BR122022026833B1 - PROCESS FOR PREPARING A COMPOSITION AND (-)-AMBROX - Google Patents

Abstract

The present invention relates to a process for the carbonylation of allylic alcohols at low temperature, low pressure and/or low catalyst load. In an alternative embodiment, an allyl alcohol acylation product is used for the carbonylation. The present invention also relates to the preparation of by-product products of these carbonylation products and specifically of (-)ambrox.

Description

BACKGROUND OF THE INVENTION

[001] The present invention relates to a process for carbonylation of allylic alcohols at low temperature, low pressure and/or low catalyst load. In an alternative embodiment, an allyl alcohol acylation product is used for the carbonylation. The present invention also relates to the preparation of conversion products of these carbonylation products and specifically of (-)-ambrox.

STATE OF THE TECHNIQUE

[002] The carbonylation products of allyl alcohols are valuable intermediates for the preparation of a multitude of commercial products. By carbonylation of the allylic alcohols nerolidol and farnesol, it is possible, for example, to obtain carboxylic acids which, after reduction to the corresponding alcohols, can be cyclized to give valuable flavor chemicals. For example, (3E,7E)-homofarnesilic acid from the E-nerolidol carbonylation can undergo a reduction to obtain (3E,7E)-homofarnesol and the latter can be further cyclized to obtain (-)-ambrox

[003] Processes for carbonylation of allylic alcohols to give their C1-extended linear carboxylic acids or carboxylic esters in the presence of homogeneous and also heterogeneous catalysts are known from the literature. However, these processes are economically disadvantageous for several reasons. For example, it is known that the direct carbonylation of allylic alcohols requires adverse conditions with regard to temperature and pressure and high catalyst loads; in most cases, moreover, high conversions are only achievable with the addition of halide-containing additives, even when using high pressures or temperatures or catalyst loads. There is therefore a need for a process which allows for the economically advantageous preparation of allyl alcohol carbonylation products.

[004] Bertleff, W., Roeper, M., and Sava X. 2007, in Ullmann's Encyclopedia of Industrial Chemistry, vol. 7, pages 74-98, 2012, Wiley-VCH describe carbonylation methods of industrial relevance.

[005] Tsuji et al. in J. Am. Chem. Soc. 86, 1964, 4350-4353 describe the catalytic carbonylation of allylic compounds using palladium(II) chloride. Specifically, allyl chloride, allyl alcohol and analogous compounds react with CO in organic solvents, giving the corresponding carboxylic esters with ethanol. 3-Butenoic anhydride is obtained from allyl alcohol in benzene as a solvent. The amount of palladium chloride used, based on the allyl compound, is greater than 5 mol% at pressures of 100 to 150 bar and at temperatures greater than 80°C.

[006] B. Gabriele et al. in Journal of Molecular Catalysis A, 111, 1996, 43-48 describe the carbonylation of allylic alcohols to give unsaturated acids or esters. The conversion is carried out in dimethylacetamide or methanol/dimethylacetamide mixtures at pressures of 50-100 bar and temperatures greater than 80°C using a Pd catalyst at 2 mol% to 4 mol% loadings.

[007] T. Mandai in a review article of the Handbook of Organopalladium Chemistry for Organic Synthesis, editor: E. Negishi, Wiley-VCH, New York, vol. 2, 2002, 2505-2517 describes, inter alia, the carbonylation of allyl compounds with homogeneous palladium catalysts. It should be noted that the carbonylation of allylic alcohols requires severe reaction conditions. It is also stated that the carbonylation of acetylated allylic alcohols, such as the structurally isomeric compounds (A) and (B), is generally difficult. According to the teaching of this document, however, the conversion succeeds in the presence of catalytic amounts of NaBr.

[008] ACS Catal., 4, 2014, 2977-2989, in a review article, also describes the carbonylation of allyl compounds with homogeneous palladium catalysts.

[009] By the process as described in the literature, the direct carbonylation of allylic alcohols requires high pressures or temperatures or catalyst loads or the addition of halides as an additive, and usually even a combination of at least two of these conversion enhancement measures, in order to achieve sufficiently high reaction rates.

[0010] For example, US 4,801,743 describes the carbonylation of allyl alcohol (2-propene-1-ol) using a heterogeneous Pd catalyst in the absence of water and in the presence of a catalytically active amount of a hydrogen halide selected from HF, HCl, HBr and HI at pressures greater than 150 bar and temperatures greater than 80°C.

[0011] EP 0428979 A2 describes the carbonylation of allylic butenoyls and butenol esters using a homogeneous Rh catalyst in the presence of HBr or Hl at CO pressures from 1 to 200 bar and temperatures from 10 to 250°C.

[0012] The aforementioned documents describe processes for carbonylation of allyl alcohols to give their C1-extended linear carboxylic acids or carboxylic esters. What is not described, however, is the carbonylation of allyl alcohols having terpene-type hydrocarbyl radicals and specifically the carbonylation of linalool to give E/Z-4,8-dimethyl-3,7-nonadienoic acid and E-nerolidol or farnesol to give E/Z-homofarnesilic acid. All processes described in the aforementioned documents also have one or more drawbacks that make them seem unsuitable for use for said conversions. For example, the catalysts described in the above-mentioned documents have too low an activity or the processes involve excessively severe reaction conditions (with respect to acid, CO pressure, temperature) to allow effective economical carbonylation of allylic alcohols in general, and specifically the mentioned allylic alcohols having hydrocarbyl radicals of the terpene type.

[0013] For example, processes that require high pressure operation are industrially very expensive. In many of the mentioned processes, the amount of catalyst used based on the substrate to be carbonylated is also very high. In the case of using homogeneous catalyst systems which are generally discharged together with the product, high costs arise as a result of catalyst recycling and unavoidable catalyst losses. Also problematic is the use of added hydrohalic acids and salts thereof. Due to the high corrosiveness of these compounds, it is necessary to use reactors made of particularly high quality steels. Furthermore, process conditions of this type are unsuitable for the conversion of E-nerolidol to homofarnesilic acid, since E-nerolidol does not have adequate stability towards strong acids such as HI.

[0014] Processes for carbonylation of E-nerolidol in the presence of homogeneous catalysts to give homofarnesilic acid or homofarnesilic acid alkyl esters are known in principle.

[0015] WO 92/06063 describes a process for preparing unsaturated carboxylic acids by carbonylation of the corresponding allylic alcohols, for example, the carbonylation of (E)-nerolidol with the addition of catalytic amounts of palladium(II) chloride.

[0016] What is also described is the reduction of the carbonylation product thus obtained to give homofarnesol or monocyclohomofarnesol and the acid-catalyzed cyclization of homofarnesol to obtain 3a,6,6,9a-tetramethyldodecahydronaphtho-[2,1 -b]-furan, an ambergris-like fragrance. A disadvantage of this process is that the carbonylation reaction takes place at high CO pressures of around 70 bar. Furthermore, a high catalyst loading of 0.6 mol% is used.

[0017] EP 0146859 A2 describes a process for the preparation of 4-substituted but-3-ene-1-carboxylic acids and esters thereof by carbonylation in the presence or absence of a lower alkanol (specifically methanol) with complexes of a halide of palladium and a tertiary organic phosphine. The conversion is carried out at pressures from 200 to 700 bar and temperatures from 50 to 150°C.

[0018] It is also known that substitutes for CO that allow the conversion of ambient pressure can be used for carbonylation. WO 2015/061764 and Tetrahedron: Asymmetry, 20, 2009, 16371640 describe the Pd-catalyzed use of N,N-dimethylformamide dimethyl acetal (DMFDMA) as a CO substitute in the conversion of E-nerolidol and subsequent hydrolysis in methanol to ester homofarnesilic acid methyl. However, this two-stage process is synthetically complex and is also expensive due to the CO substitutes used, and is therefore not economical on an industrial scale for the carbonylation of allyl alcohols.

[0019] It is also known that allyl alcohols can be converted into the corresponding acetates and these acetates can be used as substrates in carbonylation reactions under comparatively mild conditions (pressures, for example, 30 bar below 100°C).

[0020] JOC, 53 1988, 3832-3828 describes the Pd or Pt catalyzed cyclizing carbonylation of cinnamyl acetates to 1-naphthol derivatives. The reaction is carried out in the presence of acetic anhydride and triethylamine at 160°C and 60 bar of CO. The reason given for the addition of acetic anhydride is the need to convert the 1-naphthol formed as an intermediate to the corresponding acetate, since free 1-naphthol would inhibit cyclocarbonylation. In terms of type, this reaction is a carbonylation in the presence of Pd and acetic anhydride, but does not lead to carboxylic acid derivatives.

[0021] Tetrahedron Letters, 29, 1988, 4945-4948 describes the conversion of allyl acetates in ethanol to the corresponding C1-extended carboxylic esters. Conversions are carried out at 30 to 80 bar of CO and at 50 to 80°C. However, the conversion is performed not only in the presence of a base, but also catalytic amounts of bromide ions, which is said to dramatically speed up the reaction. This document further notes that poor results have been obtained with Pd(II) catalysts such as palladium(II) acetate (Pd(OAc) 2 ).

[0022] JOC, 58, 1993, 1538-1545 describes the Pd(0) catalyzed alkoxycarbonylation of allyl acetates. This document also refers to the need for the presence of halide ions to accelerate the reaction. In contrast, only low carbonylation reactivity is attributed to allyl acetates.

[0023] There is thus no specific method in the literature for the direct carbonylation of allyl alcohols and specifically of E-nerolidol to give homofarnesilic acid (or homofarnesilic acid derivatives such as the corresponding salts or esters) which proceeds efficiently and economically under conditions of moderate reactions. This means that the conversion takes place at pressures in the region of no more than 30 bar of CO and/or at temperatures below 100°C and/or in the absence of halogen compounds selected from hydrohalic acids and alkali metal, alkaline earth metal or ammonium halides. or a combination of at least two of these measures.

[0024] It has been surprisingly found that even the addition of catalytic amounts of a carboxylic anhydride such as Ac2O (acetic anhydride) is sufficient to fully carbonylate allyl alcohols under mild reaction conditions and with low catalyst loadings for the corresponding carboxylic acid . Particularly advantageous results are achieved here with the addition of a nucleophilic reagent, such as an alkylpyridine, 4-(1-pyrrolidinyl)pyridine or a dialkylaminopyridine, specifically DMAP (4-dimethylaminopyridine). Particularly surprisingly, even the addition of catalytic amounts of acylation products of allyl alcohols without the addition of carboxylic anhydrides is sufficient to accelerate the reaction by several orders of magnitude. These acylation products of allylic alcohols can also be esters of allylic alcohols other than the substrate itself with carboxylic acids (for example, allyl acetate). In light of the prior art, the person skilled in the art, if considering the use of allyl alcohol acylating products entirely, would have used at least a stoichiometric amount of acylated allyl alcohol (or of an acylating agent). The fact that this reaction regime works as described with catalytic amounts of the activating reagent was unknown, was not obvious and is very advantageous for the efficiency of the overall process.

[0025] It is therefore an object of the present invention to provide a process for carbonylating allylic alcohols or their acylation products to obtain unsaturated carboxylic acids or salts thereof, in which the aforementioned disadvantages are avoided.

[0026] In a specific embodiment, it is an object of the invention to provide a process for carbonylation of E-nerolidol in which a product mixture comprising acid (3E,7E)-4,8,12-trimethyltrideca-3,7,11- trienoic acid (homofarnesilic acid) and (3Z,7E)-4,8,12-trimethyltrideca-3,7,11-trienoic acid or salts thereof are obtained.

[0027] It has now been found that, surprisingly, the carbonylation of allyl alcohols and allyl alcohol derivatives to give C1-extended unsaturated carboxylic acids or corresponding carboxylic salts can be conducted at temperatures not exceeding 100°C. It has been found that, advantageously, the carbonylation of alcohols and allyl alcohol derivatives to give C1-extended unsaturated carboxylic acids or corresponding carboxylic salts can be carried out at temperatures not exceeding 100°C and at low pressure, for example at a pressure not over 30 bar. It has further been found that, advantageously, the carbonylation of alcohols and allyl alcohol derivatives to give C1-extended unsaturated carboxylic acids or corresponding carboxylic salts can be conducted at temperatures not exceeding 100°C with simultaneously low catalyst loadings of less than 0, 3 mol% and simultaneously at low pressure, for example at a pressure not exceeding 30 bar. It has further been found that the conversion can also be carried out without addition of accelerating halides.

SUMMARY OF THE INVENTION

[0028] The invention firstly provides a process for preparing a composition comprising at least one unsaturated carboxylic acid of general formula (I). or a salt thereof, wherein R1 is hydrogen, straight or branched C1-C24-alkyl, straight or branched C2-C24-alkenyl with 1, 2, 3 or more than 3 CC double bonds, unsubstituted C5-C12-cycloalkyl or C5-C12-cycloalkyl substituted by 1, 2 or 3 C1-C6-alkyl radicals or unsubstituted aryl or aryl substituted with 1, 2 or 3 C1-C6-alkyl radicals, R2 is hydrogen, linear C1-C24-alkyl or branched or C2-C24-alkenyl straight or branched with 1, 2, 3 or more than 3 CC double bonds, or R1 and R2 together with the carbon atom to which they are attached are unsubstituted C5-C7-cycloalkyl or are cycloalkyl -C5-C7 containing 1, 2 or 3 linear or branched C1-C6-alkyl radicals, in which an allylic alcohol selected from compounds of general formulas (II.1) and (II.2) is subjected to a carbonylation by reaction with carbon monoxide in the presence of a transition metal catalyst comprising at least one metal from groups 8, 9 and 10 of the Periodic Table of Elements, wherein the reaction is additionally carried out in the presence of at least an organic phosphorus compound as binder and in the presence of a substoichiometric amount, based on the allylic alcohol, of a compound A) selected from aliphatic C1-C12-monocarboxylic acid anhydrides, aliphatic C4-C20-dicarboxylic acid anhydrides, aliphatic acid anhydrides cycloaliphatic C7-C20-dicarboxylic acids, anhydrides of aromatic C8-C20-dicarboxylic acids and acylated allylic alcohols of formulas (III.1) and (III.2) in which R3 is hydrogen, straight or branched C1-C24-alkyl, straight or branched C2-C24-alkenyl with 1, 2, 3 or more than 3 CC double bonds, unsubstituted C5-C12-cycloalkyl or C5-C12-cycloalkyl substituted by 1, 2 or 3 C1-C6-alkyl radicals or unsubstituted aryl or aryl substituted with 1, 2 or 3 C1-C6-alkyl radicals, R4 is hydrogen, linear or branched C1-C24-alkyl or C2-alkenyl C24 linear or branched with 1, 2, 3 or more than 3 CC double bonds, or R3 and R4 together with the carbon atom to which they are attached are unsubstituted C5-C7-cycloalkyl or are C5-C7-cycloalkyl containing 1 , 2 or 3 linear or branched C1-C6-alkyl radicals, R5 is C1-C5-alkyl, and wherein the reaction is carried out at a temperature not exceeding 100°C.

[0029] The embodiment of the process of the invention in which an allyl alcohol is selected from compounds of the general formulas (II.1) and (II.2) is used in the presence of a compound A) for the reaction is also referred to hereinafter as “Variant 1”.

[0030] A specific embodiment of variant 1 a process for preparing a composition comprising at least one unsaturated carboxylic acid of general formula (I). or a salt thereof, wherein R1 is hydrogen, straight or branched C1-C24-alkyl, straight or branched C2-C24-alkenyl with 1, 2, 3 or more than 3 CC double bonds, non-C5-C12-cycloalkyl unsubstituted or C5-C12-cycloalkyl substituted by 1, 2 or 3 C1-C6-alkyl radicals or unsubstituted aryl or aryl substituted with 1, 2 or 3 C1-C6-alkyl radicals, R2 is hydrogen, linear C1-C24-alkyl or branched or straight or branched C2-C24-alkenyl with 1, 2, 3 or more than 3 CC double bonds, or R1 and R2 together with the carbon atom to which they are attached are unsubstituted C5-C7-cycloalkyl or are C5-C7-cycloalkyl containing 1, 2 or 3 linear or branched C1-C6-alkyl radicals, in which an allylic alcohol selected from compounds of general formulas (II.1) and (II.2) is subjected to a carbonylation by reaction with carbon monoxide in the presence of a transition metal catalyst comprising at least one metal from groups 8, 9 and 10 of the Periodic Table of Elements, wherein the reaction is additionally carried out in the presence of at least an organic phosphorus compound as binder and in the presence of a substoichiometric amount, based on the allylic alcohol, of a compound A) selected from aliphatic C1-C12-monocarboxylic acid anhydrides, aliphatic C4-C20-dicarboxylic acid anhydrides, aliphatic acid anhydrides cycloaliphatic C7-C20-dicarboxylic acids, anhydrides of aromatic C8-C20-dicarboxylic acids and acylated allylic alcohols of formulas (III.1) and (III.2) in which R3 is hydrogen, straight or branched C1-C24-alkyl, straight or branched C2-C24-alkenyl with 1, 2, 3 or more than 3 CC double bonds, unsubstituted C5-C12-cycloalkyl or C5-C12-cycloalkyl substituted by 1, 2 or 3 C1-C6-alkyl radicals or unsubstituted aryl or aryl substituted with 1, 2 or 3 C1-C6-alkyl radicals, R4 is hydrogen, linear or branched C1-C24-alkyl or C2-alkenyl C24 linear or branched with 1, 2, 3 or more than 3 CC double bonds, or R3 and R4 together with the carbon atom to which they are attached are unsubstituted C5-C7-cycloalkyl or are C5-C7-cycloalkyl containing 1 , 2 or 3 linear or branched C1-C6-alkyl radicals, R5 is C1-C5-alkyl, and wherein the reaction is carried out at a temperature not exceeding 100°C and a pressure not exceeding 30 bar.

[0031] In an alternative embodiment, it is possible to use an acylated allylic alcohol for the carbonylation. In this variant too, it is possible to carry out the reaction under advantageously mild reaction conditions. According to the invention, the conversion into this variant is carried out in the presence of water. Therefore, the invention further provides a process for preparing a composition comprising at least one unsaturated carboxylic acid of general formula (I). or a salt thereof, wherein R1 is hydrogen, straight or branched C1-C24-alkyl, straight or branched C2-C24-alkenyl with 1, 2, 3 or more than 3 CC double bonds, non-C5-C12-cycloalkyl unsubstituted or C5-C12-cycloalkyl substituted by 1, 2 or 3 C1-C6-alkyl radicals or unsubstituted aryl or aryl substituted with 1, 2 or 3 C1-C6-alkyl radicals, R2 is hydrogen, linear C1-C24-alkyl or branched or straight or branched C2-C24-alkenyl with 1, 2, 3 or more than 3 CC double bonds, or R1 and R2 together with the carbon atom to which they are attached are unsubstituted C5-C7-cycloalkyl or are C5-C7-cycloalkyl containing 1, 2 or 3 linear or branched C1-C6-alkyl radicals, in which an acylated allylic alcohol is selected from compounds of the general formulas (IV.1) and (IV.2) wherein R6 is C1-C5-alkyl, is subjected to carbonylation by reaction with carbon monoxide in the presence of a transition metal catalyst comprising at least one metal from groups 8, 9 and 10 of the Periodic Table of Elements, wherein the reaction is additionally carried out in the presence of at least one organic phosphorus compound as a binder and in the presence of water and wherein the reaction is carried out at a temperature not exceeding 100°C.

[0032] The embodiment of the process of the invention in which an acylated allyl alcohol selected from compounds of the general formulas (IV.1) and (IV.2) is used for the reaction is also referred to hereinafter as "variant 2".

[0033] A specific embodiment of variant 2 is a process for preparing a composition comprising at least one unsaturated carboxylic acid of general formula (I). or a salt thereof, in which R1 is hydrogen, straight or branched C1-C24-alkyl, straight or branched C2-C24-alkenyl with 1, 2, 3 or more than 3 CC double bonds, non-C5-C12-cycloalkyl unsubstituted or C5-C12-cycloalkyl substituted by 1, 2 or 3 C1-C6-alkyl radicals or unsubstituted aryl or aryl substituted with 1, 2 or 3 C1-C6-alkyl radicals, R2 is hydrogen, linear C1-C24-alkyl or branched or straight or branched C2-C24-alkenyl with 1, 2, 3 or more than 3 CC double bonds, or R1 and R2 together with the carbon atom to which they are attached are unsubstituted C5-C7-cycloalkyl or are C5-C7-cycloalkyl containing 1, 2 or 3 linear or branched C1-C6-alkyl radicals, in which an acylated allylic alcohol is selected from compounds of the general formulas (IV.1) and (IV.2) wherein R6 is C1-C5-alkyl, is subjected to carbonylation by reaction with carbon monoxide in the presence of a transition metal catalyst comprising at least one metal from groups 8, 9 and 10 of the Periodic Table of Elements, wherein the reaction is additionally carried out in the presence of at least one organic phosphorus compound as a binder and in the presence of water and wherein the reaction is carried out at a temperature not exceeding 100°C and a pressure not exceeding 30 bar.

[0034] Another alternative embodiment relates to processes for preparing a composition comprising at least one unsaturated carboxylic acid of general formula (I). or a salt thereof, wherein R1 is hydrogen, straight or branched C1-C24-alkyl, straight or branched C2-C24-alkenyl with 1, 2, 3 or more than 3 CC double bonds, unsubstituted C5-C12-cycloalkyl or C5-C12-cycloalkyl substituted by 1, 2 or 3 C1-C6-alkyl radicals or unsubstituted aryl or aryl substituted with 1, 2 or 3 C1-C6-alkyl radicals, R2 is hydrogen, linear C1-C24-alkyl or branched or C2-C24-alkenyl straight or branched with 1, 2, 3 or more than 3 CC double bonds, or R1 and R2 together with the carbon atom to which they are attached are unsubstituted C5-C7-cycloalkyl or are cycloalkyl -C5-C7 containing 1, 2 or 3 linear or branched C1-C6-alkyl radicals, in which an allylic alcohol selected from compounds of general formulas (II.1) and (II.2) is subjected to a carbonylation by reaction with carbon monoxide in the presence of a transition metal catalyst comprising at least one metal from groups 8, 9 and 10 of the Periodic Table of Elements, wherein the reaction is additionally carried out in the presence of at least an organic phosphorus compound as binder and in the presence of a substoichiometric amount, based on allyl alcohol, of a compound B) in which R10 and R11, independently of one another, are C1-C6-alkyl, C1-C6-fluoroalkyl or phenyl which is unsubstituted or substituted with a substituent selected from bromine, nitro and C1-C4-alkyl; and wherein the reaction is carried out at a temperature not exceeding 100°C. Specifically, the reaction is carried out at a temperature not exceeding 100°C and a pressure not exceeding 30 bar.

[0035] In this variant too, it is possible to conduct the reaction under advantageously moderate reaction conditions. The embodiment of the process of the invention in which an allylic alcohol selected from compounds of the general formulas (II.1) and (II.2) is used for reaction in the presence of a compound B) is also referred to hereinafter as "variant 3". .

[0036] The invention also provides a process for preparing (-)-ambrox (VIII) in which a1) a mixture of (3E,7E)-4,8,12-trimethyltrideca-3,7,11-trienoic acid and (3Z,7E)-4,8,12-trimethyltrideca-3,7,11 -trienoic acid obtained by a process as defined above is provided; b1) the mixture of (3E,7E)-4,8,12-trimethyltrideca-3,7,11-trienoic acid and (3Z,7E)-4,8,12-trimethyltrideca-3,7,11-trienoic acid it is subjected to a separation to obtain (3E,7E)-4,8,12-trimethyltrideca-3,7,11-trienoic acid; c1) (3E,7E)-4,8,12-trimethyltrideca-3,7,11-trienoic acid is subjected to a reduction to obtain (3E,7E)-homofarnesol (VI); d1) (3E,7E)-homofarnesol (VI) is subjected to a cyclization to obtain (-)-ambrox (VIII); or a2) a mixture of (3E,7E)-4,8,12-trimethyltrideca-3,7,11-trienoic acid and (3Z,7E)-4,8,12-trimethyltrideca-3,7,11- trienoic acid obtained by a process as defined above; b2) the mixture of (3E,7E)-4,8,12-trimethyltrideca-3,7,11-trienoic acid and (3Z,7E)-4,8,12-trimethyltrideca-3,7,11-trienoic acid it is subjected to a separation to obtain (3E,7E)-4,8,12-trimethyltrideca-3,7,11-trienoic acid; c2) (3E,7E)-4,8,12-trimethyltrideca-3,7,11-trienoic acid is subjected to cyclization to obtain sclareolide (VII); d2) sclareolide (VII) is subjected to a reduction to obtain (-)-ambrox (VIII).

DESCRIPTION OF THE INVENTION

[0037] The processes of the invention for preparing a composition comprising at least one unsaturated carboxylic acid of general formula (I) have the following advantages:

[0038] - Process variant 1 allows the economical and effective conversion of allylic alcohols into their C1-extended unsaturated carboxylic acids or the corresponding carboxylic salts. Much milder reaction conditions (with simultaneously very low catalyst loadings) are possible here than in known processes from the prior art. Specifically, the conversion is possible at lower temperatures and/or at a lower pressure and/or at a lower catalyst loading than in known processes.

[0039] - It is particularly advantageous that, in variant 1 of the process of the invention, the conversion in the presence of catalytic amounts of anhydride (i.e., substoichiometric) is sufficient to fully carbonylate allyl alcohols under moderate reaction conditions and at low loads of catalyst for the corresponding carboxylic acids. Particularly surprisingly, even the addition of catalytic amounts of other anhydride formers such as allyl acetate (propenyl acetate) or different acylation products of allyl alcohols is sufficient to distinctly accelerate the reaction. Addition of additional anhydride is not necessary here. Without wishing to be bound by any theory, it is assumed that this is attributable to the fact that, under the reaction conditions, there is initial carbonylation of the added acylated allyl alcohol (e.g. allyl acetate CH2=CHCH2OAc) to give an intermediate anhydride (e.g. , CH2= CHCH2C(O)OAc) and the anhydride formed in situ activates the used allylic alcohol (e.g. nerolidol) with carboxylic acid elimination (e.g. CH2=CHCH2CO2H), simultaneously generating new acylated allyl alcohol (e.g. nerolidyl acetate) in turn be carbonylated again to give the corresponding intermediate anhydride (mixed anhydride of acetic acid and homofarnesilic acid).

[0040] - The possibility of using catalytic amounts of a nucleophilic reagent in process variant 1 is very advantageous for the overall process efficiency.

[0041] - The process of the invention according to variant 1 allows the carbonylation of allylic alcohols to obtain the corresponding carboxylic acids or carboxylic salts in a single reaction stage, that is, without the isolation of an intermediate. For example, it is unnecessary to activate allyl alcohol used in a first reaction step using stoichiometric amounts of the acylating agent.

[0042] - If the allyl alcohols used for carbonylation comprise other internal double bonds, these are essentially neither carbonylated nor isomerized.

[0043] - The alternative variant 2 of the process is based on the carbonylation of acylated alcohols to give their C1-extended unsaturated carboxylic acids in the presence of water under mild reaction conditions.

[0044] - The processes according to variants 1 and 2 make it possible to dispense with the use of added hydrohalic acids and their salts.

[0045] - The process according to variant 1 specifically allows the carbonylation of allylic alcohols having hydrocarbyl radicals of the terpene type and specifically the carbonylation of linalool to give E/Z-4,8-dimethyl-3,7-nonadienoic acid and of E-nerolidol or farnesol to give E/Z-homofarnesilic acid under mild reaction conditions.

[0046] - By the process according to variant 1, it is advantageously possible to carbonylate E-nerolidol to obtain a reaction mixture composed of (3E,7E)-4,8,12-trimethyltrideca-3,7,11-trienoic acid (homofarnesilic acid) and (3Z,7E)-4,8,12-trimethyltrideca-3,7,11-trienoic acid or their salts.

[0047] In the compounds of general formulas (I), (II.2), (III.2) and (IV.2) the wavy bond is supposed to indicate that the compound could be the pure Z isomer, the pure E isomer, or any E/Z mixture. It will be obvious to the person skilled in the art that, in the compounds of general formulas (I), (II.2) and (IV.2), the E and Z isomers can only exist when two different substituents R1 and R2 are attached to the double bond . In compounds of the general formula (III.2), the E and Z isomers can only exist when two different substituents R3 and R4 are attached to the double bond. The stereochemical configuration at the double bond is verified with the aid of the Cahn-Ingold-Prelog rules (see E/Z notation, https://en.wikipedia.org/wiki/E-Z_notation).

[0048] In the context of the present invention, the E/Z mixture of general formula (I) is also referred to as E/Z acid mixture of formula (I). In the E/Z acid mixture of the general formula (I), R1 and R2 have different meanings. The E/Z acid mixture of formula (I) comprises the 3-(E) isomer of the unsaturated carboxylic acid of formula I and the 3-(Z) isomer of the unsaturated carboxylic acid of formula I. The 3-(E) isomer of the unsaturated carboxylic acid of formula I is hereinafter referred to as the 3-(E) isomer of formula (I-E), and the 3-(Z) isomer of the unsaturated carboxylic acid as the 3-(Z) isomer of formula (I-Z ).

[0049] In the general formulas of compounds IZ and IE the R1 substituent has a higher priority according to IUPAC (International Union of Pure and Applied Chemistry) than the R2 substituent. According to IUPAC, the priority sequence of substituents is in accordance with the Cahn-Ingold-Prelog rule.

[0050] It is generally assumed that the transition metal catalyzed carbonylation and specifically the Pd catalyzed carbonylation proceeds via a pi-allyl complex which makes it possible to obtain respective reaction products comprising the compounds (I) from the compounds (II .1) or the compounds (II.2).

[0051] Preferably, the carbonylation is not carried out in the presence of an added hydrohalic acid and not in the presence of added alkali metal halide, alkaline earth metal halide or ammonium halide. The term "ammonium salt" means both salts deriving from NH4+ and mono-, di-, tri- and tetraorganylammonium salts. Specifically, carbonylation is not carried out in the presence of an added alkyl halide such as NaCl, NaBr, KCl, KBr, LiCl, LiBr, etc.

[0052] Preferably, the halide content of the carbonylation reaction mixture is not more than 2 mol%, preferably not more than 1 mol%, based on the allyl alcohol content of the general formulas (II .1) and (II.2) .

[0053] In the context of the present invention, the terms "acylated allyl alcohol", "allyl carboxylate", "acylation product of allyl alcohol" and "acylation product of an allyl alcohol" are used interchangeably.

[0054] The expression "aliphatic" in the context of the present invention comprises hydrocarbyl radicals in which the carbon atoms are arranged in straight or branched chains.

[0055] The expression "alkyl" and all alkyl moieties in alkoxy, alkylamino and dialkylamino in the context of the present invention comprises saturated, linear or branched hydrocarbon radicals having 1 to 4 ("C1-C4 alkyl"), 1 to 6 (“C1-C6-alkyl”), 1 to 10 (“C1-C10-alkyl”), 1 to 20 (“C1-C20-alkyl”) or 1 to 24 (“C1-C24-alkyl”) carbon atoms carbon. Examples of linear or branched C1-C4-alkyl are methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl. Examples of linear or branched C1-C6-alkyl, in addition to the definitions given for C1-C4-alkyl, are n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl. Examples of linear or branched C1-C10-alkyl, in addition to the definitions given for C1-C6-alkyl, are heptyl, octyl, nonyl, decyl and positional isomers thereof. Examples of C1-C20-alkyl, in addition to the definitions given for C1-C10-alkyl, are undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, heneicosyl, docosyl, tricosyl, tetracosyl, pentacosyl, hexacosyl, heptacosyl, octacosyl, nonacosyl, eicosyl and positional isomers thereof.

[0056] The expression "alkenyl" in the context of the present invention comprises unsaturated hydrocarbon radicals, linear or branched with 2 to 4 (C2-C4-alkenyl), 6, 8, 10, 16, 20 or 24 carbon atoms and one, two, three or more than three double bonds in any position. Examples of linear or branched C2-C24-alkenyl having one double bond are vinyl, allyl (2-propen-1-yl), 1-methylprop-2-en-1-yl, 2-buten-1-yl, 3- buten-1-yl, n-pentenyl, n-hexenyl, n-heptenyl, n-octenyl, n-nonyl, n-decenyl, n-undecenyl, n-dodecenyl, n-tridecenyl, n-tetradecenyl, n-pentadecenyl, n-hexadecenyl, n-heptadecenyl, n-octadecenyl, oleyl, n-nonadecenyl, n-eicosenyl, n-heneicosenyl, n-docosenyl, n-tricosenyl, n-tetracosenyl and the constitutional isomers thereof. Examples of linear or branched C4-C24-alkenyl having two or three double bonds in any position are n-butadienyl, n-pentadienyl, n-hexadienyl, n-heptadienyl, n-octadienyl, n-octatrienyl, n-nonadienyl, n- nonatrienyl, n-decadienyl, n-decatrienyl, n-undecadienyl, n-undecatrienyl, n-dodecadienyl, n-dodecatrienyl, n-tridecadienyl, n-tridecatrienyl, n-tetradecadienyl, n-tetradecatrienyl, n-pentadecadienyl, n-pentadecatrienyl, n-hexadecadienyl, n-hexadecatrienyl, n-heptadecadienyl, n-heptadecatrienyl, n-octadecadienyl, n-octadecatrienyl, n-nonadecadienyl, n-nonadecatrienyl, n-eicosadienyl, eicosatrienyl, n-heneicosadienyl, n-heneicosatrienyl, n-docosadienyl, n-docosatrienyl, n-tricosatrienyl, n-tricosatrienyl, n-tetracosadienyl, n-tetracosatrienyl, linolenyl and constitutional isomers thereof. Each double bond in C2-C24-alkenyl can (unless otherwise stated) in each case independently be in the E configuration or the Z configuration.

[0057] The expression "cycloalkyl" in the context of the present invention comprises monocyclic saturated hydrocarbon radicals having 3 to 8 ("C3-C8-cycloalkyl"), preferably 5 to 7 carbon ring members ("C5-C7-cycloalkyl ”). Examples of C3-C8-cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

[0058] The expression "heterocyclyl" (also referred to as heterocycloalkyl) in the context of the present invention encompasses monocyclic saturated cycloaliphatic groups generally having 5 to 8 ring atoms, preferably 5 or 6 ring atoms, in which 1 or 2 of the carbon atoms of the ring are replaced by heteroatoms or heteroatom-containing groups selected from oxygen, nitrogen, NH and N(C1-C4-alkyl). Examples of such heterocycloaliphatic groups are pyrrolidinyl, piperidinyl, tetrahydrofuranyl and tetrahydropyranyl.

[0059] The expression "aryl" in the context of the present invention comprises a mono-, di- or tricyclic aromatic ring system comprising 6 to 20 carbon ring members. Examples of unsubstituted C6-C10-aryl are phenyl and naphthyl. Examples of C6-C14-aryl are phenyl, naphthyl, anthracenyl and phenanthrenyl. Substituted aryl groups generally have 1, 2, 3, 4 or 5 identical or different substituents, preferably 1, 2 or 3 substituents. Suitable substituents are especially selected from alkyl, cycloalkyl, aryl, alkoxy, dialkylamino. Examples of aryl having 1, 2 or 3 substituents selected from C1-C6-alkyl are tolyl, xylyl and mesityl.

[0060] The expression "hetaryl" in the context of the present invention comprises a five- to six-membered aromatic heteromonocycle comprising one, two, three or four heteroatoms from the oxygen, nitrogen and sulfur group and 9- or 10-membered aromatic heterobicycles, for example , carbon-linked 5-membered heteroaryl comprising one to three nitrogen atoms or one or two nitrogen atoms and one sulfur or oxygen atom as ring members, such as furyl, thienyl, pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, oxazolyl, thiazolyl, imidazolyl, 4-imidazolyl, 1,2,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,2,4-triazolyl, 1,3,4-oxadiazolyl; 5-membered nitrogen-linked heteroaryl comprising one to three nitrogen atoms as ring members, such as pyrrol-1-yl, pyrazol-1-yl, imidazol-1-yl, 1,2,3-triazol-1-yl and 1,2,4-triazol-1-yl; 6-membered heteroaryl comprising one to three nitrogen atoms as ring members, such as pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl and 1,2,4-triazinyl.

[0061] Halogen is fluorine, chlorine, bromine or iodine. The halide is fluorine, chloride, bromide or iodide.

[0062] Alkali metals correspond to elements in group 1 of the Periodic Table of Elements according to IUPAC, for example lithium, sodium, potassium, rubidium or cesium, preferably lithium, sodium or potassium, especially sodium or potassium.

[0063] The alkaline earth metals correspond to the elements of group 2 of the Periodic Table of Elements according to IUPAC, for example, beryllium, magnesium, calcium, strontium or barium, preferably magnesium or calcium.

[0064] Group 8 of the Periodic Table of Elements according to IUPAC comprises, among others, iron, ruthenium and osmium. Group 9 of the Periodic Table of Elements according to IUPAC comprises, inter alia, cobalt, rhodium, iridium. Group 10 of the Periodic Table of Elements according to IUPAC comprises, inter alia, nickel, palladium and platinum.

[0065] The term “ammonium salts” in the context of the present invention comprises both salts derived from NH4+ and mono-, di-, tri- and tetraorganyl-ammonium salts. The radicals attached to the ammonium nitrogen are generally each independently selected from aliphatic, alicyclic and aromatic hydrogen and hydrocarbon groups. Preferably, the ammonium nitrogen-linked radicals are each independently selected from hydrogen and aliphatic radicals, especially selected from hydrogen and C1-C20-alkyl.

[0066] The expression "acyl" in the context of the present invention comprises alkanoyl or aroyl groups generally having 1 to 11 and preferably 2 to 8 carbon atoms, for example, the formyl, acetyl, propionyl, butyryl, pentanoyl, benzoyl or naphthoyl.

[0067] Acetylation in the context of the present invention is the exchange of hydrogen by an acetyl group (-C(= O)-CH3).

[0068] Unless indicated more specifically below, the general formulas (I), (II.2), (III.2) and (IV.2) refer to E/Z mixtures of any composition and the pure configurational isomers . Furthermore, general formulas (I), (II.2), (III.2) and (IV.2) refer to all stereoisomers in pure form and to racemic and optically active mixtures of the compounds of formulas (II .2), (III.2) and (IV.2).

[0069] “Stereoisomers” are compounds of the same constitution but different atomic arrangements in three-dimensional space.

[0070] “Enantiomers” are stereoisomers that behave towards each other as an image and a mirror image.

[0071] The term "terpene-type hydrocarbyl radicals" in the context of the present invention comprises hydrocarbyl radicals that derive in a formal sense from one, two, three or more than three isoprene units. Terpene-type hydrocarbyl radicals may still have double bonds or may be fully saturated. Double bonds can take any desired positions, excluding accumulated double bonds.

[0072] The term "farnesol (3,7,11-trimethyl-2,6,10-dodecatrien-1-ol)" in the context of the present invention comprises the isomers (2E,6E), (2Z,6Z), ( 2Z,6E) and (2E,6Z) and mixtures of two, three or all of the mentioned farnesol isomers. Farnesol is commercially available.

[0073] Nerolidol has a chiral center and can be in the form of an E/Z mixture, meaning that there are four stereoisomers. The term "nerolidol (3,7,11-trimethyl-1,6,10-dodecatrien-3-ol)" in the context of the present invention comprises the isomer (3S), (6Z), isomer (3R), (6Z) , (3S)-isomer, (6E)-isomer, (3R-isomer), (6E)-isomer and any mixtures thereof. Nerolidol is commercially available. Nerolidyl acetate (3,7,11-trimethyl-1,6,10-octatrienyl acetate) is the acetylation product of nerolidol. It is also commercially available.

[0074] Another name for homofarnesilic acid is 4,8,12-trimethyltrideca-3,7,11-trienoic acid.

[0075] A first embodiment of the present invention (variant 1) relates to the carbonylation of an allylic alcohol (allyl alcohol) selected from compounds of formulas (II.1) and (II.2) to give the corresponding unsaturated carboxylic acids extended in C1 of formula (I).

[0076] The starting compounds of formula (II.1) are commercially available or can be prepared, for example, from the corresponding carbonyl compounds R1-CO-R2 and vinylmagnesium halides. Compounds of formula (II.1) can also be prepared from the corresponding carbonyl compound and acetylides such as sodium acetylide and subsequent partial hydrogenation of the ethynyl group to give the vinyl group.

[0077] The allylic alcohols of formula (II.1) and (II.2) that are preferred in the context of the process of the invention are those in which the radicals R1 and R2 are the same or different and are hydrogen, C1-C16-alkyl straight or branched, straight or branched C2-C16-alkenyl with one or two unconjugated double bonds, or R1 and R2 together with the carbon atom to which they are attached are unsubstituted C5-C7-cycloalkyl or C5-C7-cycloalkyl containing 1, 2 or 3 linear or branched C1-C6 alkyl radicals.

[0078] Especially preferred are compounds of formulas (II.1) and (II.2) having hydrocarbyl radicals of the terpene type. R1 is preferably straight or branched C6-C16-alkyl or straight or branched C6-C16-alkenyl having one or two non-conjugated double bonds. R2 is preferably hydrogen or C1-C4-alkyl, especially C1-C2-alkyl. Allyl alcohols of formula (II.1) which are particularly preferred according to the invention are 3-methyl-1-penten-3-ol, 1-hepten-3-ol, 1-vinylcyclohexanol, linalool and nerolidol, especially linalool and nerolidol, specifically nerolidol 6E. Allyl alcohols of formula (II.2) which are particularly preferred according to the invention are geraniol and farnesol.

[0079] If the compounds of formulas (II.1) and (II.2) have one or more centers of asymmetry, it is also possible to use mixtures of enantiomers or mixtures of diastereomers. The process of the invention can be carried out with a mixture of the compounds of formulas (II.1) and (II.2).

[0080] According to the invention, the process is carried out according to variant 1 in which an allyl alcohol selected from compounds of general formulas (II.1) and (II.2) is used for the reaction, in the presence of a compound A). Useful compounds A) preferably include linear or branched monobasic C1-C12-alkanecarboxylic acid anhydrides. Examples of such anhydrides are acetic anhydride, propionic anhydride, isopropionic anhydride, butyric anhydride, n-valeric anhydride, mixed anhydride of formic acid and acetic acid and the like. Especially preferred are the symmetrical anhydrides of alkanemonocarboxylic acids having up to 5 carbon atoms. Equally suitable are linear or branched monobasic C3-C12-alkenecarboxylic acid anhydrides. Examples of these are (meth)acrylic anhydride, crotonic anhydride and isocrotonic anhydride. Also suitable are linear or branched dibasic C4-C20-alkanecarboxylic acid anhydrides, for example the anhydride of succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid, sebacic acid, undecanedioic acid, dodecanedioic acid, brasilic acid, tetradecanedioic acid, pentadecanedioic acid, hexadecanedioic acid, heptadecanedioic acid, octadecanedioic acid. Also suitable are linear or branched dibasic C4-C20-alkenecarboxylic acid anhydrides, for example maleic anhydride or itaconic anhydride. Also suitable are C7-C20-cycloaliphatic dicarboxylic acid anhydrides such as cyclopentanedicarboxylic anhydride or cyclohexanecarboxylic anhydride. Also suitable are aromatic C8-C20-dicarboxylic acid anhydrides, such as phthalic anhydride, 1,8-naphthalenecarboxylic anhydride or 2,3-naphthalenecarboxylic anhydride. Particular preference is given to the use of acetic anhydride, propionic anhydride, isopropionic anhydride, butyric anhydride, succinic anhydride, maleic anhydride or phthalic anhydride, especially acetic anhydride.

[0081] Suitable compounds A) are also the esters of formulas (III.1) and (III.2). In the process of the invention, it does not matter whether the double bond is disposed in a terminal position (compound of formula (III.1)) or whether the double bond is disposed in an internal position (compound of formula (III.2)). Therefore, it is also possible to use a mixture of compounds of formulas (III.1) and (III.2). In general, however, no mixture of the compounds of formulas (III.1) and (III.2) is used.

[0082] Preference is given to compounds of formulas (III.1) and (III.2) in which the radicals R3 and R4 are the same or different and are hydrogen, linear or branched C1-C16-alkyl, C2-C16-alkenyl linear or branched having one or two non-conjugated double bonds, or R3 and R4 together with the carbon atom to which they are attached are unsubstituted C5-C7-cycloalkyl or C5-C7-cycloalkyl containing 1, 2 or 3 alkyl-radicals C1-C6 linear or branched. Alternatively, in the compounds of formulas (III.1) and (III.2), R3 and R4 together with the carbon atom to which they are attached are preferably unsubstituted C5-C7-cycloalkyl. In compounds of formulas (III.1) and (III.2), R5 is preferably hydrogen or C1-C4-alkyl. Specifically, R5 is C1-C2-alkyl. Particular preference is given to allyl acetate.

[0083] Also preferred as compound A) is an ester of the formula (III.1) or (III.2) derived from the alcohol of the formula (II.1) or (II.2) used as a reagent for the carbonylation . The esters of formula (III.1) which are particularly preferred according to the invention are esters of a linear or branched monobasic C1-C3-alkanecarboxylic acid and an alcohol selected from 3-methyl-1-penten-3-ol, 1 -hepten-3-ol, 1-vinylcyclohexanol, linalool and nerolidol. Especially preferred are linaloyl acetate and nerolidyl acetate, specifically 6E-nerolidyl acetate. A compound of formula (III.2) which is particularly preferred according to the invention is farnesyl acetate.

[0084] If the compounds of formulas (III.1) and (III.2) have one or more centers of asymmetry, it is also possible to use mixtures of enantiomers or mixtures of diastereomers.

[0085] In variant 1, in which an allyl alcohol selected from the compounds of general formulas (II.1) and (II.2) is used for the reaction, the carbonylation is carried out according to the invention in the presence of a substoichiometric amount , based on the allyl alcohol used, of a compound A), i.e. the molar amount of compound A) is less than the molar amount of allyl alcohol. The molar ratio of compound A) to the allyl alcohol selected from the compounds of formulas (II.1) and (II.2) is typically in the range of 0.001:1 to about 0.95:1. Preferably, the total amount of compound A) is not more than 50 mol%, preferably not more than 40 mol%, preferably not more than 30 mol%, based on the total molar amount of the compounds (II.1) and (II.2). Molar ratios in the range of 0.1:1 to 0.35:1 and specifically 0.15:1 to 0.30:1 are particularly preferred.

[0086] In the processes of the invention for preparing the carboxylic acid of formula (I), the effect of the anhydride added is equivalent to the effect of the acylated allylic alcohol of formulas (III.1) and (III.2) added.

[0087] Furthermore, it may be appropriate to carry out the carbonylation according to variant 1 in the presence of a nucleophilic reagent. Examples of nucleophilic reagents are 4-(C1-C4-alkyl)pyridines, 4-(1-pyrrolidinyl)pyridine and 4-(di(C1-C4-alkyl)amino)pyridine. Suitable 4-(C1-C4-alkyl)pyridines are 4-methylpyridine and 4-ethylpyridine. Suitable 4-(di(C1-C4-alkyl)amino)pyridines are 4-(dimethylamino)pyridine and 4-(diethylamino)pyridine, especially 4-dimethylaminopyridine. Typically, the nucleophilic reagent selected from 4-(C1-C4-alkyl)pyridine, 4-(1-pyrrolidinyl)pyridine and 4-(di(C1-C4-alkyl)amino)pyridine is used in an amount of 0.01 to 5 mol%, preferably from 0.05 to 2 mol%, especially from 0.1 to 1 mol%, based on the total molar amount of compounds (II.1) and (II.2).

[0088] The following observations concerning the preparation of a composition comprising at least one unsaturated carboxylic acid of general formula (I) relate to all variants of the process of the invention (variant 1, variant 2 and variant 3), to unless explicitly indicated.

[0089] In all variants, the upper limit for the amount of carbon monoxide is determined for economic reasons, although the use of an excessive amount does not adversely affect the reaction. Advantageously, carbon monoxide is used in excess. Carbon monoxide is normally used in an amount of at least 1.1 mol per total molar amount of compounds (II.1) and (II.2) or per total molar amount of compounds (IV.1) and (IV. two).

[0090] The carbonylation (by all variants) is carried out according to the invention in the presence of a transition metal catalyst comprising at least one metal from group 8, 9 or 10 of the Periodic Table of Elements. The transition metals used are preferably palladium, ruthenium, rhodium, iridium and iron, most preferably palladium.

[0091] Typically, the transition metal catalyst is used in an amount of not more than 0.5 mol%, in particular 0.001 to 0.3 mol%, based on the total amount of compounds (II.1) and (II .2) or based on the total amount of compounds (IV.1) and (IV.2).

[0092] According to the invention, at least one organic phosphorus compound is additionally used as a binder. Suitable organic phosphorus compounds are monodentate and bidentate phosphorus binders. The nature of the organic phosphorus compound is, in principle, not important, and therefore it is generally advisable to use low-cost tertiary monodentate phosphines of formula (V). in which R7, R8 and R9 are independently selected from unsubstituted and substituted alkyl, unsubstituted and substituted cycloalkyl, unsubstituted and substituted heterocyclyl, unsubstituted and substituted aryl, and unsubstituted and substituted heteroaryl.

[0093] Preferably, R7, R8 and R9 are independently - C1-C18-alkyl which is unsubstituted or substituted by phenyl - C5-C8-cycloalkyl which is unsubstituted or substituted by 1, 2 or 3 C1-alkyl radicals -C6; - C6-C10-aryl that is unsubstituted or substituted by 1, 2 or 3 C1-C6-alkyl radicals, C1-C6-alkoxyl radicals, di(C1-C4-dialkyl)amino, SO3H or SO3M where M is Li , NaK, NH4; - aryl-C6-C10 substituted by 1, 2 or 3 radicals selected from fluorine, chlorine and fluoroalkyl-C1-C10; - saturated 5- or 6-membered heterocyclyl comprising, as well as carbon atoms, a nitrogen heteroatom or an oxygen heteroatom as a ring member; - C5-C8-cycloalkyl; or - 5- or 6-membered heteroaryl comprising, as well as carbon atoms, a heteroatom selected from nitrogen and oxygen.

[0094] Examples of preferred phosphines of formula (V) are trialkylphosphines, triarylphosphines, dialkylarylphosphines, alkyldiarylphosphines, cycloalkyldiariphosphines, dicycloalkylarylphosphines and tricycloalkylphosphines. Examples of preferred phosphines of formula (V) are likewise triheterocyclylphosphines and triethylarylphosphines. Examples of preferred trialkylphosphine are triethylphosphine, tri-n-butylphosphine, tri-tert-butylphosphine, tribenzylphosphine and the like. Examples of preferred tricycloalkylphosphines are tri(cyclopentyl)phosphine, tri(cyclohexyl)phosphine and the like. Examples of preferred triarylphosphines are triphenylphosphine, tri(p-tolyl)phosphine, tri(m-tolyl)phosphine, tri(o-tolyl)phosphine, tri(p-methoxyphenyl)phosphine, tri(p-dimethylamino)phenyl)phosphine, tri (sodium metasulfonatephenyl)phosphine, diphenyl(2-sulfononophenyl)phosphine, tri(1-naphthyl)phosphine and diphenyl-2-pyridylphosphine. Examples of preferred dialkylarylphosphine are dimethylphenylphosphine and di-tert-butylphenylphosphine. Examples of preferred alkyldiarylphosphines are ethyldiphenylphosphine and isopropyldiphenylphosphine. An example of a preferred cycloalkyldiarylphosphine is cyclohexyldiphenylphosphine. An example of a preferred dicycloalkylarylphosphine is dicyclohexylphenylphosphine. Other examples of preferred triarylphosphines are tri(o-methoxyphenyl)phosphine, tri(m-methoxyphenyl)phosphine, tri(p-fluorophenyl)phosphine, tri(m-fluorophenyl)phosphine, tri(o-fluorophenyl)phosphine, tri(p- chlorophenyl)phosphine, tri(m-chlorophenyl)phosphine, tri(pentafluorophenyl)phosphine, tris(p-trifluoromethylphenyl)phosphine, tri[3,5-bis(trifluoromethyl)phenyl]phosphine, diphenyl(o-methoxyphenyl)phosphine, diphenyl( o-methylphenyl)phosphine, tris(3,5-dimethylphenyl)phosphine and tri-2-naphthylphosphine. An example of a preferred triethylarylphosphine is tri(o-furyl)phosphine. Another example of a preferred trialkylphosphine is triisobutylphosphine. An example of a preferred triethercyclylphosphine is tris(1-pyrrolidinyl)phosphine. Especially preferred are triphenylphosphine, di-tert-butylphenylphosphine, cyclohexyldiphenylphosphine, dicyclohexylphenylphosphine, tri(p-tolyl)phosphine and tri(cyclohexyl)phosphine.

[0095] Suitable bidentate phosphine ligands are 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP), 2-bis(diphenylphosphino)ethane (DPPE), 1,3-bis(diphenylphosphino)propane ( DPPP), 1,4-bis(diphenylphosphino)butane (DPPB), 1,1'-bis(diphenylphosphino)ferrocene (DPPF), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos), 1, 2-bis(di-tert-butylphosphinomethyl)benzene, 1,2-bis(di-tert-pentylphosphinomethyl)benzene and 1,2-bis(di-tert-butylphosphinomethyl)naphthalene.

[0096] Additionally, it may be appropriate to conduct the reaction in the presence of phosphine of formula (V) in free form, ie not bound in the complex and/or bidentate phosphine.

[0097] The molar ratio of organic phosphorus compound to transition metal is typically from 1:1 to 10:1, preferably from 2:1 to 5:1. Specifically, the molar ratio of the organic phosphorus compound of formula (V) to the transition metal is typically from 1:1 to 10:1, preferably from 2:1 to 5:1.

[0098] It is advantageous to carry out the carbonylation with exclusion of or with a reduced content of atmospheric oxygen.

[0099] In addition to the organic phosphorus compounds described as a binder above, the carbonylation catalysts used according to the invention may also include at least one additional binder selected from halides, amines, acetates, carboxylates, acetylacetonate, aryl or alkyl sulfonates , hydride, CO, olefins, dienes, cycloolefins, nitrile, N-containing heterocycles, aromatic and heteroaromatic compounds, ethers and monodentate phosphine, phosphonite, phosphoramidite and phosphite ligands. Additional particularly suitable binders are carbonyl, acetate, acetylacetonate and cycloolefins such as cyclooctadiene or norbornadiene. Halides are equally suitable, specifically chlorides and bromides.

[00100] Suitable transition metal sources are generally transition metals, transition metal compounds and transition metal complexes, from which the carbonylation catalyst is formed in situ under the conditions of carbonylation in the reaction zone.

[00101] Suitable compounds of the mentioned transition metals are especially those that are soluble in the chosen feed medium, for example salts or complexes with suitable ligands, for example carbonyl, acetylacetonate, hydroxyl, cyclooctadiene, norbornadiene, cyclooctene, methoxyl, acetyl or others aliphatic or aromatic carboxylates. Transition metal compounds that are preferred in the context of the process of the invention are compounds Ru(II), Ru(III), Ru(IV), Ru(0), Rh(I), Rh(III), Rh(0 ), Ir(I), Ir(III), Ir(IV), Ir(0), Pd(II), compounds Pd(IV), Pd(0), Pt(II), Pt(IV), Pt( 0 ) and Fe(II) and Fe(III) compounds.

[00102] Suitable ruthenium salts are, for example, ruthenium(III) chloride, ruthenium(IV) oxide, ruthenium(VI) oxide or ruthenium(VIII) oxide, alkali metal salts of oxygen-ruthenium acids , such as K2RuO4 or KRuO4, or ruthenium complexes. These include the metal carbonyls, such as trisruthenium dodecacarbonyl or hexaruthenium octadecacarbonyl, or mixed forms in which the CO has been partially replaced by ligands of formula PR7R8R9, such as Ru(CO)3(P(C6H5)3)2 or tris (acetylacetonate) of ruthenium(III).

[00103] Examples of transition metal sources for suitable palladium compounds or complexes include palladium(II) acetate, palladium(II) chloride, palladium(II) bromide, palladium(II) nitrate, palladium(II) acetylacetonate II), palladium(0) dibenzylideneacetone complex, palladium(0) tetrakis(triphenylphosphine), palladium(0) bis(tri-o-tolylphosphine), palladium(II) propionate, palladium(II) bis(triphenylphosphine) dichloride palladium(II), palladium(II) nitrate, palladium(II) bis(acetonitrile) dichloride, palladium(II) bis(benzonitrile) dichloride.

[00104] Examples of rhodium compounds or complexes suitable as a source of transition metal include rhodium(II) and rhodium(III) salts, such as rhodium(II) or rhodium(III) carboxylate, rhodium(II) acetate and rhodium(III), etc. Additionally suitable are rhodium complexes such as rhodium biscarbonyl acetylacetonate, rhodium(I) bisethylene acetylacetonate, rhodium(I) cyclooctadienyl acetylacetonate, rhodium(I) acetylacetonatonorbornadienyl, rhodium(I) acetylacetonatecarbonyltriphenylphosphine, Rh4(CO)12, Rh6(CO)16, etc.

[00105] Suitable iron compounds as a source of transition metal are Fe2(CO)10, Fe2(CO)9, iron(III) tris(acetylacetonate).

[00106] The catalyst used can be homogeneously dissolved in the liquid reaction medium or, in the case of a polyphase reaction, it can be dissolved in the liquid phase of the reaction medium as what is called a homogeneous catalyst, or it can be in supported form or not supported as what is called a heterogeneous catalyst.

[00107] If the conversion is carried out in the absence of other co-reactants, the acid of formula (I) is obtained. The acid of formula (I) obtained can be removed from the reaction mixture by methods known per se to those skilled in the art, for example by distillation, and the remaining catalyst can be used in further reactions. The acid of formula (I) can also be obtained by extraction from the reaction mixture.

[00108] The carbonylation can (in all variants) be conducted in the presence or absence of a base. The base is different from the nucleophilic reagent. Suitable bases are inorganic and organic bases. Examples of preferred inorganic bases are alkali metal carbonates and alkaline earth metal carbonates. Preferred alkali metals are sodium and potassium, with particular preference given to sodium. Preferred alkaline earth metals are magnesium and calcium. Suitable bases are also organic bases other than the nucleophilic reagent which is selected from 4-(C1-C4-alkyl)pyridine, 4-(1-pyrrolidinyl)pyridine and 4-(di-(C1-C4-alkyl)amino)pyridine such as 4-(dimethylamino)pyridine. The presence of the base, for example an additional amine, promotes the formation of the carboxylic acid salt of general formula (I), such that the conversion rate is markedly improved. Furthermore, acids that form from the anhydrides under the reaction conditions are neutralized or buffered by the base. It is in turn possible to generate the free acid from the carboxylic acid salts of formula (I) by thermal means, for example by distillation of the reaction output, or by acidification. Preference is given to carrying out the carbonylation in the presence of an amine other than the nucleophilic reagent such as 4-(dimethylamino)pyridine. More particularly, a tertiary amine or a basic N-heteroaromatic is used.

[00109] Examples of the tertiary amine comprise a trialkylamine, specifically a tri(C1-C15-alkyl)amine such as trimethylamine, triethylamine, tripropylamine, tributylamine, trihexylamine, trioctylamine, tridecylamine, N,N-dimethylethylamine, dimethylpropylamine or 1,4-diaza-bicyclo[2.2.2]octane (DABCO); an aromatic amine such as dimethylaniline or tribenylamine; a cyclic amine such as N-methylpyrrolidine, N-methylpiperidine, N-methylmorpholine, N,N'-dimethylpiperazine. Among these, preference is given to a trialkylamine such as triethylamine. Also suitable are N-heteroaromatics such as pyridine, N-methylimidazole or quinoline. The base other than the nucleophilic reagent selected from 4-(C1-C4-alkyl)pyridine, 4-(1-pyrrolidinyl)pyridine and 4-(di-(C1-C4-alkyl)amino)pyridine such as 4-(dimethyl) amino)-pyridine, is typically used in an amount of 0.8 mol to 1.2 mol per mol of compound (I).

[00110] Especially in the case of carbonylation in the presence of an amine, acidification of the reaction mixture and extraction is a suitable method of obtaining the free acid. Alternatively, the free acid can be separated from the reaction mixture by distillation, as the unsaturated acid salt of formula (I) decomposes under the action of heat to give the unsaturated free acid of formula (I) and the amine .

[00111] The carbonylation (in all variants) can be carried out in the presence or absence of an added inert solvent. Inert solvents are understood as solvents that do not chemically react under the reaction conditions with the compounds used, that is, the reagents, products and catalysts. Suitable inert solvents are aprotic organic solvents, for example aromatic hydrocarbons such as toluene or xylenes, alicyclic hydrocarbons such as cyclohexane and cyclic ethers such as tetrahydrofuran or dioxane. For practical reasons, the carbonylation is preferably conducted in the absence of an inert solvent. If the reagent used, however, is sparingly soluble under the reaction conditions, the use of a solvent is advisable.

[00112] The carbonylation can be conducted continuously, semi-continuously or in batches.

[00113] The pressure (in all variants) can be chosen within a wide range such as atmospheric pressure up to not more than 90 bar, preferably not more than 30 bar, more preferably not more than 25 bar, most preferably not more than 20 bar and especially not more than 15 bar. Suitable pressure ranges are, for example, 1.1 to 90 bar, 1.1 to 30 bar, 2 to 20 bar, 5 to 15 bar.

[00114] The reaction temperature (in all variants) can be chosen within a wide range from room temperature (2°C) to 100°C, but preferably not higher than 80°C, especially not higher than 75° W.

[00115] In a specific embodiment of the process of the invention, the carbonylation is carried out at a temperature not exceeding 90°C and a pressure not exceeding 20 bar.

[00116] Suitable pressure-resistant reactors are also known to those skilled in the art and are described, for example, in Ullmanns Enzyklopadie der technischen Chemie [Ullmann's Encyclopedia of Industrial Chemistry], vol. 1, 3rd edition, 1951, p. 769 et seq. In general, an autoclave which can be provided, if desired, with a stirring apparatus and an inner liner, is used for the process of the invention.

[00117] The catalysts used according to the invention can be separated from the carbonylation reaction output by usual methods known to those skilled in the art and can be reused for a carbonylation.

[00118] The reaction mixture can be subjected to processing by customary methods known to those skilled in the art. For this purpose, the reaction mixture obtained in the carbonylation may be subjected to at least one processing step to remove at least one of the following components: - carbonylation catalyst, - unconverted compounds of formulas (II.1) and (II .2) or (IV.1) and (IV.2), - reaction products other than compounds of formula (I), - solvents.

[00119] Another embodiment of the present invention (variant 2) relates, as explained above, to the carbonylation of an acylated allylic alcohol selected from compounds of formulas (IV.1) and (IV.2) to give the corresponding carboxylic acids C1-extended unsaturated compounds of formula (I) or a salt thereof, comprising reacting selected compounds of compounds of formulas (IV.1) and (IV.2) with carbon monoxide in the presence of a transition metal catalyst comprising at least one metal of group 8, 9 or 10 of the Periodic Table of Elements, wherein the reaction is further carried out in the presence of at least one organic phosphorus compound as a ligand and in the presence of water, and wherein the reaction is carried out at a temperature not exceeding 100°C.

[00120] Compounds of formulas (IV.1) and (IV.2) that are preferred in the context of the process of the invention are those in which the radicals R1 and R2 are the same or different and are hydrogen, linear-C1-C16-alkyl or branched, straight or branched C2-C16-alkenyl with one or two unconjugated double bonds, or R1 and R2 together with the carbon atom to which they are attached are unsubstituted C5-C7-cycloalkyl or C5-C7-cycloalkyl containing 1 , 2 or 3 linear or branched C1-C16-alkyl radicals.

[00121] Especially preferred are compounds of formulas (IV.1) and (IV.2) with hydrocarbyl radicals of the terpene type. R1 is preferably straight or branched C6-C16-alkyl or straight or branched C6-C16-alkenyl having one or two non-conjugated double bonds. R2 is preferably hydrogen or C1-C4-alkyl, especially C1-C2-alkyl. R6 is preferably C1-C2-alkyl. Particular preference is given according to the invention to esters of a linear or branched monobasic C1-C3-alkanecarboxylic acid and of an allylic alcohol selected from 3-methyl-1-pentene-3-ol, 1-hepten-3-ol, 1 -vinylcyclohexanol, linalool and nerolidol. Particular preference is given according to the invention to linaloyl acetate and nerolidyl acetate, specifically to 6E-nerolidyl acetate. A compound of formula (IV.2) which is particularly preferred according to the invention is farnesyl acetate.

[00122] If the compounds of formulas (IV.1) and (IV.2) have one or more centers of asymmetry, it is also possible to use mixtures of enantiomers or mixtures of diastereomers. The process of the invention can be carried out with a mixture of the compounds of formulas (IV.1) and (IV.2). However, preference is given to the use of a compound of formula (IV.1) or formula (IV.2).

[00123] The compounds of the formula (IV.1) are obtained, for example, by the esterification of carboxylic acids of the formula R6-C(O)OH with the allyl alcohol of the formula (II.1), and compounds of the formula (IV 2), for example, by esterification of carboxylic acids of formula R6-C(O)OH with the allyl alcohol of formula (II.2).

[00124] According to the invention, the carbonylation is carried out in the presence of water. The molar ratio of water to the total molar amount of compounds of formulas (IV.1) and (IV.2) is typically in the range 1:1 to 10:1, but preferably in the range 1.1:1 to 3 :1.

[00125] Regarding suitable transition metal catalysts, suitable organic phosphorus compounds as binders, reaction temperature, reaction pressure, reaction time, use of solvent, use of a nucleophilic reagent, use of bases other than the reagent nucleophilic, specifically the use of 4-(dimethylamino)pyridine amines and reaction apparatus, reference is made to the above statements.

[00126] Another embodiment of the present invention (variant 3) concerns, as indicated above, carbonylation of compounds of general formulas (II.1) and (II.2) to give the corresponding unsaturated carboxylic acids extended to C-1 of formula (I) or a salt thereof, comprising reacting compounds selected from compounds of formulas (II.1) and (II.2) with carbon monoxide in the presence of a transition metal catalyst comprising at least one metal of groups 8, 9 and 10 of the Periodic Table of Elements, wherein the reaction is additionally carried out in the presence of at least one organic phosphorus compound as a ligand and in the presence of a substoichiometric amount, based on the allyl alcohol, of a compound B ) , and wherein the reaction is carried out at a temperature not exceeding 100°C. In compounds B, R10 and R11 preferably have the same meaning. Useful compounds B) preferably include methanesulfonic anhydride, trifluoromethanesulfonic anhydride, phenylsulfonic anhydride, p-toluenesulfonic anhydride, 4-bromophenylsulfonic anhydride and 4-nitrophenylsulfonic anhydride.

[00127] In variant 3, in which an allyl alcohol selected from compounds of general formulas (II.1) and (II.2) is used for reaction, the carbonylation, according to the invention, is carried out in the presence of an amount substoichiometric, based on the allyl alcohol used, of a compound B), meaning that the molar amount of compound B) is less than the molar amount of allyl alcohol. The molar ratio of compound B) to the allyl alcohol selected from the compounds of formulas (II.1) and (II.2) is typically in the range of 0.001:1 to about 0.95:1. Preferably, the total amount of compound B) is not more than 50 mol%, preferably not more than 40 mol%, based on the total molar amount of compounds (II.1) and (II.2 ). Molar ratios in the range of 0.1:1 to 0.35:1 and especially 0.15:1 to 0.30:1 are particularly preferred.

[00128] In the processes of the invention to prepare the carboxylic acid of formula (I) by variant 3, the effect of the added sulfonic anhydride is equivalent to the effect of the added compound A) in variant 1.

[00129] With regard to suitable transition metal catalysts, suitable organic phosphorus compounds as a binder, reaction temperature, reaction pressure, reaction time, use of solvents, use of nucleophilic agents, use of bases other than the reagent nucleophilic and reaction apparatus, reference is made to the above statements.

[00130] The carbonylation by variant 3 is preferably carried out at a temperature not exceeding 100°C and a pressure not exceeding 30 bar.

[00131] In variants 1, 2 and 3 of the process of the invention, it is possible to obtain homofarnesilic acid from commercial substances, such as farnesol or nerolidol, in high yield under moderate reaction conditions.

[00132] More particularly, the process of the invention is suitable for preparing E/Z-4,8-dimethyl-3,7-nonadienoic acid from linalool under mild reaction conditions.

[00133] More particularly, the process of the invention is also suitable for the preparation of (3E,7E)-4,8,12-trimethyltrideca-3,7,11-trienoic acid or a salt thereof and (3Z,7E) acid )-4,8,12-trimethyltrideca-3,7,11-trienoic acid or a salt thereof in a weight ratio of 80:20 to 50:50, preferably 70:30 to 55:45, from E- nerolidol. The (3E,7E)-4,8,12-trimethyltrideca-3,7,11-trienoic acid ratio in the isomer mixtures obtained is generally higher than the (3E,7E)-4,8,12-trimethyltrideca acid ratio - 3,7,11-trienoic. The obtained composition can be subjected to at least partial enrichment of an isomer.

[00134] In the processes according to variants 1, 2 and 3, in general, E/Z isomeric mixtures of formula (I) or salts thereof are obtained when R1 and R2 in formula (I) have different meanings. E/Z isomeric mixtures of formula (I) comprise a 3-(E) acid of formula (IE) and a 3-(Z) acid of formula (IZ). where R1 and R2 have different definitions and R1 has a higher priority according to IUPAC.

[00135] Often only one of the two isomers is the valuable product. Preference is given to subjecting the mixture of E/Z isomers of the formula (I) which is obtained by the process of the invention to at least partial enrichment of one isomer. A possible separation of isomers from such a mixture for partial enrichment of an isomer can be carried out by chromatography or distillation or as described in EP 17157974.1.

[00136] The product of value is often the 3-(E) acid of the formula (I-E) and not the 3-(Z) acid of the formula (I-Z) which is also obtained in significant amounts.

[00137] Therefore, it would be economically advisable to first separate at least a portion of the 3-(E) acid of formula (I-E) from the composition obtained according to the invention comprising the mixture of E/Z isomers of formula I, and convert the unwanted 3-(Z) acid of formula (I-Z) at least partially in the valuable product, i.e. 3-(E) acid of formula (I-E).

[00138] Therefore, in a preferred embodiment of the present invention, the process of the invention for preparing a mixture of E/Z isomers of formula (I) comprises the following additional steps: (1) the composition comprising the mixture of E/Z isomers Z of formula (I), in the presence of an alcohol and a lipase enzyme, is subjected to an enzyme-catalyzed esterification, whereby the 3-(E) acid of formula (I-E) is converted at least partially to a 3-ester -(E), in order to obtain a composition comprising the 3-(E) ester, unconverted 3-(E) acid of formula (I-E) and unconverted 3-(Z) acid of formula (I-Z); (2) the composition obtained in (1) separated to obtain a composition depleted in 3-(E) acid of formula (I-E) and enriched in 3-(Z) acid of formula (I-Z), and to obtain a composition comprising the 3-(E)-ester; (3) the composition obtained in (2) which is depleted of 3-(E) acid of formula (I-E) and enriched in 3-(Z) acid of formula (I-Z) is subjected to an isomerization to increase the acid content 3-(E) of formula (IE); and (4) optionally, the 3-(E) ester obtained in (2) is cleaved to obtain the 3-(E) acid of formula (I-E).

[00139] Processes for enzymatically catalyzed esterifications of a mixture of 3-(E)-unsaturated carboxylic acid and 3-(Z)-unsaturated carboxylic acid with an alcohol are known, for example, from EP 17157974.1.

[00140] Many lipases are able to catalyze esterifications with high substrate selectivity. Preferably, the lipase is Candida antarctica lipase (CALB) or an immobilized form in a polymeric vehicle, such as Novozym 435®. Enzyme-catalyzed esterification is preferably carried out in the presence of an aliphatic alcohol. Suitable aliphatic alcohols are C1-C20-alkanols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol, n-pentanol, n-hexanol, n-heptanol and n-octanol. The enzyme-catalyzed esterification can optionally be conducted in the presence of a diluent or solvent. Examples of suitable diluents or solvents are especially aliphatic hydrocarbons such as hexane, cyclohexane, heptane, octane; aromatic hydrocarbons, for example toluene, xylene; dialkyl ethers, such as methyl tert-butyl ether and diisopropyl ether. Typically, 1-5 equivalents of alcohol per equivalent of 3-(E) acid are used. The esterification is typically conducted at a temperature within the range of 0 to 80°C.

[00141] Lipase esterifies the 3-(E) acid of formula (I-E) with alcohols much faster than the corresponding 3-(Z) acid of formula (I-Z). Therefore, a separable composition is obtained, comprising the 3-(E) ester, the unconverted 3-(E) acid of formula (I-E) and the unconverted 3-(Z) acid of formula (I-Z).

[00142] The composition obtained in step (1) can be separated by extraction or distillation.

[00143] In step (4), the 3-(E) ester isolated in step (2) is optionally subjected to an acid, base, or enzyme catalyzed ester cleavage to obtain the 3-(E) acid of formula (I-E) ). or salt thereof. Since the compound of formula (I-E) is often the valuable product, it is suitable to conduct ester cleavage.

[00144] In another preferred embodiment, the process of the invention for preparing a mixture of E/Z isomers of formula (I) comprises the following additional steps: (i) the composition comprising the mixture of E/Z isomers of formula (I) ) is subjected to an esterification in the presence of an alcohol to obtain the 3-(E) ester and the 3-(Z) ester; (ii) the 3-(E) ester and the 3-(Z) ester obtained in (i) are subjected to a lipase-catalyzed enzymatic hydrolysis, in which the lipase cleaves, at least in part, the 3-(E) ester ) to give the 3-(E) acid of formula (I-E) to obtain a composition comprising the 3-(E) acid of the compound of formula (I-E), unconverted 3-(E) ester and 3-( Z) not converted; (iii) the composition obtained in (ii) is separated to obtain a composition comprising the 3-(E) acid of the compound of formula (I-E) and to obtain a composition comprising the unconverted 3-(E) ester and 3-(E) ester (Z) not converted; (iv) the composition which is obtained in (iii) and comprises unconverted 3-(E) ester and unconverted 3-(Z) ester is subjected to an ester cleavage to obtain a depleted 3-(E) acid composition of the formula (I-E) or a salt thereof and enriched in 3-(Z) acid of the formula (I-Z) or a salt thereof; and (v) the composition which is obtained in (iv) and is depleted of 3-(E) acid of formula (I-E) and enriched in 3-(Z) acid of formula (I-Z) is subjected to an isomerization to increase the 3-(E) acid content of formula (I-E).

[00145] Preferably, the esterification in step (i) is carried out with an aliphatic alcohol. Suitable aliphatic alcohols are C1-C20-alkanols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol, n-pentanol, n-hexanol, n-heptanol and n-octanol. The esterification can be conducted under acid, base or enzymatic catalysis. The esterification is typically conducted at a temperature within the range of 0 to 80°C.

[00146] Processes for enzymatically catalyzed ester cleavage and a mixture of 3-(E) unsaturated carboxylic acid and 3-(Z) unsaturated carboxylic acid in the presence of water are known, for example, from EP 17157974.1.

[00147] Many lipases are able to catalyze ester cleavages with high substrate selectivity. In step (ii), the composition obtained in step (i), in the presence of water and a lipase enzyme, is subjected to an enzyme-catalyzed ester cleavage to obtain a composition comprising 3-(E) acid of formula (I-E ), unconverted 3-(E) ester and unconverted 3-(Z) ester. Lipases are preferably Candida antarctica lipase (CALB) or an immobilized form in a polymeric vehicle, such as Novozym 435®.

[00148] The composition obtained in step (ii) can be separated by distillation or extraction. This gives a composition comprising 3-(E) acid of formula (I-E). Also obtained is a composition comprising the 3-(E) ester and the 3-(Z) ester.

[00149] The ester cleavage in step (iv) can be performed under acidic, basic or enzymatic catalysis. This gives a composition comprising 3-(E) acid of formula (I-E) or a salt thereof and 3-(Z) acid of formula (I-Z) or a salt thereof, with a reduced content of 3-( E) of formula (IE) and an increased 3-(Z) acid content of formula (I-Z) compared to the composition used in step (i).

[00150] In steps (3) and (v) of the aforementioned processes, the composition obtained is subjected to an isomerization of the 3-(Z) acid of formula (I-Z) to the 3-(E) acid of formula (I-E) to order to increase the proportion of value product. The isomerization is preferably carried out in the presence of an anhydride of an organic acid and a base. Suitable anhydrides are C1-C12 aliphatic monocarboxylic acid anhydrides, C4-C20 aliphatic dicarboxylic acid anhydrides, C7-C20 cycloaliphatic dicarboxylic acid anhydrides, C8-C20 aromatic dicarboxylic acid anhydrides, aliphatic sulfonic acid anhydrides and aromatic sulfonic acid anhydrides . Suitable bases are alkali metal carbonates, alkaline earth metal carbonates, alkali metal hydrogencarbonates, alkaline earth metal hydrogen carbonates, alkali metal phosphates, alkaline earth metal phosphates, amines, basic N-heteroaromatics, basic ion exchangers and mixtures thereof. The isomerization is preferably carried out in the presence of an anhydride of an organic acid and a base. The process may advantageously be carried out at a temperature of 60 to 175°C, preferably 70 to 160°C.

[00151] The pressure is not critical. Therefore, the isomerization can be conducted at elevated pressure, reduced pressure or atmospheric pressure. When using a base and/or an anhydride having a boiling point below the reaction temperature at standard pressure, the process is suitably conducted in a pressure reactor. Advantageously, the isomerization can also be carried out under the conditions of the process of the invention. Advantageously, the presence of a transition metal catalyst is not required for the isomerization.

[00152] The compounds of the general formula (I) obtained by the process of the invention can be subjected to a reduction with conversion of the acid or ester group into the corresponding alcohols. In a specific embodiment, first, a mixture of (3E,7E)-4,8,12-trimethyltrideca-3,7,11-trienoic acid and (3Z,7E)-4,8,12-trimethyltrideca- 3,7,11-trienoic acid, obtainable as described above, is subjected to a separation to obtain (3E,7E)-4,8,12-trimethyltrideca-3,7,11-trienoic acid, for example, as described above , and (3E,7E)-4,8,12-trimethyltrideca-3,7,11-trienoic acid to a reduction to give (3E,7E)-homofarnesol (VI)

[00153] (3E,7E)-Homofarnesol (VI) is also an important intermediate for the preparation of flavor chemicals.

[00154] The invention further provides the preparation of (-)-ambrox. Preparation can be carried out by known methods from stereoisomerically pure (3E/7E)-homofarnesilic acid as shown in Scheme 1 below. Scheme 1:

[00155] Full reference is made here to the disclosure of documents EP 16156410, WO 2010/139719 and WO 2012/066059, which describe the biocatalytic cyclization of unsaturated substrates, for example terpene-type hydrocarbons, using cyclase enzymes.

[00156] Sclareolide (VII) can be obtained, for example, by cyclase-catalyzed conversion of (3E/7E)-homofarnesilic acid prepared according to the invention. Sclareolide (VII) can then be chemically reduced, for example by reaction with LiAlH4 or NaBH4, to give ambrox-1,4-diol (see Mookherjee et al.; Perfumer and Flavourist (1990), 15: 27). The ambrox-1,4-diol can then be converted to (-)-ambrox by known methods.

[00157] Hydrogenation catalysts that allow a good selectivity towards the hydrogenation of the terminal carboxylic acid group to obtain the corresponding alcohol are also known to those skilled in the art. Hydrogenation and isomerization of the double bonds present in compounds (I) can essentially be avoided.

[00158] Also known is the cyclization of (3E,7E)-homofarnesol to ambrox, with descriptions of enzymatic and chemical cyclizations. In this regard, reference is made to the disclosure of the following documents:

[00159] P.F. Vlad et al. Khimiya Geterotsiklicheskikh Soedinenii, Engl. Transl. 1991, 746 describe cyclization reactions using a superacid (fluorosulfonic acid in 2-nitropropane). Another suitable method comprises the cyclization of homofarnesyl triethylsilyl ether enantioselective polyenes in the presence of O-(o-fluoro-benzyl)binol and SnCl4, as described by H. Yamamoto et al. J. Am. Chem. Soc. 2002, 3647.

[00160] Preference is given to biocatalytic cyclization, as described in WO 2010/139719. Accordingly, the cyclization in step d1) is carried out in the presence of a polypeptide having the activity of a homofarnesol ambroxcyclase enzyme.

[00161] For the preparation of (-)-ambrox by this variant, homofarnesol is placed in contact and/or incubated with homofarnesol-ambroxan cyclase and then the ambrox formed is isolated.

[00162] In one embodiment, homofarnesol is contacted with homofarnesol-ambroxan cyclase in a medium and/or incubated with the same in such a way that homofarnesol is converted to ambrox in the presence of cyclase. Preferably, the medium is an aqueous reaction medium. The aqueous reaction media are preferably buffered solutions which generally have a pH of preferably 5 to 8. The buffer used can be a citrate, phosphate, TRIS (tris(hydroxymethyl)aminomethane) or MES (2-(N-morpholino) acid) buffer ethanesulfonic). Furthermore, the reaction medium may comprise other additives, for example detergents (for example taurodeoxycholate).

[00163] Homoarnesol is preferably used in the enzymatic reaction in a concentration of 5 to 100 mM, more preferably 15 to 25 mM. This reaction can be conducted continuously or in batches.

[00164] The enzymatic cyclization is appropriately performed at a reaction temperature below the deactivation temperature of the cyclase used. The reaction temperature in step d1) is preferably within a range of -10 to 100°C, more preferably from 0 to 80°C, particularly from 15 to 60°C and especially from 20 to 40°C.

[00165] The ambrox reaction product can be extracted with organic solvents and optionally distilled for purification. Suitable solvents are specified below.

[00166] As well as single-phase aqueous systems, it is also possible to use two-phase systems. In this variant, it is possible to enrich the ambrox formed in the non-aqueous phase in order to isolate it. The second phase here is preferably selected from ionic liquids and water-immiscible organic solvents. After the reaction, the ambrox in the organic phase is easily separable from the aqueous phase comprising the biocatalyst. By non-aqueous reaction medium is meant reaction medium comprising less than 1% by weight and preferably less than 0.5% by weight of water, based on the total weight of the liquid reaction medium. More particularly, the reaction can be conducted in an organic solvent. Suitable organic solvents are, for example, aliphatic hydrocarbons preferably with 5 to 8 carbon atoms, such as pentane, cyclopentane, hexane, cyclohexane, heptane, octane or cyclooctane, halogenated aliphatic hydrocarbons, preferably with one or two carbon atoms , such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane or tetrachloroethane, aromatic hydrocarbons such as benzene, toluene, xylenes, chlorobenzene or dichlorobenzene, aliphatic acyclic and cyclic ethers or alcohols, preferably with 4 to 8 carbon atoms, such as ethanol , isopropanol, diethyl ether, methyl tert-butyl ether, ethyl tert-butyl ether, dipropyl ether, diisopropyl ether, dibutyl ether, tetrahydrofuran or esters such as ethyl acetate or n-butyl acetate, or ketones such as methyl isobutyl ketone or dioxane or mixtures thereof. Particular preference is given to the use of the aforementioned heptane, methyl tert-butyl ether, diiso-propyl ether, tetrahydrofuran, ethyl acetate.

[00167] Suitable enzymes are described in WO 2010/139719, which is hereby incorporated by reference in full. Accordingly, the enzyme is a polypeptide encoded by a nucleic acid molecule comprising at least one nucleic acid molecule selected from: a) nucleic acid molecule encoding a polypeptide comprising nucleic acid molecule of SEQ ID NO 2, 5 , 6, 7, 8, 9, 10 or 11; b) comprising at least one polynucleotide of the nucleic acid molecule of the sequence shown in SEQ ID NO 1; c) encoding a polypeptide whose sequence has at least 46% identity with the nucleic acid molecule of sequences SEQ ID NO 2, 5, 6, 7, 8, 9, 10 or 11; d) according to (a) to (c) which is a functionally equivalent polypeptide or a fragment of the nucleic acid molecule of the sequence according to SEQ ID NO 2, 5, 6, 7, 8, 9, 10 or 11 ; e) which codes for a functionally equivalent polypeptide with the activity of a homofarnesol-ambroxan cyclase which is obtained by amplifying a nucleic acid molecule from a cDNA bank or from genomic DNA by means of the primer according to sequence No. 3 and 4 or chemically synthesizing the nucleic acid molecule by de novo synthesis; f) nucleic acid molecule encoding a functionally equivalent polypeptide with the activity of a homofarnesol-ambroxan cyclase which hybridizes under stringent conditions to a nucleic acid molecule according to (a) to (c); g) nucleic acid molecule encoding a functionally equivalent polypeptide with the activity of a homofarnesol-ambroxan cyclase which can be isolated from a DNA bank using a nucleic acid molecule according to (a) to (c) or fragments thereof same of at least 15 nt, preferably 20 nt, 30 nt, 50 nt, 100 nt, 200 nt or 500 nt as a probe under stringent hybridization conditions; and h) nucleic acid molecule encoding a functionally equivalent polypeptide with the activity of a homofarnesol-ambroxan cyclase, wherein the polypeptide sequence has at least 46% identity with the nucleic acid molecule of sequences SEQ ID NO 2, 5, 6, 7, 8, 9, 10 or 11; i) encoding a functionally equivalent polypeptide with the activity of a homofarnesol-ambroxan cyclase, wherein the polypeptide encoded by a nucleic acid molecule selected from the group described in a) to h) and has been isolated, or may be isolated, by medium of a monoclonal antibody; j) nucleic acid molecule encoding a functionally equivalent polypeptide with the activity of a homofarnesol-ambroxan cyclase, wherein the polypeptide has a binding site analogous or similar to a polypeptide encoded by a nucleic acid molecule selected from the group of those described in a) to h).

[00168] Despite the multitude of existing aroma chemicals (fragrance and flavoring) and processes for their preparation, there is a constant need for new components to be able to satisfy the multiplicity of desired properties for extremely diverse fields of use and for simple synthesis routes in order to make them available. The process of the invention allows the efficient preparation of compounds of the general formula (I) that can serve as synthetic units of interest in the supply of new and already known aroma chemicals, such as (-)-ambrox. After the hydrogenation of the acid function, it is possible to obtain alcohols that can, in turn, be units of interest in synthesis and be suitable for use as surfactant alcohols.

[00169] The invention is elucidated in detail by the following working examples. The examples which follow demonstrate that the invention can be advantageously carried out with different transition metal reagents and catalysts.

Abbreviations:

[00170] Ac2O represents acetic anhydride; DMAP means 4-(dimethylamino)pyridine; eq. means equivalent(s); Fe(acac)3 represents iron(III) tris(acetylacetonate); Area% represents the percentage of the area; GC means gas chromatography; [Ir(COD)Cl] 2 represents bis(1,5-cyclooctadiene)diiridium(I) dichloride; MTBE means methyl tert-butyl ether; NEt3 represents triethylamine; org. means organic; P(Cy)3 represents tricyclohexylphosphine; Pd(acac) 2 represents palladium(II) bis(acetylacetonate); Pd(dba)2 represents palladium(0) bis(dibenzylideneacetone); Pd(OAc)2 represents palladium(II) acetate; Rh(CO)2(acac) represents rhodium(I)(acetylacetonate) dicarbonyl; Ru(acac)3 represents ruthenium(III) tris(acetylacetonate); Acid sel. means acid selectivity; THF means tetrahydrofuran; TPP means triphenylphosphine; rpm means revolutions per minute.

[00171] The products were identified with the aid of analysis by GC, 1H NMR and 13C NMR. Processing of reaction mixtures was not optimized.

Example 1: Pd-catalyzed carbonylation procedure from linalool

[00172] Palladium(II) acetate (19 mg, 0.085 mmol), triphenylphosphine (51 mg, 0.195 mmol) and DMAP (49 mg, 0.4 mmol) were initially loaded into a glass autoclave under argon. Linalool (10.8 g, 70 mmol), triethylamine (6.9 g, 68 mmol) and acetic anhydride (2 g, 20 mmol) were added in an argon counterflow. Subsequently, 10 bar of CO was applied and the mixture was stirred at 1000 rpm at this pressure and at an internal temperature of 60°C for 24 h. Then, the mixture was cooled to room temperature and decompressed. GC analysis of the reaction output gave a conversion of 94% with a selectivity for the E/Z-4,8-dimethyl-3,7-nonadienoic acid target product of 62%.

[00173] After the reaction was over, MTBE (25 ml) and aqueous NaOH (5%, 70 ml) were added. The phases were separated and the aqueous phase was washed with MTBE (2 x 50 ml). The aqueous phase was brought to pH = 1 with H2SO4 (20%) and extracted with MTBE (3 x 50 ml). The organic phases from the acid extraction were combined, washed to neutrality with water (3 x 70 ml) and dried over MgSO4. After concentration, 7.1 g (56%) of E/Z-4,8-dimethyl-3,7-nonadienoic acid were obtained with an E/Z ratio of 55:45 (1H NMR). NMR data correspond to data from Snyder et al. Angew. Chem., 121, 2009, 8039. 13C NMR (CDCl3), E-homomycenylcarboxylic acid: 179.9, 139.5, 131.7, 125.1, 116.2, 40.2, 34.0, 27 .2, 26.2, 18.0, 16.6; Z-homomyrcenylcarboxylic acid: 179.9, 139.5, 132.1, 124.8, 117.0, 34.0, 32.6, 27.0, 26.2, 23.7, 18.0.

Examples 1.1 - 1.12: Pd-catalyzed carbonylation procedure from linalool

[00174] Example 1 has been repeated. The feeds for linalool carbonylation, the conversion after 24 h and the selectivity for the target product of E/Z-4,8-dimethyl-3,7-nonadienoic acid are reported in table I. Table I: Carbonylation of linalool a) addition of 10 ml of pyridine instead of NEt3; b) addition of 10 ml of THF instead of NEt3; c) addition of 10 ml of toluene instead of NEt3; d) addition of 10 ml of dioxane instead of NEt3; e) 80°C instead of 60°C; f) addition of 10 ml of THF instead of NEt3, 100°C, instead of 60°C; g) addition of 10 ml of THF instead of NEt3, 80°C instead of 60°C.

[00175] Comparative example 1.10 shows that no conversion was achieved at 10 bar under the conditions of EP 0146859 (PdCl2/TPP) in the absence of an anhydride source, and even at 100°C only very small conversions at most for the target product (comparative example 1.11). Comparative example 1.12 shows that only minimal conversion was achieved in the case of using Pd(OAc)2 in the absence of an anhydride source.

Examples 1.13 - 1.17: Carbonylation procedure from linalool using transition metal catalysts of groups 8 and 9 of the Periodic Table

[00176] Example 1 has been repeated. Feeds for linalool carbonylation, conversion after 24 h and selectivity for the target product (E/Z-4,8-dimethyl-3,7-nonadienic acid) are reported in Table II. Table II: Linalool carbonylation

Example 2: Carbonylation of 3-methyl-1-penten-3-ol

[00177] Palladium(II) acetate (22 mg, 0.1 mmol), triphenylphosphine (52 mg, 0.2 mmol) and DMAP (49 mg, 0.4 mmol) were initially loaded into a glass autoclave under argon . 3-Methyl-1-penten-3-ol (6.7 g, 67 mmol), triethylamine (6.7 g, 67 mmol) and acetic anhydride (2 g, 20 mmol) were added in an argon counterflow. Subsequently, 10 bar of CO was applied and the mixture was stirred at 1000 rpm at this pressure and at an internal temperature of 60°C for 24 h. Then, the mixture was cooled to room temperature and decompressed. GC analysis of the reaction output gave a 70% conversion with a selectivity for the E/Z-(4-methyl)-3-hexenoic acid target product of 75%.

[00178] After completion of the reaction, MTBE (25 ml) and aqueous NaOH (5%, 50 ml) were added. The phases were separated and the aqueous phase was washed with MTBE (2 x 25 ml). The aqueous phase was brought to pH = 1 with H2SO4 (20%) and extracted with MTBE (3 x 25 ml). The organic phases from the acid extraction were combined, washed to neutrality with water (5 x 25 ml) and dried over MgSO4. After concentration, 2.3 g (27%) of E/Z-(4-methyl)-3-hexenoic acid were obtained as a pale yellow oil with an E/Z ratio of 3:2 (1H NMR ). 13 C NMR (d8-toluene): E-(4-methyl)-3-hexenoic acid: 179.7, 140.8, 114.5, 33.7, 32.5, 16.1, 12.6; Z-(4-methyl)-3-hexenoic acid: 179.7, 141.1, 115.5, 33.4, 25.2, 22.8, 12.6.

Example 3: Carbonylation of 1-hepten-3-ol

[00179] Palladium(II) acetate (22 mg, 0.1 mmol), triphenylphosphine (52 mg, 0.22 mmol) and DMAP (55 mg, 0.45 mmol) were initially loaded into a glass autoclave under argon . 1-Hepten-3-ol (7.6 g, 66 mmol), triethylamine (6.7 g, 67 mmol) and acetic anhydride (1.8 g, 17 mmol) were added in an argon counterflow. Subsequently, 10 bar of CO was applied and the mixture was stirred at 1000 rpm at this pressure and at an internal temperature of 60°C for 24 h. Then, the mixture was cooled to room temperature and decompressed. GC analysis of the reaction output gave a conversion of 75% with a selectivity for the E/Z-3-octenoic acid target product of 50%.

[00180] After completion of the reaction, MTBE (25 ml) and aqueous NaOH (5%, 50 ml) were added. The phases were separated and the aqueous phase was washed with MTBE (2 x 50 ml). The aqueous phase was brought to pH = 1 with H2SO4 (ca. 20 ml, 20%) and extracted with MTBE (3 x 50 ml). The organic phases from the acid extraction were combined, washed to neutrality with water (4 x 50 ml) and dried over MgSO4. After concentration, 2.4 g (26%) of E/Z-3-octenoic acid with an E/Z ratio of 78:22 (1H NMR) were obtained. The NMR data correspond to data from Wirth et al. Org. Lett., 9, 2007, 3169. 13 C NMR (d8-toluene), E-3-octenoic acid: 179.4, 135.0, 121.4, 38.0, 32.5, 31.6 , 22.6, 14.1.

Example 4: Carbonylation of E-nerolidol

[00181] Palladium(II) acetate (46 mg, 0.2 mmol), triphenylphosphine (120 mg, 0.46 mmol) and DMAP (56 mg, 0.46 mmol) were initially loaded into a steel autoclave under argon . E-nerolidol (34 g, 152.6 mmol), triethylamine (17 g, 167 mmol) and acetic anhydride (3.6 g, 35 mmol) were added in an argon counterflow. Subsequently, 10 bar of CO was applied and the mixture was stirred at 1000 rpm at this pressure and internal temperature at 70 °C for 24 h. After 24 h, the mixture was cooled to room temperature and decompressed. GC analysis of the reaction output gave a conversion of 95% with a selectivity for the E/Z-homofarnesilic acid target product of 81%.

[00182] After completion of the reaction, the crude product was purified by Kugelrohr distillation (1 mbar, at 170°C). This gave 23 g (61%) of E/Z-homofarnesilic acid at a purity (GC) of 97% with an isomer ratio of E-homofarnesilic acid: Z-homofarnesilic acid of 64:36 (GC).

[00183] 13C NMR (CDCl3): E-homofarnesilic acid: 179.1, 139.8, 135.4, 131.4, 124.4, 123.8, 114.9, 33.6, 39.8 , 39.6, 26.8, 25.8, 26.4, 17.8, 16.5, 16.1; Z-homofarnesilic acid: 179.2, 139.7, 135.7, 131.2, 124.5, 123.7, 115.9, 39.8, 33.5, 32.2, 26.8, 26 .3, 25.7, 23.4, 17.7, 16.0.

[00184] Example 4 has been repeated. The feeds for carbonylation of E-nerolidol, conversion after 24 h and 6 h and the yield of E/Z-homofarnesilic acid target product (sum of the two isomers) are reported in Table III. Table III: Carbonylation of E-nerolidol a) half the amount of NEt3; b) 23 mol% allyl acetate (CAS 591-87-7) instead of Ac2O; c) 30 mol% E-nerolidyl acetate instead of Ac2O; d) 30 mol% E-nerolidyl acetate instead of Ac2O; e) 120°C; f) THF instead of NEt3; g) 0.3 mol% of P(Cy)3 instead of TPP; h) 0.3 mol% tri(p-tolyl)phosphine instead of TPP; i) 0.3 mol% di(tert-butyl)phenylphosphine instead of TPP; k) 0.3 mol% of cyclohexyldidiphenylphosphine instead of TPP; # yield determined via % GC area as product of selectivity and conversion

Example 5: Carbonylation of E-nerolidyl acetate

[00185] Palladium(II) acetate (50 mg, 0.22 mmol), triphenylphosphine (130 mg, 0.5 mmol) and DMAP (70 mg, 0.57 mmol) were initially loaded into a steel autoclave under argon . E-nerolidyl acetate (42.5 g, 142 mmol), triethylamine (9 g, 89 mmol) and water (2.8 g, 156 mmol) were added in an argon counterflow. Subsequently, 10 bar of CO was applied and the mixture was stirred at 1000 rpm at this pressure and internal temperature at 70 °C for 24 h. Then, the mixture was cooled to room temperature and decompressed. GC analysis of the reaction result gave a conversion of 97% with a selectivity for E/Z-homofarnesilic acid of 71%. Ratio of E-homofarnesilic acid: Z-homofarnesilic acid = 64:36 (GC).

[00186] Example 5 has been repeated. The feeds for carbonylation of E-nerolidyl acetate, conversion after 4 h and 24 h and the yield of E/Z-homofarnesilic acid target product (sum of the two isomers) are reported in Table IV. Table IV: Carbonylation of E-nerolidyl acetate

Example 6: Carbonylation of 1-vinylcyclohexanol

[00187] Palladium(II) acetate (22 mg, 0.1 mmol), triphenylphosphine (54 mg, 0.21 mmol) and DMAP (50 mg, 0.41 mmol) were initially loaded into a glass autoclave under argon . 1-Vinylcyclohexanol (8.35 g, 66 mmol), triethylamine (6.7 g, 67 mmol) and acetic anhydride (1.8 g, 17 mmol) were added in an argon counterflow and 10 bar of CO was added. applied. The mixture was stirred at 1000 rpm at internal temperature 60 °C for 20 h, the pressure was maintained at 10 bar and after 48 h the mixture was cooled to room temperature and decompressed. GC Conversion: 54%; selectivity for 3-cyclohexylidene-propanoic acid: 63%.

[00188] After completion of the reaction, MTBE (25 ml) and aqueous NaOH (5%, 50 ml) were added. The phases were separated and the aqueous phase was washed with MTBE (2 x 50 ml). The aqueous phase was brought to pH = 1 with H2SO4 (ca. 30 ml, 20%) and extracted with MTBE (3 x 50 ml). The organic phases from the acid extraction were combined, washed to neutrality with water (4 x 50 ml) and dried over MgSO4. Concentration gave 3.1 g (31%) of 3-cyclohexylidene-propanoic acid. 13C NMR (d8-toluene): 180.0, 143.8, 112.9, 37.5, 33.3, 29.4, 29.0, 28.1, 27.4.

Example 7: Separation of isomers from a composition comprising E/Z-homofarnesilic acid and isomerization to enrich E-homofarnesilic acid Separation of isomers:

[00189] The mixture obtained in example 4 was dissolved in n-heptane (100 g), isopropanol (10 g) and Novozym 435 (0.5 g) were added and the mixture was stirred at 60 °C for about 17 h . The enzyme was then removed by filtration. At a temperature of 0°C, methanol and water were added and the pH of the reaction mixture was adjusted to 12-13 at a temperature below 10°C by adding aqueous NaOH. The phases were separated, giving an organic phase comprising (3E,7E)-homofarnesylic acid isopropyl ester as the main component and an aqueous phase having a composition comprising 3Z,7E-homofarnesylic acid: 3E,7E-homofarnesilic acid: 2E ,7E-homofarnesyl: additional compounds in a ratio of 68%: 14%: 17%: 1% (HPLC).

Isomerization:

[00190] Palladium(II) acetate (22 mg, 0.098 mmol), triphenylphosphine (58 mg, 0.22 mmol) and DMAP (25 mg, 0.2 mmol) were initially charged under argon in a steel autoclave. The acid mixture of 3Z,7E-homofarnesilic acid: 3E,7E-homofarnesilic acid: 2E,7E-homofarnesilic acid: other compounds (in a ratio of 68%: 14%: 17%: 1%) (17.5 g, 51 mmol), triethylamine (8.1 g, 80 mmol) and acetic anhydride (1.7 g, 17 mmol) were added in an opposite flow of argon and CO was injected at 20 bar. Subsequently, the mixture was stirred at an internal temperature of 140 °C for 14 h (1000 rpm). During this, the pressure was maintained at 20 bar. This was followed by cooling to room temperature and decompression. This gave a composition comprising 3Z,7E-homofarnesilic acid: 3E,7E-homofarnesilic acid: 2E,7E-homofarnesilic acid: additional compounds in a ratio of 22%: 33%: 21%: 24% (HPLC). v

Claims (15)

1. Process for preparing a composition comprising at least one unsaturated carboxylic acid of general formula (I). or a salt thereof, wherein R1 is hydrogen, straight or branched C1-C24-alkyl, straight or branched C2-C24-alkenyl with 1, 2, 3 or more than 3 CC double bonds, unsubstituted C5-C12-cycloalkyl or C5-C12-cycloalkyl substituted by 1, 2 or 3 C1-C6-alkyl radicals or unsubstituted aryl or aryl substituted with 1, 2 or 3 C1-C6-alkyl radicals, R2 is hydrogen, linear C1-C24-alkyl or branched or C2-C24-alkenyl straight or branched with 1, 2, 3 or more than 3 CC double bonds, or R1 and R2 together with the carbon atom to which they are attached are unsubstituted C5-C7-cycloalkyl or are cycloalkyl -C5-C7 containing 1, 2 or 3 linear or branched C1-C6-alkyl radicals, in which an allylic alcohol selected from compounds of general formulas (IV.1) and (IV.2) wherein R6 is C1-C5-alkyl, is subjected to carbonylation by reaction with carbon monoxide in the presence of a transition metal catalyst comprising at least one metal from groups 8, 9 and 10 of the Periodic Table of Elements, wherein the reaction is additionally carried out in the presence of at least one organic phosphorus compound as a binder and in the presence of water and wherein the reaction is carried out at a temperature not exceeding 100°C, said process characterized in that the carbonylation is conducted in the absence of an added hydrohalic acid, an alkali metal halide, an alkaline earth metal halide, or an added ammonium halide; and wherein the halide content of the carbonylation reaction mixture is not more than 2 mol%, based on the total ester content of general formulas (IV.1) and (IV.2). 2. Process according to claim 1, characterized in that the reaction is carried out at a pressure not exceeding 30 bar. 3. Process according to claim 1 or 2, characterized in that the halide content of the carbonylation reaction mixture is not more than 1 mol%, based on the total ester content of the general formulas (IV.1 ) and (IV.2). 4. Process according to any one of the preceding claims, characterized in that the transition metal is used for the reaction in an amount not greater than 0.5% mol, preferably not greater than 0.3% mol, with based on the total molar amount of compounds (IV.1) and (IV.2). 5. Process according to any one of the preceding claims, characterized in that the transition metal is selected from Pd, Ru, Rh, Ir and Fe, with preference given to the use of Pd as transition metal. 6. Process according to any one of the preceding claims, characterized in that the organic phosphorus compound is selected from monodentate and bidentate phosphines, preferably from trialkylphosphines, triarylphosphines, dialkylarylphosphines, alkyldiarylphosphines, cycloalkyldiarylphosphines, dicycloalkylarylphosphines, tricycloalkylphosphines, triheterocyclylphosphines and trihetylarylphosphines, the phosphorus compound used especially being triphenylphosphine, di-tert-butylphenylphosphine, cyclohexyldiphenylphosphine, dicyclohexylphenylphosphine, tri(p-tolyl)phosphine or tricyclohexylphosphine. 7. Process according to any one of the preceding claims, characterized in that the reaction is additionally carried out in the presence of a base other than the nucleophilic reagent selected from 4-(dimethylamino)-pyridine, 4-(C1-C4-alkyl) pyridine and 4-(1-pyrrolidinyl)pyridine, preferably in the presence of a basic N-heteroaromatic, a trialkylamine, alkali metal carbonate or alkaline earth metal carbonate, in particular triethylamine. 8. Process according to any one of the preceding claims, characterized in that the reaction is carried out in the presence of an added aprotic organic solvent. 9. Process according to any one of the preceding claims, characterized in that the reaction is carried out at a temperature not exceeding 80°C, preferably not exceeding 75°C. Process according to any one of the preceding claims, characterized in that the reaction is carried out at a pressure not exceeding 25 bar, preferably not exceeding 20 bar, especially not exceeding 15 bar. 11. Process according to any one of the preceding claims, characterized in that the composition comprising the at least one unsaturated carboxylic acid of formula (I) is a mixture of E/Z isomers of formula (I) comprising an acid 3 -(E) of formula (IE) and a 3-(Z) acid of formula (IZ) in which R1 and R2 have different definitions and R1 has a higher priority according to IUPAC; and this mixture of E/Z isomers of formula (I) is subjected to an isomer enrichment. 12. Process according to claim 11, characterized in that the composition comprising the at least one unsaturated carboxylic acid of formula (I) is a mixture of E/Z isomers of formula (I) comprising a 3-(E ) of formula (I-E) and a 3-(Z) acid of formula (I-Z), wherein, in addition, (1) the composition comprising the mixture of E/Z isomers of formula (I) in the presence of an alcohol and a lipase enzyme, is subjected to an enzyme-catalyzed esterification, in which the 3-(E) acid of formula (I-E) is converted at least partially into a 3-(E) ester, so as to obtain a composition comprising the 3-(E) ester, unconverted 3-(E) acid of formula (I-E) and unconverted 3-(Z) acid of formula (I-Z); (2) the composition obtained in (1) is separated to obtain a composition depleted of 3-(E) acid of formula (I-E) and enriched in 3-(Z) acid of formula (I-Z), and to obtain a composition comprising the 3-(E) ester; (3) the composition obtained in (2) which is depleted of 3-(E) acid of formula (I-E) and enriched in 3-(Z) acid of formula (I-Z) is subjected to an isomerization to increase the acid content 3-(E) of formula (I-E); and (4) optionally, the 3-(E) ester obtained in (2) is cleaved to obtain the 3-(E) acid of formula (I-E). 13. Process according to claim 11, characterized in that the composition comprising at least one unsaturated carboxylic acid of formula (I) is a mixture of E/Z isomers of formula (I) comprising a 3-(E) acid of the formula. (I-E) and a 3-(Z) acid of the formula (I-Z), in which, in addition, (i) the composition comprising the mixture of E/Z isomers of the formula (I) is subjected to an esterification in the presence of a alcohol to obtain the 3-(E) ester and the 3-(Z) ester; (ii) the 3-(E) ester and the 3-(Z) ester obtained in (i) are subjected to a lipase-catalyzed enzymatic hydrolysis, in which the lipase cleaves, at least in part, the 3-(E) ester ) to give the 3-(E) acid of formula (I-E) to obtain a composition comprising the 3-(E) acid of the compound of formula (I-E), unconverted 3-(E) ester and 3-(Z ) not converted; (iii) the composition obtained in (ii) is separated to obtain a composition comprising the 3-(E) acid of the compound of formula (I-E) and to obtain a composition comprising unconverted 3-(E) ester and 3-( Z) not converted; (iv) the composition which is obtained in (iii) and comprises unconverted 3-(E) ester and unconverted 3-(Z) ester is subjected to an ester cleavage to obtain a depleted 3-(E) acid composition of the formula (I-E) or a salt thereof and enriched in 3-(Z) acid of the formula (I-Z) or a salt thereof; and (v) the composition which is obtained in (iv) and is depleted of 3-(E) acid of formula (I-E) and enriched in 3-(Z) acid of formula (I-Z) is subjected to an isomerization to increase the 3-(E) acid content of formula (I-E). Process according to claim 12 or 13, characterized in that the isomerization to increase the 3-(E) acid content of formula (I-E) is carried out in the presence of an anhydride of an organic acid and a base. 15. Process for preparing (-)-ambrox (VIII) characterized by the fact that a1) a mixture of (3E,7E)-4,8,12-trimethyltrideca-3,7,11-trienoic acid and (3Z,7E)-4,8,12-trimethyltrideca-3, 7,11-trienoic acid obtained by a process as defined in any one of claims 1 to 14; b1) the mixture of (3E,7E)-4,8,12-trimethyltrideca-3,7,11-trienoic acid and (3Z,7E)-4,8,12-trimethyltrideca-3,7,11-trienoic acid it is subjected to a separation to obtain (3E,7E)-4,8,12-trimethyltrideca-3,7,11-trienoic acid; c1) (3E,7E)-4,8,12-trimethyltrideca-3,7,11-trienoic acid is subjected to a reduction to obtain (3E,7E)-homofarnesol (VI); d1) (3E,7E)-homofarnesol (VI) is subjected to a cyclization to obtain (-)-ambrox (VIII); or a2) a mixture of (3E,7E)-4,8,12-trimethyltrideca-3,7,11-trienoic acid and (3Z,7E)-4,8,12-trimethyltrideca-3,7,11- trienoic acid obtained by a process as defined in any one of claims 1 to 14; b2) the mixture of (3E,7E)-4,8,12-trimethyltrideca-3,7,11-trienoic acid and (3Z,7E)-4,8,12-trimethyltrideca-3,7,11-trienoic acid it is subjected to a separation to obtain (3E,7E)-4,8,12-trimethyltrideca-3,7,11-trienoic acid; c2) (3E,7E)-4,8,12-trimethyltrideca-3,7,11-trienoic acid is subjected to cyclization to obtain sclareolide (VII); d2) sclareolide (VII) is subjected to a reduction to obtain (-)-ambrox (VIII).