Preparation of allyl alcohols having terminal carboxyl groups via ethynylation and Lindla hydrogenation

Abstract

The present invention relates to the synthesis of certain allyl alcohols having terminal carboxyl groups based on the steps of ethynylation and hydrogenation in the presence of a Lindla catalyst. These allyl alcohols are particularly useful for providing a pathway to the synthesis of isophytol or tocopherol having terminal carboxyl groups by a very small number of reaction steps.

Description

Technology Field

[0001] The present invention relates to the field of forming allylic alcohols, and is particularly useful for the synthesis of isophytol or tocopherol having terminal carboxyl groups, and thus is particularly useful for the field of isoprenoids, particularly derivatives of vitamin E. Background Technology

[0002] Literature [Weichet J., Bl [ha L., Collect. Czech. Chem. Commun. 1966, Vol. 31, 2424 - 2433] The synthesis of 14-hydroxy-2,6,10,14-tetramethylhexadec-15-en-acid, which corresponds to isophytol (3,7,11,15-tetramethylhexadec-1-en-3-ol) having a terminal carboxyl group, is disclosed.

[0003] To date, the above compound is prepared through a very complex reaction sequence starting from 2-methyl-6-oxoheptanoic acid. The described route involves the formation of 2,6-dimethyl-10-oxoundec-6-enic acid, a mono-unsaturated ketone having a C=C double bond at the γ,δ position relative to the carbonyl carbon atom of the keto group and a terminal carboxyl group. This synthesis route requires multiple chemical reactions (see also the left portion of Fig. 4) involving several chlorination reactions with highly toxic and corrosive hydrogen chloride gas or high concentrations of hydrochloric acid.

[0004] In the synthesis of isophytol, the molecule is generally constructed by a sequence of C2 / C3 extension reactions. One known synthetic approach uses tertiary vinyl carbinol or ketal / acetal. G. Saucy et al. [Helv. Chim. Acta 1967, 50, 2091-2095] and [Helv. Chim. Acta 1967, 50, 2095-2100] described phosphoric acid or sulfuric acid or as a catalyst for the reaction between tertiary vinyl carbinol and isopropene ether p-It is disclosed that toluenesulfonic acid can be used. DE 196 49 564 discloses that various acidic organophosphorus compounds act as catalysts. WO 2010 / 046199 A2 discloses that inorganic ammonium (NH4) as a potential catalyst. + ) initiates the salt. However, inorganic ammonium salts generally have unfavorable solubility, and it has been shown that inorganic ammonium salts exhibit low yield and selectivity, especially when used at concentrations of less than 1 mol-%.

[0005] However, due to the presence of the carboxyl group, it is highly doubtful whether a person skilled in the art would have used this reaction step known from isophytol for the synthesis of 14-hydroxy-2,6,10,14-tetramethylhexadec-15-enic acid.

[0006] The literature [Weichet J., Blàha L., Collect. Czech. Chem. Commun. 1966, Vol. 31, 2424–2433] additionally discloses the ethynylation of saturated ketones as well as the Lindlar hydrogenation of alkynes to alkenes. However, the ethynylation of unsaturated ketones or alkynes containing C=C double bonds was not disclosed. The literature [Weichet J., Blàha L. et al., Collect. Czech. Chem. Commun. 1966, Vol. 31, 2434 - 2443] initiates the formation of alpha-tocopheryl acid (= 13-(6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)-2,6,10-trimethyltridecanoic acid) from 10-hydroxy-2,6,10-trimethyldodeca-6,11-dienoic acid.

[0007] The reaction route for preparing carboxyl-terminated allyl alcohols involved in the synthesis of 13-(6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)-2,6,10-trimethyltridecanoic acid (VII-A), or its intermediates, particularly 14-hydroxy-2,6,10,14-tetramethylhexadec-15-enoic acid (IB) or 2,6,10-trimethyl-14-oxopentadecanoic acid (VI-A), is somewhat complex and involves a very large number of reaction steps. This large number of reaction steps is very disadvantageous in terms of time, cost, manpower, and yield.

[0008] Therefore, any process that reduces the number of steps is highly valued.

[0009] It was surprisingly discovered that the method of claim 1 enables a significant reduction in the reaction step. It was found that when starting from 3-methyloctane-2,7-dione (II-0), compound 2,6,10-trimethyl-14-oxopentadeca-6,10-dienoic acid (IV-A) can be prepared in 6 steps, 2,6,10-trimethyl-14-oxopentadecanoic acid (VI-A) can be prepared in 7 steps, 14-hydroxy-2,6,10,14-tetramethylhexadeca-15-enoic acid (IB) can be prepared in 9 steps, or 13-(6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)-2,6,10-trimethyltridecanoic acid (VII-A) can be prepared in 10 steps, which leads to a significant reduction in time and cost and a product with a favorable impurity profile.

[0010] Furthermore, it was particularly surprising to discover that chain extension involving compounds of the chemical formula (Va) or (Vb) can be carried out in the absence of any strong acid, which avoids the handling of highly corrosive materials in synthesis and thus contributes to a further reduction in cost. Additionally, it was found that the reaction can be carried out in the absence of any ammonium catalyst and exhibits high yield and selectivity.

[0011] These findings lead to a highly advantageous process due to the reduction of steps and costs in production.

[0012] Further aspects of the present invention are the subject of additional independent claims. Particularly preferred embodiments are the subject of dependent claims. Brief explanation of the drawing

[0013] Figure 1 illustrates an overview of different reactions. FIGS. 2 and 3 each schematically illustrate a particularly preferred reaction sequence from 3-methyloctane-2,7-dione (II-0) to 2,6,10-trimethyl-14-oxopentadeca-6,10-dienoic acid (IV-A) or 14-hydroxy-2,6,10,14-tetramethylhexadeca-15-enoic acid (IB) or carboxyl-terminated tocopherol or its derivative (VII). Figure 4 shows a multi-stage process of a prior art process ( REF Indicated by), and a reaction based on the present invention ( INV It illustrates (indicated as ). Specific details for implementing the invention

[0014] In a first aspect, the present invention

[0015] a) a step of ethynylating an unsaturated ketone of formula (II) to obtain a propargyl alcohol of formula (III); and subsequently

[0016] b) a step of obtaining a compound of formula (I) by hydrogenating the propargyl alcohol of formula (III) formed in step a) using molecular hydrogen (e.g., provided as a gas containing hydrogen, said gas preferably having a hydrogen content of greater than 99.9% or greater than 99.99%), or a hydrogen donor, or a transfer hydrogenation agent, preferably molecular hydrogen, and a Lindla catalyst.

[0017] The present invention relates to a method for preparing an allyl alcohol of formula (I) comprising:

[0018]

[0019]

[0020]

[0021] In the above formula,

[0022] n represents a value from 0 to 3, and m represents a value from 1 to 3, wherein the sum of n and m is 1 to 3;

[0023] s1 and s2 The substructures of chemical formula (I), (II), or (III) represented by can be in any order;

[0024] An arbitrary wavy line for the C=C double bond Z - or E - The carbon-carbon bonds in the arrangement are shown independently of each other.

[0025] For clarity, some terms used in this document are defined as follows:

[0026] In this document, "C x-y -alkyl" groups are alkyl groups comprising x to y carbon atoms, i.e., for example, C 1-3 - An alkyl group is an alkyl group containing 1 to 3 carbon atoms. The alkyl group can be linear or branched. For example, -CH(CH3)-CH2-CH3 is considered a C4-alkyl group.

[0027] In this document, strong acids are defined as having a pK of less than 4, particularly less than 2, and preferably less than 1 when measured in water at room temperature. a It is an arbitrary mountain having pK a " is the negative common logarithm of the acid dissociation constant (pK a = -log 10 K a It is generally known as ).

[0028] Where the same label for a symbol or group exists in multiple chemical formulas, in this document, the definition of said group or symbol given in the context of one specific chemical formula also applies to other chemical formulas containing the same said label.

[0029] In this document, the term “independently” means that, in the context of substituents, moiety, or group, identically designated substituents, moiety, or group may occur simultaneously in the same molecule with different meanings.

[0030] In this document, any dotted line within any chemical formula indicates a bond in which a substituent is attached to the remainder of the molecule.

[0031] In this document, any wavy line within any chemical formula represents a C=C double bond. Z -Array or E - Represents carbon-carbon bonds or mixtures thereof in an arrangement independently of each other. If there are several such wavy lines in a specific chemical formula, all double bonds are E It is desirable to be in the arrangement.

[0032] In the first step (step (a)), the unsaturated ketone of formula (II) having a terminal carboxyl group is ethynylated.

[0033] The unsaturated ketone of formula (II) comprises at least one carbon-carbon double bond. In each of the formulas in this document, in particular formula (II), and more specifically in formulas (I, I', II', III, III', IV, IV' or VI') described below s1 and s2 The substructures indicated by may be in any order. However, substructure elements ( s2 It is preferable that at least one of ) is directly bonded to a carbonyl, or C(CH3)(C≡CH)OH, or C(CH3)(C=CH)OH group, respectively. In other words, the compound of formula (II) is preferably a γ,δ-unsaturated ketone.

[0034] It is very surprising that such unsaturated ketones having a terminal carboxyl group of formula (II) can be ethynylated with high selectivity and without any unwanted byproducts, or at least with a very significantly reduced amount of unwanted byproducts. Ethynylation can be carried out by reaction with ethyne in the presence of ammonia and alkali metal hydroxide, as disclosed, for example, by WO 2004 / 018400 A1 for the ethynylation of 6,10-dimethyl-2-undecanone, or by US 4,320,236 or the literature [Chimia, 40(9), 1986, 323-330].

[0035] The unsaturated compound of chemical formula (II) can be prepared in more detail as described below in this document.

[0036] It is particularly desirable that the ethynylation in step a) be performed in the absence of any organic solvent.

[0037] In step a), the ethynylation of the unsaturated ketone of formula (II) produces the propargyll alcohol of formula (III):

[0038]

[0039] The propargyl alcohol of formula (III) is then hydrogenated in step b) using, for example, molecular hydrogen provided as a gas containing hydrogen (the gas preferably has a hydrogen content of more than 99.9%, or more than 99.99%), or a hydrogen donor, or a transfer hydrogenating agent, preferably molecular hydrogen, and a Lindla catalyst to produce a compound of formula (I).

[0040] Lindlar catalysts are generally known to be suitable for use in selectively hydrogenating C≡C triple bonds to C=C double bonds in propargylic alcohols. The conditions for this hydrogenation, as well as the Lindlar catalyst, are known to those skilled in the art from, for example, the literature [Lindlar, Helv. Chim. Acta 1952, 35(2), 446-450] or the literature [A. Ofner et al., Helv. Chim. Acta 1959, 42, 2577-2584].

[0041] A preferred Lindla catalyst is palladium on lead-doped calcium carbonate. Such Lindla catalysts are commercially available, for example, from Sigma-Aldrich, Evonik, Johnson-Matthey, or Hindustan Platinum.

[0042] It is particularly preferable that the amount of palladium in the Lindla catalyst be in the range of 1 to 10 weight%, more preferably 3 to 8 weight%, and most preferably 4 to 6 weight% based on the total weight of the Lindla catalyst.

[0043] It is further preferable that the amount of lead (Pb) in the Lindla catalyst be in the range of 0.5 to 7 weight%, more preferably 1 to 6 weight%, and most preferably 2 to 5 weight% based on the total weight of the Lindla catalyst.

[0044] The above Lindla catalyst is typically used in an amount of 0.01 to 50 weight%, preferably 0.1 to 5 weight%, with respect to the propargyl alcohol of formula (III) in the hydrogenation of step b).

[0045] It is particularly surprising that the Lindla catalyst can also be used to selectively hydrogenate a specific propargyl alcohol of formula (III) to an allyl alcohol (I) without reducing the terminal carboxyl group to a hydroxyl group in step b).

[0046] Preferably, m and n both represent a value of 1. Thus, in a preferred embodiment, the compound of formula (II) is an unsaturated compound of formula (II-A), and thus, the compound of formula (III) is a propargyl alcohol of formula (III-A), and the allyl alcohol of formula (I) is an allyl alcohol of formula (IA):

[0047]

[0048] Accordingly, the present invention also relates to an allyl alcohol of formula (IA) and a propargyl alcohol of formula (III-A).

[0049] It was found that the compound of formula (I) can be further reacted with the compound of formula (V) or (Vb) in the absence of any strong acid or ammonium catalyst:

[0050]

[0051] In the above formula,

[0052] R 3 represents a methyl or ethyl group;

[0053] R 4 represents H, or a methyl or ethyl group;

[0054] R 5 is linear or branched C 1-10 - Representing an alkyl group, particularly a methyl or ethyl group;

[0055] R 5' and R 5" is linear or branched C 1-10 -alkyl group, particularly methyl or ethyl group; or R 5' and R 5" is together linear or branched C 1-10 - Forms alkylene groups, particularly ethylene or propylene groups.

[0056] Accordingly, in another aspect, the present invention also relates to a method for producing an unsaturated ketone of formula (IV'), particularly formula (IV), by reacting an allyl alcohol of formula (I'), particularly formula (I), with a compound of formula (Va) or (Vb) in the absence of any strong acid or ammonium catalyst in step c):

[0057]

[0058]

[0059]

[0060] In the above formula,

[0061] n represents a value from 0 to 3, m' represents 0 or m, and m represents a value from 1 to 3, wherein the sum of n and m' or n and m is from 1 to 3;

[0062] s1 and s2 The substructures within the chemical formula (I') or (IV') represented by, in particular (I) or (IV), may be of any order;

[0063] R 3 represents a methyl or ethyl group;

[0064] R 4 represents H, or a methyl or ethyl group;

[0065] R 5 is linear or branched C 1-10 - Representing an alkyl group, particularly a methyl or ethyl group;

[0066] R 5' and R 5" is linear or branched C 1-10 - Represents an alkyl group, particularly a methyl or ethyl group; or R 5' and R 5" is together linear or branched C 1-10 - Forming an alkylene group, particularly an ethylene or propylene group;

[0067] Any wavy lines are independent of each other for the C=C double bond Z - or E - Represents carbon-carbon bonds in the arrangement.

[0068] Compound of chemical formula (Va)

[0069] The compound of chemical formula (Va) is a substance known to those skilled in the art.

[0070] R in the chemical formula (Va) 3 represents a methyl or ethyl group, and R 4 represents H, or a methyl group or an ethyl group, and R 5 is linear or branched C 1-10 - Represents an alkyl group, particularly a methyl or ethyl group.

[0071] Preferably, Gi R 3 It represents a methyl group.

[0072] Preferably, Gi R 4 represents H.

[0073] Preferably, Gi R 5 represents a methyl group.

[0074] The compound of formula (Va) is most preferably isopropene methyl ether (" IPM ") or isopropene ethyl ether(" IPE ") and, in particular, isopropene methyl ether(" IPM ")am.

[0075] Due to the synthesis of compounds of chemical formula (Va), chemical formula (very often) V A mixture of compounds of a) is also used in the reaction with compounds of formula (I) or (I'). For example, in the case of butenyl methyl ether, a mixture of 2-methoxybut-1-ene, (E)-2-methoxybut-2-ene and (Z)-2-methoxybut-2-ene prepared from methanol and methyl ethyl ketone is often used.

[0076] Compound of chemical formula (Vb)

[0077] The compound of chemical formula (Vb) is a substance known to those skilled in the art.

[0078] In the chemical formula (Vb), R 3 represents a methyl or ethyl group, and R 4 represents H or a methyl or ethyl group.

[0079] R 5' and R 5" In one embodiment, each is a linear or branched C 1-10 - Represents an alkyl group, particularly a methyl or ethyl group. In other embodiments, R 5' and R 5" is together linear or branched C 1-10 - Forms alkylene groups, particularly ethylene or propylene groups.

[0080] Preferably, Gi R 3 It represents a methyl group.

[0081] Preferably, Gi R 4 represents H.

[0082] In one preferred embodiment, R 5' = R 5" and especially R 5' = R 5" = methyl or ethyl, more preferably R 5' = R 5" = CH3.

[0083] In another preferred embodiment, R 5' and R 5" It forms ethylene (CH2CH2) or propylene (CH2CH2CH2 or CH(CH3)CH2) groups together.

[0084] The compound of formula (Vb) is most preferably 2,2-dimethoxypropane or 2,2-diethoxypropane or 2,2-dimethyl-1,3-dioxolane or 2,2,4-trimethyl-1,3-dioxolane or 2,2-dimethyl-1,3-dioxane.

[0085] The compound of formula (Vb) is most preferably 2,2-dimethoxypropane or 2,2-diethoxypropane, particularly 2,2-dimethoxypropane.

[0086] The use of a compound of chemical formula (Va) is preferred over a compound of chemical formula (Vb).

[0087] In step c) above, the allyl alcohol of formula (I') or (I) reacts with the compound of formula (Va) or (Vb).

[0088] G. Saucy et al. [Helv. Chim. Acta 1967, 50, 2091-2095] and [Helv. Chim. Acta 1967, 50, 2095-2100] in the literature [Helv. Chim. Acta 1967, 50, 2095-2100] phosphoric acid or sulfuric acid or p -Discloses that toluenesulfonic acid can be used as a catalyst for the reaction between tertiary vinyl carbinol and isopropene ether. Thus, G. Saucy et al. [document] this reaction Strong acid catalyst It discloses that it must be performed in the presence of.

[0089] Surprisingly, the reaction in step c) above is Arbitrary added It was discovered that it occurs smoothly even in the complete absence of a mountain.

[0090] Furthermore, it was surprisingly revealed that the reaction proceeds smoothly in the absence of any ammonium compound as a catalyst, particularly in the absence of any strong acid or ammonium catalyst.

[0091] Finally, the above reaction in step c) is Arbitrary added It was revealed to be even more surprising that it occurs smoothly even in the complete absence of a catalyst.

[0092] The reaction in step c) can be carried out without a solvent or in the presence of an organic solvent. Preferably, the reaction is carried out without a solvent.

[0093] Even if the reaction of step c) is carried out in the absence of an organic solvent, the starting material, a compound of formula (I') or (I) or (Va) or (Vb), can still be provided in an organic solvent. Thus, based on the total weight of the reaction mixture, an amount of organic solvent up to 10 weight%, preferably up to 5 weight%, and more preferably up to 3 weight% may be present.

[0094] When the reaction is carried out in an organic solvent, a polar aprotic organic solvent such as an aliphatic ketone like acetone or a hydrocarbon like hexane is preferred.

[0095] It was found that the above reaction of step c) provides compounds of formula (IV') or (IV) with high conversion rate, yield, and selectivity.

[0096] It was found that the reaction in step c) is preferably carried out when the molar ratio of the compound of formula (I') or (I) to the reaction mixture of the compound of formula (Va) or (Vb) is in the range of 1:15 to 1:1, preferably 1:12 to 1:4, and more preferably 1:10 to 1:5.

[0097] The reaction is preferably carried out in a temperature range of 50 to 170°C. In one embodiment, the temperature is preferably in the range of 70 to 150°C, and most preferably in the range of 80 to 120°C. This temperature range is particularly suitable for isopropenyl methyl ether, a compound of formula (Va).

[0098] In another embodiment, the temperature is preferably in the range of 75 to 100°C, and most preferably in the range of 80 to 95°C. This temperature range is particularly suitable for butenyl methyl ether, a compound of formula (Va).

[0099] The reaction is preferably carried out at a pressure in the range of 5 to 20 bar (0.5 to 2 MPa), more preferably at a pressure in the range of 6 to 15 bar (0.6 to 1.5 MPa).

[0100] In one embodiment, the reaction is preferably carried out at a pressure in the range of 5 to 20 bar (0.5 to 2 MPa), more preferably at a pressure in the range of 6 to 15 bar (0.6 to 1.5 MPa). This pressure range is particularly suitable for isopropenyl methyl ether, a compound of formula (Va).

[0101] In another embodiment, the reaction is preferably carried out at ambient pressure. This pressure is particularly suitable for butenyl methyl ether, a compound of formula (Va).

[0102] In a preferred embodiment of the formula (IV'), m' represents a value of m, i.e., m' = 1 to 3, particularly m' = 1.

[0103] In a preferred embodiment, the compound of formula (I') is a compound of formula (I) prepared by a method for preparing an allyl alcohol of formula (I) as described in great detail above.

[0104] In one embodiment, an unsaturated ketone of formula (IV') is prepared by a method comprising the following subsequent steps:

[0105] a) a step of ethynylating a ketone of formula (II') to obtain a propargyl alcohol of formula (III'); and subsequently

[0106] b) a step of obtaining a compound of formula (I') by hydrogenating the propargyl alcohol of formula (III') formed in step a) using molecular hydrogen (e.g., provided as a gas containing hydrogen, said gas preferably having a hydrogen content of more than 99.9%, said molecular hydrogen), or a hydrogen donor, or a transfer hydrogenating agent, preferably molecular hydrogen, and a Lindla catalyst;

[0107] c) a step of reacting an allyl alcohol of formula (I') with a compound of formula (Va) or (Vb) in the absence of any strong acid or ammonium catalyst:

[0108]

[0109]

[0110]

[0111]

[0112] In the above formula,

[0113] n represents a value from 0 to 3, m' represents 0 or m, and m represents a value from 1 to 3, wherein the sum of n and m' is 1 to 3;

[0114] In chemical formula (I') or (II') or (III') or (IV'), s1 and s2 The substructures indicated by may be in any order;

[0115] R 3 represents a methyl or ethyl group;

[0116] R 4 represents H, or a methyl or ethyl group;

[0117] R 5 is linear or branched C 1-10 - Representing an alkyl group, particularly a methyl or ethyl group;

[0118] R 5' and R 5"is linear or branched C 1-10 - Represents an alkyl group, particularly a methyl or ethyl group; or R 5' and R 5" is together linear or branched C 1-10 - Forming an alkylene group, particularly an ethylene or propylene group;

[0119] An arbitrary wavy line for the C=C double bond Z - or E - The carbon-carbon bonds in the arrangement are shown independently of each other.

[0120] In a highly preferred embodiment, the compound of formula (I') or (I) is an allyl alcohol of formula (IA):

[0121]

[0122] Therefore, in a highly preferred embodiment, the unsaturated ketone of formula (IV') is the unsaturated ketone of formula (IV-A):

[0123] .

[0124] Therefore, the unsaturated ketone of formula (IV-A) represents another aspect of the present invention.

[0125] Figure 1 illustrates an overview of different reactions:

[0126] Part 1(" I A method for preparing an allyl alcohol of formula (I) is illustrated in the box marked with "") by ethynylating an unsaturated ketone of formula (II) (step a)) and then hydrogenating it using a Lindla catalyst (step b)).

[0127] Part 2(" II A method for preparing an unsaturated ketone of formula (IV') or (IV) is illustrated in the box marked with "") by reacting an allyl alcohol of formula (I') or (I) with a compound of formula (Va) or (Vb) in the absence of any strong acid or ammonium catalyst (step c)).

[0128] Part 3((" III In the box marked with ", the combination of the first and second parts is finally shown. At this time, the unsaturated ketone of formula (IV'), particularly formula (IV), is prepared by first ethynylating the ketone of formula (II'), particularly formula (II), then hydrogenating it using a Lindla catalyst (step (b)), and reacting the allyl alcohol of formula (I') or (I) with a compound of formula (Va) or (Vb) in the absence of any strong acid or ammonium catalyst (step (c)).

[0129] An unsaturated ketone of formula (IV') as described above, particularly an unsaturated ketone of formula (IV-A), can be hydrogenated to produce a saturated ketone of formula (VI'), particularly of formula (VI-A):

[0130] .

[0131] Accordingly, in a further aspect, the present invention relates to a method for producing a saturated ketone of formula (VI'), particularly a saturated ketone of formula (VI-A), by hydrogenation of an unsaturated ketone of formula (IV'), particularly an unsaturated ketone of formula (IV-A), in the presence of d) molecular hydrogen (provided, e.g., as a gas containing hydrogen, said gas preferably having a hydrogen content of greater than 99.9%, greater than 99.99%), or a hydrogen donor, or a transfer hydrogenating agent, preferably molecular hydrogen, and a transition metal catalyst:

[0132]

[0133] .

[0134] In the above formula,

[0135] The transition metal is a transition metal of group 7, 8, 9, or 10, and is particularly selected from the group consisting of Pd, Pt, Rh, Ru, Mn, Fe, Co, Ir, and Ni, preferably Pd or Ni, and more preferably Pd;

[0136] n represents a value from 0 to 3, m' represents 0 or m, and m represents a value from 1 to 3, wherein the sum of n and m' is 1 to 3;

[0137] s1 and s2 The substructures within the chemical formula (IV') or (VI') represented by, in particular (IV-A) or (VI-A), may be in any order;

[0138] Any wavy lines are independent of each other for the C=C double bond Z - or E - Represents carbon-carbon bonds in an arrangement;

[0139] The compound of formula (IV'), particularly (IV-A), is characterized by being prepared by a method for preparing a ketone of formula (IV') or (IV-A), as already discussed in great detail above.

[0140] The hydrogenation of step d) is carried out in the presence of molecular hydrogen, provided as a gas containing hydrogen having, for example, a hydrogen content of more than 99.9%, preferably more than 99.99%, or a hydrogen donor, or a transfer hydrogenating agent, preferably molecular hydrogen, and a transition metal catalyst, wherein the transition metal is a transition metal of group 7, 8, 9, or 10, and is particularly selected from the group consisting of Pd, Pt, Rh, Ru, Mn, Fe, Co, Ir, and Ni, preferably Pd or Ni, more preferably Pd.

[0141] Hydrogenation can also be carried out in the presence of a reducing agent, a hydrogen donor, or a transfer hydrogenating agent instead of molecular hydrogen. Suitable hydrogen donors or transfer hydrogenating agents are, in particular, alcohols such as formic acid, formate salts, hydrazine, and 2-propanol.

[0142] Through this hydrogenation, all carbon-carbon double bonds present in the molecule of chemical formula (IV') are hydrogenated.

[0143] Particularly suitable transition metal catalysts are Pd or Pt catalysts. Preferably, the transition metal catalyst is a supported transition metal, that is, one attached to or deposited on a carrier.

[0144] Such hydrogenation catalysts are primarily known to those skilled in the art. Both platinum and palladium and iridium, which are particularly preferred, are precious metals. Therefore, a particularly preferred catalyst is a supported palladium or platinum catalyst. The support is a solid material.

[0145] Preferably, the carrier is a carbon or inorganic carrier. A preferred inorganic carrier is an oxide or a carbonate. A preferred oxide is an oxide of silicon, aluminum, titanium, cerium, or sulfur. Particularly preferred are silicon dioxide, alumina, titanium dioxide, ceria, and sulfate.

[0146] Silicon dioxide can be used as a carrier in the form of pyrolytic silica or precipitated or ground silica. Preferably, the silicon dioxide used as a carrier is pyrolytic or precipitated silica. The most preferred silicon dioxide is silicon dioxide that is substantially pure SiO2. In other words, it is desirable that the silicon dioxide carrier consists of more than 95%, more preferably more than 98%, and much more preferably more than 99% based on the weight of SiO2.

[0147] Calcium carbonate is one of the desirable carbonates. The desirable calcium carbonate is precipitated calcium carbonate.

[0148] The carrier used may be a mixed oxide.

[0149] More desirable hydrogenation catalysts are palladium on carbon, palladium on silica, palladium on alumina, and palladium on calcium carbonate.

[0150] The amount of palladium in the hydrogenation catalyst is preferably in the range of 0.5 to 20 weight% based on the total weight of the hydrogenation catalyst, more preferably in the range of 2 to 5 weight%, and most preferably in the range of about 5 weight%.

[0151] Another particularly suitable transition metal catalyst is a Ni catalyst, such as a nickel alloy catalyst (also known as Ra-Ni nickel or sponge nickel), Urushibara nickel, or a supported nickel catalyst such as nickel on silica-alumina.

[0152] In a more preferred embodiment, a saturated ketone of formula (VI') is prepared by a method comprising a subsequent step:

[0153] a) A step of ethynylating a ketone of formula (II') to obtain a propargyl alcohol of formula (III'):

[0154]

[0155]

[0156] ; Continuing

[0157] b) a step of providing the propargyl alcohol of formula (III') formed in step a) as a gas containing molecular hydrogen, e.g., hydrogen, said gas preferably having a hydrogen content of more than 99.9% or more than 99.99%, or hydrogenating using a hydrogen donor or transfer hydrogenating agent, preferably molecular hydrogen, and a Lindla catalyst to obtain a compound of formula (I');

[0158] c) a step of reacting an allyl alcohol of formula (I') with a compound of formula (Va) or (Vb) in the absence of any strong acid or ammonium catalyst to obtain a compound of formula (IV'):

[0159]

[0160]

[0161] [In the above formula,

[0162] n represents a value from 0 to 3, m' represents 0 or m, and m represents a value from 1 to 3, wherein the sum of n and m' is 1 to 3;

[0163] s1 and s2 The substructures of the chemical formula (I') or (II') or (III') or (IV') represented by can be in any order;

[0164] R 3 represents a methyl or ethyl group;

[0165] R 4 represents H, or a methyl or ethyl group;

[0166] R 5 is linear or branched C 1-10 - Representing an alkyl group, particularly a methyl or ethyl group;

[0167] R 5' and R 5" is linear or branched C 1-10 - Represents an alkyl group, particularly a methyl or ethyl group; or R 5' and R 5" is together linear or branched C 1-10 - Forming an alkylene group, particularly an ethylene or propylene group;

[0168] An arbitrary wavy line for the C=C double bond Z - or E - Represents carbon-carbon bonds in an arrangement independently of each other];

[0169] After repeating steps a) through c) at will,

[0170] d) a step of hydrogenating an unsaturated ketone of formula (IV'), particularly an unsaturated ketone of formula (IV-A), in the presence of a transition metal catalyst, wherein the gas is provided as a gas containing molecular hydrogen, e.g., hydrogen, and said gas preferably has a hydrogen content of more than 99.9%, or more than 99.99%, or a hydrogen donor, or a transfer hydrogenating agent, preferably molecular hydrogen;

[0171]

[0172] [In the above formula,

[0173] The transition metal is a transition metal of group 7, 8, 9, or 10, and is particularly selected from the group consisting of Pd, Pt, Rh, Ru, Mn, Fe, Co, Ir, and Ni, preferably Pd or Ni, and more preferably Pd;

[0174] n represents a value from 0 to 3, m' represents 0 or m, and m represents a value from 1 to 3, wherein the sum of n and m' is from 1 to 3;

[0175] s1 and s2 The substructures of the chemical formula (IV') or (VI') represented by, in particular (IV-A) or (VI-A), may be of any order;

[0176] Any wavy lines are independent of each other for the C=C double bond Z - or E - Represents a carbon-carbon bond arrangement].

[0177] Saturated ketones of formula (VI'), particularly saturated ketones of formula (VI-A), can be ethynylated using the ethynylation step a) as described in detail above to form the corresponding propargyl alcohol.

[0178] This is illustrated in the outline of Fig. 3.

[0179] Therefore, in particular, the propargylic alcohol of the ketone of formula (III-B) can be prepared from the ketone of formula (VI-A):

[0180] .

[0181] For step b), when a compound of formula (III-B) is hydrogenated using a Lindla catalyst as described above, an allyl alcohol of formula (IB) is obtained:

[0182] .

[0183] Accordingly, a further aspect of the present invention relates to a method for producing an allyl alcohol of formula (IB), comprising: a) ethynylating a saturated ketone of formula (VI-A) to obtain a propargyl alcohol of formula (III-B); and then b) hydrogenating the propargyl alcohol of formula (III-B) formed in step a) using molecular hydrogen (e.g., provided as a gas containing hydrogen, said gas preferably having a hydrogen content of greater than 99.9% or greater than 99.99%), or a hydrogen donor or transfer hydrogenating agent, preferably molecular hydrogen, and a Lindla catalyst to obtain an allyl alcohol of formula (IB), wherein the saturated ketone of formula (VI-A) is prepared according to the method described above:

[0184]

[0185]

[0186] .

[0187] An allyl alcohol of formula (I-0) or (IA) or (I-A') or (IB), preferably (I-0) or (IA) or (IB), may react with a compound of formula (VIII) to obtain, respectively, a compound of formula (VII-a) or (VII-b) or (VII-c) or (VII) in step e):

[0188]

[0189]

[0190] .

[0191] The preferred allyl alcohol for this reaction is (I-O) or (IA) or (IB), and most preferably (IB).

[0192] Allyl alcohol of the chemical formula (I-A') can be obtained in the following manner:

[0193] A compound of formula (II-A) is provided to the hydrogenation step d) as described above to obtain a saturated ketone of formula (II-A').

[0194] The saturated ketone of formula (II-A') thus obtained is then ethynylated in step a) to obtain the propargyl alcohol of formula (III-A').

[0195] The propargyl alcohol thus obtained of formula (III-A') is hydrogenated in step b) using molecular hydrogen (e.g., provided as a gas containing hydrogen, said gas preferably having a hydrogen content of greater than 99.9%, greater than 99.99%), or a hydrogen donor, or a transfer hydrogenating agent, preferably molecular hydrogen, and a Lindla catalyst to obtain an allyl alcohol of formula (I-A'):

[0196]

[0197] Compounds of chemical formula (VIII) are defined as follows:

[0198]

[0199] In the above formula,

[0200] R 10 and R 11 and R 12 represents hydrogen or methyl groups independently of each other;

[0201] R21 is hydrogen, or the phenol protecting group R ' It represents.

[0202] R 12 , R 11 and R 10 The following combination of is desirable:

[0203] R 12 = R 11 = R 10 = CH3

[0204] or

[0205] R 12 = R 10 = CH3, R 11 = H

[0206] or

[0207] R 12 = H, R 11 = R 10 = CH3

[0208] or

[0209] R 12 = R 11 = H, R 10 = CH3.

[0210] R 12 = R 11 = R 10 = It is more desirable to have CH3.

[0211] The phenol protecting group is the phenol group (R in the above chemical formula in the chemical formula of this document 20 = OH) in any chemical formula having H is protected, and said protecting group is, that is, a group that can be easily removed by conventional methods and as a result becomes each compound having a free phenol group again.

[0212] The phenol protecting group R' is introduced by a chemical reaction between a compound of each chemical formula having H as R and a protecting agent.

[0213] Protective agents leading to the corresponding phenol protecting group are known to those skilled in the art, as well as to the chemical processes and conditions for this reaction. For example, if the phenol protecting group forms an ester with the remainder of the molecule, suitable protective agents are, for example, acids, anhydrides, or acyl halides.

[0214] Phenol protector R ' is especially

[0215] Selected from a group consisting of;

[0216] R 30 and R 31 C independently of each other 1-15 -alkyl, fluorinated C 1-15 -alkyl, C 1-15 -cycloalkyl or C 6-15 -aryl group or C 7-15 - Representing an aralkyl group;

[0217] R 32 is C 1-15 -alkylene or C 6-15 - Representing an alkylene group;

[0218] R 33 C 1-15 - Representing an alkyl group or an alkyleneoxyalkyl group or a polyoxyalkylene group;

[0219] R 34 is hydrogen or C 1-15 - Represents an alkyl group; or

[0220] R 33 and R 34 C that forms a 5 to 7-membered ring together 3-7 - Representing an alkylene group;

[0221] R 35 and R 36 and R 37 C independently of each other 1-15 -alkyl, fluorinated C 1-15 -alkyl or C 6-15 - Representing an aryl group;

[0222] Y 1represents hydrogen or a group of the following chemical formula:

[0223] ;

[0224] A single dotted line indicates a bond in which the substituent is attached to the remainder of the molecule.

[0225] If R ' Ga R 30 If identical to, each compound is an ether that can be formed by the reaction of a phenol group (OH) and each protective agent. In this case, the protective agent is, for example, each C 1-15 -alkyl, fluorinated C 1-15 -alkyl, C 1-15 -cycloalkyl or C 7-15 - It can be an alkylating agent such as an aralkyl halide, especially iodide.

[0226] In one of the preferred embodiments, R 30 It is a methyl group.

[0227] In another preferred embodiment, R 30 C 6-10 -aryl group or C 7-15 - It is an aralkyl group, preferably a benzyl group or a substituted benzyl group, and particularly preferably a benzyl group.

[0228] If R' When represented as such, each compound is an ester of a carboxylic acid or a dicarboxylic acid that can be formed by the reaction of a phenol group (OH) and each protective agent.

[0229] If the compound of each chemical formula is an ester of a carboxylic acid or a dicarboxylic acid, R ' is C 1-7 - It is preferable that the acyl group be an acetyl, preferably an acetyl, trifluoroacetyl, propionyl, or benzoyl group, or a substituted benzoyl group.

[0230] Esters can be easily deprotected under the influence of acids or bases.

[0231] R ' go In this case, each compound is an acetal that can be formed by the reaction of a phenol group (OH) and each protective agent. In this case, the protective agent is, for example, each aldehyde, alkyl halide, e.g., MeO(CH2)2OCH2Cl, or enol ether, e.g., 3,4-dihydro- 2H - It could be a refugee day.

[0232] In this case, substituent R ' is preferably

[0233] (nn=0 or 1).

[0234] In some cases, acetals are also called "ethers," particularly in the aforementioned cases, methoxymethyl ether (MOM-ether), β-methoxyethoxymethyl ether (MEM-ether), or tetrahydropyranyl ether (THP-ether).

[0235] Acetals can be easily deprotected under the influence of acid.

[0236] In another preferred embodiment, each compound is an ester of phosphoric acid, pyrophosphate, phosphoric acid, sulfuric acid, or sulfite.

[0237] Depending on the reaction conditions, esterification may be complete or partial, so some residual acid groups of each acid remain unesterified.

[0238] Most preferably, protector R ' is a benzoyl group or C 1-4 - It is an acyl group, particularly an acetyl or trifluoroacetyl group, more particularly an acetyl group. R ' Molecules representing acyl groups, particularly acetyl groups, can be easily prepared by esterification from corresponding unprotected molecules, and unprotected phenolic compounds can be obtained by ester hydrolysis from corresponding esters.

[0239] The most desirable protector R ' is an acetyl group.

[0240] The most desirable compound of chemical formula (VIII) is 2,3,6-trimethylhydroquinone (TMHQ) (VIII-A):

[0241] .

[0242] Therefore, its most desirable reaction products are compounds of the formulas (VII-aa), (VII-bb), (VII-cc), and (VIII-A) or their mono- or diacetates:

[0243]

[0244]

[0245] Step e), which is later also labeled as step ii) in this document, refers to the literature [Weichet J., Bl It can be performed as disclosed by ha L. et al., Collect. Czech. Chem. Commun. 1966, Vol. 31, 2434 - 2443.

[0246] Accordingly, a further aspect of the present invention relates to a method for preparing a compound of formula (VII), comprising the following steps:

[0247] i) A step of preparing an allyl alcohol of formula (IB) according to the method of preparing an allyl alcohol of formula (IB) as described above:

[0248] ;

[0249] ii) A step of reacting the compound of formula (IB) with the compound of formula (VIII) to obtain the compound of formula (VII):

[0250]

[0251] In the above formula,

[0252] R 20 It is hydrogen, or the phenol protecting group R. ' Representing;

[0253] R 10 and R11 and R 12 represents hydrogen or methyl groups independently of each other;

[0254] R 21 It is hydrogen, or the phenol protecting group R. ' It represents.

[0255] The present invention has been shown to be particularly useful for the synthesis of allyl alcohols of formula (IB) and / or compounds of formula (VII), which is highly advantageous as it can be carried out more easily and in significantly fewer steps than methods based on the prior art. A particular advantage is that the reaction sequence avoids any steps requiring the handling of highly toxic and corrosive chemicals, particularly hydrogen chloride gas or high concentrations of hydrochloric acid.

[0256] FIGS. 2 and 3 each schematically illustrate a particularly preferred reaction sequence from 3-methyloctane-2,7-dione (II-0) to 2,6,10-trimethyl-14-oxopentadeca-6,10-dienoic acid (IV-A) or 14-hydroxy-2,6,10,14-tetramethylhexadeca-15-enoic acid (IB) or carboxyl-terminated tocopherol or its derivative (VII).

[0257] The reaction of FIG. 2 starts with 3-methyloctane-2,7-dione (II-O) as a starting material. It is ethynylated under the conditions of step a) to produce 6-hydroxy-2,6-dimethyloct-7-inosan (III-O), which is then hydrogenated to 6-hydroxy-2,6-dimethyloct-7-inosan (I-O) using molecular hydrogen, e.g., a gas containing hydrogen, preferably having a content of more than 99.9%, or a hydrogen donor, or a transfer hydrogenator, preferably molecular hydrogen, and a Lindla catalyst under the conditions of step b).

[0258] 6-hydroxy-2,6-dimethyloct-7-enoic acid (I-O) prepared in this manner is then formed in the absence of any strong acid or ammonium catalyst into a compound of formula (Va) or (Vb), in particular isopropene methyl ether ( IPM Reacts with ") to obtain 2,6-dimethyl-10-oxoundec-6-enosan(II-A)( II' (Refer to the box marked with ). These first three reaction steps (a, b, c) are in Fig. 2 III' The box marked with is highlighted.

[0259] Subsequently, 2,6-dimethyl-10-oxoundec-6-enosane (II-A) is re-ethynylated under the conditions of step a) to obtain 10-hydroxy-2,6,10-trimethyldodeca-6-en-11-inosane (III-A), which is then provided under the conditions of step b) as a gas containing molecular hydrogen, e.g., hydrogen, said gas, preferably molecular hydrogen having a content of more than 99.9%, or more than 99.99% hydrogen, or a hydrogen donor or transfer hydrogenator, preferably molecular hydrogen, and a Lindla catalyst to hydrogenate to 10-hydroxy-2,6,10-trimethyldodeca-6,11-dienosane (IA). These two reaction steps I" It is highlighted by the box marked with .

[0260] 10-hydroxy-2,6,10-trimethyldodeca-6,11-dienoic acid (IA) prepared in this manner is a compound of formula (Va) or (Vb), in particular isopropene methyl ether (" IPM Reacts with ") to obtain 2,6,10-trimethyl-14-oxopentadeca-6,10-dienosic acid(IV-A)( II" (Refer to the box marked with ). These last three reaction steps (a), b), and c)) are in Fig. 2 III" It is highlighted by the box marked with .

[0261] In other words, in the sequence of two subsequent reactions of steps a), b), and c), 2,6,10-trimethyl-14-oxopentadeca-6,10-dienoic acid (IV-A) can be prepared from 3-methyloctane-2,7-dione (II-O) in just six steps.

[0262] Subsequently, 2,6,10-trimethyl-14-oxopentadeca-6,10-dienosic acid (IV-A) prepared in this manner is hydrogenated in step d) as shown in FIG. 3 to become 2,6,10-trimethyl-14-oxopentadecanoic acid (VI-A), and then ethynylated under the conditions of step a) to obtain 14-hydroxy-2,6,10,14-tetramethylhexadec-15-inosic acid (III-B). 14-hydroxy-2,6,10,14-tetramethylhexadec-15-enosan (III-B) is then provided as a gas containing molecular hydrogen, e.g., hydrogen, under the conditions of step b), and said gas is hydrogenated using molecular hydrogen having a hydrogen content of preferably greater than 99.9% or greater than 99.99%, a hydrogen donor, or a transfer hydrogenating agent, preferably molecular hydrogen, and a Lindla catalyst to become 14-hydroxy-2,6,10,14-tetramethylhexadec-15-enosan (IB).

[0263] In other words, 14-hydroxy-2,6,10,14-tetramethylhexadec-15-enosane (IB) can be obtained from 3-methyloctane-2,7-dione (II-0) in just 9 steps.

[0264] Finally, 14-hydroxy-2,6,10,14-tetramethylhexadec-15-enosane (IB) is further reacted in step e)(=ii)) with a compound of formula (VIII), particularly 2,3,6-trimethylhydroquinone (TMHQ) (VIII-A), to become a carboxyl-terminated tocopherol of formula (VII) or its derivative, or particularly 13-(6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)-2,6,10-trimethyltridecanoic acid (VII-A).

[0265] In other words, the carboxyl-terminal tocopherol of formula (VII) or its derivative, in particular 13-(6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)-2,6,10-trimethyltridecanoic acid (VII-A), can be obtained from 3-methyloctane-2,7-dione (II-0) in just 10 steps.

[0266] The process described in this document is highly advantageous compared to methods based on prior art literature. For illustrative purposes, the synthesis of the present invention is illustrated in FIG. 4 [Weichet J., Bl It is compared with those of ha L., Collect. Czech. Chem. Commun.1966, Vol. 31, 2424 - 2433].

[0267] In the left part of FIG. 4, a prior art process (shown in italics and Times Roman font using compound numbering used in the cited prior art) REF A multi-stage process of (indicated by) is schematically illustrated.

[0268] In the right part, the present invention ( INV A reaction based on (indicated by) is illustrated.

[0269] As can be easily derived from FIG. 4, 2,6,10-trimethyl-14-oxopentadecanoic acid (VI-A)( XII ) is the starting product 3-methyloctane-2,7-dione(II-0)( by the reaction pathway based on the present invention II While it can be obtained in just 8 steps from ), the reaction pathway according to the prior art requires at least 16 steps.

[0270] Therefore, regarding the synthesis of alpha-tocopheryl acid (= compound of formula (VII-A)), prior art procedures, namely, literature [Weichet J., Bl ha L., Collect. Czech. Chem. Commun.1966, Vol. 31, 2424 - 2433] and literature[Weichet J., Bl Compared to [ha L. et al., Collect. Czech. Chem. Commun. 1966, Vol. 31, 2434 - 2443], at least 8 steps can be saved by the reaction pathway based on the present invention.

[0271] Examples

[0272] The present invention is further illustrated by the following experiment.

[0273] Synthesis of 2-methyl-6-oxoheptanoic acid (II-0)

[0274] 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, preheated oil bath with a bath temperature of 60°C), the oil bath was removed, and potassium permanganate (351 g, 2197 mmol) was added in 9 portions at 30-minute intervals while maintaining the internal temperature between 51 and 55°C, causing the mixture to turn purple. This was stirred at 50°C for 16 hours (oil bath).

[0275] After cooling to room temperature, the dark brown suspension was filtered, and the filter cake was washed with water (320 mL) and acetone (110 mL). Acetone was removed under reduced pressure, and solid NaCl (350 g) was added to the aqueous solution. Subsequently, this was ethyl acetate (EtOAc), tert- Butyl methyl ether ( t The mixture was washed with BME, tetrahydrofuran (THF) (250 mL each), THF (500 mL) was added, and the pH was acidified to 1 using concentrated aqueous HCl (130 mL). The phases were separated, and the aqueous phase was extracted once more with THF (250 mL). The combined organic phase was stirred with solid MgCl2 (4 g) for 30 minutes, then dried (MgSO4), filtered, and the solvent removed under reduced pressure.

[0276] 500 mL of crude product t Dissolve in BME, cool to 0°C (water / ice bath), and then add 500 mL of 2.5 N NaOH to adjust the pH to 14. Separate the phases, and the aqueous phase t Wash with BME (2 x 250 mL), then cool to 0°C and acidify to pH 1 using concentrated aqueous HCl (112 mL). t After extraction with BME (500 mL, followed by 2 x 250 mL), the combined organic phase was dried (MgSO4), filtered, and the solvent removed under reduced pressure to obtain 98.0 g of yellow oil (77%, 61% purity by q-NMR), which was further purified to 91% purity (q-NMR) by vacuum distillation. The 2-methyl-6-oxoheptanoic acid thus obtained (II-0) The identity of is confirmed by the identification of the following analytical characteristics:

[0277] Characterization of 2-methyl-6-oxoheptanoic acid:

[0278] 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).

[0279] 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 ).

[0280] HRMS (ESI) (C8H 13 O3 + ): 157.0871; Calculated value: 157.0870.

[0281] Synthesis of 6-hydroxy-2,6-dimethyloct-7-inosan(III-0)

[0282] Before contact with ethyne, all equipment was vacuumed and filled with nitrogen (4 times). In a 1 L autoclave at 15°C, ammonia (150 g, 8.81 mol) was added to a mixture of KOH (40 g) and 2-methyl-6-oxoheptanoic acid (II-O) (20 g, 120 mmol) in water (299 mmol, 42%). The reaction was carried out for 1 hour by adding ethyne (9.4 bar (0.94 MPa), 1200 rpm). The solvent (ammonia) was evaporated. The autoclave was opened, and the residue was removed by suction with water and ethyl acetate. The reaction mixture was acidified to pH 5 with aqueous HCl (25%) at 0°C. After phase separation, the organic layer was washed with water (3 x 100 mL). The combined aqueous phase was extracted with ethyl acetate (2 x 100 mL). The combined ethyl acetate phase was dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was isolated as a viscous brown oil (22.2 g, 93.1% purity (GC-ESTD, corrected), yield 94%). The 6-hydroxy-2,6-dimethyloct-7-inosan thus obtained (III-0) The identity of was verified by identifying the following analytical characteristics:

[0283] Characterization of 6-hydroxy-2,6-dimethyloct-7-inosane:

[0284] 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).

[0285] 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 (Cquat ), 182.7 (C quat ).

[0286] HRMS (ESI) (C 10 H 17 O3 + ): 185.1175; Calculated value: 185.1172.

[0287] Synthesis of 6-hydroxy-2,6-dimethyloct-7-enosan(I-O)

[0288] In a 150 mL steel autoclave, 6-hydroxy-2,6-dimethyloct-7-inosan (III-0) (30.3 g) was dissolved in ethyl acetate (60 g). Lindla catalyst (5% Pd / CaCO3 with 3.5% Pb, 1.0 g) and 3,6-dithi-1,8-octanediol (200 mg) were added. The autoclave was purged three times with nitrogen (pressurized to 5 barg and discharged) and three times with hydrogen (pressurized to 5 barg and discharged). The reaction mixture was heated to 25°C, pressurized with 5 bar (0.5 MPa) H2, and stirred for about 10 hours. After cooling, the reaction mixture was filtered, and the solvent was removed under reduced pressure to obtain the crude product 6-hydroxy-2,6-dimethyloct-7-enoic acid (30.4 g) (I-0) [It] was obtained, purified by distillation, and its characteristics were determined as follows.

[0289] Characterization of 6-hydroxy-2,6-dimethyloct-7-enosane:

[0290] 1 H NMR (300 MHz, CDCl3) δ [ppm] = 1.16 (d, J =7.0, 3H), 1.27 (s, 3H), 1.31-1.57 (m, 5H), 1.57-1.77 (m, 1H), 2.38-2.51 (m, 1H), 5.04 (dd, J =10.8, 1.2, 1H), 5.19 (dd, J=17.4, 1.2, 1H), 5.89 (dd, J =17.3, 10.7, 1H), 6.40 (s, 1H)

[0291] 13 C NMR (75 MHz, CDCl3) δ [ppm] = 17.0 (CH3), 21.6 (CH2), 27.8 (CH3), 33.9 (CH2), 39.4 (CH), 42.1 (CH2), 73.5 (C quat ), 112.0 (CH2), 145.0 (CH), 182.7 (C quat ).

[0292] FT-IR (cm -1 ) = 735, 918, 995, 1150, 1208, 1281, 1413, 1464, 1703, 2940, 2973.

[0293] HRMS (ESI) (C 10 H 17 O3 - ): 185.1185; Calculated value: 185.1183.

[0294] Synthesis of 2,6-dimethyl-10-oxoundec-6-enosan(II-A)

[0295] 6-hydroxy-2,6-dimethyloct-7-enoic acid (I-0) 2-methoxyprop-1-ene (6.86 g, 92.1 w%, 33.9 mmol) and 2-methoxyprop-1-ene (9.98 g, 13 mL, 98 w%, 136 mmol) were added to a 60 mL stainless steel reactor. The reactor was closed, and the solution was heated at 90°C for 13 hours. After cooling to room temperature, the solution was transferred to a round-bottom flask and concentrated under reduced pressure to obtain 2,6-dimethyl-10-oxoundec-6-enosan as an orange oil. (II-A) The desired product of E / Z A mixture was obtained (7.75 g, 64% combined yield of isomers by GC using an internal standard). The crude product was purified by column chromatography on silica gel.

[0296] Characterization of 2,6-dimethyl-10-oxoundec-6-enosane (mixture of (E)- and (Z)-isomers):

[0297] 1 H NMR (300 MHz, CDCl3) δ [ppm] = 1.12-1.22 (m, 3H), 1.29-1.53 ​​(m, 3H), 1.53-1.73 (m, 4H), 1.90-2.08 (m, 2H), 2.13 (s, 3H), 2.17-2.32 (m, 2H), 2.36-2.55 (m, 3H), 5.12-4.99 (m, 1H).

[0298] 13 C NMR (75 MHz, CDCl3) δ [ppm] = 15.9 (CH3), 16.97 / 16.99 (CH3), 22.4 / 22.5 (CH2), 23.4 / 30.1 (CH3), 25.4 / 25.5 (CH2), 31.6 / 39.4 (CH2), 33.1 / 33.4 (CH2), 39.3 / 39.4 (CH), 43.9 / 44.0 (CH2), 123.0 / 123.7 (CH), 136.1 / 136.3 (C) quat ), 182.9 / 183.0 (C quat ), 209.09 / 209.15 (C quat ).

[0299] HRMS (ESI) (C 21 H 40 O3Si2 - ): 225.1501; Calculated value: 225.1496.

[0300] Synthesis of 10-hydroxy-2,6,10-trimethyldodeque-6-en-11-inosan(III-A)

[0301] Subsequently, all equipment in contact with etyne was evacuated and filled with nitrogen (4 times). In a 1 L autoclave, ammonia (150 g, 8.81 mol) at 15°C in KOH (29.3 g) and 2,6-dimethyl-10-oxoundec-6-enic acid in water (219 mmol, 42%) (II-A)It was added to a mixture of (18.8 g, 56.6 mmol). The reaction was carried out for 1 hour with the addition of ethyne (9.4 bara (0.94 MPa absolute pressure, including atmospheric pressure), 1200 rpm). For post-treatment, the solvent (ammonia) was evaporated. The autoclave was opened, and the residue was extracted with water and toluene. The reaction mixture was acidified to pH 1 with aqueous H2SO4 (30%) at 0°C. After phase separation, the organic layer was washed with water (3 x 100 mL). The combined aqueous phase was extracted with toluene (2 x 100 mL). The combined toluene phase was dried (Na2SO4), filtered, and concentrated under reduced pressure.

[0302] Crude product 10-hydroxy-2,6,10-trimethyldodec-6-en-11-inosan (III-A) It was isolated as a viscous brown oil (21.1 g, 59.6% purity (GC-ESTD), 87%).

[0303] Characterization of 10-hydroxy-2,6,10-trimethyldodec-6-en-11-inosane:

[0304] 1 H NMR (300 MHz, CDCl3) δ [ppm] = 1.16-1.19 (m, 3H), 1.33-1.75 (m, 13H), 1.96-2.00 (m, 1H), 2.01-2.13 (m, 1H), 2.14-2.33 (m, 2H), 2.42-2.52 (m, 2H), 5.17 (ddq, J =7.9, 6.8, 1.3, 1H).

[0305] 13 C NMR (75 MHz, CDCl3) δ [ppm] = 16.0 / 23.5 (CH3), 17.00 / 17.01 (CH3), 23.4 / 23.6 (CH2), 25.4 / 25.5 (CH2), 29.9 (CH3), 31.6 / 39.5, 33.2 / 33.4 (CH2), 39.3 (CH), 43.3 / 43.6 (CH2), 68.38 / 68.43 (C quat ), 71.67 / 71.69 (CH sp), 87.5 / 87.6 (C quat ), 124.0 / 124.7 (CH), 135.9 / 136.1 (C quat ), 182.9 / 183.0 (C quat ).

[0306] HRMS (EI, after silylation) (C 21 H 40 O3Si2 + ): 396.2523; Calculated value: 396.2516.

[0307] Synthesis of 10-hydroxy-2,6,10-trimethyldodeque-6,11-dienoic acid (IA)

[0308] 10-hydroxy-2,6,10-trimethyldodec-6-en-11-inosan (III-A)

[0309] In a 150 mL steel autoclave, 10-hydroxy-2,6,10-trimethyldodec-5-en-11-inosan (III-A) (5.93 g) was dissolved in ethyl acetate (85 mL). Lindla catalyst (5% Pd / CaCO3 containing 3.5% Pb, 700 mg) and 3,6-dithi-1,8-octanediol (130 mg) were added. The autoclave was purged three times with nitrogen (pressurized to 5 barg and discharged) and three times with hydrogen (pressurized to 5 barg and discharged). The reaction mixture was heated to 25°C, pressurized to 5 bar (0.5 MPa) H2, and stirred for 2 hours. After cooling, the reaction mixture was filtered and the solvent removed under reduced pressure to obtain the crude product 10-hydroxy-2,6,10-trimethyldodec-6,11-dienoic acid. (IA) (5.70 g) was obtained.

[0310] Characterization of 10-hydroxy-2,6,10-trimethyldodeque-6,11-dienoic acid (mixture of (E)- and (Z)-isomers):

[0311] 1 H NMR (300 MHz, CDCl3) δ [ppm] = 1.14-1.22 (m, 3H), 1.25-1.31 (m, 3H), 1.32-1.73 (m, 10H), 1.91-2.11 (m, 4H), 2.38-2.54 (m, 1H), 5.06 (dd, J=10.7, 1.3, 1H), 5.13 (tq, J =7.2, 1.3, 1H), 5.21 (dd, J =17.3, 1.3, 1H), 5.84-5.97 (m, 1H).

[0312] 13 C NMR (75 MHz, CDCl3) δ [ppm] = 16.0 / 23.5 (CH3), 17.0 / 17.1 (CH3), 22.6 / 22.8 (CH2), 25.4 / 31.6 (CH2), 28.0 (CH3), 33.2 / 33.5 (CH2), 39.3 (CH), 39.5 (CH2), 42.2 / 42.5 (CH2), 111.9 (CH2), 124.7 / 125.3 (CH), 135.3 (C quat ), 145.1 (CH), 142.5 (C quat ).

[0313] FT-IR: [cm -1 ] = 690, 637, 842, 919, 995, 1162, 1206, 1290, 1376, 1413, 1458, 1705, 2932, 2971.

[0314] HRMS (EI) after silylation (C 21 H 42 O3Si2 + ): 398.2659; Calculated value: 398.2673.

[0315] Synthesis of 2,6,10-trimethyl-14-oxopentadecá-6,10-dienosan(IV-A)

[0316] 10-hydroxy-2,6,10-trimethyldodeque-6,11-dienoic acid (IA)(3.25 g, 82 wt%, 10.5 mmol) and 2-methoxyprop-1-ene (6 g, 8 mL, 98 wt%, 80 mmol) were added to a 100 mL stainless steel reactor. The reactor was closed, and the solution was heated at 100°C for 12 hours. After cooling to room temperature, the solution was transferred to a round-bottom flask and concentrated under reduced pressure to obtain the desired product mixture as an orange oil (3.58 g, 58% combined yield of isomers by GC using an internal standard). The crude product was 2,6,10-trimethyl-14-oxopentadeca-6,10-dienoic acid. (IV-A) It was purified by column chromatography on silica gel.

[0317] Characterization of 2,6,10-trimethyl-14-oxopentadecá-6,10-dienosic acid:

[0318] 1 H NMR (600 MHz, CDCl3) δ [ppm] = 1.18 (ddd, J =7.0, 3.8, 1.6, 3 H), 1.35-1.47 (m, 3 H), 1.56-1.69 (m, 7 H), 1.94-2.10 (m, 6 H), 2.12-2.17 (m, 3 H), 2.21-2.30 (m, 2 H), 2.41-2.52 (m, 3 H), 5.04-5.15 (m, 2 H).

[0319] 13C NMR (151 MHz, CDCl3) δ [ppm] = 136.5, 136.4, 136.3, 136.3, 135.1, 134.9, 134.8, 134.6, 125.1, 125.1, 124.4, 124.3, 123.3, 123.3, 122.6, 122.5, 77.2, 77.0, 76.8, 44.0, 43.8, 43.8, 39.9, 39.6, 39.4, 39.4, 39.3, 39.3, 39.3, 39.2, 39.2, 33.4, 33.3, 33.1, 33.1, 32.1, 31.8, 31.5, 31.5, 30.0, 30.0, 29.9, 26.4, 26.4, 26.3, 25.6, 25.4, 25.4, 25.3, 23.4, 23.4, 23.4, 23.3, 22.5, 22.5, 22.3, 22.2, 16.9, 16.9, 16.9, 16.0, 16.0, 15.8, 15.8.

[0320] Synthesis of 2,6,10-trimethyl-14-oxopentadecanoic acid (VI-A)

[0321] In a steel autoclave, 2,6,10-trimethyl-14-oxopentadeca-6,10-dienoic acid(IV-A) (100 mg, 94.1% purity, 0.32 mmol) was dissolved in EtOAc (1.7 mL). 5 mg of Pd / C was added, and the mixture was purged three times with argon (pressurized to 5 barg and released) and three times with hydrogen (pressurized to 5 barg and released). The reaction mixture was heated to 40°C, pressurized with 5 bar (0.5 MPa) H2, and stirred for 3 hours. After cooling to room temperature, the solution was filtered through a 0.45 μm membrane filter and the solvent was evaporated to obtain the desired product, 2,6,10-trimethyl-14-oxopentadecanoic acid (VI-A), 95 mg (78.6% purity by q-NMR, 0.25 mmol, 78%).

[0322] The product was characterized as follows:

[0323] Characterization of 2,6,10-trimethyl-14-oxopentadecanoic acid:

[0324] 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).

[0325] 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 ).

[0326] HRMS (EI) after silylation (C 21 H 42 O3Si + ): 370.2897; Calculated value: 370.2903.

[0327] Synthesis of 14-hydroxy-2,6,10,14-tetramethylhexadec-15-inosan(III-B)

[0328] Before contact with etyne, all equipment was vacuumed and filled with nitrogen (4 times). In a 1 L autoclave, 150 g ammonia (8807 mmol) at 15°C was mixed with 18.07 g 42% KOH and 10.81 g 2,6,10-trimethyl-14-oxopentadecanoic acid in water (135 mmol). (VI-A) It was added to a mixture of (33.21 mmol). The reaction was carried out over 1 hour by adding ethyne (9.4 bar (0.94 MPa), 1200 rpm). The solvent (ammonia) was evaporated. The autoclave was opened, and the residue was extracted with water and MTBE. The reaction mixture was acidified to pH 1 with HCl (25%) at 0°C.

[0329] After phase separation, the organic layer was washed three times with 100 mL of water. The combined aqueous phase was extracted twice with 100 mL of MTBE. The combined organic phase was dried (Na2SO4), filtered, and concentrated under reduced pressure to obtain 14-hydroxy-2,6,10,14-tetramethylhexadec-15-inosane (III-B) (80% yield) is obtained. Purification by column chromatography on silica gel yields the product with 97% purity.

[0330] Characterization of 14-hydroxy-2,6,10,14-tetramethylhexadec-15-inosane:

[0331] 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).

[0332] 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 ).

[0333] HRMS (ESI) (C 20 H 37 O3 + ): 325.2736, Calculated: 325.2737.

[0334] Synthesis of 14-hydroxy-2,6,10,14-tetramethylhexadec-15-enic acid(VI)

[0335] In a 50 mL glass insert for autoclave, 14-hydroxy-2,6,10,14-tetramethylhexadec-15-inosan (III-B) (5.0 g) was dissolved in toluene (30 mL). Lindlar catalyst (5% Pd / CaCO3 with 3.5% Pb, 1.5 g) and 3,6-dithi-1,8-octanediol (50 mg) were added. The insert was placed inside an autoclave, and the mixture was purged three times with nitrogen (pressurized to 5 barg and released) and three times with hydrogen (pressurized to 5 barg and released). The mixture was heated to 80°C, pressurized with 10 bar (1 MPa) H2, and stirred for 3 hours. After cooling to room temperature, it was filtered through a 0.45 μm membrane filter, rinsed with toluene, and the solvent was removed under reduced pressure. The crude product was 14-hydroxy-2,6,10,14-tetramethylhexadec-15-enosan (IB) The product was purified by performing column chromatography twice on silica gel to obtain 1.17 g of pale yellow oil (87% purity by q-NMR, 3.12 mmol). A portion of the product was further purified by prep-HPLC to obtain a colorless oil (>99% purity by q-NMR).

[0336] Characterization of 14-hydroxy-2,6,10,14-tetramethylhexadec-15-enosane:

[0337] 1 H NMR (300 MHz, CDCl3) δ [ppm] = 0.84 (d, J =6.4, 6 H), 0.98-1.56 (m, 25 H), 1.57-1.75 (m, 1 H), 2.37-2.55 (m, 1 H), 5.04 (dd, J =10.8, 1.3, 1 H), 5.20 (dd, J =17.3, 1.3, 1 H), 5.92 (dd, J =17.4, 10.8, 1 H).

[0338] 13C 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 ).

[0339] HRMS (EI, after silylation) (C 26 H 54 O3Si + ): 470.3631; Calculated value: 470.3612.

[0340] Synthesis of 13-(6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)-2,6,10-trimethyltridecanoic acid (VII-A)

[0341] 13-(6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)-2,6,10-trimethyltridecanoic acid (VII) is [Weichet J., Bl It was synthesized from 14-hydroxy-2,6,10,14-tetramethylhexadec-15-enoic acid (IB) and 2,3,6-trimethylhydroquinone (VIII-A) according to the procedure disclosed on page 2439 of ha L. et al., Collect. Czech. Chem. Commun. 1966, Vol. 31, 2434 - 2443.

[0342] Characterization of 13-(6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)-2,6,10-trimethyltridecanoic acid:

[0343] 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).

[0344] 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 ).

[0345] HRMS (ESI) (C 29 H 48 O4 + ): 460.3527; Calculation: 460.3547.

Claims

Claim 1 A method for preparing an allylic alcohol of formula (I) by: a) ethynylating an unsaturated ketone of formula (II) to obtain a propargyl alcohol of formula (III); and subsequently b) hydrogenating the propargyl alcohol of formula (III) formed in step a) using molecular hydrogen, a hydrogen donor or a transfer hydrogenation agent, preferably molecular hydrogen, and a Lindlar catalyst to obtain a compound of formula (I); In the above formula, n represents a value from 0 to 3 and m represents a value from 1 to 3, wherein the sum of n and m is 1 to 3; s1 and s2 The substructures within the chemical formulas (I), (II), or (III) represented by may be in any order; any wavy line for the C=C double bond Z - or E - Represents carbon-carbon bonds in the arrangement independently of each other. Claim 2 A method according to claim 1, wherein step a) is performed in the absence of any organic solvent. Claim 3 A method according to paragraph 1 or 2, wherein m=1 and n=1. Claim 4 Allyl alcohol of the following chemical formula (IA): In the above equation, any wavy lines are independent of each other for the C=C double bond Z - or E - Represents a carbon-carbon bond arrangement. Claim 5 Propargyl alcohol of the following chemical formula (III-A): In the above equation, any wavy lines are independent of each other for the C=C double bond Z - or E - Represents a carbon-carbon bond arrangement. Claim 6 c) an allyl alcohol of the following formula (I') with a compound of the following formula (Va) or (Vb), and a pq of less than 4, particularly less than 2, preferably less than 1, when measured in water at room temperature. a A method for preparing an unsaturated ketone of the following formula (IV'), comprising the step of reacting in the absence of any strong acid having, or an ammonium catalyst: In the above formula, n represents a value from 0 to 3, m' represents 0 or m, and m represents a value from 1 to 3, wherein the sum of n and m' is 1 to 3; s1 and s2 The substructures within the chemical formula (I') or (IV') represented by can be of any order; R 3 represents a methyl or ethyl group;R 4 represents H, or a methyl or ethyl group;R 5 is linear or branched C 1-10 - Represents an alkyl group, particularly a methyl or ethyl group; R 5' and R 5" is linear or branched C 1-10 - Represents an alkyl group, particularly a methyl or ethyl group; or R 5' and R 5" is together linear or branched C 1-10 - Forming alkylene groups, particularly ethylene or propylene groups; any wavy lines independently of each other for the C=C double bond Z - or E - Represents a carbon-carbon bond arrangement. Claim 7 In Paragraph 6, R 3 Method representing this methyl group. Claim 8 In Article 6 or 7, R 4 A method representing H. Claim 9 A method in any one of paragraphs 6 through 8, wherein m'=m. Claim 10 A method according to claim 6, wherein the compound of formula (I') is a compound of formula (I) prepared by a method of preparing an allyl alcohol of formula (I) according to any one of claims 1 to 3. Claim 11 In paragraph 6, the method wherein the compound of formula (I') is an allyl alcohol of formula (IA) according to paragraph 4. Claim 12 Unsaturated ketone of the following chemical formula (IV-A): In the above equation, any wavy lines are independent of each other for the C=C double bond Z - or E - Represents a carbon-carbon bond arrangement. Claim 13 A method for producing a saturated ketone of the following formula (VI') by hydrogenating a compound of an unsaturated ketone of the following formula (IV') in the presence of molecular hydrogen, a hydrogen donor or a transfer hydrogenating agent, preferably molecular hydrogen, and a transition metal catalyst, wherein the transition metal is a transition metal of group 7, 8, 9, or 10, and is particularly selected from the group consisting of Pd, Pt, Rh, Ru, Mn, Fe, Co, Ir, and Ni, preferably Pd or Ni, more preferably Pd, wherein the compound of the following formula (IV') is produced by the method for producing a ketone of the following formula (IV') according to any one of claims 6 to 8:: In the above formula, n represents a value from 0 to 3, m' represents 0 or m, and m represents a value from 1 to 3, wherein the sum of n and m' is 1 to 3; s1 and s2 The substructures within the chemical formula (IV') or (VI') represented by may be in any order; any wavy lines are independent of each other for the C=C double bond Z - or E - Represents a carbon-carbon bond arrangement. Claim 14 In paragraph 13, a method in which a compound of chemical formula (I') is prepared according to any one of paragraphs 1 to 3. Claim 15 In Paragraph 13, R 3 This represents a methyl group, and R 4 Method in which α represents an H group, and the saturated ketone of formula (VI') is the saturated ketone of formula (VI-A) below: Claim 16 a) a step of ethynylating a saturated ketone of formula (VI-A) to obtain a propargyl alcohol of formula (III-B); and subsequently b) a step of hydrogenating the propargyl alcohol of formula (III-B) formed in step a) using molecular hydrogen, a hydrogen donor or transfer hydrogenating agent, preferably molecular hydrogen, and a Lindla catalyst to obtain an allyl alcohol of formula (IB), wherein the saturated ketone of formula (VI-A) is prepared according to the method of claim 15: . Claim 17 i) a step of preparing an allyl alcohol of the following formula (IB) according to the method of preparing an allyl alcohol of formula (IB) according to claim 16; and ii) a step of reacting a compound of formula (IB) with a compound of the following formula (VIII) to obtain a compound of the following formula (VII), comprising a method of preparing a compound of formula (VII): In the above formula, R 20 It is hydrogen, or the phenol protecting group R. ' Represents;R 10 and R 11 and R 12 represents a hydrogen or methyl group independently of each other; R 21 It is hydrogen, or the phenol protecting group R. ' It represents.

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