A method for preparing 1-indanone compounds by intramolecular Friedel-Crafts reaction of α,α-dialkylmalonate derivatives

Abstract

The present invention relates to the field of perfumery. More specifically, the present invention relates to valuable new chemical intermediates for the preparation of perfuming ingredients. Furthermore, the present invention also includes a method for preparing the compound of formula (I).

Description

[Technical Field]

[0001] The present invention relates to the field of perfumery. More specifically, the present invention relates to valuable new chemical intermediates for the preparation of perfuming ingredients. Furthermore, the present invention also includes a method for preparing the compound of formula (I).

[0002] Background of the Invention Compounds of formula (IV) are highly valuable perfume ingredients, in particular (2,5-dimethyl-2,3-dihydro-1H-inden-2-yl)methanol, reported in EP 1022265 and known as Lilyflore® (manufacturer: Firmenich SA). Generally, methods for obtaining these types of 2,2-disubstituted-2,3-dihydro-1H-indene derivatives involve a cyclization step in which a 2-methyl-2,3-dihydro-1H-inden-1-one derivative is obtained, followed by a reaction with a toxic and difficult-to-handle reagent, such as formaldehyde or lithium diisopropylamide. Direct cyclization to obtain compounds of formula (I) has never been reported. Furthermore, compounds of formula (IV) are products of industrial interest, and new methods leading to improved yields and / or productivity are constantly sought.

[0003] Therefore, there is a need to develop a more direct approach to compounds of formula (I) using reagents that may be safer and that can be more easily used on a larger scale, while improving yields.

[0004] According to the present invention, it is now possible to obtain compounds of formula (I) starting from compounds of formula (II) under Friedel-Crafts conditions. Thus, Friedel-Crafts cyclization starting from tetrasubstituted substrates such as compounds of formula (II) without the need for initial acyl chloride formation has only been reported once before in Monatschefte für Chemie, 1974, 574, where the cyclization of 2,2-dibenzyl-3-ethoxy-3-oxopropanoic acid resulted in the formation of only minor by-products.

[0005] Summary of the Invention The present invention relates to a novel method by which compounds of formula (I) can be prepared starting from compounds of formula (II), which opens up a new route to compounds of formula (IV).

[0006] A first subject of the present invention is therefore the compound of formula (I) in the form of any one of its stereoisomers or a mixture thereof. [ka] [wherein n is an integer of 0 to 2, and R 1 each independently represents a substituent on an aromatic ring; C 1~6 Alkyl group, C 2~6 Alkenyl group, or C 1~6 is an alkoxy group, and R 2 is C 1~3 represents an alkyl group, and R 3 is a hydrogen atom, C 1~6 Alkyl group, or C 2~6 represents an alkenyl group] 1. A method for preparing a compound of formula (I), comprising: Formula (II) in the form of any one of its stereoisomers or a mixture thereof [ka] [where n, R 1 , R 2 , and R 3 has the same meaning as defined in formula (I), and A is C(O)OC(O)R 4 represents a group, a C(O)Cl group, or a COOH group, and R 4 is a C substituted with one or more chlorine or fluorine atoms 1~6 represents an alkyl group] in the presence of a Friedel-Crafts acylating reagent.

[0007] A second subject of the invention is the compound of formula (I) in the form of any one of its stereoisomers or a mixture thereof. [ka] [wherein n is an integer of 0 to 2, and R 1 each independently represents a substituent on an aromatic ring; C 1~6 Alkyl group, C 2~6 Alkenyl group, or C 1~6 is an alkoxy group, and R 2 is C 1~3 represents an alkyl group, and R 3 is a hydrogen atom, C 1~6 Alkyl group, or C 2~6represents an alkenyl group, with the proviso that 5-methoxy-2-methyl-1-oxo-2,3-dihydro-1H-indene-2-carboxylic acid, methyl 2-ethyl-5-methyl-1-oxo-2,3-dihydro-1H-indene-2-carboxylate, methyl 2-ethyl-6-methoxy-1-oxo-2,3-dihydro-1H-indene-2-carboxylate, ethyl 1-oxo-2-propyl-2,3-dihydro-1H-indene-2-carboxylate, methyl 2-ethyl-1-oxo-2,3-dihydro-1H-indene -2-carboxylate, methyl 2-isopropyl-1-oxo-2,3-dihydro-1H-indene-2-carboxylate, methyl 6-methoxy-1-oxo-2-propyl-2,3-dihydro-1H-indene-2-carboxylate, 2-methyl-1-oxo-2,3-dihydro-1H-indene-2-carboxylic acid, methyl 2-methyl-1-oxo-2,3-dihydro-1H-indene-2-carboxylate, ethyl 2-methyl-1-oxo-2,3-dihydro-1H-indene-2-carboxylate, Allyl 2-methyl-1-oxo-2,3-dihydro-1H-indene-2-carboxylate, methyl 6-methoxy-2-methyl-1-oxo-2,3-dihydro-1H-indene-2-carboxylate, tert-butyl 2-methyl-1-oxo-2,3-dihydro-1H-indene-2-carboxylate, methyl 4-methoxy-2-methyl-1-oxo-2,3-dihydro-1H-indene-2-carboxylate, methyl 5,6-dimethoxy-2-methyl-1-oxo-2,3-dihydro-1H-indene -2-carboxylate, methyl 6-isobutyl-2-methyl-1-oxo-2,3-dihydro-1H-indene-2-carboxylate, ethyl 5-(tert-butyl)-2-methyl-1-oxo-2,3-dihydro-1H-indene-2-carboxylate, ethyl 2,5,7-trimethyl-1-oxo-2,3-dihydro-1H-indene-2-carboxylate, and tert-butyl 5-methoxy-2-methyl-1-oxo-2,3-dihydro-1H-indene-2-carboxylate are excluded. is a compound of

[0008] A third subject of the invention is the compound of formula (I) in the form of any one of its stereoisomers or a mixture thereof. [ka] [wherein n is an integer of 0 to 2, and R 1 each independently represents a substituent on an aromatic ring; C 1~6 Alkyl group, C 2~6 Alkenyl group, or C 1~6 is an alkoxy group, and R 2 is C 1~3 represents an alkyl group, and R 3 is a hydrogen atom, C 1~6 Alkyl group, or C 2~6 represents an alkenyl group, and A is a C(O)Cl group; C(O)OC(O)R 5 represents a group, and R 5 is C 1~6 represents an alkyl group, excluding ethyl 3-chloro-2-(4-methoxy-3-methylbenzyl)-2-methyl-3-oxopropanoate. is a compound of

[0009] Description of the Invention It has now been surprisingly discovered that the perfume components reported in EP 1022265 can be obtained from a new class of precursors (or chemical intermediates), as defined herein below by formula (II), and that these new intermediates provide the corresponding perfume components reported in EP 1022265 in overall higher yields than methods known from the prior art. The method of the present invention is a Friedel-Crafts reaction, which has been reported primarily for substrates that do not contain a tetrasubstituted carbon alpha to the carbonyl group and / or for acid chlorides. However, the preparation of acyl chlorides requires an additional step that generates corrosive and toxic by-products. High-yield cyclizations for non-acid chloride substrates have only been reported for acids that form unsubstituted indanones. Unexpectedly, the present invention allows for direct access to compounds of formula (I) in high yields while limiting and preventing decarboxylation side reactions. Furthermore, the method of the present invention avoids the extra step of forming acyl chlorides and / or substituting the indanone derivative.

[0010] A first subject of the present invention is therefore the compound of formula (I) in the form of any one of its stereoisomers or a mixture thereof. [ka] [wherein n is an integer of 0 to 2, and R 1 each independently represents a substituent on an aromatic ring; C 1~6 Alkyl group, C 2~6 Alkenyl group, or C 1~6 is an alkoxy group, and R 2 is C 1~3 represents an alkyl group, and R 3 is a hydrogen atom, C 1~6 Alkyl group, or C 2~6 represents an alkenyl group] 1. A method for preparing a compound of formula (I), comprising: Formula (II) in the form of any one of its stereoisomers or a mixture thereof [ka] [where n, R 1 , R 2 , and R 3 has the same meaning as defined in formula (I), and A is C(O)OC(O)R 4 represents a group, a C(O)Cl group, or a COOH group, and R 4 is a C substituted with one or more chlorine or fluorine atoms 1~6 represents an alkyl group] in the presence of a Friedel-Crafts acylating reagent.

[0011] For clarity, expressions such as "any one of its stereoisomers or a mixture thereof" have the usual meaning understood by those skilled in the art, i.e., that the compounds of formula (I) and (II) may be pure enantiomers or enantiomeric mixtures. In other words, the compounds of formula (I) and (II) may have at least one stereocenter that can 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 in the form of enantiomeric mixtures. The compounds of formula (I) and (II) may also be in the form of pure diastereoisomers or diastereomeric mixtures when the compounds of formula (I) and (II) have more than one stereocenter. The compounds of formula (I) and (II) may also be in racemic or scalemic form. Thus, the compounds of formula (I) and (II) may be in the form of a single stereoisomer or a composition of matter that includes or consists of various stereoisomers.

[0012] For clarity, the expression "Friedel-Crafts acylating reagent" refers to any reagent known to those skilled in the art to effect acylation of aromatic rings via electrophilic aromatic substitution. This type of transformation is very familiar to those skilled in the art and is well documented in organic chemistry textbooks.

[0013] The terms "alkyl" and "alkenyl" are understood to include branched and linear alkyl and alkenyl groups.

[0014] According to an optional embodiment of the present invention, the cyclization of the compound of formula (II) can be achieved by removing R on the aromatic ring in the compound of formula (II). 1 Depending on the position of the group, it can provide one compound of formula (I) or a mixture of two isomers.For example, when there is only one substituent at the 3-position of the aromatic ring of the compound of formula (II), two isomers can be obtained.Either isomer can be further transformed or separated in subsequent steps.Those skilled in the art can easily select the most suitable method for separating each isomer.

[0015] According to any embodiment of the invention, n may be 0 or 1, in particular 1.

[0016] According to any embodiment of the present invention, the compound of formula (I) has the formula [ka] [In the formula, R 1 , R 2 , and R 3 each have the same meaning as defined above] It can be of the following type.

[0017] According to an optional embodiment of the present invention, the compound of formula (II) is of the formula [ka] [In the formula, R 1 , R 2 , R 3 , and A each have the same meaning as defined above. It can be of the following type.

[0018] According to an optional embodiment of the present invention, the compound of formula (II) or (II') may be represented by formula (III) [ka] wherein Z is a good leaving group such as an ether group, a perfluoroalkylsulfonate group, a tosylate group, a mesylate group, or a halogen atom, especially a chloride atom; and dialkyl methyl malonate or 3-alkoxy-2-methyl-3-oxopropanoic acid] When the reaction is carried out with a dialkyl methyl malonate, the compound of formula (II) [A is a COOH, C(O)Cl group, or C(O)OC(O)R 4 A monohydrolysis and optionally a monochlorination or anhydride formation step is required to obtain the compounds of formula (I), respectively. These reactions are generally known to those skilled in the art, and one particular embodiment is illustrated in the Examples.

[0019] According to a particular embodiment, when A represents a C(O)Cl group, said compound of formula (II) or (II') can be prepared in situ starting from the corresponding monoacid / monoester, i.e. starting from a compound of formula (II) or (II') in which A is a COOH group.

[0020] According to a particular embodiment, A is C(O)OC(O)R 4 group, the compounds of formula (II) or (II') can be prepared starting from the corresponding monoacids / monoesters, i.e. from compounds of formula (II) or (II') where A is a COOH group, or from acyl chlorides / monoesters, i.e. from compounds of formula (II) or (II') where A is a COCl group, or from anhydrides / monoesters, i.e. from compounds of formula (II'') as defined below where A is C(O)OC(O)R 5 is a group, wherein R 5 is C 1~6 is an alkyl group, preferably R 5 is a methyl or ethyl group].

[0021] According to any embodiment of the invention, A may be a C(O)Cl group or a COOH group, in particular a COOH group.

[0022] According to any embodiment of the present invention, R 2 is C 1~2 In particular, R 2 may represent a methyl group.

[0023] According to any embodiment of the present invention, R 3 is a hydrogen atom, C 1~5 Alkyl group, or C 2~5 In particular, R 3 is C 1~3 In particular, R 3 may represent a methyl or ethyl group.

[0024] According to any embodiment of the present invention, R 4 is a C substituted with one, two, or three chlorine or fluorine atoms 1~4 In particular, R 4 is a C substituted with one or three chlorine or fluorine atoms 1~3 In particular, R 4 may represent a CCl3, CF3, or CH2Cl group.

[0025] According to any embodiment of the present invention, R 1 is a substituent of the aromatic ring, in particular at the 5 and / or 6 positions of the aromatic ring in compounds of formula (I) or at the 3, 4 and / or 5 positions of the aromatic ring in compounds of formula (II). 1 are independent of each other, C 1~4 Alkyl group, C 2~4 Alkenyl group, or C 1~3 In particular, R 1 are independent of each other, C 1~3 Alkyl group or C 2~3 In particular, R 1 may, independently of one another, represent a methyl or ethyl group. In particular, R 1 can be a methyl group.

[0026] According to any embodiment of the present invention, the Friedel-Crafts acylating reagent can be an inorganic acid or a Lewis acid. According to certain embodiments, suitable inorganic acids include polyphosphoric acid, Eaton's reagent, and perfluorinated ion exchange resins.

[0027] For clarity, the expression "Eaton's reagent" has the ordinary meaning understood by those skilled in the art, i.e., a mixture of P2O5 and methanesulfonic acid.

[0028] According to any embodiment of the present invention, the Lewis acid is of the formula M(Y)n, where M is a metal selected from the group consisting of Al, B, Bi, Fe, Sn, Zn, and In; n is an integer from 2 to 4; and Y is a halogen atom, triflate, or acetylacetone. According to certain embodiments, suitable Lewis acids can include BF3.OEt2, Bi(OTf)3, AlCl3, FeCl2, FeCl3, FeCl3 (0.4 mmol / g) on ​​silica gel, FeCl3.6H2O, InCl3, SnCl4, Zn(acac)2, ZnBr2, ZnCl2, and ZnI2. In particular, the Lewis acid can be BF3.OEt2, Bi(OTf)3, FeCl3, FeCl3 (0.4 mmol / g) on ​​silica gel, FeCl3.6H2O, InCl3, SnCl4, ZnCl2, and ZnI2. In particular, the Lewis acid can be BF3.OEt2, Bi(OTf)3, or ZnI2.

[0029] According to a specific embodiment of the present invention, when Lewis acid is used, the method of the present invention can be carried out in the presence of an additive, and the additive can be an acid anhydride, an organic acid, or phosphoryl chloride.Particularly, examples of suitable acid anhydrides include trifluoroacetic anhydride, trichloroacetic anhydride, dichloroacetic anhydride, monochloroacetic anhydride, and methanesulfonic anhydride.Particularly, examples of suitable acids include chloroacetic acid, trichloroacetic acid, and trifluoroacetic acid.

[0030] According to a particular embodiment, when A represents a C(O)Cl group, the Friedel-Crafts acylating reagent can be a Lewis acid. Particularly suitable Lewis acids can be selected from the group consisting of AlCl3, FeCl2, FeCl3, FeCl3 (0.4 mmol / g) on ​​silica gel, FeCl3.6H2O, InCl3, SnCl4, Zn(acac)2, ZnBr2, ZnCl2, ZnI2, and mixtures thereof. Particularly suitable Lewis acids can be selected from the group consisting of FeCl3, FeCl3 (0.4 mmol / g) on ​​silica gel, FeCl3.6H2O, InCl3, SnCl4, ZnI2, and mixtures thereof. Particularly suitable Lewis acids can be selected from the group consisting of FeCl3 and ZnI2, which allow the addition of catalytic amounts of Lewis acid, i.e., less than 0.51 equivalents, in the reaction medium.

[0031] According to certain embodiments, when A represents a COOH group, the Friedel-Crafts acylating reagent may be an inorganic acid or a Lewis acid in combination with an acid anhydride or phosphoryl chloride. Particularly suitable inorganic acids may be selected from the group consisting of polyphosphoric acid, Eaton's reagent, or perfluorinated ion exchange resins. Particularly suitable Lewis acids may be selected from the group consisting of boron trifluoride diethyl etherate, ZnCl2, ZnI2, or bismuth(III) trifluoromethanesulfonate. Particularly suitable acid anhydrides may be selected from the group consisting of trifluoroacetic anhydride, methanesulfonic anhydride, trichloroacetic anhydride, or 2-chloroacetic anhydride. In particular, examples of suitable combinations of Lewis acids and acid anhydrides or phosphoryl chloride can be selected from the group consisting of boron trifluoride diethyl etherate with trifluoroacetic anhydride, boron trifluoride diethyl etherate with methanesulfonic anhydride, bismuth trifluoromethanesulfonate with trifluoroacetic anhydride, bismuth trifluoromethanesulfonate with 2-chloroacetic anhydride, boron trifluoride diethyl etherate with 2-chloroacetic anhydride, and POCl with ZnCl.

[0032] According to a particular embodiment, A is C(O)OC(O)R 4 When the Friedel-Crafts acylating reagent represents a group, it can be a Lewis acid. According to a particular embodiment, a suitable Lewis acid can be selected from the group consisting of Bi(OTf)3 and BF3.OEt2, preferably Bi(OTf)3.

[0033] The inorganic acid can be added to the reaction medium of the method of the present invention in a wide range of concentrations. Non-limiting examples include concentrations of inorganic acid ranging from 0.5 to 10 equivalents relative to the total amount of the compound of formula (II). In particular, the concentration of inorganic acid can be between 1 and 4 equivalents. It goes without saying that the method will also function with more inorganic acid. However, the optimal concentration of inorganic acid will depend on the nature of the inorganic acid, the nature of the substrate, the temperature, and the desired reaction time, as known to those skilled in the art.

[0034] The Lewis acid 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, the concentration of the Lewis acid can range from 0.01 to 2.5 equivalents relative to the total amount of the compound of formula (II). In particular, the concentration of the Lewis acid can be between 0.01 and 0.1 equivalents. It goes without saying that the method will also function with more Lewis acid. However, the optimal concentration of the Lewis acid will depend on the nature of the Lewis acid, the nature of the substrate, the temperature, and the desired reaction time, as known to those skilled in the art.

[0035] The additive can be added to the reaction medium of the method of the present invention in a wide range of concentrations. Non-limiting examples include additive concentrations ranging from 1 to 10 equivalents relative to the total amount of the compound of formula (II). In particular, the additive concentration can be between 1 and 5 equivalents. It goes without saying that the method will also function with more additives. However, the optimal additive concentration will depend on the nature of the additive, the nature of the substrate, the nature of the Lewis acid, the temperature, and the desired reaction time, as known to those skilled in the art.

[0036] The temperature of the process of the present invention may be in the range comprised between 22° C. and 150° C., more preferably between 60° C. and 110° C. Of course, the skilled person will also be able to select the preferred temperature depending on the starting temperature and the melting and boiling points of the final product, as well as the desired time of the reaction or conversion.

[0037] The process of the present invention 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 Friedel-Crafts acylation reactions can be used for the purposes of the present invention. Examples of particularly suitable solvents include C cyclohexane, such as toluene or xylene. 6~10 Aromatic solvents, such as hexane or cyclohexane 5~12 Hydrocarbon solvents, such as tetrahydrofuran or MTBE 4~8 C such as ether, ethyl acetate 4~10 C such as esters and dichloromethane 1~2 C, such as chlorinated hydrocarbons, isopropanol or ethanol 2~6 C, such as primary or secondary alcohols, acetone 2~6 The solvent may be a polar solvent, or a mixture thereof. In particular, the solvent may be a solvent such as toluene, or may be solvent-free. The choice of solvent depends on the nature of the Friedel-Crafts reagent and the compound of formula (II). Those skilled in the art can easily select the most suitable solvent in each case to optimize the method of the present invention.

[0038] According to an optional embodiment of the present invention, the compound of formula (I) may be of formula (IV) [ka] [In the formula, R 1 and n each have the same meaning as defined above. The compound of formula (IV) can be obtained via hydrogenolysis and hydrogenation of the compound of formula (I). The conversion of the compound of formula (I) to the compound of formula (IV) is shown in the experimental section below.

[0039] The compounds of formula (I) and / or (II) are generally novel compounds and offer many advantages as explained above and as shown in the examples.

[0040] Another subject of the invention is therefore the compound of formula (I) in the form of any one of its stereoisomers or a mixture thereof. [ka] [wherein n is an integer of 0 to 2, and R 1 each independently represents a substituent on an aromatic ring; C 1~6 Alkyl group, C 2~6 Alkenyl group, or C 1~6 is an alkoxy group, and R 2 is C 1~3 represents an alkyl group, and R 3 is a hydrogen atom, C 1~6 Alkyl group, or C 2~6represents an alkenyl group, with the proviso that 5-methoxy-2-methyl-1-oxo-2,3-dihydro-1H-indene-2-carboxylic acid, methyl 2-ethyl-5-methyl-1-oxo-2,3-dihydro-1H-indene-2-carboxylate, methyl 2-ethyl-6-methoxy-1-oxo-2,3-dihydro-1H-indene-2-carboxylate, ethyl 1-oxo-2-propyl-2,3-dihydro-1H-indene-2-carboxylate, methyl 2-ethyl-1-oxo-2,3-dihydro-1H-indene -2-carboxylate, methyl 2-isopropyl-1-oxo-2,3-dihydro-1H-indene-2-carboxylate, methyl 6-methoxy-1-oxo-2-propyl-2,3-dihydro-1H-indene-2-carboxylate, 2-methyl-1-oxo-2,3-dihydro-1H-indene-2-carboxylic acid, methyl 2-methyl-1-oxo-2,3-dihydro-1H-indene-2-carboxylate, ethyl 2-methyl-1-oxo-2,3-dihydro-1H-indene-2-carboxylate, Allyl 2-methyl-1-oxo-2,3-dihydro-1H-indene-2-carboxylate, methyl 6-methoxy-2-methyl-1-oxo-2,3-dihydro-1H-indene-2-carboxylate, tert-butyl 2-methyl-1-oxo-2,3-dihydro-1H-indene-2-carboxylate, methyl 4-methoxy-2-methyl-1-oxo-2,3-dihydro-1H-indene-2-carboxylate, methyl 5,6-dimethoxy-2-methyl-1-oxo-2,3-dihydro-1H-indene -2-carboxylate, methyl 6-isobutyl-2-methyl-1-oxo-2,3-dihydro-1H-indene-2-carboxylate, ethyl 5-(tert-butyl)-2-methyl-1-oxo-2,3-dihydro-1H-indene-2-carboxylate, ethyl 2,5,7-trimethyl-1-oxo-2,3-dihydro-1H-indene-2-carboxylate, and tert-butyl 5-methoxy-2-methyl-1-oxo-2,3-dihydro-1H-indene-2-carboxylate are excluded. is a compound of

[0041] Another subject of the invention is the compound of formula (I) in the form of any one of its stereoisomers or a mixture thereof. [ka] [wherein n is an integer of 0 to 2, and R 1 each independently represents a substituent on an aromatic ring; C 1~6 Alkyl group, C 2~6 Alkenyl group, or C 1~6 is an alkoxy group, and R 2 is C 1~3 represents an alkyl group, and R 3 is a hydrogen atom, C 1~6 Alkyl group, or C 2~6 represents an alkenyl group, and A is a C(O)Cl group; C(O)OC(O)R 5 represents a group, and R 5 is C 1~6 represents an alkyl group, excluding ethyl 3-chloro-2-(4-methoxy-3-methylbenzyl)-2-methyl-3-oxopropanoate. is a compound of

[0042] Typical procedures for carrying out the method of the invention are reported in the Examples herein below.

[0043] Example The invention will now be described in further detail by the following examples, in which abbreviations have their usual meaning in the art and temperatures are given in degrees Celsius (°C). NMR spectra were obtained using a 400 MHz ( 1 H) and 100MHz ( 13 Bruker Avance II Ultrashield 400 plus or 500MHz ( 1 H) and 125MHz ( 13 Bruker Avance III 500 or 600MHz ( 1 H) and 150MHz ( 13Spectra were acquired using either a Bruker Avance III 600 cryoprobe operating at 1000 Hz (C). Spectra were internally referenced to tetramethylsilane at 0.0 ppm. 1 H NMR signal shifts are expressed in δ ppm and coupling constants (J) are expressed in Hz, with the following multiplicities: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; and b, broad (indicating unresolved coupling), and were interpreted using Bruker Topspin software. 13 C NMR data are expressed as chemical shifts δ ppm and in hybrid form from DEPT90 and DEPT135 experiments: C, quaternary; CH, methine; CH, methylene; CH, methyl.

[0044] Example 1 Preparation of compounds of formula (I) starting from compounds of formula (II) in which A is a COOH group a) Preparation of 3-ethoxy-2-methyl-2-(4-methylbenzyl)-3-oxopropanoic acid A 50 mL round-bottom flask was charged with sodium hydroxide (7.55 mL, 7.55 mmol). The solution was cooled to 0°C. Diethyl 2-methyl-2-(4-methylbenzyl)malonate (2 g, 7.19 mmol) was dissolved in ethanol (20 mL, 7.19 mmol) and added dropwise over 5 minutes. The mixture was stirred at 0°C for 5 minutes and then warmed to room temperature. After 22 hours, the mixture was poured into water and extracted twice with ether. The water was acidified with hydrochloric acid (0.65 mL, 7.92 mmol). The aqueous phase was extracted twice with ether, washed once with water and twice with brine, dried over NaSO, filtered, and concentrated to give the monoacid (1.58 g, 85%) as a clear oil. A sample of the desired product was treated with MSTFA and analyzed by GC.

[0045] [Table 1]

[0046] b) Preparation of ethyl 2,6-dimethyl-1-oxo-2,3-dihydro-1H-indene-2-carboxylate Polyphosphoric acid (29.0 g, 121 mmol) was placed in a flask equipped with mechanical stirring. It was heated to 70° C. 3-Ethoxy-2-methyl-2-(4-methylbenzyl)-3-oxopropanoic acid (10 g, 40 mmol) was added portionwise over 10 minutes. After 3 hours and 30 minutes, ice cubes were added to the mixture, followed by the addition of ether. This was then extracted with ether, washed once with water, once with NaHCO3, twice with brine, dried over Na2SO4, filtered, concentrated, and distilled at a distillation pressure between the bulbs of 0.2 mbar / T°=140° C. to provide ethyl 2,6-dimethyl-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (7.90 g, 34 mmol, 85%).

[0047] [Table 2]

[0048] Example 2 Preparation of compounds of formula (I) starting from compounds of formula (II) where A is a COOH group under different conditions 3-Ethoxy-2-methyl-3-oxo-2-(p-tolylmethyl)propanoic acid (10 g, 39.9 mmol) prepared in Example 1a) in an appropriate solvent (250 mL) was placed in a flask under N2. Reagent A and reagent B were added. The solution was stirred at the indicated temperature for the indicated time. The mixture was then poured into 5 ml of HO and stirred at room temperature for 5 minutes. 20% K2CO3 was added until pH = 9. It was then extracted with ether and washed once with water and twice with brine. It was dried over Na2SO4, filtered, and concentrated. The GC yield of ethyl 2,6-dimethyl-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (i.e., the compound of formula (I)) is reported in Table 1.

[0049] [Table 3]

[0050] Example 3 Preparation of compounds of formula (I) starting from compounds of formula (II) in which A is a COCl group a) Preparation of ethyl 3-chloro-2-methyl-2-(4-methylbenzyl)-3-oxopropanoate A 500 mL round-bottom flask was charged with 3-ethoxy-2-methyl-3-oxo-2-(p-tolylmethyl)propanoic acid (10 g, 39.9 mmol) in DCM (250 mL). Thionyl chloride (14.49 mL, 199.8 mmol) was added dropwise over 3 minutes. The mixture was refluxed. After 4 hours and 30 minutes, the mixture was concentrated to give ethyl 3-chloro-2-methyl-2-(4-methylbenzyl)-3-oxopropanoate (10.3 g, 95.7%).

[0051] [Table 4]

[0052] b) Preparation of ethyl 2,6-dimethyl-1-oxo-indan-2-carboxylate A 100 mL round-bottom flask was charged with ethyl 3-chloro-2-methyl-2-(4-methylbenzyl)-3-oxopropanoate (5.32 g, 19.8 mmol) and toluene (50 mL). The mixture was stirred at room temperature, and anhydrous iron(III) chloride (0.21 g, 1.3 mmol) was added. The mixture was then refluxed. The mixture was cooled to room temperature.

[0053] The mixture was poured into water / ice and extracted with ether, which was washed once with water, once with sodium carbonate, twice with brine, dried over sodium sulfate, filtered, concentrated, and purified by bulb-to-bulb distillation (pressure = 0.1 mbar / T = 160 °C) to provide ethyl 2,6-dimethyl-1-oxo-indan-2-carboxylate (4.16 g, 17.9 mmol, 90.4%).

[0054] [Table 5]

[0055] Example 4 Preparation of compounds of formula (I) starting from compounds of formula (II) in which A is a COOH group a) Preparation of 3-methoxy-2-methyl-2-(4-methylbenzyl)-3-oxopropanoic acid 3-Methoxy-2-methyl-2-(4-methylbenzyl)-3-oxopropanoic acid (161.8 g, 685 mmol) in MeOH (42 mL) was placed in a 750 mL round-bottom flask under N2. A 30% solution of sodium hydroxide (61.8 mL, 616 mmol) was slowly added over 1 h (62 mL / h, 1 mL / min) at -10 °C and stirred overnight at -10 °C. A portion of the solvent (153 g MeOH dist, 20 g trap) was distilled under vacuum (Tmax = 40-50, delta T = 30 °C, 150-20 mbar). Water (210 mL, 1.16E+04 mmol) was added to the mixture. At room temperature, the mixture was washed three times with cyclohexane (96 mL, 890 mmol). At 40°C, 50% sulfuric acid in water (36.5 ml, 342 mmol) (9.4 ml / h) was added to the solution until pH = 3. The water was separated from the oil phase. At room temperature, the aqueous phase was extracted twice with ethyl acetate (101 ml, 1027 mmol). The combined organic layers were dried and then the solvent was removed by evaporation to give a colorless liquid (62.5% yield): [Table 6]

[0056] b) Preparation of methyl 2,6-dimethyl-1-oxo-2,3-dihydro-1H-indene-2-carboxylate Polyphosphoric acid (308 g, 1282 mmol) was placed in a flask equipped with mechanical stirring. It was heated to 70 °C. 3-Methoxy-2-methyl-2-(4-methylbenzyl)-3-oxopropanoic acid (101 g, 427 mmol) was added portionwise over 10 min. After 1 h 30 min at 70-90 °C, water was added to the mixture, which was then extracted with ethyl acetate, washed once with NaHCO3 and once with NH4Cl, dried over Na2SO4, filtered, and concentrated (crude = 70 g). The product was recrystallized in ether (63% yield).

[0057] [Table 7]

[0058] Example 5 Preparation of ethyl 2,5-dimethyl-2,3-dihydro-1H-indene-2-carboxylate starting from ethyl 2,6-dimethyl-1-oxo-2,3-dihydro-1H-indene-2-carboxylate Ethyl 2,6-dimethyl-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (1 equivalent), Pd / C (0.14–0.19 mol% Pd relative to the starting material, eggshell catalyst), acetic acid (100 wt.% relative to the starting material), and acetic anhydride (26 wt.% relative to the starting material, i.e., 0.6 equivalents) were charged together into an autoclave equipped with a mechanical stirring device, pressure and internal temperature sensors, and a heating / cooling system for internal temperature regulation. The sealed autoclave was then purged with nitrogen (three times at 5 bar) and hydrogen (three times at 5 bar) while stirring, and then pressurized to the required hydrogen pressure (28 bar) via a hydrogen tank equipped with an outlet pressure regulator and an internal pressure sensor for tracking and determining hydrogen consumption. In addition to hydrogen consumption, GC analysis of samples collected throughout the reaction was performed after the hydrogenation reaction. The reaction mixture was initially heated to 60 °C and maintained at this temperature until the starting material completely disappeared. Additional acetic anhydride (39.5 wt. % relative to the starting material, i.e., 0.9 equivalents) was then added under pressure to the reaction mixture at 60°C using several suitable pumping devices. The reaction mixture was then gradually further heated from 60°C to 140°C. At the end of the reaction (complete disappearance of both starting materials and intermediates), the autoclave was cooled to 25°C, carefully evacuated and purged with nitrogen, and the reaction mixture was transferred to several filtration devices for heterogeneous catalyst removal. After concentrating the light compounds under vacuum, the crude reaction mixture was purified by fractional distillation to give the desired ethyl 2,5-dimethyl-2,3-dihydro-1H-indene-2-carboxylate in 90% molar yield.

[0059] [Table 8]

[0060] Example 6 Preparation of (2,5-dimethyl-2,3-dihydro-1H-inden-2-yl)methanol starting from ethyl 2,5-dimethyl-2,3-dihydro-1H-indene-2-carboxylate Ethyl 2,5-dimethyl-2,3-dihydro-1H-indene-2-carboxylate, ruthenium complex [RuCl((E)-N-(2-(diphenylphosphino)benzyl)-1-(6-((diphenylphosphino)methyl)pyridin-2-yl)methanimine)] (0.0113-0.0173 wt %, i.e., 0.00333-0.005 mol % relative to the starting material), and a 21 wt % sodium ethoxide solution in ethanol (7.4 wt %, i.e., 5 mol % relative to the starting material) were charged together into an autoclave equipped with a mechanical stirring device, pressure and internal temperature sensors, and a heating / cooling system for internal temperature regulation. The sealed autoclave was then purged with nitrogen (3 times at 5 bar) and hydrogen (3 times at 5 bar) while stirring, and then pressurized to the required hydrogen pressure (50 bar) via a hydrogen tank equipped with an outlet pressure regulator and an internal pressure sensor for tracking and determining hydrogen consumption. The reaction mixture was then heated to the required temperature (100°C), and the hydrogen pressure to the autoclave was maintained at the desired value throughout the reaction. After completion of the reaction, which was also determined by GC analysis with the complete disappearance of both the starting material and the mixed ester resulting from the transesterification reaction with the product, the autoclave was cooled to 25°C. It was then depressurized and purged with nitrogen (3 times at 5 bar), and the reaction mixture was then transferred to a round-bottom flask, and light compounds were removed under vacuum. The crude product was then flash distilled under high vacuum to remove the ruthenium catalyst and salts, and then purified by fractional distillation to carefully remove light compounds to give the desired (2,5-dimethyl-2,3-dihydro-1H-inden-2-yl)methanol in 98% molar yield, which met the olfactory requirements.

[0061] (2,5-dimethyl-2,3-dihydro-1H-inden-2-yl)methanol 1 H and 13It was characterized by C NMR and the data obtained fulfilled those from several references in the literature, namely B. Winter, S. Gallo-Fluckiger, Helv. Chim. Acta 2005, 88(12), 3118-3127.

[0062] (2,5-dimethyl-2,3-dihydro-1H-inden-2-yl)methanol was obtained in 75% overall yield starting from diethyl 2-methyl-2-(4-methylbenzyl)malonate according to the sequence reported in Examples 1, 5, and 6. On the other hand, (2,5-dimethyl-2,3-dihydro-1H-inden-2-yl)methanol was obtained in 67% overall yield starting from 1-(p-tolyl)propan-1-one as reported in WO 2016113151. The process of the present invention makes it possible to produce (2,5-dimethyl-2,3-dihydro-1H-inden-2-yl)methanol derivatives in improved yields.

Claims

1. Formula in the form of any one of the stereoisomers or a mixture of stereoisomers 【Chemistry 1】 [wherein n is an integer of 0 to 2, and R １ each independently represents a substituent of an aromatic ring; C １～６ Alkyl group, C ２～６ alkenyl group, or C １～６ is an alkoxy group, and R ２ is C １～３ represents an alkyl group, and R ３ is a hydrogen atom, C １～６ alkyl group, or C ２～６ represents an alkenyl group] 1. A method for preparing a compound of formula (I), comprising: Formula (II) in the form of any one of the stereoisomers or a mixture of stereoisomers 【Chemistry 2】 [In the formula, n, R １ , R ２ , and R ３ has the same meaning as defined in formula (I), and A is C(O)OC(O)R ４ group, a C(O)Cl group, or a COOH group; R ４ is a C substituted with one or more chlorine or fluorine atoms １～６ represents an alkyl group] in the presence of a Friedel-Crafts acylating reagent.

2. The compound of formula (I) is of the formula 【Transformation 3】 [In the formula, R １ , R ２ , and R ３ have the same meaning as defined in claim 1. It is of The compound of formula (II) is of the formula 【Chemistry 4】 [In the formula, R １ , R ２ , R ３ and A each have the same meaning as defined in claim 1.

2. The method of claim 1, wherein

3. 3. The method of claim 1, wherein A is a COOH group.

4. R ２ 4. The method according to claim 1, wherein is a methyl group.

5. R ３ is C １～３ 5. The method of claim 1, wherein the alkyl group is an alkyl group.

6. R １ However, independently of each other, C １～４ 6. The method of claim 1, wherein the alkyl group is an alkyl group.

7. 7. The method of claim 1, wherein the Friedel-Crafts acylating reagent is an inorganic acid or a Lewis acid.

8. 8. The method of claim 7, wherein the inorganic acid is selected from the group consisting of polyphosphoric acid, Eaton's reagent, and perfluorinated ion exchange resins.

9. 9. The method of claim 7 or 8, wherein the Lewis acid is of the formula M(Y)n, wherein M is a metal selected from the group consisting of Al, B, Bi, Fe, Sn, Zn, and In, n is an integer from 2 to 4, and Y is a halogen atom, triflate, or acetylacetone.

10. The Lewis acid is BF ３ . OEt ２ , Bi(OTf) ３ , AlCl ３ , FeCl ２ , FeCl ３ , FeCl on silica gel ３ 0.4 mmol / g, FeCl ３ .6H ２ O, InCl ３ , SnCl ４ , Zn(acac) ２ , ZnBr ２ , ZnCl ２ , and ZnI ２ 10. The method of any one of claims 7 to 9, selected from the group consisting of:

11. 11. The process of any one of claims 1 to 7 and 9 to 10, wherein the cyclization is carried out in the presence of a Lewis acid and an acid anhydride, an organic acid, or phosphoryl chloride.

12. 12. The method of claim 11, wherein the acid anhydride is selected from the group consisting of trifluoroacetic anhydride, trichloroacetic anhydride, dichloroacetic anhydride, monochloroacetic anhydride, and methanesulfonic anhydride.

13. In the form of any one of the stereoisomers or a mixture of stereoisomers. Formula (I) 【Transformation 5】 [wherein n is an integer of 0 to 2, and R １ each independently represents a substituent of an aromatic ring; C １～６ Alkyl group, C ２～６ alkenyl group, or C １～６ is an alkoxy group, and R ２ represents a methyl group, and R ３ is a hydrogen atom, C １～６ alkyl group, or C ２～６ represents an alkenyl group], 【Transformation 6】 [In the formula, R １ and n each have the same meaning as defined in claim 1.

13. The method of any one of claims 1 to 12, further comprising converting

14. Formula in the form of any one of the stereoisomers or a mixture of stereoisomers 【Transformation 7】 [wherein n is an integer of 0 to 2, and R １ each independently represents a substituent of an aromatic ring; C １～６ Alkyl group, C ２～６ alkenyl group, or C １～６ is an alkoxy group, and R ２ is C １～３ represents an alkyl group, and R ３ is a hydrogen atom, C １～６ alkyl group, or C ２～６ represents an alkenyl group, and A represents a C(O)Cl group; C(O)OC(O)R ５ represents a group, and R ５ is C １～６ represents an alkyl group, with the exception of ethyl 3-chloro-2-(4-methoxy-3-methylbenzyl)-2-methyl-3-oxopropanoate. Compound.

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