Method for producing γ,δ-unsaturated aldehyde derivatives

Abstract

The present invention relates to the field of organic synthesis, more specifically to a method for preparing a compound of formula (I). Compounds of formula (III), compounds of formula (IV) and compounds of formula (V) are also part of the present invention.

Description

[Technical field]

[0001] The present invention relates to the field of organic synthesis, more specifically to a method for preparing a compound of formula (I). Compounds of formula (III), compounds of formula (IV) and compounds of formula (V) are also part of the present invention.

[0002] 2. Background of the Invention In the perfume industry, there is a constant need to provide compounds that impart new sensory notes. In particular, there is interest in the aldehyde note, which is one of the important sensory facets of the lily of the valley scent. Compounds that impart this note are therefore especially sought in order to reconstitute the delicate floral scent of lily of the valley, which does not tolerate even the most gentle extraction methods to obtain the essential oil. The γ,δ-unsaturated aldehydes of formula (I) are representative of compounds that impart notes of the lily of the valley-aldehyde olfactory family, such as, for example, the compounds reported in WO 2010 / 052635, WO 2013 / 117433 or WO 2015 / 000821. However, the availability of these compounds is time-consuming and provides the desired compound in low yield and / or low selectivity.

[0003] Because of the industrial importance of these products, new processes that demonstrate improved selectivity, yield and productivity are constantly being sought.

[0004] The compounds of formulae (III), (IV) and (V), which are the subject of the present invention, have never been reported or suggested in the context of the preparation of compounds of formula (I).

[0005] Summary of the Invention The present invention relates to a novel process which allows the preparation of compounds of formula (I) in high yield and high selectivity starting from compounds of formula (II). The process of the present invention represents a new and efficient route to compounds of formula (I).

[0006] Thus, a first subject of the invention is a compound of formula [ka] [wherein all dotted lines represent double bonds, or the dotted line between carbon 1 and carbon 2 is a carbon-carbon single bond or a carbon-carbon double bond, and the other dotted lines are carbon-carbon single bonds; each R 1 , R 2 and R 3 are each independently a hydrogen atom, C 1-3 Alkoxy group, C 1-6 Alkyl group or C 2-6 alkenyl group, each of which is optionally a hydroxy group or 1-3 substituted with an alkoxy group; or R 1 and R 2 Together, C 3-8 Cycloalkyl group or C 5-8 form a cycloalkenyl group; or two R 3 Together, C 1-3 Alkanediyl; R 4 and R 5 are each independently a hydrogen atom, a methyl group or an ethyl group, [ka] [Wherein, dotted line, R 1 , R 2 and R 3 has the same meaning as defined for the compounds of formula (I), and X is CR 4 (OC(=O)R 6 )CHR 5 Group or CHR 4 C(OC(=O)R 6 )(R 5 ) group, R 4 and R 5 has the same meaning as defined for the compounds of formula (I), R 6 is a hydrogen atom, C 1-3 Alkoxy group, phenyl group or C 1-3The method includes a hydroformylation step and an elimination step starting from the form of any one of the stereoisomers of a compound of the formula (I) wherein R is an alkyl group (which may be optionally substituted with 1 to 3 halogen atoms) or a mixture thereof.

[0007] A second subject of the invention is compounds of formula [ka] [wherein all dotted lines represent double bonds, or the dotted line between carbon 1 and carbon 2 is a carbon-carbon single bond or a carbon-carbon double bond, and the other dotted lines are carbon-carbon single bonds; each R 1 , R 2 and R 3 are each independently a hydrogen atom, C 1-3 Alkoxy group, C 1-6 Alkyl group or C 2-6 alkenyl group, each of which is optionally a hydroxy group or 1-3 substituted with an alkoxy group; or R 1 and R 2 Together, C 3-8 Cycloalkyl group or C 5-8 form a cycloalkenyl group; or two R 3 Together, C 1-3 alkanediyl group; X is CR 4 (OC(=O)R 6 )CHR 5 Group or CHR 4 C(OC(=O)R 6 )(R 5 ) group, R 4 and R 5 are each independently a hydrogen atom, a methyl group, or an ethyl group; R 6 is a hydrogen atom, C 1-3 Alkoxy group, phenyl group or C 1-3 and n is an alkyl group optionally substituted with 1 to 3 halogen atoms), with the exception of 5-oxo-1-phenylpentyl acetate.

[0008] Another subject of the invention is a compound of formula [ka] [wherein all dotted lines represent double bonds, or the dotted line between carbon 1 and carbon 2 is a carbon-carbon single bond or a carbon-carbon double bond, and the other dotted lines are carbon-carbon single bonds; each R 1 , R 2 and R 3 are each independently a hydrogen atom, C 1-3 Alkoxy group, C 1-6 Alkyl group or C 2-6 alkenyl group, each of which is optionally a hydroxy group or 1-3 substituted with an alkoxy group; or R 1 and R 2 Together, C 3-8 Cycloalkyl group or C 5-8 form a cycloalkenyl group; or two R 3 Together, C 1-3 alkanediyl group; X is CR 4 (OC(=O)R 6 )CHR 5 Group or CHR 4 C(OC(=O)R 6 )(R 5 ) group, R 4 and R 5 are each independently a hydrogen atom, a methyl group, or an ethyl group; R 6 is a hydrogen atom, C 1-3 Alkoxy group, phenyl group or C 1-3 an alkyl group, which may be optionally substituted with one to three halogen atoms; R a and R b are independent of each other, C 1-4 Represents an alkyl group or R a and R b Together, C 2-6 represents an alkanediyl group, preferably R a and R b Together, (CH2) nrepresents a group wherein n is 2 or 3], or in the form of any one of the stereoisomers or a mixture thereof.

[0009] A further subject of the invention is a compound of formula [ka] [wherein all dotted lines represent double bonds, or the dotted line between carbon 1 and carbon 2 is a carbon-carbon single bond or a carbon-carbon double bond, and the other dotted lines are carbon-carbon single bonds; each R 1 , R 2 and R 3 are each independently a hydrogen atom, C 1-3 Alkoxy group, C 1-6 Alkyl group or C 2-6 alkenyl group, each of which is optionally a hydroxy group or 1-3 substituted with an alkoxy group; or R 1 and R 2 Together, C 3-8 Cycloalkyl group or C 5-8 form a cycloalkenyl group; or two R 3 Together, C 1-3 R is an alkanediyl group; 4 and R 5 are each independently a hydrogen atom, a methyl group, or an ethyl group; R a and R b are independent of each other, C 1-4 Represents an alkyl group or R a and R b Together, C 2-6 represents an alkanediyl group, preferably R a and R b Together, (CH2) nrepresents a group where n is 2 or 3], with the exception of 2-(4-cyclohexylbut-3-en-1-yl)-1,3-dioxolane, 2-(4-phenylbut-3-en-1-yl)-1,3-dioxolane and 2-(4-phenylpent-3-en-1-yl)-1,3-dioxolane.

[0010] Description of the Invention It has now surprisingly been found that it is possible to obtain valuable compounds of formula (I) from novel chemical intermediates as defined herein below by formulae (III), (IV) and (V). The process of the present invention represents a new route to obtain compounds of formula (I) in overall higher yields compared to the processes known from the prior art.

[0011] Thus, a first subject of the invention is a compound of formula [ka] [wherein all dotted lines represent double bonds, or the dotted line between carbon 1 and carbon 2 is a carbon-carbon single bond or a carbon-carbon double bond, and the other dotted lines are carbon-carbon single bonds; each R 1 , R 2 and R 3 are each independently a hydrogen atom, C 1-3 Alkoxy group, C 1-6 Alkyl group or C 2-6 alkenyl group, each of which is optionally a hydroxy group or 1-3 substituted with an alkoxy group; or R 1 and R 2 Together, C 3-8 Cycloalkyl group or C 5-8 form a cycloalkenyl group; or two R 3 Together, C 1-3 R is an alkanediyl group; 4 and R 5are each independently a hydrogen atom, a methyl group or an ethyl group, [ka] [Wherein, dotted line, R 1 , R 2 and R 3 has the same meaning as defined for compounds of formula (I), and X is -C(R 4 )(OC(=O)R 6 )-CH(R 5 )-group or -CH(R 4 )-C(OC(=O)R 6 )(R 5 )-group, R 4 and R 5 has the same meaning as defined for the compounds of formula (I), R 6 is a hydrogen atom, C 1-3 Alkoxy group, phenyl group or C 1-3 The method includes a hydroformylation step and an elimination step starting from the form of any one of the stereoisomers of a compound of the formula (I) wherein R is an alkyl group (which may be optionally substituted with 1 to 3 halogen atoms) or a mixture thereof.

[0012] For the sake of clarity, expressions such as "any one of the stereoisomers or a mixture thereof" have the usual meaning understood by a person skilled in the art, i.e., the compounds of formula (I) and (II) may be pure enantiomers or a mixture of enantiomers. In other words, the compounds of formula (I) and (II) may have at least one stereocenter that may have two different stereochemistries (e.g., R or S). The compounds of formula (I) and (II) may be in the form of pure enantiomers or even in the form of a mixture of enantiomers. The compounds of formula (I) and (II) may be in the form of pure diastereomers or even in the form of a mixture of diastereomers, if the compounds of formula (I) and (II) have two or more stereoisomers. The compounds of formula (I) and (II) may be in the form of racemic or scalemic form. Thus, the compounds of formula (I) and (II) may be in the form of one stereoisomer or a composition of matter that includes or consists of various stereoisomers.

[0013] For clarity, wavy bonds and the like in compounds of formula (I) have the usual meaning understood by those skilled in the art, i.e., the double bond can have a cis configuration corresponding to the Z isomer, a trans configuration corresponding to the E isomer, or a mixture thereof. In other words, the compound of formula (I) can be in the form of its E isomer, its Z isomer, or a mixture thereof, for example, the method of the present invention results in a composition of matter consisting of one or more compounds of formula (I) having the same chemical structure but different configurations of the double bonds. In particular, compound (I) can be in the form of a mixture consisting of isomers E and Z, where said isomer E accounts for at least 25%, at least 35%, at least 50%, or even at least 75% of the total mixture (i.e., mixture E / Z=75 / 25-100 / 0).

[0014] For clarity, phrases such as "all dotted lines represent double bonds, or the dotted line between carbon 1 and carbon 2 is a carbon-carbon single bond or a carbon-carbon double bond, and the other dotted lines are carbon-carbon single bonds" have the ordinary meaning understood by one of ordinary skill in the art, i.e., mean that the entire bond (solid and dotted) between the carbon atoms connected by the dotted lines, e.g., carbon 1 and carbon 2, is a carbon-carbon single bond or a double bond.

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

[0016] For clarity, the phrase "comprising a hydroformylation and elimination step" means that the hydroformylation and elimination reactions may be carried out in any order, in other words, the process of the present invention may include a hydroformylation step followed by an elimination step, or the process of the present invention may include a hydroformylation step followed by an elimination step.

[0017] The terms "alkyl" and "alkenyl" are understood to include branched and straight chain alkyl and alkenyl groups. The terms "alkenyl" and "cycloalkenyl" are understood to include one, two or three olefinic double bonds, preferably one or two olefinic double bonds. The terms "cycloalkyl" and "cycloalkenyl" are understood to include monocyclic or fused, spiro and / or bridged bicyclic or tricyclic cycloalkyl and cycloalkenyl groups, preferably monocyclic cycloalkyl and cycloalkenyl groups.

[0018] To be clear, "R 1 and R 2 Together, C 3-8 Cycloalkyl group or C 5-8 The phrase "form a cycloalkenyl group" means that the carbon atom to which the two groups are attached is C 5-8 Cycloalkyl group or C5-8 It is meant to be included in the cycloalkenyl group.

[0019] The term "alkanediyl" is understood to include branched and straight chain alkanediyl groups.

[0020] According to any embodiment of the present invention, all dotted lines may be double bonds. In other words, the compound of formula (I) has the formula [ka] [In the formula, R 1 , R 2 , R 3 , R 4 and R 5 has the same meaning as defined above], and the compound of formula (II) is in the form of any one of the stereoisomers or a mixture thereof of the compounds of formula (II) [ka] [In the formula, R 1 , R 2 , R 3 and X has the same meaning as defined above], in the form of any one of the stereoisomers or a mixture thereof.

[0021] According to any embodiment of the present invention, R 4 may be a hydrogen atom or a methyl group. Even more specifically, R 4 may be a hydrogen atom.

[0022] According to any embodiment of the present invention, R 5 may be a methyl or ethyl group. Even more specifically, R 5 may be a methyl group.

[0023] According to any embodiment of the present invention, R 3 are each independently a hydrogen atom, a methoxy group, an ethoxy group, or C 1-4 Alkyl group or C 2-4alkenyl groups, each of which may be optionally substituted with a hydroxy, methoxy or ethoxy group. 3 are each independently a hydrogen atom, C 1-3 Alkyl group or C 2-3 alkenyl groups, each of which may be optionally substituted with a hydroxy or methoxy group. 3 are each independently a hydrogen atom or C 1-3 In particular, R 3 may each independently be a hydrogen atom or a methyl or ethyl group. Even more specifically, R 3 may be a hydrogen atom.

[0024] According to any embodiment of the present invention, when the dotted line between carbon 1 and carbon 2 is a carbon-carbon single bond or a carbon-carbon double bond and the other dotted line is a carbon-carbon single bond, the two R 3 Together, C 1-3 In particular, two R 3 may be taken together as a CH2, CHMe or C(Me)2 group. Even more specifically, R 3 together may be a CH2 group.

[0025] According to any embodiment of the present invention, the compound of formula (I) has the formula [ka] [In the formula, each R 1 and R 2 has the same meaning as defined above], and the compound of formula (II) is in the form of any one of the stereoisomers or a mixture thereof, [ka] [In the formula, each R 1 and R 2 has the same meaning as defined above, and X is CH(OC(=O)R 6 )CHMe or CH2C(OC(=O)R6 )(Me), R 6 is C 1-3 Alkoxy group, phenyl group or C 1-3 and R 1 is an alkyl group, which may be optionally substituted with 1 to 3 halogen atoms, or in the form of a mixture thereof.

[0026] According to any embodiment of the present invention, R 6 is a hydrogen atom, a phenyl group or C 1-3 It may be an alkyl group, which may be optionally substituted with one to three halogen atoms. 6 is a hydrogen atom or C 1-3 It may be an alkyl group, which may be optionally substituted with one to three fluorine atoms. 6 may be a methyl group, a trifluoromethyl group or an ethyl group. Even more specifically, R 6 may be a methyl group.

[0027] According to any embodiment of the present invention, X is CHR 4 C(OC(=O)R 6 )(R 5 ) group, R 4 , R 5 and R 6 has the same meaning as defined above.

[0028] According to any embodiment of the present invention, R 1 are each independently a hydrogen atom, a methoxy group, an ethoxy group, or C 1-4 Alkyl group or C 2-4 alkenyl groups, each of which may be optionally substituted with a hydroxy, methoxy or ethoxy group. 1 are each independently a hydrogen atom, C 1-3 Alkyl group or C 2-3 alkenyl groups, each of which may be optionally substituted with a hydroxy or methoxy group. 1may each independently be a hydrogen atom or a methyl or ethyl group. Even more specifically, R 1 may be a methyl group.

[0029] According to any embodiment of the present invention, R 2 are each independently a hydrogen atom, a methoxy group, an ethoxy group, or C 1-4 Alkyl group or C 2-4 alkenyl groups, each of which may be optionally substituted with a hydroxy, methoxy or ethoxy group. 2 are each independently a hydrogen atom, C 1-3 Alkyl group or C 2-3 alkenyl groups, each of which may be optionally substituted with a hydroxy or methoxy group. 2 may each independently be a hydrogen atom, or a methyl or ethyl group. Even more specifically, R 2 may be a hydrogen atom.

[0030] According to any embodiment of the present invention, the compound of formula (II) may be prepared according to methods known in the art.

[0031] According to a particular embodiment of the invention, the process of the invention comprises a hydroformylation starting from a compound of formula (II) followed by an elimination step. The hydroformylation of a compound of formula (II) is carried out by reacting the compound of formula [ka] [Wherein, dotted line, X, R 1 , R 2 and R 3 has the same meaning as defined above] in the form of any one of the stereoisomers or mixtures thereof.

[0032] For clarity, expressions like "hydroformylation" have their ordinary meaning as understood by those skilled in the art, i.e., the reaction is carried out in the presence of a metal catalyst, such as a rhodium, cobalt or platinum complex, preferably a rhodium complex, carbon monoxide, hydrogen and optionally a phosphorus-containing ligand.

[0033] According to any embodiment of the present invention, the hydroformylation is carried out in the presence of a rhodium complex. Rhodium complexes that can be used in the present invention include, but are not limited to, Rh(acac)(CO)2, RhCl3, Rh2AcO4, [Rh(OAc)(COD)]2, Rh4(CO) 12 , Rh6(CO) 16, 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, the rhodium complex may 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. Even more particularly, the rhodium complex may 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 complexes can be added to the reaction medium of the method of the invention in a wide range of concentrations. Non-limiting examples of complex concentration values ​​include values ​​ranging from about 0.0005 mol% to about 5 mol% relative to the substrate mass, preferably from about 0.001 mol% to about 5 mol% relative to the substrate mass. Preferably, the complex concentration is 0.0025 mol% to 2 mol%. It goes without saying that the optimum concentration of the complex depends on the nature of the complex, the nature of the substrate, the nature of the ligand, the reaction temperature and the desired reaction time, as known to those skilled in the art.

[0034] According to any embodiment of the present invention, the 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.

[0035] According to any embodiment of the present invention, the hydroformylation is carried out by reacting a compound of formula PR8 3 [wherein, R 8 is C1~C 12 a group, for example a linear, branched or cyclic alkyl, alkoxy or aryloxy group, optionally substituted, a substituted or unsubstituted phenyl, diphenyl, 2-furanyl, naphthyl or dinaphthyl group, or two R 8 The R groups together form a phosphatrioxadamantane, and another R 8 The reaction can be carried out in the presence of a monodentate phosphorus ligand of the formula R 8 may represent a substituted or unsubstituted phenyl, diphenyl, naphthyl or dinaphthyl group. Possible substituents are the groups R 9 Preferably, the monodentate phosphorus ligand is triphenylphosphine.

[0036] According to any one of the above embodiments, the hydroformylation is carried out by reacting a compound represented by the formula [ka] [In the formula, each R 9 are each independently a C4 heteroaryl group, an optionally substituted C 6-10 represents an aromatic group, or an optionally substituted cyclohexyl group, or two R 9 taken together represent 1,1'-biphenyl-2,2'-dioxy, 1,1'-biphenyl-2,2'-dimethyl, or 1,1'-biphenyl]-2,2'-diyl, each of which is optionally substituted; Q is the formula - a) [ka] [wherein q is 0 or 1, each T independently represents an oxygen atom or a CH2 group, and each R 10 are each independently a hydrogen atom or C 1-8 represents an alkyl group, Z is an oxygen atom, a sulfur atom, or a C(R 11 )2, Si(R12 )2 or NR 11 represents a group, R 11 is a hydrogen atom or R 12 is a group, R 12 is C 1-4 represents a linear or branched alkyl group, preferably a methyl group, or - b) [ka] [wherein q is 0 or 1, r is 0 or 1, each T independently represents an oxygen atom or a CH2 group, and R 13 are each independently a hydrogen atom, a methoxy group or C 1-4 alkyl, which may be optionally substituted with 1 to 3 halogen atoms or alkoxy groups; or two adjacent R 13 together can represent a (CH)4 group, - c) [ka] [Wherein, T, q and R 13 represents the enantiomeric form of any one of the groups Q, Q having the same meaning as above and the wavy line indicating the position of the bond between said Q group and the remainder of compound (A).

[0037] According to any one of the above embodiments, Q may be a group of formula (i) or (ii).

[0038] According to any one of the above embodiments, each R 9 is a furan-2-yl group, a 1H-pyrrol-1-yl group, an optionally substituted C 6-10 It may be an aromatic group or an optionally substituted cyclohexyl group.

[0039] According to any one of the above embodiments, "aromatic group or ring" means a phenyl or naphthyl group, in particular a phenyl group.

[0040] According to any one of the above embodiments, each R 9 may be a phenyl group, a cyclohexyl group, a 3,5-dimethylphenyl group, a 3,5-di(CF3)-phenyl group, a 3,5-dimethyl-4-methoxyphenyl group.

[0041] According to any one of the above embodiments, R 10 may be a hydrogen atom.

[0042] 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.

[0043] According to any one of the above embodiments, R 9 Non-limiting examples of possible substituents are halogen atoms, or C 1-10 The two substituents taken together are one, two, three or four groups selected from the group consisting of alkoxy, alkyl, alkenyl, pyridyl or perhalohydrocarbon groups. 4-8 A cycloalkyl group can be formed, where the term "perhalohydrocarbon" has its usual meaning in the art, such as groups like CF3. In particular, the substituents can be 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.

[0044] According to any one of the above embodiments, the R 9 may be unsubstituted.

[0045] According to any one of the above embodiments, the ligand of formula (A) may be in racemic or optically active form.

[0046] Non-limiting examples of bidentate phosphorus ligands include 2,2'-bis((di(1H-pyrrol-1-yl)phosphanyl)oxy)-1,1'-binaphthalene, 1,1'-((naphthalen-2-yloxy)phosphanediyl)bis(1H-pyrrole), 2,2'-bis((di(1H-pyrrol-1-yl)phosphanyl)oxy)-1,1'-biphenyl, (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine), 2,2'-bis((di(1H-pyrrol-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(phosphanetryl))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]dioxaphosphepine), (oxydi-2,1-phenylene)bis(diphenylphosphine), 2,2'-bis(di phenylphosphinomethyl)-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]dioxaphosphepin-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]dioxaphosphepin-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]dioxaphosphepin-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]dioxaphosphepin-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(naphthalen-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-di Methyl-9H-xanthene-4,5-diyl)bis((2-naphthyl)(phenyl)phosphine), (1S,1'S)-(-)-(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(naphthalen-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-9,9-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), (4,4',6,6'-tetramethoxybiphenyl-2,2'-diyl)bis{bis[3,5-bis(trifluoromethyl)phenyl]phosphine}.

[0047] In particular, the ligand is a bidentate phosphorus ligand, such as (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(phosphanetryl))tetrakis(1H-pyrrole), 6,6'-[(3,3'-di-tert-butyl-5,5'-dimethoxy-1,1'-biphenyl-2,2'-di 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]dioxaphosphepine), (oxydi-2,1-phenylene)bis(diphenylphosphine), 2-((3,3'-di-tert-butyl-2'-((4,8-di-tert-butyl-2,10-dimethoxydibenzo[d,f][1,3,2]dioxaphosphepin-6-yl)oxy)-5,5'-dimethoxy-[1,1'-biphenyl]-2-yl)oxy)-8-methyl- It may be selected from the group consisting of 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).

[0048] The phosphorus ligand can be added to the reaction medium of the method of the present invention in a wide range of concentrations. Non-limiting examples of phosphorus ligand concentration values ​​include values ​​ranging from about 0.001 mol% to about 50 mol% based on the substrate mass, preferably from about 0.005 mol% to about 50 mol% based on the substrate mass, preferably from about 0.005 mol% to about 15 mol% based on the substrate mass. As known to those skilled in the art, the optimal concentration of the phosphorus ligand depends on the nature of the phosphorus ligand, the nature of the substrate, the nature of the metal complex, the reaction temperature and the desired reaction time.

[0049] According to any one of the above embodiments, carbon monoxide and hydrogen gas can be generated in situ by methods known to those skilled in the art, for example from methyl formate, formic acid or formaldehyde. The CO / H2 gas volume ratio is 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, this ratio is 1 / 1.

[0050] The reaction can be carried out in the presence or absence of a solvent. Where a solvent is required or used for practical reasons, any solvent currently used in such reaction types can be used for the purposes of the present invention. Non-limiting examples include C toluene, 1,3-diisopropylbenzene, cumene or pseudocumene or mixtures thereof. 6-12 These include aromatic solvents, alcoholic solvents such as methanol, ethanol, 2-methylbutan-2-ol or mixtures thereof, hydrocarbon solvents such as cyclohexane, heptane or mixtures thereof, ester solvents such as n-butyl acetate, isopropyl acetate, ethyl acetate, or ether solvents such as methyltetrahydrofuran, tetrahydrofuran or mixtures thereof. The choice of solvent depends on the nature of the substrate and / or catalyst, and the skilled person is fully capable of choosing the most suitable solvent in each case to optimize the reaction.

[0051] The hydroformylation reaction can be carried out at a temperature ranging from 50° C. to 150° C., more preferably at a temperature ranging from 80° C. to 130° C., or even at a temperature ranging from 90° C. to 110° C. Of course, the skilled person can also select the preferred temperature depending on the melting and boiling points of the starting and final products and the desired reaction time or conversion.

[0052] The hydroformylation can be carried out at CO / H2 pressures ranging from 1 bar to 50 bar, preferably from 10 bar to 50 bar, more preferably from 10 bar to 25 bar. Of course, the skilled person is fully capable of adjusting the pressure depending on the catalyst loading and the dilution of the substrate in the solvent.

[0053] According to any embodiment of the present invention, the aldehyde group of the compound of formula (III) can be protected prior to the elimination step, or the elimination step can be carried out directly on the compound of formula (III) to provide the compound of formula (I). When the elimination step is carried out on the compound of formula (III), the elimination is carried out under acidic conditions or under thermolysis, in particular under thermolysis. Acids include pTsOH, MsOH, TfOH, H2SO4, H3PO4, KHSO4, NaHSO4, oxalic acid, formic acid, BF3·Et2O, BF3·AcOH, Alox acidic (Axsorb A2-5, Al2O3504C), Amberlyst 15, SiO2, TFA, Wayphos, polyphosphoric acid, zeolites (CBV 21A sold by Zeolyst, CBV 780 sold by Zeolyst, CP814E sold by Zeolyst), boric acid, Al2(SO4)3, CSA, pyridinium p-toluenesulfonate, ZnBr2, K10-S300 (bentonite) sold by Clariant, F24 X (clay) sold by EP minerals, Siral® 40 sold by Sasol The pyrolysis may be carried out at a temperature ranging from 300°C to 600°C.

[0054] The elimination reaction of the aldehyde substrate can be carried out in the presence or absence of a solvent. If a solvent is required or used for practical reasons, any solvent currently used in such reaction types can be used for the purposes of the present invention. Non-limiting examples include C toluene, xylene, 1,3-diisopropylbenzene, cumene or pseudocumene or mixtures thereof. 6-12 These include aromatic solvents, chlorinated solvents such as dichloromethane, dichloroethane or mixtures thereof, and hydrocarbon solvents such as cyclohexane or heptane. The choice of solvent depends on the nature of the substrate and / or catalyst, and the skilled person is fully capable of choosing the most suitable solvent in each case to optimize the reaction.

[0055] The elimination step for the aldehyde substrate under acidic conditions can be carried out at a temperature ranging from 20° C. to 110° C. Of course, the skilled person can also select the preferred temperature depending on the melting and boiling points of the starting and final products and the desired reaction time or conversion rate.

[0056] According to certain embodiments, the elimination on the aldehyde substrate can form a mixture containing different regioisomers, which can be isomerized to the desired regioisomer, i.e., the compound of formula (I), by carrying out the protection of the aldehyde function in the form of an acetal and subsequent isomerization and deprotection. The protection, isomerization and deprotection can be carried out as reported below.

[0057] According to any embodiment of the present invention, the method comprises: a) hydroformylating a compound of formula (II) to give a compound of formula [ka] [Wherein, dotted line, X, R 1 , R 2 and R 3has the same meaning as defined above] in the form of any one of the stereoisomers or a mixture thereof; b) converting the aldehyde group of the compound of formula (III) obtained in step a) into a compound of formula [ka] [Wherein, dotted line, X, R 1 , R 2 and R 3 has the same meaning as defined above, and R a and R b are independent of each other, C 1-4 Represents an alkyl group or R a and R b Together, C 2-6 represents an alkanediyl group, preferably R a and R b Together, (CH2) n wherein n is 2 or 3; c) O-C(=O)R of a compound of formula (IV) 6 group and then optionally isomerized to give [ka] [Wherein, dotted line, R 1 , R 2 , R 3 , R 4 and R 5 has the same meaning as defined above, and R a and R b has the same meaning as defined above] in the form of any one of the stereoisomers or a mixture thereof; d) deprotecting the acetal group to obtain a compound of formula (I); Includes.

[0058] According to any embodiment of the present invention, R a and R b Together, C 2-6In particular, R a and R b Together, C 2-4 More specifically, R a and R b Together, (CH2) n group, where n may be 2 or 3, preferably n is 2.

[0059] According to any embodiment of the present invention, the protection of the aldehyde group of the compound of formula (III) obtained in step a) in the form of an acetal of formula (IV) can be carried out under conventional conditions known to those skilled in the art, i.e. 1-4 Trialkyl orthoformate, C 1-4 Alcohol and C 2-6 It can be carried out using a diol 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 and Al2(SO4)3, F24 X (clay), boric acid and mixtures thereof.

[0060] C 1-4 Trialkyl orthoformate, C 1-4 Alcohol and C 2-6Specific non-limiting examples of diols 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, 2,2-dimethyl-1,3-propanediol. In particular, acetal formation can be achieved by the reaction of C 2-6 It can be carried out using diols, especially ethylene glycol.

[0061] C 1-4 Trialkyl orthoformate, C 1-4 Alcohol or C 2-6 The diol can be added to the reaction medium of the process of the present invention in a wide range of concentrations. As a non-limiting example, values ​​ranging from about 1 to about 2 equivalents relative to the amount of substrate are used. 1-4 Trialkyl orthoformate or C 2-5 As a non-limiting example, a value in the range of about 2 to about 4 equivalents relative to the amount of the substrate can be used as the diol concentration value. 1-4 As those skilled in the art know, the C 1-4 Trialkyl orthoformate, C 1-4 Alcohol or C 2-6 The optimal concentration of diol is C 1-4 Trialkyl orthoformate, C 1-4 Alcohol or C 2-6 It depends on the nature of the diol, the nature of the substrate, the reaction temperature and the desired reaction time.

[0062] 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 invention in a wide range of concentrations. As a non-limiting example, values ​​of acid concentration in the range of about 0.1 to about 5 mol% relative to the substrate mass can be mentioned. As the skilled person knows, the optimal concentration of the acid depends on the nature of the acid, the nature of the substrate, the reaction temperature and the desired reaction time.

[0063] According to any one of the embodiments of the present invention, the formation of the compound of formula (IV) by the method of the present invention is carried out at a temperature of 25° C. to 120° C. In particular, the temperature ranges from 50° C. to 110° C. Of course, the skilled person can also select the preferred temperature depending on the melting and boiling points of the starting and final products and the desired reaction time or conversion rate.

[0064] The acetal formation can be carried out in the presence or absence of a solvent. If a solvent is required or used for practical reasons, any solvent currently used in such reaction types can be used for the purposes of the present invention. Non-limiting examples include C 2 benzene such as xylene, toluene, 1,3-diisopropylbenzene, cumene or pseudocumene. 6-12 Examples of suitable solvents include aromatic solvents or mixtures thereof, hydrocarbon solvents such as cyclohexane, heptane, or mixtures thereof. The choice of solvent depends on the nature of the substrate and / or catalyst, and the skilled person is fully capable of choosing the most suitable solvent in each case to optimize the reaction.

[0065] According to any embodiment of the present invention, the O-C(=O)R 6 The elimination of the group and, optionally, subsequent isomerization to form a compound of formula (V) can be carried out under conventional conditions known to those skilled in the art, such as, for example, pyrolysis followed by isomerization under acidic conditions, or in the presence of a metal catalyst, either in pure form or supported, such as a rhodium, ruthenium, iridium, platinum or palladium complex. The elimination gives a compound of formula (V) and a compound of formula (V'). [ka] [Wherein, dotted line, R 1 , R 2 , R 3 , R 4 , R 5 , R a and R b has the same meaning as defined above], and / or R 5 is not a hydrogen atom, formula (V'') [ka] [Wherein, dotted line, R 1 , R 2 , R 3 , R 4 , R a and R b has the same meaning as defined above, and R 5’ may be a hydrogen atom or a methyl group] may form any one of the stereoisomers or a mixture thereof.

[0066] The isomer of formula (V') and the isomer of formula (V'') can be converted to the compound of formula (V) by isomerization. In particular, the elimination and isomerization can be a one-pot process carried out in the presence of an acid. The acid can be a Lewis acid or a Bronsted acid. Specific, non-limiting examples of acids include pTsOH, MsOH, TfOH, H2SO4, H3PO4, KHSO4, NaHSO4, oxalic acid, formic acid, BF3·Et2O, BF3·AcOH, Alox acidic (Axsorb A2-5, Al2O3504C), Amberlyst 15, SiO2, TFA, Wayphos, polyphosphoric acid, zeolites (CBV 21A sold by Zeolyst, CBV 780 sold by Zeolyst, CP814E sold by Zeolyst), boric acid, Al2(SO4)3, CSA, pyridinium p-toluenesulfonate, ZnBr2, K10-S300 (bentonite) sold by Clariant, F24 X (bentonite) sold by EP minerals, Siral® 40 sold by Sasol. It may be selected from the group consisting of HPV, HCl, HBr, Zn(SO4)2, ZnCl2, MgI2 and mixtures thereof.

[0067] The acid used in the one-pot elimination / isomerization reaction can be added to the reaction medium of the method of the present invention in a wide range of concentrations. Non-limiting examples of acid concentration values ​​include values ​​ranging from about 1 mol% to about 20 mol% based on the substrate mass, preferably from about 2 mol% to about 10 mol% based on the substrate mass, and preferably from about 3 mol% to about 6 mol% based on the substrate mass. As known to those skilled in the art, the optimal concentration of the acid depends on the nature of the acid, the nature of the substrate, the reaction temperature and the desired reaction time.

[0068] According to any one of the embodiments of the present invention, the formation of the compound of formula (V) by the method of the present invention is carried out at a temperature between room temperature (RT) and 160° C. In particular, the temperature ranges from 90° C. to 140° C. Of course, the skilled person can also select the preferred temperature depending on the melting and boiling points of the starting and final products and the desired reaction time or conversion rate.

[0069] The one-pot elimination / isomerization reaction can be carried out in the presence or absence of a solvent. If a solvent is required or used for practical reasons, any solvent currently used in such reaction types can be used for the purposes of the present invention. Non-limiting examples include C 2 -based solvents such as xylene, toluene, 1,3-diisopropylbenzene, cumene or pseudocumene or mixtures thereof. 6-12 These include aromatic solvents, hydrocarbon solvents such as cyclohexane, heptane or mixtures thereof, ester or ether solvents such as butyl acetate, diisopropyl ether, dioxane, dimethoxyethane or mixtures thereof. The choice of solvent depends on the nature of the substrate and / or catalyst, and the skilled person is fully capable of choosing the most suitable solvent in each case to optimize the reaction.

[0070] According to certain embodiments, the protection, elimination and isomerization reactions can be carried out in one pot.

[0071] 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 conventional conditions known to those skilled in the art, i.e., in water with a large molar excess of carboxylic acid. Specific and non-limiting examples of carboxylic acid can be selected from the group consisting of acetic acid, propionic acid, citric acid, formic acid, TFA, oxalic acid or mixtures thereof.

[0072] The carboxylic acid used for deprotection can be added to the reaction medium of the method of the present invention in a wide range of concentrations. As a non-limiting example, values ​​of acid concentration in the range of about 5 to about 20 equivalents relative to the substrate mass, preferably 5 to about 10 equivalents relative to the substrate mass, can be mentioned. As known to those skilled in the art, the optimal concentration of acid depends on the nature of the acid, the nature of the substrate, the reaction temperature and the desired reaction time.

[0073] According to any one of the embodiments of the present invention, the formation of the compound of formula (I) by deprotection can be carried out at a temperature of 40° C. to 120° C. In particular, the temperature ranges from 70° C. to 90° C. Of course, the skilled person can also select the preferred temperature depending on the melting and boiling points of the starting and final products and the desired reaction time or conversion rate.

[0074] According to any one of the embodiments of the present invention, the formation of the compound of formula (I) by deprotection can be carried out in the presence or absence of a solvent. If a solvent is required or used for practical reasons, any solvent currently used in such reaction types can be used for the purposes of the present invention. As non-limiting examples, C toluene, xylene, 1,3-diisopropylbenzene, cumene or pseudocumene or mixtures thereof can be used. 6-12 Examples of suitable solvents include aromatic solvents, alcoholic solvents such as methanol, ethanol, 2-methylbutan-2-ol or mixtures thereof, hydrocarbon solvents such as cyclohexane, heptane or mixtures thereof, ester solvents such as n-butyl acetate, isopropyl acetate, ethyl acetate, or ether solvents such as methyltetrahydrofuran, tetrahydrofuran or mixtures thereof. The choice of solvent depends on the nature of the substrate and the carboxylic acid derivative, and the skilled person is fully capable of choosing the most convenient solvent in each case to optimize the reaction.

[0075] According to certain embodiments, the protection, elimination, isomerization and deprotection reactions can be carried out in one pot.

[0076] The process for preparing the compound of formula (I) of the present invention can be carried out under batch and / or continuous conditions. In particular, the elimination step can be carried out under continuous conditions.

[0077] The compounds of formulae (III), (IV) and (V) are generally novel compounds and exhibit many advantages as described above and illustrated in the examples.

[0078] Another subject of the invention is therefore a compound of formula [ka] [wherein all dotted lines represent double bonds, or the dotted line between carbon 1 and carbon 2 is a carbon-carbon single bond or a carbon-carbon double bond, and the other dotted lines are carbon-carbon single bonds; each R 1 , R 2 and R 3 are each independently a hydrogen atom, C 1-3 Alkoxy group, C 1-6 Alkyl group or C 2-6 alkenyl group, each of which is optionally a hydroxy group or 1-3 substituted with an alkoxy group; or R 1 and R 2 Together, C 3-8 Cycloalkyl group or C 5-8 form a cycloalkenyl group; or two R 3 Together, C 1-3 alkanediyl group; X is CR 4 (OC(=O)R 6 )CHR 5 or CHR 4 C(OC(=O)R 6 )(R 5 ), and R 4 and R 5 are each independently a hydrogen atom, a methyl group, or an ethyl group; R 6 is C 1-3 Alkoxy group, phenyl group or C 1-3 and n is an alkyl group optionally substituted with 1 to 3 halogen atoms), with the exception of 5-oxo-1-phenylpentyl acetate.

[0079] Another subject of the invention is a compound of formula [ka] [wherein all dotted lines represent double bonds, or the dotted line between carbon 1 and carbon 2 is a carbon-carbon single bond or a carbon-carbon double bond, and the other dotted lines are carbon-carbon single bonds; each R 1 , R 2 and R 3 are each independently a hydrogen atom, C 1-3 Alkoxy group, C 1-6 Alkyl group or C 2-6 alkenyl group, each of which is optionally a hydroxy group or 1-3 substituted with an alkoxy group; or R 1 and R 2 Together, C 3-8 Cycloalkyl group or C 5-8 form a cycloalkenyl group; or two R 3 Together, C 1-3 alkanediyl group; X is CR 4 (OC(=O)R 6 )CHR 5 or CHR 4 C(OC(=O)R 6 )(R 5 ), and R 4 and R 5 are each independently a hydrogen atom, a methyl group, or an ethyl group; R 6 is C 1-3 Alkoxy group, phenyl group or C 1-3 an alkyl group, which may be optionally substituted with one to three halogen atoms; R a and R b are independent of each other, C 1-4 Represents an alkyl group or R a and R b Together, C 2-6 represents an alkanediyl group, preferably R a and R b Together, (CH2) n represents a group wherein n is 2 or 3], or in the form of any one of the stereoisomers or a mixture thereof.

[0080] Another subject of the invention is a compound of formula [ka] [wherein all dotted lines represent double bonds, or the dotted line between carbon 1 and carbon 2 is a carbon-carbon single bond or a carbon-carbon double bond, and the other dotted lines are carbon-carbon single bonds; each R 1 , R 2 and R 3 are each independently a hydrogen atom, C 1-3 Alkoxy group, C 1-6 Alkyl group or C 2-6 alkenyl group, each of which is optionally a hydroxy group or 1-3 substituted with an alkoxy group; or R 1 and R 2 Together, C 3-8 Cycloalkyl group or C 5-8 form a cycloalkenyl group; or two R 3 Together, C 1-3 R is an alkanediyl group; 4 and R 5 are each independently a hydrogen atom, a methyl group or an ethyl group; R a and R b are independent of each other, C 1-4 Represents an alkyl group or R a and R b Together, C 2-6 represents an alkanediyl group, preferably R a and R b Together, (CH2) n represents a group where n is 2 or 3], with the exception of 2-(4-cyclohexylbut-3-en-1-yl)-1,3-dioxolane, 2-(4-phenylbut-3-en-1-yl)-1,3-dioxolane and 2-(4-phenylpent-3-en-1-yl)-1,3-dioxolane. Another subject of the invention is a compound of formula [ka] [wherein all dotted lines represent double bonds, or the dotted line between carbon 1 and carbon 2 is a carbon-carbon single bond or a carbon-carbon double bond, and the other dotted lines are carbon-carbon single bonds; each R 1 , R 2 and R 3 are each independently a hydrogen atom, C 1-3 Alkoxy group, C 1-6 Alkyl group or C 2-6 alkenyl group, each of which is optionally a hydroxy group or 1-3 substituted with an alkoxy group; or R 1 and R 2 Together, C 3-8 Cycloalkyl group or C 5-8 form a cycloalkenyl group; or two R 3 Together, C 1-3 alkanediyl group; X is CR 4 (OC(=O)R 6 )CHR 5 or CHR 4 C(OC(=O)R 6 )(R 5 ), and R 4 and R 5 are each independently a hydrogen atom, a methyl group, or an ethyl group; R 6 is C 1-3 Alkoxy group, phenyl group or C 1-3 is an alkyl group, said group being optionally substituted with 1 to 3 halogen atoms, in the form of any one of the stereoisomers or a mixture thereof, in the preparation of a compound of formula (I).

[0081] Another subject of the invention is a compound of formula [ka] [wherein all dotted lines represent double bonds, or the dotted line between carbon 1 and carbon 2 is a carbon-carbon single bond or a carbon-carbon double bond, and the other dotted lines are carbon-carbon single bonds; each R 1 , R 2 and R 3are each independently a hydrogen atom, C 1-3 Alkoxy group, C 1-6 Alkyl group or C 2-6 alkenyl group, each of which is optionally a hydroxy group or 1-3 substituted with an alkoxy group; or R 1 and R 2 Together, C 3-8 Cycloalkyl group or C 5-8 form a cycloalkenyl group; or two R 3 Together, C 1-3 alkanediyl group; X is CR 4 (OC(=O)R 6 )CHR 5 or CHR 4 C(OC(=O)R 6 )(R 5 ), and R 4 and R 5 are each independently a hydrogen atom, a methyl group, or an ethyl group; R 6 is C 1-3 Alkoxy group, phenyl group or C 1-3 an alkyl group, which may be optionally substituted with one to three halogen atoms; R a and R b are independent of each other, C 1-4 Represents an alkyl group or R a and R b Together, C 2-6 represents an alkanediyl group, preferably R a and R b Together, (CH2) n represents a group wherein n is 2 or 3] in the form of any one of the stereoisomers or a mixture thereof, in the preparation of a compound of formula (I).

[0082] A further subject of the invention is a compound of formula [ka] [wherein all dotted lines represent double bonds, or the dotted line between carbon 1 and carbon 2 is a carbon-carbon single bond or a carbon-carbon double bond, and the other dotted lines are carbon-carbon single bonds; each R 1 , R 2 and R 3 are each independently a hydrogen atom, C 1-3 Alkoxy group, C 1-6 Alkyl group or C 2-6 alkenyl group, each of which is optionally a hydroxy group or 1-3 substituted with an alkoxy group; or R 1 and R 2 Together, C 3-8 Cycloalkyl group or C 5-8 form a cycloalkenyl group; or two R 3 Together, C 1-3 R is an alkanediyl group; 4 and R 5 are each independently a hydrogen atom, a methyl group or an ethyl group; R a and R b are independent of each other, C 1-4 Represents an alkyl group or R a and R b Together, C 2-6 represents an alkanediyl group, preferably R a and R b Together, (CH2) n represents a group wherein n is 2 or 3] in the form of any one of the stereoisomers or a mixture thereof, in the preparation of a compound of formula (I).

[0083] Typical modes for carrying out the method of the invention are reported in the following examples. EXAMPLES

[0084] The invention will now be described in more detail by the following examples, in which abbreviations have their usual meaning in the art and temperatures are given in degrees Celsius (°C). Preparation of precatalyst and ligand solutions was carried out using standard Schlenk techniques under an inert atmosphere (argon). Solvents were routinely dried and distilled under an argon atmosphere. NMR spectra were recorded on a Bruker AV 300, AV 400, or AV 500 MHz spectrometer at 20°C. Chemical shifts were expressed as solvent signals (chloroform, δ H = 7.26 ppm, δ C = 77.0 ppm. Signal assignments are 1 H, 1 H-COSY, -NOESY, 13 C, 1 Confirmation was performed by recording H-HSQC and -HMBC experiments. Gas chromatography was performed on an Agilent 7890 A series equipped with an HP5 column (30 m × 0.25 mm inner diameter, 0.25 μm film thickness) and tetradecane was used as the internal standard.

[0085] [Example 1] (Production of 2-methyl-1-(p-tolyl)but-3-en-2-ol from 4-methylphenylacetone) To a cooled solution (0°C) of 139.9 mL of vinylmagnesium chloride (1.6 M in THF, 254.4 mmol, 1.1 eq) was slowly added a solution of 1-(p-tolyl)propan-2-one (37.7 g, 254.4 mmol) in 153 mL of THF. During the addition of the ketone, the internal temperature did not exceed 5°C. The mixture was further stirred overnight (16 h) at 0°C. The reaction mixture was slowly added to a cooled solution of 18.3 g of AcOH (305.2 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 over Na2SO4, the solvent was evaporated under reduced pressure (500-20 mbar, 50°C). The crude product (48.2 g) was purified by distillation through a Vigreux column under reduced pressure (oil bath 40°C-125°C, 50-4 mbar, bp 97°C / 4 mbar) to obtain 35.5 g (201.4 mmol, 79% yield) of 2-methyl-1-(p-tolyl)but-3-en-2-ol as a colorless liquid.

[0086] 2-Methyl-1-(p-tolyl)but-3-en-2-ol: In CDCl3 1 The H-NMR analysis results were consistent with the data in the literature: Araki, S.; Ohmura, M.; Butsugan, Y. Bulletin of the Chemical Society of Japan(1986),59(6),2019-20.

[0087] [ka]

[0088] [Example 2] (Production of 2-methyl-1-(p-tolyl)but-3-en-2-yl acetate from 2-methyl-1-(p-tolyl)but-3-en-2-ol) To a stirred solution of 2-methyl-1-(p-tolyl)but-3-en-2-ol (5 g, 28.37 mmol) and acetic anhydride (5.8 g, 56.7 mmol) in toluene (5 mL) was added DMAP (173 mg, 1.42 mmol, 5 mol%) and triethylamine (2.87 g, 28.37 mmol) under N2. The mixture was heated at 80 °C for 5 h. The mixture was cooled in a cold water bath (10 °C) and 5 mL of water was added slowly (hydrolysis of residual Ac2O). 6.97 g of 25% aqueous NaOH (1.5 eq) was added slowly. After stirring for 30 min, 20 mL of MTBE was added. The phases were separated and the organic phase was washed twice with water (10 mL) and then once with saturated aqueous NaHCO3 (15 mL). After a final wash with brine (10 mL), the organic phase was dried over sodium sulfate, filtered and evaporated under reduced pressure (45° C., 30 mbar). The crude product (6.1 g) was purified by flash chromatography (120 g cartridge, eluent 100% pentane to 95% pentane / 5% MTBE). 2-Methyl-1-(p-tolyl)but-3-en-2-yl acetate was isolated as a colorless liquid (5.5 g, 25.196 mmol, 88.8 yield).

[0089] 2-Methyl-1-(p-tolyl)but-3-en-2-yl acetate [ka]

[0090] [Example 3] (Hydroformylation of 2-methyl-1-(p-tolyl)but-3-en-2-yl acetate) The autoclave was charged with 2-methyl-1-(p-tolyl)but-3-en-2-yl acetate (5.01 g, 22.951 mmol), Rh(CO)2acac (3.0 mg, 0.0116 mmol) and BiPhePhos (27.3 mg, 0.0347 mmol). The vessel was purged with H2 / CO (1:1, 4 x 5 bar) and heated at 90 °C and 10 bar syngas pressure for 24 h with vigorous stirring. After cooling and depressurization, GLC analysis of the crude yellow oil revealed total conversion and the presence of linear 2-methyl-5-oxo-1-(p-tolyl)pentan-2-yl acetate (89%), the hydrogenated starting material 2-methyl-1-(p-tolyl)butan-2-yl acetate (8%) and some unidentified by-products. This crude reaction mixture (5 g) was carried further to the next step.

[0091] 2-Methyl-5-oxo-1-(p-tolyl)pentan-2-yl acetate: [ka]

[0092] [Example 4] (Production of 4-(1,3-dioxolan-2-yl)-2-methyl-1-(p-tolyl)butan-2-yl acetate from 2-methyl-5-oxo-1-(p-tolyl)pentan-2-yl acetate) The crude product from the previous experiment (GC 89%, 5 g) (containing 19.5 mmol of 2-methyl-5-oxo-1-(p-tolyl)pentan-2-yl acetate) was stirred in the presence of 1.8 g (29.25 mmol, 1.5 eq) of ethylene glycol and 133 mg of KHSO4 (0.975 mmol, 5 mol%) at 105-113 °C in 5 mL of toluene under Dean-Stark conditions for 1 h (internal temperature, water was removed during 1 h). The mixture was cooled to room temperature and 15 mL of TBME was added. After washing with 5 mL of water, 5 mL of saturated aqueous NaHCO3 and 5 ml of brine, the organic phase was dried over Na2SO4 and the solvent was evaporated under reduced pressure. The crude product (GC 86%) was purified by column chromatography (120 g cartridge, from cyclohexane / MTBE 97 / 3 to cyclohexane / MTBE 7 / 3). 5.13 g (17.55 mmol) of 4-(1,3-dioxolan-2-yl)-2-methyl-1-(p-tolyl)butan-2-yl acetate was isolated as a colorless liquid (76% yield over two steps).

[0093] [ka]

[0094] [Example 5] (Production of (E)-2-(3-methyl-4-(p-tolyl)but-3-en-1-yl)-1,3-dioxolane from 4-(1,3-dioxolan-2-yl)-2-methyl-1-(p-tolyl)butan-2-yl acetate) a) Under pyrolysis 2 g (6.84 mmol) of 4-(1,3-dioxolan-2-yl)-2-methyl-1-(p-tolyl)butan-2-yl acetate in 20 mL of heptane was added slowly (12.5 mL / h) from the top into a heated pyrolysis column (pyrolysis oven at 500 °C) packed with 20 g of quartz cylinder (Rashg 4 × 3 mm) under N2 flow. After the addition was complete, the oven was cooled and 5 ml of heptane was added to wash the quartz cylinder. After adding another 5 mL of heptane, the mixture was washed with 5 mL of water, 5 mL of saturated aqueous NaHCO3 solution and 5 mL of water. 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 evaporated under reduced pressure (Rotavap 10 mbar, 50 °C). A mixture of unsaturated dioxolanes, 1.40 g (6.03 mmol, 88% yield), containing (E)-2-(3-methyl-4-(p-tolyl)but-3-en-1-yl)-1,3-dioxolane, (Z)-2-(3-methyl-4-(p-tolyl)but-3-en-1-yl)-1,3-dioxolane, (E / Z)-2-(3-methyl-4-(p-tolyl)but-2-en-1-yl)-1,3-dioxolane, 2-(3-(4-methylbenzyl)but-3-en-1-yl)-1,3-dioxolane (ratio 29.4 / 24.1 / 17.7 / 28.8) was obtained after column filtration.

[0095] The amounts of (E)-2-(3-methyl-4-(p-tolyl)but-3-en-1-yl)-1,3-dioxolane and (Z)-2-(3-methyl-4-(p-tolyl)but-3-en-1-yl)-1,3-dioxolane were adjusted to 100 mM NaCl, 10 mM NaCl, 10 mM Mg ... The mixture of -(3-methyl-4-(p-tolyl)but-3-en-1-yl)-1,3-dioxolane / (E / Z)-2-(3-methyl-4-(p-tolyl)but-2-en-1-yl)-1,3-dioxolane / 2-(3-(4-methylbenzyl)but-3-en-1-yl)-1,3-dioxolane (6.03 mmol, ratio 29.4 / 24.1 / 17.7 / 28.8) can be concentrated by heating. After heating at 110° C. for 4 hours, the ratio of (E)-2-(3-methyl-4-(p-tolyl)but-3-en-1-yl)-1,3-dioxolane / (Z)-2-(3-methyl-4-(p-tolyl)but-3-en-1-yl)-1,3-dioxolane / (E / Z)-2-(3-methyl-4-(p-tolyl)but-2-en-1-yl)-1,3-dioxolane / 2-(3-(4-methylbenzyl)but-3-en-1-yl)-1,3-dioxolane was found to be 45 / 32 / 20 / 3. The amount of (E)-2-(3-methyl-4-(p-tolyl)but-3-en-1-yl)-1,3-dioxolane increased from 1.77 mmol to 2.71 mmol in 4 hours (40% yield for two steps). The amount of (Z)-2-(3-methyl-4-(p-tolyl)but-3-en-1-yl)-1,3-dioxolane increased from 1.45 to 1.93 mmol in 4 h (40+28% yield over two steps for both isomers).

[0096] (E)-2-(3-methyl-4-(p-tolyl)but-3-en-1-yl)-1,3-dioxolane: [ka] GC 4.49 min (column DB-1 10 m, 80°C to 320°C (30°C / min)

[0097] (Z)-2-(3-methyl-4-(p-tolyl)but-3-en-1-yl)-1,3-dioxolane (signal from mixture): [ka] GC 4.25 min (column DB-1 10 m, 80°C to 320°C (30°C / min)

[0098] (E)-2-(3-methyl-4-(p-tolyl)but-2-en-1-yl)-1,3-dioxolane (characteristic signal): [ka] GC 4.23 min (column DB-1 10 m, 80°C to 320°C (30°C / min)

[0099] (Z)-2-(3-methyl-4-(p-tolyl)but-2-en-1-yl)-1,3-dioxolane (characteristic signals): [ka] GC 4.23 min (column DB-1 10 m, 80°C to 320°C (30°C / min)

[0100] 2-(3-(4-methylbenzyl)but-3-en-1-yl)-1,3-dioxolane (characteristic signal): [ka] GC 4.18 min (column DB-1 10 m, 80°C to 320°C (30°C / min)

[0101] b) Acidic conditions 123 mg (0.855 mmol, 5 mol%) of pTsOH·H2O was heated in 15 mL of toluene under stirring under Dean-Stark conditions (reflux) at 110 °C for 30 min. 5.0 g (17.1 mmol) of 4-(1,3-dioxolan-2-yl)-2-methyl-1-(p-tolyl)butan-2-yl acetate was added slowly (15 min) in 1 mL of toluene. The mixture was further stirred at 110 °C for 2.5 h. After cooling to room temperature, 25 mL of cyclohexane was added. After washing twice with 25 mL of saturated aqueous NaHCO3, 25 ml of water and 25 ml of brine, the organic phase was dried over Na2SO4 and the solvent was evaporated under reduced pressure (50 °C, crude 4.03 g, GC ratio 40 / 27 / 27 / 6 (E)-2-(3-methyl-4-(p-tolyl)but-3-en-1-yl)-1,3-dioxolane / (Z)-2-(3-methyl-4-(p-tolyl)but-3-en-1-yl)-1,3-dioxolane / (E / Z)-2-(3-methyl-4-(p-tolyl)but-3-en-1-yl) but-2-en-1-yl)-1,3-dioxolane / 2-(3-(4-methylbenzyl)but-3-en-1-yl)-1,3-dioxolane, 94% yield (16.0 mmol) of all isomers of unsaturated dioxolanes, 6.4 mmol of (E)-2-(3-methyl-4-(p-tolyl)but-3-en-1-yl)-1,3-dioxolane, 4.32 mmol of (Z)-2-(3-methyl-4-(p-tolyl)but-3-en-1-yl)-1,3-dioxolane, 37+25% yield.

[0102] The amounts of (E)-2-(3-methyl-4-(p-tolyl)but-3-en-1-yl)-1,3-dioxolane and (Z)-2-(3-methyl-4-(p-tolyl)but-3-en-1-yl)-1,3-dioxolane were adjusted to 100 mM KOH / g / g / methanol in the presence of 6 mol % pTsOH and toluene (110 °C) to obtain the isomers (E)-2-(3-methyl-4-(p-tolyl)but-3-en-1-yl)-1, The mixture of 3-dioxolane / (Z)-2-(3-methyl-4-(p-tolyl)but-3-en-1-yl)-1,3-dioxolane / (E / Z)-2-(3-methyl-4-(p-tolyl)but-2-en-1-yl)-1,3-dioxolane / 2-(3-(4-methylbenzyl)but-3-en-1-yl)-1,3-dioxolane can be further concentrated by heating: 7.2 mmol of (E)-2-(3-methyl-4-(p-tolyl)but-3-en-1-yl)-1,3-dioxolane, 5.12 mmol of (Z)-2-(3-methyl-4-(p-tolyl)but-3-en-1-yl)-1,3-dioxolane, yield 42+30%.

[0103] [Example 6] (Production of 2-methyl-1-(p-tolyl)but-3-en-1-ol from 4-methylbenzaldehyde) To a cooled solution (0°C) of 494.4 mL of 1-methyl-2-propenylmagnesium chloride (0.5 M in THF, 247.2 mmol, 1.1 eq) was slowly added a solution of 4-methylbenzaldehyde (27.0 g, 224.7 mmol) in 135 mL of THF. During the addition of the aldehyde, the internal temperature did not exceed 5°C. The mixture was further stirred overnight (16 h) at 0°C and analyzed by GC. The reaction mixture was slowly added to a cooled solution of 16.2 g of AcOH (269.7 mmol) in 200 ml of water. The phases were separated and the aqueous phase was extracted twice with 150 mL of TBME. The combined organic phases were washed with saturated aqueous NaHCO3 and saturated aqueous NaCl. After drying over Na2SO4, the solvent was evaporated under reduced pressure (500-4 mbar, 50°C). The crude product (44.3 g) was purified by distillation through a Vigreux column under reduced pressure (oil bath 120 °C, 900-3 mbar, bp 90 °C / 3 mbar) to obtain 39.0 g (221.3 mmol, 98.4% yield) of 2-methyl-1-(p-tolyl)but-3-en-1-ol (syn / anti mixture) as a colorless liquid.

[0104] NMR analysis in CDCl3 was consistent with literature data for the syn isomer: Shibata, I.; Yoshimura, N.; Yabu, M. Baba, A. Eur. J. Org. Chem. 2001, 3207-3211. S. Hayashi, K. Hirano, H. Yorimitsu, K. Oshima Org. Lett. 2005, 7, 16, 3577-3579.

[0105] 2-Methyl-1-(p-tolyl)but-3-en-1-ol (syn isomer): [ka]

[0106] 2-Methyl-1-(p-tolyl)but-3-en-1-ol (anti isomer): [ka]

[0107] [Example 7] (Production of 2-methyl-1-(p-tolyl)but-3-en-1-yl acetate from 2-methyl-1-(p-tolyl)but-3-en-1-ol) To 9.94 g (56.397 mmol) of 2-methyl-1-(p-tolyl)but-3-en-1-ol, under stirring and under N2 atmosphere, was added DMAP (172 mg, 1.41 mmol, 2.5 mol%) and triethylamine (5.71 g, 56.4 mmol, 1 eq). Then, acetic anhydride (11.515 g, 112.79 mmol, 2 eq) was added slowly (exothermic). The mixture was stirred at room temperature for 1.5 h (complete conversion). The mixture was cooled in an ice bath (0° C.) and 5 mL of water was added slowly (hydrolysis of residual Ac2O). 13.8 g of 25% aqueous NaOH (1.5 eq) was added slowly. After stirring for 30 min, 25 mL of MTBE was added. The phases were separated. The aqueous phase was extracted once with 25 mL of MTBE. The combined organic phases were washed twice with water (15 mL), then once with saturated aqueous NaHCO3 (15 mL) and once with water (15 mL). After a final wash with brine (10 mL), the organic phase was dried over sodium sulfate, filtered and evaporated under reduced pressure (50° C., 50 mbar). The crude product (12.3 g) was purified by flash chromatography (220 g cartridge, eluent 100% pentane to 95% pentane / 5% MTBE). 2-Methyl-1-(p-tolyl)but-3-en-2-yl acetate (1 / 1 mixture of diastereomers) was isolated as a colorless liquid (11.93 g, 54.64 mmol, 97% yield).

[0108] 2-Methyl-1-(p-tolyl)but-3-en-2-yl acetate (1 / 1 mixture of diastereomers) [ka]

[0109] [Example 8] (Hydroformylation of 2-methyl-1-(p-tolyl)but-3-enyl acetate, racemic 1:1 diastereomeric mixture)

[0110] An autoclave was charged with 2-methyl-1-(p-tolyl)-but-3-enyl acetate (5.04 g, 23.0089 mmol), Rh(CO)2acac (3.1 mg, 0.012 mmol) and a racemic diastereomeric mixture of 6,6'-((3,3'-di-tert-butyl-5,5'-dimethoxy-[1,1'-biphenyl]-2,2'-diyl)bis(oxy))didibenzo[d,f][1,3,2]dioxaphosphepine, abbreviated as BiPhePhos (27.9 mg, 0.0355 mmol). The vessel was purged with H2 / CO (1:1, 4 x 5 bar) and heated at 90 °C with vigorous stirring at 10 bar synthesis gas pressure for 24 h. After cooling and depressurization, GLC analysis of the crude colorless oil revealed total conversion and the presence of linear racemic 1:1 diastereomeric 2-methyl-5-oxo-1-(p-tolyl)pentyl acetate (85%, 82% yield, no baseline separation), hydrogenated starting material (7.1%, no baseline separation), and two unidentified products (1.4% / 5.5%) presumed to be isomerized starting material. This crude reaction mixture (5.5 g) was carried further to the next step.

[0111] 2-Methyl-5-oxo-1-(p-tolyl)pentyl acetate (approximately 1:1 mixture of diastereomers): [ka]

[0112] [Example 9] (Preparation of 4-(1,3-dioxolan-2-yl)-2-methyl-1-(p-tolyl)butyl acetate from 2-methyl-5-oxo-1-(p-tolyl)pentyl acetate) 4.5 g (GC 85%) of the crude product from the previous experiment (2-methyl-5-oxo-1-(p-tolyl)pentyl acetate, containing 15.4 mmol of a 1 / 1 mixture of diastereomers) was stirred in 4.5 mL of toluene under Dean-Stark conditions at 105-113 °C for 1 h (internal temperature, water was removed during 1 h) in the presence of 1.51 g (23.1 mmol, 1.5 eq) of ethylene glycol and 105 mg of KHSO4 (0.770 mmol, 5 mol%). The mixture was cooled to room temperature and 15 mL of TBME was added. After washing with 5 mL of water, 5 mL of saturated aqueous NaHCO3 and 5 ml of brine, the organic phase was dried over Na2SO4 and the solvent was evaporated under reduced pressure. The crude material (5.7 g, GC 84.4%) was purified by column chromatography (120 g cartridge, cyclohexane / MTBE 97 / 3 to cyclohexane / MTBE 7 / 3). 4.0 g (13.681 mmol) of 4-(1,3-dioxolan-2-yl)-2-methyl-1-(p-tolyl)butyl acetate (1 / 1 mixture of diastereomers) was isolated as a colorless liquid (89% yield, 73% yield for two steps).

[0113] 4-(1,3-Dioxolan-2-yl)-2-methyl-1-(p-tolyl)butyl acetate (1 / 1 mixture of diastereomers) [ka]

[0114] [Example 10] (Production of (E)-2-(3-methyl-4-(p-tolyl)but-3-en-1-yl)-1,3-dioxolane and (Z)-2-(3-methyl-4-(p-tolyl)but-3-en-1-yl)-1,3-dioxolane from 4-(1,3-dioxolan-2-yl)-2-methyl-1-(p-tolyl)butan-2-yl acetate) 570 mg (1.95 mmol) of the mixture of 4-(1,3-dioxolan-2-yl)-2-methyl-1-(p-tolyl)butan-2-yl acetate (1 / 1 mixture of diastereomers) and 130 mg of heptane were added slowly (12 mL / h) from the top into a heated pyrolysis column (pyrolysis oven at 500 °C) packed with a 20 g quartz cylinder (Rashg 4 × 3 mm) under N2 flow. After the addition was complete, the oven was cooled and 5 ml of heptane was added to wash the quartz cylinder. After the addition of another 5 mL of heptane, the mixture was washed with 5 mL of water, 5 mL of saturated aqueous NaHCO3 solution and 5 mL of water. The aqueous phases were combined and extracted once with 10 mL of heptane. The combined organic phases were washed with brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure (Rotavap 10 mbar, 50 °C).

[0115] It was possible to isolate a product mixture (433 mg) containing 88 mg (0.300 mmol, 15% yield) of 4-(1,3-dioxolan-2-yl)-2-methyl-1-(p-tolyl)butan-2-yl acetate (1 / 1 mixture of diastereomers, recycled starting material), 190 mg (0.819 mmol, 42% yield) of (E)-2-(3-methyl-4-(p-tolyl)but-3-en-1-yl)-1,3-dioxolane, and 155 mg (0.667 mmol, 34% yield) of (Z)-2-(3-methyl-4-(p-tolyl)but-3-en-1-yl)-1,3-dioxolane.

[0116] [Example 11] (Production of 4-methyl-5-(p-tolyl)pent-4-enal from 2-(3-methyl-4-(p-tolyl)but-3-en-1-yl)-1,3-dioxolane) 9.6 g (41.32 mmol) 2-(3-methyl-4-(p-tolyl)but-3-en-1-yl)-1,3-dioxolane, 14.5 mL heptane, 15 g water and 15 g AcOH (5 eq) were mixed and heated under stirring at 80° C. for 4 h (63% conversion). The mixture was cooled to 0° C.-5° C. and 26% aqueous NaOH (9 g NaOH, 25 g water) was added in 1.5 h (internal temperature <10° C.). The aqueous phase was separated (pH 6) and re-extracted with 15 mL heptane. The combined organic phase was washed with 10 mL water and 15 mL saturated aqueous NaHCO3. The organic phase was dried over Na2SO4 and the solvent was evaporated under reduced pressure. 8.73 g of a mixture of 4-methyl-5-(p-tolyl)pent-4-enal (GC 63%, 29.2 mmol, yield 71%) and 2-(3-methyl-4-(p-tolyl)but-3-en-1-yl)-1,3-dioxolane (GC 32%, 12.0 mmol, yield 29%) was obtained (conversion yield 99%).

[0117] 4-Methyl-5-(p-tolyl)pent-4-enal In CDCl3 1 H and 13 The C NMR analysis results were consistent with literature data (R. Moretti, see WO 2010052635).

Claims

1. formula 【Chemistry 1】 [wherein all dotted lines represent double bonds, or the dotted line between carbon 1 and carbon 2 is a carbon-carbon single bond or a carbon-carbon double bond, and the other dotted lines are carbon-carbon single bonds; each R １ , R ２ and R ３ are each independently a hydrogen atom, C １－３ Alkoxy group, C １－６ Alkyl group or C ２－６ alkenyl group, each of which is optionally a hydroxy group or １－３ substituted with an alkoxy group; or R １ and R ２ Together, C ３－８ Cycloalkyl group or C ５－８ form a cycloalkenyl group; or two R ３ Together, C １－３ R is an alkanediyl group; ４ and R ５ are each independently a hydrogen atom, a methyl group, or an ethyl group. A process for the preparation of any one of the stereoisomers of the compound of formula (I) or a mixture thereof, comprising the steps of: The method comprises reacting a compound represented by formula (II) 【Chemistry 2】 [Wherein, dotted line, R １ , R ２ and R ３ has the same meaning as defined for the compounds of formula (I), and X is CR ４ (OC(=O)R ６ ) CHR ５ Group or CHR ４ C(OC(=O)R ６ ) (R ５ ) group, R ４ and R ５ has the same meaning as defined for the compounds of formula (I), R ６ is a hydrogen atom, C １－３ Alkoxy group, phenyl group or C １－３ an alkyl group, which may be optionally substituted with 1 to 3 halogen atoms. The process comprises a hydroformylation step and an elimination step starting from the form of any one of the stereoisomers of the compound of formula (I) or a mixture thereof.

2. R ５ The method of claim 1 , wherein is a methyl group.

3. R ４ The method according to claim 1 or 2, wherein is a hydrogen atom.

4. R １ , R ２ and R ３ are each independently a hydrogen atom or C １－３ 4. The method of claim 1, wherein the alkyl group is an alkyl group.

5. The compound of formula (I) is represented by the formula 【Chemistry 3】 [In the formula, each R １ and R ２ have the same meaning as defined in claim 1. or a mixture thereof, The compound of formula (II) has the formula 【Chemistry 4】 [In the formula, each R １ and R ２ has the same meaning as defined in claim 1, and X is CH(OC(=O)R ６ ) CHMe or CH ２ C(OC(=O)R ６ ) (Me), R ６ is a hydrogen atom, C １－３ Alkoxy group, phenyl group or C １－３ an alkyl group, which may be optionally substituted with 1 to 3 halogen atoms.

5. The process according to claim 1 , wherein the compound is in the form of any one of the stereoisomers of formula (I) or a mixture thereof.

6. R ６ 6. The method according to claim 1, wherein is a methyl group.

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

8. R １ 8. The method of claim 1, wherein is a methyl group or an ethyl group.

9. The method further comprising: a) hydroformylating a compound of formula (II) to give a compound of formula 【Chemistry 5】 [Wherein, dotted line, X, R １ , R ２ and R ３ has the same meaning as defined in any one of claims 1 to 8. obtaining the form of any one of the stereoisomers of the compound of formula (I) or a mixture thereof; b) converting the aldehyde group of the compound of formula (III) obtained in step a) into a compound of formula 【Chemistry 6】 [Wherein, dotted line, X, R １ , R ２ and R ３ has the same meaning as defined in any one of claims 1 to 8, R ａ and R ｂ are independent of each other, C １－４ represents an alkyl group, or R ａ and R ｂ Together, C ２－６ represents an alkanediyl group, and preferably R ａ and R ｂ Together, (CH ２ ) ｎ group, and n is 2 or 3. in the form of any one of the stereoisomers of the acetal of formula (I) or a mixture thereof; c) the OC(=O)R group of the compound of formula (IV) ６ group and optionally subsequent isomerization to give a compound of the formula 【Chemistry 7】 [Wherein, dotted line, R １ , R ２ , R ３ , R ４ and R ５ has the same meaning as defined in any one of claims 1 to 8, R ａ and R ｂ have the same meaning as defined above. forming any one or mixture of stereoisomers of the compound of formula (I) d) deprotecting the acetal group to obtain a compound of formula (I); 9. The method according to any one of claims 1 to 8, comprising:

10. 10. The process according to claim 1, wherein the hydroformylation is carried out in the presence of a rhodium catalyst.

11. formula 【Chemistry 8】 [wherein all dotted lines represent double bonds, or the dotted line between carbon 1 and carbon 2 is a carbon-carbon single bond or a carbon-carbon double bond, and the other dotted lines are carbon-carbon single bonds; each R １ , R ２ and R ３ are each independently a hydrogen atom, C １－３ Alkoxy group, C １－６ Alkyl group or C ２－６ alkenyl group, each of which is optionally a hydroxy group or １－３ substituted with an alkoxy group; or R １ and R ２ Together, C ３－８ Cycloalkyl group or C ５－８ form a cycloalkenyl group; or two R ３ Together, C １－３ alkanediyl group; X is CR ４ (OC(=O)R ６ ) CHR ５ or CHR ４ C(OC(=O)R ６ ) (R ５ ), R ４ and R ５ are each independently a hydrogen atom, a methyl group, or an ethyl group; R ６ is a hydrogen atom, C １－３ Alkoxy group, phenyl group or C １－３ an alkyl group, which may be optionally substituted with 1 to 3 halogen atoms. or a mixture thereof (with the exception of 5-oxo-1-phenylpentyl acetate).

12. formula 【Chemistry 9】 [wherein all dotted lines represent double bonds, or the dotted line between carbon 1 and carbon 2 is a carbon-carbon single bond or a carbon-carbon double bond, and the other dotted lines are carbon-carbon single bonds; each R １ , R ２ and R ３ are each independently a hydrogen atom, C １－３ Alkoxy group, C １－６ Alkyl group or C ２－６ alkenyl group, each of which is optionally a hydroxy group or １－３ substituted with an alkoxy group; or R １ and R ２ Together, C ３－８ Cycloalkyl group or C ５－８ form a cycloalkenyl group; or two R ３ Together, C １－３ alkanediyl group; X is CR ４ (OC(=O)R ６ ) CHR ５ or CHR ４ C(OC(=O)R ６ ) (R ５ ), R ４ and R ５ are each independently a hydrogen atom, a methyl group, or an ethyl group; R ６ is a hydrogen atom, C １－３ Alkoxy group, phenyl group or C １－３ an alkyl group, which may be optionally substituted with 1 to 3 halogen atoms; R ａ and R ｂ are independent of each other, C １－４ represents an alkyl group, or R ａ and R ｂ Together, C ２－６ represents an alkanediyl group, preferably R ａ and R ｂ Together, (CH ２ ) ｎ group, where n is 2 or 3. The compound of formula (I) in the form of any one of the stereoisomers or a mixture thereof.

13. Formula (V) 【Chemistry 10】 [wherein all dotted lines represent double bonds, or the dotted line between carbon 1 and carbon 2 is a carbon-carbon single bond or a carbon-carbon double bond, and the other dotted lines are carbon-carbon single bonds; each R １ , R ２ and R ３ are each independently a hydrogen atom, C １－３ Alkoxy group, C １－６ Alkyl group or C ２－６ alkenyl group, each of which is optionally a hydroxy group or １－３ substituted with an alkoxy group; or R １ and R ２ Together, C ３－８ Cycloalkyl group or C ５－８ form a cycloalkenyl group; or two R ３ Together, C １－３ R is an alkanediyl group; ４ and R ５ are each independently a hydrogen atom, a methyl group or an ethyl group; R ａ and R ｂ are independent of each other, C １－４ represents an alkyl group, or R ａ and R ｂ Together, C ２－６ represents an alkanediyl group, preferably R ａ and R ｂ Together, (CH ２ ) ｎ group, where n is 2 or 3. or a mixture thereof (with the exception of 2-(4-cyclohexylbut-3-en-1-yl)-1,3-dioxolane, 2-(4-phenylbut-3-en-1-yl)-1,3-dioxolane and 2-(4-phenylpent-3-en-1-yl)-1,3-dioxolane).

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