Isomerization process

Abstract

The present invention relates to the field of organic synthesis. More particularly, it provides a process for the preparation of a mixture comprising at least a compound of formula (Ia) and at least one compound of formula (Ib) comprising the step of reacting a compound of formula (II) with a catalyst system comprising palladium (Pd) and molecular hydrogen or a hydrogen source.

Description

[0001] ISOMERIZATION PROCESS

[0002] Technical field

[0003] The present invention relates to the field of organic synthesis. More particularly, it provides a process for the preparation of a mixture comprising at least a compound of formula (la) and at least one compound of formula (lb) comprising the step of reacting a compound of formula (II) with a catalyst system comprising palladium (Pd) and molecular hydrogen or a hydrogen source.

[0004] Background

[0005] The compounds of formula (la) or (lb), as defined below, can be useful as perfuming ingredients or as starting material for the construction of compounds having a more complex skeleton.

[0006] The methods of preparation of said compounds reported in the prior art are in general quite long and expensive. Moreover, each of said methods allows to obtain only one or the other of said compounds. Consequently, to obtain said compounds a person skilled in the art has to carry out two separate processes with an evident loss of time.

[0007] It is therefore highly desirable to access such compounds by means of a simple and efficient isomerization process wherein the starting material is an easily accessible material and it is possible to obtain both compounds (la) and (lb). Preparation of a mixture comprising at least one compound of formula (la) and at least one compound of formula (lb) by isomerization using ruthenium complex has been reported in EP1697290. Alternative catalysts such as base, acid or rhodium complex have been disclosed in EPl 162190. Being products of industrial interest, there is always a need for new processes showing improved yields and increased conversions while limiting waste.

[0008] So, there is a need to develop an approach toward the mixture comprising at least one compound of formula (la) and at least one compound of formula (lb) using less expensive and recyclable catalysts while limiting the formation of side product.

[0009] The present invention is a process for obtaining the mixture comprising at least one compound of formula (la) and at least one compound of formula (lb) starting from compound of formula (II) via an isomerization of a double bond with high selectivity in the presence of a catalyst system comprising palladium (Pd) and molecular hydrogen or a hydrogen source.

[0010] Description of the invention

[0011] Unless specified otherwise, all percentages refer to percent by weight, based on the total weight of the referenced composition.

[0012] We have now found that the mixture comprising at least one compound of formula (la) and at least one compound of formula (lb) can be produced in an advantageous manner by means of a catalytic isomerization as described and result in higher productivity while improving the environmental impact by a better conversion; lower amount of by product and recyclability of the catalyst.

[0013] Therefore, a first object of the present invention is a process for the preparation of a mixture comprising at least one compound of formula (la) and at least one compound of formula (lb) in the form of any one of their stereoisomers or a mixture thereof; wherein each R1, R3and R4represent, simultaneously or independently, a hydrogen atom or a Ci-6 alkyl group and R2represents a hydrogen atom, a Ci-6 alkyl, a Ci-6 alkoxyl or a C2-6 alkenyl group; the process comprising the step of reacting a compound of formula (II), in the form of any one of its stereoisomers or a mixture thereof; wherein one dotted line is a carbon-carbon double bond and the others are a carboncarbon single bond and R1, R2, R3and R4have the same meaning as defined above; with a catalyst system comprising i) palladium (Pd); and ii) molecular hydrogen or a hydrogen source.

[0014] For the sake of clarity, by the expression “any one of its stereoisomers or a mixture thereof’, or the similar, it is meant the normal meaning understood by a person skilled in the art, i.e. that the compound of formula (la), the compound of formula (lb) or compound of formula (II) can be a pure enantiomer or diastereomer. In other words, the compound of formula (la), the compound of formula (lb) or compound of formula (II) may possess several stereocenters and each of said stereocenter can have two different stereochemistries (e.g. R or S). The compound of formula (la), the compound of formula (lb) or compound of formula (II) may even be in the form of a pure enantiomer or in the form of a mixture of enantiomers or diastereoisomers. The compound of formula (la), the compound of formula (lb) or compound of formula (II) can be in a racemic form or scalemic form. Therefore, the compound of formula (la), the compound of formula (lb) or compound of formula (II) can be one stereoisomer or in the form of a composition of matter comprising, or consisting of, various stereoisomers.

[0015] For the sake of clarity, by the expression “one dotted line is a carbon-carbon double bond and the others are a carbon-carbon single bond”, or the similar, it is meant the normal meaning understood by a person skilled in the art, i.e. that the whole bonding (solid and dotted line) between the carbon atoms connected by said dotted line is a carbon-carbon single or double bond.

[0016] For the sake of clarity, it is understood that by the expression “hydrogen source” it is intended the usual meaning in the art, i.e. a compound capable of producing molecular hydrogen (i.e. H2), hydrogen atom or the equivalent in the reaction medium.

[0017] The terms “alkyl”, “alkoxyl” and “alkenyl” are understood as comprising branched and linear alkyl, alkoxyl and alkenyl groups. The term “alkenyl” is understood as comprising 1 olefinic double bond.

[0018] According to a particular embodiment of the invention, the compound of formula (II) is a compound of formula (IF) in the form of any one of its stereoisomers or a mixture thereof; wherein each R1, R3and R4represent, simultaneously or independently, a hydrogen atom or a Ci-6 alkyl group and R2represents a hydrogen atom, a Ci-6 alkyl, a Ci-6 alkoxyl or a C2-6 alkenyl group.

[0019] According to another particular embodiment of the invention, the compound of in the form of any one of its stereoisomers or a mixture thereof; wherein each R1, R3and R4represent, simultaneously or independently, a hydrogen atom or a C1-6 alkyl group and R2represents a hydrogen atom, a C1-6 alkyl, a C1-6 alkoxyl or a C2-6 alkenyl group.

[0020] According to another particular embodiment of the invention, the compound of formula (II) is a compound of formula (11”’) in the form of any one of its stereoisomers or a mixture thereof; wherein each R1, R3and R4represent, simultaneously or independently, a hydrogen atom or a C1-6 alkyl group and R2represents a hydrogen atom, a C1-6 alkyl, a C1-6 alkoxyl or a C2-6 alkenyl group.

[0021] According to another particular embodiment of the invention, the compound of formula (II) is a compound of formula (II””) in the form of any one of its stereoisomers or a mixture thereof; wherein each R1, R3and R4represent, simultaneously or independently, a hydrogen atom or a C1-6 alkyl group and R2represents a hydrogen atom, a C1-6 alkyl, a C1-6 alkoxyl or a C2-6 alkenyl group. According to another particular embodiment of the invention, the compound of formula (II) is in the form of a mixture of compound of formula (II’), compound of formula (II”), compound of formula (II’”) and compound of formula (II””). Particularly, said mixture comprises at least 50% by weight, of compound of formula (II’), based on the total weight of the mixture.

[0022] According to any embodiments of the invention, the mixture may comprise at least 40% by weight, of compound of formula (la), based on the total weight of the mixture. Preferably, the mixture may comprise at least 50% by weight, of compound of formula (la), based on the total weight of the mixture. Preferably, the mixture may comprise at least 60% by weight, of compound of formula (la), based on the total weight of the mixture. Preferably, the mixture may comprise at least 70% by weight, of compound of formula (la), based on the total weight of the mixture. Even more preferably, the mixture may comprise at least 80% by weight, of compound of formula (la), based on the total weight of the mixture.

[0023] According to any embodiments of the invention, the mixture may comprise at most 35% by weight, of compound of formula (lb), based on the total weight of the mixture. Preferably, the mixture may comprise at most 20% by weight, of compound of formula (lb), based on the total weight of the mixture. Preferably, the mixture may comprise at most 15% by weight, of compound of formula (la), based on the total weight of the mixture. Even more preferably, the mixture may comprise at most 10% by weight, of compound of formula (la), based on the total weight of the mixture. The mixture may comprise compound of formula (lb) in a range comprised between 1% by weight and 35 % by weight, based on the total weight of the mixture.

[0024] According to any embodiments of the invention, the weight ratio of compound of formula (la) to compound of formula (lb) in the mixture is in the range comprised between 1 : 0 and 1 : 0.5, preferably between 1 : 0.01 and 1 : 0.5.

[0025] According to any embodiments of the invention, R4may be a hydrogen atom or a Ci-4 alkyl group; preferably, a hydrogen atom or a C1-3 alkyl group; preferably, a hydrogen atom or a C1-2 alkyl group; preferably a hydrogen atom or a methyl group; even more preferably a hydrogen atom.

[0026] According to any embodiments of the invention, the compound of formula (la) is a compound of formula (la’) in the form of any one of its stereoisomers or a mixture thereof and wherein R1, R2and R3have the same meaning as defined above.

[0027] According to any embodiments of the invention, the compound of formula (lb) is in the form of any one of its stereoisomers or a mixture thereof and wherein R1, R2and R3have the same meaning as defined above.

[0028] According to any embodiments of the invention, the compound of formula (II) is of in the form of any one of its stereoisomers or a mixture thereof and wherein R1, R2and R3have the same meaning as defined above.

[0029] According to another particular of the invention, the compound of formula (III) is in the form of any one of its stereoisomers or a mixture thereof and wherein R1, R2and R3have the same meaning as defined above.

[0030] According to another particular of the invention, the compound of formula (III) is of formula (III”) in the form of any one of its stereoisomers or a mixture thereof and wherein R1, R2and R3have the same meaning as defined above.

[0031] According to another particular of the invention, the compound of formula (III) is in the form of any one of its stereoisomers or a mixture thereof and wherein R1, R2and R3have the same meaning as defined above.

[0032] According to another particular of the invention, the compound of formula (III) is in the form of any one of its stereoisomers or a mixture thereof and wherein R1, R2and R3have the same meaning as defined above.

[0033] According to any embodiments of the invention, R3may be a hydrogen atom or a Ci-4 alkyl group; preferably, a hydrogen atom or a C1-3 alkyl group; preferably, a hydrogen atom or a C1-2 alkyl group; preferably a hydrogen atom or a methyl group; even more preferably a hydrogen atom.

[0034] According to any embodiments of the invention, each R1may be, simultaneously or independently, a hydrogen atom or a C1-4 alkyl group; preferably, a hydrogen atom or a C1-3 alkyl group; preferably, a hydrogen atom or a C1-2 alkyl group; preferably a hydrogen atom or a methyl group; even more preferably a methyl group.

[0035] According to any embodiments of the invention, at least one R1is not a hydrogen atom.

[0036] According to any embodiments of the invention, the compound of formula (la) or the compound of formula (la’) are a compound of formula (la”) in the form of any one of its stereoisomers or a mixture thereof and wherein R2has the same meaning as defined above.

[0037] According to any embodiments of the invention, the compound of formula (lb) or the compound of formula (lb’) are of formula (lb”); in the form of any one of its stereoisomers or a mixture thereof and wherein R2has the same meaning as defined above.

[0038] According to any embodiments of the invention, the compound of formula (II) or the compound of formula (III) are of formula (IV) in the form of any one of its stereoisomers or a mixture thereof and wherein the dotted lines, R2has the same meaning as defined above.

[0039] According to a particular of the invention, the compound of formula (IV) is of formula (IV’) in the form of any one of its stereoisomers or a mixture thereof and wherein R2has the same meaning as defined above.

[0040] According to another particular of the invention, the compound of formula (IV) is of formula (IV”) in the form of any one of its stereoisomers or a mixture thereof and wherein R2has the same meaning as defined above.

[0041] According to another particular of the invention, the compound of formula (IV) is in the form of any one of its stereoisomers or a mixture thereof and wherein R2has the same meaning as defined above.

[0042] According to another particular of the invention, the compound of formula (IV) is in the form of any one of its stereoisomers or a mixture thereof and wherein R2has the same meaning as defined above.

[0043] According to any embodiments of the invention, R2may be a hydrogen atom, a Ci-4 alkyl, a C1-4 alkoxyl or a C2-4 alkenyl group; preferably, a hydrogen atom, a C1-3 alkyl, a C1-3 alkoxyl or a C2-3 alkenyl group; preferably, a hydrogen atom, a C1-2 alkyl, a C1-2 alkoxyl or a C2-3 alkenyl group; even more preferably, a hydrogen atom, a methyl group or a prop-l-en-l-yl group.

[0044] Non-limiting examples of suitable compounds of formula (lb) may include (2E)- l-(2,6,6-trimethyl-l-cyclohexen-l-yl)-2-buten-l-one or l-(2,6,6-trimethyl-l-cyclohexen- l-yl)-l -ethanone.

[0045] Non-limiting examples of suitable compounds of formula (la) may include (2E)- l-(2,6,6-trimethyl-2-cyclohexen-l-yl)-2-buten-l-one or l-(2,6,6-trimethyl-2-cyclohexen- l-yl)-l -ethanone. Non-limiting examples of suitable compounds of formula (II) may include trans- l-(2,6,6-trimethyl-3-cyclohexen-l-yl)-l-ethanone, cis-l-(2,6,6-trimethyl-3-cyclohexen- 1 -yl)- 1 -ethanone or 1 -(2, 6, 6-trimethyl-3 -cycloh exen- 1 -yl)-2-buten- 1 -one.

[0046] According to any embodiments of the invention, the catalyst system comprises palladium (Pd) in a form of a homogeneous complex or in elemental metallic form. Particularly, the catalyst system comprises palladium (Pd) in elemental metallic form. Suitable forms of such metal for carrying out chemical reactions are well known to a person skilled in the art.

[0047] According to any one of the above embodiments of the invention, said palladium (Pd) is supported on a carrying material.

[0048] For the sake of clarity, by carrying material it is intended a material wherein it is possible to deposit such metal and which is inert toward the hydrogen source and the substrate.

[0049] According to any one of the above embodiments of the invention, specific and non-limiting examples of carrying material is carbon, silica or aluminum oxide. Such supports are well known to a person skilled in the art.

[0050] The supported palladium (Pd) are known compounds and are commercially available. A person skilled in the art is able to select the preferred kind of metal as the way that it was deposit on the support, as the proportion of metal on support material, as the form (powder, granules, pellets, extrudates, mousses....) and as the surface area of the support.

[0051] According to any one of the above embodiments of the invention, the amount of metal relative to the support can range between 0.05% and 25% w / w, or even between 1% and 6%, relative to the weight on the support used.

[0052] The palladium (Pd), in a supported form or as such, can be added into the reaction medium of the invention’s process in a large range of concentrations. As nonlimiting examples, one can cite as metal concentration values those ranging from 0.01 mol% to 10 mol%, relative to the total amount of substrate. Preferably, the metal concentration will be comprised between 0.02 mol% to 5 mol%, or even between 0.04 mol% to 2 mol%. It goes without saying that the optimum concentration of metal will depend, as the person skilled in the art knows, on the nature of the latter, on the nature of the substrate, if the process is run in batch or continuously, on the temperature and on the pressure of H2 used during the process, as well as the desired time of reaction.

[0053] The supported palladium may be recycled at the end of the invention’s process. In other words, the supported palladium may be recovered at the end of the invention’s process and use several times in the invention’s process.

[0054] The process according to the invention is carried out in the presence of molecular hydrogen or hydrogen source.

[0055] According to any one of the above embodiments of the invention, said hydrogen source can be a transfer hydrogenation agent. Specific and non-limiting examples of catalytic transfer hydrogenation agents are tetralin, formic acid, formate salt (such as sodium formate, potassium formate or ammonium formate), limonene or a mixture thereof. Particularly, the transfer hydrogenation agent may be tetralin, formic acid, formate salt, limonene or a mixture thereof. Even more particularly, the transfer hydrogenation agent may be formic acid, formate salt, limonene or a mixture thereof.

[0056] The transfer hydrogen agent can be added into the reaction medium of the invention’s process in a large range of concentrations. As non-limiting examples, one can cite as hydrogen source concentration values those ranging from 0.01 mol% to 100 mol%, or even between 0.01 mol% to 10 mol%, or even more between 0.01 mol% to 5 mol% relative to the amount of the substrate. A large amount of transfer hydrogenation agent is used when only a small part generates molecular hydrogen. For instance, approximately around 10 % of tetralin are converted into molecular hydrogen. It goes without saying that the optimum concentration of hydrogen source will depend, as the person skilled in the art knows, on the nature of the latter, on the nature of the substrate, of the temperature and on the catalyst used during the process, as well as the desired time of reaction.

[0057] According to any one of the above embodiments of the invention, as an alternative to the transfer hydrogenation agent, the molecular hydrogen can be used pure or mixed with an inert gas. Specific and non-limiting examples of such inert gas are nitrogen or argon. The EE / inert gas volume ratio is comprised between 1 / 1 to 0.01 / 1 and more preferably the ratio is 0.05 / 1.

[0058] The molecular hydrogen can be added into the reaction medium of the invention’s process in a large range of concentrations. As non-limiting examples, one can cite as molecular hydrogen concentration values those ranging from 0.01 mol% to 100 mol%, relative to the amount of the substrate. Preferably, the hydrogen source concentration will be comprised between 0.01 mol% to 10 mol% relative to the amount of the substrate. Preferably, the hydrogen source concentration will be comprised between 0.01 mol% to 8 mol% relative to the amount of the substrate. Even more preferably, the hydrogen source concentration will be comprised between 0.01 mol% to 5 mol% relative to the amount of the substrate. Of course, a person skilled in the art is well able to adjust the pressure or the flow (e.g. in a continuous process) of molecular hydrogen to obtain this range of concentration as a function of the process is batch or continuous. The person skilled in the art is also well able to adjust the concentration of molecular hydrogen as a function of the catalyst load and of dilution of the substrate in the solvent.

[0059] From 0.01 mol% to 10 mol%, even from 0.01 mol% to 8 mol%, even more from 0.01 mol% to 5 mol% of the hydrogen source or the molecular hydrogen, relative to the amount of the substrate, is present in the invention’s process.

[0060] The invention’s process can be carried out under batch or continuous conditions. According to a particular embodiment of the invention, the process is a continuous one, as it allows higher productivity.

[0061] The reaction can be carried out in the presence or absence of a solvent. When a solvent is required or used for practical reasons, then any solvent current in such reaction type can be used for the purposes of the invention. Non-limiting examples include Ce-i2 aromatic solvents such as toluene, 1,3-diisopropylbenzene, paracymene, cumene, pseudocumene, benzyl acetate, xylene or a mixture thereof, C3-16 alkane such as hexadecane, ether solvents such as tetrahydrofuran, butyl ether, methyltetrahydrofuran or a mixture thereof. The choice of the solvent is a function of the nature of the substrate and of the catalyst and the person skilled in the art is well able to select the solvent most convenient in each case to optimize the reaction.

[0062] The temperature at which the isomerization can be carried out is comprised between 50°C and 600°C. More preferably in the range of between 150 °C and 250°C for a continuous process and between 150 °C to 200 °C for a batch process. Of course, a person skilled in the art is also able to select the preferred temperature as a function of the melting and boiling point of the starting and final products as well as the desired time of reaction or conversion.

[0063] According to any one of the above embodiments of the invention, the compound of formula (II) may be prepared according to several methods known in the art such as Diels-Alder, cyclisation or Friedel Craft reaction. The person skilled in the art will be able to select best conditions to prepare compound of formula (II).

[0064] According to any embodiments of the invention, the compound of formula (la) being l-(2,6,6-trimethyl-2-cyclohexen-l-yl)-l-ethanone and the compound of formula (lb) being l-(2,6,6-trimethyl-l-cyclohexen-l-yl)-l-ethanone may further be converted into a mixture comprising l-(2,6,6-trimethyl-2-cyclohexen-l-yl)-2-buten-l-one and 1- (2,6,6-trimethyl-l-cyclohexen-l-yl)-2-buten-l-one. The preparation of a mixture comprising l-(2,6,6-trimethyl-2-cyclohexen-l-yl)-2-buten-l-one and l-(2,6,6-trimethyl-

[0065] 1-cyclohexen-l-yl)-2-buten-l-one from a mixture comprising at least l-(2,6,6-trimethyl-

[0066] 2-cyclohexen-l-yl)-l -ethanone and l-(2,6,6-trimethyl-l-cyclohexen-l-yl)-l-ethanone is well known in the art such as aldol conditions. Alternatively, l-(2,6,6-trimethyl-2- cyclohexen-l-yl)-l -ethanone and l-(2,6,6-trimethyl-l-cyclohexen-l-yl)-l-ethanone are separated and then converted into respectively l-(2,6,6-trimethyl-2-cyclohexen-l-yl)-2- buten-l-one and l-(2,6,6-trimethyl-l-cyclohexen-l-yl)-2-buten-l-one. The person skilled in the art will be able to select best conditions to prepare l-(2,6,6-trimethyl-2- cyclohexen-l-yl)-2-buten-l-one, l-(2,6,6-trimethyl-l-cyclohexen-l-yl)-2-buten-l-one and a mixture thereof. So another object of the present invention is a process for the preparation of l-(2,6,6-trimethyl-2-cyclohexen-l-yl)-2-buten-l-one, l-(2,6,6-trimethyl- l-cyclohexen-l-yl)-2-buten-l-one or a mixture thereof comprising the step of a) isomerizing l-(2,6,6-trimethyl-3-cyclohexen-l-yl)-l-ethanone by contacting l-(2,6,6-trimethyl-3-cyclohexen-l-yl)-l-ethanone with a catalyst system comprising i) palladium (Pd); and ii) molecular hydrogen or a hydrogen source. to obtain a mixture comprising l-(2,6,6-trimethyl-2-cyclohexen-l-yl)-l- ethanone and l-(2,6,6-trimethyl-l-cyclohexen-l-yl)-l-ethanone; b) optionally separating l-(2,6,6-trimethyl-2-cyclohexen-l-yl)-l-ethanone and l-(2,6,6-trimethyl-l-cyclohexen-l-yl)-l-ethanone c) converting l-(2,6,6-trimethyl-2-cyclohexen-l-yl)-l-ethanone, l-(2,6,6- trimethyl-l-cyclohexen-l-yl)-l -ethanone or a mixture thereof into l-(2,6,6-trimethyl-2- cyclohexen-l-yl)-2-buten-l-one, l-(2,6,6-trimethyl-l-cyclohexen-l-yl)-2-buten-l-one or a mixture thereof by aldol condensations with acetaldehyde.

[0067] The aldol condensation may be carried out under normal condition known by the person skilled in the art, i.e. under basic or acid conditions.

[0068] The separation may be carried out under normal condition known by the person skilled in the art, i.e. distillation.

[0069] Typical manners to execute the invention’s process are reported herein below in the examples.

[0070] Examples

[0071] The invention will now be described in further detail by way of the following examples, wherein the abbreviations have the usual meaning in the art, the temperatures are indicated in degrees centigrade (°C). NMR spectra were acquired using either a Bruker Avance II Ultrashield 400 plus operating at 400 MHz, (XH) and 100 MHz (13C) or a Bruker Avance III 500 operating at 500 MHz (' H) and 125 MHz (13C) or a Bruker Avance III 600 cry oprobe operating at 600 MHz (' H) and 150 MHz (13C). Spectra were internally referenced relative to tetramethyl silane 0.0 ppm. 'H NMR signal shifts are expressed in 6 ppm, coupling constants (J) are expressed in Hz with the following multiplicities: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; b, broad (indicating unresolved couplings) and were interpreted using Bruker Topspin software.13C NMR data are expressed in chemical shift 5 ppm and hybridization from DEPT 90 and DEPT 135 experiments, C, quaternary (s); CH, methine (d); CH2, methylene (t); CH3, methyl (q).

[0072] Example 1

[0073] Catalytic isomerization of l-[(lS,2R)-2,6,6-trimethyl-3-cyclohexen-l-yl1ethan-l-one using 4% Pd / C

[0074] Protocol 1: l-[(lS,2R)-2,6,6-trimethyl-3-cyclohexen-l-yl]ethan-l-one (20.0 g, 99%) and 4% Pd / C (0.4 g, 2 wt%) were stirred at 175 °C under N2 atmosphere. Then, 1.1 g (20 mol%) of formic acid were slowly dosed over 20 h. After reacting for 4 more hours, the reaction mixture was cooled to room temperature, filtered off, and analyzed by GC and GC-MS.

[0075] Protocol 2: l-[(lS,2R)-2,6,6-trimethyl-3-cyclohexen-l-yl]ethan-l-one (200.0 g, 99%) and 4% Pd / C (4.0 g, 2wt%) were stirred at 175 °C under N2 atmosphere. Then, hydrogen gas was bubbled through the suspension over 8 h at a rate of 6 mL / min. The reaction mixture was cooled to room temperature, filtered off, and analyzed by GC and GC-MS.

[0076] The results are reported in below table

[0077] 1) Comparative example

[0078] Example 2 Catalytic isomerization of l-[(lS,2S)-2,6,6-trimethyl-3-cyclohexen-l-yl1ethan-l-one using 5% Pd / C Catalytic isomerization of l-[(lS,2S)-2,6,6-trimethyl-3-cyclohexen-l-yl]ethan-l-one was performed following Protocol 1 described in Example 1. The final composition was determined by GC and GC-MS.

[0079] Example 3

[0080] Catalytic isomerization of l-[(lS,2S)-2 6-trimethyl-3-cyclohexen-l-yl]ethan-l-one using 5% Pd / C

[0081] Catalytic isomerization of l-[(lS,2S)-2,6,6-trimethyl-3-cyclohexen-l-yl]ethan-l-one was performed following Protocol 1 described in Example 1, except that 10wt% of paracymene were added at the beginning. The final composition was determined by GC and GC-MS.

[0082] Example 4

[0083] Catalytic isomerization of l -('2.6.6-trimethyl-2-cyclohexen- l -yl )ethan- l -one using 5% Pd / C l-(2,6,6-trimethyl-2-cyclohexen-l-yl)ethan-l-one was isomerized following Protocol 1 described in Example 1. The final composition was determined by GC and GC-MS.

[0084] Example 5

[0085] Catalytic isomerization of l-('2.6.6-trimethyl-l-cyclohexen-l-yl)ethan-l-one using 5% Pd / C l-(2,6,6-trimethyl-l-cyclohexen-l-yl)ethan-l-one was isomerized following Protocol 1 described in Example 1. The final composition was determined by GC and GC-MS.

Claims

AMENDED CLAIMS received by the International Bureau on 28 February 2025 (28.02.2025)1. A process for the preparation of a mixture comprising at least one compound of formula (la) and at least one compound of formula (lb)in the form of any one of their stereoisomers or a mixture thereof; wherein each R1, R3and R4represent, simultaneously or independently, a hydrogen atom or a Ci-6 alkyl group and R2represents a hydrogen atom, a Ci-6 alkyl, a Ci-6 alkoxyl or a C2-6 alkenyl group; the process comprising the step of reacting a compound of formula (II),(IDin the form of any one of its stereoisomers or a mixture thereof; wherein one dotted line is a carbon-carbon double bond and the others are a carbon-carbon single bonds and R1, R2, R3and R4have the same meaning as defined above; with a catalyst system comprising i) palladium (Pd); and ii) molecular hydrogen or a hydrogen source.

2. The process according to claim 1, wherein the compound of formula (II) isin the form of any one of its stereoisomers or a mixture thereof; whereineach R1, R3and R4represent, simultaneously or independently, a hydrogen atom or a Ci-6 alkyl group and R2represents a hydrogen atom, a Ci-6 alkyl, a Ci-6 alkoxyl or a C2-6 alkenyl group.

3. The process according to any one of claims 1 to 2; wherein R4represents a hydrogen atom or a C1-4 alkyl group; preferably, a hydrogen atom or a C1-3 alkyl group; preferably, a hydrogen atom or a C1-2 alkyl group; preferably a hydrogen atom or a methyl group; even more preferably a hydrogen atom.

4. The process according to any one of claims 1 to 3; wherein the compound of formula (la) is a compound of formula (la’)in the form of any one of its stereoisomers or a mixture thereof and wherein each R1and R3represent, simultaneously or independently, a hydrogen atom or a Ci-6 alkyl group and R2represents a hydrogen atom, a Ci-6 alkyl, a Ci-6 alkoxyl or a C2- 6 alkenyl group; wherein the compound of formula (lb) is of formula (lb’);in the form of any one of its stereoisomers or a mixture thereof and wherein each R1and R3represent, simultaneously or independently, a hydrogen atom or a C1-6 alkyl group and R2represents a hydrogen atom, a C1-6 alkyl, a Ci-6 alkoxyl or a C2-6 alkenyl group; wherein the compound of formula (II) is of formula (III)in the form of any one of its stereoisomers or a mixture thereof and wherein one dotted line is a carbon-carbon double bond and the others are a carbon-carbon single bonds and each R1and R3represent, simultaneously or independently, a hydrogen atom or a C1-6 alkyl group and R2represents a hydrogen atom, a C1-6 alkyl, a Ci-6 alkoxyl or a C2-6 alkenyl group.

5. The process according to any one of claims 1 to 4, wherein R3represents, a hydrogen atom or a C1-4 alkyl group; preferably, a hydrogen atom or a C1-3 alkyl group; preferably, a hydrogen atom or a C1-2 alkyl group; even more preferably a hydrogen atom or a methyl group.

6. The process according to any one of claims 1 to 5, wherein each R1represents, simultaneously or independently, a hydrogen atom or a C1-4 alkyl group; preferably, a hydrogen atom or a C1-3 alkyl group; preferably, a hydrogen atom or a C1-2 alkyl group; even more preferably a hydrogen atom or a methyl group.

7. The process according to any one of claims 1 to 6, wherein the compound of formula (la) or the compound of formula (la’) are a compound of formula (la”) da")in the form of any one of its stereoisomers or a mixture thereof and wherein R2represents a hydrogen atom, a Ci.6 alkyl, a Ci -6 alkoxyl or a C2-6 alkenyl group; the compound of formula (lb) or the compound of formula (lb’) is are of formula (lb”);in the form of any one of its stereoisomers or a mixture thereof and wherein R2represents a hydrogen atom, a Ci-6 alkyl, a C1-6 alkoxyl or a C2-6 alkenyl group; and the compound of formula (III) is of formula (IV’)in the form of any one of its stereoisomers or a mixture thereof and wherein R2represents a hydrogen atom, a C1-6 alkyl, a C1-6 alkoxyl or a C2-6 alkenyl group.

8. The process according to any one of claims 1 to 7, wherein R2is a hydrogen atom, a Ci-4 alkyl, a Ci-4 alkoxyl or a C2-4 alkenyl group; preferably, a hydrogen atom, a Ci-3 alkyl, a C1-3 alkoxyl or a C2-3 alkenyl group; preferably, a hydrogen atom, a C1-2 alkyl, a Ci-2 alkoxyl or a C2-3 alkenyl group; even more preferably a hydrogen atom, a methyl group or a prop-l-en-l-yl group.

9. The process 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 process according to any one of claims 1 to 9, wherein said hydrogen source is tetralin, formic acid, formate salt, limonene or a mixture thereof.

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

12. The process according to any one of claims 1 to 11, wherein R2is a methyl group.

13. The process according to any of the preceding claims characterized in that the compound of the formula (la) 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 -ethanone; the compound of the formula (lb) 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 -ethanone; and the compound of the formula (II) istrans- 1 -(2,6,6-trimethyl-3 -cyclohexen- 1 -yl)- 1 -ethanone, cis- 1 -(2,6,6-trimethyl-3 - cyclohexen- 1 -yl)- 1 -ethanone or 1 -(2,6,6-trimethyl-3 -cyclohexen- 1 -yl)-2-buten- 1 - one.

14. A process for the preparation of l-(2,6,6-trimethyl-2-cyclohexen-l-yl)-2- buten-l-one, 1 -(2,6, 6-trimethyl-l -cyclohexen- l-yl)-2-buten-l -one or a mixture thereof comprising the step of a) isomerizing l-(2,6,6-trimethyl-3-cyclohexen-l-yl)-l-ethanone by contacting l-(2,6,6-trimethyl-3 -cyclohexen- l-yl)-l -ethanone with a catalyst system comprising i) palladium (Pd); and ii) molecular hydrogen or a hydrogen source. to obtain a mixture comprising l-(2,6,6-trimethyl-2-cyclohexen-l-yl)-l -ethanone and 1 -(2, 6,6-trimethyl- 1 -cyclohexen- 1 -yl)- 1 -ethanone; b) optionally separating l-(2,6,6-trimethyl-2-cyclohexen-l-yl)-l -ethanone and l-(2,6,6-trimethyl-l-cyclohexen-l-yl)-l-ethanone; and c) converting l-(2,6,6-trimethyl-2-cyclohexen-l-yl)-l -ethanone, l-(2,6,6- trimethyl-1 -cyclohexen- l-yl)-l -ethanone or a mixture thereof into l-(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 a mixture thereof by aldol condensations with acetaldehyde.