Process for preparing phenyl propanal derivatives

Abstract

The present invention relates to the field of organic synthesis and more specifically it concerns a process for preparing compound of formula (I). More particularly, it concerns valuable new chemical intermediates for producing perfuming ingredients. Moreover, the present invention also comprises a process for producing compounds of formula (I).

Description

[0001] PROCESS FOR PREPARING PHENYL PROP ANAL DERIVATIVES

[0002] Technical field

[0003] The present invention relates to the field of perfumery. More particularly, it concerns valuable new chemical intermediates for producing perfuming ingredients. Moreover, the present invention also comprises a process for producing compounds of formula (I).

[0004] Background of the invention

[0005] In the perfumery industry, there is a constant need to provide compounds imparting novel organoleptic notes. In particular, there is an interest towards ingredients imparting the lily of the valley odor or at least one of the key organoleptic facets of the lily of the valley odor. So, compounds imparting said note are particularly sought after to reconstitute the delicate floral odor of muguet which does not survive even the mildest of extraction methods to yield an essential oil. Towards this goal, compounds of formula (I) were previously reported in W02017009175 which were obtained via the oxidation with PCC of the corresponding alcohol; i.e. 3-(phenyl)propanol derivatives. However, PCC is a highly toxic reagent. Safer processes have been developed as disclosed in WO 2018134220 and WO 2018134221 wherein the compound of formula (I) was prepared via a Heck coupling or a hydroformylation reaction. However, the reported routes to obtain compounds of formula (I) suffer from the use of costly precious metal such as rhodium, palladium or ruthenium and from the generation of a complex mixture of isomers. In addition, said products being of industrial interest, there is always a need for new processes showing improved yields and better selectivity.

[0006] So, there is a need to develop an approach toward compounds of formula (I) more sustainable allowing avoiding the generation of waste and using abundant and less expensive reagents while limiting the formation of isomers and using starting material easily available.

[0007] The present invention is a process for obtaining compound of formula (I) starting from compound of formula (II) via a novel route through novel intermediate, never disclosed before. Said novel access allows controlling the isomers formed. In particular, most of the compounds of formula (II) which are an object of the present invention, have never been reported or suggested in the context of the preparation of compounds of formula (I).

[0008] Description of the invention

[0009] It has now been surprisingly found that compound of formula (I) may be obtained from compound of formula (II) allowing to reduce the number of steps and the cost of the preparation while avoiding the presence of other isomers. The invention’s process opens a new route allowing obtaining compound of formula (I) in less steps with overall higher yield, compared to the methods known from the prior arts.

[0010] So, the first object of the invention is a process for the preparation of a compound of formula (I) in the form of any one of its isomers or a mixture thereof; comprising the oxidative cleavage of compound of formula (II) in the form of any one of its isomers or a mixture thereof; wherein Raand Rb, independently from each other, are a hydrogen atom or a Ci-16 hydrocarbon up of formula in the form of any one of its isomers or a mixture thereof.

[0011] 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 (II) can be a pure enantiomer or diastereomer. In other words, the 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 (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 (II) can be in a racemic form or scalemic form. Therefore, the compound of formula (II) can be one stereoisomer or in the form of a composition of matter comprising, or consisting of, various stereoisomers.

[0012] According to any one of the above embodiments of the invention, the compound of formula (II) can be in the form of its E or Z isomer or of a mixture thereof, e.g. the invention comprises compositions of matter consisting of one or more compounds of formula (II), having the same chemical structure but differing by the configuration of the double bond. In particular, compound (II) can be in the form of a mixture consisting of isomers E and Z and wherein said isomers E represent at least 50 % of the total mixture, or even at least 75% (i.e a mixture E / Z comprised between 75 / 25 and 100 / 0).

[0013] It is understood that by “... hydrocarbon group ...” it is meant that said group consists of hydrogen and carbon atoms and can be in the form of an aliphatic hydrocarbon, i.e. linear or branched saturated hydrocarbon (e.g. alkyl group), a linear or branched unsaturated hydrocarbon (e.g. alkenyl or alkynyl group), a saturated cyclic hydrocarbon (e.g. cycloalkyl) or an unsaturated cyclic hydrocarbon (e.g. cycloalkenyl or cycloalkynyl), or can be in the form of an aromatic hydrocarbon, i.e. aryl group, or can also be in the form of a mixture of said type of groups, e.g. a specific group may comprise a linear alkyl, a branched alkenyl (e.g. having one or more carbon-carbon double bonds), a (poly)cycloalkyl and an aryl moiety, unless a specific limitation to only one type is mentioned. Similarly, in all the embodiments of the invention, when a group is mentioned as being in the form of more than one type of topology (e.g. linear, cyclic or branched) and / or being saturated or unsaturated (e.g. alkyl, aromatic or alkenyl), it is also meant a group which may comprise moieties having any one of said topologies or being saturated or unsaturated, as explained above. Similarly, in all the embodiments of the invention, when a group is mentioned as being in the form of one type of saturation or unsaturation, (e.g. alkyl), it is meant that said group can be in any type of topology (e.g. linear, cyclic or branched) or having several moieties with various topologies. It is preferred that the hydrocarbon group does not have any C-C-double bonds.

[0014] As a consequence, the term " any one of its isomers or a mixture thereof' used for compound of the formula (I) is used in the sense of "any one of its stereoisomers or a mixture thereof, as described above.

[0015] The term " any one of its isomers or a mixture thereof used for compound of the formula (II), however, is used in the sense of "any one of its stereoisomers or a mixture thereof, as described above, as well "in the form of its E or Z isomer or of a mixture thereof, as described above.

[0016] It is understood that with the term “. . . a hydrocarbon group, optionally comprising one or more oxygen atoms. . .” it is meant that said hydrocarbon group optionally comprises one, two, three or more oxygen atoms in a form of alcohol, ketone, aldehyde, ether, ester, carboxylic acid, carbonate groups. These groups can either substitute a hydrogen atom of the hydrocarbon group and thus be laterally attached to said hydrocarbon, or substitute a carbon atom (if chemically possible) of the hydrocarbon group and thus be inserted into the hydrocarbon chain. For example, a -CH2-CH2-CHOH-CH2- group represents a C4 hydrocarbon group comprising an alcohol group (substitution of a hydrogen atom), i.e. a C4 hydrocarbon comprising an oxygen atom; a -CH2-CH2-COO-CH2-CH2CH2-CH2- group represents a C7 hydrocarbon group comprising one ester group (substitution of carbon atoms / insertion into the hydrocarbon chain), i.e. a C7 hydrocarbon comprising two oxygen atoms and, similarly, a -CH2-CH2-O-CH2-CH2-O-CH2-CH2- group represents a Ce hydrocarbon group comprising two ether groups, i.e. a Ce hydrocarbon comprising two oxygen atoms.

[0017] By the term “oxidative cleavage” or similar, it is meant the normal meaning in the art; i.e. a reaction in which a carbon-carbon double bond is cleaved and oxidized generating two compounds having a carbon-oxygen double bond, such as aldehyde, ketone, acid, ester. Under certain conditions, the aldehyde or ketone formed may be converted in situ in the corresponding acetal.

[0018] According to any embodiments of the invention, Ramay be a hydrogen atom or a Ci-14 hydrocarbon group, optionally comprising one to three oxygen atoms or a group of formula (a). Particularly; Ramay be a hydrogen atom or a C1-12 hydrocarbon group, optionally comprising one to three oxygen atoms or a group of formula (a). Particularly; Ramay be a hydrogen atom or a C1-10 hydrocarbon group, optionally comprising one to three oxygen atoms or a group of formula (a). Particularly; Ramay be a hydrogen atom or a C1-8 hydrocarbon group, optionally comprising one to three oxygen atoms or a group of formula (a). Particularly; Ramay be a hydrogen atom or a C1-6 hydrocarbon group, optionally comprising one to two oxygen atoms or a group of formula (a). Particularly; Ramay be a hydrogen atom or a Ci-6 hydrocarbon group, optionally comprising one to two oxygen atoms or a group of formula (a). Particularly; Ramay be a hydrogen atom or a Ci-6 alkyl or a Ce aryl group or a group of formula (a). Particularly; Ramay be a hydrogen atom or a Ci- 6 alkyl or a Ce aryl group. Particularly; Ramay be a hydrogen atom or a Ci-6 alkyl or a phenyl group. Particularly; Ramay be a hydrogen atom or a Ci-4 alkyl or a phenyl group. Particularly; Ramay be a hydrogen atom or a C1-3 alkyl or a phenyl group. Particularly; Ramay be a hydrogen atom or a C1-2 alkyl group. Particularly; Ramay be a hydrogen atom or a methyl group. Particularly; Ramay be a hydrogen atom.

[0019] According to any embodiments of the invention, Rbmay be a hydrogen atom or a Ci-14 hydrocarbon group, optionally comprising one to three oxygen atoms or a group of formula (a). Particularly; Rbmay be a hydrogen atom or a C1-12 hydrocarbon group, optionally comprising one to three oxygen atoms or a group of formula (a). Particularly; Rbmay be a hydrogen atom or a C1-10 hydrocarbon group, optionally comprising one to three oxygen atoms or a group of formula (a). Particularly; Rbmay be a hydrogen atom or a C1-8 hydrocarbon group, optionally comprising one to three oxygen atoms or a group of formula (a). Particularly; Rbmay be a hydrogen atom or a C1-6 hydrocarbon group, optionally comprising one to two oxygen atoms or a group of formula (a). Particularly; Rbmay be a hydrogen atom or a C1-6 hydrocarbon group, optionally comprising one to two oxygen atoms or a group of formula (a). Particularly; Rbmay be a hydrogen atom or a C1-6 alkyl or a Ce aryl group or a group of formula (a). Particularly; Rbmay be a hydrogen atom or a Ci- 6 alkyl or a Ce aryl group. Particularly; Rbmay be a hydrogen atom or a C1-6 alkyl or a phenyl group. Particularly; Rbmay be a hydrogen atom or a C1-4 alkyl or a phenyl group. Particularly; Rbmay be a hydrogen atom or a C1-3 alkyl or a phenyl group. Particularly; Rbmay be a hydrogen atom or a C1-2 alkyl group. Particularly; Rbmay be a hydrogen atom or a methyl group. Particularly; Rbmay be a hydrogen atom.

[0020] It is particularly preferred that neither Ranor Rbcomprise any C-C double bond.

[0021] It is, furthermore, preferred that the compound of the formula (II) is a compound of the formula (III) or (Illa), particularly of formula (III). According to any embodiments of the invention, the compound of formula (II) is preferably of formula

[0022] According to any embodiments of the invention, the oxidative cleavage may be carried out under normal condition known by the person skilled in the art, i.e. in the presence of an oxidizing agent such as ozone, reaction also known as ozonolysis, OsO4 / NaIO4, KMnO4 / NaIO4, RuC13 / NaIO4, RuCh / NaOCl, H2O2 / NaIO4 or organic peroxide / NaIO4. Particularly, the oxidative cleavage may be an ozonolysis; i.e. compound of formula (II) reacts with ozone. Even more particularly, the oxidative cleavage may be an ozonolysis, followed by a reductive step.

[0023] As pointed before, pyridinium chlorochromate (PCC) is a highly toxic reagent. It is therefore obvious, and hereby to be explicitly stressed PCC is excluded reagent used for the oxidative cleavage of this invention.

[0024] For the sake of clarity, by the expression “reductive step” or similar, it is understood by a person skilled in the art that the intermediate formed, to obtain compound of formula (I), is treated with at least one reducing agent, which is well known to a person skilled in the art. Such treatment with a reducing agent can be performed during the work-up. As nonlimiting examples of said reducing agents one may cite the following: an amine in particular a tertiary amine or a pyridine, a sulfite, such as an alkaline sulfite (e.g. sodium or potassium sulfite, sodium bisulfite), a C2-6 dialkyl sulfide such as dimethyl sulfide or methylphenylsulfide, Na salt of 3,3 '-Thiodipropionic acid, triphenylphosphine, Zn / AcOH, Zn / AcOH / water, Na2S, thiourea, thiodiglycol, 3,3 '-thiodipropanol, 3,3 '-thiodipropionitrile, H2and Pd / C or Raney / Ni, P(OMe)3, P(OEt)3, P(OPh)3MeO(SO)OMe, MeSSMe, etc. In particular one may cite a sulfite, such as an alkaline sulfite (e.g. sodium or potassium sulfite, sodium bisulfite) optionally in combination with Na salt of 3,3 '-thiodipropionic acid or a C2-6 dialkyl sulfide such as dimethyl sulfide.

[0025] The ozonolysis 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 of current use in ozonolysis reactions can be used for the purposes of the invention. Non-limiting examples include water, C5-10 saturated hydrocarbon solvents such as hexane or cyclohexane, saturated C4-10 ethers or esters such as AcOEt, tetrahydrofuran, dioxane or MTBE, saturated carboxylic acids such as acetic or propionic acid, saturated polar solvents such as acetonitrile, alcohols such as isopropanol, methanol, butanol or ethanol, saturated ketones such as butanone or isobutylmethylketone, chlorinated alkane such as chloroform or dichloromethane, or mixtures thereof. The exact choice of the solvent is a function of the compound of formula (II) and reaction speed required. The person skilled in the art is well able to select the solvent most convenient in each case to optimize the ozonolysis reaction. Particularly, the solvent used in the ozonolysis comprise water; i.e. water only or at least one of organic solvent and water. Surfactants may also be added in the reaction medium, particularly when the solvent used in the ozonolysis comprises water. The water can be added to the reaction medium in a large range of concentrations. As non-limiting examples, one can cite as water concentration values ranging from 0.5 wt% to 5 wt%, relative to the amount of the compound of formula (II). Non-limiting examples of suitable surfactant may include sodium dodecyl sulfate, bis[4-({2-(methoxycarbonyl) phenyl }amino)-4- oxobutanoic acid]-polyethylene glycol 1000, Triton X-100, TPGS-750-M.

[0026] The temperature at which the oxidation can be carried out is preferably in the range of between -100°C and 40°C, particularly, in the range of between -80°C and 20°C, particularly, in the range of between -40°C and 10°C, particularly, in the range of between -20°C and 10°C, particularly, in the range of between -10°C and 10°C, even more particularly, in the range of between 0°C and 10°C. Of course, a person skilled in the art is 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.

[0027] The ozone can be added to the reaction medium in a large range of concentrations. As non-limiting examples, one can cite as ozone concentration values ranging from 0.5 wt% to 20 wt% in oxygen or air. It goes without saying that the optimum concentration of ozone will depend, as the person skilled in the art knows, on the nature of the compound of formula (II), if the process is run in batch or continuously, the desired conversion, as well as the desired time of reaction. 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 the ozone to obtain this range of concentration as a function of the process is batch or continuous.

[0028] The reducing agent can be added to the reaction medium in a large range of concentrations. As non-limiting examples, one can cite as reducing agent concentration values those ranging from 0.5 molar equivalents to 10 molar equivalents, relative to the amount of compound of formula (II). Preferably, the reducing agent concentration will be comprised between 0.8 molar equivalents to 10 molar molar equivalents. Even more preferably, the reducing agent concentration will be comprised between 1 molar equivalents to 5 molar equivalents. It goes without saying that the optimum concentration of reducing agent will depend, as the person skilled in the art knows, on the nature of the latter, on the nature of the compound of formula (II), the desired conversion, as well as the desired time of reaction.

[0029] 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.

[0030] According to any embodiments of the invention, the process for preparing compound of formula (I) comprises preferably the steps of a) reacting ( compound of formula (IV) erein Raand Rb, independently from each other, are a hydrogen atom or i-i6 hydrocarbon group, optionally comprising one to three oxygen atoms; is a halogen atom; s MgY or a halogen atom th the proviso that if Z is MgY then X is a halogen atom; if Z is a halogen atom then X is MgY; to obtain a compound of formula (V) wherein Y has the same meaning as defined in formula (IV); b) reacting the compound of formula (V) with magnesium; c) reacting the compound obtain in step b) with isobutylene oxide in a presence of a copper catalyst to obtain a compound of formula (II); and d) the oxidative cleavage of compound of formula (II) as defined above.

[0031] According to any embodiments of the invention, Ramay preferably be a hydrogen atom or a C1-14 hydrocarbon group, optionally comprising one to three oxygen atoms. Particularly; Ramay be a hydrogen atom or a C1-12 hydrocarbon group, optionally comprising one to three oxygen atoms. Particularly; Ramay be a hydrogen atom or a C1-10 hydrocarbon group, optionally comprising one to three oxygen atoms. Particularly; Ramay be a hydrogen atom or a C1-8 hydrocarbon group, optionally comprising one to three oxygen atoms. Particularly; Ramay be a hydrogen atom or a C1-6 hydrocarbon group, optionally comprising one to two oxygen atoms. Particularly; Ramay be a hydrogen atom or a C1-6 alkyl or a Ce aryl group. Particularly; Ramay be a hydrogen atom or a C1-6 alkyl or a phenyl group. Particularly; Ramay be a hydrogen atom or a C1-4 alkyl or a phenyl group. Particularly; Ramay be a hydrogen atom or a C1-3 alkyl or a phenyl group. Particularly; Ramay be a hydrogen atom or a C1-2 alkyl group. Particularly; Ramay be a hydrogen atom or a methyl group. Particularly; Ramay be a hydrogen atom.

[0032] According to any embodiments of the invention, Rbmay be a hydrogen atom or a Ci-14 hydrocarbon group, optionally comprising one to three oxygen atoms. Particularly; Rbmay be a hydrogen atom or a C1-12 hydrocarbon group, optionally comprising one to three oxygen atoms. Particularly; Rbmay be a hydrogen atom or a C1-10 hydrocarbon group, optionally comprising one to three oxygen atoms. Particularly; Rbmay be a hydrogen atom or a C1-8 hydrocarbon group, optionally comprising one to three oxygen atoms. Particularly; Rbmay be a hydrogen atom or a C1-6 hydrocarbon group, optionally comprising one to two oxygen atoms. Particularly; Rbmay be a hydrogen atom or a C1-6 alkyl or a Ce aryl group. Particularly; Rbmay be a hydrogen atom or a C1-6 alkyl or a Ce aryl group. Particularly; Rbmay be a hydrogen atom or a C1-6 alkyl or a phenyl group. Particularly; Rbmay be a hydrogen atom or a C1-4 alkyl or a phenyl group. Particularly; Rbmay be a hydrogen atom or a C1-3 alkyl or a phenyl group. Particularly; Rbmay be a hydrogen atom or a C1-2 alkyl group. Particularly; Rbmay be a hydrogen atom or a methyl group. Particularly; Rbmay be a hydrogen atom.

[0033] According to any preferred embodiments of the invention, the compound of formula (V) is preferably of formula (VI) wherein Y has the same meaning as defined in formula (IV).

[0034] According to any preferred embodiments of the invention, Y is a Cl atom.

[0035] According to any preferred embodiments of the invention, Z is MgCl then X is a Cl atom or Z is a Cl atom then X is MgCl.

[0036] The (Ra)(Rb)C=CH-CHR2-X can be added to the reaction medium in a large range of concentrations. As non-limiting examples, one can cite as (Ra)(Rb)C=CH-CHR2-X concentration values ranging from 1 to 2 equivalents, relative to the amount of the compound of formula (IV). Preferably, the (Ra)(Rb)C=CH-CHR2-X concentration will be comprised between 1.1 to 1,5 equivalents, relative to the amount of the compound of formula (IV). It goes without saying that the optimum concentration of (Ra)(Rb)C=CH- CHR2-X will depend, as the person skilled in the art knows, on the nature of the compound of formula (IV), the desired conversion, as well as the desired time of reaction.

[0037] The preparation of compound of formula (V) or (VI) 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 wherein the compound of formula (IV) is soluble and which is of current use in this kind reactions can be used for the purposes of the invention. Non-limiting examples include C5-10 saturated hydrocarbon solvents such as hexane or cyclohexane, aromatic solvent such as toluene, saturated C4-10 ethers such as tetrahydrofuran, methyltetrahydrofuran, 4-methyltetrahydropyran, dioxane or MTBE, or mixture thereof. The exact choice of the solvent is a function of the compound of formula (V) or (VI) and reaction speed required. The person skilled in the art is well able to select the solvent most convenient in each case to optimize this reaction

[0038] The temperature at which the preparation of the compound of formula (V) or (VI) can be carried out is comprised between -100°C and 100°C, particularly, in the range of between -80°C and 100°C, particularly, in the range of between -40°C and 80°C, particularly, in the range of between -20°C and 80°C, particularly, in the range of between -10°C and 80°C, even more particularly, in the range of between 0°C and 80°C. Of course, a person skilled in the art is 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.

[0039] The magnesium in step b) can be added to the reaction medium in a large range of concentrations. As non-limiting examples, one can cite as magnesium concentration values ranging from 1 to 5 equivalents, relative to the amount of the compound of formula (V) or (VI). Preferably, the magnesium concentration will be comprised between 1 to 2 equivalents. It goes without saying that the optimum concentration of magnesium will depend, as the person skilled in the art knows, on the nature of the compound of formula (V) or (VI), the desired conversion, as well as the desired time of reaction.

[0040] The step b) 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 wherein the compound of formula (V) or (VI) is soluble and which is of current use in this kind reactions can be used for the purposes of the invention. Non-limiting examples include C5-10 saturated hydrocarbon solvents such as hexane or cyclohexane, aromatic solvent such as toluene, saturated C4-10 ethers such as tetrahydrofuran, methyltetrahydrofuran, 4- methyltetrahydropyran, dioxane or MTBE, or mixture thereof. The exact choice of the solvent is a function of the compound of formula (V) or (VI) and reaction speed required. The person skilled in the art is well able to select the solvent most convenient in each case to optimize this reaction.

[0041] The temperature at which the step b) can be carried out is comprised between 0°C and 100°C, particularly, in the range of between 0°C and 80°C, even more particularly, in the range of between 10°C and 70°C. Of course, a person skilled in the art is 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.

[0042] According to any embodiments of the invention, the copper catalyst is of formula CuW or CuW2wherein W is a halogen atom or a C1-6 carboxylate group. Non-limiting examples of suitable copper catalyst may include CuCl, CuCl2, Cu(OAc)2, Cu(OAc), Cu(OPiv) or Cu(OPiv)2

[0043] The copper catalyst in step c) can be added to the reaction medium in a large range of concentrations. As non-limiting examples, one can cite as copper catalyst concentration values ranging from 0.001 to 1 equivalents, relative to the amount of the compound obtained in step b). Preferably, the copper catalyst concentration will be comprised between 0.005 to 0.5 equivalents. It goes without saying that the optimum concentration of copper catalyst will depend, as the person skilled in the art knows, on the nature of the compound obtained in step b), the desired conversion, as well as the desired time of reaction.

[0044] The isobutylene oxide in step c) can be added to the reaction medium in a large range of concentrations. As non-limiting examples, one can cite as isobutylene oxide concentration values ranging from 0.8 to 2 equivalents, relative to the amount of the compound obtained in step b). Preferably, the isobutylene oxide concentration will be comprised between 0.9 to 1,2 equivalents. It goes without saying that the optimum concentration of isobutylene oxide will depend, as the person skilled in the art knows, on the nature of the compound obtained in step b), the desired conversion, as well as the desired time of reaction.

[0045] The step c) 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 wherein the compound obtained in step b) is soluble and which is of current use in this kind reactions can be used for the purposes of the invention. Non-limiting examples include C5-10 saturated hydrocarbon solvents such as hexane or cyclohexane, aromatic solvent such as toluene, saturated C4-10 ethers such as tetrahydrofuran, methyltetrahydrofuran, 4-methyltetrahydropyran, dioxane or MTBE, or mixture thereof. The exact choice of the solvent is a function of the compound obtained in step b) and reaction speed required. The person skilled in the art is well able to select the solvent most convenient in each case to optimize this reaction

[0046] The temperature at which the step c) can be carried out is comprised between 0°C and 100°C, particularly, in the range of between 0°C and 80°C, particularly, in the range of between 0°C and 50°C, even more particularly, in the range of between 10°C and 20°C. Of course, a person skilled in the art is 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.

[0047] The compound of formula (II) is, generally, a novel compound and present a number of advantages as explained above and shown in the Examples. Therefore, another object of the present invention is a compound of formula (II) in the form of any one of its isomers or a mixture thereof; wherein Raand Rb, independently from each other, are a hydrogen atom or a C1-16 hydrocarbon group, optionally comprising one to three oxygen atoms or a group of formula ) in the form of any one of its isomers or a mixture thereof.

[0048] Typical manners to execute the invention’s process are reported herein below in the examples.

[0049] Examples

[0050] 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 (XH) and 125 MHz (13C) or a Bruker Avance III 600 cryoprobe operating at 600 MHz (XH) and 150 MHz (13C). Spectra were internally referenced relative to tetramethyl silane 0.0 ppm. 'H NMR signal shifts are expressed in 8 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 8 ppm and hybridization from DEPT 90 and DEPT 135 experiments, C, quaternary; CH, methine; CH2, methylene; CH3, methyl.

[0051] Example 1

[0052] Preparation of compound of formula (I) according to the invention process a) Preparation of l-(4-(but-3-en-l-yl)phenyl)-2-methylpropan-2-ol: l-(3-buten-l-yl)-4-chlorobenzene:

[0053] In a 250 ml round bottomed flask was charged allylmagnesium chloride (52.3 g, 2M in tetrahydrofuran, 105 mmol). This solution was stirred at 25 °C. A solution of 4-chlorobenzyl chloride (15.4 g, 91 mmol) in tetrahydrofuran (30.4 g) was added over a period of 2 hours. Reaction mixture was then stirred further for 1 hour. Reaction mixture was quenched with acetic acid (31 g, 20% aqueous solution) at 15°C. After decantation, phases were separated. The organic phase was washed twice with water, 5% NaHCOs solution and evaporated down to yield crude l-(3-buten-l-yl)-4-chlorobenzene (15.7 g) which was purified by distillation (12.7 g, 84% yield). 5 H (500 MHz; CDC13; Me4Si) in ppm : 7.26-7.21 (m, 2H), 7.13-7.08 (m, 2H), 5.87-5.76 (m, 1H), 5.05- 4.95 (m, 2H), 2.67 (t, 2H), 2.38-2.31 (m, 2H) ppm.

[0054] 5 C (125 MHz; CDC13; Me4Si) in ppm : 140.2 (C), 137.6 (CH), 131.5 (C), 129.8 (CH), 128.4 (CH), 115.3 (CH2), 35.3 (CH2), 34.7 (CH2). l-(4-(3-buten-l-yl)phenyl)-2-methylpropan-2-ol:

[0055] In a 500 ml round bottomed flask were charged magnesium (2.97 g, 122 mmol) and tetrahydrofuran (80 g). Reaction mixture was stirred and heated at 60°C. l-(3-buten-l-yl)-4- chlorobenzene (20 g, 120 mmol) was added over a period of 2 hours. Reaction mixture was then stirred 20 hours at 60°C. Reaction mixture was then cooled down to 15°C, copper (I) chloride (0.12 g, 1.2 mmol) was added and isobutylene oxide (8.65 g, 120 mmol) was introduced over a period of 1 hour. Reaction mixture was quenched with citric acid (57.6 g, 20% aqueous solution) at 15°CAfter decantation, phases were separated. Organic phase was washed with 10% potassium citrate solution, 5% NaHCO3 solution and evaporated down to yield crude l-(4-(3-buten-l- yl)phenyl)-2-methylpropan-2-ol (22.6 g) which was purified by distillation (16.2 g, 66% yield).

[0056] 5 H (500 MHz; CDC13; Me4Si) in ppm : 7.16-7.10 (m, 4H), 5.90-5.82 (m, 1H), 5.07-4.96 (m, 2H), 2.73 (s, 2H), 2.69 (t, 2H), 2.40-2.33 (m, 2H) 1.49 (br, 1H), 1.22 (s, 6H) ppm.

[0057] 5 C (125 MHz; CDC13; Me4Si) in ppm : 140 (C), 138.1 (CH), 135.1 (C), 130.4 (CH), 128.3 (CH), 114.9 (CH2), 70.7 (C), 49.3 (CH2), 35.5 (CH2), 35.0 (CH2), 29.1 (CH3). b) Ozonolysis of l-(4-(but-3-en-l-yl)phenyl)-2-methylpropan-2-ol in a ace tonitrile / w citer mixture.

[0058] A 1.5L glass reactor equipped with a magnetic stirring bar was charged in air with l-(4-(but-3- en-l-yl)phenyl)-2-methylpropan-2-ol (20g, 96 mmol) followed by acetonitrile (800 g) and water (80 g). The reaction mixture was stirred and cooled to 1°C with an ice / water bath. Then a O3 / O2 mixture at 0.55wt% of ozone with a flow of 40 L / h was sparge into the reaction mixture for a period of 8h. GC analysis of an aliquot showed a full conversion and formation of aldehyde 3- (4-(2-hydroxy-2-methylpropyl)phenyl)propanal. The reaction mixture is then poured into a separation funnel and diluted with toluene (800 ml). The organic phase is then washed successively with a solution of Na2SOs 10% (2 x 250 ml and 3 x 125 ml) followed by water (2 x 250 ml). The organic phase is then dried over anh. Na2SO4, filtered. The peroxide index was measured and then the reaction mixture was concentrated in vacuo to give the desired crude aldehyde (17.8 g). Distillation under reduced pressure (bp: 96°C / 0.001 mbar) gave 3-(4-(2- hydroxy-2 -methylpropyl) phenyl)propanal (14.4 g, GC 99%, 69 mmol, 72% yield) as a colorless oil. 5H (500 MHz; CD2C12; Me4Si) in ppm: 1.17 (6H, s, Me), 1.43 (1H, br s, OH), 2.70 (2H, s), 2.75 (2H, t, J = 7.4 Hz, CH2), 2.92 (2H, t, J = 7.5 Hz, CH2), 7.13 (4H, s, CH arom.), 9.78 (1H, br s, CHO).

[0059] 5 C (125 MHz; CD2C12; Me4Si) in ppm : 28.06 (CH2), 29.39 (CH3), 45.63 (CH2), 49.61 (CH2), 70.89 (C), 128.36 (CH arom.), 131.03 (CH arom.), 136.35 (C arom.), 139.01 (C arom.), 201.98 (CHO).

[0060] Example 2 a) Preparation o / 2-methyl-l-(4-(4-methylpent-3-en-l-yl)phenyl)propan-2-ol

[0061] 1-chloro-4-(4-methylpent-3-en-l-yl)benzene

[0062] In a 2 L round bottomed flask were charged magnesium (15.1 g, 0.621 mol) and methyl tetrahydrofuran (300 g). This suspension was stirred at 20°C. A solution of 4-chlorobenzyl chloride (100 g, 0.621 mol) in methyl tetrahydrofuran (100 g) was added over a period of 2 hours. Reaction mixture was then stirred further for 1 hour. Prenyl chloride (74 g, 0.621 mol) was added over a period of 2 hours at 20°C. After 1 hour, reaction mixture was quenched with acetic acid (187 g, 20% aqueous solution) at 15°C. After decantation, phases were separated. Organic phase was washed twice with water, twice with 5% NaHCCh solution and evaporated down to yield crude l-chloro-4-(4-methylpent-3-en-l-yl)benzene (116.8 g) which was purified by distillation (88,3 g, 89% GC purity, 73% yield).

[0063] 'H NMR (500 MHz, CDC13): l-(3-buten-l-yl)-4-chlorobenzene; 5 = 7.25-7.22 (m, 2H), 7.12-7.08 (m, 2H), 5.15-5.10 (m, 1H), 2.59 (t, 2H), 2.29-2.23 (m, 2H), 1.68 (s, 3H) 1.54 (s, 3H) ppm.13C NMR (125 MHz, CDCI3): 5 = 140.8 (s), 132.5 (s), 131.4 (s), 129.8 (d), 128.3 (d), 123.2 (d), 35.4 (t), 29.9 (t), 25.7 (q), 17.7 (q) ppm.

[0064] 2-methyl-l-( 4-( 4-methylpent-3-en-l-yl)phenyl)propan-2-ol

[0065] In a 1 L round bottomed flask were charged magnesium (10.15 g, 0.418 mol) and methyl tetrahydrofuran (320 g). Reaction mixture was stirred and heated at 65°C. l-chloro-4-(4- methylpent-3-en-l-yl)benzene (80 g, 0.41 mol) was added over a period of 2 hours. Reaction mixture was then stirred 44 hours at 65°C. Reaction mixture was then cooled down to 15°C, copper (I) chloride (0.41 g, 4.1 mmol) was added, and isobutylene oxide (29.5 g, 0.41 mol) was introduced over a period of 2 hours. Reaction mixture was quenched with citric acid (200 g, 20% aqueous solution) at 15°C. Reaction mixture was stirred for 1 hour. After decantation, phases were separated. Organic phase was washed with 10% potassium citrate solution, 5% NaHCOs solution and evaporated down to yield crude 2- methyl-l-(4-(4-methylpent-3-en-l-yl)phenyl)propan-2-ol (108.6 g) which was purified by distillation (63.7 g, 67% yield).

[0066] 'H NMR (500 MHz, CDC13):2-methyl-l-(4-(4-methylpent-3-en-l-yl)phenyl)propan-2-ol

[0067] ; 5 = 7.15-7.10 (m, 4H), 5.20-5.15 (m, 1H), 2.73 (s, 2H), 2.63-2.58 (m, 2H), 2.25-2.31 (m, 2H) 1.68 (s, 3H), 1.56 (s, 3H), 1.22 (s, 6H) ppm.13C NMR (125 MHz, CDC13): 5 = 140.6 (s), 134.9 (s), 132.1 (s), 130.3 (d), 128.3 (d), 123.8 (d), 70.7 (s), 49.3 (t), 35.7 (t), 30.1 (t), 29.1 (q), 5.7 (q), 17.7 (q) ppm. b) Ozonolysis of 2-methyl-l-(4-(4-methylpent-3-en-l-yl)phenyl)propan-2-ol

[0068] A 150mL glass reactor equipped with a magnetic stirring bar was charged in air with 2-methyl- l-(4-(4-methylpent-3-en-l-yl)phenyl)propan-2-ol (5g, 21 mmol) followed by di chloromethane (100 mL). The reaction mixture was stirred and cooled to -75°C. Then a O3 / O2 mixture at 2.5wt% of ozone with a flow of 30L / h was sparge into the reaction mixture for a period of Ih. GC analysis of an aliquot showed a full conversion and formation of aldehyde 3-(4-(2-hydroxy-2- methylpropyl)phenyl)propanal. The reaction mixture is then quenched at -60°C with dimethylsulfide (3,lmL, 42mmol, 2eq) and stirred overnight. The reaction mixture peroxide content was checked and then solvent was removed with rotavap to give 6.3g of crude material. Purification by bulb to bulb distillation gave the desired aldehyde 3-(4-(2-hydroxy-2- methylpropyl)phenyl)propanal (3g, 14.5mmol, 70% yield) as a slightly yellow colored oil.

[0069] 5H (500 MHz; CD2CI2; Me4Si) in ppm: 1.17 (6H, s, Me), 1.43 (IH, br s, OH), 2.70 (2H, s), 2.75 (2H, t, J = 7.4 Hz, CH2), 2.92 (2H, t, J = 7.5 Hz, CH2), 7.13 (4H, s, CH arom.), 9.78 (IH, br s, CHO).

[0070] 5 C (125 MHz; CD2CI2; Me4Si) in ppm : 28.06 (CH2), 29.39 (CH3), 45.63 (CH2), 49.61 (CH2), 70.89 (C), 128.36 (CH arom.), 131.03 (CH arom.), 136.35 (C arom.), 139.01 (C arom.), 201.98 (CHO).

Claims

Claims1. A process for the preparation of a compound of formula (I)comprising the oxidative cleavage of compound of formula (II)in the form of any one of its isomers or a mixture thereof; wherein Raand Rb, independently from each other, are a hydrogen atom or a Ci-16 hydrocarbon group optionally comprising one to three oxygen atoms or a group of formulain the form of any one of its isomers or a mixture thereof.

2. The process according to claim 1, wherein Rais a hydrogen atom or a C1-6 alkyl or a Ce aryl group; preferably Rais a hydrogen atom.

3. The process according to any one of claims 1 to 2, wherein Rbis a hydrogen atom or a C1-6 alkyl, a Ce aryl group; preferably Rbis a hydrogen atom.

4. The process according to any one of claims 1 to 3, wherein the oxidative cleavage is an ozonolysis5. The process according to claim 4, wherein the ozonolysis is followed by a reductive step.

6. The process according to claim 5, wherein the reductive step is carried out with a reducing agent being selected from the group consisting of an amine in particular a tertiary amine or a pyridine, supported amine, a sulfite, a sulfide, Na salt of 3,3'- thiodipropionic acid, triphenylphosphine, Zn / AcOH, Zn / AcOH / water, Na?S, thiourea, thiodiglycol, 3,3 '-thiodipropanol, thioethanediol, 3,3 '-thiodipropionitrile, H2 and Pd / C or Raney / Ni, P(OMe)3, P(OEt)3, P(Oct)3, P(Ph)3P(OPh)3MeO(SO)OMe, MeSSMe.

7. The process according to any one of claims 1 to 6, wherein the ozonolysis is carried out in presence of water.

8. The process according to any one of claims 1 to 7, wherein the compound of formula (II) is of formula (III).

9. The process according to claim 8, wherein the process for preparing compound of formula (III) comprises the step of a) reacting CH2=CH-CH2-X with a compound of formulawherein Y is a halogen atom;Z is MgY or a halogen atom with the proviso that if Z is MgY then X is a halogen atom; or if Z is a halogen atom then X is MgY; to obtain a compound of formulawherein Y has the same meaning as defined in formula (IV);b) reacting the compound of formula (VI) with magnesium; c) reacting the compound obtain in step b) with isobutylene oxide in a presence of a copper catalyst to obtain a compound of formula (III); and d) the oxidative cleavage of compound of formula (III) as defined in claims 1 to 8.in the form of any one of its isomers or a mixture thereof; wherein Raand Rb, independently from each other, are a hydrogen atom or a Ci-16 hydrocarbon group optionally comprising one to three oxygen atoms or a group of formulain the form of any one of its isomers or a mixture thereof.

11. The compound according to claim 10, wherein the compound of formula (II) is of formula12. The compound according to claim 10, wherein the compound of formula