Preparation process of cyclohomogeranate

Abstract

The present invention relates to a process for preparing cyclohomogeranate. The present invention relates to a one-step synthesis from a fully available ester of homogeranic acid to cyclohomogeranate. The cyclohomogeranate prepared according to the process of the present invention can be used in the fragrance industry as an intermediate, or the compound can be used as an aromatic compound or the like.

Description

Technical Field

[0001] The present invention relates to a process for the preparation of cyclohomogeranate. The present invention relates to a one-step synthesis of cyclohomogeranate from a fully available ester of homogeranic acid.

Background Art

[0002] Cyclohomogeranate is an ester of cyclohomogeranic acid and has been used as a synthetic intermediate (Helv. Chem. Acta 1969, 1732 - 1734). The corresponding esters, for example, methyl cyclohomogeranate (in CAS, methyl α-cyclohomogeranate: 64108 - 19 - 6; methyl β-cyclohomogeranate: 2365417 - 61 - 2) and ethyl cyclohomogeranate (in CAS, (S)-ethyl α-cyclohomogeranate: 143658 - 43 - 9; ethyl β-cyclohomogeranate: 773136 - 09 - 7) have been described several times in the literature (Helv. Chem. Acta 2019, e1900097). Two double bond isomers, namely the α-isomer and the β-isomer, are described.

Chemical formula

[0003] The prior art discloses several methods for the synthesis of cyclohomogeranate, including processes starting from myrcene, cyclogeranic acid or 2,4,4-trimethyl-2-cyclohexenone. However, synthetic routes starting from precursors such as linalool, or homogeranic acid and / or its esters are not described.

[0004] Helv. Chem. Acta 2019, e1900097 discloses a synthetic route starting from myrcene. This route involves adding LiNEt2 to form the corresponding allylamine (yield 77 - 87%). Following this step, cyclization using stoichiometric amounts of H2SO4 is carried out with a yield of 54%. The final step is a low-yield step (yield 25 - 31%) that involves methoxycarbonylation using CO and highly toxic methyl iodide to obtain methyl cyclohomogeranenoate. Therefore, the overall reported yield starting from myrcene is less than 20%.

[0005] Liebigs Ann. Chem. 1991, 1053 - 1056 discloses the synthesis of esters of cyclohemogenic acid starting from 2,4,4 - trimethyl - 2 - cyclohexenone. This route involves reducing the alcohol with lithium aluminum hydride and then generating ethyl α - cyclohomogeranate by ortho - ester Claisen rearrangement.

[0006] The route starting from cyclogenic acid, a compound available from geranic acid (Zhurnal Org. Kim. 1991, 27, 2149 and J. fuer Prakt. Chemie 1936, 147, 199 - 202) involves seven consecutive steps up to ethyl β - cyclohomogeranate (Helv. Chem. Acta 1969, 1732 - 1734), resulting in a very low overall yield.

[0007] Furthermore, there are also laboratory - scale processes that cannot be scaled up to industrial - scale synthesis due to the reagents generating a large amount of waste (e.g., silyl protecting groups or MsCl) and the limited availability of starting materials (J. Org. Chem. 1995, 3580 - 3585 and Angew. Chem. 2000, 569 - 573).

[0008] J.Chem.Soc.Perkin Trans 1, 1983, 1579 - 1589 discloses the synthesis of 2,3 - unsaturated methylcyclohomogeranate (as an E / Z isomer mixture), which is a positional isomer of methylcyclohomogeranate. The synthetic route starts from 2,4,4 - trimethyl - 2 - cyclohexenone. The synthesis of these 2,3 - unsaturated positional isomers is not the object of the present invention.

Chemical formula

[0009] In conclusion, the described synthetic route of cyclohomogeranate is either a multi - step synthesis and as a result has a low yield or includes a very low - yield single step. Therefore, it is not suitable for industrial applications. Furthermore, when the process is a multi - step synthesis, many purification steps are required. This further leads to the generation of more waste and an increase in energy costs.

[0010] The desired synthesis of α - / β - cyclohomogeranate from homogelenic acid requires the 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 step of different 3,4 / 7,8 - unsaturated esters. Such conditions are not suitable for factory applications because a large amount of waste is generated.

[0011] The prior art also teaches that the ester g of cyclohomogelenic acid leads to the formation of tetrahydroactinidiolide instead of the desired cyclohomogeranate (Synthesis 1972, 573 - 574).

[0012] Therefore, it is necessary to develop an efficient process for synthesizing α - or β - cyclohomogeranate or a mixture of both, which is scalable in a short time, gives a good yield, and can utilize readily available starting materials.

[0013] The object of the present invention is to provide a process for the preparation of esters of cyclohomogelenic acid. A further object of the present invention is to provide an economical process for producing esters of cyclohomogelenic acid, which process produces α- or β-cyclohomogelenate or a mixture of both in a short sequence of synthetic steps from readily available starting materials in high yields. This process should be scalable, avoid the generation of waste and require only a few simple purification steps.

[0014] A further object of the present invention is to arrive at a process that can be efficiently carried out as a batch process or a continuous process.

Summary of the Invention

Means for Solving the Problems

[0015] The present applicants have found that α- / β-cyclohomogelenate can be prepared from technical homogelenic acid in only two synthetic steps. This cyclohomogelenate can be produced as two isomers, α-cyclohomogelenate or β-cyclohomogelenate. Also, an α / β-mixture of isomers may be obtained, and the ratio of the resulting isomer composition depends on the process conditions.

[0016] Accordingly, in one aspect, the present invention relates to a process for the synthesis of an ester compound of general formula (I)

Chemical formula

Chemical formula

[0017] In a further aspect, the reaction of the present invention is carried out as a batch process or a continuous process

[0018] In another aspect, by varying the reaction conditions of the present invention, mixtures of α- / β-cyclohemogeranates can be obtained in various ratios

[0019] In a further aspect, the process employed according to the present invention results in the formation of less than 15% by weight of a compound of formula (IV) or a stereoisomer thereof [Chemical formula] a compound of formula (IV)

[0020] In another aspect, a compound of formula (V) or a stereoisomer thereof is obtained by the process employed according to the present invention [Chemical formula] (In the formula, R is selected from linear or branched C1-C5 alkyl and linear or branched C3-C5 alkenyl) is obtained in an amount of less than 10% by weight.

[0021] The compound of formula (V) can be formed in the synthesis of compound (I) or in the purification process by isomerization.

Mode for Carrying Out the Invention

[0022] The following detailed description is merely illustrative in nature and is not intended to limit the presently claimed invention or the uses and applications of the presently claimed invention. Further, there is no intention to be bound by the theories presented in the foregoing technical field, background, summary, or the following detailed description.

[0023] As used herein, the terms "comprising", "comprises" and "comprised of" are synonymous with "including", "includes" or "containing", "contains", and are inclusive or unlimited and do not exclude additional, unrecited members, elements or method steps. It should be understood that the terms "comprising", "comprises" and "comprised of" as used herein include the terms "consisting of", "consists" and "consists of".

[0024] Furthermore, terms such as "(a)", "(b)", "(c)", "(d)", etc. in the specification and claims are used to distinguish similar elements and are not necessarily used to describe an order or time sequence. Terms used in this way are interchangeable under appropriate circumstances, and it should be understood that embodiments of the subject matter described herein can be operated in an order other than that described or illustrated herein. For the sake of preparation, terms such as "(A)", "(B)", and "(C)" or "(AA)", "(BB)", and "(CC)" or "(a)", "(b)", "(c)", "(d)", "(i)", "(ii)", etc., when related to steps of a method or use or assay, there is no consistency of time or time interval between the steps, i.e., the steps can be performed simultaneously, or, as described above or below in this specification, there can be a time interval of seconds, minutes, hours, days, weeks, months, or even years between such steps, unless otherwise indicated for the use.

[0025] In the following text, various aspects of the subject matter are defined in more detail. Each aspect so defined can be combined with any other aspect unless the contrary is clearly indicated. In particular, any feature shown to be preferred or advantageous can be combined with any other feature shown to be preferred or advantageous.

[0026] References to "one embodiment", "an embodiment", or "a preferred embodiment" throughout this specification mean that the particular features, structures, or characteristics described in connection with that embodiment are included in at least one embodiment of the presently claimed invention. Thus, the appearances of the phrases "in one embodiment", "In a preferred embodiment", or "in a preferred embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment, although they may. Further, as will be apparent to those of ordinary skill in the art from this disclosure, the features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Further, as will be understood by those of ordinary skill in the art, some embodiments described herein include some features but not other features included in other embodiments, and combinations of features of different embodiments are within the scope of the subject matter and mean different embodiments are formed. For example, in the appended claims, any of the claimed embodiments may be used in any combination.

[0027] Further, ranges defined throughout this specification include the end values as well, i.e., the range from 1 to 10 means both 1 and 10 are included within the range. To avoid doubt, Applicant reserves the right to obtain any equivalents in accordance with applicable law.

[0028] The term "C1-C5-alkyl" refers to a straight-chain or branched-chain 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, etc.

[0029] The term "C3-C5 alkenyl" refers to a straight-chain or branched unsaturated hydrocarbon group having 3 to 5 carbon atoms and a double bond at any position.

[0030] Examples include "C3-C5 alkenyl" groups such as 1-propenyl, 2-propenyl, 1-methylethenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, and the like.

[0031] The term "halogen" in each case indicates fluorine, bromine, chlorine or iodine, especially fluorine, chlorine or bromine.

[0032] The term "Bronsted acid" as used herein is a term used for molecular entities (atoms, ions, molecules, compounds, complexes, etc.) that can donate one or more protons to other chemical species according to the IUPAC definition.

[0033] The term "Lewis acid" as used herein is a term used for molecular entities that are electron pair acceptors and can thus react with a Lewis base to form a Lewis adduct by sharing the electron pair donated by the Lewis base according to the IUPAC definition.

[0034] The terms "cyclohomogeranate" and "ester of cyclohomogeranic acid" are used interchangeably herein. The term "cyclohomogeranate" includes the α- or β-isomer, γ-isomer or a mixture of both isomers unless otherwise specified. Thus, for example, the terms "methyl α-cyclohomogeranate" and "methyl ester of α-cyclohomogeranic acid" are used interchangeably.

[0035] As used herein, the term "compound (X) or a stereoisomer thereof or a mixture of stereoisomers thereof" refers to a compound of formula (X) in all of its stereoisomeric forms (stereoisomers) in any ratio. Thus, the term "compound of formula (Ia) or a stereoisomer thereof or a mixture of stereoisomers thereof" refers to the compound Ia in racemic form, or one of its enantiomerically pure forms (R or S), or a mixture of the two possible enantiomers in any ratio, where the ratio of enantiomers ranges from 0.01:99.99 to 99.99:0.01.

[0036] The term "stereoisomer" is a general term described by IUPAC and is used for all isomers of individual compounds that differ only in the arrangement of atoms in space, not in the connectivity of atoms. Thus, the term "stereoisomer" includes enantiomers (mirror image isomers), geometric isomers (cis / trans or E / Z), and diastereoisomers. For the exact definition of the terms, reference may be made to the IUPAC definition or G. Helmchen: "Vocabulary and Nomenclature of Organic Stereochemistry". In Houben-Weyl E21a, Stereoselective Synthesis. Helmchen, R.W. Hoffmann, J. Mulzer, E. Schaumann (Hrsg.), 1995, 1 - 74. The possible isomers can exist as a mixture (i.e., a racemate, a cis / trans mixture, or a mixture of diastereoisomers).

[0037] The invention claimed herein is an ester compound of general formula (I)

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0038] In one embodiment, R is selected from methyl, ethyl, propyl, butyl, isobutyl, isopropyl, 1-propenyl, or 2-propenyl.

[0039] Preferably, R is selected from methyl or ethyl.

[0040] Catalyst In one embodiment, the catalyst in step B) is selected from the group consisting of Lewis acids or Bronsted acids.

[0041] In another embodiment, the catalyst of step B) is - MA x a Lewis acid in the form of (wherein M is a metal, A is a non-coordinating, i.e., weakly coordinating anion or halogen, and x is the valence of M), or - a Bronsted acid selected from the group consisting of mineral acids, mineral acid salts, organic acids, acid anhydrides (which act as Bronsted acid precursors and can form free acids upon contact with a protic reagent), solid acid catalysts, or combinations thereof selected from the group consisting of.

[0042] In one embodiment, the catalyst of step B) is a Lewis acid in the form of MA x wherein M is a metal, A is a non-coordinating, i.e., weakly coordinating anion, alcoholate or halogen, x is the valence of M, and M includes transition metals, lanthanoid metals, or metals of Groups 2, 3, 4, 5, 12, 13, 14, and 15 of the periodic table of the elements, and combinations thereof.

[0043] The Lewis acid (also referred to as a Lewis acid catalyst) can be any Lewis acid based on transition metals, lanthanoid metals, and metals of Groups 2, 3, 4, 5, 12, 13, 14, and 15 of the periodic table of the elements.

[0044] In one embodiment, the metal M is selected from the group of elements consisting of iron, magnesium, zinc, boron, scandium, yttrium, lanthanum, europium, zirconium, titanium, manganese, aluminum, ytterbium, tin, vanadium, bismuth, scandium, or hafnium.

[0045] The catalyst of the present invention is a Lewis acid, for example, of the general formula MA x(wherein A is a non-coordinating or weakly coordinating anion, M is a Group IIIB, rare earth, or lanthanide, actinide or Group IVB cation, and x is the valence of M) is a metal salt catalyst. The term "non-coordinating or weakly coordinating anion" means that the anion is not bound 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] - ), teflate ([TeOF5] - ), BArF ([B(ArH x F y )4] - (wherein Ar is aryl, x + y = 5, for example, [B(C6F5)4] - ), tosylate ([CH3C6H4SO3] - , mesylate ([CH3SO3] - ), and antimony hexafluoride ([SbF6] - ).

[0046] It should be noted that whether a particular anion is "non-coordinating or weakly coordinating" depends on its environment, such as the solvent, the presence of impurities, especially the presence of cations.

[0047] Examples of Group IIIB metals are scandium and yttrium. An example of a Group IVB metal is hafnium. Examples of rare earth or lanthanide cations are lanthanum, europium, and ytterbium. Examples of the water-tolerant Lewis acids in the present invention are scandium triflate [Sc(CF3SO3)3], europium triflate [Eu(CF3SO3)3], hafnium triflate [Hf(CF3SO3)4], yttrium triflate [Y(CF3SO3)3], lanthanum triflate [La(CF3SO3)3], and ytterbium triflate [Yb(CF3SO3)3]. Many of these water-tolerant Lewis acids are commercially available or can be synthesized by methods known in the art.

[0048] In a preferred embodiment, the Lewis acid is selected from scandium triflate [Sc(CF3SO3)3], aluminum triflate [Al(CF3SO3)3], hafnium triflate [Hf(CF3SO3)4], yttrium triflate [Y(CF3SO3)3], bismuth triflate [Bi(CF3SO3)3], or ytterbium triflate [Yb(CF3SO3)3].

[0049] Lewis acids based on transition metals, lanthanoid metals, and metals of Groups 2, 3, 4, 5, 12, 13, 14, and 15 are generally represented by the formula MX4, where M is a transition metal or a metal of Groups 2, 4, 5, 12, 13, or 14, 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.

[0050] Lewis acids of Group 4, Group 5, or Group 14 may contain two or more types of halogens. Examples include titanium bromide trichloride, titanium dibromide dichloride, vanadium bromide trichloride, and tin chloride trifluoride.

[0051] In one embodiment, A is a halogen selected from the group consisting of chlorine, fluorine, and bromine, preferably chlorine.

[0052] 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.

[0053] In a preferred embodiment, the Lewis acid is selected from scandium triflate [Sc(CF3SO3)3], aluminum triflate [Al(CF3SO3)3], hafnium triflate [Hf(CF3SO3)4], yttrium triflate [Y(CF3SO3)3], bismuth triflate [Bi(CF3SO3)3], or ytterbium triflate [Yb(CF3SO3)3], FeCl3, FeBr3, Me2AlCl, TiCl3(OiPr), AlCl3, ZnCl2, MgCl2, BCl3, Al(OTf)3, BF3, SnCl4, or TiCl4.

[0054] Group 4, Group 5, and Group 14 Lewis acids useful in the method also have the general formula MR n X 4-nmay have, wherein M is a Group 4, Group 5 or Group 14 metal; R is a monovalent hydrocarbon group selected from the group consisting of C-1 to C-12 alkyl, aryl, arylalkyl, alkylaryl and cycloalkyl groups; n is an integer from 0 to 4; 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, benzyldizirconium trichloride, dibenzylzirconium dibromide, methyltitanium trichloride, dimethyltitanium difluoride, dimethyltin dichloride, and phenylvanadium trichloride.

[0055] Group 4, Group 5 and Group 14 Lewis acids useful in the method may also have the general formula M(RO) n R’ m X (m+n) may have, wherein M is a Group 4, Group 5 or Group 14 metal; RO is a monovalent hydrocarbyloxy group selected from the group consisting of C1 to C30 alkoxy, aryloxy, arylalkoxy, alkylaryloxy groups; R’ is a monovalent hydrocarbon group selected from the group consisting of C1 to C12 alkyl, aryl, arylalkyl, alkylaryl and cycloalkyl groups; 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; 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 methoxytitanium trichloride, n-butoxytitanium trichloride, di(isopropoxy)titanium dichloride, phenoxytitanium tribromide, phenylmethoxyzirconium trifluoride, methylmethoxytitanium dichloride, methylmethoxytin dichloride and benzylisopropoxyvanadium dichloride.

[0056] Group 5 Lewis acids may also have the general formula MOX3, where 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.

[0057] Group 13 Lewis acids useful in the method may have the general formula: MR n X 3-n where M is a Group 13 metal; R is a monovalent hydrocarbon group selected from the group consisting of C1-C12 alkyl, aryl, arylalkyl, alkylaryl, and cycloalkyl groups; n is an integer from 0 to 3; 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.

[0058] Group 13 Lewis acids useful in the present disclosure may also have the general formula M(RO) n R’ m X 3-(m+n)may also have the formula M(RO)

[0059] The 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; RO is a monovalent hydrocarbyloxy group selected from the group consisting of C1-C30 alkoxy, aryloxy, arylalkoxy, and alkylaryloxy groups; R’ is a monovalent hydrocarbon group selected from the group consisting of C1-C12 alkyl, aryl, arylalkyl, alkylaryl, and cycloalkyl groups; n is an integer from 0 to 3; m is an integer from 0 to 3 such that the sum of n and m is 3 or less; 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 methoxyaluminum dichloride, ethoxyaluminum dichloride, 2,6-di-tert-butylphenoxyaluminum dichloride, methoxymethylaluminum chloride, 2,6-di-tert-butylphenoxymethylaluminum chloride, isopropoxygallium dichloride, and phenoxymethylindium fluoride.

[0060] In one embodiment, in the presence of water, a part of the Lewis acid is decomposed to form a Bronsted acid.

[0061] The term "Bronsted acid" as used herein is a term used for molecular entities (atoms, ions, molecules, compounds, complexes, etc.) that can donate one or more protons to other chemical species according to the IUPAC definition.

[0062] In one embodiment, the catalyst of step B) is a Bronsted acid selected from the group consisting of mineral acids, mineral acid salts, organic acids, acid anhydrides (which act as Bronsted acid precursors and can form free acids upon contact with protic reagents), solid acid catalysts, zeolites, acidic ion exchange resins, and combinations thereof.

[0063] In one embodiment, the Bronsted acid is selected from the group consisting of mineral acids, mineral acid salts, organic acids, solid acid catalysts, or combinations thereof.

[0064] In one embodiment, the mineral acid is selected from hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, boric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, or phosphonic acid.

[0065] In one embodiment, the mineral acid is immobilized on silica or any other thermally stable support.

[0066] In another embodiment, the mineral acid salt is selected from potassium bisulfate, sodium bisulfate, and sodium dihydrogen phosphate.

[0067] In a further embodiment, the organic acid is selected from p-toluenesulfonic acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, or trifluoroacetic acid.

[0068] In another embodiment, the acid anhydride is used as a catalyst. The acid anhydride acts as an acid precursor and can form a Bronsted acid when contacted with a protic reagent. In one embodiment, the acid anhydride is selected from phosphorus pentoxide (P2O5), carbon dioxide (CO2), sulfur trioxide (SO3), acetic anhydride (Ac2O), and methanesulfonic anhydride.

[0069] In another embodiment, the solid acid catalyst can be used alone or in combination with one or more mineral acids or other types of catalysts. Exemplary solid acid catalysts that can be used include heteropolyacids on a thermally stable support, acidic resin type catalysts, mesoporous silica, acidic clay, sulfated zirconia, molecular sieve materials, zeolites, and acidic substances. When an acidic substance is imparted to a thermally stable support, examples of the thermally stable support can include one or more of silica, tin oxide, zirconia, titania, carbon, α-alumina, etc. Optionally, additional acidic groups, such as SO4 2- or SO3H - etc. may be doped, and the oxides themselves (e.g., ZrO2, SnO2, TiO2, etc.) can also be used as solid acid catalysts.

[0070] The terms "solid acid" and "solid acid catalyst" are used synonymously herein and can include one or more solid acid materials.

[0071] As further examples of solid acid catalysts, strongly acidic ion exchangers, such as crosslinked polystyrene containing sulfonic acid groups, can be mentioned. For example, Amberlyst® resins are functionalized styrene - divinylbenzene copolymers with various surface properties and porosities. The functional groups are generally of the sulfuric acid type. Amberlyst® brand resins are supplied as beads (Amberlyst® is a registered trademark of Dow Chemical Co.). Similarly, Nafion® brand resins are sulfonated tetrafluoroethylene - based fluoropolymer copolymers and are solid acid catalysts. Nafion® is a registered trademark of E.I. du Pont de Nemours & Co., and DOWEX 50WX8® is an ion exchange resin having a styrene - divinylbenzene copolymer matrix with sulfonic acid functional groups (this is a registered trademark of Dow Chemical).

[0072] The solid catalyst can be in any shape or form currently known or developed in the future, such as granules, powders, beads, tablets, pellets, flakes, cylinders, spheres, or other shapes.

[0073] The support for the metal catalyst can be any suitable support (currently known or developed in the future) having sufficient robustness to withstand the reaction conditions disclosed herein. Suitable catalyst supports include alumina, carbon, ceria, magnesia, silica, titania, zirconia, zeolites (preferably Y, ZSM5, MWW, and β), hydrotalcite, molecular sieves, clays, iron oxide, silicon carbide, aluminosilicates, and their modifications, mixtures, or combinations thereof.

[0074] Zeolites may also be used as solid acid catalysts. Among these, generally H-type zeolites, such as zeolites of the mordenite group or pore zeolites, such as zeolites X, Y, and L, such as mordenite, erionite, chabazite, or faujasite, are preferred. Dealuminated ultrastable zeolites of the faujasite group are also suitable.

[0075] 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.

[0076] Preferably, the Bronsted acid is selected from phosphoric acid or trifluoroacetic acid. More preferably, it is phosphoric acid.

[0077] In one embodiment, the mineral acid, especially phosphoric acid, is immobilized on silica or any other thermally stable support.

[0078] 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.

[0079] In another preferred embodiment, the phosphoric acid used is crystalline.

[0080] In another preferred embodiment, polyphosphoric acid is used as the catalyst.

[0081] In a preferred embodiment of the present disclosure, the catalyst for step B) is selected from FeCl3, scandium triflate [Sc(CF3SO3)3], aluminum triflate [Al(CF3SO3)3], hafnium triflate [Hf(CF3SO3)4], yttrium triflate [Y(CF3SO3)3], bismuth triflate [Bi(CF3SO3)3], ytterbium triflate [Yb(CF3SO3)3], phosphoric acid (85% aqueous solution), phosphoric acid (crystalline), or polyphosphoric acid.

[0082] Depending on the type of catalyst, the ratio of the α-isomer to the β-isomer in the final product varies. Therefore, according to the requirements of the final product, by changing the reaction conditions, especially the selection of the catalyst, the α-isomer and the β-isomer can be obtained in various ratios. The selection of the catalyst also affects the formation of by-products.

[0083] Thus, by carefully selecting an appropriate Bronsted acid catalyst or Lewis acid catalyst, the isomer ratio of cyclohomogerranate can be advantageously changed to either the α-isomer or the β-isomer.

[0084] In one embodiment, the catalyst during the reaction is present in an amount in the range of 0.01 to 100 mol% based on the total amount of the compound of formula (III).

[0085] In another embodiment, the catalyst during the reaction is present in an amount in the range of 1 to 50 mol% based on the total amount of the compound of formula (III).

[0086] In a preferred embodiment, the catalyst in the reaction is 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).

[0087] In a preferred embodiment, the catalyst in the reaction is 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), and the catalyst is crystalline phosphoric acid.

[0088] In a preferred embodiment, the temperature in step B) is in the range of 0 °C to 150 °C, especially the temperature is in the range of 20 °C to 120 °C, preferably in the range of 50 °C to 120 °C.

[0089] In a more preferred embodiment, the temperature in step B) is any temperature between 80°C and 120°C.

[0090] In a further embodiment, step B) is carried out in the presence or absence of a solvent.

[0091] In one 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.

[0092] 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.

[0093] Preferably, the solvent is selected from toluene, cyclohexane, n - heptane, ethanol, or methanol.

[0094] The process of step B) may be carried out on an industrial scale as a batch process, or a semi - continuous process, or a continuous process. The choice of the optimal setup depends on many factors such as the phase behavior of the reaction system (two - phase liquid / liquid system, or reaction in a homogeneous phase using a dissolved acid catalyst, or reaction in a liquid phase using a solid catalyst), the required stirring, the production volume, the required reaction temperature, the required residence time, etc.

[0095] In one embodiment, the reaction is carried out as a batch reaction for a time in the range of 10 minutes to 24 hours, preferably in the range of 10 minutes to 10 hours, more preferably in the range of 10 minutes to 5 hours.

[0096] In another embodiment, the reaction is carried out in a continuous reactor setup such as a mixing pump with a residence time in the range of 1 minute to 10 hours, preferably in the range of 1 minute to 5 hours, more preferably in the range of 1 minute to 2 hours.

[0097] In one embodiment, the compound of formula (I) is selected from the following.

Chemical formula

[0098] In one embodiment, the compound of formula (I) comprises a compound of formula (Ic)

Chemical formula

[0099] In one embodiment, the compound of formula (I) comprises a compound of formula (Ic), and the compound of formula (Ic) is γ-1 or γ-2.

Chemical formula

[0100] In one embodiment, the compound of formula (I) contains less than 15%, preferably less than 10%, more preferably less than 5% of the compound of formula (IV).

Chemical formula

[0101] The compound of formula (IV) (tetrahydroactinidiolide), especially cis-IV, can be formed as a by-product of 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.

[0102] In one embodiment, the compound of formula (I) is the compound of formula (V) [Chemical formula] or a stereoisomer thereof or a mixture of stereoisomers thereof (wherein R is selected from C1-C5 straight-chain or branched-chain alkyl and C3-C5 straight-chain or branched-chain alkenyl) is included in an amount of less than 10% by weight, preferably less than 9% by weight, more preferably less than 8% by weight.

[0103] The compound of formula (V) can be produced in the synthesis of compound (I) or in the purification process by isomerization.

[0104] In one embodiment, the compound of formula (III) is at least AA) providing a compound of formula (II); [Chemical formula] BB) subjecting the compound of formula (II) to an esterification reaction to obtain a compound of formula (III) and is obtained by a process comprising

[0105] Homogentisic acid (mixture of isomers), a compound of formula (II), can be converted to the respective homogentisic acid esters by using esterification techniques known in the art (see M.B. Smith, J. March, March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure. New York: Wiley, 2013). The resulting esters can be purified by distillation. The purified or crude homogentisic acid esters can be used in step B) as a mixture of its 3E / Z-isomers with a chemical purity of more than 70%, most preferably more than 90%, most preferably more than 95%. Trace compounds that may be present in the technically used homogentisic acid esters can also be 2E / Z homogentisic acid esters or further E / Z-methyl-3-ethylidene-7-methyloct-6-enoate. The ratio of 3E:3Z-isomers in the homogentisic acid esters can vary.

[0106] In one embodiment, the esterification step is carried out in the presence of sulfuric acid, NaHSO4, KHSO4, Amberlyst®, p-toluenesulfonic acid, methanesulfonic acid, formic acid or any other acidic catalyst. Preferably, it is in the presence of sulfuric acid or NaHSO4.

[0107] Use: In one embodiment, the compound prepared according to the process of the present invention can be used in the fragrance industry as an intermediate, or the compound can be used as an aromatic compound.

[0108] Despite numerous existing aroma chemicals (fragrances and flavoring agents) and their preparation processes, new components are always needed in order to satisfy the numerous properties desired in a very diverse range of fields of use, and also for a simple synthetic route to make them available. The process of the present invention enables the effective preparation of compounds of general formula (I) which can be an interesting synthetic unit in the provision of new aroma chemicals.

[0109] In a preferred embodiment, the compound of formula (I) can be used as an aroma chemical in a composition selected from perfumes, detergents and cleaning compositions, cosmetics, body care products, hygiene products, oral and dental hygiene products, fragrance dispensers, fragrances and pharmaceuticals.

[0110] Embodiment A list of embodiments is provided below to further illustrate the present disclosure, but it is not intended to limit the present disclosure to the specific embodiments listed below.

[0111] 1. Ester compound of general formula (I)

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0112] Advantages of the present invention 1) The product can be obtained in a high yield. 2) By changing the reaction conditions, α- / β-cyclohemogerranate can be obtained in various ratios. Depending on the various ratios of α / β-cyclohomogerranate in the final product, uses in some applications can be found. 3) This process can be carried out as a batch process or a continuous process. 4) The reaction time is relatively short. 5) The reaction does not require expensive reagents. 6) This process avoids the use of reagents that produce waste (without the chemistry of protecting groups) and reduces the number of purification steps. 7) This process forms less amount of by-products in the form of the compound of formula (IV).

Examples

[0113] The present invention has been described, and it can be further understood by referring to the specific examples provided herein for illustrative purposes only. The examples are not intended to be limiting unless otherwise specified.

[0114] 1. Materials and Methods Materials Chemical substances Chemical substances were purchased from commercial vendors (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 an argon atmosphere before use.

[0115] Analytical methods Thin-layer chromatography (TLC) Monitoring of reactions, analysis of column fractions, and determination of the retardation factor (R F value) were performed by thin-layer chromatography on silica gel 60 (0.20 mm) using a fluorescent indicator. Qualitative analysis and visualization were carried out by irradiation with UV light at λ = 254 nm and / or by immersion in different staining reagents (specified for each compound in the respective experimental procedure) followed by heating with a heat gun at 300 °C until dry. The following stains were used (CAM stain was found to be particularly useful for visualization of cyclic lactone and ether products): Ce(SO4)2 (cerium sulfate: 5.0 g) and (NH4)6Mo7O 254 4H2O (ammonium molybdate 25.0 g) were dissolved in H2O (450 mL) and concentrated H2SO4 (50 mL). 24

[0116] Nuclear magnetic resonance spectroscopy (NMR) Characterization was performed by 13 13C NMR and 1 1H NMR. 13 13C NMR and 1 1H NMR spectra were measured on a Bruker AV-500 spectrometer.

[0117] (Flash) column chromatography (Flash) Column chromatography was carried out using Merck silica gel (60 Å, 230 - 400 mesh, particle size: 43 - 63 μm) or using distilled technical grade solvents. The solvent mixtures and volume ratios (v / v) used as the mobile phase for chromatography are specified in the corresponding experiments. Flash column chromatography was performed in a glass column by applying a slightly elevated air or argon (0.3 mbar) pressure.

[0118] Gas chromatography (GC) Gas chromatography (GC) was carried out using a HP6890N and 5890 series instrument equipped with a split mode capillary injection system and a flame ionization detector, with hydrogen (H2) as the carrier gas. For the quantitative GC analysis of the reaction mixture, the sensitivity coefficients of the starting materials, identified intermediates, products and internal standards were determined, and quantification was verified using the calibration curve method for each component.

[0119] 2. Basic procedures 2.1 Basic procedure A (Reactions at room temperature (r.t.) were carried out between 25 - 30 °C on a 0.20 mmol scale) The corresponding catalyst (amount is specified in the table) was transferred under ambient atmosphere and ambient pressure to a 1.5 mL headspace screw cap type glass vial and dissolved / suspended in the respective solvent (concentration is specified in the respective table). Methyl (E / Z)-homogeranate (43.5 μL, 39.3 mg, 0.20 mmol) and an electromagnetic stirring bar coated with PTFE were added, the vial was closed with a screw cap containing a PTFE / silicone septum, and electromagnetic stirring (500 rpm) was carried out at r.t. (between 25 - 30 °C) for the indicated time. After the elapsed time, 1,3,5-trimethylbenzene (28 μL, 24.2 mg, 1.0 equivalent) was added as an internal standard, the vial was shaken, and stirred at r.t. for 5 minutes. An aliquot (typically 5 - 10 μL) was taken out, diluted with CDCl3 (0.6 mL), and filtered over solid anhydrous sodium carbonate and sodium sulfate. Thereafter, the conversion rate and yield of each individual component were 1Analysis was performed by ¹H NMR spectroscopy. Alternatively, the filtered solution was analyzed by GC spectroscopy.

[0120] 2.2 Basic Procedure B (Reaction at T ≥ 30 °C on a 0.20 mmol scale) The corresponding catalyst (each amount is specified in the table) was transferred to a 2 mL headspace thick-walled crimp-cap glass vial under ambient atmosphere and ambient pressure and dissolved / suspended in the specified solvent (the concentration is specified in each table). Methyl (E / Z)-homogerranate (43.5 μL, 39.3 mg, 0.20 mmol) and an electromagnetic stirring bar coated with PTFE were added, the vial was sealed with a crimp-cap containing a PTFE / silicone septum, placed in an aluminum block preheated to the specified temperature, and magnetically stirred (1000 rpm in the case of a reaction of heterogeneous nature) for the time indicated at this temperature. After the elapsed time, the reaction mixture was cooled to room temperature and 1,3,5-trimethylbenzene (28 μL, 24.2 mg, 1.0 equivalent) was added as an internal standard. The vial was shaken and stirred at room temperature for 5 minutes. An aliquot (typically 5 - 10 μL) was taken out, diluted with CDCl₃ (0.6 mL), and filtered over solid anhydrous sodium carbonate and sodium sulfate. Thereafter, the conversion and yield of each individual component were 1 Analysis was performed by ¹H NMR spectroscopy. Alternatively, the filtered solution was analyzed by GC spectroscopy.

[0121] The methyl homogerranate used as the starting material in the examples was used with different isomeric compositions. As described in each individual example, either pure methyl (3E)-homogerranate or methyl (E / Z)-homogerranate, which is an isomer mixture with a composition of 3E:3Z:2E = 48:39:6, was used as the starting material.

[0122] 3. Specific Example: Synthesis of Methyl Cyclohomogerranate (α-1) from Methyl (E / Z) Homogerranate 3.1 Evaluation of Bronsted Acids The reaction was carried out on a 0.20 mmol scale according to the basic procedure B using the specified catalyst. The conversion and yield were determined by 1 1H NMR spectroscopy using CH2Br2 and / or (preferably) 1,3,5-trimethylbenzene as internal standards. The reactions using solid acid catalysts (Table 1, experimental example numbers 1.4 to 1.9) were carried out as follows: DOWEX 50WX8 was treated with H2SO4 (0.05 M), then washed with ethanol and dichloromethane, and acidified by air drying before use. Montmorillonite K10, Amberlyst 15, and zeolite were commercially available and used as received. H3PO4 (20%, immobilized on silica) was available as beads and was ground to a powder before use. Each solid acid catalyst (10 mg, 50 mg / mmol loading) was transferred to a 2 mL headspace crimp-cap glass vial equipped with a PTFE-coated magnetic stir bar. Anhydrous toluene and the starting materials (0.2 mmol) were added according to the basic procedure B, the vial was capped with a crimp-cap, and placed in an aluminum heating block preheated to 110 °C. The resulting suspension was vigorously stirred (1000 rpm) at this temperature for 2 hours. After the elapsed time, the mixture was diluted with MTBE (1 mL), filtered over NaHCO3 and Na2SO4 (eluted with 2 × 1 mL MTBE), and concentrated under reduced pressure to obtain the crude product as a yellow oil. The conversion and isomer ratio of the crude product were determined by gas chromatography.

[0123] Table 1: Catalyst screening in the cyclization reaction of methyl homogerranate to methylcyclohomogerranate

Chemical formula

[0124]

Table 1

[0125] 3.2 Evaluation of phosphoric acid as a Brønsted acid catalyst

[0126]

Table 2

[0127] The reaction was carried out at 110 °C according to the basic procedure B using the specified catalyst. The conversion and yield were determined by 1H NMR spectroscopy using 1,3,5-trimethylbenzene as an internal standard. 1 The results are summarized in Table 2.

[0128] 3.2.1 Influence of water in the reaction with phosphoric acid as a Brønsted acid catalyst The influence of water on the conversion, yield, and selectivity in the cyclization reaction was investigated. A certain amount of water was added to the reaction mixture (the results are shown in Table 3 below).

[0129] Table 3: Influence of the amount of water on the results of the phosphoric acid-catalyzed cyclization reaction from methyl homogerranate to methyl cyclohomogerranate

Chemical formula

[0130]

Table 3

[0131] The reaction was carried out at 110 °C according to the basic procedure B using crystalline phosphoric acid as a catalyst. The amount of water added is specified in each entry. The conversion and yield were determined by 1H NMR spectroscopy using 1,3,5-trimethylbenzene as an internal standard. 1 The results were determined by 1H NMR spectroscopy.

[0132] This result supported the previous finding (see Table 2) that the source of phosphoric acid-free aqueous solution provides consistently higher yields and selectivities in the cyclization reaction compared to the aqueous phosphoric acid solution. As the water content was gradually increased, the conversion and yield gradually decreased (see Table 3, Examples 3.2 - 3.5).

[0133] 3.3 Evaluation of Lewis acids Various Lewis acids were tested as catalysts in the cyclization reaction of methyl homogeranate to methyl cyclohomogeranate (Table 4).

Chemical formula

[0134]

Table 4

[0135] The reaction was carried out at 110 °C according to the basic procedure B using the specified catalyst. The conversion and yield were determined by gas chromatography using 1,3,5-trimethylbenzene as an internal standard and / or 1 1H NMR spectroscopy.

[0136] Among the catalysts tested, anhydrous FeCl3, Sc(OTf)3, and Y(OTf)3 had the highest selectivity for methyl cyclohomogeranate (over 80%), and the cis-tetrahydroactinide by-product was less than 15%. In particular, in contrast to the reaction using crystalline phosphoric acid or 85% aqueous phosphoric acid, where the α-isomer is typically obtained as the main product, the Lewis acid-catalyzed process appears to give the β-isomer as the main product (up to 56% in the case of yttrium triflate).

[0137] 3.4 Changes in reaction conditions 3.4.1 Solvent selection The cyclization reaction gives comparable results in terms of the yield and selectivity for methyl cyclohemogeranate and can be carried out in various solvents, preferably aliphatic or aromatic hydrocarbon solvents such as toluene, cyclohexane, and n-heptane. The ratio of the isomers to the cis-lactone by-product varies slightly with the solvent (Table 4).

[0138]

Table 5

[0139] The reaction was carried out on a 0.20 mmol scale in the specified solvent according to basic procedure B using crystalline phosphoric acid (5 mol%) as the catalyst. The conversion and yield were determined by 1 1H NMR spectroscopy using 1,3,5-trimethylbenzene as the internal standard.

[0140] 3.4.2 Concentration Selection of Starting Materials The cyclization reaction can be carried out in the concentration range of 0.5 - 10 M, and it was found that a concentration of 2 - 10 M is optimal for the conversion of the methyl homogenerate starting material (see Table 5). The formation of the cis-THA byproduct was gradually suppressed as the dilution increased (below 2 M).

[0141] [Table 6]

[0142] The reaction was carried out on a 0.20 mmol scale in toluene (2 M) according to basic procedure B using crystalline phosphoric acid (5 mol%) as the catalyst. The conversion and yield were determined by 1 1H NMR spectroscopy using 1,3,5-trimethylbenzene as the internal standard. n.d.: 1 Not detected by 1H NMR analysis.

[0143] 3.4.3 Variation of Catalyst Loading The catalyst loading of crystalline phosphoric acid was varied between 2.5 - 100 mol%, preferably 5 - 10 mol% to ensure complete consumption of the starting material (within 2 hours of reaction time) and minimize the amount of the cis-THA byproduct (Table 6).

[0144] [Table 7]

[0145] The reaction was carried out on a 0.20 mmol scale in toluene (2 M) according to basic procedure B using crystalline phosphoric acid as the catalyst. The conversion and yield were determined by 1 1H NMR spectroscopy using 1,3,5-trimethylbenzene as the internal standard. n.d.: 1 not detected by 1H NMR analysis.

[0146] 3.4.4 Influence of temperature

[0147]

Table 8

[0148] The reaction was carried out on a 0.20 mmol scale in toluene (2 M) according to basic procedure B using crystalline phosphoric acid as the catalyst at the indicated temperatures. The conversion and yield were determined by 1 1H NMR spectroscopy using 1,3,5-trimethylbenzene as the internal standard. n.d.: 1 not detected by 1H NMR analysis.

[0149] Example 4: Cyclization of isopropyl (3E)-homogeranate The influence of isomer purity on the results of the cyclization reaction using isomerically pure isopropyl and methyl (3E)-homogeranate as starting materials was evaluated.

[0150] The reactivity of the pure (3E)-isomer in the cyclization reaction catalyzed by phosphoric acid was investigated (Table 8: Cyclization of isomerically pure methyl or isopropyl (3E)-homogeranate catalyzed by phosphoric acid). Screening revealed that the methyl ester is more reactive than the isopropyl ester. In addition, the amount of (β)-1 increased significantly compared to the reaction with an isomer mixture (α)-1 / (β)-1 ≒ 1:1.2, where it is 1:1.7 for the pure isomer.

[0151] Table 8: Cyclization of isomerically pure methyl or isopropyl (3E)-homogeranate catalyzed by phosphoric acid

Chem.

[0152]

Table 9

[0153] The reaction was carried out on a 0.20 mmol scale in toluene (2 M) according to basic procedure B using crystalline phosphoric acid as a catalyst at the indicated temperature. The conversion and yield were determined by 1H NMR spectroscopy using 1,3,5-trimethylbenzene as an internal standard. n.d.: 1 Not detected by 1H NMR spectroscopy. 1 Not detected by 1H NMR analysis.

[0154] Example 5: Preparation of Methyl α-Cyclohemogellarate (α-1), Methyl β-Cyclohemogellarate (β-1), and Methyl γ-Cyclohemogellarate (γ-1) To a 4 mL screw-cap glass vial dried under argon were added (E / Z)-methyl homogellarate (a mixture of 3E:3Z:2E in a ratio of 48:39:6, 392 mg, 2.00 mmol, 1.00 equiv) and a PTFE-coated magnetic stir bar. The starting material was dissolved in dry toluene (0.60 mL, 3.33 M), and the vial was placed in a preheated aluminum heating block, and the resulting colorless transparent solution was heated to 100 °C. Next, 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 one, and the mixture was stirred at 100 °C for 2 h (500 rpm) (a gradual color change from a colorless solution with pink droplets of H3PO4 to a yellow solution with brown droplets was observed within 15 min of the reaction time). After the elapsed time, the yellow reaction mixture was cooled to r.t., and a small aliquot was 1Analysis by \(^1\)H NMR spectroscopy and TLC indicated that the starting material was completely consumed and the desired product was formed (excluding the conjugated 2E-isomer, which was not thought to react under these reaction conditions). Saturated aqueous Na\(_2\)CO\(_3\) 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 Na\(_2\)SO\(_4\), filtered, concentrated under reduced pressure, and the crude product was obtained as a yellow oil. Purification by flash column chromatography on silica gel (Merck, 40 - 63 μm, 230 - 400 mesh, 30 g) using hexane / MTBE as the eluent gave the product as a pale yellow oil, a mixture of isomers (315 mg, 1.61 mmol, 80% yield, 84% GC purity, the mixture containing approximately 6% of the 2E-isomer of methyl homogeranate).

[0155]

Table 10

[0156] The second reaction was carried out in parallel on the same scale using crystalline H\(_3\)PO\(_4\) (over 99.9999%, 9.80 mg, 0.10 mmol, 0.05 eq). In this case, H\(_3\)PO\(_4\) was weighed directly into the vial, suspended in toluene, and then methyl homogeranate was added. Otherwise, the procedure, observations, extraction, and purification steps were essentially the same as those described above. Purification by flash column chromatography gave the cyclized product as a colorless or pale yellow oil in three fractions (318 mg, 1.62 mmol, 81% yield, the corrected yield based on GC purity is shown in the table below).

[0157]

Table 11

[0158] The analytical data / characterization of the compound isolated from the reaction described in Example 5 are shown below.

[0159] Methyl racβ-cyclohemogellarate (α-1) [Chemical formula] In fraction 4 of the column chromatography of the second reaction of Example 5, the analytical data of α-1 isolated as a pure compound ( 1 purity over 95% according to 1H NMR and GC analysis).

[0160] Appearance: Colorless oil TLC (SiO2, hexane / MTBE 19:1) R f = 0.37 (CAM staining, light blue spot) 1 1H NMR (CD2Cl2, 501 MHz) δ (ppm) 5.38 - 5.32 (m, 1H), 3.64 (s, 3H), 2.35 (dd, J = 17.3, 8.1 Hz, 1H), 2.27 - 2.14 (m, 2H), 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). 13 13C NMR (CD2Cl2, 126 MHz) 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.

[0161] GC DB-Waxetr 0.25 mm / 0.25 μm, 30 m, temperature: 220 °C (injector) / 2 °C / min from 60 °C to 130 °C, then 12 °C / min to 260 °C, 350 °C (detector), gas: 0.60 bar H2, sample size: 0.2 μL, t R = 25.39 min.

[0162] HRMS (GC-Cl, ammonia) (m / z) C 12 H 21 O2 + [M + H] + Calculated value 197.1536; measured value 197.1537.

[0163] Methyl β-cyclohemogellarate (β-1)

Chem.

[0164] Appearance: Pale yellow oily substance TLC (SiO2, hexane / MTBE 19:1) R f = 0.31) CAM staining, light blue spot) 1 1H NMR (CDCl3, 501 MHz) 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). 13 13C NMR (CDCl3, 126 MHz) δ (ppm) = 173.5, 131.6, 130.5, 51.8, 39.5, 34.9, 33.7, 32.8, 28.1, 20.4, 19.5.

[0165] GC DB-Waxetr 0.25 mm / 0.25 mm, 30 m, temperature: 220 °C (injector) / 2 °C / min from 60 °C to 135 °C, then 6 °C / min to 220 °C, then 12 °C / min to 260 °C, 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).

[0166] HRMS (GC-EI) m / z C 12 H 20 O2+ [M] + Calculated value: 196.1458; Measured value: 196.1457.

[0167] rac-Methyl γ-cyclohemogellarate (γ-1)

Chem.

[0168] TLC (SiO2, hexane / MTBE 19:1) R f = 0.31) CAM staining, light blue spot) 1 1H NMR (CDCl3, 501 MHz) δ (ppm) = 4.75 (q, J = 1.4 Hz, 1H), 4.56 (s, 1H), 3.64 (s, 3H), 2.50 (t, J = 10.2 Hz, 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, 5.3 Hz, 1H), 1.43 (ddd, J = 11.6, 7.2, 4.3 Hz, 1H), 1.35 (ddd, J = 13.3, 8.1, 4.9 Hz, 1H), 0.96 (s, 3H), 0.79 (s, 3H).

[0169] GC DB-Waxetr 0.25 mm / 0.25 mm, 30 m, temperature: 220 °C (injector) / 2 °C / min from 60 °C to 135 °C, then 6 °C / min to 220 °C, then 12 °C / min to 260 °C, 5 min at 260 °C, 350 °C (detector), gas: 0.60 bar H2, sample size: 0.2 μL, t R = 29.71 min (99%).

[0170] HRMS (GC-CI, ammonia) (m / z) C 12 H 21 O2 + [M + H] + Calculated value: 197.1536; Measured value: 197.1537.

[0171] Example 6: Preparation of Methyl α-Cyclohemogellarate (α-1), Methyl β-Cyclohemogellarate (β-1), and Methyl γ-Cyclohemogellarate (γ-1) A 100 mL round-bottom flask was charged with (E / Z)-methyl homogeranate (3.92 g, 20 mmol, 1.0 equiv) and a PTFE-coated magnetic stir bar. The starting material was dissolved in hexafluoroisopropanol (20 mL, 9.5 equiv, 1 M), and TFA (trifluoroacetic acid, 2.38 g, 20.9 mmol, 1.04 equiv) was added dropwise to the stirred solution (an immediate color change from colorless to bright yellow, then from bright orange to dark orange-red was observed within 1 minute upon addition of TFA), and the resulting red solution was stirred at 25 °C for 24 h. After the elapsed time, the dark reddish-brown reaction mixture was concentrated under reduced pressure. The residue was dissolved in hexane / MTBE (19:1 v / v, 20 mL), celite was added, and the slurry was concentrated under reduced pressure. After purification by flash column chromatography on silica gel (Merck, 40 - 63 μm, 300 g) using hexane / MTBE as the eluent and drying under vacuum overnight, methyl cyclohemogeranate was obtained as a colorless oil (2.34 g, 11.9 mmol, 60% yield, α-1:β-1:γ-1 = 31:68:1 based on GC).

Claims

1. Ester compounds of general formula (I) 【Chemistry 1】 (In the formula, X １ and X ３ These are, together, the second bond of the double bond between the carbon atoms to which they are bonded, where X ２ and X ４ is hydrogen; or X ３ and X ４ These are, together, the second bond of the double bond between the carbon atoms to which they are bonded, where X １ and X ２ (It is hydrogen.) or a process for preparing the stereoisomer thereof, Equation (I) is, Compound of formula (Ia) 【Chemistry 2】 or its stereoisomer or a mixture thereof, Compound of formula (Ib) 【Transformation 3】 (wherein, R is selected from linear or branched alkyl of C １ ~C ５ and linear or branched alkenyl of C ３ ~C ５ ) and Includes, at least: A) Compounds of formula (III) 【Chemistry 4】 The steps of providing either a stereoisomer thereof or a mixture thereof, B) The step of cyclizing the compound of formula (III) in the presence of a catalyst selected from Brønsted acids or Lewis acids to obtain the compound of formula (I), C) Optionally, a step to purify the compound of formula (I) obtained in step B) and A process that includes this.

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

3. In step B), the catalyst is a) MA ｘ Lewis acids of the form (wherein M is a metal, A is non-coordinating, i.e., weakly coordinating anions, alkoxides, or halogens, and x is the valence of M), Or, b) Brønsted acids selected from the group consisting of mineral acids, mineral salts, organic acids, solid acid catalysts, or combinations thereof. The process according to claim 1, selected from the group consisting of the following.

4. Step B) is - A mineral acid selected from hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, boric acid, hydrofluoric acid, hydrobromic acid, or hydroiodic acid, phosphonic acid, which is immobilized on silica or any other heat-stable carrier. - Mineral salts selected from potassium bicarbonate, sodium bicarbonate, and sodium dihydrogen phosphate, - Organic acids selected from p-toluenesulfonic acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, or trifluoroacetic acid, - Solid acid catalysts selected from heteropoly acids, acidic resin-type catalysts, strongly acidic ion exchangers, mesoporous silica, acidic clay, sulfated zirconia, molecular sieve materials, or acidic substances or zeolites in thermally stable carriers. Or a combination of those The process according to claim 3, carried out in the presence of a Brønsted acid selected from the following.

5. The process according to claim 3, wherein step B) is carried out in the presence of a Brønsted acid selected from phosphoric acid, p-toluenesulfonic acid, phosphonic acid, or a strongly acidic ion exchanger.

6. The process according to claim 5, wherein the Brønsted acid is phosphoric acid, trifluoroacetic acid, or silica-supported phosphoric acid.

7. Step B) is MA ｘ The process according to claim 3, carried out in the presence of a Lewis acid of the form, wherein M is a metal, A is a non-coordinating, i.e., weakly coordinating anion, alkoxide or halogen, x is the valence of M, and M includes transition metals, lanthanide metals, or metals of groups 2, 3, 4, 5, 7, 8, 12, 13, 14 and 15 of the periodic table of elements, and combinations thereof.

8. The process 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. A is trifluoromethanesulfonate, i.e., triflate ([CF ３ SO ３ ] － ), hexafluorophosphate ([PF ６ ] － ), [Al[OC(CF ３ ) ３ ] ４ ] － , tetrafluoroborate ([BF ４ ] － ), perchlorate ([ClO ４ ] － ), BArF([B(ArH ｘ F ｙ ) 4] － (In the formula, Ar is aryl and x + y = 5), tosylate ([CH ３ C ６ H ４ SO ３ ] － , mesylate ([CH ３ SO ３ ] － ), or antimony hexafluoride ([SbF ６ ] － The process according to claim 7, wherein the anion is non-coordinating, i.e., weakly coordinating, selected from ).

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

11. The Lewis acid is scandium triflate [Sc(CF ３ SO ３ ) ３ ], aluminum triflate [Al(CF ３ SO ３ ) ３ ], hafnium triflate [Hf(CF ３ SO ３ ) ４ ], yttrium triflate [Y (CF ３ SO ３ ) ３ ], bismuth triflate [Bi (CF ３ SO ３ ) ３ ], or ytterbium triflate [Yb(CF ３ SO ３ ) ３ ], FeCl ３ , FeBr ３ , MnCl ２ BiCl ３ Me ２ AlCl, TiCl ３ (OiPr), AlCl ３ ZnCl ２ , ZnBr ２ , Zn(OTf) ２ , MgCl ２ , BCl ３ Al(OTf) ３ BF ３ SnCl ４ , or TiCl ４ The process according to claim 7, selected from the following.

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

13. The process according to any one of claims 1 to 11, wherein in step B), the reaction is carried out at a temperature in the range of 0°C to 150°C.

14. The process according to any one of claims 1 to 11, wherein in step B), the reaction is carried out in the presence or absence of a solvent.

15. The process 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 process 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 process according to any one of claims 1 to 11, wherein in step B), the reaction is carried out as a batch reaction or in a continuous reactor setup.

18. The compound of formula (I) is of formula (Ic) 【Transformation 5】 (In the formula, X ２ and X ３ Together, they form the second bond of the double bond between the carbon atoms to which they are bonded. R is C １ ~C ５ Linear or branched alkyl and C ３ ~C ５ (Selected from linear or branched alkenyls) The process according to any one of claims 1 to 11, further comprising the compound.

19. The compound of formula (I) is the compound of formula (V). 【Transformation 6】 or its stereoisomer or mixture thereof (In the formula, R is C １ ~C ５ Linear or branched alkyl and C ３ ~C ５ (Selected from linear or branched alkenyls) The process according to any one of claims 1 to 11, comprising in an amount of less than 10% by weight.

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