture thereof; Furthermore, any dashed line indicates a substituent of formula (IVa) or (IVb) bonded to the remainder of formula (I) or (Ia); and, R 20 R' represents a hydrogen or phenolic hydroxyl protecting group; R 10 R 11 and R 12 Each can be independently represented by hydrogen or methyl; and The phenolic hydroxyl protecting group is selected from the group consisting of: , , , and ; Among them, R 30 and R 31 Each can be represented independently as C 1-15 -alkyl, fluorinated C 1-15 -alkyl, C 1-15 -cycloalkyl, C 6-15 -Aryl or C 7-15 -Aryl group; R 32 C represents 1-15 -alkylene or C 6-15 -alkylene; And among them, R 33 C represents 1-15 -alkyl, alkyleneoxyalkyl, or polyoxyalkylene R 34 C represents 1-15 alkyl; or R 33 With R 34 Together, they represent C forming 5 to 7-membered rings. 3-7 -alkylene; R 35 R 36 and R 37 Each can be represented independently as C 1-15 -alkyl, fluorinated C 1-15 -alkyl or C 6-15 -Aryl; And among them, Y 1 Groups representing hydrogen or the following formula: Furthermore, the single-dot dashed line represents the bond where the substituent is bonded to the rest of the molecule.

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