Method and intermediate for producing 3-(cyclohex-1-en-1-yl)propanal derivatives

Abstract

The present invention relates to the field of perfumery. More specifically, it relates to novel valuable chemical intermediates for the preparation of perfuming ingredients. Furthermore, the present invention also encompasses a process for preparing the compounds of formula (I).

Description

[Technical Field]

[0001] This invention relates to the field of fragrances. More specifically, it relates to novel chemical intermediates of value for producing fragrance components. Furthermore, this invention also encompasses a method for producing the compound of formula (I).

[0002] Background of the Invention The fragrance industry is constantly seeking compounds that impart new sensory stimuli. Particular interest lies in aldehyde notes, which represent one of the key sensual aspects of the lily of the valley fragrance. Therefore, compounds that impart these notes are especially needed to recreate the delicate floral scent of lily of the valley, which is not retained even by the gentlest extraction methods used to obtain the essential oil. 3-(cyclohex-1-en-1-yl)propanal derivatives are representative of compounds that impart the olfactory classification note of lily of the valley, such as 3-(4,4-dimethyl-1-cyclohexen-1-yl)propanal reported in European Patent No. 1529770 or 3-[4-(2-methyl-2-propanyl)-1-cyclohexen-1-yl]propanal reported in European Patent No. 1054053. However, obtaining these derivatives is laborious and requires Grignard reagents, radical chemistry, hydrogenation of dienal, or thermal decomposition, resulting in the acquisition of the target compound in low yield and / or selectivity.

[0003] Because it is a product of industrial interest, there is a constant demand for new processes that demonstrate improvements in yield and productivity.

[0004] The compounds of formulas (II), (III), and (IV), which are the subject of this invention, have never been reported or proposed in connection with the production of the compound of formula (I). Only a few of the aforementioned compounds of formulas (II) and (III) have been reported in the prior art, but none of them have been reported as intermediates to the compound of formula (I).

[0005] Therefore, although the prior art reports several derivatives of formula (II) and (III), it cannot be regarded as proposing the present invention.

[0006] Summary of the Invention The present invention relates to a novel process which makes it possible to prepare the compound of formula (I) in high yield and high selectivity starting from the novel compound of formula (II). The process of the present invention represents a new efficient route to the compound of formula (I).

[0007] Accordingly, a first object of the present invention is a compound of the following formula in the form of any one of stereoisomers or a mixture thereof Chemical Formula [wherein each R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 , independently of each other, are each a hydrogen atom, or a C 1~3 alkyl or C 1~6 alkenyl group optionally substituted by hydroxy or a C 2~6 alkoxy group, or two groups of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 together form a C 3~8 cycloalkyl or C 5~8 cycloalkenyl group, and the remaining groups have the same meanings as defined above] which is a process for preparing the compound, compound of formula (II) in the form of any one of stereoisomers or a mixture thereof Chemical Formula [wherein R 1 , R 2 , R 3 , R 4, R 5 , R 6 , and R 7 This has the same meaning as defined in formula (I), where X represents a C(O)R group or a Si(R')3 group, and R is a hydrogen atom, C 1~4 Alkyl alkyl group, C 1~4 An alkoxy group or a phenyl group, where R' is independently C 1~4 It is an alkyl group. The method comprises hydroformylation and elimination steps starting from a compound.

[0008] The second object of the present invention is the following formula in the form of one or a mixture thereof of stereoisomers [ka] [In the formula, X represents a C(O)R group or a Si(R')3 group, and R is a hydrogen atom, C 1~4 Alkyl alkyl group, C 1~4 An alkoxy group or a phenyl group, where R' is independently C 1~4 It is an alkyl group, and each R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 These are, independently of each other, a hydrogen atom, or hydroxyl or C, respectively. 1~3 C is optionally substituted with an alkoxy group. 1~6 Alkyl or C 2~6 Represents an alkenyl group, or R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 Two of the groups combine to form C 3~8 Cycloalkyl or C 5~8 It forms a cycloalkenyl group, and the other groups have the same meaning as defined above. These are compounds, but 1-(3-oxopropyl)cyclohexylacetate is excluded.

[0009] Another subject of the present invention is the following formula in the form of one or a mixture thereof of stereoisomers. [ka] [In the formula, X' is a hydrogen atom, C 1~3 Alkyl alkyl group, C 2~3 It is an alkenyl group, a benzyl group, a C(O)R group, or a Si(R')3 group, where R is a hydrogen atom, C 1~4 Alkyl alkyl group, C 1~4 An alkoxy group or a phenyl group, where R' is independently C 1~4 It is an alkyl group, and each R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 These are, independently of each other, a hydrogen atom, or hydroxyl or C, respectively. 1~3 C is optionally substituted with an alkoxy group. 1~6 Alkyl or C 2~6 Represents an alkenyl group, or R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 Two of the groups combine to form C 3~8 Cycloalkyl or C 5~8 It forms a cycloalkenyl group, and the other groups have the same meaning as defined above, R a and R b C is independent of each other. 1~4 Represents an alkyl group, or R a and R b together C 2~6 [Represents an alkanediyl group] is a compound, with the exception of 1-(2-(1,3-dioxolan-2-yl)ethyl)-4-isobutyl-2-methylcyclohexan-1-ol, 1-(2-(1,3-dioxolan-2-yl)ethyl)-4-(tert-butyl)-2-methylcyclohexan-1-ol, 1-(3,3-diethoxypropyl)cyclohexan-1-ol, 1-(2-(1,3-dioxolan-2-yl)ethyl)-4-isopropyl-2-methylcyclohexan-1-ol, 1-(2-(1,3-dioxolan-2-yl)ethyl)-4-(tert-butyl)cyclohexan-1-ol, and 1-(2-(1,3-dioxan-2-yl)ethyl)-4-(tert-butyl)cyclohexan-1-ol.

[0010] Another object of the present invention is a compound of the following formula in the form of any one of stereoisomers or a mixture thereof

Chemical

[0011] A further object of the present invention is a compound of the following formula in the form of any one of stereoisomers or a mixture thereof

Chemical

[0012] Description of the Invention Surprisingly, it has now been discovered that the valuable fragrance component, the 3-(cyclohex-1-en-1-yl)propanal derivative of formula (I), can be obtained from novel chemical intermediates defined herein by formulas (II), (III), and (IV). The method of the present invention represents a new pathway to the compound of formula (I) with overall higher yields compared to methods known from the prior art.

[0013] Therefore, the subject of the first invention is the following formula in the form of one or a mixture thereof of stereoisomers. [ka] [In the formula, each R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 These are, independently of each other, a hydrogen atom, or hydroxyl or C, respectively. 1~3 C is optionally substituted with an alkoxy group. 1~6 Alkyl or C 2~6 Represents an alkenyl group, or R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 Two of the groups combine to form C 3~8 Cycloalkyl or C 5~8 It forms a cycloalkenyl group, and the other groups have the same meaning as defined above. A method for producing the compound, Formula (II) of one of the stereoisomers or a mixture thereof [ka] [In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7This has the same meaning as defined in formula (I), where X represents a C(O)R group or a Si(R')3 group, and R is a hydrogen atom, C 1~4 Alkyl alkyl group, C 1~4 An alkoxy group or a phenyl group, where R' is independently C 1~4 It is an alkyl group. The method comprises hydroformylation and elimination steps starting from a compound.

[0014] For clarity, it should be stated that the phrase "one of the stereoisomers or a mixture thereof" or similar expressions have the usual meaning as understood by those skilled in the art, i.e., the compounds of formulas (I) and (II) may be pure enantiomers or mixtures thereof. In other words, the compounds of formulas (I) and (II) may have at least one stereocenter that can have two different stereochemistrys (e.g., R or S). The compounds of formulas (I) and (II) may be in the form of pure enantiomers or mixtures thereof. If the compounds of formulas (I) and (II) have two or more stereocenters, they may be in the form of pure diastereoisomers or mixtures thereof. The compounds of formulas (I) and (II) may be in racemic or scalemic form. Therefore, the compounds of formulas (I) and (II) may be a single stereoisomer, or may be in the form of a composition of various stereoisomers.

[0015] The term "optionally" is understood to mean that a particular group to be optionally substituted may or may not be substituted with a particular functional group.

[0016] To clarify, the phrase "including hydroformylation and elimination steps" means that the hydroformylation and elimination reactions can be carried out in any order. In other words, the method of the present invention may include a hydroformylation step followed by an elimination step, or the method of the present invention may include an elimination step followed by a hydroformylation step.

[0017] The terms “alkyl” and “alkenyl” are understood to include branched and linear alkyl and alkenyl groups. The terms “alkenyl” and “cycloalkenyl” are understood to include one, two, or three olefin double bonds, preferably one or two olefin double bonds. The terms “cycloalkyl” and “cycloalkenyl” are understood to include monocyclic, or condensed, spiro, and / or crosslinked bicyclic or tricyclic cycloalkyl and cycloalkenyl groups, preferably monocyclic cycloalkyl and cycloalkenyl groups.

[0018] To make it clear, "R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 Two of the groups combine to form C 3~8 Cycloalkyl or C 5~8 The expression "forms a cycloalkenyl group" means that the carbon atom to which both groups are bonded is C 5~8 Cycloalkyl groups or C 5~8 This means it is contained within a cycloalkenyl group.

[0019] According to any embodiment of the present invention, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 At least one of the groups is either hydroxyl or C 1~3C is optionally substituted with an alkoxy group. 1~6 Alkyl or C 2~6 The group may be an alkenyl group, and the remainder may be a hydrogen atom, or each may be a hydroxyl group or a carbon atom, independently of each other. 1~3 C is optionally substituted with an alkoxy group. 1~6 Alkyl or C 2~6 It may be an alkenyl group. In particular, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 At least three of these groups may be hydrogen atoms, and the rest may be hydrogen atoms, or each may be a hydroxyl group or a C group, independently of each other. 1~3 C is optionally substituted with an alkoxy group. 1~6 Alkyl or C 2~6 It may be an alkenyl group. In particular, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 Four of these groups may be hydrogen atoms, and the rest may be hydrogen atoms, hydroxyl groups, or C groups, independently of each other. 1~3 C is optionally substituted with an alkoxy group. 1~6 Alkyl or C 2~6 It may be an alkenyl group. In particular, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 One, two, three, or four of these groups are hydroxyl or C 1~3 C is optionally substituted with an alkoxy group. 1~6 Alkyl or C 2~6 It may be an alkenyl group, and the remainder may be hydrogen atoms. More specifically, R 1 , R 2 , R 3 , R 4 , R 5 , R6 , and R 7 One or two of these groups are hydroxyl or C, respectively. 1~3 C is optionally substituted with an alkoxy group. 1~6 Alkyl or C 2~6 The group may be an alkenyl group, and the remainder may be hydrogen atoms.

[0020] According to any embodiment of the present invention, R 3 , R 4 , R 5 , R 6 , and R 7 These are, independently of each other, hydrogen atoms, or hydroxyl or C 1~3 C is optionally substituted with an alkoxy group. 1~4 It may be an alkyl group. In particular, R 3 , R 4 , R 5 , R 6 , and R 7 These are, independently of each other, hydrogen atoms or C 1~3 It may be an alkyl group. In particular, R 3 , R 4 , R 5 , R 6 , and R 7 These can be hydrogen atoms, independently of each other.

[0021] According to a particular embodiment of the present invention, R 1 , R 2 , R 3 , R 6 , and R 7 These may be hydrogen atoms independently of each other, and R 4 and R 5 is a hydrogen atom or C 1~3 It may be an alkyl group. In particular, R 1 , R 2 , R 3 , R 6 , and R 7 These may be hydrogen atoms independently of each other, and R 4 R may be a hydrogen atom, 5 is C 1~3 It may be an alkyl group, or R 4 is C1~3 It may be an alkyl group, R 5 It can be a hydrogen atom.

[0022] According to any embodiment of the present invention, the compound of formula (I) is in the form of one or a mixture thereof of the following stereoisomers. [ka] [In the formula, each R 1 and R 2 This has the same meaning as defined above. The compound of formula (II) is a compound of the following formula in the form of one of its stereoisomers or a mixture thereof. [ka] [In the formula, each X, R 1 , and R 2 This has the same meaning as defined above. It is a compound of [the compound].

[0023] According to any embodiment of the present invention, R 1 C 1~4 Alkyl or C 2~4 It may be an alkenyl group. In particular, R 1 R may be a methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, or n-butyl group. In particular, R 1 R may be a methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, or n-butyl group. More specifically, R 1 It may be a methyl group.

[0024] According to any embodiment of the present invention, R 2 is a hydrogen atom or C 1~3 Alkyl or C 2~3 It may be an alkenyl group. In particular, R 2 R may be a hydrogen atom, a methyl, ethyl, propyl, or isopropyl group. More specifically, 2 It may be a methyl group.

[0025] According to a particular embodiment of the present invention, R 2 When is a hydrogen atom, preferably R 1 It is not a tert-butyl group.

[0026] According to any embodiment of the present invention, X may be a C(O)R group, where R is a hydrogen atom or C 1~4 It may be an alkyl group. In particular, X may be a C(O)R group, where R is C 1~3 It may be an alkyl group. More specifically, X may be an acetate group.

[0027] According to a particular embodiment of the present invention, the method of the present invention comprises a hydroformylation step starting from a compound of formula (II) and a subsequent elimination step. By hydroformylation of the compound of formula (II), the following formula is obtained in the form of one or a mixture thereof of stereoisomers. [ka] [where X, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 This has the same meaning as defined above. The following compounds are obtained.

[0028] Hydroformylation produces, as a byproduct, one or a mixture thereof of the following formula in the form of one of the stereoisomers. [ka] [where X, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 This has the same meaning as defined above. Compounds of formula (III') may be formed. Up to 40% by weight of compound (III') may be formed. In particular, up to 35% by weight of compound (III') may be formed. In particular, up to 30% by weight of compound (III') may be formed. In particular, up to 20% by weight of compound (III') may be formed. In particular, up to 10% by weight of compound (III') may be formed. In particular, up to 5% by weight of compound (III') may be formed. More specifically, compound (III') is not formed by hydroformylation.

[0029] For clarity, the term "hydroformylation" or similar expression is intended to be used in the ordinary sense as understood by those skilled in the art. That is, the reaction is carried out in the presence of a metal catalyst such as a rhodium, cobalt, or platinum complex, preferably a rhodium complex, and a ligand such as carbon monoxide, hydrogen, and an optional phosphorus atom.

[0030] According to any embodiment of the present invention, hydroformylation is carried out in the presence of a rhodium complex. The rhodium complex that can be used in the present invention is not limited to, but includes Rh(acac)(CO)2, RhCl3, Rh2AcO4, [Rh(OAc)(COD)]2, and Rh4(CO). 12 , Rh6(CO) 16Examples include RhCl(CO)(PPh3)2, Rh(C2H4)2(acac), [Rh(Cl)(COD)]2, [Rh(Cl)(COE)2]2, [Rh(OAc)(CO)2]2, Rh(acac)(COD), HRh(CO)(PPh3)3, RhCl(PPh3)3, [Rh(NBD)2]BF4, [Rh(OMe)(COD)]2, and [Rh(OH)(COD)]2, where acac represents an acetylacetonate group, Ac represents an acetyl group, COD represents a 1,5-cyclooctadiene group, COE represents a cyclooctene group, and Ph represents a phenyl group. In particular, rhodium complexes can be selected from the group consisting of Rh(acac)(CO)2, [Rh(OAc)(COD)]2, RhCl(CO)(PPh3)2, Rh(C2H4)2(acac), [Rh(Cl)(COD)]2, [Rh(Cl)(COE)2]2, [Rh(OAc)(CO)2]2, Rh(acac)(COD), HRh(CO)(PPh3)3, RhCl(PPh3)3, [Rh(NBD)2]BF4, [Rh(OMe)(COD)]2, and [Rh(OH)(COD)]2. More specifically, rhodium complexes can be selected from the group consisting of Rh(acac)(CO)2, Rh(acac)(COD), HRh(CO)(PPh3)3, [Rh(OMe)(COD)]2, and [Rh(OH)(COD)]2. The complex can be added to the reaction medium of the method of the present invention at a wide range of concentrations. Non-limiting examples include complex concentrations ranging from about 0.0005 mol% to about 5 mol% relative to the amount of substrate, preferably from 0.001 mol% to about 5 mol% relative to the amount of substrate. Preferably, the complex concentration falls within 0.0025 mol% to 2 mol%. Naturally, as is recognized by those skilled in the art, the optimal concentration of the complex depends on the properties of the latter, the properties of the substrate, the properties of the ligand, the reaction temperature, and the desired reaction time.

[0031] According to any embodiment of the present invention, hydroformylation is carried out in the presence of a monodentate or bidentate phosphorus ligand. In particular, the phosphorus ligand may be a bidentate phosphorus ligand. In particular, the monodentate or bidentate phosphorus ligand is [1-[2-(12,14-dioxa-13-phosphapentacyclo[13.8.0.0 2,11.0 3,8 .0 18,23 Not selected from the group consisting of ]tricosa-1(15),2(11),3,5,7,9,16,18,20,22-decaen-13-yloxy)naphthalen-1-yl]naphthalen-2-yl]-diphenylphosphine or diazaphosphorane ligands.

[0032] According to any embodiment of the present invention, hydroformylation is performed using the formula PR 8 This can be done in the presence of 3 monodentate phosphorus ligands, where R 8 C1~C are optionally substituted. 12 The group is, for example, a linear, branched, or cyclic alkyl, alkoxy, or aryloxy group, or a substituted or unsubstituted phenyl, diphenyl, 2-furanyl, naphthyl, or dinaphthyl group, or two R groups. 8 The groups combine to form phosphatrioxa-adamantane, and other R 8 The base has the same meaning as above. More specifically, R 8 This can represent a substituted or unsubstituted phenyl, diphenyl, naphthyl, or di-naphthyl group. Possible substituents are the group R 9 The following are listed regarding these. Preferably, the monodentate phosphorus ligand is triphenylphosphine.

[0033] According to any one of the above embodiments, hydroformylation is performed by the following formula [ka] This can be done in the presence of a bidentate phosphorus ligand, where each R 9 These are C which are replaced separately and optionally. 6~10 Represents an aromatic group or an optionally substituted cyclohexyl group, or two R atoms bonded to the same P atom. 9 Together, they represent 1,1'-biphenyl-2,2'-dioxy which is optionally substituted. Q is, a) The following formula [ka] [In the formula, q is 0 or 1, each T independently represents an oxygen atom or a CH2 group, and each R 10 These are hydrogen atoms or C, independently of each other. 1~8 It represents an alkyl group, where Z is an oxygen atom, a sulfur atom, or C(R 11 )2, Si(R 12 )2, or NR 11 Represents the base, R 11 is a hydrogen atom or R 12 It is a base, R 12 is C 1~4 [representing a linear or branched alkyl group, preferably a methyl group], or b) The following formula for one of the enantiomers [ka] [In the formula, q is 0 or 1, r is 0 or 1, each T independently represents an oxygen atom or a CH2 group, R 13 C is a carbon atom that is optionally substituted with hydrogen atoms, or 1 to 3 halogen atoms or alkoxy groups, independently of each other. 1~4 [Represents alkyl] c) The following formula for one of the enantiomers [ka] [In the formula, R 13 [This has the same meaning as above] The tilde represents the group, and the wavy line indicates the position of the bond between the Q group and the rest of compound (A).

[0034] According to any one of the above embodiments, Q may be the base of formula (i) or (ii).

[0035] According to any one of the above embodiments, each R 9 C is optionally substituted. 6~10 It may be an aromatic group or an optionally substituted cyclohexyl group.

[0036] According to any one of the embodiments described above, "aromatic group or ring" means a phenyl group or a naphthyl group, in particular a phenyl group.

[0037] According to any one of the above embodiments, each R 9 This may be a phenyl group, a cyclohexyl group, a 3,5-dimethylphenyl group, a 3,5-di(CF3)-phenyl group, or a 3,5-dimethyl-4-methoxyphenyl group.

[0038] According to any one of the above embodiments, R 10 It can be a hydrogen atom.

[0039] According to any one of the above embodiments, Z may be a CMe2, SiMe2, NH, or NMe group. In particular, Z may be a CMe2 group.

[0040] According to any one of the above embodiments, R 9 Non-limiting examples of possible substituents include halogen atoms, or C 1~10 One, two, three, or four groups selected from alkoxy, alkyl, alkenyl, pyridyl, or perhalohydrocarbon groups. Two substituents together form C 4~8 They may form a cycloalkyl group. In this specification, the expression “perhalohydrocarbon” has the meaning common in the art, such as a group such as CF3. In particular, the substituents are one or two halogen atoms such as F or Cl, or C 1~4 It is an alkoxy or alkyl group, or a CF3 group.

[0041] According to any one of the above embodiments, the R 9 This can be a non-substitutional case.

[0042] According to any one of the embodiments described above, the ligand of formula (A) may be a racemic mixture or an optically active form.

[0043] Non-limiting examples of bidentate phosphorus ligands include 2,2'-bis((di(1H-pyrrole-1-yl)phosphanyl)oxy)-1,1'-binaphthalene, 1,1'-((naphthalene-2-yloxy)phosphandiyl)bis(1H-pyrrole), 2,2'-bis((di(1H-pyrrole-1-yl)phosphanyl)oxy)-1,1'-biphenyl, (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine), 2,2'-bis((di(1H-pyrrole-1-yl)phosphanyl)oxy)-5,5',6,6',7, 7',8,8'-Octahydro-1,1'-binaphthalene, 1,1',1'',1'''-(((2,7-di-tert-butyl-9,9-dimethyl-9H-xanthene-4,5-diyl)bis(oxy))bis(phosphantriyl))tetrakis(1H-pyrrole), 6,6'-[(3,3'-di-tert-butyl-5,5'-dimethoxy-1,1'-biphenyl-2,2'-diyl)bis(oxy)]bis(dibenzo[d,f][1,3,2]dioxaphosphine), (oxydi-2,1-phenylene)bis(diphenylphosphine), 2,2'-Bis(diphenylphosphinomethyl)-1,1'-biphenyl, 4,6-Bis(diphenylphosphanyl)-10H-phenoxazine, 2-((3,3'-di-tert-butyl-2'-((4,8-di-tert-butyl-2,10-dimethoxydibenzo[d,f][1,3,2]dioxaphosfepin-6-yl)oxy)-5,5'-dimethoxy-[1,1'-biphenyl]-2-yl)oxy)-4H-naphtho[2,3-d][1,3,2]dioxaphosphinin-4-one, 2-((3,3'-di-tert-butyl-2'- ((4,8-di-tert-butyl-2,10-dimethoxydibenzo[d,f][1,3,2]dioxaphosfepin-6-yl)oxy)-5,5'-dimethoxy-[1,1'-biphenyl]-2-yl)oxy)-8-methyl-4H-benzo[d][1,3,2]dioxaphosphinin-4-one, (1S,1'S)-(-)-(2,7-di-tert-butyl-9,9-dimethyl-9H-xanthene-4,5-diyl)bis((1-naphthyl)(phenyl)phosphine), (1S,1'S)-(-)-(2,7-di-tert-butyl-9,9-dimethyl-9H-xanthene-4,5-diyl)bis((4-methylphenyl)(phenyl)phosphine), 8-methyl-2-((3,3',5,5'-tetra-tert-butyl-2'-((2,4,8,10-tetra-tert-butyldibenzo[d,f][1,3,2]dioxaphosfepin-6-yl)oxy)-[1,1'-biphenyl]-2-yl)oxy)-4H-benzo[d][1,3,2]dioxaphosphinin-4-one, 2-((3,3'-di-tert-butyl-2'-((4,8-di-tert-butyl-2,10 -Dimethoxydibenzo[d,f][1,3,2]dioxaphosfepin-6-yl)oxy)-5,5'-dimethoxy-[1,1'-biphenyl]-2-yl)oxy)-8-isopropyl-5-methyl-4H-benzo[d][1,3,2]dioxaphosphinin-4-one, (1S,1'S)-(+)-(9,9-dimethyl-9H-xanthene-4,5-diyl)bis((2-methoxyphenyl)(phenyl)phosphine), (1S,1'S)-(+)-(2,7-di-tert-butyl-9,9-dimethyl-9H-xanthene-4,5-diyl )bis((2-methoxyphenyl)(phenyl)phosphine), (1S,1'S)-(+)-(9,9-dimethyl-9H-xanthene-4,5-diyl)bis((2-methylphenyl)(phenyl)phosphine), (1S,1'S)-(-)-(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(naphthalene-2-yl(phenyl)phosphine), (1S,1'S)-(-)-(9,9-dimethyl-9H-xanthene-4,5-diyl)bis((4-methoxyphenyl)(phenyl)phosphine), (1S,1'S)-(-)-(2, 7-di-tert-butyl-9,9-dimethyl-9H-xanthene-4,5-diyl)bis((2-naphthyl)(phenyl)phosphine), (1S,1'S)-(-)-(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(naphthalene-1-yl(phenyl)phosphine), (1S,1'S)-(+)-(2,7-di-tert-butyl-9,9-dimethyl-9H-xanthene-4,5-diyl)bis((2-isopropoxyphenyl)(phenyl)phosphine), (1S,1'S)-(+)-(2,7-di-tert-butyl-9,Examples include 9-dimethyl-9H-xanthene-4,5-diyl)bis((2-isopropylphenyl)(phenyl)phosphine) or (1S,1'S)-(-)-(2,7-di-tert-butyl-9,9-dimethyl-9H-xanthene-4,5-diyl)bis((dibenzo[b,d]-furan-4-yl)(phenyl)phosphine), (2,7-di-tert-butyl-9,9-dimethyl-9H-xanthene-4,5-diyl)bis((4-methoxyphenyl)(phenyl)phosphine), and (4,4',6,6'-tetramethoxybiphenyl-2,2'-diyl)bis{bis[3,5-bis(trifluoromethyl)phenyl]phosphine}.

[0044] In particular, the ligands are (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine), 1,1',1'',1'''-(((2,7-di-tert-butyl-9,9-dimethyl-9H-xanthene-4,5-diyl)bis(oxy))bis(phosphantriyl))tetrakis(1H-pyrrole), 6,6'-[(3,3'-di-tert-butyl-5,5'-dimethoxy-1,1'-biphenyl-2,2'-diyl)bis(oxy)]bis (Dibenzo[d,f][1,3,2]dioxaphosfepine), (oxydi-2,1-phenylene)bis(diphenylphosphine), 2,2'-bis(diphenylphosphinomethyl)-1,1'-biphenyl, 4,6-bis(diphenylphosphanyl)-10H-phenoxazine, 2-((3,3'-di-tert-butyl-2'-((4,8-di-tert-butyl-2,10-dimethoxydibenzo[d,f][1,3,2]dioxaphosfepine-6-yl) Xy)-5,5'-dimethoxy-[1,1'-biphenyl]-2-yl)oxy)-4H-naphtho[2,3-d][1,3,2]dioxaphosphinin-4-one, 2-((3,3'-di-tert-butyl-2'-((4,8-di-tert-butyl-2,10-dimethoxydibenzo[d,f][1,3,2]dioxaphosfepin-6-yl)oxy)-5,5'-dimethoxy-[1,1'-biphenyl]-2-yl)oxy)-8-methyl-4H-benzo[d [1,3,2]dioxaphosphinin-4-one, (1S,1'S)-(-)-(2,7-di-tert-butyl-9,9-dimethyl-9H-xanthene-4,5-diyl)bis((1-naphthyl)(phenyl)phosphine) or (1S,1'S)-(-)-(2,7-di-tert-butyl-9,9-dimethyl-9H-xanthene-4,5-diyl)bis((4-methylphenyl)(phenyl)phosphine) are bidentate phosphorus ligands that can be selected from the group consisting of [1,3,2]dioxaphosphinin-4-one, (1S,1'S)-(-)-(2,7-di-tert-butyl-9,9-dimethyl-9H-xanthene-4,5-diyl)bis((4-methylphenyl)(phenyl)phosphine).

[0045] Phosphorus ligands can be added to the reaction medium of the method of the present invention at a wide range of concentrations. Non-limiting examples include phosphorus ligand concentrations ranging from about 0.001 mol% to about 50 mol% relative to the amount of substrate, preferably 0.005 mol% to about 50 mol%, and more preferably about 0.005 mol% to about 15 mol% relative to the amount of substrate. The optimal concentration of phosphorus ligand depends, as will be recognized by those skilled in the art, on the properties of the latter, the properties of the substrate, the properties of the metal complex, the reaction temperature, and the desired reaction time.

[0046] According to any one of the embodiments described above, carbon monoxide and hydrogen gas can be generated in situ from, for example, methyl formate, formic acid, or formaldehyde by methods known to those skilled in the art. The CO / H2 gas volume ratio is in the range of 2 / 1 to 1 / 5, preferably 1 / 1 to 1 / 5, or preferably 2 / 1 to 1 / 2, preferably 1.5 / 1 to 1 / 1.5, and more preferably 1 / 1.

[0047] The reaction can be carried out in or without a solvent. Where a solvent is required or used for practical reasons, any solvent stream of such reaction type can be used for the purposes of the present invention. A non-limiting example is C 6~12 Examples of solvents include aromatic solvents such as toluene, 1,3-diisopropylbenzene, cumene, or pseudocumene, or mixtures thereof; alcoholic solvents such as methanol, ethanol, 2-methylbutan-2-ol, or mixtures thereof; hydrocarbon solvents such as cyclohexane, heptane, or mixtures thereof; esteric solvents such as n-butyl acetate, isopropyl acetate, or ethyl acetate; or etheric solvents such as methyltetrahydrofuran, tetrahydrofuran, or mixtures thereof. The choice of solvent depends on the properties of the substrate and / or catalyst, and those skilled in the art can adequately select the most suitable solvent in each case to optimize the reaction.

[0048] The hydroformylation reaction can be carried out at temperatures ranging from 50°C to 150°C, more preferably from 80°C to 130°C, and even further from 90°C to 110°C. Of course, those skilled in the art can also select a preferred temperature depending on the melting and boiling points of the starting and final products, as well as the desired duration of the reaction or transformation.

[0049] Hydroformylation can be carried out at a CO / H2 pressure in the range of 1 bar to 50 bar, preferably 10 bar to 50 bar, and more preferably 25 bar to 35 bar. Naturally, those skilled in the art can adjust the pressure sufficiently according to the amount of catalyst added and the dilution of the substrate in the solvent.

[0050] According to any embodiment of the present invention, the aldehyde group of the compound of formula (III) can be protected before the removal step, or the removal step can be performed directly on the compound of formula (III) to give the compound of formula (I). When the elimination step is performed on the compound of formula (III), the elimination is carried out under acidic conditions or under thermal decomposition. The acid is pTsOH, MsOH, TfOH, H2SO4, H3PO4, KHSO4, NaHSO4, oxalic acid, formic acid, BF3·Et2O, BF3·AcOH, Alox acid (Axsorb A selection can be made from the group consisting of A2-5 (Al2O3504C), Amberlyst15, SiO2, TFA, Wayphos, polyphosphate, zeolite (CBV21A, CBV780, and CP814E sold by Zeolist), boric acid, Al2(SO4)3, CSA, pyridinium p-toluenesulfonate, ZnBr2, K10-S300 (bentonite) sold by Clariant, F24X (bentonite) sold by Clariant, Siral® 40HPV sold by Sasol, HCl, HBr, Zn(SO4)2, ZnCl2, MgI2, and mixtures thereof. Pyrolysis can be carried out at temperatures within the range of 300°C to 600°C.

[0051] Elimination reactions on aldehyde substrates can be carried out in or without a solvent. Where a solvent is required or used for practical reasons, any solvent stream of such reaction type can be used for the purposes of the present invention. A non-limiting example is C 6~12 Examples of solvents include aromatic solvents such as toluene, xylene, 1,3-diisopropylbenzene, cumene, or pseudocumene, or mixtures thereof; chlorinated solvents such as dichloromethane, dichloroethane, or mixtures thereof; and hydrocarbon solvents such as cyclohexane or heptane. The choice of solvent depends on the properties of the substrate and / or catalyst, and those skilled in the art can adequately select the most suitable solvent in each case to optimize the reaction.

[0052] The elimination process on an aldehyde substrate under acidic conditions can be carried out at temperatures within the range of 20°C to 110°C. Of course, those skilled in the art can also select a preferred temperature depending on the melting and boiling points of the starting and final products, as well as the desired duration of the reaction or transformation.

[0053] According to any embodiment of the present invention, the method is a) Hydroformyating the compound of formula (II) to obtain one of the stereoisomers or a mixture thereof in the form of the following formula [ka] [where X, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 This has the same meaning as defined above. The process of obtaining the compound, b) The aldehyde group of the compound of formula (III) obtained in step a) is converted into one of the stereoisomers or a mixture thereof in the form of the following formula [ka] [where X, R1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 have the same meanings as defined above, and R a and R b each independently represent a C 1~4 alkyl group, or R a and R b together represent a C 2~6 alkanediyl group] protecting in the form of an acetal, c) eliminating the OX group from the compound of formula (IV), followed by obtaining the following formula in the form of any one of stereoisomers or a mixture thereof

Chemical Formula

[0054] The term "alkanediyl" is understood to include branched and straight-chain alkanediyl groups.

[0055] According to any embodiment of the present invention, R a and R b together can represent a C 2~6 alkanediyl group. In particular, R a and R b together can represent a C 2~4 alkanediyl group. Even more specifically, R a and R b together form (CH2)n represents a group, and n in the formula may be 2 or 3. Preferably, n may be 2.

[0056] According to any embodiment of the present invention, protection of the aldehyde group in the acetal form of formula (IV) of the compound of formula (III) obtained in step a) can be carried out under conventional conditions known to those skilled in the art. That is, C orthoformate 1~4 trialkyl, C 1~4 alcohol, and C 2~6 diol can be used for the reaction in the presence of an acid. Specific non-limiting examples of the acid can be selected from the group consisting of H2SO4, KHSO4, NaHSO4, H3PO4, NaHSO4, Amberlyst 15, pTsOH, MsOH, TfOH, CSA, oxalic acid, formic acid, TFA, BF3·Et2O, BF3·AcOH, HBF4, wayphos, SiO2, pyridinium p-toluenesulfonate, zeolite, Al2(SO4)3, F24X (bentonite), boric acid, and mixtures thereof.

[0057] C orthoformate 1~4 trialkyl, C 1~4 alcohol, and C 2~6 specific non-limiting examples of the diol can be selected from the group consisting of trimethyl orthoformate, triethyl orthoformate, methanol, ethanol, ethylene glycol, 1,2-butanediol, 2,3-butanediol, 2,3-dimethyl-3-hydroxy-2-butanol, diglycerol, trans-1,2-cyclohexanediol, neopentyl glycol, 1,3-propanediol, 2-methyl-2-propyl-1,3-propanediol, 1,2-propanediol, 2-methyl-1,2-propanediol, and 2,2-dimethyl-1,3-propanediol. In particular, acetal formation is carried out using C 2~6 diol, particularly ethylene glycol.

[0058] C orthoformate 1~4 trialkyl, C 1~4 alcohol, or C 2~6Diols can be added to the reaction medium of the method of the present invention at a wide range of concentrations. As a non-limiting example, orthoformic acid C can be added in an amount ranging from about 1 to about 2 equivalents relative to the amount of substrate. 1~4 Trialkyl or C 2~5 The concentration values ​​of the diol can be given. As a non-limiting example, C in the range of approximately 2 to 4 equivalents relative to the amount of substrate. 1~4 The alcohol concentration can be increased. C orthoformate 1~4 Trialkyl, C 1~4 Alcohol, or C 2~6 The optimal concentration of the diol depends, as those skilled in the art will recognize, on the properties of the latter, the properties of the substrate, the reaction temperature, and the desired reaction time.

[0059] The acid used in the step of protecting the aldehyde group of formula (III) in the form of an acetal can be added to the reaction medium of the method of the present invention at a wide range of concentrations. Non-limiting examples include acid concentrations ranging from about 0.1 to about 5 mol% relative to the amount of substrate. The optimal concentration of the acid depends, as will be recognized by those skilled in the art, on the properties of the latter, the properties of the substrate, the reaction temperature, and the desired reaction time.

[0060] According to any one embodiment of the present invention, the method of the present invention for forming the compound of formula (IV) is carried out at a temperature within the range of 25°C to 120°C. In particular, the temperature is in the range of 50°C to 110°C. Of course, those skilled in the art may also select a preferred temperature depending on the melting and boiling points of the starting and final products, as well as the desired time for the reaction or transformation.

[0061] Acetal formation can be carried out in or without a solvent. Where a solvent is required or used for practical reasons, any solvent stream of such reaction type can be used for the purposes of the present invention. A non-limiting example is C 6~12Aromatic solvents include, for example, xylene, toluene, 1,3-diisopropylbenzene, cumene or pseudocumene, or mixtures thereof; hydrocarbon solvents include, for example, cyclohexane, heptane, or mixtures thereof. The choice of solvent depends on the properties of the substrate and / or catalyst, and those skilled in the art can adequately select the most suitable solvent in each case to optimize the reaction.

[0062] According to any embodiment of the present invention, the elimination of the OX group of the compound of formula (IV) and subsequent isomerization to the compound of formula (V) can be carried out under ordinary conditions known to those skilled in the art, i.e., for example, thermal decomposition followed by acidic conditions, or isomerization in the presence of a metal catalyst in elemental form or a supported metal catalyst, such as a rhodium, ruthenium, iridium, platinum, or palladium complex. Elimination can form an exosomer (double bond in the alkyl chain), an endoisomer (double bond in the ring - the target compound), or a mixture thereof. Isomerization can convert the exosomer to an endoisomer. In particular, the elimination and isomerization may be a one-pot process carried out in the presence of an acid. The acid may be a Lewis acid or a Brønsted acid. Specific and non-limiting examples of acids include p-TsOH, MsOH, TfOH, H2SO4, H3PO4, KHSO4, NaHSO4, oxalic acid, formic acid, BF3·Et2O, BF3·AcOH, and Alox acid (Axsorb). The following substances can be selected from the group consisting of A2-5 (Al2O3504C), Amberlyst15, SiO2, TFA, Wayphos, polyphosphate, zeolite (CBV21A, CBV780, and CP814E sold by Zeolist), boric acid, Al2(SO4)3, CSA, pyridinium p-toluenesulfonate, ZnBr2, K10-S300 (bentonite) and F24X (bentonite) sold by Clariant, Siral® 40HPV sold by Sasol, HCl, HBr, Zn(SO4)2, ZnCl2, MgI2, and mixtures thereof.

[0063] The acid used in the one-pot elimination / isomerization reaction can be added to the reaction medium of the method of the present invention at a wide range of concentrations. Non-limiting examples include acid concentrations ranging from about 1 mol% to about 20 mol% relative to the amount of substrate, preferably 2 mol% to about 10 mol%, and preferably about 3 mol% to about 6 mol% relative to the amount of substrate. The optimal acid concentration depends, as will be recognized by those skilled in the art, on the properties of the latter, the properties of the substrate, the reaction temperature, and the desired reaction time.

[0064] According to any one embodiment of the present invention, the method of the present invention for forming the compound of formula (V) is carried out at a temperature ranging from room temperature to 160°C. In particular, the temperature is in the range of 90°C to 140°C. Of course, those skilled in the art may also select a preferred temperature depending on the melting and boiling points of the starting and final products, as well as the desired time for the reaction or transformation.

[0065] One-pot elimination / isomerization reactions can be carried out in or without a solvent. Where a solvent is required or used for practical reasons, any solvent stream of such reaction type can be used for the purposes of the present invention. A non-limiting example is C 6~12 Examples of solvents include aromatic solvents such as xylene, toluene, 1,3-diisopropylbenzene, cumene or pseudocumene, or mixtures thereof; hydrocarbon solvents such as cyclohexane, heptane, or mixtures thereof; and ester or ether solvents such as butyl acetate, diisopropyl ether, dioxane, dimethoxyethane, or mixtures thereof. The choice of solvent depends on the properties of the substrate and / or catalyst, and those skilled in the art can adequately select the most suitable solvent in each case to optimize the reaction.

[0066] According to certain embodiments, the protection, elimination, and isomerization reactions can be carried out in a one-pot process.

[0067] According to any embodiment of the present invention, the deprotection of the acetal group to obtain the compound of formula (I) can be carried out under ordinary conditions known to those skilled in the art, i.e., using a large molar excess of carboxylic acid in water. Specific and non-limiting examples of carboxylic acids can be selected from the group consisting of acetic acid, propionic acid, citric acid, formic acid, TFA, oxalic acid, or mixtures thereof.

[0068] The carboxylic acid used for deprotection can be added to the reaction medium of the method of the present invention at a wide range of concentrations. Non-limiting examples include acid concentrations ranging from about 5 to about 20 equivalents relative to the amount of substrate, preferably 5 to about 10 equivalents relative to the amount of substrate. The optimal concentration of the acid depends, as those skilled in the art will recognize, on the properties of the latter, the properties of the substrate, the reaction temperature, and the desired reaction time.

[0069] According to any one embodiment of the present invention, deprotection for forming the compound of formula (I) can be carried out at a temperature within the range of 40°C to 120°C. In particular, the temperature is in the range of 70°C to 90°C. Of course, those skilled in the art can also select a preferred temperature depending on the melting and boiling points of the starting and final products, as well as the desired time for the reaction or transformation.

[0070] According to any one embodiment of the present invention, deprotection for forming the compound of formula (I) can be carried out in or without a solvent. Where a solvent is required or used for practical reasons, any solvent stream of such reaction type can be used for the purposes of the present invention. A non-limiting example is C 6~12Examples of solvents include aromatic solvents such as toluene, xylene, 1,3-diisopropylbenzene, cumene, or pseudocumene, or mixtures thereof; alcoholic solvents such as methanol, ethanol, 2-methylbutan-2-ol, or mixtures thereof; hydrocarbon solvents such as cyclohexane, heptane, or mixtures thereof; esteric solvents such as n-butyl acetate, isopropyl acetate, or ethyl acetate; or etheric solvents such as methyltetrahydrofuran, tetrahydrofuran, or mixtures thereof. The choice of solvent depends on the properties of the substrate and carboxylic acid derivative, and those skilled in the art can adequately select the most suitable solvent in each case to optimize the reaction.

[0071] According to certain embodiments, protection, elimination, isomerization, and deprotection reactions can be performed in a one-pot process.

[0072] According to a particular embodiment of the present invention, the method of the present invention comprises an elimination step starting with a compound of formula (II) and subsequent hydroformylation. The method of the present invention is a) Formula (II'') of one of the stereoisomers or a mixture thereof. [ka] [In the formula, X' is a hydrogen atom, C 1~3 Alkyl alkyl group, C 2~3 It is an alkenyl group, a benzyl group, or a C(O)R group, or a Si(R')3 group, where R is a hydrogen atom, C 1~4 Alkyl alkyl group, C 1~4 An alkoxy group or a phenyl group, where R' is independently C 1~4 It is an alkyl group, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 [It has the meaning as defined.] The OX' group of the compound is removed to obtain one of the stereoisomers or a mixture thereof in the form of the following formula

Chem.

[0073] The conditions for elimination and hydroformylation are the same as those described above. When X' is a hydrogen atom, the elimination of the OX' group from the compound of formula (II') can also be carried out in the presence of phosphoryl chloride and an amine such as pyridine, or in the presence of mesyl chloride and triethylamine.

[0074] The process of the present invention for preparing the compound of formula (I) can be carried out under batch and / or continuous conditions. In particular, the elimination step can be carried out under continuous conditions.

[0075] The compounds of formula (II), (III), (IV), and (V') are generally novel compounds and exhibit numerous advantages, as explained above and as shown in the examples.

[0076] Accordingly, another object of the present invention is a compound of the following formula in the form of any one of stereoisomers or a mixture thereof

Chem.

[0077] Another subject of the present invention is the following formula in the form of one or a mixture thereof of stereoisomers. [ka] [In the formula, X' is a hydrogen atom, C 1~3 Alkyl alkyl group, C 2~3 It is an alkenyl group, a benzyl group, a C(O)R group, or a Si(R')3 group, where R is a hydrogen atom, C 1~4 Alkyl alkyl group, C 1~4 An alkoxy group or a phenyl group, where R' is independently C 1~4 It is an alkyl group, and each R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 These are, independently of each other, a hydrogen atom, or hydroxyl or C, respectively. 1~3 C is optionally substituted with an alkoxy group. 1~6 Alkyl or C 2~6 Represents an alkenyl group, or R 1 , R 2 , R3 , R 4 , R 5 , R 6 , and R 7 Two of the groups combine to form C 3~8 Cycloalkyl or C 5~8 It forms a cycloalkenyl group, and the other groups have the same meaning as defined above, R a and R b C is independent of each other. 1~4 Represents an alkyl group, or R a and R b together become C 2~6 [Represents an alkanediyl group] The compounds are as follows, but excluding 1-(2-(1,3-dioxolan-2-yl)ethyl)-4-isobutyl-2-methylcyclohexane-1-ol, 1-(2-(1,3-dioxolan-2-yl)ethyl)-4-(tert-butyl)-2-methylcyclohexane-1-ol, 1-(2-(1,3-dioxolan-2-yl)ethyl)-4-isopropyl-2-methylcyclohexane-1-ol, 1-(3,3-diethoxypropyl)cyclohexane-1-ol, 1-(2-(1,3-dioxolan-2-yl)ethyl)-4-(tert-butyl)cyclohexane-1-ol, and 1-(2-(1,3-dioxane-2-yl)ethyl)-4-(tert-butyl)cyclohexane-1-ol. In particular, the compounds of formula (IV') are in the form of one or a mixture thereof of the following formulas. [ka] [In the formula, X represents a C(O)R group or a Si(R')3 group, and R is a hydrogen atom, C 1~4 Alkyl alkyl group, C 1~4 An alkoxy group or a phenyl group, where R' is independently C 1~4 It is an alkyl group, and each R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 These are, independently of each other, a hydrogen atom, or hydroxyl or C, respectively.1~3 C is optionally substituted with an alkoxy group. 1~6 Alkyl or C 2~6 Represents an alkenyl group, or R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 Two of the groups combine to form C 3~8 Cycloalkyl or C 5~8 It forms a cycloalkenyl group, and the other groups have the same meaning as defined above, R a and R b C is independent of each other. 1~4 Represents an alkyl group, or R a and R b together C 2~6 [Represents an alkanediyl group] It is a compound of [the compound].

[0078] Another subject of the present invention is the following formula in the form of one or a mixture thereof of stereoisomers. [ka] [In the formula, each R 1 and R 2 These are, independently of each other, hydrogen atoms, hydroxyl or C, respectively. 1~3 C is optionally substituted with an alkoxy group. 1~6 Alkyl or C 2~6 Represents an alkenyl group, R a and R b C is independent of each other. 1~4 Represents an alkyl group, or R a and R b together C 2~6 [Represents an alkanediyl group] It is a compound of [the compound].

[0079] Another subject of the present invention is the following formula in the form of one or a mixture thereof of stereoisomers. [ka] [In the formula, X represents a C(O)R group or a Si(R')3 group, and R is a hydrogen atom, C 1~4 Alkyl alkyl group, C 1~4 An alkoxy group or a phenyl group, where R' is independently C 1~4 It is an alkyl group, and each R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 These are, independently of each other, a hydrogen atom, or hydroxyl or C, respectively. 1~3 C is optionally substituted with an alkoxy group. 1~6 Alkyl or C 2~6 Represents an alkenyl group, or R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 Two of the groups combine to form C 3~8 Cycloalkyl or C 5~8 It forms a cycloalkenyl group, and the other groups have the same meaning as defined above. A method for producing the compound, Formula (VII) of one of the stereoisomers or a mixture thereof [ka] [In the formula, X'' is a hydrogen atom, a C(O)R group, or a Si(R')3 group, and R is a hydrogen atom, C 1~4 Alkyl alkyl group, C 1~4 An alkoxy group or a phenyl group, where R' is independently C 1~4 It is an alkyl group, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 [It has the meaning as defined.] The method includes a step of reducing the compound.

[0080] According to a particular embodiment, the method of the present invention is a) Formula (VII') of one of the stereoisomers or a mixture thereof. [ka] [In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 [This has the same meaning as defined above] The compound is expressed in the form of one of its stereoisomers or a mixture thereof, as shown in the following formula. [ka] [In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 [This has the same meaning as defined above] A process of reducing to a compound, and b) A step to protect compound (II''') in order to obtain the compound of formula (II), Includes.

[0081] According to another specific embodiment, the method of the present invention is a) Formula (VII') of one of the stereoisomers or a mixture thereof. [ka] [In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 [This has the same meaning as defined above] The compound is expressed in the form of one of its stereoisomers or a mixture thereof, as shown in the following formula. [ka] [In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 The above definition has the same meaning, where X is a C(O)R group or a Si(R')3 group, and R is a hydrogen atom, C 1~4 Alkyl alkyl group, C 1~4 An alkoxy group or a phenyl group, where R' is independently C 1~4 It is an alkyl group. A process of protecting the compound, and b) A step of reducing compound (VII'') to obtain the compound of formula (II), Includes.

[0082] For the sake of clarity, the statement "the dotted lines in the formula represent double or triple bonds" or similar expressions is intended to be understood in the ordinary sense by those skilled in the art, namely that the entire bond between carbon atoms connected by the dotted lines (solid and dotted lines) is a carbon-carbon double bond or a carbon-carbon triple bond.

[0083] According to any embodiment of the present invention, reduction is hydrogenation. In particular, hydrogenation can be carried out in the presence of a heterogeneous catalyst such as palladium in elemental metallic form. In particular, the palladium can be supported on a support material. For clarity, a support material means a material on which such a metal can be deposited and which is inert to the hydrogen source and the substrate. Supported palladium is a known compound and is commercially available. Those skilled in the art can select the method of deposition on the support material in terms of the proportion of metal on the support material, in terms of form (powder, granules, pellets, extruded material, mousse, etc.), and in terms of the surface area of ​​the support. In particular, the heterogeneous catalyst may be a Lindler catalyst, palladium on carbon powder (known as Nanoselect® LF100, supplied by BASF), or palladium on titanium silicate powder (known as Nanoselect® LF200, supplied by BASF). Hydrogenation can be carried out under ordinary conditions known to those skilled in the art, which allow for the setting of the best conditions for converting a compound of formula (VII') to a compound of formula (II''') or a compound of formula (VII'') to a compound of formula (II).

[0084] The reduction can be carried out in the presence of additives such as 3,6-dithia-1,8-octanediol.

[0085] Palladium can be added to the reaction medium of the method of the present invention at a wide range of concentrations. Non-limiting examples include palladium concentrations ranging from about 0.005 mol% to about 10 mol% relative to the amount of substrate, preferably 0.01 mol% to about 1 mol%, preferably about 0.01 mol% to about 0.2 mol%, and preferably about 0.03 mol% to about 0.1 mol% relative to the amount of substrate. The optimal concentration of palladium depends, as will be recognized by those skilled in the art, on the properties of the latter, the properties of the substrate, the properties of the catalyst, the reaction temperature, and the desired reaction time.

[0086] Additives such as 3,6-dithia-1,8-octanediol can be added to the reaction medium of the method of the present invention at a wide range of concentrations. Non-limiting examples include additive concentrations of about 1 mol% to 50 mol% relative to the amount of palladium, preferably 5 mol% to 50 mol%, preferably 5 mol% to 40 mol%, and preferably 5 mol% to 25 mol% relative to the amount of palladium. The optimal concentration of the additive depends, as will be recognized by those skilled in the art, on the properties of the latter, the properties of the substrate, the properties of the catalyst, the reaction temperature, and the desired reaction time.

[0087] Hydrogenation is 10 4 Pa~3×10 5 This can be carried out at H2 pressures contained in Pa (0.1~3 bar). In particular, hydrogenation is 3 × 10 4 Pa~10 5 This can be carried out at an H2 pressure contained in Pa (0.3 to 1 bar). Here again, those skilled in the art can adequately adjust the pressure according to the amount of catalyst added.

[0088] According to any one embodiment of the present invention, hydrogenation is carried out at a temperature within the range of 10°C to 50°C. In particular, the temperature is in the range of 20°C to 35°C. Of course, those skilled in the art may also select a preferred temperature depending on the melting and boiling points of the starting and final products, as well as the desired time for the reaction or transformation.

[0089] Hydrogenation can be carried out in or without a solvent. Where a solvent is required or used for practical reasons, any solvent stream of such reaction type can be used for the purposes of the present invention. A non-limiting example is C 6~12Examples of solvents include aromatic solvents such as xylene, toluene, 1,3-diisopropylbenzene, cumene or pseudocumene, or mixtures thereof; hydrocarbon solvents such as cyclohexane, heptane, or mixtures thereof; alcoholic solvents such as methanol, ethanol, 2-methylbutan-2-ol, or mixtures thereof; ketone solvents such as acetone, acetophenone, butanone, cyclopentanone, or mixtures thereof; etheric solvents such as diethyl ether, tert-butyl methyl ether, tetrahydrofuran, methyltetrahydrofuran, or mixtures thereof; and esteric solvents such as ethyl acetate, isopropyl acetate, or mixtures thereof. The choice of solvent depends on the properties of the substrate and / or catalyst, and those skilled in the art can adequately select the most suitable solvent in each case to optimize the reaction.

[0090] According to any embodiment of the present invention, the protection step may depend on the properties of the X group. Those skilled in the art are familiar with the conditions applied to protect alcohols in the form of esters where X is C(O)R, or in the form of silanes where X is a Si(R')3 group. Typical conditions can be found in the extensive literature in the field of organic chemistry, such as Protective Groups in Organic Synthesis, 3rd Edition. Theodora W. Green (The Rowland Institute for Science) and Peter GM Wuts (Pharmacia and Upjohn Company). John Wiley & Sons, Inc., New York, NY. 1999. xxi + 779 pp. 15.5 × 23 cm. ISBN 0-471-16019-9.

[0091] According to any embodiment of the present invention, the compound of formula (VII') is in the form of one or a mixture thereof of the stereoisomers of formula (VIII) [ka] [In the formula, each R1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 These are, independently of each other, a hydrogen atom, or hydroxyl or C, respectively. 1~3 C is optionally substituted with an alkoxy group. 1~6 Alkyl or C 2~6 Represents an alkenyl group, or R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 Two of the groups combine to form C 3~8 Cycloalkyl or C 5~8 It forms a cycloalkenyl group, and the other groups have the same meaning as defined above. It can be produced by the ethynylation reaction of the ketone. Those skilled in the art are well aware of the conditions to apply to obtain compound (VII') starting from compound (VIII). Many reactions of this type have been reported in the prior art. Therefore, those skilled in the art can set the best conditions for converting the compound of formula (VIII) to the compound of formula (VII'). As a non-limiting example, the reaction can be carried out under the conditions reported in Angewandte Chemie, International Edition, 2020, 1666-1673, International Publication No. 2009126584, or International Publication No. 2014056851.

[0092] Another subject of the present invention is the following formula in the form of one or a mixture thereof of stereoisomers. [ka] [In the formula, the dotted line represents a double or triple bond, X represents a C(O)R group or Si(R')3 group, R is a hydrogen atom, C 1~4 Alkyl alkyl group, C 1~4 An alkoxy group or a phenyl group, where R' is independently C 1~4It is an alkyl group, and each R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 These are, independently of each other, a hydrogen atom, or hydroxyl or C, respectively. 1~3 C is optionally substituted with an alkoxy group. 1~6 Alkyl or C 2~6 Represents an alkenyl group, or R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 Two of the groups combine to form C 3~8 Cycloalkyl or C 5~8 It forms a cycloalkenyl group, and the other groups have the same meaning as defined above. The compounds are as follows, but excluding 1-vinylcyclohexyl acetate, 1-ethynylcyclohexyl acetate, 1-vinylcyclohexyl propionate, 4-methyl-1-vinylcyclohexyl acetate, 2-methyl-1-vinylcyclohexyl acetate, 1-ethynyl-2-methylcyclohexyl acetate, 2-ethyl-1-vinylcyclohexyl acetate, 2-isopropyl-1-vinylcyclohexyl acetate, 2-sec-butyl-1-vinylcyclohexyl acetate, 2-isopropyl-5-methyl-1-vinylcyclohexyl acetate, 2-allyl-1-vinylcyclohexyl acetate, 4-tert-butyl-1-vinylcyclohexyl acetate, 1-vinyldecahydronaphthalene-1-yl acetate, and 1-ethynyldecahydronaphthalene-1-yl acetate.

[0093] In this specification, the following formulas are used to describe the form of one or a mixture thereof of stereoisomers. [ka] [In the formula, each R 2 ' is C 1~4 [Represents an alkyl group] A method for producing the compound, Formula (XI) of one of the stereoisomers or a mixture thereof [ka] [In the formula, R 2 The ' has the same meaning as defined in formula (X), where X represents a C(O)R group or a Si(R')3 group, and R is a hydrogen atom, C 1~4 Alkyl alkyl group, C 1~4 An alkoxy group or a phenyl group, where R' is independently C 1~4 It is an alkyl group. A method is disclosed that includes a hydroformylation and elimination step starting from a compound.

[0094] The method for producing compound (X) is carried out according to the same embodiments as the method for preparing the compound of formula (I), except for the compound itself.

[0095] A typical method for carrying out the method of the present invention is reported in the following examples.

[0096] Examples The present invention will be described in more detail below by the following examples. In these examples, abbreviations have their usual meanings in the art, and temperatures are given in degrees Celsius (°C). The pre-catalyst and ligand solutions were prepared in an inert atmosphere (argon) using standard Schlenk techniques. The solvents were dried by conventional procedures and distilled in an argon atmosphere. NMR spectra were recorded at 20°C using a Bruker AV300, AV400, or AV 500 MHz spectrometer. Chemical shifts were measured against the solvent signal (chloroform, δ). H =7.26 ppm, δ C It is reported in ppm relative to (=77.0 ppm). 1 H, 1 H-COSY, -NOESY, 13 C, 1Signal assignment was confirmed by recording H-HSQC and -HMBC experiments. Gas chromatography was performed on an Agilent 7890A series with an HP5 column (30 m × 0.25 mm inner diameter, 0.25 μm film thickness), using tetradecane as the internal standard.

[0097] Example 1 Production of 4,4-dimethyl-1-vinylcyclohexyl acetate by hydrogenation and subsequent esterification. a) Step 1: Production of 1-vinyl-4,4-dimethylcyclohexanol In a 100 mL or 1 L autoclave equipped with a mechanical stirrer, pressure and internal temperature sensors, and a heating / cooling system for internal temperature control, 1-ethynyl-4,4-dimethylcyclohexanol (CAS No.: 68483-62-5), acetone (100 wt%), Lindler catalyst (0.5 wt%, 0.036 mol% Pd), and 3,6-dithia-1,8-octanediol (Lindler catalyst poison, CAS No.: 5244-34-8) (0.005 wt%, 12 mol% relative to Pd) were placed together. The sealed autoclave was then purged with nitrogen while stirring (three times at 5 bar), and the mixture was stirred at 25°C for 30 minutes under a nitrogen pressure of 1 bar. After this period, the autoclave was purged with hydrogen while stirring (three times at 1 bar), and then pressurized to a hydrogen pressure of 1 bar using a hydrogen tank equipped with an outlet pressure regulator and an internal pressure sensor to track and determine hydrogen consumption. The reaction mixture was then stirred at 25°C (1000 rpm) under a hydrogen pressure of 1 bar, maintaining the pressure at this value throughout the reaction. Immediately after the completion of alkyne hydrogenation (2-3 hours), which was also determined by GC analysis on a short polar column (DB-Wax 10m × 0.1mm × 0.1μm), stirring was stopped, the autoclave was depressurized, and purged with nitrogen (three times at 5 bar). The reaction mixture was passed through several filters to remove the Lindler catalyst and transferred to a round-bottom flask to remove the solvent under vacuum. The target 1-vinyl-4,4-dimethylcyclohexanol was obtained with a GC purity of 93-95%, a GC conversion rate exceeding 99.5%, and no residue formation (determined by valve-to-valve distillation of the sample).

[0098] [ka]

[0099] b) Step 2: Production of 4,4-dimethyl-1-vinylcyclohexyl acetate To a stirred solution of 4,4-dimethyl-1-vinylcyclohexanol (13.6 g, 96% purity, 84.8 mmol) and acetic anhydride (26.77 g, 254.3 mmol) in toluene (30 mL), DMAP (104 mg, 0.85 mmol, 1 mol%) and triethylamine (8.6 g, 84.8 mmol) were added under N2 conditions. The mixture was heated to 90°C. After 5 hours, DMAP (104 mg, 0.85 mmol, 1 mol%) was added, and the mixture was stirred for a further 5 hours. The mixture was cooled in a cold water bath (10°C), and 30 mL of water was slowly added (hydrolysis of residual Ac2O). After stirring for 30 minutes, 50 mL of diethyl ether was added. The phases were separated, and the organic phase was washed once with 40 mL of 1 M aqueous HCl, then once with 50 mL of water, and then twice with 50 mL of saturated aqueous NaHCO3. Finally, after washing with brine, the organic phase was dried over sodium sulfate, filtered, and removed by vacuum distillation (45°C, 30 mbar). The crude product was purified by flash chromatography (elution of 330 g of SiO2 with cyclohexane 95 / diisopropyl ether 5 and cyclohexane 9 / AcOEt1). 4,4-dimethyl-1-vinylcyclohexyl acetate was isolated as a colorless liquid (volatile) (14.93 g, purity 97%, 78.4 mmol, yield 92.5%).

[0100] [ka]

[0101] Example 2 Production of 4,4-dimethyl-1-vinylcyclohexyl acetate by esterification and subsequent hydrogenation a) Step 1: Preparation of 1-ethynyl-4,4-dimethylcyclohexyl acetate In a round-bottom flask equipped with a magnetic stirrer and an internal temperature sensor, 1-ethynyl-4,4-dimethylcyclohexanol (CAS No.: 68483-62-5), acetonitrile (100 wt%), and acetic anhydride (1.3 equivalents) were placed together. The reaction mixture was cooled to 3°C, and solid iron(III) toluenesulfonate hexahydrate (CAS No.: 312619-41-3) (2 mol%) was added in small amounts to maintain the temperature below 10°C. The reaction was tracked by GC analysis on a short nonpolar column (DB-1, 10 m × 0.1 mm × 0.1 μm), and complete conversion was achieved in 3 hours under these conditions. The crude product was obtained with a GC selectivity of 98%. The reaction mixture was heated to room temperature, and lighter compounds were removed under vacuum. Et2O (160 wt%) was added to the concentrated crude product, and the solution was washed with 10% Na2CO3 aqueous solution, water, 1% H2SO4 aqueous solution, and water. After drying with Na2SO4, Et2O was removed under vacuum. The product was purified by flash distillation in the presence of Primol® 352 as ballast, and the final lighter compound was removed by fractional distillation to obtain the desired pure 1-ethynyl-4,4-dimethylcyclohexyl acetate in 90% molar yield.

[0102] [ka]

[0103] b) Step 2: Production of 4,4-dimethyl-1-vinylcyclohexyl acetate In a 100 mL or 1 L autoclave equipped with a mechanical stirrer, pressure and internal temperature sensors, and a heating / cooling system for internal temperature control, 1-ethynyl-4,4-dimethylcyclohexyl acetate (unknown compound), acetone (100 wt%), Lindler catalyst (0.75 wt%, 0.068 mol% Pd), and 3,6-dithia-1,8-octanediol (Lindler catalyst poison, CAS number: 5244-34-8) (0.00765 wt%, 12 mol% relative to Pd) were placed together. The sealed autoclave was then purged with nitrogen while stirring (three times at 5 bar), followed by stirring at 25°C for 30 minutes under a nitrogen pressure of 1 bar. After this period, the autoclave was purged with hydrogen while stirring (three times at 1 bar), followed by pressurization to a hydrogen pressure of 1 bar using a hydrogen tank equipped with an outlet pressure regulator and an internal pressure sensor for tracking and determining hydrogen consumption. Next, the reaction mixture was stirred at 25°C under a hydrogen pressure of 1 bar (1000 rpm), maintaining the overall reaction pressure at this value. After the completion of alkyne hydrogenation (5-7 hours), which was also determined by GC analysis on a short polar column (DB-Wax 10m × 0.1mm × 0.1μm), stirring was stopped, the autoclave was depressurized, and purged with nitrogen (three times at 5 bar). The reaction mixture was passed through several filters to remove the Lindler catalyst and transferred to a round-bottom flask to remove the solvent under vacuum. The target 4,4-dimethyl-1-vinylcyclohexyl acetate was obtained with a GC purity of 97.5%, above a complete GC conversion rate, and without residue formation (determined by valve-to-valve distillation of the sample).

[0104] Example 3 Production of 4,4-dimethyl-1-vinylcyclohex-1-ene 46.5 g (99.1% purity, 234.8 mmol) of 4,4-dimethyl-1-vinylcyclohexyl acetate was slowly added (12 mL / h) from above to a heated pyrolysis column (pyrolysis oven, 500°C) packed with a 20 g quartz cylinder (cyclinder) under a N2 flow. After the addition was complete, the oven was cooled. When the oven temperature reached 50°C, the crude product was transferred to a separatory funnel and 50 mL of pentane was added. The mixture was washed twice with 50 mL of water and once with 100 mL of saturated NaHCO3 aqueous solution. The organic phase was dried over sodium sulfate and the pentane was carefully removed by distillation (900 mbar, rotary evaporator bath temperature 40-80°C). 35.1 g of yellow liquid was obtained (conversion rate 99%, GC purity 98.1%). The crude product was distilled (by Biglieu column, 50-20 mbar, bp 76°C) to obtain 29.23 g (purity 99.0%, 232.42 mmol, yield 90.5%) of volatile 4,4-dimethyl-1-vinylcyclohex-1-ene.

[0105] [ka]

[0106] Example 4 Hydroformylation of 4,4-dimethyl-1-vinylcyclohexyl acetate 4,4-dimethyl-1-vinylcyclohexyl acetate (196 mg, 1.0 mmol), ligand (3.5 mM in ethyl acetate, 2.0 mL), and Rh(acac)(CO)2 (1.0 mM in ethyl acetate, 1.43 mL) were placed in an autoclave (HEL 20 mL / 200 bar). The autoclave was purged three times with 8 bar of argon and four times with 10 bar of synthesis gas (H2:CO, 1:1) under stirring (500 rpm). The autoclave was then filled with 10 bar of synthesis gas, and the reaction mixture was heated until the temperature reached 75°C. Subsequently, the autoclave was further pressurized with synthesis gas to 40 bar, the stirring speed was adjusted to 900 rpm, and the temperature was set to 80°C. Hydroformylation was continued while supplementing gas intake with H2:CO (1:1). After 22 hours, the reaction mixture was cooled to room temperature, the pressure was released, and the autoclave was purged five times with 12 bar of argon. The product was analyzed by gas chromatography using tetradecane as an internal standard.

[0107] The results obtained are shown in Table 1.

[0108] [Table 1]

[0109] 4,4-Dimethyl-1-(3-oxopropyl)cyclohexylacetate (1) [ka]

[0110] 4,4-Dimethyl-1-(1-oxopropan-2-yl)cyclohexyl acetate (2) [ka]

[0111] Example 5 Hydroformylation of 4,4-dimethyl-1-vinylcyclohexyl acetate using xanthophos-Rh catalyst a) Basic procedure: 4,4-dimethyl-1-vinylcyclohexyl acetate (589 mg, 3.0 mmol), xanthophos (i.e., (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (in ethyl acetate), and Rh(acac)(CO)2 (in ethyl acetate) were placed in an autoclave (HEL 20 mL / 200 bar) according to Table 2. The autoclave was purged three times with 8 bar argon and four times with 10 bar synthesis gas (H2:CO, 1:1) under stirring (500 rpm). Then, the autoclave was filled with 1 The autoclave was filled with 0 bar of synthesis gas, and the reaction mixture was heated until the temperature reached 75°C. The autoclave was then further pressurized with synthesis gas to 40 bar, the stirring speed was adjusted to 900 rpm, and the temperature was set to 80°C. Hydroformylation was continued while supplementing gas uptake with H2:CO (1:1). After the reaction times shown in Table 2, the reaction mixture was cooled to room temperature, the pressure was released, and the autoclave was purged five times with 12 bar of argon. Product analysis was performed by gas chromatography using tetradecane as an internal standard.

[0112] The results obtained are shown in Table 2.

[0113] [Table 2]

[0114] Example 6 Hydroformylation of 4,4-dimethyl-1-vinylcyclohexyl acetate using a bifefos-Rh catalyst a) Basic procedure: 4,4-dimethyl-1-vinylcyclohexyl acetate (785 mg, 4.0 mmol), bifefos (i.e., 6,6'-[(3,3'-di-tert-butyl-5,5'-dimethoxy-1,1'-biphenyl-2,2'-diyl)bis(oxy)]bis(dibenzo[d,f][1,3,2]dioxaphosfepine)) (in ethyl acetate) and Rh(acac)(CO)2 (in ethyl acetate) were placed in an autoclave (HEL 20 mL / 200 bar) according to Table 2. The autoclave was purged three times with 8 bar argon and four times with 10 bar synthesis gas (H2:CO, 1:1) under stirring (500 rpm). The autoclave was then filled with 10 bar synthesis gas and the reaction mixture was heated until the temperature reached 85°C. Subsequently, the autoclave was further pressurized to 40 bar with synthesis gas, the stirring speed was adjusted to 900 rpm, and the temperature was set to 90°C. Hydroformylation was continued while supplementing gas intake with H2:CO (1:1). After the reaction times shown in Table 2, the reaction mixture was cooled to room temperature, the pressure was released, and the autoclave was purged five times with argon at 12 bar. The product was analyzed by gas chromatography using tetradecane as an internal standard.

[0115] The results obtained are shown in Table 3.

[0116] [Table 3]

[0117] Example 7 Hydroformylation of 4,4-dimethyl-1-vinylcyclohexyl acetate using bifefos-Rh (scale-up) Rh(CO)2acac (6.0 mM in HCl, 16.4 mL), bifefos (15 mM in HCl, 33 mL), 4,4-dimethyl-1-vinylcyclohexyl acetate (39.0 g, 98.9% purity, 196.5 mmol), and ethyl acetate (3 mL) were placed in an autoclave (Premex 150 mL / 200 bar) kept under argon. The autoclave was filled with 10 bar of synthesis gas (H2:CO, 1:1), and the reaction mixture was heated with vigorous stirring until the temperature reached 90°C. The autoclave was then further pressurized with synthesis gas to 42 bar, and hydroformylation was continued while supplementing gas uptake with H2:CO (1:1). After 3.5 hours, the reaction mixture was cooled to room temperature, the pressure was released, and the autoclave was purged with Ar. The mixture (94.8 g, linear aldehyde 1 with 98% GC, branched aldehyde 2 with <0.1%, yield 97%, selectivity of branched / linear 1 / 2 > 98 / 0.1) was filtered, and the solvent was removed under reduced pressure (150 mbar, 45°C). After adding 90 mL of heptane and removing the solvent (20 mbar, 45°C), 4,4-dimethyl-1-(3-oxopropyl)cyclohexyl acetate 45.1 g (purity 94.2%, 187.7 mmol, yield 95.5%) was isolated as a yellow liquid.

[0118] Example 8 Hydroformylation of 4,4-dimethyl-1-vinylcyclohexyl acetate using a bifefos analog-Rh catalyst 4,4-dimethyl-1-vinylcyclohexyl acetate (491 mg, 2.5 mmol), ligand (1.0 mM in ethyl acetate, 0.25 mL), Rh(acac)(CO)2 (0.5 mM in ethyl acetate, 0.25 mL), and ethyl acetate (0.34 mL) were placed in an autoclave (HEL 20 mL / 200 bar). The autoclave was purged three times with 8 bar argon and four times with 10 bar synthesis gas (H2:CO, 1:1) under stirring (500 rpm). The autoclave was then filled with 10 bar synthesis gas, and the reaction mixture was heated until the temperature reached 85°C. Subsequently, the autoclave was further pressurized to 30 bar with synthesis gas, the stirring speed was adjusted to 900 rpm, and the temperature was set to 90°C. Hydroformylation was continued while supplementing gas intake with H2:CO (1:1). After 20 hours, the reaction mixture was cooled to room temperature, the pressure was released, and the autoclave was purged five times with argon at 12 bar. The product was analyzed by gas chromatography using tetradecane as an internal standard.

[0119] The results obtained are shown in Table 4.

[0120] [Table 4]

[0121] Example 9 Manufacturing of 3-(4,4-dimethylcyclohex-1-en-1-yl)propanal A heated pyrolysis column (pyrolysis oven, 500°C) packed with a 20g quartz cylinder (cyclinder) (Raschig 4mm) was slowly added from above (12 mL / h) to 12g of cyclohexane under a N2 flow, with 3g (GC purity 97%, 12.86 mmol) of 4,4-dimethyl-1-(3-oxopropyl)cyclohexyl acetate. After the addition was complete, the oven was cooled, and the quartz cylinder (cyclinder) was washed with 5g of cyclohexane. 20 g of the mixture was obtained, and since the product was volatile, it was analyzed by GC (GC purity 75.7% → estimated to be 3-(4,4-dimethylcyclohex-1-en-1-yl)propanal: 9.70 mmol, yield 75%, GC purity 14.4% → estimated to be 3-(4,4-dimethylcyclohexylidene)propanal: 0.31 mmol, 1.84 mmol, yield 14.3%, GC purity 4.3% → estimated to be 4,4-dimethyl-1-(3-oxopropyl)cyclohexyl acetate: 0.55 mmol, yield 4.3%).

[0122] After post-treatment (washing with saturated NaHCO3 aqueous solution and water), the volatile product mixture could be purified by column chromatography.

[0123] 3-(4,4-dimethylcyclohex-1-en-1-yl)propanal [ka]

[0124] 3-(4,4-dimethylcyclohexylidene)propanal [ka]

[0125] Example 10 Preparation of 1-(2-(1,3-dioxolan-2-yl)ethyl)-4,4-dimethylcyclohexyl acetate 34.1 g (94.2% purity, 141.4 mmol) of 4,4-dimethyl-1-(3-oxopropyl)cyclohexyl acetate was stirred for 1 hour at 105-113°C under Dean-Stark conditions in 50 mL of toluene in the presence of 13.9 g (212.0 mmol, 1.5 equivalents) of ethylene glycol and 962 mg of KHSO4 (7.1 mmol, 5 mol%) (internal temperature; water was removed after 1 hour). The mixture was cooled to room temperature and 150 mL of diethyl ether was added. After washing with 75 mL of water, 75 mL of saturated aqueous NaHCO3 solution, and 75 mL of brine, the organic phase was dried over Na2SO4 and the solvent was removed under reduced pressure (crude product 39.5 g). Kugellool distillation of the crude product yielded two fractions: 33.8 g (125.0 mmol) of 1-(2-(1,3-dioxolan-2-yl)ethyl)-4,4-dimethylcyclohexyl acetate and 1.71 g (8.15 mmol) of 2-(2-(4,4-dimethylcyclohex-1-en-1-yl)ethyl)-1,3-dioxolane (yield 94.2%, 133.15 mmol).

[0126] 1-(2-(1,3-dioxolan-2-yl)ethyl)-4,4-dimethylcyclohexyl acetate: [ka]

[0127] 2-(2-(4,4-dimethylcyclohex-1-en-1-yl)ethyl)-1,3-dioxolane: [ka]

[0128] Example 11 Preparation of 2-(2-(4,4-dimethylcyclohex-1-en-1-yl)ethyl)-1,3-dioxolane 66 mg (0.349 mmol, 5 mol%) of pTsOH·H2O was heated in 20 mL of toluene at 110°C for 30 minutes under Dean-Stark conditions (reflux) with stirring. 1.9 g (98.7% purity, 6.93 mmol) of 1-(2-(1,3-dioxolan-2-yl)ethyl)-4,4-dimethylcyclohexyl acetate was slowly added over 1 hour. The mixture was stirred for a further 1 hour to isomerize the exo double bond to the endo double bond. After cooling to room temperature, 30 mL of diethyl ether was added. After washing with 5 mL of saturated aqueous NaHCO3 and 10 mL of brine, the organic phase was dried over Na2SO4 and the solvent was removed under reduced pressure (crude product 1.53 g). Kugellool distillation of the crude product yielded two fractions containing 1.29 g of 2-(2-(4,4-dimethylcyclohex-1-en-1-yl)ethyl)-1,3-dioxolane (6.13 mmol, 89% yield), 68 mg of 2-(2-(4,4-dimethylcyclohexylidene)ethyl)-1,3-dioxolane (0.323 mmol, 4.6% yield), and 14 mg of 3-(4,4-dimethylcyclohex-1-en-1-yl)propanal (0.0842 mmol, 1.2% yield).

[0129] 2-(2-(4,4-dimethylcyclohex-1-en-1-yl)ethyl)-1,3-dioxolane(endo): [ka]

[0130] 2-(2-(4,4-dimethylcyclohexylidene)ethyl)-1,3-dioxolane(exo) [ka]

[0131] 3-(4,4-dimethylcyclohex-1-en-1-yl)propanal [ka]

[0132] Example 12 Preparation of 2-(2-(4,4-dimethylcyclohex-1-en-1-yl)ethyl)-1,3-dioxolane A heated pyrolysis column (pyrolysis oven, 500°C) packed with an 18g quartz cylinder (cyclinder) (Raschig 4mm) was slowly added from above (12 mL / h) under a N2 flow to a column containing 2g (7.39 mmol) of 1-(2-(1,3-dioxolan-2-yl)ethyl)-4,4-dimethylcyclohexyl acetate. After the addition was complete, the oven was cooled and the quartz cylinder (cyclinder) was washed with 10 ml of cyclohexane. After adding another 20 mL of cyclohexane, the mixture was washed twice with 10 mL of saturated NaHCO3 aqueous solution. The aqueous phases were combined and extracted once with 10 mL of cyclohexane. The combined organic phases were washed with brine and dried over sodium sulfate. The solvent was removed under reduced pressure (rotary evaporator, 10 mbar, 45°C). 1.452 g of product was obtained (2-(2-(4,4-dimethylcyclohex-1-en-1-yl)ethyl)-1,3-dioxolane, 70.6% purity, 4.87 mmol, yield 65.9%, 2-(2-(4,4-dimethylcyclohexylidene)ethyl)-1,3-dioxolane, 24.6% purity, 1.70 mmol, yield 23.0%, 3-(4,4-dimethylcyclohex-1-en-1-yl)propanal, 1.3% purity, 0.0148 mmol, yield 1.5%).

[0133] The amount of 2-(2-(4,4-dimethylcyclohexylidene)ethyl)-1,3-dioxolane could be increased by heating at 110°C in the presence of 5 mol% pTsOH·H2O in 15 mL of toluene. After 3 hours, GC analysis yielded 94.0% 2-(2-(4,4-dimethylcyclohex-1-en-1-yl)ethyl)-1,3-dioxolane, 3.7% 2-(2-(4,4-dimethylcyclohexylidene)ethyl)-1,3-dioxolane, and 0.2% 3-(4,4-dimethylcyclohex-1-en-1-yl)propanal.

[0134] Example 13 Manufacturing of 3-(4,4-dimethylcyclohex-1-en-1-yl)propanal 6.24 g of 2-(2-(4,4-dimethylcyclohex-1-en-1-yl)ethyl)-1,3-dioxolane (91.7% purity, 27.20 mmol, containing 1.08 mmol of 3-(4,4-dimethylcyclohex-1-en-1-yl)propanal), 9.25 g of AcOH (155.7 mmol, 5.5 equivalents), and 9.25 g of water (519 mmol, 19.1 equivalents) were heated in 9.1 mL of heptane with stirring at 85°C (reflux) for 3 hours. After cooling to room temperature, 25 mL of diethyl ether was added. The acetic acid was neutralized to pH 6 at 10°C with a 25% NaOH aqueous solution. The organic phase was separated and washed with 15 mL of saturated NaHCO3 aqueous solution and 15 mL of brine. After drying with Na2SO4, the solvent was removed under reduced pressure (500-100 mbar, 40°C). The crude product (still containing some heptane) was purified by flash chromatography (220 g of SiO2, pentane, pentane 9 / diisopropyl ether 1 eluent). 3.348 g (98% purity, 19.73 mmol, 69.8% yield) of 3-(4,4-dimethylcyclohex-1-en-1-yl)propanal was obtained, and 1.46 g (90.0% purity, 6.25 mmol, 22.1% yield) of the starting material 2-(2-(4,4-dimethylcyclohex-1-en-1-yl)ethyl)-1,3-dioxolane was recycled.

[0135] 3-(4,4-dimethylcyclohex-1-en-1-yl)propanal was obtained from 1-ethynyl-4,4-dimethylcyclohexanol in an overall yield of at least 60% by following the procedures reported in Examples 2, 6, 8, 9, and 11. On the other hand, 3-(4,4-dimethylcyclohex-1-en-1-yl)propanal was obtained from 4,4-dimethylcyclohexanol in an overall yield of 27%, as reported in European Patent No. 1529770. The method of the present invention allows for the production of 3-(cyclohex-1-en-1-yl)propanal derivatives in improved yields.

[0136] Example 14 Hydroformylation of 4,4-dimethyl-1-vinylcyclohex-1-ene 4,4-dimethyl-1-vinylcyclohex-1-ene (136 mg, 1.0 mmol), ligand (3.5 mM in ethyl acetate, 2.0 mL), and Rh(acac)(CO)2 (1.0 mM in ethyl acetate, 1.43 mL) were placed in an autoclave (HEL 20 mL / 200 bar). The autoclave was purged three times with 8 bar argon and four times with 10 bar synthesis gas (H2:CO, 1:1) while stirring (500 rpm). The autoclave was then filled with 10 bar synthesis gas, and the reaction mixture was heated until the temperature reached 75°C. Subsequently, the autoclave was further pressurized with synthesis gas to 40 bar, the stirring speed was adjusted to 900 rpm, and the temperature was set to 80°C. Hydroformylation was continued while supplementing gas intake with H2:CO (1:1). After 22 hours, the reaction mixture was cooled to room temperature, the pressure was released, and the autoclave was purged five times with argon at 12 bar. The product was analyzed by gas chromatography.

[0137] The results obtained are shown in Table 5.

[0138] [Table 5]

[0139] 3-(4,4-dimethylcyclohex-1-en-1-yl)propanal(3) [ka]

[0140] 2-(4,4-dimethylcyclohex-1-en-1-yl)propanal(4) [ka]

[0141] 6-Ethylidene-3,3-dimethylcyclohex-1-ene(6) [ka]

[0142] 1-Ethyl-4,4-dimethylcyclohex-1-ene(7) [ka]

[0143] Example 15 Hydroformylation of 4,4-dimethyl-1-vinylcyclohex-1-ene by bifefos-Rh catalyst a) Basic procedure: 4,4-dimethyl-1-vinylcyclohex-1-ene (136 mg, 1.0 mmol), bifefos (in siRNA), and Rh(acac)(CO)2 (in siRNA) were placed in an autoclave (HEL 20 mL / 200 bar) according to Table 6 (total volume of siRNA = 3.5 mL). The autoclave was purged three times with 8 bar argon and four times with 10 bar synthesis gas (H2:CO, 1:1) under stirring (500 rpm). The autoclave was then filled with 10 bar synthesis gas, and the reaction mixture was heated until the temperature reached 95°C. Subsequently, the autoclave was further pressurized to 20 bar with synthesis gas, the stirring speed was adjusted to 900 rpm, and the temperature was set to 100°C. Hydroformylation was continued while supplementing gas intake with H2:CO (1:1). After the reaction times shown in Table 6, the reaction mixture was cooled to room temperature, the pressure was released, and the autoclave was purged five times with 12 bar argon. The product was analyzed by gas chromatography using tetradecane as an internal standard.

[0144] The results obtained are shown in Table 6.

[0145] [Table 6]

[0146] Example 16 Hydroformylation of 4,4-dimethyl-1-vinylcyclohex-1-ene by bifefos-Rh catalyst a) Basic procedure: 4,4-dimethyl-1-vinylcyclohex-1-ene (136 mg, 1.0 mmol), bifefos (in siRNA), and HRh(CO)(PPh3)3 (in siRNA) were placed in an autoclave (HEL 20 mL / 200 bar) according to Table 3 (total volume of siRNA = 3.5 mL). The autoclave was purged three times with 8 bar argon and four times with 10 bar synthesis gas (H2:CO, 1:1) under stirring (500 rpm). The autoclave was then filled with 10 bar synthesis gas, and the reaction mixture was heated until the temperature reached 95°C. Subsequently, the autoclave was further pressurized to 20 bar with synthesis gas, the stirring speed was adjusted to 900 rpm, and the temperature was set to 100°C. Hydroformylation was continued while supplementing gas intake with H2:CO (1:1). After 72 hours, the reaction mixture was cooled to room temperature, the pressure was released, and the autoclave was purged five times with argon at 12 bar. The product was analyzed by gas chromatography using tetradecane as an internal standard.

[0147] The results obtained are shown in Table 7.

[0148] [Table 7]

[0149] Example 17 Hydroformylation of 4,4-dimethyl-1-vinylcyclohex-1-ene by xanthophos-Rh catalyst a) Basic procedure: 4,4-dimethyl-1-vinylcyclohex-1-ene (136 mg, 1.0 mmol), xanthophos (in siRNA), and Rh(acac)(CO)2 (in siRNA) were placed in an autoclave (HEL 20 mL / 200 bar) according to Table 2 (total volume of siRNA = 3.5 mL unless otherwise specified). The autoclave was purged three times with 8 bar argon and four times with 10 bar synthesis gas (H2:CO, 1:1) under stirring (500 rpm). The autoclave was then filled with 10 bar synthesis gas, and the reaction mixture was heated until the temperature reached 65–105°C. Subsequently, the autoclave was further pressurized to 60 bar with synthesis gas, the stirring speed was adjusted to 900 rpm, and the temperature was set to 70–110°C. Hydroformylation was continued while supplementing gas intake with H2:CO (1:1). After 72 hours, the reaction mixture was cooled to room temperature, the pressure was released, and the autoclave was purged five times with argon at 12 bar. The product was analyzed by gas chromatography.

[0150] The results obtained are shown in Table 8.

[0151] [Table 8]

[0152] Example 18 Hydroformylation of 4,4-dimethyl-1-vinylcyclohex-1-ene using a xanthophos analog-Rh catalyst a) Basic procedure: 4,4-dimethyl-1-vinylcyclohex-1-ene (136 mg, 1.0 mmol), ligand (3.5 mM in ethyl acetate, 2.0 mL), and Rh(acac)(CO)2 (0.67 mM in ethyl acetate, 1.49 mL) were placed in an autoclave (HEL 20 mL / 200 bar). The autoclave was purged three times with 8 bar argon and four times with 10 bar synthesis gas (H2:CO, 1:1) under stirring (500 rpm). The autoclave was then filled with 10 bar synthesis gas, and the reaction mixture was heated until the temperature reached 85°C. Subsequently, the autoclave was further pressurized to 60 bar with synthesis gas, the stirring speed was adjusted to 900 rpm, and the temperature was set to 90°C. Hydroformylation was continued while supplementing gas intake with H2:CO (1:1). After 72 hours, the reaction mixture was cooled to room temperature, the pressure was released, and the autoclave was purged five times with argon at 12 bar. The product was analyzed by gas chromatography.

[0153] The results obtained are shown in Table 9.

[0154] [Table 9]

[0155] Example 19 Hydroformylation of 4,4-dimethyl-1-vinylcyclohex-1-ene by bifefos-Rh catalyst A solution of 4,4-dimethyl-1-vinylcyclohex-1-ene (3.75 g, 27.52 mmol) in Rh(acac)(CO)2 (6.0 mM in siRNA, 4.6 mL), bifefos (14.6 mM in siRNA, 9.5 mL), and siRNA (80 mL) was placed in an autoclave (Premex 200 mL / 200 bar) maintained under 1 bar of Ar. The autoclave was filled with 10 bar of synthesis gas (H2:CO, 1:1), and the reaction mixture was heated with vigorous stirring until the temperature reached 100°C. The autoclave was then further pressurized to 23 bar with synthesis gas, and hydroformylation was continued while supplementing gas uptake with H2:CO (1:1). After 24 hours, the reaction mixture was cooled to room temperature, the pressure was released, and the autoclave was purged with Ar. (GC yield (with internal standard) 66%). The solvent was removed by distillation under reduced pressure (45°C, 200 mbar). The crude product was purified by flash chromatography (120 g of SiO2, cyclohexane / AcOEt99 / 1 eluent, cyclohexane / AcOEt95 / 5). 4.9 g of the product, 3-(4,4-dimethylcyclohex-1-en-1-yl)propanal / 2-(4,4-dimethylcyclohex-1-en-1-yl)propanal 93 / 6, was obtained. This still contained some solvent. Kugellool distillation yielded 2.90 g of 3-(4,4-dimethylcyclohex-1-en-1-yl)propanal (GC purity 92.8%, 16.18 mmol, yield 59%) and 2-(4,4-dimethylcyclohex-1-en-1-yl)propanal (GC purity 6.3%). Due to volatility, some product was lost.

[0156] Example 20 Hydroformylation of 6-ethylidene-3,3-dimethylcyclohex-1-ene - Recycling of by-product 6 formed during hydroformylation 6-Ethylidene-3,3-dimethylcyclohex-1-ene (136 mg, 1.0 mmol), ligand (3.5 mM in ethyl, 2.0 mL), and Rh(acac)(CO)2 (1.0 mM in ethyl, 1.43 mL) were placed in an autoclave (HEL 20 mL / 200 bar). The autoclave was purged three times with 8 bar argon and four times with 10 bar synthesis gas (H2:CO, 1:1) under stirring (500 rpm). The autoclave was then filled with 10 bar synthesis gas, and the reaction mixture was heated until the temperature reached 95°C. Subsequently, the autoclave was further pressurized to 20 bar with synthesis gas, the stirring speed was adjusted to 900 rpm, and the temperature was set to 100°C. Hydroformylation was continued while supplementing gas intake with H2:CO (1:1). After the reaction times shown in Table 6, the reaction mixture was cooled to room temperature, the pressure was released, and the autoclave was purged five times with 12 bar argon. The product was analyzed by gas chromatography.

[0157] The results obtained are shown in Table 10.

[0158] [Table 10]

[0159] Example 21 Preparation of different compounds of formula (II) The starting materials, 4-(tert-butyl)cyclohexane-1-one (CAS 98-53-3, Aldrich), 3-isopropylcyclohexane-1-one (CAS 23396-36-3, Aldrich), 4-butylcyclohexane-1-one (CAS 61203-82-5, Aurumpharmatech), 2-ethyl-4,4-dimethylcyclohexane-1-one (CAS 55739-89-4, Aurorafinechemicals), and 3-isopropylcyclopentan-1-one (CAS 10264-56-9, Alfa-chemistry), are commercially available or can be manufactured according to the literature.

[0160] a) Step 1: Production of vinyl alcohol by adding vinyl Grignard reagent to cyclic substituted ketones Basic procedure for adding cyclic substituted ketones to a magnesium vinyl chloride solution: To 196.6 mL of a cooled solution of magnesium vinyl chloride (1.6 M, 314.5 mmol, 1.1 equivalents in THF) and 150 mL of THF (0°C), a solution of cyclic ketone (285.9 mmol) in 60 mL of THF was slowly added. During the addition of the cyclic substituted ketone, the internal temperature did not exceed 5°C. The mixture was stirred overnight (16 hours) at 0°C and analyzed by GC. The reaction mixture was slowly added to a cooled solution of 21 g of AcOH (343.1 mmol) in 200 mL of water. The phases were separated, and the aqueous phase was extracted with 150 mL of TBME. The combined organic phases were washed with saturated aqueous NaHCO3 and saturated aqueous NaCl. After drying with Na2SO4, the solvent was removed by distillation under reduced pressure (500-50 mbar, 50°C). The crude product was purified by flash chromatography or by distillation through a Bigrieux column under reduced pressure.

[0161] 4-(tert-butyl)-1-vinylcyclohexane-1-ol This compound was prepared using 4-(tert-butyl)cyclohexane-1-one as the cyclic ketone, following a basic procedure.

[0162] GC of the crude product: 91.2% 4-(tert-butyl)-1-vinylcyclohexane-1-ol.

[0163] Purity after purification (GC): 94.0% (Yield: 78%) The NMR analysis results in CDCl3 were consistent with data from the literature (N. Miralles, R. Alam, KJ Szabo, E. Fernandez, Angew. Chem. Int. Ed. 2016, 55, 4303-4307).

[0164] trans-4-(tert-butyl)-1-vinylcyclohexane-1-ol: Main isomer (52 / 48 trans / cis) [ka]

[0165] 3-Isopropyl-1-vinylcyclohexane-1-ol The compound was prepared using 3-isopropylcyclohexane-1-one (containing 10% 4-isopropylcyclohexane-1-one) as the cyclic ketone, following a basic procedure.

[0166] From the crude product GC:3-isopropylcyclohexane-1-one (purity 85.7%), 3-isopropyl-1-vinylcyclohexane-1-ol with a purity of 82.6% was obtained. The purified product has a purity (GC) of 88.8% (yield 86%) and contains 10% of 4-isopropyl-1-vinylcyclohexane-1-ol, a mixture of trans and cis isomers.

[0167] (1SR,3SR)-3-isopropyl-1-vinylcyclohexane-1-ol: Main isomer (51 / 49 trans / cis) [ka]

[0168] (1SR,3RS)-3-isopropyl-1-vinylcyclohexane-1-ol: subisomer [ka]

[0169] NMR analysis results for 4-isopropyl-1-vinylcyclohexane-1-ol (a mixture of trans and cis isomers) in CDCl3 were consistent with data from the literature (CA Discolo, EE Touney, SV Pronin, J. Am. Chem. Soc. 2019 141(44), 17527-17532).

[0170] 4-butyl-1-vinylcyclohexane-1-ol The compound was prepared using 4-butylcyclohexane-1-one as the cyclic ketone, following a basic procedure.

[0171] GC of the crude product: 96.1% 4-butyl-1-vinylcyclohexane-1-ol.

[0172] Purity after purification (GC) 94.5% (yield 99%).

[0173] trans-4-butyl-1-vinylcyclohexane-1-ol: Main isomer (58 / 42 trans / cis) [ka]

[0174] cis-4-butyl-1-vinylcyclohexane-1-ol: subisomer [ka]

[0175] 2-ethyl-4,4-dimethyl-1-vinylcyclohexane-1-ol The compound was prepared using 2-ethyl-4,4-dimethylcyclohexane-1-one as the cyclic ketone, following a basic procedure.

[0176] GC of the crude product: 94.1% 2-ethyl-4,4-dimethyl-1-vinylcyclohexane-1-ol.

[0177] Purity after purification (GC) 95.5% (yield 85%).

[0178] (1SR,2SR)-2-ethyl-4,4-dimethyl-1-vinylcyclohexane-1-ol (main isomer, cis / trans 87 / 13) [ka]

[0179] (1SR,2RS)-2-ethyl-4,4-dimethyl-1-vinylcyclohexane-1-ol (biisomer) [ka]

[0180] 3-Isopropyl-1-vinylcyclopentan-1-ol The compound was prepared using 3-isopropylcyclopentan-1-one as the cyclic ketone, following a basic procedure.

[0181] GC of the crude product: 94.8% 3-isopropyl-1-vinylcyclopentan-1-ol (a mixture of 57 / 43 isomers (cis / trans)).

[0182] Purity after purification (GC) 96.7% (yield 84%).

[0183] (1SR,3RS)-3-isopropyl-1-vinylcyclopentan-1-ol / (1SR,3SR)-3-isopropyl-1-vinylcyclopentan-1-ol(57 / 43 cis / trans) [ka]

[0184] b) Step 2: Production of vinyl acetate from vinyl alcohol (compound of formula (II)) The procedure from Example 1b was used to produce vinyl acetate using the alcohol prepared in Example 21a). For the preparation of 2-ethyl-4,4-dimethyl-1-vinylcyclohexyl acetate, the solvent was switched from toluene to THF and 5 mol% DMAP was used (conversion rate of 21% after 1 day). The crude product was purified by flash chromatography or by distillation through a Bigrieux column under reduced pressure.

[0185] 4-(tert-butyl)-1-vinylcyclohexyl acetate The compound was prepared by following a basic procedure, using trans-4-(tert-butyl)-1-vinylcyclohexane-1-ol / cis-4-(tert-butyl)-1-vinylcyclohexane-1-ol as the starting alcohol.

[0186] GC of the crude product: 4-(tert-butyl)-1-vinylcyclohexyl acetate at 89.7% purity (94.0%).

[0187] Purity after purification (GC) 98.2% (yield 86%).

[0188] NMR analysis results of the trans isomer in CDCl3 were consistent with data from the literature (JC Fiaud, JY Legros, J. Organomet. Chem. 1989, 370, 383).

[0189] trans-4-(tert-butyl)-1-vinylcyclohexyl acetate / cis-4-(tert-butyl)-1-vinylcyclohexyl acetate (trans / cis 54.5 / 44.5) [ka]

[0190] Trans-4-(tert-butyl)-1-vinylcyclohexyl acetate [ka]

[0191] cis-4-(tert-butyl)-1-vinylcyclohexyl acetate [ka]

[0192] 3-Isopropyl-1-vinylcyclohexyl acetate The compound was prepared according to a basic procedure, using (1SR,3SR)-3-isopropyl-1-vinylcyclohexane-1-ol / (1SR,3RS)-3-isopropyl-1-vinylcyclohexane-1-ol (containing a mixture of 10% 4-isopropyl-1-vinylcyclohexane-1-ol, trans / cis isomers) as the starting alcohol.

[0193] Crude product GC: 3-isopropyl-1-vinylcyclohexyl acetate at 83.8% purity (88.8%).

[0194] Purity after purification (GC) 88.7% (yield 83%, 42 / 47 mixture of isomers (cis / trans)).

[0195] (1SR,3RS-3-isopropyl-1-vinylcyclohexyl acetate / (1SR,3SR)-3-isopropyl-1-vinylcyclohexyl acetate (containing 10% 4-isopropyl-1-vinylcyclohexyl acetate, trans / cis isomer mixture).

[0196] [ka]

[0197] (1SR,3SR)-3-isopropyl-1-vinylcyclohexyl acetate: trans isomer (main) [ka]

[0198] (1SR,3RS)-3-isopropyl-1-vinylcyclohexyl acetate: cis isomer (secondary) [ka]

[0199] 4-Isopropyl-1-vinylcyclohexyl acetate (10% in the mixture, a mixture of trans and cis isomers): 1 1.96 (s, 3H) characteristic signal at 1.96 Hz-NMR (500.15 MHz).

[0200] 4-Butyl-1-vinylcyclohexyl acetate The compound was prepared according to the basic procedure, using (trans-4-butyl-1-vinylcyclohexane-1-ol / cis-4-butyl-1-vinylcyclohexane-1-ol) as the starting alcohol.

[0201] GC of the crude product: 4-butyl-1-vinylcyclohexane-1-ol (purity 95.2%) yields 95.2% 4-butyl-1-vinylcyclohexyl acetate.

[0202] Purity after purification (GC) 97.0% (yield 86%, 61 / 36 mixture of isomers (trans / cis)).

[0203] Trans-4-butyl-1-vinylcyclohexyl acetate / cis-4-butyl-1-vinylcyclohexyl acetate [ka]

[0204] 2-Ethyl-4,4-dimethyl-1-vinylcyclohexyl acetate The compound was prepared using (1SR,2SR)-2-ethyl-4,4-dimethyl-1-vinylcyclohexane-1-ol as the starting alcohol, following a basic procedure (using THF as the solvent).

[0205] The reaction was carried out with a conversion rate of 21% (1 day). Unreacted starting material (2-ethyl-4,4-dimethyl-1-vinylcyclohexane-1-ol) was readily recycled by distillation or column chromatography.

[0206] Purity after purification (GC) 95.7% (49.5 / 46.2 mixture of isomers (cis / trans)).

[0207] (1SR,2SR)-2-ethyl-4,4-dimethyl-1-vinylcyclohexane-1-ol / (1SR,2RS)-2-ethyl-4,4-dimethyl-1-vinylcyclohexane-1-ol (mixture of cis / trans isomers) [ka]

[0208] 3-Isopropyl-1-vinylcyclopentyl acetate The compound was prepared according to the basic procedure using (1SR,3RS)-3-isopropyl-1-vinylcyclopentan-1-ol as the starting alcohol.

[0209] Crude product GC: 3-isopropyl-1-vinylcyclopentan-1-ol (purity 96.7%) yields 95.4% 3-isopropyl-1-vinylcyclopentyl acetate. Purity after purification (GC) 97.5% (yield 94.4%, mixture of cis / trans isomers): 59 / 39.

[0210] (1SR,3RS)-3-isopropyl-1-vinylcyclopentyl acetate / (1SR,3SR)-3-isopropyl-1-vinylcyclopentyl acetate [ka]

[0211] Main isomer (cis) [ka]

[0212] Trans isomer [ka]

[0213] c) Preparation of the ((4,4-dimethyl-1-vinylcyclohexyl)oxy)trimethylsilane compound of formula (II) To a stirred solution of 4,4-dimethyl-1-vinylcyclohexanol (30 g, 95.9% purity, 186.5 mmol) obtained in Example 1a) in dichloromethane (750 mL), triethylamine (56.62 g, 559.6 mmol, 3 equivalents) and chlorotrimethylsilane (28.37 g, 261.1 mmol, 1.4 equivalents) were added under N2 and water cooling. After 22 hours at room temperature, complete conversion of the starting materials was observed. Saturated NaHCO3 aqueous solution (750 mL) was slowly added to separate the organic phase. The aqueous phase was extracted twice with 500 mL of diethyl ether and 250 mL of dichloromethane. The combined organic phase was washed with saturated NaCl aqueous solution and dried over sodium sulfate. The solvent was removed by distillation under reduced pressure (40 °C, 500-4.8 mbar). The crude red solid (44.8 g, 96.1% purity) was filtered off (40.9 g of crude product).

[0214] The crude product was purified by distillation (Vigreux) at 0.2–0.099 mbar, boiling point 32.6–36.7°C, wok 70°C, and cuve 83°C. ((4,4-dimethyl-1-vinylcyclohexyl)oxy)trimethylsilane was isolated in 94.5% yield (40.0 g, purity 99.8%, 176.3 mmol).

[0215] [ka]

[0216] Example 22 Preparation of different compounds of formula (I) a) Preparation of 3-(4-(tert-butyl)cyclohex-1-en-1-yl)propanal Step 1: Hydroformylation of (4-tert-butyl-1-vinyl-cyclohexyl)acetate with bifefos-Rh (4-tert-butyl-1-vinylcyclohexyl) acetate (trans / cis ratio: 54.5% / 44.5%, 5.06 g, 22.56 mmol), Rh(CO)2acac (3.2 mg, 0.0124 mmol), and bifefos (26.8 mg, 0.034 mmol) were placed in an autoclave. The container was purged with H2 / CO (1:1, 4 × 5 bar) and heated at 90°C and a synthesis gas pressure of 10 bar for 24 hours with vigorous stirring. After cooling and depressurization, GLC analysis of the semi-crystallized crude product (DB-1, 10 m, 100 microns, 80°C, 1 min; up to 240°C at 40°C / min; 5 min, or DB-WAX, 10 m, 100 microns, 80°C, 1 min; from 40°C / min to 240°C; 5 min) revealed complete conversion and the presence of 4-(tert-butyl)-1-(3-oxopropyl)cyclohexyl acetate (92.2%; trans / cis ratio: 54.4% / 37.8%).

[0217] cis-4-(tert-butyl)-1-(3-oxopropyl)cyclohexyl acetate: [ka]

[0218] Trans-4-(tert-butyl)-1-(3-oxopropyl)cyclohexyl acetate: [ka]

[0219] Step 2: Preparation of trans-1-(2-(1,3-dioxolan-2-yl)ethyl)-4-(tert-butyl)cyclohexyl acetate / cis-1-(2-(1,3-dioxolan-2-yl)ethyl)-4-(tert-butyl)cyclohexyl acetate The compound was prepared using the compound produced in the previous step as a starting material, following the procedure reported in Example 10.

[0220] Crude product GC: 52.0% / 30.6% of 1-(2-(1,3-dioxolan-2-yl)ethyl)-4-(tert-butyl)cyclohexyl acetate from 4-(tert-butyl)-1-(3-oxopropyl)cyclohexyl acetate (54.4% / 37.8%).

[0221] Purity after purification (GC) is 55.2% / 38.3%. The product contains 2.6% 4-(tert-butyl)-1-(3-oxopropyl)cyclohexyl acetate and 3.9% trans-4-(tert-butyl)-1-(3-oxopropyl)cyclohexyl acetate.

[0222] 1-(2-(1,3-dioxolan-2-yl)ethyl)-4-(tert-butyl)cyclohexyl acetate [ka]

[0223] Trans isomer (main) [ka]

[0224] cis isomer (secondary) [ka]

[0225] Step 3: Production of 2-(2-(4-(tert-butyl)cyclohex-1-en-1-yl)ethyl)-1,3-dioxolane To a solution of dioxolane acetate (3.126 mmol) prepared in the previous step in 5 mL of dry toluene, 0.15 equivalents of BF3·Et2O were added. The mixture was stirred at room temperature for 30 minutes (to complete conversion of the starting materials), and then added to 20 mL of saturated NaHCO3 aqueous solution. When no gas production was observed, 15 mL of MTBE was added, and the mixture was stirred for 10 minutes. The organic phase was separated and washed with water and saturated NaCl aqueous solution. After drying over Na2SO4, the solvent was removed under reduced pressure (500-50 mbar, 50°C). The crude product was purified by flash chromatography.

[0226] Crude product GC: 91.8% 2-(2-(4-(tert-butyl)cyclohex-1-en-1-yl)ethyl)-1,3-dioxolane / 3.7% 2-(2-(4-(tert-butyl)cyclohexylidene)ethyl)-1,3-dioxolane from 1-(2-(1,3-dioxolane-2-yl)ethyl)-4-(tert-butyl)cyclohexylacetate (purity 93.5%).

[0227] Purity after purification (GC): 94.0% / 3.5%.

[0228] 2-(2-(4-(tert-butyl)cyclohex-1-en-1-yl)ethyl)-1,3-dioxolane [ka]

[0229] Step 4: Production of 3-(4-(tert-butyl)cyclohex-1-en-1-yl)propanal The compound was prepared using the compound prepared in the previous step as a starting material, following the procedure reported in Example 13.

[0230] In CDCl3 1 H and 13 The results of the 1C-NMR analysis were consistent with data from the literature (see European Patent Application Publication No. 1054053 by B. Winter).

[0231] 3-(4-(tert-butyl)cyclohex-1-en-1-yl)propanal [ka]

[0232] b) Preparation of 3-(5-isopropylcyclohex-1-en-1-yl)propanal / 3-(3-isopropylcyclohex-1-en-1-yl)propanal Step 1: Hydroformylation of (3-isopropyl-1-vinyl-cyclohexyl)acetate with bifefos-Rh A mixture of 3-isopropyl-1-vinylcyclohexyl acetate (1SR,3RS / 1SR,3SR, 42% / 47%) and 4-isopropyl-1-vinylcyclohexyl acetate (cis / trans, 4% / 6.5%) (5.04 g, 23.965 mmol), Rh(CO)2acac (2.5 mg, 0.0119 mmol), and bifefos (28.7 mg, 0.0365 mmol) were placed in an autoclave. The container was purged with H2 / CO (1:1, 4 × 5 bar) and heated at 90°C and a synthesis gas pressure of 10 bar for 24 hours with vigorous stirring. After cooling and depressurization, GLC analysis of the colorless oil of the crude product revealed complete conversion and the presence of linear 3-isopropyl-1-(3-oxopropyl)cyclohexyl acetate (1SR,3SR / 1SR,3RS, 39.7% / 45.3%) and 4-isopropyl-1-(3-oxopropyl)cyclohexyl acetate (cis / trans, 4% / 6.3%).

[0233] 1SR,3SR / 1SR,3RS-3-Isopropyl-1-(3-Oxopropyl)Cyclohexyl Acetate [ka]

[0234] Step 2: Preparation of 1-(2-(1,3-dioxolan-2-yl)ethyl)-3-isopropylcyclohexyl acetate The compound was prepared using the compound produced in the previous step as a starting material, following the procedure reported in Example 10.

[0235] Crude product GC: 3-isopropyl-1-(3-oxopropyl)cyclohexyl acetate (39.7% / 45.3%) to 40.5% / 46.1% 1-(2-(1,3-dioxolan-2-yl)ethyl)-3-isopropylcyclohexyl acetate and 2.7% 2-(2-(5-isopropylcyclohex-1-en-1-yl)ethyl)-1,3-dioxolane.

[0236] Purity after purification (GC) 41.9% / 47.4% (the product contained 10% of 1-(2-(1,3-dioxolan-2-yl)ethyl)-4-isopropylcyclohexyl acetate, a mixture of trans / cis isomers).

[0237] (1SR,3RS)-1-(2-(1,3-dioxolan-2-yl)ethyl)-3-isopropylcyclohexyl acetate (main isomer) (1SR,3SR)-1-(2-(1,3-dioxolan-2-yl)ethyl)-3-isopropylcyclohexyl acetate (a secondary isomer) [ka]

[0238] 1-(2-(1,3-dioxolan-2-yl)ethyl)-4-isopropylcyclohexyl acetate (characteristic signal, mixture of trans / cis isomers) [ka]

[0239] Step 3: Production of 2-(2-(5-isopropylcyclohex-1-en-1-yl)ethyl)-1,3-dioxolane / 2-(2-(3-isopropylcyclohex-1-en-1-yl)ethyl)-1,3-dioxolane The compound was prepared using the compound prepared in the previous step as a starting material, following the procedure reported for the production of 2-(2-(4-(tert-butyl)cyclohex-1-en-1-yl)ethyl)-1,3-dioxolane.

[0240] Crude product GC: 1-(2-(1,3-dioxolan-2-yl)ethyl)-3-isopropylcyclohexyl acetate 41.9% / 47.4% to 55.8% 2-(2-(5-isopropylcyclohex-1-en-1-yl)ethyl)-1,3-dioxolane, 23.9% 2-(2-(3-isopropylcyclohex-1-en-1-yl)ethyl)-1,3-dioxolane, 7.2% 2-(2-(3-isopropylcyclohexylidene)ethyl)-1,3-dioxolane Purity after purification (GC) was 57.2% / 24.7% / 7.3% (the product contained 10% 2-(2-(4-isopropylcyclohex-1-en-1-yl)ethyl)-1,3-dioxolane).

[0241] 2-(2-(5-isopropylcyclohex-1-en-1-yl)ethyl)-1,3-dioxolane (main isomer) / 2-(2-(3-isopropylcyclohex-1-en-1-yl)ethyl)-1,3-dioxolane (secondary isomer) [ka]

[0242] 2-(2-(5-isopropylcyclohex-1-en-1-yl)ethyl)-1,3-dioxolane (main isomer) [ka]

[0243] 2-(2-(3-isopropylcyclohex-1-en-1-yl)ethyl)-1,3-dioxolane (a secondary isomer) [ka]

[0244] 2-(2-(4-isopropylcyclohex-1-en-1-yl)ethyl)-1,3-dioxolane (10% of the mixture).

[0245] [ka]

[0246] Step 4: Production of 3-(5-isopropylcyclohex-1-en-1-yl)propanal / 3-(3-isopropylcyclohex-1-en-1-yl)propanal / 3-(4-butylcyclohex-1-en-)1-yl)propanal The compound (7 / 3 mixture) was prepared using the compound prepared in the previous step as a starting material, following the procedure reported in Example 13. 1 H and 13The results of the 1C-NMR analysis were consistent with data from the literature (see International Publication No. 2017046071 by R. Moretti and A. Birkbeck).

[0247] 3-(5-isopropylcyclohex-1-en-1-yl)propanal (main isomer) [ka]

[0248] 3-(3-isopropylcyclohex-1-en-1-yl)propanal (a secondary isomer) [ka]

[0249] 3-(4-isopropylcyclohex-1-en-1-yl)propanal (10% of the mixture) [ka]

[0250] c) Production of 3-(4-butylcyclohex-1-en-1-yl)propanal Step 1: Hydroformylation of (4-butyl-1-vinylcyclohexyl acetate) with bifefos-Rh A mixture of (4-butyl-1-vinyl-cyclohexyl)acetate (cis / trans, 36% / 61%, 5.06 g, 22.555 mmol), Rh(CO)2acac (3.1 mg, 0.012 mmol), and bifefos (26.3 mg, 0.0334 mmol) was placed in an autoclave. The container was purged with H2 / CO (1:1, 4 × 5 bar) and heated at 90°C and a synthesis gas pressure of 10 bar for 24 hours with vigorous stirring. After cooling and depressurization, GLC analysis of the colorless oil of the crude product revealed complete conversion and the presence of linear 4-butyl-1-(3-oxopropyl)cyclohexyl acetate (89.9%, cis / trans, 33.2% / 56.7%).

[0251] 4-Butyl-1-(3-oxopropyl)cyclohexyl acetate: [ka]

[0252] Step 2: Preparation of 1-(2-(1,3-dioxolan-2-yl)ethyl)-4-butylcyclohexyl acetate The compound was prepared using the compound produced in the previous step as a starting material, following the procedure reported in Example 10.

[0253] Crude product GC: 4-butyl-1-(3-oxopropyl)cyclohexyl acetate (33.2% / 56.7%) yielded 50.1% / 31.7% 1-(2-(1,3-dioxolan-2-yl)ethyl)-4-butylcyclohexyl acetate and 4.3% 2-(2-(4-butylcyclohex-1-en-1-yl)ethyl)-1,3-dioxolane / 1.8% 2-(2-(4-butylcyclohexylidene)ethyl)-1,3-dioxolane.

[0254] Purity after purification (GC): 33.8% / 66.2%.

[0255] (2-(4-(tert-butyl)cyclohex-1-en-1-yl)ethyl)-1,3-dioxolane [ka]

[0256] Main isomer: trans [ka]

[0257] Cis isomer [ka]

[0258] Step 3: Production of 2-(2-(4-butylcyclohex-1-en-1-yl)ethyl)-1,3-dioxolane This compound was prepared using the compound prepared in the previous step as a starting material, following the procedure reported for the production of 2-(2-(4-(tert-butyl)cyclohex-1-en-1-yl)ethyl)-1,3-dioxolane.

[0259] Crude product GC: 91.2% 2-(2-(4-butylcyclohex-1-en-1-yl)ethyl)-1,3-dioxolane / 5.2% 2-(2-(4-butylcyclohexylidene)ethyl)-1,3-dioxolane from 1-(2-(1,3-dioxolane-2-yl)ethyl)-4-butylcyclohexyl acetate (purity 33.8% / 66.2%).

[0260] Purity after purification (GC): 92.9% / 5.8%.

[0261] 2-(2-(4-butylcyclohex-1-en-1-yl)ethyl)-1,3-dioxolane [ka]

[0262] Step 4: Production of 3-(4-butylcyclohex-1-en-1-yl)propanal The compound was prepared using the compound prepared in the previous step as a starting material, following the procedure reported in Example 13. 1 H and 13 The results of the 1C-NMR analysis were consistent with data from the literature (see R. Moretti, International Publication No. 2019185599).

[0263] 3-(4-butylcyclohex-1-en-1-yl)propanal [ka]

[0264] d) Preparation of 3-(2-ethyl-4,4-dimethylcyclohex-1-en-1-yl)propanal / 3-(6-ethyl-4,4-dimethylcyclohex-1-en-1-yl)propanal Step 1: Hydroformylation of 2-ethyl-4,4-dimethyl-1-vinylcyclohexyl acetate with bifefos-Rh A mixture of (1SR,2SR)- and (1SR,2RS)-2-ethyl-4,4-dimethyl-1-vinylcyclohexyl acetate (49.5% / 46.2%, 3.02 g, 13.462 mmol), Rh(CO)2acac (2.1 mg, 0.0081 mmol), and bifefos (16.8 mg, 0.0214 mmol) were placed in an autoclave. The container was purged with H2 / CO (1:1, 4 × 5 bar) and heated at 90°C and a synthesis gas pressure of 10 bar for 24 hours with vigorous stirring. After cooling and depressurization, GLC analysis of the crude yellow oil revealed complete conversion and the presence of linear (1SR,2SR)- and (1SR,2RS)-2-ethyl-4,4-dimethyl-1-(3-oxopropyl)cyclohexyl acetate (49% / 42%).

[0265] (1SR,2SR)- and (1SR,2RS)-2-ethyl-4,4-dimethyl-1-(3-oxopropyl)cyclohexylacetate: [ka]

[0266] Step 2: Preparation of 1-(2-(1,3-dioxolan-2-yl)ethyl)-2-ethyl-4,4-dimethylcyclohexyl acetate The compound was prepared using the compound produced in the previous step as a starting material, following the procedure reported in Example 10.

[0267] Crude product GC: 49% / 42% of 2-ethyl-4,4-dimethyl-1-(3-oxopropyl)cyclohexyl acetate yielded 44.1% / 38.4% of 1-(2-(1,3-dioxolan-2-yl)ethyl)-2-ethyl-4,4-dimethylcyclohexyl acetate and 2-(2-(2-ethyl-4,4-dimethylcyclohex-1-en-1-yl)ethyl)-1,3-dioxolane / 2-(2-(6-ethyl-4,4-dimethylcyclohex-1-en-1-yl)ethyl)-1,3-dioxolane (5.6% / 2.6%).

[0268] Purity after purification (GC): 51.9% / 45.3% (containing 2.7% 2-ethyl-4,4-dimethyl-1-(3-oxopropyl)cyclohexyl acetate).

[0269] 1-(2-(1,3-dioxolan-2-yl)ethyl)-2-ethyl-4,4-dimethylcyclohexyl acetate [ka]

[0270] (1SR,2SR)-1-(2-(1,3-dioxolan-2-yl)ethyl)-2-ethyl-4,4-dimethylcyclohexyl acetate (main isomer) [ka]

[0271] (1SR,2RS)-1-(2-(1,3-dioxolan-2-yl)ethyl)-2-ethyl-4,4-dimethylcyclohexyl acetate (a secondary isomer) [ka]

[0272] Step 3: Production of 2-(2-(2-ethyl-4,4-dimethylcyclohex-1-en-1-yl)ethyl)-1,3-dioxolane / 2-(2-(6-ethyl-4,4-dimethylcyclohex-1-en-1-yl)ethyl)-1,3-dioxolane The compound was prepared using the compound prepared in the previous step as a starting material, following the procedure reported for the preparation of 2-(2-(4-(tert-butyl)cyclohex-1-en-1-yl)ethyl)-1,3-dioxolane.

[0273] From the crude product GC: 1-(2-(1,3-dioxolan-2-yl)ethyl)-2-ethyl-4,4-dimethylcyclohexyl acetate (purity 51.9% / 45.3%), 71.9% / 13.8% of 2-(2-(2-ethyl-4,4-dimethylcyclohex-1-en-1-yl)ethyl)-1,3-dioxolane / 2-(2-(6-ethyl-4,4-dimethylcyclohex-1-en-1-yl)ethyl)-1,3-dioxolane and 2.9% of 2-(2-(2-ethyl-4,4-dimethylcyclohexylidene)ethyl)-1,3-dioxolane.

[0274] Purity after purification (GC): 81.8% / 15.4% / 2.7%.

[0275] 2-(2-(2-ethyl-4,4-dimethylcyclohex-1-en-1-yl)ethyl)-1,3-dioxolane / 2-(2-(6-ethyl-4,4-dimethylcyclohex-1-en-1-yl)ethyl)-1,3-dioxolane [ka]

[0276] 2-(2-(2-ethyl-4,4-dimethylcyclohex-1-en-1-yl)ethyl)-1,3-dioxolane (main isomer) [ka]

[0277] 2-(2-(6-ethyl-4,4-dimethylcyclohex-1-en-1-yl)ethyl)-1,3-dioxolane (a secondary isomer) [ka]

[0278] Step 4: Production of 3-(2-ethyl-4,4-dimethylcyclohex-1-en-1-yl)propanal and 3-(6-ethyl-4,4-dimethylcyclohex-1-en-1-yl)propanal Compound (84 / 16 mixture) was prepared using the compound prepared in the previous step as a starting material, following the procedure reported in Example 13.

[0279] 3-(2-ethyl-4,4-dimethylcyclohex-1-en-1-yl)propanal (main isomer) [ka]

[0280] 3-(6-ethyl-4,4-dimethylcyclohex-1-en-1-yl)propanal (a secondary isomer) [ka]

[0281] e) Manufacture of 3-(4-isopropylcyclopent-1-en-1-yl)propanal / 3-(3-isopropylcyclopent-1-en-1-yl)propanal Step 1: Hydroformylation of 3-isopropyl-1-vinylcyclopentyl acetate with bifefos-Rh A mixture of (1SR,3RS)- and (1SR,3RS)-(3-isopropyl-1-vinyl-cyclopentyl) acetate (59% / 39%, 5.02 g, 25.574 mmol), [Rh(CO)2acac] (3.3 mg, 0.0128 mmol), and bifefos (30.7 mg, 0.039 mmol) were placed in an autoclave. The container was purged with H2 / CO (1:1, 4 × 5 bar) and heated at 90°C and a synthesis gas pressure of 10 bar for 24 hours with vigorous stirring. After cooling and depressurization, GLC analysis of the crude yellow oil revealed complete conversion and the presence of linear (1SR,3SR)- and (1SR,3RS)-3-isopropyl-1-(3-oxopropyl)cyclopentyl acetate (57% / 35%).

[0282] (1SR,3SR)- and (1SR,3RS)-3-isopropyl-1-(3-oxopropyl)cyclopentyl acetate: [ka]

[0283] (1SR,3SR)-3-isopropyl-1-(3-oxopropyl)cyclopentyl acetate (main ingredient) [ka]

[0284] (1SR,3RS)-3-isopropyl-1-(3-oxopropyl)cyclopentyl acetate (auxiliary) [ka]

[0285] Step 2: Preparation of 1-(2-(1,3-dioxolan-2-yl)ethyl)-3-isopropylcyclopentyl acetate The compound was prepared using the compound produced in the previous step as a starting material, following the procedure reported in Example 10.

[0286] Crude product GC: 3-isopropyl-1-(3-oxopropyl)cyclopentyl acetate (57% / 35%) to 38.2% / 27.6% 1-(2-(1,3-dioxolan-2-yl)ethyl)-3-isopropylcyclopentyl acetate and 7.3% / 6.0% 2-(2-(4-isopropylcyclopent-1-en-1-yl)ethyl)-1,3-dioxolane / 2-(2-(3-isopropylcyclopent-1-en-1-yl)ethyl)-1,3-dioxolane.

[0287] Purity after purification (GC): 57.4% / 41.6%.

[0288] 1-(2-(1,3-dioxolan-2-yl)ethyl)-3-isopropylcyclopentyl acetate [ka]

[0289] (1SR,3SR)-1-(2-(1,3-dioxolan-2-yl)ethyl)-3-isopropylcyclopentyl acetate (main isomer) [ka]

[0290] (1SR,3RS)-1-(2-(1,3-dioxolan-2-yl)ethyl)-3-isopropylcyclopentyl acetate (a secondary isomer) [ka]

[0291] Step 3: Preparation of 2-(2-(4-isopropylcyclopent-1-en-1-yl)ethyl)-1,3-dioxolane / 2-(2-(3-isopropylcyclopent-1-en-1-yl)ethyl)-1,3-dioxolane The compound was prepared using the compound prepared in the previous step as a starting material, following the procedure reported for the preparation of 2-(2-(4-(tert-butyl)cyclohex-1-en-1-yl)ethyl)-1,3-dioxolane.

[0292] Crude product GC: 42.9% / 40.2% of 2-(2-(4-isopropylcyclopent-1-en-1-yl)ethyl)-1,3-dioxolane / 2-(2-(3-isopropylcyclopent-1-en-1)-yl)ethyl)-1,3-dioxolane and 7.3% of 2-(2-(3-isopropylcyclopentylidene)ethyl)-1,3-dioxolane from 1-(2-(1,3-dioxolane-2-yl)ethyl)-3-isopropylcyclopentyl acetate (purity 57.4% / 41.6%).

[0293] Purity after purification (GC): 47.8% / 47.6% / 4.6%.

[0294] 2-(2-(4-isopropylcyclopent-1-en-1-yl)ethyl)-1,3-dioxolane / 2-(2-(3-isopropylcyclopent-1-en-1-yl)ethyl)-1,3-dioxolane [ka]

[0295] Characteristic signals of 2-(2-(4-isopropylcyclopent-1-en-1-yl)ethyl)-1,3-dioxolane: 13¹³C NMR (125 MHz, CDCl3): 46.2 ppm Characteristic signals of 2-(2-(3-isopropylcyclopent-1-en-1-yl)ethyl)-1,3-dioxolane: 13 ¹³C NMR (125 MHz, CDCl3): 52.8 ppm

[0296] Step 4: Preparation of 3-(4-isopropylcyclopent-1-en-1-yl)propanal / 3-(3-isopropylcyclopent-1-en-1-yl)propanal The compound (1 / 1 mixture) was prepared using the compound prepared in the previous step as a starting material, following the procedure reported in Example 13.

[0297] [ka]

[0298] 3-(4-isopropylcyclopent-1-en-1-yl)propanal [ka]

[0299] 3-(3-isopropylcyclopent-1-en-1-yl)propanal [ka]

[0300] Example 23 Hydroformylation of ((4,4-dimethyl-1-vinylcyclohexyl)oxy)trimethylsilane by bifefos-Rh (4,4-dimethyl-1-vinyl-cyclohexoxy)-trimethyl-silane (96%, 5.04 g, 22.26 mmol), Rh(CO)2acac (3.3 mg, 0.0128 mmol), and bifefos (27.3 mg, 0.0347 mmol) were placed in an autoclave. The container was purged with H2 / CO (1:1, 4 × 5 bar) and heated at 90°C and a synthesis gas pressure of 10 bar for 24 hours with vigorous stirring. After cooling and depressurization, GLC analysis of the crude product revealed complete conversion and the presence of 3-(4,4-dimethyl-1-((trimethylsilyl)oxy)cyclohexyl)propanal (92.2%) and ((1-ethyl-4,4-dimethylcyclohexyl)oxy)trimethylsilane (6.8%).

[0301] 3-(4,4-dimethyl-1-((trimethylsilyl)oxy)cyclohexyl)propanal: [ka]

[0302] Example 24 Screening of acids / Lewis acids for the conversion of dioxolane acetate to unsaturated dioxolane. For acid / Lewis acid screening, the substrate (1-(2-(1,3-dioxolan-2-yl)ethyl)-4,4-dimethylcyclohexyl acetate, 216 mg, 0.8 mmol) was heated in a sealed glass vial in 1 mL of dry toluene in the presence of a catalyst (acid, Lewis acid) (1 hour at room temperature, 1 hour at 50°C, 1 hour at 120°C, and 2 hours at 120°C). The conversion of the starting material to the target product ((2-(2-(4,4-dimethylcyclohex-1-en-1-yl)ethyl)-1,3-dioxolan, 3-(4,4-dimethylcyclohex-1-en-1-yl)propanal (by-product)) was determined by GC analysis.

[0303] The results obtained are shown in Table 11.

[0304] [Table 11-1] Table 11-2

Claims

1. The following formulas represent one of the stereoisomers or a mixture thereof. 【Chemistry 1】 [In the formula, each R １ , R ２ , R ３ , R ４ , R ５ , R ６ , and R ７ each independently represent a hydrogen atom, or C １～３ alkyl or C １～６ alkenyl optionally substituted with hydroxy or C ２～６ alkoxy, respectively] A method for producing the compound, Formula (II) of one of the stereoisomers or a mixture thereof 【Chemistry 2】 [In the formula, R １ , R ２ , R ３ , R ４ , R ５ , R ６ , and R ７ This has the same meaning as defined in formula (I), where X is a C(O)R group or Si(R') ３ It represents a group, where R is a hydrogen atom and C is a hydrogen atom. １～４ Alkyl alkyl group, C １～４ The group is an alkoxy group or a phenyl group, and R' is independently C １～４ It is an alkyl group. A method comprising hydroformylation and elimination steps starting from a compound.

2. R ３ , R ４ , R ５ , R ６ , and R ７ However, hydrogen atoms or C are independent of each other. １～３ The method according to claim 1, which represents an alkyl group.

3. The compound of formula (I) is in the form of one of its stereoisomers or a mixture thereof, as shown below. 【Transformation 3】 [In the formula, each R １ and R ２ [This has the same meaning as defined in claim 1] It is a compound of, The compound of formula (II) is in the form of one of its stereoisomers or a mixture thereof, as shown below. 【Chemistry 4】 [In the formula, each X, R １ , and R ２ [This has the same meaning as described in claim 1] The method according to claim 1 or 2, wherein the compound is [the compound].

4. R １ C １～４ Alkyl or C ２～４ The method according to any one of claims 1 to 3, wherein the group is an alkenyl group.

5. R １ The method according to any one of claims 1 to 4, wherein is a methyl group.

6. R ２ However, hydrogen atoms, C １～３ alkyl group, or C ２～３ The method according to any one of claims 1 to 5, wherein the group is an alkenyl group.

7. R ２ The method according to any one of claims 1 to 6, wherein is a methyl group.

8. a) Hydroformyrating the compound of formula (II) to obtain one of the stereoisomers or a mixture thereof in the form of the following formula 【Transformation 5】 [wherein, X, R １ , R ２ , R ３ , R ４ , R ５ , R ６ , and R ７ [This has the same meaning as defined in claim 1] The process of obtaining the compound, b) The aldehyde group of the compound of formula (III) obtained in step a) is converted into one of the stereoisomers or a mixture thereof in the form of the following formula 【Transformation 6】 [wherein, X, R １ , R ２ , R ３ , R ４ , R ５ , R ６ , and R ７ This has the same meaning as defined in claim 1, and R ａ and R ｂ C is independent of each other. １～４ Represents an alkyl group, or R ａ and R ｂ Together, C ２～６ [Represents an alkanediyl group] A process of protecting in the form of acetal, c) The OX group of the compound of formula (IV) above is removed, followed by isomerization to obtain one of the stereoisomers or a mixture thereof in the form of the following formula 【Transformation 7】 [In the formula, R １ , R ２ , R ３ , R ４ , R ５ , R ６ , and R ７ This has the same meaning as defined in claim 1, and R ａ and R ｂ [This has the same meaning as defined above.] The process of forming the compound, and d) A step of deprotecting the acetal group to obtain the compound of formula (I), The method according to any one of claims 1 to 7, including

9. a) Formula (II'') of one of the stereoisomers or a mixture thereof 【Transformation 8】 [In the formula, X' is a C(O)R group or Si(R') ３ It is a group, where R is a hydrogen atom, and C １～４ alkyl group, C １～４ The group is an alkoxy group or a phenyl group, and R' is independently C １～４ It is an alkyl group, R １ , R ２ , R ３ , R ４ , R ５ , R ６ , and R ７ This has the same meaning as claim 1. The OX' group of the compound is removed to obtain one of the stereoisomers or a mixture thereof in the form of the following formula 【Chemistry 9】 [In the formula, R １ , R ２ , R ３ , R ４ , R ５ , R ６ , and R ７ [This has the same meaning as defined in claim 1] The process of obtaining the compound, and b) A step of obtaining the compound of formula (I) by hydroformylating the compound of formula (VI), The method according to any one of claims 1 to 7, including

10. The method according to any one of claims 1 to 9, wherein the hydroformylation is carried out in the presence of a rhodium catalyst.

11. The following formulas represent one of the stereoisomers or a mixture thereof. 【Chemistry 10】 [In the formula, X represents a C(O)R group or Si(R') ３ group, R represents a hydrogen atom, C １～４ alkyl group, C １～４ alkoxy group, or a phenyl group, each R' is independently C １～４ alkyl group, and each R １ , R ２ , R ３ , R ４ , R ５ , R ６ , and R ７ are each independently a hydrogen atom, or C １～３ optionally substituted by hydroxy or C １～６ alkyl or C ２～６ alkenyl group] The production of the compound Formula (VII) of one of the stereoisomers or a mixture thereof 【Chemistry 11】 [In the formula, X'' is a hydrogen atom, a C(O)R group, or a Si(R') ３ It is a group, where R is a hydrogen atom, and C １～４ alkyl group, C １～４ The group is an alkoxy group or a phenyl group, and R' is independently C １～４ It is an alkyl group, R １ , R ２ , R ３ , R ４ , R ５ , R ６ , and R ７ [It has the same meaning as defined.] The method according to any one of claims 1 to 10, comprising the step of reducing the compound.

12. The following formulas represent one of the stereoisomers or a mixture thereof. 【Chemistry 12】 [In the formula, X is a C(O)R group or Si(R') ３ It represents a group, where R is a hydrogen atom and C is a hydrogen atom. １～４ alkyl group, C １～４ The group is an alkoxy group or a phenyl group, and R' is independently C １～４ It is an alkyl group, R １ This is methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, or n-butyl group or C ２～６ These represent alkenyl groups, which are hydroxyl or C respectively. １～３ Optionally substituted with an alkoxy group, R ２ These are hydrogen atoms, or hydroxyl or C, respectively. １～３ A methyl group or C that is optionally substituted with an alkoxy group. ２～６ Represents an alkenyl group, and each R ３ , R ４ , R ５ , R ６ , and R ７ These are, independently of each other, a hydrogen atom, or hydroxyl or C, respectively. １～３ C is optionally substituted with an alkoxy group. １～６ Alkyl or C ２～６ R represents an alkenyl group. １ , R ２ , R ３ , R ６ and R ７ R is a hydrogen atom. ４ is a hydrogen atom, and R ５ is C １～３ Is it an alkyl group, or R １ , R ２ , R ３ , R ６ and R ７ R is a hydrogen atom. ４ is C １～３ Alkyl alkyl group, and R ５ [is a hydrogen atom] A compound of [this].

13. The following formulas represent one of the stereoisomers or a mixture thereof. 【Chemistry 13】 [In the formula, X' is C １～３ alkyl group, C ２～３ Alkenyl group, benzyl group, C(O)R group, or Si(R') ３ It is a group, where R is a hydrogen atom, and C １～４ alkyl group, C １～４ The group is an alkoxy group or a phenyl group, and R' is independently C １～４ Each R is an alkyl group. １ , R ２ , R ３ , R ４ , R ５ , R ６ , and R ７ These are, independently of each other, a hydrogen atom, or hydroxyl or C, respectively. １～３ C is optionally substituted with an alkoxy group. １～６ Alkyl or C ２～６ Represents an alkenyl group, R ａ and R ｂ C is independent of each other. １～４ Represents an alkyl group, or R ａ and R ｂ together C ２～６ [Represents an alkanediyl group] A compound of [this].

14. The following formulas represent one of the stereoisomers or a mixture thereof. 【Chemistry 14】 [In the formula, R １ is methyl or C ２～６ These represent alkenyl groups, which are hydroxyl or C respectively. １～３ Optionally substituted with an alkoxy group, R ２ is a hydrogen atom, or hydroxyl or C １～３ A methyl group or C that is optionally substituted with an alkoxy group. ２～６ Represents an alkenyl group, R ａ and R ｂ C is independent of each other. １～４ Represents an alkyl group, or R ａ and R ｂ together C ２～６ [Represents an alkanediyl group] A compound of [this].

15. The following formulas represent one of the stereoisomers or a mixture thereof. 【Chemistry 15】 [In the formula, the dotted line represents a double bond, and X is a C(O)R group or Si(R') ３ It represents a group, where R is a hydrogen atom and C is a hydrogen atom. １～４ alkyl group, C １～４ The group is an alkoxy group or a phenyl group, and R' is independently C １～４ It is an alkyl group, R １ This is methyl, ethyl, propyl, isobutyl, sec-butyl, or n-butyl group or C ２～６ These represent alkenyl groups, which are hydroxyl or C respectively. １～３ Optionally substituted with an alkoxy group, each R ２ , R ３ , R ４ , R ５ , R ６ , and R ７ These are, independently of each other, a hydrogen atom, or hydroxyl or C, respectively. １～３ C is optionally substituted with an alkoxy group. １～６ Alkyl or C ２～６ Does it represent an alkenyl group? R １ , R ２ , R ３ , R ６ and R ７ R is a hydrogen atom. ４ is a hydrogen atom, and R ５ is C １～３ Is it an alkyl group? R １ , R ２ , R ３ , R ６ and R ７ R is a hydrogen atom. ４ is C １～３ Alkyl alkyl group, and R ５ [is a hydrogen atom] The compounds (excluding 4-methyl-1-vinylcyclohexyl acetate and 1-vinyldecahydronaphthalene-1-yl acetate).

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