Isomerization process

Abstract

The present invention relates to the field of organic synthesis. More specifically, a process for preparing a mixture comprising at least one compound of formula (la) and at least one compound of formula (lb) is provided, which process comprises the step of reacting a compound of formula (II) with a catalyst system comprising palladium (Pd) and molecular hydrogen or a source of hydrogen.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis. More specifically, it provides a method for preparing a mixture comprising at least one compound of formula (Ia) and at least one compound of formula (Ib), the method comprising reacting the compound of formula (II) with a catalyst system comprising palladium (Pd) and molecular hydrogen or a hydrogen source. Background Technology

[0002] Compounds of formula (Ia) or (Ib) as defined below can be used as flavoring ingredients or as starting materials for constructing compounds with more complex skeletons.

[0003] The methods for preparing the compounds reported in the prior art are typically very time-consuming and costly. Furthermore, each of these methods yields only one of the compounds. Therefore, those skilled in the art must perform two separate steps to obtain the compounds, which is clearly time-consuming.

[0004] Therefore, there is an urgent need for a simple and efficient isomerization method to prepare such compounds, using readily available starting materials and simultaneously yielding compounds (Ia) and (Ib). EP1697290 reports the preparation of a mixture containing at least one compound of formula (Ia) and at least one compound of formula (Ib) via an isomerization reaction using ruthenium complexes. EP1162190 discloses other catalysts, such as bases, acids, or rhodium complexes. Due to the significant industrial applications of these products, there is a continuous need to develop new methods with improved yields and conversion rates while limiting waste.

[0005] Therefore, there is a need to develop a method to prepare a mixture comprising at least one compound of formula (Ia) and at least one compound of formula (Ib) by using a less expensive and recyclable catalyst, while limiting the generation of byproducts.

[0006] The present invention is a method for obtaining a mixture containing at least one compound of formula (Ia) and at least one compound of formula (Ib) with high selectivity by double bond isomerization, starting from a compound of formula (II) in the presence of a catalyst system containing palladium (Pd) and molecular hydrogen or a hydrogen source. Summary of the Invention

[0007] Unless otherwise stated, all percentages refer to weight percentages based on the total weight of the composition referenced.

[0008] We have now discovered that, through the described catalytic isomerization, it is advantageous to produce mixtures comprising at least one compound of formula (Ia) and at least one compound of formula (Ib), and that productivity is improved while environmental impact is mitigated through better conversion, fewer byproducts and recyclability of the catalyst.

[0009] Therefore, the first object of the present invention is a method for preparing a mixture comprising at least one compound of formula (Ia) and at least one compound of formula (Ib).

[0010]

[0011] These compounds are in the form of any of their stereoisomers or mixtures thereof; wherein

[0012] Each R 1 R 3 and R 4 Simultaneously or independently representing a hydrogen atom or a C atom 1-6 Alkyl, and R 2 Represents hydrogen atom, C 1-6 Alkyl, C 1-6 Alkoxy or C 2-6 alkenyl;

[0013] The method includes the step of reacting a compound of formula (II) with a catalyst system.

[0014]

[0015] The compound is in the form of any of its stereoisomers or mixtures thereof; wherein

[0016] One dashed line represents a carbon-carbon double bond, and the remaining dashed lines represent carbon-carbon single bonds, and R 1 R 2 R 3 and R 4 It has the same meaning as the definition above;

[0017] The catalyst system comprises:

[0018] i) Palladium (Pd); and

[0019] ii) Molecular hydrogen or hydrogen source.

[0020] For clarity, the phrase "any of its stereoisomers or mixtures thereof" or similar expressions refer to the normal meaning understood by those skilled in the art, namely, that compounds of formula (Ia), (Ib), or (II) can be pure enantiomers or diastereomers. In other words, compounds of formula (Ia), (Ib), or (II) can have multiple stereocenters, and each stereocenter can have two different stereochemical configurations (e.g., R or S). Compounds of formula (Ia), (Ib), or (II) can be in the form of pure enantiomers or mixtures of multiple enantiomers or multiple diastereomers. Compounds of formula (Ia), (Ib), or (II) can also be in racemic or scalemic (proportional optical rotation) forms. Therefore, a compound of formula (Ia), formula (Ib) or formula (II) may be a single stereoisomer or a composition of substances containing or composed of various stereoisomers.

[0021] For clarity, the use of phrases such as "one dashed line represents a carbon-carbon double bond, and the remaining dashed lines represent carbon-carbon single bonds" or similar expressions refers to the normal meaning understood by those skilled in the art, that is, the entire bond (solid and dashed lines) between carbon atoms connected by the dashed lines is a carbon-carbon single or double bond.

[0022] For clarity, it should be understood that the term "hydrogen source" refers to a hydrogen source in the conventional sense of the art, namely a compound that can produce molecular hydrogen (i.e., H2), hydrogen atoms, or equivalents in a reaction medium.

[0023] The terms “alkyl,” “alkoxy,” and “alkenyl” should be understood to include both branched and straight-chain alkyl, alkoxy, and alkenyl groups. The term “alkenyl” should be understood to contain an olefinic double bond.

[0024] According to a specific embodiment of the present invention, compound (II) is compound (II').

[0025]

[0026] The compound is in the form of any of its stereoisomers or mixtures thereof; wherein

[0027] Each R 1 R 3 and R 4 Simultaneously or independently representing a hydrogen atom or a C atom 1-6 Alkyl, and R 2 Represents hydrogen atom, C 1-6 Alkyl, C 1-6 Alkoxy or C 2-6 Alkenyl group.

[0028] According to another specific embodiment of the invention, compound (II) is compound (II'').

[0029]

[0030] The compound is in the form of any of its stereoisomers or mixtures thereof; wherein

[0031] Each R 1 R 3 and R 4 Simultaneously or independently representing a hydrogen atom or a C atom 1-6 Alkyl, and R 2 Represents hydrogen atom, C 1-6 Alkyl, C 1-6 Alkoxy or C 2-6 Alkenyl group.

[0032] According to another specific embodiment of the invention, compound (II) is compound (II''').

[0033]

[0034] The compound is in the form of any of its stereoisomers or mixtures thereof; wherein

[0035] Each R 1 R 3 and R 4 Simultaneously or independently representing a hydrogen atom or a C atom 1-6 Alkyl, and R 2 Represents hydrogen atom, C 1-6 Alkyl, C 1-6 Alkoxy or C 2-6 Alkenyl group.

[0036] According to another specific embodiment of the invention, compound (II) is compound (II'''').

[0037]

[0038] The compound is in the form of any of its stereoisomers or mixtures thereof; wherein

[0039] Each R 1 R 3 and R 4 Simultaneously or independently representing a hydrogen atom or a C atom 1-6 Alkyl, and R 2 Represents hydrogen atom, C 1-6 Alkyl, C 1-6 Alkoxy or C 2-6 Alkenyl group.

[0040] According to another specific embodiment of the invention, the compound of formula (II) is a mixture of compound (II'), compound (II''), compound (II'''), and compound (II''''). Specifically, based on the total weight of the mixture, the mixture contains at least 50% by weight of compound (II').

[0041] According to any embodiment of the invention, the mixture may contain at least 40% by weight of compound (Ia) (based on the total weight of the mixture). Preferably, the mixture may contain at least 50% by weight of compound (Ia) (based on the total weight of the mixture). Preferably, the mixture may contain at least 60% by weight of compound (Ia) (based on the total weight of the mixture). Preferably, the mixture may contain at least 70% by weight of compound (Ia) (based on the total weight of the mixture). Even more preferably, the mixture may contain at least 80% by weight of compound (Ia) (based on the total weight of the mixture).

[0042] According to any embodiment of the invention, the mixture may contain up to 35% by weight of compound (Ib) (based on the total weight of the mixture). Preferably, the mixture may contain up to 20% by weight of compound (Ib) (based on the total weight of the mixture). Preferably, the mixture may contain up to 15% by weight of compound (Ia) (based on the total weight of the mixture). More preferably, the mixture may contain up to 10% by weight of compound (Ia) (based on the total weight of the mixture). The mixture may contain from 1% by weight to 35% by weight of compound (Ib) (based on the total weight of the mixture).

[0043] According to any embodiment of the invention, the weight ratio of compound (Ia) to compound (Ib) in the mixture is in the range of 1:0 to 1:0.5, preferably in the range of 1:0.01 to 1:0.5.

[0044] According to any embodiment of the invention, R 4 It can be a hydrogen atom or a carbon atom. 1-4 Alkyl group; preferably, it is a hydrogen atom or a C atom. 1-3 Alkyl group; preferably, it is a hydrogen atom or a C atom. 1-2 Alkyl group; preferably, it is a hydrogen atom or a methyl group; even more preferably, it is a hydrogen atom.

[0045] According to any embodiment of the present invention, compound (Ia) is compound (Ia').

[0046]

[0047] The compound is in the form of any of its stereoisomers or mixtures thereof, wherein R 1 R 2 and R 3 It has the same meaning as the definition above.

[0048] According to any embodiment of the invention, the compound of formula (Ib) conforms to formula (Ib');

[0049]

[0050] The compound is in the form of any of its stereoisomers or mixtures thereof, wherein R 1 R 2 and R 3 It has the same meaning as the definition above.

[0051] According to any embodiment of the invention, compound (II) conforms to formula (III).

[0052]

[0053] The compound is in the form of any of its stereoisomers or mixtures thereof, wherein R 1 R 2 and R 3 It has the same meaning as the definition above.

[0054] According to another specific embodiment of the invention, the compound of formula (III) conforms to formula (III').

[0055]

[0056] The compound is in the form of any of its stereoisomers or mixtures thereof, wherein R 1 R 2 and R 3 It has the same meaning as the definition above.

[0057] According to another specific embodiment of the invention, the compound of formula (III) conforms to formula (III'').

[0058]

[0059] The compound is in the form of any of its stereoisomers or mixtures thereof, wherein R 1 R 2 and R 3 It has the same meaning as the definition above.

[0060] According to another specific embodiment of the present invention, the compound of formula (III) is of formula (III''').

[0061]

[0062] The compound is in the form of any of its stereoisomers or mixtures thereof, wherein R 1 R 2 and R 3 It has the same meaning as the definition above.

[0063] According to another specific embodiment of the invention, the compound of formula (III) conforms to formula (III'''').

[0064]

[0065] The compound is in the form of any of its stereoisomers or mixtures thereof, wherein R 1 R 2 and R 3 It has the same meaning as the definition above.

[0066] According to any embodiment of the invention, R 3 It can be a hydrogen atom or a carbon atom. 1-4 Alkyl group; preferably, it is a hydrogen atom or a C atom. 1-3 Alkyl group; preferably, it is a hydrogen atom or a C atom. 1-2 Alkyl group; preferably, it is a hydrogen atom or a methyl group; even more preferably, it is a hydrogen atom.

[0067] According to any embodiment of the invention, each R 1 It can be a hydrogen atom or a carbon atom simultaneously or independently. 1-4 Alkyl group; preferably, a hydrogen atom or a C atom. 1-3 Alkyl group; preferably, a hydrogen atom or a C atom. 1-2 Alkyl group; preferably, a hydrogen atom or a methyl group; even more preferably, a methyl group.

[0068] According to any embodiment of the invention, at least one R 1 It is not a hydrogen atom.

[0069] According to any embodiment of the invention, the compound of formula (Ia) or the compound of formula (Ia') is a compound of formula (Ia'').

[0070]

[0071] The compound is in the form of any of its stereoisomers or mixtures thereof, wherein R 2 It has the same meaning as the definition above.

[0072] According to any embodiment of the invention, the compound of formula (Ib) or the compound of formula (Ib') conforms to formula (Ib'');

[0073]

[0074] The compound is in the form of any of its stereoisomers or mixtures thereof, wherein R 2 It has the same meaning as the definition above.

[0075] According to any embodiment of the invention, the compound of formula (II) or the compound of formula (III) conforms to formula (IV);

[0076]

[0077] The compound is in the form of any of its stereoisomers or mixtures thereof, wherein the dashed line, R 2 It has the same meaning as the definition above.

[0078] According to a specific embodiment of the present invention, the compound of formula (IV) conforms to formula (IV').

[0079]

[0080] The compound is in the form of any of its stereoisomers or mixtures thereof, wherein R 2 It has the same meaning as the definition above.

[0081] According to another specific embodiment of the invention, the compound of formula (IV) conforms to formula (IV'').

[0082]

[0083] The compound is in the form of any of its stereoisomers or mixtures thereof, wherein R 2 It has the same meaning as the definition above.

[0084] According to another specific embodiment of the invention, the compound of formula (IV) conforms to formula (IV''').

[0085]

[0086] The compound is in the form of any of its stereoisomers or mixtures thereof, wherein R 2 It has the same meaning as the definition above.

[0087] According to another specific embodiment of the invention, the compound of formula (IV) conforms to formula (IV'''').

[0088]

[0089] The compound is in the form of any of its stereoisomers or mixtures thereof, wherein R 2It has the same meaning as the definition above.

[0090] According to any embodiment of the invention, R 2 It can be a hydrogen atom, C 1-4 Alkyl, C 1-4 Alkoxy or C 2-4 Alkenyl group; preferably, it is a hydrogen atom, C 1-3 Alkyl, C 1-3 Alkoxy or C 2-3 Alkenyl group; preferably, it is a hydrogen atom, C 1-2 Alkyl, C 1-2 Alkoxy or C 2-3 Alkenyl; or even more preferably, hydrogen atom, methyl or prop-1-en-1-yl.

[0091] Non-limiting examples of suitable compounds of formula (Ib) may include (2E)-1-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2-buten-1-one or 1-(2,6,6-trimethyl-1-cyclohexen-1-yl)-1-ethylone.

[0092] Non-limiting examples of suitable compounds of formula (Ia) may include (2E)-1-(2,6,6-trimethyl-2-cyclohexen-1-yl)-2-buten-1-one or 1-(2,6,6-trimethyl-2-cyclohexen-1-yl)-1-ethylone.

[0093] Non-limiting examples of suitable compounds of formula (II) may include trans-1-(2,6,6-trimethyl-3-cyclohexen-1-yl)-1-ethyl ketone, cis-1-(2,6,6-trimethyl-3-cyclohexen-1-yl)-1-ethyl ketone, or 1-(2,6,6-trimethyl-3-cyclohexen-1-yl)-2-buten-1-one.

[0094] According to any embodiment of the invention, the catalyst system comprises palladium (Pd), which may be in the form of a homogeneous complex or an elemental metal. In particular, the catalyst system comprises palladium (Pd) in the form of an elemental metal. Various forms of such metals suitable for carrying out chemical reactions are well known to those skilled in the art.

[0095] According to any of the above embodiments of the present invention, the palladium (Pd) is loaded on a carrier material.

[0096] For clarity, by carrier material, we mean a material that can deposit such metals and is inert to both the hydrogen source and the substrate.

[0097] According to any embodiment of the invention, specific and non-limiting examples of carrier materials are carbon, silicon dioxide, or aluminum oxide. These carriers are well known to those skilled in the art.

[0098] Supported palladium (Pd) is a known compound and is commercially available. Those skilled in the art can select the preferred metal type based on the type of metal, its deposition method on the support, the proportion of the metal on the support material, its morphology (powder, granules, pallets, extrudates, mice, etc.), and the surface area of ​​the support.

[0099] According to any of the above embodiments of the present invention, the amount of metal relative to the load can range from 0.05% to 25% w / w, or even from 1% to 6%, relative to the weight of the load used.

[0100] Palladium (Pd) in supported or unreacted form can be added to the reaction medium of the method of the present invention at a wide range of concentrations. As a non-limiting example, metal concentrations ranging from 0.01 mol% to 10 mol% relative to the total amount of substrate can be cited. Preferably, the metal concentration ranges from 0.02 mol% to 5 mol%, or even from 0.04 mol% to 2 mol%. It will be understood by those skilled in the art that the optimal metal concentration depends on the nature of the substrate, whether the method is batch or continuous, the reaction temperature and H2 pressure, and the required reaction time.

[0101] The supported palladium can be recycled after the method of the present invention is completed. In other words, the supported palladium can be recycled after the method of the present invention is completed and used multiple times in the method of the present invention.

[0102] The method according to the invention is carried out in the presence of molecular hydrogen or a hydrogen source.

[0103] According to any embodiment of the invention, the hydrogen source may be a transfer hydrogenating agent. Specific and non-limiting examples of catalytic transfer hydrogenating agents include tetrahydronaphthalene, formic acid, formate (e.g., sodium formate, potassium formate, or ammonium formate), limonene, or mixtures thereof. In particular, the transfer hydrogenating agent may be tetrahydronaphthalene, formic acid, formate, limonene, or mixtures thereof. Even more specifically, the transfer hydrogenating agent may be formic acid, formate, limonene, or mixtures thereof.

[0104] The transfer hydrogenating agent can be added to the reaction medium of the method of the present invention at a wide range of concentrations. For example, by way of non-limiting example, hydrogen source concentrations ranging from 0.01 mol% to 100 mol% relative to the substrate, or even from 0.01 mol% to 10 mol%, or even from 0.01 mol% to 5 mol%, can be listed. When only a small amount of transfer hydrogenating agent is used to generate molecular hydrogen, a large amount of transfer hydrogenating agent is required. For example, only about 10% of tetrahydronaphthalene is converted to molecular hydrogen. It goes without saying that those skilled in the art will understand that the optimal concentration of the hydrogen source depends on the nature of the hydrogen source, the nature of the substrate, the reaction temperature, the catalyst used, and the required reaction time.

[0105] According to any of the above embodiments of the invention, molecular hydrogen can be used in its pure state or mixed with an inert gas as an alternative to the transfer hydrogenating agent. Specific and non-limiting examples of such inert gases include nitrogen or argon. The volume ratio of H2 to inert gas is from 1 / 1 to 0.01 / 1, more preferably 0.05 / 1.

[0106] Molecular hydrogen can be added to the reaction medium of the method of the present invention at a wide range of concentrations. As a non-limiting example, molecular hydrogen concentrations ranging from 0.01 mol% to 100 mol% relative to the substrate can be cited. Preferably, the hydrogen source concentration is from 0.01 mol% to 10 mol% relative to the substrate. More preferably, the hydrogen source concentration is from 0.01 mol% to 8 mol% relative to the substrate. Even more preferably, the hydrogen source concentration is from 0.01 mol% to 5 mol% relative to the substrate. Of course, those skilled in the art can obtain the above concentration ranges by adjusting the pressure or flow rate of the molecular hydrogen (e.g., in a continuous process), depending on whether the method is batch or continuous. Those skilled in the art can also adjust the concentration of molecular hydrogen according to the amount of catalyst and the degree of dilution of the substrate in the solvent.

[0107] In the method of the present invention, the amount of hydrogen source or molecular hydrogen present relative to the amount of substrate is 0.01 mol% to 10 mol%, or even 0.01 mol% to 8 mol%, or even 0.01 mol% to 5 mol%.

[0108] The method of the present invention can be carried out under intermittent or continuous conditions. According to a specific embodiment of the invention, the method is a continuous method because it can achieve higher productivity.

[0109] This reaction can be carried out with or without a solvent. Any solvent commonly used in such reactions can be used in this invention when a solvent is required or used for practical reasons. Non-limiting examples include C. 6-12 Aromatic solvents, such as toluene, 1,3-diisopropylbenzene, p-cymene, cumene, pseudocumene, benzyl acetate, xylene, or mixtures thereof; C3-16 Alkanes, such as hexadecane; ether solvents, such as tetrahydrofuran, butyl ether, methyltetrahydrofuran, or mixtures thereof. The choice of solvent depends on the properties of the substrate and the catalyst, and those skilled in the art can select the most suitable solvent for the specific circumstances to optimize the reaction.

[0110] The temperature range for isomerization reactions is 50°C to 600°C. More preferably, the temperature range for continuous methods is 150°C to 250°C, and the temperature range for batch methods is 150°C to 200°C. Of course, those skilled in the art can also select the preferred reaction temperature based on the melting and boiling points of the starting and final products, as well as the desired reaction or conversion time.

[0111] According to any embodiment of the invention, the compound of formula (II) can be prepared by a variety of methods known in the art, such as the Diels-Alder reaction, cyclization reaction, or Friedel-Craft reaction. Those skilled in the art can select the optimal conditions to prepare the compound of formula (II).

[0112] According to any embodiment of the invention, compound (Ia) 1-(2,6,6-trimethyl-2-cyclohexen-1-yl)-1-ethyl ketone and compound (Ib) 1-(2,6,6-trimethyl-1-cyclohexen-1-yl)-1-ethyl ketone can be further converted into a mixture comprising 1-(2,6,6-trimethyl-2-cyclohexen-1-yl)-2-buten-1-one and 1-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2-buten-1-one. The preparation of mixtures comprising 1-(2,6,6-trimethyl-2-cyclohexen-1-yl)-1-ethyl ketone and 1-(2,6,6-trimethyl-1-cyclohexen-1-yl)-1-ethyl ketone from a mixture comprising at least 1-(2,6,6-trimethyl-2-cyclohexen-1-yl)-2-buten-1-one is well known in the art, for example, under aldol condensation reaction conditions. Alternatively, 1-(2,6,6-trimethyl-2-cyclohexen-1-yl)-1-ethylone and 1-(2,6,6-trimethyl-1-cyclohexen-1-yl)-1-ethylone can be separated and then converted to 1-(2,6,6-trimethyl-2-cyclohexen-1-yl)-2-buten-1-one and 1-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2-buten-1-one, respectively. Those skilled in the art can select optimal conditions to prepare 1-(2,6,6-trimethyl-2-cyclohexen-1-yl)-2-buten-1-one and 1-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2-buten-1-one, as well as mixtures thereof. Therefore, another object of the present invention is to provide a method for preparing 1-(2,6,6-trimethyl-2-cyclohexen-1-yl)-2-buten-1-one or mixtures thereof, comprising the following steps:

[0113] a) Isomerization of 1-(2,6,6-trimethyl-3-cyclohexen-1-yl)-1-ethylone by contacting a catalyst system comprising:

[0114] i) Palladium (Pd); and

[0115] ii) Molecular hydrogen or hydrogen source,

[0116] To obtain a mixture comprising 1-(2,6,6-trimethyl-2-cyclohexen-1-yl)-1-ethyl ketone and 1-(2,6,6-trimethyl-1-cyclohexen-1-yl)-1-ethyl ketone;

[0117] b) Optionally, 1-(2,6,6-trimethyl-2-cyclohexen-1-yl)-1-ethyl ketone is separated from 1-(2,6,6-trimethyl-1-cyclohexen-1-yl)-1-ethyl ketone;

[0118] c) Converting 1-(2,6,6-trimethyl-2-cyclohexen-1-yl)-1-ethylone, 1-(2,6,6-trimethyl-1-cyclohexen-1-yl)-1-ethylone, or mixtures thereof into 1-(2,6,6-trimethyl-2-cyclohexen-1-yl)-2-buten-1-one, 1-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2-buten-1-one, or mixtures thereof by aldol condensation with acetaldehyde.

[0119] The aldol condensation reaction can be carried out under normal conditions known to those skilled in the art, i.e., under alkaline or acidic conditions.

[0120] The separation can be carried out under normal conditions known to those skilled in the art, namely distillation conditions.

[0121] The following examples illustrate typical ways of implementing the method of the present invention. Detailed Implementation

[0122] Example

[0123] The invention will now be described in further detail through the following embodiments, wherein abbreviations have their usual meanings in the art, and temperature is expressed in degrees Celsius (°C). Using 400MHz ( 1 H) and 100MHz ( 13 Bruker Avance II Ultrashield 400 plus operating at C) or 500MHz ( 1 H) and 125MHz ( 13 Bruker Avance III 500 operating at C), or at 600MHz ( 1 H) and 150MHz ( 13 NMR spectra were obtained using a Bruker Avance III 600 cryoprobe operated under C) conditions. Spectra were used as an internal reference relative to 0.0 ppm tetramethylsilane. 1 The H NMR signal shift is expressed in δ ppm, and the coupling constant (J) is expressed in Hz. It exhibits the following multiplicity: s, singlet; d, doublet; t, triplet; q, quartet; m, multiply; b, broad peak (indicating unresolved coupling), and is interpreted using Bruker Topspin software. 13 C10 NMR data are expressed as chemical shift δ ppm and hybridization from DEPT 90 and DEPT 135 experiments: C, quaternary (s); CH, methine (d); CH2, methylene (t); CH3, methyl (q).

[0124] Example 1

[0125] Catalytic isocyanation of 1-[(1S,2R)-2,6,6-trimethyl-3-cyclohexen-1-yl]ethyl-1-one was carried out using 4% Pd / C. Structure

[0126] Scheme 1: 20.0 g (99%) of 1-[(1S,2R)-2,6,6-trimethyl-3-cyclohexen-1-yl]ethyl-1-one and 4% Pd / C (0.4 g, 2 wt%) were stirred at 175 °C under a nitrogen atmosphere. Then, 1.1 g (20 mol%) of formic acid was slowly added dropwise over 20 hours. After reacting for 4 hours, the reaction mixture was cooled to room temperature, filtered, and analyzed by GC and GC-MS.

[0127] Scheme 2: 1-[(1S,2R)-2,6,6-trimethyl-3-cyclohexen-1-yl]ethyl-1-one (200.0 g, 99%) and 4% Pd / C (4.0 g, 2 wt%) were stirred at 175 °C under a nitrogen atmosphere. Hydrogen was then bubbled into the suspension at a rate of 6 mL / min for 8 hours. The reaction mixture was cooled to room temperature, filtered, and analyzed by GC and GC-MS.

[0128] The results are reported in the table below.

[0129]

[0130] 1) Comparative Example

[0131] Example 2

[0132] Catalytic isocyanation of 1-[(1S,2S)-2,6,6-trimethyl-3-cyclohexen-1-yl]ethyl-1-one was carried out using 5% Pd / C. Structure

[0133] Following Scheme 1 described in Example 1, 1-[(1S,2S)-2,6,6-trimethyl-3-cyclohexen-1-yl]ethyl-1-one was catalytically isomerized. The final composition was determined by GC and GC-MS.

[0134] Example 3

[0135] Catalytic isocyanation of 1-[(1S,2S)-2,6,6-trimethyl-3-cyclohexen-1-yl]ethyl-1-one was carried out using 5% Pd / C. Structure

[0136] Catalytic isomerization of 1-[(1S,2S)-2,6,6-trimethyl-3-cyclohexen-1-yl]ethyl-1-one was carried out according to Scheme 1 described in Example 1, except that 10 wt% of p-cymene was added at the start of the reaction. The composition of the final product was determined by GC and GC-MS.

[0137]

[0138] Example 4

[0139] Catalytic isomerization of 1-(2,6,6-trimethyl-2-cyclohexen-1-yl)ethyl-1-one using 5% Pd / C

[0140] 1-(2,6,6-trimethyl-2-cyclohexen-1-yl)ethyl-1-one was isomerized according to Scheme 1 described in Example 1. The final composition was determined by GC and GC-MS.

[0141]

[0142] Example 5

[0143] Catalytic isomerization of 1-(2,6,6-trimethyl-1-cyclohexen-1-yl)ethyl-1-one using 5% Pd / C

[0144] 1-(2,6,6-trimethyl-1-cyclohexen-1-yl)ethyl-1-one was isomerized according to Scheme 1 described in Example 1. The final composition was determined by GC and GC-MS.

[0145] . Claims (as amended under Article 19 of the Treaty) 1. A method for preparing a mixture comprising at least one compound of formula (Ia) and at least one compound of formula (Ib), These compounds are in the form of any of their stereoisomers or mixtures thereof; wherein Each R 1 R 3 and R 4 Simultaneously or independently representing a hydrogen atom or a C atom 1-6 Alkyl, and R 2 Represents hydrogen atom, C 1-6 Alkyl, C 1-6 Alkoxy or C 2-6 alkenyl; The method includes the step of reacting a compound of formula (II) with a catalyst system. The compound is in the form of any of its stereoisomers or mixtures thereof; wherein One dashed line represents a carbon-carbon double bond, and the remaining dashed lines represent carbon-carbon single bonds, and R 1 R 2 R 3 and R 4 It has the same meaning as the definition above; The catalyst system comprises: i) Palladium (Pd); and ii) Molecular hydrogen or hydrogen source. 2. The method according to claim 1, wherein the compound of formula (II) is a compound of formula (II'). The compound is in the form of any of its stereoisomers or mixtures thereof; wherein Each R 1 R 3 and R 4 Simultaneously or independently representing a hydrogen atom or a C atom 1-6 Alkyl, and R 2 Represents hydrogen atom, C 1-6 Alkyl, C 1-6 Alkoxy or C 2-6 Alkenyl group. 3. The method according to any one of claims 1 to 2; wherein R 4 Represents a hydrogen atom or C 1-4 Alkyl group; preferably, representing a hydrogen atom or C. 1-3 Alkyl group; preferably, representing a hydrogen atom or C. 1-2 Alkyl; preferably, representing a hydrogen atom or a methyl group; even more preferably, representing a hydrogen atom. 4. The method according to any one of claims 1 to 3; wherein, the compound of formula (Ia) is a compound of formula (Ia'), The compound is in the form of any one of its stereoisomers or mixtures thereof, wherein each R 1 and R 3 Simultaneously or independently representing a hydrogen atom or a C atom 1-6 Alkyl, and R 2 Represents hydrogen atom, C 1-6 Alkyl, C 1-6 Alkoxy or C 2-6 alkenyl; Compound of formula (Ib) conforms to formula (Ib'); The compound is in the form of any one of its stereoisomers or mixtures thereof, wherein each R 1 and R 3 Simultaneously or independently representing a hydrogen atom or a C atom 1-6 Alkyl, and R 2 Represents hydrogen atom, C 1-6 Alkyl, C 1-6 Alkoxy or C 2-6 alkenyl; Compound (II) conforms to formula (III). The compound is in the form of any of its stereoisomers or mixtures thereof, where one dashed line represents a carbon-carbon double bond and the remaining dashed lines represent carbon-carbon single bonds, and each R 1 and R 3 Simultaneously or independently representing a hydrogen atom or a C atom 1-6 Alkyl, and R 2 Represents hydrogen atom, C 1-6 Alkyl, C 1-6 Alkoxy or C 2-6 Alkenyl group. 5. The method according to any one of claims 1 to 4, wherein R 3 Represents a hydrogen atom or C 1-4 Alkyl group; preferably, representing a hydrogen atom or C. 1-3 Alkyl group; preferably, representing a hydrogen atom or C. 1-2 Alkyl; or even more preferably, representing a hydrogen atom or a methyl group. 6. The method according to any one of claims 1 to 5, wherein each R 1 Simultaneously or independently representing a hydrogen atom or a C atom 1-4 Alkyl group; preferably, representing a hydrogen atom or C. 1-3 Alkyl group; preferably, representing a hydrogen atom or C. 1-2 Alkyl; or even more preferably, representing a hydrogen atom or a methyl group. 7. The method according to any one of claims 1 to 6, wherein the compound of formula (Ia) or the compound of formula (Ia') is a compound of formula (Ia''). The compound is in the form of any of its stereoisomers or mixtures thereof, wherein R 2 Represents hydrogen atom, C 1-6 Alkyl, C 1-6 Alkoxy or C 2-6 alkenyl; Compounds of formula (Ib) or (Ib') are compounds of formula (Ib''); The compound is in the form of any of its stereoisomers or mixtures thereof, wherein R 2 Represents hydrogen atom, C 1-6 Alkyl, C 1-6 Alkoxy or C 2-6 alkenyl; and Compound (III) conforms to formula (IV'); The compound is in the form of any of its stereoisomers or mixtures thereof, wherein R 2 Represents hydrogen atom, C 1-6Alkyl, C 1-6 Alkoxy or C 2-6 Alkenyl group. 8. The method according to any one of claims 1 to 7, wherein R 2 For hydrogen atoms, C 1-4 Alkyl, C 1-4 Alkoxy or C 2-4 Alkenyl group; preferably, it is a hydrogen atom or a C atom. 1-3 Alkyl, C 1-3 Alkoxy or C 2-3 Alkenyl group; preferably, it is a hydrogen atom or a C atom. 1-2 Alkyl, C 1-2 Alkoxy or C 2-3 Alkenyl; even more preferably, hydrogen atom, methyl or prop-1-en-1-yl. 9. The method according to any one of claims 1 to 8, wherein the palladium is a supported palladium, preferably, the palladium is supported on carbon. 10. The method according to any one of claims 1 to 9, wherein the hydrogen source is tetrahydronaphthalene, formic acid, formate, limonene, or a mixture thereof. 11. The method according to any one of claims 1 to 10, wherein the method is a continuous method. 12. The method according to any one of claims 1 to 11, wherein R 2 It is a methyl group. 13. The method according to any one of the preceding claims, characterized in that: Compound of formula (Ia) is (2E)-1-(2,6,6-trimethyl-2-cyclohexen-1-yl)-2-buten-1-one or 1-(2,6,6-trimethyl-2-cyclohexen-1-yl)-1-ethylone; Compound of formula (Ib) is (2E)-1-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2-buten-1-one or 1-(2,6,6-trimethyl-1-cyclohexen-1-yl)-1-ethylone; and Compound (II) is trans-1-(2,6,6-trimethyl-3-cyclohexen-1-yl)-1-ethyl ketone, cis-1-(2,6,6-trimethyl-3-cyclohexen-1-yl)-1-ethyl ketone, or 1-(2,6,6-trimethyl-3-cyclohexen-1-yl)-2-buten-1-one. 14. A method for preparing 1-(2,6,6-trimethyl-2-cyclohexen-1-yl)-2-buten-1-one, 1-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2-buten-1-one, or mixtures thereof, comprising the following steps: a) Isomerization of 1-(2,6,6-trimethyl-3-cyclohexen-1-yl)-1-ethylone by contacting a catalyst system comprising: i) Palladium (Pd); and ii) Molecular hydrogen or hydrogen source, To obtain a mixture comprising 1-(2,6,6-trimethyl-2-cyclohexen-1-yl)-1-ethyl ketone and 1-(2,6,6-trimethyl-1-cyclohexen-1-yl)-1-ethyl ketone; b) Optionally, 1-(2,6,6-trimethyl-2-cyclohexen-1-yl)-1-ethyl ketone is separated from 1-(2,6,6-trimethyl-1-cyclohexen-1-yl)-1-ethyl ketone; c) Converting 1-(2,6,6-trimethyl-2-cyclohexen-1-yl)-1-ethylone, 1-(2,6,6-trimethyl-1-cyclohexen-1-yl)-1-ethylone, or mixtures thereof into 1-(2,6,6-trimethyl-2-cyclohexen-1-yl)-2-buten-1-one, 1-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2-buten-1-one, or mixtures thereof by aldol condensation with acetaldehyde.

Claims

1. A method for preparing a mixture comprising at least one compound of formula (Ia) and at least one compound of formula (Ib), These compounds are in the form of any of their stereoisomers or mixtures thereof; wherein Each R 1 R 3 and R 4 Simultaneously or independently representing a hydrogen atom or a C atom 1-6 Alkyl, and R 2 Represents hydrogen atom, C 1-6 Alkyl, C 1-6 Alkoxy or C 2-6 alkenyl; The method includes the step of reacting a compound of formula (II) with a catalyst system. The compound is in the form of any of its stereoisomers or mixtures thereof; wherein One dashed line represents a carbon-carbon double bond, and the remaining dashed lines represent carbon-carbon single bonds, and R 1 R 2 R 3 and R 4 It has the same meaning as the definition above; The catalyst system comprises: i) Palladium (Pd); and ii) Molecular hydrogen or hydrogen source.

2. The method according to claim 1, wherein the compound of formula (II) is a compound of formula (II'). The compound is in the form of any of its stereoisomers or mixtures thereof; wherein Each R 1 R 3 and R 4 Simultaneously or independently representing a hydrogen atom or a C atom 1-6 Alkyl, and R 2 Represents hydrogen atom, C 1-6 Alkyl, C 1-6 Alkoxy or C 2-6 Alkenyl group.

3. The method according to any one of claims 1 to 2; wherein R 4 Represents a hydrogen atom or C 1-4 Alkyl group; preferably, representing a hydrogen atom or C. 1-3 Alkyl group; preferably, representing a hydrogen atom or C. 1-2 Alkyl; preferably, representing a hydrogen atom or a methyl group; even more preferably, representing a hydrogen atom.

4. The method according to any one of claims 1 to 3; wherein, Compound of formula (Ia) is compound of formula (Ia'). The compound is in the form of any one of its stereoisomers or mixtures thereof, wherein each R 1 and R 3 Simultaneously or independently representing a hydrogen atom or a C atom 1-6 Alkyl, and R 2 Represents hydrogen atom, C 1-6 Alkyl, C 1-6 Alkoxy or C 2-6 alkenyl; Compound of formula (Ib) conforms to formula (Ib'); The compound is in the form of any one of its stereoisomers or mixtures thereof, wherein each R 1 and R 3 Simultaneously or independently representing a hydrogen atom or a C atom 1-6 Alkyl, and R 2 Represents hydrogen atom, C 1-6 Alkyl, C 1-6 Alkoxy or C 2-6 alkenyl; Compound (II) conforms to formula (III). The compound is in the form of any of its stereoisomers or mixtures thereof, where one dashed line represents a carbon-carbon double bond and the remaining dashed lines represent carbon-carbon single bonds, and each R 1 and R 3 Simultaneously or independently representing a hydrogen atom or a C atom 1-6 Alkyl, and R 2 Represents hydrogen atom, C 1-6 Alkyl, C 1-6 Alkoxy or C 2-6 Alkenyl group.

5. The method according to any one of claims 1 to 4, wherein R 3 Represents a hydrogen atom or C 1-4 Alkyl group; preferably, representing a hydrogen atom or C. 1-3 Alkyl group; preferably, representing a hydrogen atom or C. 1-2 Alkyl; or even more preferably, representing a hydrogen atom or a methyl group.

6. The method according to any one of claims 1 to 5, wherein each R 1 Simultaneously or independently representing a hydrogen atom or a C atom 1-4 Alkyl group; preferably, representing a hydrogen atom or C. 1-3 Alkyl group; preferably, representing a hydrogen atom or C. 1-2 Alkyl; or even more preferably, representing a hydrogen atom or a methyl group.

7. The method according to any one of claims 1 to 6, wherein the compound of formula (Ia) or the compound of formula (Ia') is a compound of formula (Ia''). The compound is in the form of any of its stereoisomers or mixtures thereof, wherein R 2 Represents hydrogen atom, C 1-6 Alkyl, C 1-6 Alkoxy or C 2-6 alkenyl; Compounds of formula (Ib) or (Ib') are compounds of formula (Ib''); The compound is in the form of any of its stereoisomers or mixtures thereof, wherein R 2 Represents hydrogen atom, C 1-6 Alkyl, C 1-6 Alkoxy or C 2-6 alkenyl; and Compound (III) conforms to formula (IV'); The compound is in the form of any of its stereoisomers or mixtures thereof, wherein R 2 Represents hydrogen atom, C 1-6 Alkyl, C 1-6 Alkoxy or C 2-6 Alkenyl group.

8. The method according to any one of claims 1 to 7, wherein R 2 For hydrogen atoms, C 1-4 Alkyl, C 1-4 Alkoxy or C 2-4 Alkenyl group; preferably, it is a hydrogen atom or a C atom. 1-3 Alkyl, C 1-3 Alkoxy or C 2-3 Alkenyl group; preferably, it is a hydrogen atom or a C atom. 1-2 Alkyl, C 1-2 Alkoxy or C 2-3 Alkenyl; even more preferably, hydrogen atom, methyl or prop-1-en-1-yl.

9. The method according to any one of claims 1 to 8, wherein the palladium is a supported palladium, preferably, the palladium is supported on carbon.

10. The method according to any one of claims 1 to 9, wherein the hydrogen source is tetrahydronaphthalene, formic acid, formate, limonene, or a mixture thereof.

11. The method according to any one of claims 1 to 10, wherein the method is a continuous method.

12. The method according to any one of claims 1 to 11, wherein R 2 It is a methyl group.

13. The method according to any one of the preceding claims, characterized in that: Compound of formula (Ia) is (2E)-1-(2,6,6-trimethyl-2-cyclohexen-1-yl)-2-buten-1-one or 1-(2,6,6-trimethyl-2-cyclohexen-1-yl)-1-ethylone; Compound of formula (Ib) is (2E)-1-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2-buten-1-one or 1-(2,6,6-trimethyl-1-cyclohexen-1-yl)-1-ethylone; and Compound (II) is trans-1-(2,6,6-trimethyl-3-cyclohexen-1-yl)-1-ethyl ketone, cis-1-(2,6,6-trimethyl-3-cyclohexen-1-yl)-1-ethyl ketone, or 1-(2,6,6-trimethyl-3-cyclohexen-1-yl)-2-buten-1-one.

14. A method for preparing 1-(2,6,6-trimethyl-2-cyclohexen-1-yl)-2-buten-1-one, 1-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2-buten-1-one, or mixtures thereof, comprising the following steps: a) Isomerization of 1-(2,6,6-trimethyl-3-cyclohexen-1-yl)-1-ethylone by contacting a catalyst system comprising: i) Palladium (Pd); and ii) Molecular hydrogen or hydrogen source, To obtain a mixture comprising 1-(2,6,6-trimethyl-2-cyclohexen-1-yl)-1-ethyl ketone and 1-(2,6,6-trimethyl-1-cyclohexen-1-yl)-1-ethyl ketone; b) Optionally, 1-(2,6,6-trimethyl-2-cyclohexen-1-yl)-1-ethyl ketone is separated from 1-(2,6,6-trimethyl-1-cyclohexen-1-yl)-1-ethyl ketone; c) Converting 1-(2,6,6-trimethyl-2-cyclohexen-1-yl)-1-ethylone, 1-(2,6,6-trimethyl-1-cyclohexen-1-yl)-1-ethylone, or mixtures thereof into 1-(2,6,6-trimethyl-2-cyclohexen-1-yl)-2-buten-1-one, 1-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2-buten-1-one, or mixtures thereof by aldol condensation with acetaldehyde.

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