Method for preparing indene acrylaldehyde derivatives

Abstract

The present invention relates to the field of perfumery. More particularly, the present invention relates to valuable novel chemical intermediates for the production of flavoring ingredients. Furthermore, the present invention also includes a method for producing the compound of formula (I).

Description

[Technical Field]

[0001] This invention relates to the field of fragrances. More specifically, this invention relates to a valuable novel chemical intermediate for producing fragrance components. Furthermore, this invention also includes a method for producing a compound of formula (I). [Background technology]

[0002] In the fragrance industry, there is a constant demand for compounds that impart novel organoleptic notes. Particular interest lies in compounds that impart the scent of lily of the valley or at least one of its major organoleptic facets. Therefore, compounds that impart the aforementioned scent are especially needed to reconstruct the delicate floral aroma of lily of the valley, which cannot withstand even the mildest extraction methods used to obtain essential oils. To this end, a compound of formula (V) was previously reported in European Patent No. 685444, specifically 2,3-dihydro-1,1-dimethyl-1H-indene-ar-propanal (also known as Hivernal® (manufacturer: Firmenich SA)), obtained by condensation of a 2,3-dihydro-1H-indene derivative with an unsaturated diaceate in the presence of TiCl4. Catalytic conditions have been developed as disclosed in International Publication No. 2006120639. However, the reported routes for obtaining the compound of formula (I) are plagued by the generation of chlorinated waste, as well as the complex mixture of isomers. Furthermore, as it is an industrially important product, there is a constant need for new methods that demonstrate improved yields and increased conversion rates.

[0003] Therefore, there is a need to develop an approach to the compound of formula (V) using reagents that may be safer while suppressing isomer formation.

[0004] The present invention relates to a method for obtaining a compound of formula (V) while suppressing the formation of isomers, starting from a compound of formula (II) through a novel route via a novel intermediate that has never been disclosed before. In particular, the compounds of formula (III) and (IV) that are the subject of the present invention have never been reported or suggested in the context of the preparation of the compound of formula (V). Some of the compounds of formula (III) are known and reported in the prior art, but none of these compounds have been used as intermediates in the synthesis of the compound of formula (V). It is impossible for the reports of some derivatives of formula (III) to be regarded as suggesting the present invention.

[0005] Summary of the Invention The present invention relates to a novel method that opens a new route to a compound of formula (V), enabling the preparation of a compound of formula (I) starting from a compound of formula (II).

[0006] Therefore, a first object of the present invention is a formula [Chemical formula] [wherein, R 7 and R 2 each independently represent a hydrogen atom or a C 1~2 alkyl group, R 9 represents a hydrogen atom or a methyl group, and R 3 , R 4 , R 5 , R 6 , R 7 and R 8 each independently represent a hydrogen atom or a C<​​​​​​​​​​​​​​​​A method for preparing a morphological compound of any one or a mixture thereof of stereoisomers of a cycloalkenyl group having the same meaning as defined above, wherein the method is: a) Formula [ka] [In the formula, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 [This has the same meaning as defined above], a form compound of any one of those stereoisomers or a mixture thereof, formula [ka] [In the formula, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 This has the same meaning as defined above, R a and R b C 1~4 Represents an alkyl group, or R a and R b When they come together C 2~5 The step of converting an acetal in the form of one or a mixture thereof of its stereoisomers [representing an alkanediyl group], b) The acetal obtained in step a) is treated with an acid and formula CHR 1 =CH-OR c [In the formula, R c C 1~4 R represents an alkyl group. 1 This is treated with a compound having the same meaning as defined above, and formula [ka] [In the formula, R1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R a , R b and R c The steps include obtaining a morphological compound of one of the stereoisomers or a mixture thereof of the terms [which have the same meaning as defined above], c) The step of treating the compound of formula (IV) with acid to obtain the compound of formula (I) This method includes [something].

[0007] The second object of the present invention is the formula [ka] [In the formula, R 2 is a hydrogen atom or C 1~2 R represents an alkyl group. 3 , R 4 , R 5 , R 6 , R 7 and R 8 These are, independently of each other, hydrogen atoms or C 1~4 Represents an alkyl group, or R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Two of the groups combine to form C 3~8 Cycloalkyl groups or C 5~8 It forms a cycloalkenyl group, and the other groups have the same meaning as defined above, R 9 R represents a hydrogen atom or a methyl group. a and R b C 1~4 Represents an alkyl group, or R a and R b When they come together C 2~5 Represents an alkanediyl group, however, R a and R bWhen it is an ethyl group, R 3 R 4 R 5 R 6 R 7 and R 8 are not hydrogen atoms, and R a and R b are a methyl group or an ethyl group, or when R a and R b together represent a 1,2-ethanediyl group, R 3 R 4 R 5 R 7 and R 8 are methyl groups, R 6 is a hydrogen atom, or except that R 3 R 4 and R 8 are methyl groups, R 7 is an ethyl group, and R 5 and R 6 are hydrogen atoms, the compound is in the form of any one of those stereoisomers or a mixture thereof.

[0008] The third object of the present invention is a compound of the formula <​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​It forms a cycloalkenyl group, and the other groups have the same meaning as defined above, R 9 R represents a hydrogen atom or a methyl group. a and R b C 1~4 Represents an alkyl group, or R a and R b When they come together C 2~5 Represents an alkanediyl group, R c is C 1~4 A compound in the form of one of its stereoisomers or a mixture thereof, representing an alkyl group.

[0009] Further subjects of the present invention are formula [ka] [In the formula, R 1 and R 2 These are, independently of each other, hydrogen atoms or C 1~2 R represents an alkyl group. 9 R represents a hydrogen atom or a methyl group. 3 , R 4 , R 5 , R 6 , R 7 and R 8 These are, independently of each other, hydrogen atoms or C 1~4 Represents an alkyl group, or R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Two of the groups combine to form C 3~8 Cycloalkyl groups or C 5~8 It forms a cycloalkenyl group, and the other groups have the same meaning as defined above. However, R 9 When R is a hydrogen atom, 3 , R 4 , R 5 , R 6 , R 7 and R 8 At least one of the groups is C 1~4 It is an alkyl group, or R9 is a hydrogen atom, and R 5 When R is a methyl group or an n-propyl group, 1 , R 3 , R 4 , R 6 , R 7 and R 8 At least one of the groups is not a hydrogen atom, or 3-(3-methyl-2,3-dihydro-1H-inden-5-yl)propanal, 3-(3-methyl-2,3-dihydro-1H-inden-5-yl)butanal, 3-(1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)propanal, 3-(1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-2-methyl The compound is in the form of one of the stereoisomers of [excluding ropanal, 3-(3,3-dimethyl-2,3-dihydro-1H-inden-5-yl)propanal, 3-(3,3-dimethyl-2,3-dihydro-1H-inden-5-yl)-2-methylpropanal, or 3-(1,1,6-trimethyl-2,3-dihydro-1H-inden-5-yl)propanal] or a mixture thereof.

[0010] Detailed description of the invention Thus, it was unexpectedly discovered that the fragrance components reported in European Patent No. 685444 can be obtained from a new class of precursors (or chemical intermediates) as defined below herein by formulas (III) and (IV), and that these new intermediates allow for the acquisition of the corresponding fragrance components in a less complex isomer mixture with a generally higher yield compared to methods known from the prior art.

[0011] Therefore, the first object of the present invention is formula [ka] [In the formula, R 1 and R 2 These are, independently of each other, hydrogen atoms or C 1~2 R represents an alkyl group. 9 R represents a hydrogen atom or a methyl group.3 , R 4 , R 5 , R 6 , R 7 and R 8 These are, independently of each other, hydrogen atoms or C 1~4 Represents an alkyl group, or R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Two of the groups combine to form C 3~8 Cycloalkyl groups or C 5~8 A method for preparing a compound in the form of one or a mixture thereof of stereoisomers of a cycloalkenyl group, wherein the other group has the same meaning as defined above, the method is: a) Formula [ka] [In the formula, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 [This has the same meaning as defined above], a form compound of any one of those stereoisomers or a mixture thereof, formula [ka] [In the formula, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 This has the same meaning as defined above, R a and R b C 1~4 Represents an alkyl group, or R a and R b When they come together C 2~5The step of converting an acetal in the form of one or a mixture thereof of its stereoisomers [representing an alkanediyl group], b) The acetal obtained in step a) is treated with an acid and formula CHR 1 =CH-OR c [In the formula, R c C 1~4 R represents an alkyl group. 1 This is treated with a compound having the same meaning as defined above, and formula [ka] [In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R a , R b and R c The steps include obtaining a compound in the form of one of those stereoisomers or a mixture thereof, [which has the same meaning as defined above] The steps include treating the compound of formula (IV) with acid to obtain the compound of formula (I) and This method includes [something].

[0012] To clarify, expressions such as "any one of those stereoisomers or a mixture thereof" are used in the usual sense understood by those skilled in the art, meaning that the compounds of formulas (I), (II), (III), and (IV) can be pure enantiomers or mixtures of enantiomers. In other words, the compounds of formulas (I), (II), (III), and (IV) can have at least one stereocenter that can have two different stereochemistrys (e.g., R or S). The compounds of formulas (I), (II), (III), and (IV) may be in the form of pure enantiomers or mixtures of enantiomers. When the compounds of formulas (I), (II), (III), and (IV) have two or more stereocenters, they may be in the form of pure diastereoisomers or mixtures of diastereoisomers. The compounds of formulas (I), (II), (III), and (IV) may be in the form of racemic or scalemic forms. Therefore, the compounds of formulas (I), (II), (III), and (IV) may be a single stereoisomer, contain various stereoisomers, or be in the form of a composition of substances comprising them.

[0013] According to any one of the above embodiments of the present invention, the compound of formula (I) may be in the form of its E or Z isomer or a mixture thereof. For example, the present invention includes a material composition comprising one or more compounds of formula (I) having the same chemical structure but differing in the arrangement of double bonds. In particular, compound (I) may be in the form of a mixture comprising isomers E and Z, where the aforementioned isomer E represents at least 50%, and moreover at least 75%, of the total mixture (i.e., a mixture E / Z consisting of 75 / 25 to 100 / 0).

[0014] The terms “alkyl” and “alkanediyl” are understood to include branched and linear alkyl and alkanediyl groups. The term “cycloalkenyl” is 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 condensed, spiro and / or crosslinked bicyclic or tricyclic cycloalkyl and cycloalkenyl groups, preferably monocyclic cycloalkyl and cycloalkenyl groups.

[0015] To clarify, "R 3 , R 4 , R 5 , R 6 , R 7 and R 8 One or two of these groups combine to form C 3~8 Cycloalkyl groups or C 5~8 The expression "forming a cycloalkenyl group..." means that one or more carbon atoms to which both groups are bonded are C 5~8 Cycloalkyl groups or C 5~8 This means it is contained within a cycloalkenyl group.

[0016] According to any embodiment of the present invention, R 1 and R 2 These represent, independently of each other, a hydrogen atom or a methyl group. In particular, R 1 R may be a hydrogen atom or a methyl group, 2 R may be a hydrogen atom. Furthermore, in particular, 1 and R 2 may be a hydrogen atom. In other words, the compound of formula (II) is a compound of formula [ka] [In the formula, R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9[This has the same meaning as defined above], and is a carvalenthide in the form of one of its stereoisomers or a mixture thereof. Acetal is, formula [ka] [In the formula, R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 This has the same meaning as defined above, R a and R b C 1~4 Represents an alkyl group, or R a and R b When C 2~5 An acetal in the form of one or a mixture thereof of the stereoisomers of an alkanediyl group, Formula CHR 1 =CH-OR c The compound is represented by the formula CH2=CH-OR c And here, R c is C 1~4 Represents an alkyl group, The compound of formula (IV) is, [ka] [In the formula, R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R a , R b and R c [The term has the same meaning as defined above] and is in the form of one of those stereoisomers or a mixture thereof.

[0017] According to any embodiment of the present invention, R 3 , R 4 , R 5 , R 6, R 7 and R 8 These are, independently of each other, hydrogen atoms or C 1~3 Represents an alkyl group. In particular, R 3 , R 4 , R 5 , R 6 , R 7 and R 8 At least one of the groups is C 1~3 It may be an alkyl group, and the other groups may be a hydrogen atom or C, independently of each other. 1~3 Alkyl may also be used. In particular, R 3 , R 4 , R 5 , R 6 , R 7 and R 8 At least three of these groups may be hydrogen atoms, and the other groups may be hydrogen atoms or C, independently of each other. 1~3 Alkyl alkyl groups may also be used. In particular, R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Four of the groups may be hydrogen atoms, and the other groups may be hydrogen atoms or C, independently of each other. 1~3 Alkyl alkyl groups may also be used. In particular, R 3 , R 4 , R 5 , R 6 , R 7 and R 8 One, two, three, or four of these groups are C 1~3 It may be an alkyl group, and the other group may be a hydrogen atom. In particular, R 3 , R 4 , R 5 , R 6 , R 7 and R 8 One or two of the groups is C 1~3 The group may be an alkyl group, and the other group may be a hydrogen atom.

[0018] According to any embodiment of the present invention, R a and R b C1~3 Alkyl alkyl groups may also be used. In particular, R a and R b These may be methyl or ethyl groups, independently of each other. In particular, R a and R b These may be methyl groups, independently of each other.

[0019] According to any embodiment of the present invention, R c is C 1~3 Alkyl alkyl groups may also be used. In particular, R c R may be a methyl group or an ethyl group. In particular, c It is an ethyl group.

[0020] According to any embodiment of the present invention, R 9 It may be a hydrogen atom.

[0021] Non-limiting examples of compounds of formula (II) include 3,3-dimethyl-2,3-dihydro-1H-indene-5-carbaldehyde, 1,1-dimethyl-2,3-dihydro-1H-indene-5-carbaldehyde, 1,3-dimethyl-2,3-dihydro-1H-indene-5-carbaldehyde, 2,2-dimethyl-2,3-dihydro-1H-indene-5-carbaldehyde, 3-methyl-2,3-dihydro-1H-indene-5-carbaldehyde, 1-methyl-2, 3-dihydro-1H-indene-5-carbaldehyde, 2-methyl-2,3-dihydro-1H-indene-5-carbaldehyde, 3,6-dimethyl-2,3-dihydro-1H-indene-5-carbaldehyde, 1,6-dimethyl-2,3-dihydro-1H-indene-5-carbaldehyde, 3-ethyl-2,3-dihydro-1H-indene-5-carbaldehyde, 1-ethyl-2,3-dihydro-1H-indene-5-carbaldehyde, 2-ethyl-2,3- Dihydro-1H-indene-5-carbaldehyde, 3-isopropyl-2,3-dihydro-1H-indene-5-carbaldehyde, 1-isopropyl-2,3-dihydro-1H-indene-5-carbaldehyde, 2-isopropyl-2,3-dihydro-1H-indene-5-carbaldehyde, 3-n-propyl-2,3-dihydro-1H-indene-5-carbaldehyde, 1-n-propyl-2,3-dihydro-1H-indene-5-carbaldehyde, 2-n Examples include -propyl-2,3-dihydro-1H-indene-5-carbaldehyde, 3-ethyl-3-methyl-2,3-dihydro-1H-indene-5-carbaldehyde, 1-ethyl-1-methyl-2,3-dihydro-1H-indene-5-carbaldehyde, 2,2,3,3-tetramethyl-2,3-dihydro-1H-indene-5-carbaldehyde, or 1,1,2,2-tetramethyl-2,3-dihydro-1H-indene-5-carbaldehyde.

[0022] Non-limiting examples of compounds of formula (I) include 3,3-dimethyl-2,3-dihydro-1H-indene-5-acrylaldehyde, 1,1-dimethyl-2,3-dihydro-1H-indene-5-acrylaldehyde, 1,3-dimethyl-2,3-dihydro-1H-indene-5-acrylaldehyde, 2,2-dimethyl-2,3-dihydro-1H-indene-5-acrylaldehyde, 3-methyl-2,3-dihydro-1H-indene-5-acrylaldehyde, 1-methyl-2, 3-dihydro-1H-indene-5-acrylaldehyde, 2-methyl-2,3-dihydro-1H-indene-5-acrylaldehyde, 3,6-dimethyl-2,3-dihydro-1H-indene-5-acrylaldehyde, 1,6-dimethyl-2,3-dihydro-1H-indene-5-acrylaldehyde, 3-ethyl-2,3-dihydro-1H-indene-5-acrylaldehyde, 1-ethyl-2,3-dihydro-1H-indene-5-acrylaldehyde, 2-ethyl-2 ,3-dihydro-1H-indene-5-acrylaldehyde, 3-isopropyl-2,3-dihydro-1H-indene-5-acrylaldehyde, 1-isopropyl-2,3-dihydro-1H-indene-5-acrylaldehyde, 2-isopropyl-2,3-dihydro-1H-indene-5-acrylaldehyde, 3-n-propyl-2,3-dihydro-1H-indene-5-acrylaldehyde, 1-n-propyl2,3-dihydro-1H-indene-5-acrylaldehyde Examples include 2-n-propyl-2,3-dihydro-1H-indene-5-acrylaldehyde, 3-ethyl-3-methyl-2,3-dihydro-1H-indene-5-acrylaldehyde, 1-ethyl-1-methyl-2,3-dihydro-1H-indene-5-acrylaldehyde, 2,2,3,3-tetramethyl-2,3-dihydro-1H-indene-5-acrylaldehyde, or 1,1,2,2-tetramethyl-2,3-dihydro-1H-indene-5-acrylaldehyde.

[0023] According to any embodiment of the present invention, the compound of formula (II) may be in the form of a mixture of positional isomers. Starting from the fact that the compound of formula (II) is in the form of a mixture of positional isomers, the compound of formula (I) obtained through the method of the present invention will be in the form of a mixture of positional isomers. The ratios between each isomer are maintained throughout the method of the present invention.

[0024] To clarify, the expression "in the form of a mixture of positional isomers," or similar, is understood in the ordinary sense by those skilled in the art, namely, that the compound of formula (II) may be in the form of a mixture containing at least two different positional isomers in which the carbonyl functional group is located at the ortho, meta, or para position for one positional isomer and at a different position from the other positional isomer for the second positional isomer. For example, the compound of formula (II) may be in the form of a mixture containing 3,3-dimethyl-2,3-dihydro-1H-indene-5-carbaldehyde and 1,1-dimethyl-2,3-dihydro-1H-indene-5-carbaldehyde. The compound of formula (II) may be in the form of a mixture containing up to three different positional isomers. In other words, the compound of formula (II) may be in the form of a mixture containing compounds that have the same chemical structure but differ only in the position of the carbonyl functional group or acrylaldehyde group relative to the compound of formula (I). Positional isomers differ only in the position of one or more substituents on the aromatic ring of the compounds of formulas (I), (II), (III), (IV), and (V).

[0025] According to any embodiment of the present invention, the conversion of the compound of formula (II) to the acetal of formula (III) is performed under ordinary conditions known to those skilled in the art, namely, an acid such as a Lewis acid that is compatible with alcohols such as Brønsted acid or lanthanide trifluoride, and C 1~4 Trialkyl orthoformate, C 1~4 Alcohol and C 2~5The process may be carried out in the presence of a reagent selected from the group consisting of diols. The conversion of benzaldehyde or benzaldehyde derivatives to their corresponding acetals is well known and largely reported in the prior art. Therefore, those skilled in the art will be able to set the optimal conditions for converting the compound of formula (II) to the compound of formula (III). As a non-limiting example, step a) may be carried out under the conditions reported in Green Chemistry, 2013, 15(10), 2740-2746; Synthesis, 2009, (23), 4082-4086; Synlett, 2002, (2), 319-321; Tetrahedron Letters, 2004, 45(26), 5135-5138; Current Organocatalysis, 2018, 5(3), 196-200 or Tetrahedron Letters, 2004, 45(44), 8141-8144. According to certain embodiments of the present invention, the acid used in step a) may have a pKa of less than 3. Specific and non-limiting examples of Brønsted acids may be selected from the group consisting of p-toluenesulfonic acid, methanesulfonic acid, camphorsulfonic acid, methanedisulfonic acid, methanetrisulfonic acid, and 2,4-dinitrobenzenesulfonic acid. In particular, the Brønsted acid may be p-toluenesulfonic acid. Specific and non-limiting examples of Lewis acids compatible with alcohols may be selected from the group consisting of metal triflates such as Al(OTf)3, lanthanide triflates such as Sc(OTf)3 and Bi(OTf)3, metal tetrafluoroborates such as Zn(BF4)2, and zinc halides such as ZnCl2 and ZnBr2. 1~4 Trialkyl orthoformate, C 1~4 Alcohol or C 2~5 Specific and non-limiting examples of diols may be selected from the group consisting of methanol, ethanol, ethylene glycol, trimethyl orthoformate, and triethyl orthoformate.

[0026] C 1~4 Trialkyl orthoformate, C 1~4 Alcohol or C2~5 Diols 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, C 1~4 Trialkyl or C orthoformate 2~5 As a diol concentration, values ​​in the range of approximately 1 to approximately 2 equivalents relative to the amount of substrate, preferably 1 to approximately 1.5 equivalents relative to the amount of substrate, can be cited. As a non-limiting example, C 1~4 Examples of alcohol concentration values ​​include those in the range of approximately 2 to approximately 15 equivalents relative to the amount of substrate, preferably 3 to approximately 5 equivalents relative to the amount of substrate. 1~4 Trialkyl orthoformate, C 1~4 Alcohol or C 2~5 As those skilled in the art will know, the optimal concentration of the diol will depend on the properties of the latter, the properties of the substrate, the reaction temperature, and the desired reaction time.

[0027] Brønsted acid 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%, preferably about 0.5 to about 3 mol%, relative to the amount of substrate. The optimal concentration of Brønsted acid depends on the properties of the latter, the properties of the substrate, and C, as those skilled in the art will know. 1~4 Trialkyl orthoformate, C 1~4 Alcohol or C 2~5 It will depend on the properties of the diol, the reaction temperature, and the desired reaction time.

[0028] According to any one embodiment of the present invention, the process of forming the compound of formula (III) is carried out at a temperature range of 20°C to 55°C. In particular, the temperature is in the range of 20°C to 30°C. Of course, those skilled in the art can also select a preferred temperature as a function of the melting and boiling points of the starting and final products, as well as the desired time of the reaction or transformation.

[0029] Acetal formation can be carried out in or without a solvent. Where a solvent is required or used for practical reasons, any solvent stream in such a reaction can be used for the purposes of the present invention. Non-limiting examples include toluene, C 6~12 Examples of solvents include aromatic solvents such as 1,3-diisopropylbenzene, cumene, or pseudocumene, or mixtures thereof; alcoholic solvents such as methanol, ethanol, or mixtures thereof; hydrocarbon solvents such as cyclohexane or heptane, ethyl acetate; or ether solvents such as methyltetrahydrofuran, tetrahydrofuran, or mixtures thereof. The choice of solvent is a function of the properties of the substrate and / or catalyst, and it is quite possible for those skilled in the art to select the most suitable solvent in each case to optimize the reaction.

[0030] According to any embodiment of the present invention, the treatment of the acetal of formula (III) is performed by formula CHR 1 =CH-OR c [In the formula, R c is C 1~3 R represents an alkyl group. 1 This may be done with compounds of the same meaning as defined above. In particular, R 1 R may be a hydrogen atom, c is C 1~2 It may also represent an alkyl group. In particular, R c ∫ may represent an ethyl group. Specific and non-limiting examples of the acid used in step b) may be selected from the group consisting of boron trifluoride complexes, e.g., BF3·OEt2, BF3·OBu2, BF3·(AcOH)2 or BF3·MeCN, anhydrous zinc chloride, and p-toluenesulfonic acid. In particular, the acid used in step b) is a Lewis acid.

[0031] Formula CHR 1 =CH-OR cThe compound can be added to the reaction medium of the method of the present invention at a wide range of concentrations. Non-limiting examples include enol ether concentrations of about 1 to about 5 equivalents relative to the amount of substrate, preferably in the range of 1.1 to about 1.2 equivalents relative to the amount of substrate. Formula CHR 1 =CH-OR c As those skilled in the art will know, the optimal concentration of the compound will depend on the properties of the latter, the properties of the substrate, the reaction temperature, and the desired reaction time.

[0032] The acid used in step b) 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 0.001 mol% to about 10 mol%, preferably about 0.01 mol% to about 5 mol%, relative to the amount of substrate. The optimal concentration of the acid used in step b) will depend, as those skilled in the art will know, on the properties of the latter, the properties of the substrate, the reaction temperature, and the desired reaction time.

[0033] According to any one embodiment of the present invention, the process of forming the compound of formula (IV) is carried out at a temperature comprising 10°C to 100°C. In particular, the temperature is in the range of 15°C to 25°C. Of course, those skilled in the art can also select a preferred temperature as a function of the melting and boiling points of the starting and final products, as well as the desired time of the reaction or transformation.

[0034] Step b) of the method of the present invention may be carried out in or without a solvent. Where a solvent is required or used for practical reasons, any solvent stream in such a reaction type may be used for the purposes of the present invention. Non-limiting examples include toluene, C 6~12Examples of solvents include aromatic solvents such as 1,3-diisopropylbenzene, cumene, or pseudocumene, or mixtures thereof; ethyl acetate; or ether solvents such as methyltetrahydrofuran, tetrahydrofuran, or mixtures thereof; or chlorinated solvents such as dichloromethane, dichloroethane, or mixtures thereof. The choice of solvent is a function of the properties of the substrate and / or catalyst, and it is quite possible for those skilled in the art to select the most suitable solvent in each case to optimize the reaction. In particular, step b) may be carried out in the absence of a solvent.

[0035] According to any one embodiment of the present invention, steps a) and b) of the method of the present invention are carried out in a one-pot using an acid such as borotetraacetic acid trifluoride, p-toluenesulfonic acid, or camphorsulfonic acid.

[0036] According to any one embodiment of the present invention, the acid used in step c) may be selected from the group consisting of acetic acid, aqueous acetic acid, propionic acid, aqueous sulfuric acid, sulfuric acid, and aqueous hydrochloric acid. In particular, the acid used in step c) may be acetic acid.

[0037] The acid used in step c) can be added to the reaction medium of the method of the present invention at a wide range of concentrations. Non-limiting examples include concentrations of about 1 to about 10 equivalents relative to the amount of substrate, preferably in the range of 3 to about 8 equivalents relative to the amount of substrate. The optimal concentration of the acid used in step c) will depend, as those skilled in the art will know, on the properties of the latter, the properties of the substrate, the reaction temperature, and the desired reaction time.

[0038] According to any one embodiment of the present invention, the process of forming the compound of formula (I) is carried out at a temperature range of 25°C to 150°C. In particular, the temperature is in the range of 90°C to 120°C. Of course, those skilled in the art can also select a preferred temperature as a function of the melting and boiling points of the starting and final products, as well as the desired time of the reaction or transformation.

[0039] Step c) can be carried out in or without a solvent. If a solvent is required or used for practical reasons, any solvent stream in such a reaction can be used for the purposes of the present invention. Non-limiting examples include toluene, C 6~12 Examples of solvents include aromatic solvents such as 1,3-diisopropylbenzene, cumene, or pseudocumene, or mixtures thereof; alcoholic solvents such as methanol, ethanol, or mixtures thereof; hydrocarbon solvents such as cyclohexane or heptane, ethyl acetate, or ether solvents such as methyltetrahydrofuran, tetrahydrofuran, 1,4-dioxane, or mixtures thereof. The choice of solvent is a function of the properties of the substrate and / or catalyst, and it is quite possible for those skilled in the art to select the most suitable solvent in each case to optimize the reaction.

[0040] According to any one embodiment of the present invention, the method of the present invention can be carried out in one pot, i.e., steps a) to c) may be carried out without any intermediate isolation step.

[0041] According to any embodiment of the present invention, the method of the present invention for preparing the compound of formula (I) may be carried out under batch conditions or continuous conditions.

[0042] According to any embodiment of the present invention, a compound of formula (I) is a compound of formula [ka] [In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9[The same meaning as defined above] may be hydrogenated into a compound in the form of one of their stereoisomers or a mixture thereof. Those skilled in the art will have a good understanding of the conditions that must be applied to obtain a compound of formula (V).

[0043] The compounds of formulas (III), (IV), and (V) are generally novel compounds and offer many advantages as described above and shown in the examples.

[0044] Therefore, another subject of the present invention is formula [ka] [In the formula, R 2 is a hydrogen atom or C 1~2 R represents an alkyl group. 3 , R 4 , R 5 , R 6 , R 7 and R 8 These are, independently of each other, hydrogen atoms or C 1~4 Represents an alkyl group, or R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Two of the groups combine to form C 3~8 Cycloalkyl groups or C 5~8 It forms a cycloalkenyl group, and the other groups have the same meaning as defined above, R 9 R represents a hydrogen atom or a methyl group. a and R b C 1~4 Represents an alkyl group, or R a and R b When they come together C 2~5 Represents an alkanediyl group, however, R a and R b When R is an ethyl group, 3 , R 4 , R 5 , R 6 , R 7 and R8 It is not a hydrogen atom, and R a and R b Is it a methyl group or an ethyl group, or R a and R b When these two groups together represent a 1,2-ethanediyl group, R 3 , R 4 , R 5 , R 7 and R 8 R is a methyl group, 6 is a hydrogen atom, or R 3 , R 4 and R 8 R is a methyl group, 7 is an ethyl group, R 5 and R 6 A compound in the form of one of its stereoisomers or a mixture thereof, except that it is a hydrogen atom.

[0045] Another subject of the present invention is formula [ka] [In the formula, R 1 and R 2 These are, independently of each other, hydrogen atoms or C 1~2 R represents an alkyl group. 3 , R 4 , R 5 , R 6 , R 7 and R 8 These are, independently of each other, hydrogen atoms or C 1~4 Represents an alkyl group, or R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Two of the groups combine to form C 3~8 Cycloalkyl groups or C 5~8 It forms a cycloalkenyl group, and the other groups have the same meaning as defined above, R 9 R represents a hydrogen atom or a methyl group. a and R b C1~4 Represents an alkyl group, or R a and R b When they come together C 2~5 Represents an alkanediyl group, R c is C 1~4 A compound in the form of one of its stereoisomers or a mixture thereof, representing an alkyl group.

[0046] Further subjects of the present invention are compounds of formula (V) as defined above, provided that R 9 When R is a hydrogen atom, 3 , R 4 , R 5 , R 6 , R 7 and R 8 At least one of the groups is C 1~4 It is an alkyl group, or R 9 is a hydrogen atom, and R 5 When R is a methyl group or an n-propyl group, 1 , R 3 , R 4 , R 6 , R 7 and R 8 At least one of the groups is not a hydrogen atom, except for 3-(3-methyl-2,3-dihydro-1H-inden-5-yl)propanal, 3-(3-methyl-2,3-dihydro-1H-inden-5-yl)butanal, 3-(1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)propanal, 3-(1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-2-methylpropanal, 3-(3,3-dimethyl-2,3-dihydro-1H-inden-5-yl)propanal, 3-(3,3-dimethyl-2,3-dihydro-1H-inden-5-yl)-2-methylpropanal, or 3-(1,1,6-trimethyl-2,3-dihydro-1H-inden-5-yl)propanal.

[0047] A typical manner for carrying out the method of the present invention is reported in the following examples herein.

[0048] Examples Next, the present invention will be described in more detail by the following examples, where abbreviations have their usual meanings in the art, and temperatures are given in degrees Celsius (°C). NMR spectra are shown at 400 MHz, ( 1 H) and 100MHz ( 13 Bruker Avance II Ultrashield 400 plus operating at C) or 500MHz ( 1 H) and 125MHz ( 13 C) Bruker Avance III 500 or 600MHz ( 1 H) and 150MHz ( 13 Spectra were obtained using a Bruker Avance III 600 cryoprobe operating in C). The spectra were internally referenced to tetramethylsilane at 0.0 ppm. 1 The 1H NMR signal shift is expressed in δppm, and the coupling constant (J) is expressed in Hz with the following multiplicities: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; b, and broad (indicating unresolved coupling), and was interpreted using Bruker Topspin software. 13 ¹³C NMR data were expressed as chemical shifts δppm and hybridizations from DEPT 90 and DEPT 135 experiments, represented as C, quaternary; CH, methine; CH2, methylene; CH3, methyl.

[0049] Example 1 Preparation of 3-(3,3-dimethyl-2,3-dihydro-1H-inden-5-yl)acrylaldehyde and a mixture containing 3-(1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)acrylaldehyde according to the method of the present invention. a) Step a): Preparation of a mixture containing 6-(diethoxymethyl)-1,1-dimethyl-2,3-dihydro-1H-indene and 6-(diethoxymethyl)-3,3-dimethyl-2,3-dihydro-1H-indene 3,3-dimethyl-2,3-dihydro-1H-indene-5-carbaldehyde and 1,1-dimethyl-2,3-dihydro-1H-indene-5-carbaldehyde (15 g, 1 equivalent), ethanol (15 mL), and triethyl orthoformate (19.1 g, 1.5 equivalents) were added to a three-necked flask at room temperature. p-TSA (0.13 g, 0.008 equivalents) was dissolved in 5 mL of ethanol and slowly added. The reaction mixture was heated to 50-55°C, and the progress of the reaction was monitored by GC. After the reaction was complete, sodium ethoxide (21%) (0.141 g, 0.02 equivalents) was added, and the mixture was cooled to room temperature. The solvent was removed under reduced pressure to obtain a crude mixture of 6-(diethoxymethyl)-1,1-dimethyl-2,3-dihydro-1H-indene and 6-(diethoxymethyl)-3,3-dimethyl-2,3-dihydro-1H-indene. The crude product was purified by flash distillation to obtain a pure diethyl acetal mixture (20 g, 92%) containing 6-(diethoxymethyl)-1,1-dimethyl-2,3-dihydro-1H-indene and 6-(diethoxymethyl)-3,3-dimethyl-2,3-dihydro-1H-indene in the same proportion as the starting materials.

[0050] [ka]

[0051] b) Step b): Preparation of a mixture containing 1,1-dimethyl-6-(1,3,3-triethoxypropyl)-2,3-dihydro-1H-indene and 3,3-dimethyl-6-(1,3,3-triethoxypropyl)-2,3-dihydro-1H-indene Under a nitrogen atmosphere, anhydrous zinc chloride (0.03 equivalents, 172 mg) was added at 20°C (water bath) to a stirred solution of diethyl acetal (9.3 g, 42.3 mmol) obtained in step a) in dichloromethane (50 mL). Next, ethyl vinyl ether (3.2 g, 44 mmol) was slowly added dropwise over 20 minutes using a water bath to maintain the reaction temperature at 15-20°C. The reaction mixture was stirred at ambient temperature for a further 90 minutes, then tripotassium citrate solution (1.0 M) was added, and the mixture was stirred at ambient temperature for a further 60 minutes. The organic phase was re-extracted with dichloromethane, and the combined organic phase was washed with water, sodium bicarbonate solution, and brine, dried over MgSO4, and filtered. The solvent was removed under vacuum, and the residue was further purified by Kugellohr distillation (110-115°C, 0.1 mbar) to obtain 9.8 g of a mixture containing 1,1-dimethyl-6-(1,3,3-triethoxypropyl)-2,3-dihydro-1H-indene and 3,3-dimethyl-6-(1,3,3-triethoxypropyl)-2,3-dihydro-1H-indene, which was used in the next step without further purification.

[0052] c) Step c): Preparation of a mixture containing 3-(3,3-dimethyl-2,3-dihydro-1H-inden-5-yl)acrylaldehyde and 3-(1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)acrylaldehyde. The solution of triethyl acetal (9.8 g, 33.5 mmol) obtained in step b), 1,4-dioxane (18 g), and 10% H2SO4 (2.0 g) was heated at 100°C for 12 hours, then cooled, and the mixture was partitioned between diethyl ether and water. The aqueous phase was re-extracted with diethyl ether, and the combined organic phase was then washed with water, saturated sodium bicarbonate, and brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under vacuum to obtain 6.6 g of a mixture containing 3-(3,3-dimethyl-2,3-dihydro-1H-inden-5-yl)acrylaldehyde and 3-(1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)acrylaldehyde. Further purification by Kugelloll distillation (110-115°C, 0.5 mbar) yielded 5.8 g of a mixture containing 3-(3,3-dimethyl-2,3-dihydro-1H-inden-5-yl)acrylaldehyde and 3-(1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)acrylaldehyde in the same proportion as the starting material.

[0053] [ka]

[0054] Example 2 Preparation of a mixture containing 3-(3,3-dimethyl-2,3-dihydro-1H-inden-5-yl)acrylaldehyde and 3-(1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)acrylaldehyde according to the one-pot process of the present invention. pTSA (0.8 g, 1 mol%) was added all at once to a solution of 3,3-dimethyl-2,3-dihydro-1H-indene-5-carbaldehyde and 1,1-dimethyl-2,3-dihydro-1H-indene-5-carbaldehyde (82.1 g, 462 mmol) and triethyl orthoformate (96.2 g, 650 mmol). The mixture was heated at 90°C for 60 minutes, then cooled to 60°C, and zinc chloride (1.9 g, 0.03 equivalent) was added, followed by butyl vinyl ether (55.0 g, 550 mmol) slowly added dropwise over 60 minutes. The mixture was stirred at 60°C for 5 hours, then at 20°C overnight. Hydroquinone (2.0 g) was added, followed by isopropanol (160 g) and 10% sulfuric acid (80 g, over 15 minutes). The reaction mixture was heated at 90°C for 6 hours, and the volatile components were collected. The solution was cooled, diluted with toluene (200 g), washed with water (2 × 100 g), dried over MgSO4 with a saturated sodium bicarbonate solution (120 g), filtered, and the solvent was removed under vacuum to obtain 113.7 g of a crude mixture containing 3-(3,3-dimethyl-2,3-dihydro-1H-inden-5-yl)acrylaldehyde and 3-(1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)acrylaldehyde. Further distillation at 100-120°C and 0.5 mbar yielded 65.5 g (71% total yield) of a pure mixture containing 3-(3,3-dimethyl-2,3-dihydro-1H-inden-5-yl)acrylaldehyde and 3-(1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)acrylaldehyde in the same proportion as the starting material.

[0055] Example 3 Hydrogenation of a mixture containing 3-(3,3-dimethyl-2,3-dihydro-1H-inden-5-yl)acrylaldehyde and 3-(1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)acrylaldehyde Palladium carbon (5% Pd / C, 0.2 g), the mixture obtained in Example 1 (5.8 g, 29 mmol), and a suspension of ethyl acetate (20 mL) in potassium acetate (60 mg) were evacuated under vacuum, purged with hydrogen gas (3 times), stirred under a hydrogen atmosphere for 12 hours, and then filtered. The solvent was removed under vacuum, and the residue (6.2 g) was purified by flash chromatography (220 g cartridge, heptane:MTBE99:1~3:97 as eluent) to separate the small amount of alcohol formed (approximately 20%), yielding 4.0 g of the desired aldehyde as a mixture of positional isomers (same ratio as the starting material). This was further purified by Cugelrolle distillation (105~110°C, 1.0 mbar) to obtain 3.2 g of 54% pure aldehyde as a mixture of positional isomers (same ratio as the starting material).

[0056] [ka]

Claims

1. formula 【Chemistry 1】 [wherein, R １ and R ２ each independently represents a hydrogen atom or a C １～２ alkyl group, R ９ represents a hydrogen atom or a methyl group, and R ３ , R ４ , R ５ , R ６ , R ７ and R ８ each independently represents a hydrogen atom or a C １～４ alkyl group, or two of the groups of R ３ , R ４ , R ５ , R ６ , R ７ and R ８ combine to form a C ３～８ cycloalkyl group or a C ５～８ cycloalkenyl group, and the other groups have the same meanings as defined above], a method for preparing a compound in the form of any one of its stereoisomers or a mixture thereof, the method comprising a) Formula 【Chemistry 2】 [In the formula, R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , R ８ and R ９ A compound in the form of one of its stereoisomers or a mixture thereof, [which has the same meaning as defined above] formula 【Transformation 3】 [In the formula, R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , R ８ and R ９ This has 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 When they come together C ２～５ The steps include converting an acetal in the form of one or a mixture thereof of its stereoisomers, representing an alkanediyl group, b) The acetal obtained in step a) is treated with an acid and formula CHR １ = CH - OR ｃ [In the formula, R ｃ C １～４ R represents an alkyl group. １ This is treated with a compound of the same meaning as defined above, and formula 【Chemistry 4】 [In the formula, R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , R ８ , R ９ , R ａ , R ｂ and R ｃ The steps include obtaining a compound [which has the same meaning as defined above] in the form of one of its stereoisomers or a mixture thereof, c) The step of treating the compound of formula (IV) with an acid to obtain the compound of formula (I) Methods that include...

2. R ａ and R ｂ However, C is independent of each other. １～３ The method according to claim 1, which represents an alkyl group.

3. R ａ and R ｂ The method according to claim 1 or 2, wherein each of the methyl groups is independently represented.

4. R ｃ The method according to any one of claims 1 to 3, wherein the group is a methyl group or an ethyl group.

5. R ｃ The method according to any one of claims 1 to 4, wherein the group is an ethyl group.

6. R １ and R ２ The method according to any one of claims 1 to 5, wherein each represents a hydrogen atom or a methyl group independently of the other.

7. R ３ , R ４ , R ５ , R ６ , R ７ and R ８ However, independently of each other, hydrogen atoms or C １～３ A method according to any one of claims 1 to 6, which represents an alkyl group.

8. R ３ , R ４ , R ５ , R ６ , R ７ and R ８ One or two of the groups is C １～３ The method according to any one of claims 1 to 7, wherein one group represents an alkyl group and the other group represents a hydrogen atom.

9. Step a) Acid, and C １～４ Trialkyl orthoformate, C １～４ Alcohol and C ２～５ The method according to any one of claims 1 to 8, carried out in the presence of a reagent selected from the group consisting of diols.

10. The method according to any one of claims 1 to 9, wherein the acid used in step b) is selected from the group consisting of boron trifluoride complex, anhydrous zinc chloride, and p-toluenesulfonic acid.

11. The method according to any one of claims 1 to 10, wherein the acid used in step c) is selected from the group consisting of acetic acid, aqueous acetic acid, propionic acid, aqueous sulfuric acid, sulfuric acid, and aqueous hydrochloric acid.

12. The compound of formula (I) obtained in the method according to any one of claims 1 to 11, 【Transformation 5】 [wherein, R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , R ８ and R ９ have the same meanings as defined in claim 1], a method of further hydrogenating the compound in the form of any one of those stereoisomers or a mixture thereof.

13. Formula 【Transformation 6】 [wherein, R １ and R ２ each independently represents a hydrogen atom or a C １～２ alkyl group, and R ３ , R ４ , R ５ , R ６ , R ７ and R ８ each independently represents a hydrogen atom or a C １～４ alkyl group, or two of the groups of R ３ , R ４ , R ５ , R ６ , R ７ and R ８ combine to form a C ３～８ cycloalkyl group or a C ５～８ cycloalkenyl group, and the other groups have the same meaning as defined above, and R ９ represents a hydrogen atom or a methyl group, and R ａ and R ｂ each independently represents a C １～４ alkyl group, or when R ａ and R ｂ combine, they represent a C ２～５ alkanediyl group, and R ｃ represents a C １～４ alkyl group], a compound in the form of any one of its stereoisomers or a mixture thereof.

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