Process for preparation of cyclohyperxic folates

Abstract

The invention relates to a method for preparing cyclic high-aroma folate. The present invention relates to the synthesis of cyclic high-aroma folate esters from well available esters of high-aroma folate in only one step. The cyclophoxim folates prepared according to the method of the present invention can be used as intermediates in the perfume industry, or these compounds can be used as aromatic compounds as it is.

Description

Technical Field

[0001] The present invention relates to a process for preparing cyclic homogeranic acid esters. The present invention relates to the synthesis of cyclic homogeranic acid esters in one step from readily available homogeranic acid esters. Background Art

[0002] Cyclic homogeranyl esters are esters of cyclic homogeranic acid and have been used as synthetic intermediates (Helv. Chem. Acta [Swiss Chemical Journal] 1969, 1732-1734). The corresponding esters such as methyl cyclohomogeranate (CAS α-cyclohomogeranate methyl ester: 64108-19-6; β-cyclohomogeranate methyl ester: 2365417-61-2) and ethyl cyclohomogeranate (CAS (S)-α-cyclohomogeranate ethyl ester: 143658-43-9; β-cyclohomogeranate ethyl ester: 773136-09-7) have been described several times in the literature (Helv. Chem. Acta [Swiss Chemical Journal] 2019, e1900097). Two double bond isomers are described, namely the α-isomer and the β-isomer.

[0003]

[0004] The prior art discloses several methods for synthesizing cyclic homogeranyl esters, including methods starting from myrcene, cyclogeranic acid or 2,4,4-trimethyl-2-cyclohexenone. However, no synthetic routes starting from precursors such as linalool or homogeranic acid and / or its esters are described.

[0005] Helv.Chem.Acta [Swiss Chemical Journal] 2019, e1900097 discloses a synthetic route starting from myrcene. The route involves the addition of LiNEt2 to form the corresponding allylamine (77%-87% yield). This step is followed by cyclization with a stoichiometric amount of H2SO4 (yield 54%). The final step is a low-yield (25%-31% yield) step, which involves methoxycarbonylation with CO and highly toxic iodomethane to give methyl cyclohomogeranate. Thus, starting from myrcene, the reported overall yield is less than 20%.

[0006] Liebigs Ann. Chem. 1991, 1053-1056 discloses the synthesis of esters of cyclohomogeranic acid starting from 2,4,4-trimethyl-2-cyclohexenone. The route involves reduction to the alcohol with lithium aluminum hydride followed by Claisen rearrangement of the ortho-ester, which leads to the formation of ethyl α-cyclohomogeranic acid ester.

[0007] The pathway starting from cyclogeranic acid, a compound obtainable from geranic acid (Zhurnal Org. Kim. [Journal of Organic Chemistry] 1991, 27, 2149 and J. für Prakt. Chemie [Journal of Practical Chemistry] 1936, 147, 199–202)), involves seven sequential steps from cyclogeranic acid to β-cyclohomogeranic acid ethyl ester (Helv. Chem. Acta [Swiss Chemical Journal] 1969, 1732-1734), resulting in very low overall yields.

[0008] In addition, there are laboratory-scale methods that cannot be scaled up to industrial-scale synthesis because of the large amount of waste generated by the reagents (e.g., silyl protecting groups or MsCl) and also because of the limited availability of starting materials (J. Org. Chem. [Journal of Organic Chemistry] 1995, 3580-3585 and Angew. Chem. [Applied Chemistry] 2000, 569-573).

[0009] J. Chem. Soc. Perkin Trans 1 [Journal of the Chemical Society Perkin Journal 1], 1983, 1579-1589 discloses the synthesis of positional isomers of methyl cyclohomogeranate, namely 2,3-unsaturated methyl cyclohomogeranate (as an isomer E / Z-mixture). The synthetic route starts from 2,4,4-trimethyl-2-cyclohexenone. The synthesis of these 2,3-unsaturated positional isomers is not the purpose of the present invention.

[0010]

[0011] In summary, the described approaches for the synthesis of cyclic homogeranate are either multi-step syntheses and therefore low in yield, or comprise single steps with very low yields. This makes them irrelevant for industrial use. In addition, if the method is a multi-step synthesis, many purification steps are involved. This further leads to the generation of additional waste and increased energy costs.

[0012] The desired synthesis of α- / β-cyclic homogeranic acid esters from homogeranic acid requires cyclization of 3,4 / 7,8 unsaturated esters. The prior art (Liebigs Ann. Chem. 1992, 1049-1053) teaches that stoichiometric amounts of BF3 are required for the cyclization steps of the different 3,4 / 7,8 unsaturated esters. Such conditions are not suitable for industrial applications because they produce large amounts of waste products.

[0013] The prior art also teaches that esters of cyclic homogeranic acid lead to the formation of tetrahydroactinolide rather than the desired cyclic homogeranic acid ester (Synthesis 1972, 573-574).

[0014] Therefore, there is a need to develop an efficient process for the synthesis of α- or β-cyclic homogeranyl esters or a mixture of both, wherein the process is short, scalable, provides good yields and can utilize readily available starting materials.

[0015] An object of the present invention is to provide a process for preparing esters of cyclic homogeranic acid. Another object of the present invention is to provide an economical process for producing esters of cyclic homogeranic acid, which produces α- or β-cyclic homogeranic acid esters or mixtures of the two from well-available starting materials in a short sequence of high-yield synthetic steps. The process should be scalable, should avoid the generation of waste materials, and should require only a few and simple purification steps.

[0016] Another object of the present invention is to obtain a process which can be efficiently run as a batch or continuous process. Summary of the invention

[0017] We have unexpectedly found that α- / β-cyclic homogeranate can be made from industrial homogeranate with only two synthesis steps. Cyclic homogeranate can be produced as two isomers (α-cyclic homogeranate or β-cyclic homogeranate). In addition, it may be possible to obtain an α / β-mixture of isomers, and the ratio of the isomeric composition obtained depends on the process conditions.

[0018] Therefore, in one aspect, the present invention relates to a method for synthesizing an ester compound having the general formula (I) or a stereoisomer thereof

[0019]

[0020] in,

[0021] X1 and X3 together form a double bond between the carbon atoms to which they are attached, provided that X2 and X4 are hydrogen; or

[0022] X3 and X4 together form a double bond between the carbon atoms to which they are bound, provided that X1 and X2 are hydrogen,

[0023] Wherein formula (I) comprises,

[0024] Compounds having formula (Ia)

[0025]

[0026] or a stereoisomer thereof or a mixture of stereoisomers thereof,

[0027] Compounds having formula (Ib)

[0028]

[0029] wherein R is selected from C1-C5 straight chain or branched alkyl and C3-C5 straight chain or branched alkenyl,

[0030] The method comprises at least the following steps:

[0031] A) Providing a compound having formula (III)

[0032]

[0033] Wherein R is a C1-C5 straight or branched chain alkyl group,

[0034] or a stereoisomer thereof, or a mixture of stereoisomers thereof,

[0035] B) cyclizing the compound of formula (III) in the presence of a catalyst selected from Bronsted acids or Lewis acids to obtain a compound of formula (I),

[0036] C) optionally purifying the compound of formula (I) obtained in step B).

[0037] In another aspect, the reaction of the present invention is carried out as a batch process or as a continuous process.

[0038] In another aspect, the reaction conditions of the present invention can be varied to obtain mixtures of α- / β-cyclic homogeranate esters in various ratios.

[0039] In another aspect, the process used according to the invention results in the formation of a compound of formula (IV) or a stereoisomer thereof in an amount of less than 15 wt. %

[0040]

[0041] A compound having formula (IV).

[0042] In another aspect, the process used according to the invention results in the formation of a compound of formula (V) or a stereoisomer thereof in an amount of less than 10 wt.%

[0043]

[0044] in,

[0045] R is selected from C1-C5 straight chain or branched chain alkyl and C3-C5 straight chain or branched chain alkenyl.

[0046] The compound of formula (V) may be formed during the synthesis of compound (I) or during its purification by isomerization. DETAILED DESCRIPTION

[0047] The following detailed description is merely exemplary in nature and is not intended to limit the invention claimed herein or the application and use of the invention claimed herein. In addition, it is not intended to be bound by any theory presented in the foregoing technical field, background technology, summary of the invention or the following detailed description.

[0048] As used herein, the terms "comprising" or "comprises" and "comprised of" are synonymous with "including" or "includes" or "containing" and are inclusive or open-ended and do not exclude additional unrecited members, elements, or method steps. It should be understood that, as used herein, the terms "comprising" or "comprises" and "comprised of" encompass the terms "consisting of" or "consists of" and "consists".

[0049] In addition, the terms "(a)", "(b)", "(c)", "(d)", etc. in the specification and claims are used to distinguish similar elements and are not necessarily used to describe a sequential order or a chronological order. It should be understood that the terms so used are interchangeable where appropriate, and that the embodiments of the subject matter described herein are capable of operating in other sequences than those described or shown herein. If the terms "(A)", "(B)" and "(C)" or AA), BB) and CC) or "(a)", "(b)", "(c)", "(d)", "(i)", "(ii)", etc. refer to steps of a method or use or an assay, there is no temporal or temporal continuity between these steps, that is, these steps can be performed simultaneously or there can be a time interval of seconds, minutes, hours, days, weeks, months or even years between these steps, unless otherwise indicated in the application described above or below.

[0050] In the following paragraphs, different aspects of the subject matter are defined in more detail. Unless explicitly indicated to the contrary, each aspect so defined can be combined with any one or more other aspects. In particular, any feature indicated as preferred or advantageous can be combined with any one or more other features indicated as preferred or advantageous.

[0051] References throughout this specification to "one embodiment" or "embodiment" or "preferred embodiment" mean that a particular feature, structure, or property described in conjunction with that embodiment is included in at least one embodiment of the invention claimed herein. Therefore, the phrases "in one embodiment" or "in a preferred embodiment" appearing in different places throughout this specification do not necessarily all refer to the same embodiment, but may refer to the same embodiment. In addition, in one or more embodiments, as will be apparent to those skilled in the art from this disclosure, the features, structures, or properties may be combined in any suitable manner. In addition, although some embodiments described herein include some but not other features included in other embodiments, the combination of features of different embodiments is intended to be within the scope of this subject matter and to form different embodiments, as will be understood by those skilled in the art. For example, in the appended claims, any of the claimed embodiments is used in any combination.

[0052] Furthermore, ranges defined throughout this specification also include the endpoints, ie, a range of 1 to 10 means that both 1 and 10 are included in the range. For the avoidance of doubt, the applicant shall be entitled to any equivalent means under applicable law.

[0053] The term C1-C5-alkyl denotes a straight-chain or branched alkyl group containing 1 to 5 carbon atoms, such as methyl, ethyl, propyl, 1-methylethyl(isopropyl), butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl.

[0054] The term "C3-C5-alkenyl" refers to a straight-chain or branched unsaturated hydrocarbon group having 3 to 5 carbon atoms and having a double bond at any position.

[0055] Examples are "C3-C5-alkenyl" radicals such as 1-propenyl, 2-propenyl, 1-methylvinyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl.

[0056] The term halogen denotes in each case fluorine, bromine, chlorine or iodine, in particular fluorine, chlorine or bromine.

[0057] The term Bronsted acid ( Acid) is used herein as defined by IUPAC for a molecular entity (atom, ion, molecule, compound, complex, etc.) that is capable of donating one or more protons to another chemical species.

[0058] The term Lewis acid is used herein as defined by IUPAC for a molecular entity that acts as an electron pair acceptor and is therefore capable of reacting with a Lewis base to form a Lewis adduct by sharing the electron pair donated by the Lewis base.

[0059] The terms "cyclohomogeranate" and "ester of cyclohomogeranic acid" are used interchangeably in this specification. Unless otherwise specified, the term cyclohomogeranate includes α- or β-isomers, γ-isomers or a mixture of both isomers. Thus, for example, the terms α-cyclohomogeranate methyl ester and α-cyclohomogeranic acid methyl ester are used interchangeably.

[0060] As used herein, the term "compound (X) or its stereoisomer or mixture of stereoisomers" refers to one or more compounds of formula (X), including all stereoisomeric forms (stereoisomers) thereof in all ratios. Thus, the term "compound of formula (Ia) or its stereoisomer or mixture of stereoisomers" refers to compound Ia in its racemic form, or one of its enantiomerically pure forms (R or S), or a mixture of the two possible enantiomers in any ratio, wherein the ratio of the enantiomers is in the range of 0.01:99.99 to 99.99 to 0.01.

[0061] The term "stereoisomer" is a general term for all isomers of a single compound as described by IUPAC, which differ only in the arrangement of their atoms in space, not in the way the atoms are connected. Thus, the term stereoisomer includes mirror image isomers (enantiomers), geometric (cis / trans or E / Z) isomers, and diastereomers. For the precise definition of the term, see IUPAC definitions or G. Helmchen: "Vocabulary and Nomenclature of Organic Stereochemistry". In Houben-Weyl E21a, Stereoselective Synthesis. Helmchen, RW Hoffmann, J. Mulzer, E. Schaumann (eds.), 1995, 1-74. Possible isomers may exist as mixtures (i.e., racemates, cis / trans mixtures or mixtures of diastereomers).

[0062] The invention claimed herein relates to a process for preparing an ester compound having the general formula (I) or a stereoisomer thereof:

[0063]

[0064] in,

[0065] X1 and X3 together are the second bond of a double bond between the carbon atoms to which they are bonded, provided that X2 and X4 are hydrogen; or

[0066] X3 and X4 together are the second bond of the double bond between the carbon atoms to which they are bound, provided that X1 and X2 are hydrogen;

[0067] Wherein formula (I) comprises,

[0068] Compounds having formula (Ia)

[0069]

[0070] or a stereoisomer thereof or a mixture of stereoisomers thereof,

[0071] and compounds having formula (Ib)

[0072]

[0073] wherein R is selected from C1-C5 straight chain or branched alkyl and C3-C5 straight chain or branched alkenyl,

[0074] The method comprises at least the following steps:

[0075] A) Providing a compound having formula (III)

[0076]

[0077] Wherein R is a C1-C5 straight or branched chain alkyl group,

[0078] or a stereoisomer thereof, or a mixture of stereoisomers thereof,

[0079] B) cyclizing the compound of formula (III) in the presence of a catalyst selected from Bronsted acids or Lewis acids to obtain a compound of formula (I),

[0080] C) optionally purifying the compound of formula (I) obtained in step B).

[0081] In an embodiment, R is selected from methyl, ethyl, propyl, butyl, isobutyl, isopropyl, 1-propenyl, or 2-propenyl.

[0082] Preferably, R is selected from methyl or ethyl.

[0083] catalyst

[0084] In an embodiment, the catalyst in step B) is selected from the group consisting of Lewis acids or Bronsted acids.

[0085] In another embodiment, the catalyst in step B) is selected from the group consisting of

[0086] -Present MA x Lewis acids of the form wherein M is a metal and A is a non-coordinating, weakly coordinating anion or a halogen and x is the valence of M;

[0087] or

[0088] - a Bronsted acid selected from the group consisting of an inorganic acid, an inorganic acid salt, an organic acid, an anhydride (which can serve as a Bronsted acid precursor and can form a free acid upon contact with a protic agent), a solid acid catalyst, or a combination thereof.

[0089] In an embodiment, the catalyst in step B) is MA x Lewis acids of the form wherein M is a metal and A is a non-coordinating, weakly coordinating anion, an alkoxide or a halogen, and x is the valence of M, wherein M includes a transition metal, a lanthanide metal, or a metal from Groups 2, 3, 4, 5, 12, 13, 14 and 15 of the Periodic Table of the Elements, and combinations thereof.

[0090] The Lewis acid (also called Lewis acid catalyst) can be any Lewis acid based on transition metals, lanthanide metals and metals from Groups 2, 3, 4, 5, 12, 13, 14 and 15 of the Periodic Table of Elements.

[0091] In an embodiment, the metal M is selected from the group of elements iron, magnesium, zinc, boron, scandium, yttrium, lanthanum, europium, zirconium, titanium, manganese, aluminum, ytterbium, tin, vanadium, bismuth, scandium, or hafnium.

[0092] The catalyst of the present invention is a Lewis acid, such as a catalyst having the general formula MA x A metal salt catalyst wherein A is a non-coordinating or weakly coordinating anion and M is a Group IIIB, rare earth or lanthanide, actinide or Group IVB cation, wherein x is the valence of M. The term "non-coordinating or weakly coordinating anion" means that the anion does not bind to the metal in aqueous solution. Examples of non-coordinating or weakly coordinating anions in the present invention are trifluoromethanesulfonate (also known as triflate ([CF3SO3] - )), hexafluorophosphate ([PF6] - )、[Al[OC(CF3)3]4] - , tetrafluoroborate ([BF4] - ), perchlorate ([ClO4] - ), pentafluorooxytellurate ([TeOF5] - )、BArF([B(ArH x F y )4]- , wherein Ar is aryl and x+y=5, for example, [B(C6F5)4] - ), toluenesulfonate ([CH3C6H4SO3] - ), methanesulfonate ([CH3SO3] - ) and antimony hexafluoride ion ([SbF6] - ).

[0093] It should be noted that whether a particular anion is "non-coordinating or weakly coordinating" depends on its environment, for example, the presence of solvents, impurities and especially cations.

[0094] Examples of Group IIIB metals are scandium and yttrium. An example of Group IVB metals is hafnium. Examples of rare earth or lanthanide cations are lanthanum, europium and ytterbium. Examples of water-resistant Lewis acids in the present invention are scandium trifluoromethanesulfonate [Sc(CF3SO3)3], europium trifluoromethanesulfonate [Eu(CF3SO3)3], hafnium trifluoromethanesulfonate [Hf(CF3SO3)4], yttrium trifluoromethanesulfonate [Y(CF3SO3)3], lanthanum trifluoromethanesulfonate [La(CF3SO3)3] and ytterbium trifluoromethanesulfonate [Yb(CF3SO3)3]. Many of these water-resistant Lewis acids are commercially available or can be synthesized by methods known in the art.

[0095] In a preferred embodiment, the Lewis acid is selected from scandium trifluoromethanesulfonate [Sc(CF3SO3)3], aluminum trifluoromethanesulfonate [Al(CF3SO3)3], hafnium trifluoromethanesulfonate [Hf(CF3SO3)4], yttrium trifluoromethanesulfonate [Y(CF3SO3)3], bismuth trifluoromethanesulfonate [Bi(CF3SO3)3] or ytterbium trifluoromethanesulfonate [Yb(CF3SO3)3].

[0096] Lewis acids based on transition metals, lanthanide metals, and metals from Groups 2, 3, 4, 5, 12, 13, 14, and 15 are generally designated by the formula MX4; wherein M is a transition metal or a Group 2, 4, 5, 12, 13, or 14 metal, and X is a halogen independently selected from the group consisting of fluorine, chlorine, bromine, and iodine. X may also be a pseudohalogen. Examples include titanium tetrachloride, titanium tetrabromide, vanadium tetrachloride, tin tetrachloride, and zirconium tetrachloride.

[0097] The Group 4, 5, or 14 Lewis acids may also contain more than one type of halogen. Examples include titanium trichloride bromide, titanium dichloride dibromide, vanadium trichloride bromide, and tin trifluoride chloride.

[0098] In an embodiment, A is a halogen selected from the group of chlorine, fluorine and bromine, preferably chlorine.

[0099] In a preferred embodiment, the Lewis acid is selected from FeCl3, FeBr3, Me2AlCl, TiCl3(OiPr), AlCl3, ZnCl2, MnCl2, MgCl2, MnCl2, BCl3, BiCl3, SbCl5 and its salts, SiCl4, InCl3 and its salts, GaCl3, ZrCl4, NbCl5, TaCl5, and its salts, BF3, SnCl4 and TiCl4; more preferably FeCl3.

[0100] In a preferred embodiment, the Lewis acid is selected from scandium trifluoromethanesulfonate [Sc(CF3SO3)3], aluminum trifluoromethanesulfonate [Al(CF3SO3)3], hafnium trifluoromethanesulfonate [Hf(CF3SO3)4], yttrium trifluoromethanesulfonate [Y(CF3SO3)3], bismuth trifluoromethanesulfonate [Bi(CF3SO3)3] or ytterbium trifluoromethanesulfonate [Yb(CF3SO3)3], FeCl3, FeBr3, Me2AlCl, TiCl3(OiPr), AlCl3, ZnCl2, MgCl2, BCl3, Al(OTf)3, BF3, SnCl4, or TiCl4.

[0101] Group 4, 5 and 14 Lewis acids useful in the process may also have the general formula MR n X 4-n ; wherein M is a Group 4, 5, or 14 metal; wherein R is a monovalent hydrocarbon group selected from the group consisting of C-1 to C-12 alkyl, aryl, arylalkyl, alkylaryl, and cycloalkyl; wherein n is an integer from 0 to 4; and wherein X is a halogen independently selected from the group consisting of fluorine, chlorine, bromine, and iodine, preferably chlorine. X may also be a pseudohalogen. Examples include benzyltitanium trichloride, dibenzyltitanium dichloride, benzylzirconium trichloride, dibenzylzirconium dibromide, methyltitanium trichloride, dimethyltitanium difluoride, dimethyltin dichloride, and phenylvanadium trichloride.

[0102] The Group 4, 5 and 14 Lewis acids useful in the process may also have the general formula M(RO) n R' m X (m+n); wherein M is a Group 4, 5, or 14 metal; RO is a monovalent hydrocarboxy selected from the group consisting of C1 to C30 alkoxy, aryloxy, arylalkoxy, alkylaryloxy; R' is a monovalent hydrocarbon group selected from the group consisting of C1 to C12 alkyl, aryl, arylalkyl, alkylaryl, and cycloalkyl; n is an integer from 0 to 4; m is an integer from 0 to 4 such that the sum of n and m is 3 or 4; and X is a halogen independently selected from the group consisting of fluorine, chlorine, bromine, and iodine, preferably chlorine. X can also be a pseudohalogen. Examples include methoxytitanium trichloride, n-butoxytitanium trichloride, di(isopropoxy)titanium dichloride, phenoxytitanium tribromide, phenylmethoxyzirconium trifluoride, methylmethoxytitanium dichloride, methylmethoxytin dichloride, and benzylisopropoxyvanadium dichloride.

[0103] The Group 5 Lewis acid may also have the general formula MOX3; wherein M is a Group 5 metal; X is a halogen independently selected from the group consisting of fluorine, chlorine, bromine, and iodine, preferably chlorine. An example is vanadium oxytrichloride.

[0104] The Group 13 Lewis acids useful in the method may also have the following general formula: MR n X 3-n , wherein M is a Group 13 metal; R is a monovalent hydrocarbon group selected from the group consisting of C1 to C12 alkyl, aryl, arylalkyl, alkylaryl and cycloalkyl; and n is a number from 0 to 3; and X is a halogen independently selected from the group consisting of fluorine, chlorine, bromine, and iodine, preferably chlorine. X may also be a pseudohalogen. Examples include ethylaluminum dichloride, methylaluminum dichloride, benzylaluminum dichloride, isobutylgallium dichloride, diethylaluminum chloride, dimethylaluminum chloride, ethylaluminum sesquichloride, methylaluminum sesquichloride, trimethylaluminum and triethylaluminum.

[0105] Group 13 Lewis acids useful in the present disclosure may also have the general formula M(RO) n R' m X 3-(m+n) ; wherein M is a Group 13 metal; RO is a monovalent hydrocarbonoxy group selected from the group consisting of C1 to C30 alkoxy, aryloxy, arylalkoxy, alkylaryloxy; R' is a monovalent hydrocarbon group selected from the group consisting of C-1 to C-12 alkyl, aryl, arylalkyl, alkylaryl and cycloalkyl; n is a number from 0 to 3; m is a number from 0 to 3 such that the sum of n and m is not greater than 3; and X is a halogen independently selected from the group consisting of fluorine, chlorine, bromine, and iodine, preferably chlorine. X can also be a pseudohalogen. Examples include methoxyaluminum dichloride, ethoxyaluminum dichloride, 2,6-di-tert-butylphenoxyaluminum dichloride, methoxymethylaluminum chloride, 2,6-di-tert-butylphenoxymethylaluminum chloride, isopropoxygallium dichloride and phenoxymethylindium fluoride.

[0106] Group 13 Lewis acids useful in the present disclosure may also have the general formula M(RC(O)O) n R' m X 3-(m+n) ; wherein M is a Group 13 metal; RC(O)O is a monovalent hydrocarbacyl selected from the group consisting of C2 to C30 alkanoyloxy, aryl acyloxy, aryl alkyl acyloxy, alkyl aryl acyloxy; R' is a monovalent hydrocarbon group selected from the group consisting of C1 to C12 alkyl, aryl, aryl alkyl, alkyl aryl and cycloalkyl; n is a number from 0 to 3, and m is a number from 0 to 3, such that the sum of n and m is not greater than 3; and X is a halogen independently selected from the group consisting of fluorine, chlorine, bromine, and iodine, preferably chlorine. X can also be a pseudohalogen. Examples include acetoxyaluminum dichloride, benzoyloxyaluminum dibromide, benzoyloxygallium difluoride, methylacetoxyaluminum chloride, and isopropionyloxyindium trichloride.

[0107] In embodiments, some Lewis acids may decompose in the presence of water to form Bronsted acids.

[0108] The term Bronsted acid is used herein as defined by IUPAC for a molecular entity (atom, ion, molecule, compound, complex, etc.) that is capable of donating one or more protons to another chemical species.

[0109] In an embodiment, the catalyst in step B) is a Bronsted acid selected from the group consisting of an inorganic acid, an inorganic acid salt, an organic acid, an anhydride (which can serve as a Bronsted acid precursor and can form a free acid upon contact with a protic agent), a solid acid catalyst, a zeolite, an acidic ion exchange resin, and combinations thereof.

[0110] In an embodiment, the Bronsted acid is selected from the group consisting of an inorganic acid, an inorganic acid salt, an organic acid, a solid acid catalyst, or a combination thereof.

[0111] In an embodiment, the inorganic acid is selected from hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, boric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, or phosphonic acid.

[0112] In an embodiment, the inorganic acid is immobilized on silica or any other thermally stable support.

[0113] In another embodiment, the inorganic acid salt is selected from potassium bisulfate, sodium bisulfate, sodium dihydrogen phosphate.

[0114] In another embodiment, the organic acid is selected from p-toluenesulfonic acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, or trifluoroacetic acid.

[0115] In another embodiment, an anhydride is used as a catalyst. The anhydride acts as an acid precursor and can form a Bronsted acid when in contact with a protic agent. In an embodiment, the anhydride is selected from phosphorus pentoxide (P2O5), carbon dioxide (CO2), sulfur trioxide (SO3), acetic anhydride (Ac2O), methanesulfonic anhydride.

[0116] In another embodiment, solid acid catalyst can be used independently or can be used in combination with one or more inorganic acids or other types of catalysts alternatively.Operable exemplary solid acid catalysts include heteropolyacids, acid resin catalysts, mesoporous silica, acid clay, sulfated zirconium oxide, molecular sieve materials, zeolites and acidic materials on heat-stable carriers.When acidic materials are provided on heat-stable carriers, heat-stable carriers can include, for example, one or more of the following: silicon dioxide, tin oxide, zirconium oxide, titanium dioxide, carbon, alpha-alumina, etc.Can be optionally doped with additional acid groups (such as SO4 2- or SO3H - ) oxides themselves (e.g., ZrO2, SnO2, TiO2, etc.) can also be used as solid acid catalysts.

[0117] The terms "solid acid" and "solid acid catalyst" are used synonymously herein and may comprise one or more solid acid materials.

[0118] Other examples of solid acid catalysts include strongly acidic ion exchangers, such as cross-linked polystyrene containing sulfonic acid groups. For example, - The resins are functionalized styrene-divinylbenzene copolymers with different surface properties and porosity. The functional groups are usually of the sulfonic acid type. -Branded resins supplied as beads ( is a registered trademark of The Dow Chemical Co.). Similarly, - brand resin is a sulfonated tetrafluoroethylene based fluoropolymer-copolymer which is a solid acid catalyst. is a registered trademark of EI du Pont de Nemours & Co. Dow(R) is an ion exchange resin having a styrene-divinylbenzene copolymer matrix containing sulfonic acid functional groups. (It is a registered trademark of the Dow Chemical Company).

[0119] The solid catalyst may be in any shape or form known or developed in the future, such as granules, powders, beads, pills, pellets, flakes, cylinders, spheres, or other shapes.

[0120] The support of the metal catalyst can be any suitable support (now known or developed in the future) that is sufficiently strong and durable to withstand the reaction conditions disclosed herein. Suitable catalyst supports include alumina, carbon, ceria, magnesia, silica, titania, zirconia, zeolites (preferably Y, ZSM 5, MWW and β), hydrotalcites, molecular sieves, clays, iron oxides, silicon carbide, aluminosilicates, and modifications, mixtures or combinations thereof.

[0121] Zeolites can also be used as solid acid catalysts. Among them, H-type zeolites are generally preferred, such as zeolites in the mordenite group or fine-pore zeolites such as zeolites X, Y and L, for example, mordenite, erionite, chabazite, or faujasite. Also suitable are ultrastable zeolites in the faujasite group that have been dealuminated.

[0122] In a preferred embodiment, step B) is carried out in the presence of a Bronsted acid selected from phosphoric acid, p-toluenesulfonic acid, phosphonic acid or a strongly acidic ion exchanger.

[0123] Preferably, the Bronsted acid is selected from phosphoric acid or trifluoroacetic acid, more preferably phosphoric acid.

[0124] In an embodiment, the mineral acid, especially phosphoric acid, is immobilized on silica or any other thermally stable support.

[0125] In a preferred embodiment, the phosphoric acid is an aqueous solution, which is a 50% aqueous solution, an 80% aqueous solution, or an 85% aqueous solution.

[0126] In another preferred embodiment, the phosphoric acid used is in its crystalline form.

[0127] In another preferred embodiment, polyphosphoric acid is used as catalyst.

[0128] In a preferred embodiment of the present invention, the catalyst of step B) is selected from FeCl3, scandium trifluoromethanesulfonate [Sc(CF3SO3)3], aluminum trifluoromethanesulfonate [Al(CF3SO3)3], hafnium trifluoromethanesulfonate [Hf(CF3SO3)4], yttrium trifluoromethanesulfonate [Y(CF3SO3)3], bismuth trifluoromethanesulfonate [Bi(CF3SO3)3], ytterbium trifluoromethanesulfonate [Yb(CF3SO3)3], phosphoric acid (85% aqueous solution), phosphoric acid (crystalline) or polyphosphoric acid.

[0129] Depending on the type of catalyst, the ratio of α isomer to β isomer in the final product varies. Therefore, depending on the requirements of the final product, the reaction conditions, especially the choice of catalyst, can be changed to obtain different ratios of α isomer and β isomer. The choice of catalyst also affects the formation of by-products.

[0130] Thus, judicious choice of an appropriate Bronsted or Lewis acid catalyst enables the isomer ratio to be altered in favor of either the α- or β-isomer of the cyclic homogeranate.

[0131] In embodiments, the catalyst in the reaction is present in an amount ranging from 0.01 to 100 mol % based on the total amount of the compound having formula (III).

[0132] In another embodiment, the catalyst in the reaction is present in an amount ranging from 1 to 50 mol % based on the total amount of the compound having formula (III).

[0133] In a preferred embodiment, the catalyst in the reaction is present in an amount in the range of 2.5 mol% to 25 mol% based on the total amount of the compound of formula (III), more preferably in the range of 5 mol% to 25 mol% based on the total amount of the compound of formula (III), and even more preferably in the range of 5 mol% to 10 mol% based on the total amount of the compound of formula (III).

[0134] In a preferred embodiment, the catalyst in the reaction is present in an amount in the range of 2.5 mol% to 25 mol% based on the total amount of the compound of formula (III), more preferably in the range of 5 mol% to 25 mol% based on the total amount of the compound of formula (III), and even more preferably in the range of 5 mol% to 10 mol% based on the total amount of the compound of formula (III), wherein the catalyst is crystalline phosphoric acid.

[0135] In a preferred embodiment, the temperature in step B) is in the range of 0°C to 150°C, in particular the temperature is in the range of 20°C to 120°C, preferably in the range of 50°C to 120°C.

[0136] In a more preferred embodiment, the temperature in step B) is at every temperature between 80°C and 120°C.

[0137] In another embodiment, step B) is performed in the presence or absence of a solvent.

[0138] In an embodiment, the solvent is selected from the group consisting of ketones, esters, aromatic solvents, aliphatic solvents, cyclic ethers, alcohols, water, nitriles, ethers, and mixtures thereof.

[0139] In another embodiment, the solvent is selected from toluene, benzene, benzyl alcohol, chlorobenzene, benzonitrile, xylene, trifluorotoluene, nitrobenzene, cyclohexane, or n-heptane, hexane, octane, tetrahydrofuran, 2-methyltetrahydrofuran, methyl-tert-butyl ether, 1-pentanol, 1-hexanol, methanol, 1-butanol, 1-propanol, 2-propanol, acetonitrile, water, dimethylformamide, tetrahydrofuran, toluene, ethyl acetate, dichloromethane, 1,1,1,3,3,3-hexafluoroisopropanol, dioxane or ethanol.

[0140] Preferably, the solvent is selected from toluene, cyclohexane, n-heptane, ethanol or methanol.

[0141] The process in step B) can be carried out on an industrial scale as a batch or semi-continuous or continuous process. The choice of the optimal setup depends on many factors, such as the phase behavior of the reaction system (biphasic liquid / liquid system or one homogeneous phase in the case of dissolved acid catalysts or reaction in the liquid phase in the case of solid catalysts) the required stirring, the production volume, the required reaction temperature, the necessary residence time and many other factors.

[0142] In an embodiment, the reaction is carried out as a batch reaction for a time period in the range of 10 minutes to 24 hours, preferably for a time period in the range of 10 minutes to 10 hours, more preferably for a time period in the range of 10 minutes to 5 hours.

[0143] In another embodiment, the reaction is carried out in a continuous reactor apparatus (such as a mixing pump) with a residence time in the range of 1 minute to 10 hours, preferably for a time period in the range of 1 minute to 5 hours, more preferably for a time period in the range of 1 minute to 2 hours.

[0144] In an embodiment, the compound of formula (I) is selected from

[0145]

[0146] In an embodiment, the compound having formula (I) includes a compound having formula (Ic)

[0147]

[0148] in,

[0149] X2 and X3 together form a double bond between the carbon atoms to which they are bound.

[0150] R is selected from C1-C5 straight chain or branched chain alkyl and C3-C5 straight chain or branched chain alkenyl.

[0151] In an embodiment, the compound of formula (I) includes a compound of formula (Ic), wherein the compound of formula (Ic) is γ-1 or γ-2

[0152]

[0153] In an embodiment, the compound of formula (I) comprises less than 15%, preferably less than 10%, more preferably less than 5% of the compound of formula (IV)

[0154]

[0155] Compounds of formula (IV) (tetrahydroactinol), in particular cis-IV, may be formed as by-products in the reaction. The formation of this by-product depends on the process conditions. However, by changing the process conditions, the amount of this by-product can be controlled.

[0156] In an embodiment, the compound of formula (I) comprises less than 10 wt.%, preferably less than 9 wt.%, more preferably less than 8 wt.% of the compound of formula (V)

[0157]

[0158] or a stereoisomer thereof or a mixture of stereoisomers thereof,

[0159] in,

[0160] R is selected from C1-C5 straight chain or branched chain alkyl and C3-C5 straight chain or branched chain alkenyl.

[0161] The compound of formula (V) may be formed during the synthesis of compound (I) or during its purification by isomerization.

[0162] In an embodiment, the compound of formula (III) is obtained by a process comprising at least the following steps:

[0163] AA) provides a compound having formula (II)

[0164]

[0165] BB) subjecting the compound of formula (II) to an esterification reaction to obtain the compound of formula (III).

[0166] The compound of formula (II) (homogeranic acid (mixture of isomers)) can be converted into the corresponding homogeranic acid ester by using esterification techniques known in the art (see MB Smith, J. March, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure. New York: Wiley Press, 2013). The ester obtained can be purified by distillation. The purified or crude homogeranic acid ester can be used in step B with a chemical purity of >70%, most preferably >90%, and most preferably with a purity of >95% as a mixture of its 3E / Z-isomers. Trace compounds that may be present in the industrially used homogeranic acid esters may be 2E / Z homogeranic acid esters or also E / Z-methyl-3-ethylidene-7-methyloct-6-enoate. The ratio of 3E-isomer:3Z-isomer in the homogeranic acid ester can vary.

[0167] In an embodiment, the esterification step is carried out in the presence of sulfuric acid, NaHSO4, KHSO4, The reaction can be carried out in the presence of p-toluenesulfonic acid, methanesulfonic acid, formic acid or any other acidic catalyst, preferably in the presence of sulfuric acid or NaHSO4.

[0168] use:

[0169] In embodiments, the compounds prepared according to the method of the present invention can be used as intermediates in the perfume industry, or these compounds can be used as aromatic compounds as they are.

[0170] Despite the multitude of existing aroma chemicals (flavors and flavorings) and processes for their preparation, there is a constant need for novel components that can satisfy the multiple properties desired for extremely diverse fields of use and for simple synthetic routes to make them available. The process of the present invention enables the efficient preparation of compounds of general formula (I) that can be used as interesting synthetic units in providing novel aroma chemicals.

[0171] In a preferred embodiment, the compounds of formula (I) can be used as aroma chemicals in compositions selected from perfumes, detergents and cleaning compositions, cosmetic agents, body care agents, hygiene preparations, products for oral and dental hygiene, fragrance dispensers, perfumes and medicaments.

[0172] Example

[0173] Hereinafter, a list of examples is provided to further illustrate the present disclosure without intending to limit the present disclosure to the specific examples listed below.

[0174] 1. A method for preparing an ester compound having the general formula (I) or a stereoisomer thereof

[0175]

[0176] in,

[0177] X1 and X3 together are the second bond of a double bond between the carbon atoms to which they are bonded, provided that X2 and X4 are hydrogen; or

[0178] X3 and X4 together are the second bond of a double bond between the carbon atoms to which they are bonded, provided that X1 and X2 are hydrogen; or

[0179] Wherein formula (I) comprises,

[0180] Compounds having formula (Ia)

[0181]

[0182] or its stereoisomers or mixtures of its stereoisomers

[0183] and compounds having formula (Ib)

[0184]

[0185] wherein R is selected from C1-C5 straight chain or branched alkyl and C3-C5 straight chain or branched alkenyl,

[0186] The method comprises at least the following steps:

[0187] A) Providing a compound having formula (III)

[0188]

[0189] wherein R is selected from C1-C5 straight chain or branched alkyl and C3-C5 straight chain or branched alkenyl,

[0190] or a stereoisomer thereof, or a mixture of stereoisomers thereof,

[0191] B) cyclizing the compound of formula (III) in the presence of a catalyst selected from Bronsted acids or Lewis acids to obtain a compound of formula (I),

[0192] C) optionally purifying the compound of formula (I) obtained in step B).

[0193] 2. The method according to embodiment 1, wherein R is selected from C1-C5 straight chain or branched chain alkyl and C3-C5 straight chain or branched chain alkenyl.

[0194] 3. The method according to embodiment 1 or 2, wherein R is selected from methyl, ethyl, propyl, butyl, isobutyl, isopropyl, 1-propenyl, or 2-propenyl, preferably, R is selected from methyl or ethyl.

[0195] 4. The method according to embodiment 1, wherein in step B), the catalyst is selected from the group consisting of

[0196] a) Shows MA x Lewis acids of the form wherein M is a metal and A is a non-coordinating, weakly coordinating anion, alkoxide, or halogen, and x is the valence of M;

[0197] or

[0198] b) a Bronsted acid selected from the group consisting of an inorganic acid, an inorganic acid salt, an organic acid, an anhydride (which can serve as a Bronsted acid precursor and can form a free acid upon contact with a protic agent), a solid acid catalyst, or a combination thereof.

[0199] 5. The method according to embodiment 4, wherein step B) is carried out in the presence of a Bronsted acid selected from the group consisting of:

[0200] - an inorganic acid selected from hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, boric acid, hydrofluoric acid, hydrobromic acid, or hydroiodic acid, phosphonic acid, wherein these inorganic acids are fixed on silica or any other thermally stable support,

[0201] - an inorganic acid salt selected from potassium hydrogen sulfate, sodium hydrogen sulfate, sodium dihydrogen phosphate,

[0202] - an organic acid selected from p-toluenesulfonic acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, or trifluoroacetic acid,

[0203] - anhydrides which can act as Bronsted acid precursors and which can form free acids upon contact with protic agents, such as phosphorus pentoxide (P2O5), carbon dioxide (CO2), sulfur trioxide (SO3), acetic anhydride (Ac2O), methanesulfonic anhydride,

[0204] - a solid acid catalyst selected from heteropolyacids, acid resin-type catalysts, strongly acidic ion exchangers, mesoporous silica, acid clays, sulfated zirconia, molecular sieve materials, or acidic materials on a thermally stable support, or zeolites,

[0205] or a combination thereof.

[0206] 6. The process according to any one of embodiments 4 to 5, wherein step B) is carried out in the presence of a Bronsted acid selected from phosphoric acid, p-toluenesulfonic acid, phosphonic acid or a strongly acidic ion exchanger.

[0207] 7. The method according to embodiment 6, wherein the Bronsted acid is phosphoric acid or trifluoroacetic acid or phosphoric acid supported on silica.

[0208] 8. The method of embodiment 7, wherein the Bronsted acid is phosphoric acid.

[0209] 9. The method according to embodiment 4, wherein the step B) is performed in the presence of MA x The method is carried out in the presence of a Lewis acid of the form of a catalyst, wherein M is a metal and A is a non-coordinating, weakly coordinating anion, an alkoxide or a halogen, and x is the valence of M, wherein M includes a transition metal, a lanthanide metal, or a metal from Groups 2, 3, 4, 5, 12, 13, 14 and 15 of the Periodic Table of the Elements, and combinations thereof.

[0210] 10. The method according to embodiment 9, wherein the metal M is selected from the group consisting of iron, magnesium, zinc, boron, titanium, manganese, scandium, yttrium, lanthanum, europium, zirconium, aluminum, ytterbium, tin, vanadium, bismuth, scandium, or hafnium.

[0211] 11. The method of embodiment 9, wherein A is a non-coordinating, weakly coordinating anion selected from the group consisting of trifluoromethanesulfonate or trifluoromethanesulfonate ([CF3SO3] - ), hexafluorophosphate ([PF6] - )、[Al[OC(CF3)3]4] - , tetrafluoroborate ([BF4] - ), perchlorate ([ClO4] - )、BArF([B(ArH x F y )4] - , wherein Ar is aryl and x+y=5), toluenesulfonate ([CH3C6H4SO3] - ), methanesulfonate ([CH3SO3] - ), or antimony hexafluoride ion ([SbF6] - ).

[0212] 12. The method of embodiment 9, wherein A is a halogen selected from the group consisting of chlorine, fluorine, iodine, and bromine.

[0213] 13. The method of any one of embodiments 9 to 12, wherein the Lewis acid is selected from scandium trifluoromethanesulfonate [Sc(CF3SO3)3], aluminum trifluoromethanesulfonate [Al(CF3SO3)3], hafnium trifluoromethanesulfonate [Hf(CF3SO3)4], yttrium trifluoromethanesulfonate [Y(CF3SO3)3], bismuth trifluoromethanesulfonate [Bi(CF3SO3)3] or ytterbium trifluoromethanesulfonate [Yb(CF3SO3)3], FeCl3, FeBr3, Me2AlCl, TiCl3(OiPr), AlCl3, ZnCl2, MgCl2, BCl3, SbCl5 and its salts, SiCl4, InCl3 and its salts, GaCl3, ZrCl4, NbCl5, TaCl5, and its salts, Al(OTf)3, BF3, SnCl4, or TiCl4.

[0214] 14. The method of any one of embodiments 9 to 13, wherein the Lewis acid is selected from FeCl3, scandium trifluoromethanesulfonate [Sc(CF3SO3)3], aluminum trifluoromethanesulfonate [Al(CF3SO3)3], hafnium trifluoromethanesulfonate [Hf(CF3SO3)4], yttrium trifluoromethanesulfonate [Y(CF3SO3)3], bismuth trifluoromethanesulfonate [Bi(CF3SO3)3], or ytterbium trifluoromethanesulfonate [Yb(CF3SO3)3].

[0215] 15. The process according to any one of embodiments 1 to 14, wherein the catalyst in step B) is present in an amount ranging from 0.01 mol% to 100 mol% based on the total amount of compounds having formula (III).

[0216] 16. The method according to any one of embodiments 1 to 15, wherein the catalyst in the reaction is present in an amount ranging from 0.01 mol% to 50 mol% based on the total amount of compounds having formula (III).

[0217] 17. The method according to any one of embodiments 1 to 16, wherein the catalyst in the reaction is present in an amount ranging from 0.1 mol% to 10 mol% based on the total amount of compounds having formula (III).

[0218] 18. The method according to any one of embodiments 1 to 17, wherein the catalyst in the reaction is present in an amount ranging from 0.1 mol% to 5 mol% based on the total amount of compounds having formula (III).

[0219] 19. The process of any one of embodiments 1 to 18, wherein in step B), the reaction is carried out at a temperature in the range of 0°C to 150°C.

[0220] 20. The process of any one of embodiments 1 to 19, wherein in step B), the reaction is carried out at a temperature in the range of 20°C to 130°C.

[0221] 21. The process of any one of embodiments 1 to 20, wherein in step B), the reaction is carried out at a temperature in the range of 50°C to 120°C.

[0222] 22. The method of any one of embodiments 1 to 21, wherein in step B), the reaction is carried out in the presence or absence of a solvent.

[0223] 23. The method of embodiment 22, wherein the solvent is selected from the group consisting of ketones, esters, aromatic solvents, aliphatic solvents, cyclic ethers, alcohols, ethers, and mixtures thereof.

[0224] 24. The method of embodiment 23, wherein the solvent is selected from toluene, benzene, benzyl alcohol, chlorobenzene, benzonitrile, xylene, trifluorotoluene, nitrobenzene, cyclohexane, or n-heptane, hexane, octane, tetrahydrofuran, 2-methyltetrahydrofuran, methyl-tert-butyl ether, 1-pentanol, 1-hexanol, methanol, 1-butanol, 1-propanol, 2-propanol, acetonitrile, water, dimethylformamide, tetrahydrofuran, toluene, ethyl acetate, dichloromethane, 1,1,1,3,3,3-hexafluoroisopropanol, dioxane or ethanol.

[0225] 25. The method of embodiment 24, wherein the solvent is selected from toluene, cyclohexane, n-heptane, ethanol or methanol.

[0226] 26. The method of embodiment 25, wherein the solvent is selected from toluene, cyclohexane or n-heptane.

[0227] 27. The process according to any one of embodiments 1 to 26, wherein in step B), the reaction is carried out as a batch reaction or as a continuous reaction in a continuous reactor apparatus.

[0228] 28. The process of any one of embodiments 1 to 27, wherein in step B), the reaction is carried out as a batch reaction for a time period ranging from 10 minutes to 24 hours.

[0229] 29. The process according to any one of embodiments 1 to 27, wherein in step B), the reaction is carried out in a continuous reactor apparatus (such as a mixing pump) with a residence time in the range of 1 minute to 10 hours.

[0230] 30. The method of any one of embodiments 1 to 29, wherein the compound of formula (I) comprises a compound of formula (Ic)

[0231]

[0232] in,

[0233] X2 and X3 together are the second bond of the double bond between the carbon atoms to which they are bound,

[0234] R is selected from C1-C5 straight chain or branched chain alkyl and C3-C5 straight chain or branched chain alkenyl.

[0235] 31. The method according to embodiment 30, wherein the compound of formula (Ic) is

[0236]

[0237] 32. The method of embodiment 1, wherein the compound of formula (III) is obtained by a method comprising at least the following steps:

[0238] AA) provides a compound having formula (II)

[0239]

[0240] BB) subjecting the compound of formula (II) to an esterification reaction to obtain the compound of formula (III).

[0241] 33. The method according to embodiment 32, wherein the esterification step is carried out in the presence of sulfuric acid, KHSO4, The reaction can be carried out in the presence of PTSA, MSA, formic acid or any other acid catalyst.

[0242] 34. The method of embodiment 33, wherein the esterification step is performed in the presence of sulfuric acid.

[0243] 35. The method of any one of embodiments 1 to 29, wherein the compound of formula (I) comprises a compound of formula (V) in an amount less than 10 wt.%

[0244]

[0245] or a stereoisomer thereof or a mixture of stereoisomers thereof,

[0246] in,

[0247] R is selected from C1-C5 straight chain or branched chain alkyl and C3-C5 straight chain or branched chain alkenyl.

[0248] Advantages of the Invention

[0249] 1) The product is obtained in high yield.

[0250] 2) The reaction conditions can be varied to obtain different ratios of α / β-cyclic homogeranyl esters. Different ratios of α / β-cyclic homogeranyl esters in the final product can find use in a variety of applications.

[0251] 3) The process can be carried out as a batch process, or as a continuous process.

[0252] 4) Relatively short reaction time.

[0253] 5) The reaction does not involve expensive reagents.

[0254] 6) The method avoids the use of waste-generating reagents (no protecting group chemistry) and thereby reduces the number of purification steps.

[0255] 7) This process leads to the formation of lower amounts of by-products in the form of compounds of formula (IV).

[0256] Examples:

[0257] Having described the invention, a further understanding may be obtained by reference to certain specific examples, which are provided herein for purposes of illustration only. Unless otherwise specified, these examples are not intended to be limiting.

[0258] 1. Materials and Methods

[0259] Material

[0260] Chemicals

[0261] Chemicals were purchased from commercial suppliers (ABCR, Acros Organics, Alfa Aesar, Apollo Scientific, Fluorochem, Manchester Organics, Sigma-Aldrich, TCI) and used without further purification unless otherwise noted. Triethylamine, diisopropylamine, and diisopropylethylamine were distilled over CaH2 under argon atmosphere prior to use.

[0262] Analytical methods

[0263] Thin layer chromatography (TLC)

[0264] Monitoring of reactions, analysis of column fractions and retardation factor (R F The value of the F 254Fluorescence indicators were performed by thin layer chromatography on silica gel 60 (0.20 mm). Qualitative analysis and visualization were done by irradiation with UV light at λ = 254 nm and / or by immersion in different staining reagents (specified for each compound in the corresponding experimental procedures) followed by heating with a heat gun at 300°C until dry. The following stains were used (CAM stain proved to be particularly useful for visualization of cyclized lactone and ether products): Ce(SO4)2 (cerium sulfate: 5.0 g) and (NH4)6Mo7O 24 4H2O (ammonium molybdate 25.0 g) was dissolved in H2O (450 mL) and concentrated H2SO4 (50 mL).

[0265] Nuclear Magnetic Resonance Spectroscopy (NMR)

[0266] Characterization by 13 C NMR and 1 H NMR was performed. 13 C NMR and 1 H NMR spectra were measured on a Bruker AV-500 spectrometer.

[0267] (Flash) column chromatography

[0268] (Flash) column chromatography was performed using silica gel (Merck) 230-400 mesh, particle size: 43-63 μm) or using distilled technical grade solvents. The solvent mixture and volume ratio (v / v) used as mobile phase for chromatography are specified in the corresponding experiments. Flash column chromatography is carried out in a glass column by applying a slightly elevated air or argon (0.3 mbar) pressure.

[0269] Gas chromatography (GC)

[0270] Gas chromatography (GC) was performed on an HP 6890 and 5890 series instrument equipped with a split mode capillary injection system and a flame ionization detector (FID) using hydrogen (H2) as the carrier gas. For quantitative GC analysis of the reaction mixture, the response factors of the starting materials, identified intermediates, products and internal standards were determined and the quantification was verified using a calibration curve method for each corresponding component.

[0271] 2. General Procedures

[0272] 2.1 General Procedure A (Reactions at room temperature (rt) were performed between 25°C and 30°C on a 0.20 mmol scale)

[0273] The corresponding catalyst (amount specified in the table) was transferred to a 1.5 mL headspace screw-cap glass vial under ambient atmosphere and pressure and dissolved / suspended in the corresponding solvent (concentration indicated in the corresponding table). (E / Z)-homogeranic acid methyl ester (43.5 μL, 39.3 mg, 0.20 mmol) and a PTFE-coated magnetic stirring bar were added, the vial was closed with a screw cap containing a PTFE / silicone septum and magnetically stirred (500 rpm) at rt (between 25°C and 30°C) for the indicated time. After the elapsed time, 1,3,5-trimethylbenzene (28 μL, 24.2 mg, 1.0 equiv) was added as an internal standard, the vial was shaken and stirred at rt for 5 minutes. A sample (typically between 5-10 μL) was removed, diluted with CDCl3 (0.6 mL), and filtered through solid anhydrous sodium carbonate and sodium sulfate. It was then filtered through 1 The conversion and yield of each individual component were analyzed by H NMR spectroscopy. Alternatively, the filtered solution was analyzed by GC spectroscopy.

[0274] 2.2 General Procedure B (Reaction at 0.20 mmol scale at T ≥ 30 °C)

[0275] The corresponding catalyst (the corresponding amount is specified in the table) was transferred to a 2 mL headspace thick-walled crimp-cap glass vial under ambient atmosphere and pressure and dissolved / suspended in the specified solvent (the concentration is indicated in the corresponding table). (E / Z)-homogeranic acid methyl ester (43.5 μL, 39.3 mg, 0.20 mmol) and a PTFE-coated magnetic stirring bar were added, and the vial was sealed with a crimp cap containing a PTFE / silicone diaphragm, placed in an aluminum block preheated at the specified temperature, and magnetically stirred (1000 rpm in the case of a reaction of heterogeneous nature) at this temperature for the indicated time. After the elapsed time, the reaction mixture was cooled to room temperature and 1,3,5-trimethylbenzene (28 μL, 24.2 mg, 1.0 equiv) was added as an internal standard. The vial was shaken and stirred at room temperature for 5 minutes. A sample (typically between 5-10 μL) was taken out, diluted with CDCl3 (0.6 mL), and filtered through solid anhydrous sodium carbonate and sodium sulfate. It was then passed through 1 The conversion and yield of each individual component were analyzed by H NMR spectroscopy. Alternatively, the filtered solution was analyzed by GC spectroscopy.

[0276] Homogeranic acid methyl ester used as starting material in these examples was used with different isomer compositions. As described in separate examples, pure (3E)-homogeranic acid methyl ester was used as starting material, or an isomer mixture (E / Z)-homogeranic acid methyl ester having a composition of 3E:3Z:2E=48:39:6 was used as starting material.

[0277] 3. Specific Example: Synthesis of Cyclic Homogeranic Acid Methyl Ester (α-1) from (E / Z) Homogeranic Acid Methyl Ester

[0278] 3.1 Evaluation of Bronsted Acid

[0279] Reactions were performed on a 0.20 mmol scale using the indicated catalysts according to General Procedure B. Conversions and yields were calculated by 1 H NMR spectroscopy was determined using CH2Br2 and / or 1,3,5-trimethylbenzene (preferred) as internal standards. The reactions using solid acid catalysts (Table 1, Experiment Nos. 1.4-1.9) were performed as follows: DOWEX 50WX8 was acidified by treatment with H2SO4 (0.05m), and subsequently washed with ethanol and dichloromethane, and then air dried before use. Montmorillonite K10, Amberlyst 15, and zeolite are commercially available and used as is. H3PO4 (20%, fixed on silica) is available as beads and ground into powder before use. The corresponding solid acid catalyst (10 mg, 50 mg / mmol loading) was transferred to a 2 mL headspace crimped glass vial equipped with a PTFE-coated magnetic stirring bar. Anhydrous toluene and starting material (0.2 mmol) were added according to General Procedure B, and the vial was capped with a crimped lid and placed in an aluminum heating block preheated at 110°C. At this temperature, the obtained suspension was stirred vigorously (1000rpm) for 2 hours. After the time passed, the mixture was diluted with MTBE (1mL), filtered through NaHCO and Na2SO4 (eluted with 2×1mL MTBE) and concentrated under reduced pressure to obtain the crude product in the form of a yellow oil. The conversion rate and isomer ratio of the crude product were determined by gas chromatography.

[0280] Table 1: Catalyst screening in the cyclization of methyl homogeranate to methyl cyclohomogeranate.

[0281]

[0282]

[0283] 3.2 Evaluation of phosphoric acid as a Brønsted acid catalyst

[0284] Table 2: Catalyst screening in the cyclization of methyl homogeranate to methyl cyclohomogeranate.

[0285]

[0286] Reactions were performed according to General Procedure B at 110 °C using the indicated catalysts. Conversions and yields were calculated by 1 H NMR spectroscopy was determined using 1,3,5-trimethylbenzene as an internal standard. The results are summarized in Table 2.

[0287] 3.2.1 Effect of water on reactions using phosphoric acid as a Brønsted acid catalyst

[0288] The effect of water on conversion, yield and selectivity in the cyclization reaction was studied. Specific amounts of water were added to the reaction mixture (the results are listed in Table 3 below).

[0289] Table 3: Effect of water content on the outcome of the phosphoric acid-catalyzed cyclization of methyl homogeranate to methyl cyclohomogeranate.

[0290]

[0291]

[0292]

[0293] Reactions were performed according to General Procedure B at 110 °C using crystalline phosphoric acid as catalyst. The amount of water added is specified in each entry. Conversions and yields were calculated by 1 H NMR spectroscopy was determined using 1,3,5-trimethylbenzene as an internal standard.

[0294] The results confirmed previous findings (see Table 2) that anhydrous phosphoric acid sources consistently provided higher yields and selectivities in the cyclization reaction than aqueous phosphoric acid. A gradual increase in water content resulted in a gradual decrease in conversion and yield (see Table 3, Examples 3.2-3.5).

[0295] 3.3 Evaluation of Lewis Acids

[0296] Various Lewis acids were tested as catalysts in the cyclization of methyl homogeranate to methyl cyclogeranate (Table 4)

[0297]

[0298] Table 4: Evaluation of Lewis acid catalysts for the cyclization of methyl homogeranate to methyl cyclohomogeranate. For comparison, the results obtained with crystalline phosphoric acid and 85% aqueous phosphoric acid are provided in entries 4.8 and 4.9.

[0299]

[0300] Reactions were performed at 110 °C using the indicated catalysts according to General Procedure B. Conversions and yields were determined by gas chromatography and / or 1 H NMR spectroscopy was determined using 1,3,5-trimethylbenzene as an internal standard.

[0301] Among the catalysts tested, anhydrous FeCl3, Sc(OTf)3 and Y(OTf)3 proved to have the best selectivity for methyl cyclohomogeranate (>80%), while providing <15% of cis-tetrahydroactinolide byproduct. It is worth noting that, in contrast to the reaction with crystalline phosphoric acid or 85% aqueous phosphoric acid (where the α-isomer is typically obtained as the major product), the Lewis acid-catalyzed process appears to provide the β-isomer as the major product (up to 56% in the case of yttrium triflate).

[0302] 3.4 Changes in reaction conditions

[0303] 3.4.1 Choice of solvent

[0304] The cyclization reaction can be carried out in various solvents, preferably aliphatic or aromatic hydrocarbon solvents (such as toluene, cyclohexane and n-heptane), with comparable results regarding yield and selectivity to methyl cyclohomogeranate. The ratio between the isomers and the cis-lactone byproduct varies slightly depending on the solvent (Table 4).

[0305] Table 4: Optimization of reaction solvents in the cyclization reaction of methyl homogeranate to methyl cyclohomogeranate.

[0306]

[0307] Reactions were performed on a 0.20 mmol scale according to General Procedure B using crystalline phosphoric acid (5 mol%) as catalyst in the indicated solvents. Conversions and yields were calculated by 1 H NMR spectroscopy was determined using 1,3,5-trimethylbenzene as an internal standard.

[0308] 3.4.2 Choice of starting material concentration.

[0309] The cyclization reaction can be carried out in the concentration range of 0.5 to 10 M, and the concentration range of 2 to 10 M was found to be optimal with respect to the conversion of the homogeranate methyl ester starting material (see Table 5). The formation of cis-THA byproduct was gradually suppressed with increasing dilution (≤2 M).

[0310] Table 5: Changes in concentration in the synthesis of cyclohomogeranic acid methyl ester (α-1) from (E / Z)-homogeranic acid methyl ester.

[0311]

[0312]

[0313] The reaction was carried out on a 0.20 mmol scale in toluene (2 M) according to General Procedure B using crystalline phosphoric acid (5 mol%) as catalyst. Conversions and yields were calculated by 1H NMR spectroscopy was used as an internal standard using 1,3,5-trimethylbenzene. 1 H NMR analysis did not detect any.

[0314] 3.4.3 Changes in catalyst loading

[0315] The catalyst loading of crystalline phosphoric acid was varied between 2.5 and 100 mol%, preferably between 5 and 10 mol%, in order to ensure complete consumption of the starting material (within 2 h reaction time) and to minimize the amount of cis-THA by-product (Table 6).

[0316] Table 6: Changes in catalyst loading in the synthesis of cyclohomogeranic acid methyl ester (α-1) from (E / Z)-homogeranic acid methyl ester

[0317]

[0318] The reaction was carried out on a 0.20 mmol scale in toluene (2 M) according to General Procedure B using crystalline phosphoric acid as catalyst. Conversions and yields were calculated by 1 H NMR spectroscopy was used as an internal standard using 1,3,5-trimethylbenzene. 1 HNMR analysis did not detect any.

[0319] 3.4.4 Effect of temperature

[0320] Table 7: Changes in temperature in the synthesis of cyclohomogeranic acid methyl ester (α-1) from (E / Z)-homogeranic acid methyl ester.

[0321]

[0322] Reactions were performed on a 0.20 mmol scale in toluene (2 M) at the indicated temperatures according to General Procedure B using crystalline phosphoric acid as catalyst. Conversions and yields were calculated by 1 H NMR spectroscopy was used to determine the internal standard using 1,3,5-trimethylbenzene. 1 H NMR analysis did not detect any.

[0323] Example 4: Cyclization of (3E)-homogeranic acid isopropyl ester

[0324] The effect of isomeric purity on the outcome of the cyclization reaction was evaluated using isomerically pure (3E)-isopropyl homogeranate and (3E)-methyl homogeranate as starting materials.

[0325] The reactivity of the pure (3E)-isomers in phosphoric acid-catalyzed cyclization reactions was investigated (Table 8: Phosphoric acid-catalyzed cyclization of isomerically pure (3E)-homogeranic acid methyl ester or (3E)-homogeranic acid isopropyl ester). The screening revealed that the methyl ester was more reactive than the isopropyl ester. In addition, the amount of (β)-1 was significantly increased compared to the reaction with the isomer mixture, with (α)-1 / (β)-1≈1:1.2 for the isomer mixture compared to 1:1.7 for the pure isomers.

[0326] Table 8: Phosphoric acid-catalyzed cyclization of isomerically pure (3E)-homogeranic acid methyl ester or (3E)-homogeranic acid isopropyl ester.

[0327]

[0328]

[0329] Reactions were performed on a 0.20 mmol scale in toluene (2 M) at the indicated temperatures according to General Procedure B using crystalline phosphoric acid as catalyst. Conversions and yields were calculated by 1 H NMR spectroscopy was used to determine the internal standard using 1,3,5-trimethylbenzene. 1 H NMR analysis did not detect any.

[0330] Example 5: Preparation of α-cyclohomogeranic acid methyl ester (α-1), β-cyclohomogeranic acid methyl ester (β-1), and γ-cyclohomogeranic acid methyl ester (γ-1)

[0331] Under argon, a flame-dried 4 mL screw-cap glass vial was charged with (E / Z)-homogeranic acid methyl ester (a 48:39:6 mixture of 3E:3Z:2E, 392 mg, 2.00 mmol, 1.00 equiv) and a PTFE-coated magnetic stirring bar. The starting material was dissolved in dry toluene (0.60 mL, 3.33 m), the vial was placed in a preheated aluminum heating block, and the resulting clear colorless solution was heated to 100 ° C. Then, H3PO4 (85% w / w solution in H2O, 11.5 mg, 0.10 mmol, 0.05 equiv) was added to the stirred reaction mixture, the pierced screw cap was quickly replaced with a new screw cap, and the mixture was stirred (500 rpm) at 100 ° C for 2 hours (a gradual color change from a colorless solution with pink droplets of H3PO4 to a yellow solution with brown droplets was observed within 15 minutes of reaction time). After the elapsed time, the yellow reaction mixture was cooled to rt and purified by 1H NMR spectroscopy and TLC analysis of a small sample indicated complete consumption of the starting material and formation of the desired product (except for the conjugated 2E-isomer which did not appear to react under these reaction conditions). Saturated Na2CO3 aqueous solution was carefully added (gas evolution), the mixture was diluted with MTBE (2 mL), the organic phase was removed and the aqueous phase was extracted with MTBE (5×2 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product as a yellow oil. Purification was performed by flash column chromatography on silica gel (Merck, 40-63 μm, 230-400 mesh, 30 g) using hexane / MTBE as eluent to give the product as a mixture of isomers (315 mg, 1.61 mmol, 80% yield, 84% GC-purity, the mixture containing approximately 6% of the 2E-isomer of homogeranic acid methyl ester).

[0332]

[0333] Use crystal H3PO4 (> 99.9999%, 9.80mg, 0.10mmol, 0.05 equivalent) to set up the second reaction in parallel with the same scale. In this case, H3PO4 is directly weighed into a vial, suspended in toluene, and then homogeranic acid methyl ester is added. In addition, the procedure, observation, extraction and purification steps are substantially the same as those described above. Purification by flash column chromatography provides the cyclized product (318mg, 1.62mmol, 81% yield, the corrected yield based on GC-purity is shown in the table below) in three fractions.

[0334]

[0335] Analytical data / characterization of compounds isolated from the reaction described in Example 5 are provided below.

[0336] Racemic β-cyclohomogeranic acid methyl ester (α-1)

[0337]

[0338] In fraction 4 of column chromatography of the second reaction of Example 5 as a pure compound (according to 1 Analytical data for α-1 isolated (>95% purity) by H NMR and GC analysis.

[0339] Physical appearance: colorless oil

[0340] TLC (SiO2, hexane / MTBE 19:1) R f =0.37 (CAM stain, light blue spots)

[0341] 1 H NMR(CD2Cl2,501MHz)δ(ppm)5.38–5.32(m,1H),3.64(s,3H),2.35(dd,J=17.3,8.1Hz,1H),2.27–2.14(m,2 H),2.02–1.91(m,2H),1.70–1.59(m,3H),1.41–1.34(m,1H),1.21–1.14(m,1H),0.91(s,3H),0.82(s,3H).

[0342] 13 C NMR (CD2Cl2, 126MHz) δ (ppm) 175.0, 135.6, 121.7, 51.8, 46.1, 36.0, 32.5, 31.7, 27.1, 26.3, 23.3, 22.8.

[0343] GC DB-Waxetr 0.25 mm / 0.25 μm, 30 m, temperature: 220 °C (injector) / 60 °C to 130 °C at 2 °C / min, then 12 °C / min to 260 °C, 350 °C (detector), gas: 0.60 bar H2, sample size: 0.2 μL, t R =25.39 minutes.

[0344] C 12 H 21 O2 + [M+H] + HRMS (GC–CI, NH3) (m / z) calcd., 197.1536; found, 197.1537.

[0345] β-Cyclohomogeranic acid methyl ester (β-1)

[0346]

[0347] In fraction 8 of column chromatography of the second reaction of Example 5 as the main component in the isomer mixture (according to 1 Analytical data of β-1 obtained by H NMR and GC analysis).

[0348] Physical appearance: light yellow oil

[0349] TLC (SiO2, hexane / MTBE 19:1) R f =0.31 (CAM stain, light blue spots)

[0350] 1H NMR (CDCl3, 501MHz) δ (ppm) = 3.66 (s, 3H), 3.05 (s, 2H), 2.01–1.96 (m, 2H), 1.65–1.54 (m, 2H), 1.58 (s, 3H), 1.48–1.44 (m, 2H), 0.96 (s, 6H).

[0351] 13 C NMR (CDCl3, 126MHz) δ (ppm) = 173.5, 131.6, 130.5, 51.8, 39.5, 34.9, 33.7, 32.8, 28.1, 20.4, 19.5.

[0352] GC DB-Waxetr 0.25 mm / 0.25 mm, 30 m, temperature: 220 °C (injector) / 60 °C to 135 °C at 2 °C / min, then 6 °C / min to 220 °C, then 12 °C / min to 260 °C, then 5 min at 260 °C, 350 °C (detector), gas: 0.60 bar H2, sample size: 0.2 μL, t R =29.0 min (GC-MS: m / z [M]+ =196).

[0353] C 12 H 20 O2+[M] + HRMS (GC-EI) m / z calculated value: 196.1458; found value: 196.1457.

[0354] Racemic-γ-cyclohomogeranic acid methyl ester (γ-1)

[0355]

[0356] The γ-isomer was identified as a minor compound in fractions 5-7 and 8 of the second reaction of Example 5 and isolated.

[0357] TLC (SiO2, hexane / MTBE 19:1) R f =0.31 (CAM stain, light blue spots)

[0358] 1H NMR (CDCl3, 501MHz) δ (ppm) = 4.75 (q, J = 1.4Hz, 1H), 4.56 (s, 1H), 3.64 (s, 3H), 2.50 (t, J = 10.2Hz, 1H), 2.46–2.38 (m, 2H), 2.22 (dt, J = 12.7, 6.1 Hz,1H),2.05(ddd,J=13.1,8.2,5.3Hz,1H),1.43(ddd,J=11.6,7.2,4.3Hz,1H),1.35(ddd,J=13.3,8.1,4.9Hz,1H),0.96(s,3H),0.79(s,3H).

[0359] GC DB-Waxetr 0.25 mm / 0.25 mm, 30 m, temperature: 220 °C (injector) / 60 °C to 135 °C at 2 °C / min, then 6 °C / min to 220 °C, then 12 °C / min to 260 °C, then 5 min at 260 °C, 350 °C (detector), gas: 0.60 bar H2, sample size: 0.2 μL, t R =29.71 minutes (99%).

[0360] C 12 H 21 O2 + [M+H] + HRMS (GC–CI, NH3) (m / z) calcd.: 197.1536; found, 197.1537.

[0361] Example 6: Preparation of α-cyclohomogeranic acid methyl ester (α-1), β-cyclohomogeranic acid methyl ester (β-1), and γ-cyclohomogeranic acid methyl ester (γ-1)

[0362] In 100mL round-bottomed flask, load (E / Z)-homogeranic acid methyl ester (3.92g, 20mmol, 1.0 equivalent) and the magnetic stirring bar of coating PTFE.Starting material is dissolved in hexafluoroisopropanol (20mL, 9.5 equivalents, 1M), and TFA (trifluoroacetic acid, 2.38g, 20.9mmol, 1.04 equivalents) is added dropwise (observed from colorless through bright yellow, then to bright orange to deep orange-red immediate color change after adding TFA in 1 minute) in the solution stirred, and gained red solution is stirred at 25 DEG C for 24 hours.After the time passed, dark brown-red reaction mixture is concentrated under reduced pressure.Residue is dissolved in hexane / MTBE (19:1v / v, 20mL), diatomite is added and slurry is concentrated under reduced pressure. Purification was carried out by flash column chromatography on silica gel (Merck, 40-63 μm, 300 g) using hexane / MTBE as eluent, and then dried in vacuo overnight to give methyl cyclohomogeranate (2.34 g, 11.9 mmol, 60% yield, where α-1:β-1:γ-1=31:68:1 based on GC) as a colorless oil.

Claims

1. A method for preparing an ester compound having the general formula (I) or a stereoisomer thereof in, X1 and X3 together are the second bond of a double bond between the carbon atoms to which they are bonded, provided that X2 and X4 are hydrogen; or X3 and X4 together are the second bond of a double bond between the carbon atoms to which they are bonded, provided that X1 and X2 are hydrogen; or Wherein formula (I) comprises, Compounds having formula (Ia) or a stereoisomer thereof or a mixture of stereoisomers thereof, and Compounds having formula (Ib) wherein R is selected from C1-C5 straight chain or branched alkyl and C3-C5 straight chain or branched alkenyl, The method comprises at least the following steps: A) Providing a compound having formula (III) or a stereoisomer thereof, or a mixture of stereoisomers thereof, B) cyclizing the compound of formula (III) in the presence of a catalyst selected from Bronsted acids or Lewis acids to obtain a compound of formula (I), C) optionally purifying the compound of formula (I) obtained in step B).

2. The method according to claim 1, wherein: R is selected from methyl, ethyl, propyl, butyl, isobutyl, isopropyl, 1-propenyl, or 2-propenyl.

3. The method according to claim 1, wherein: In step B), the catalyst is selected from the group consisting of, a) Shows MA x A Lewis acid of the form wherein M is a metal and A is a non-coordinating, weakly coordinating anion, alkoxide or halogen, and x is the valence of M, or b) a Bronsted acid selected from the group consisting of an inorganic acid, an inorganic acid salt, an organic acid, a solid acid catalyst, or a combination thereof.

4. The method according to claim 3, wherein: This step B) is carried out in the presence of a Bronsted acid selected from the group consisting of, - an inorganic acid selected from hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, boric acid, hydrofluoric acid, hydrobromic acid, or hydroiodic acid, phosphonic acid, wherein these inorganic acids are fixed on silica or any other thermally stable support, - an inorganic acid salt selected from potassium hydrogen sulfate, sodium hydrogen sulfate, sodium dihydrogen phosphate, - an organic acid selected from p-toluenesulfonic acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, or trifluoroacetic acid, - a solid acid catalyst selected from heteropolyacids, acid resin-type catalysts, strongly acidic ion exchangers, mesoporous silica, acid clays, sulfated zirconia, molecular sieve materials, or acidic materials on a thermally stable support, or zeolites, or a combination thereof.

5. The method according to any one of claims 3 to 4, wherein: Step B) is carried out in the presence of a Bronsted acid selected from phosphoric acid, p-toluenesulfonic acid, phosphonic acid or a strongly acidic ion exchanger.

6. The method according to claim 5, wherein: The Bronsted acid is phosphoric acid, trifluoroacetic acid, or silica-supported phosphoric acid.

7. The method according to claim 3, wherein: This step B) is presented in MA x The method is carried out in the presence of a Lewis acid of the form of a catalyst, wherein M is a metal and A is a non-coordinating, weakly coordinating anion, an alkoxide or a halogen, and x is the valence of M, wherein M includes a transition metal, a lanthanide metal, or a metal from Groups 2, 3, 4, 5, 7, 8, 12, 13, 14 and 15 of the Periodic Table of the Elements, and combinations thereof.

8. The method according to claim 7, wherein: The metal M is selected from the group of elements iron, magnesium, zinc, boron, titanium, scandium, yttrium, lanthanum, europium, zirconium, manganese, aluminum, ytterbium, tin, vanadium, bismuth, scandium, or hafnium.

9. The method according to claim 7, wherein: A is a non-coordinating, weakly coordinating anion selected from the group consisting of trifluoromethanesulfonate or triflate ([CF3SO3] - ), hexafluorophosphate ([PF6] - )、[Al[OC(CF3)3]4] - , tetrafluoroborate ([BF4] - ), perchlorate ([ClO4] - )、BArF([B(ArH x F y )4] - , wherein Ar is aromatic and x+y=5), toluenesulfonate ([CH3C6H4SO3] - ), methanesulfonate ([CH3SO3] - ), or antimony hexafluoride ion ([SbF6] - ).

10. The method according to claim 7, wherein: A is a halogen selected from the group consisting of chlorine, fluorine, iodine and bromine.

11. The method according to claims 7 to 10, wherein: The Lewis acid is selected from scandium trifluoromethanesulfonate [Sc(CF3SO3)3], aluminum trifluoromethanesulfonate [Al(CF3SO3)3], hafnium trifluoromethanesulfonate [Hf(CF3SO3)4], yttrium trifluoromethanesulfonate [Y(CF3SO3)3], bismuth trifluoromethanesulfonate [Bi(CF3SO3)3] or ytterbium trifluoromethanesulfonate [Yb(CF3SO3)3], FeCl3, FeBr3, MnCl2, BiCl3, Me2AlCl, TiCl3(OiPr), AlCl3, ZnCl2, ZnBr2, Zn(OTf)2, MgCl2, BCl3, Al(OTf)3, BF3, SnCl4, or TiCl4.

12. The method according to any one of claims 1 to 11, wherein: The catalyst in the reaction is present in an amount ranging from 0.01 to 100 mol % based on the total amount of the compound having the formula (III).

13. The method according to any one of claims 1 to 12, wherein: In step B), the reaction is carried out at a temperature in the range of 0°C to 150°C.

14. The method according to any one of claims 1 to 13, wherein: In step B), the reaction is carried out in the presence or absence of a solvent.

15. The method according to claim 14, wherein: The solvent is selected from the group consisting of ketones, esters, aromatic solvents, aliphatic solvents, cyclic ethers, alcohols, water, nitriles, ethers and mixtures thereof.

16. The method according to claim 15, wherein: The solvent is selected from toluene, benzene, benzyl alcohol, chlorobenzene, benzonitrile, xylene, trifluorotoluene, nitrobenzene, cyclohexane, or n-heptane, hexane, octane, tetrahydrofuran, 1-pentanol, 1-hexanol, methanol, 1-butanol, 1-propanol, 2-propanol, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, toluene, ethyl acetate, acetonitrile, water, dimethylformamide, dichloromethane, 1,1,1,3,3,3-hexafluoroisopropanol, dioxane or ethanol.

17. The method according to any one of claims 1 to 16, wherein: In step B), the reaction is carried out as a batch reaction or in a continuous reactor apparatus.

18. The method according to any one of claims 1 to 17, wherein: The compound of formula (I) further includes a compound of formula (Ic) in, X2 and X3 together are the second bond of the double bond between the carbon atoms to which they are bound, R is selected from C1-C5 straight chain or branched chain alkyl and C3-C5 straight chain or branched chain alkenyl.

19. The method according to any one of claims 1 to 17, wherein: The compound of formula (I) comprises a compound of formula (V) or a stereoisomer thereof or a mixture of stereoisomers thereof in an amount less than 10 wt.% in, R is selected from C1-C5 straight chain or branched chain alkyl and C3-C5 straight chain or branched chain alkenyl.

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