Production of menthane carboxylic aldehyde, menthane carboxylic acid and derivatives

Abstract

Process for the preparation of menthanecarbaldehyde, comprising the following steps: - Reaction of menthone with a haloacetic acid ester of the formula XCH2COOR, with X = chlorine or bromine and R = methyl or ethyl, to form the ester of menthaneglycitic acid, - Reaction of the ester of menthaneglycitic acid thus prepared to menthanecarbaldehyde, wherein, in order to react the prepared ester of menthaneglycitic acid to menthanecarbaldehyde, the ester is reacted with a strong base such that the ester is hydrolyzed, and the hydrolysis product, as menthaneglycitic acid or as a salt of menthaneglycitic acid, is decarboxylated after intermediate isolation or without intermediate isolation.

Description

[0001] The present invention relates to the production of menthane carbaldehyde, menthane carboxylic acid, or a derivative of menthane carboxylic acid, such as the corresponding esters or amides. The compound produced is typically present as a component of a stereoisomeric mixture; the derivative menthane carboxylic acid amide is thus, for example, a mixture with neomenthane, isomenthane, and neoisomenthane carboxylic acid amides. Preferably, the menthane carboxylic acid amide has the (1R, 2S, 5R) configuration. Preferably, the derivative of menthane carboxylic acid is selected from the group consisting of menthane carboxylic acid amides and menthane carboxylic acid esters, wherein the menthane carboxylic acid is converted to a menthane carboxylic acid halide in the interim.

[0002] Menthane carboxylic acid amides, e.g., menthane carboxylic acid ethylamide (WS-3) and menthane carboxylic acid N-(4-methoxyphenyl)-amide (WS-12), have long been used as physiological cooling agents. More recently, they have also been described as potential agents for the treatment of cancer, particularly prostate cancer; see, for example, WO 2005 / 002582 and US 2005 / 054651. WO 2010 / 019730 discloses a surprisingly strong and long-lasting cooling effect of neomenthane carboxylic acid amides.

[0003] The synthesis of menthane carboxylic acid amides and esters is frequently carried out via the menthane carboxylic acid stage. Various methods for the preparation of menthane carboxylic acid and its subsequent reactions are described in the literature.

[0004] For example, the conversion of menthol to menthyl chloride, its subsequent conversion to mentylmagnesium chloride, and the subsequent reaction with carbon dioxide to yield menthane carboxylic acid are described. Examples of this preparation route include DG Rowsell, GB 1392907, AK Bose et al., Journal of Organic Chemistry, 1963, 28, 1223; H.-P. Pfeiffer et al., Liebigs Annalen der Chemie, 1987, 725; JG Smith, GF Wright, Journal of Organic Chemistry, 1952, 17, 1116; and D. Cunningham et al., Journal of the Chemical Society, Perkin Transactions 1, 2002, 2692. Carrying out this preparation route is particularly difficult on an industrial scale and typically yields menthane carboxylic acid in a yield of only 50 percent or less.

[0005] C. Spino and C. Gobdout, in the Journal of the American Chemical Society, 2003, 125, 1206, disclose the oxidation of menthanecarbaldehyde with Jones' reagent to menthanecarboxylic acid. They further disclose that this carboxylic acid is converted to the acid chloride, see below.

[0006] A. Kato et al. describe the reaction of menthylmagnesium chloride with formaldehyde to form menthylcarbinol, from which menthane carboxylic acid is obtained in a further reaction step by oxidation with a large excess of manganese dioxide.

[0007] N. Yang et al., Jingxi Huagong 2010, 27, 622 (CA 153: 643682) discloses the reaction of menthylmagnesium chloride with N,N-dimethylformamide to form menthanecarbaldehyde.

[0008] M. Botton, Bulletin De La Societe Chimique France, 1973, 2472–2478 discloses the autoxidation of menthanecarbaldehyde, prepared from menthone and ethoxymethylmagnesium chloride, to menthanecarboxylic acid.

[0009] Several methods are known for the production of menthane carboxylic acid amides. It is possible to start with menthane carboxylic acid as the starting material, or to select different starting materials.

[0010] The publication by C. Spino, C. Gobdout, Journal American Chemical Society, 2003, 125, 1206, already cited, reveals not only the synthesis of menthane carboxylic acid (see above) but also its reaction with oxalyl chloride to form menthane carboxylic acid chloride.

[0011] WO 2010 / 019730 describes the production of N-aryl menthane carboxylic acid amides by a copper-catalyzed coupling of aryl halides with menthane carboxylic acid amide.

[0012] WO 2004 / 031128 describes the reaction of nitriles with alcohols in polyphosphoric acid in the presence of phosphorus pentoxide, phosphorus oxychloride, or sulfuryl chloride to form N-substituted amides, such as menthone carboxylic acid ethylamide. This manufacturing process has the disadvantage of using phosphorus-containing compounds, which, for example, results in the generation of phosphate-containing wastewater.

[0013] WO 2007 / 096074 specifies the reaction of menthylmagnesium halides with isocyanates for the production of menthane carboxylic acid amides. Due to their toxicity and strong irritant effect on the skin, mucous membranes, and especially the respiratory tract, handling isocyanates is problematic.

[0014] The objective of the present invention was to provide a simple manufacturing process for menthane carbaldehyde, menthane carboxylic acids, and / or derivatives of menthane carboxylic acid, in particular the corresponding amides or esters, which does not exhibit the disadvantages of the aforementioned processes. The process should preferably function without the use of expensive, sensitive, and / or toxicologically questionable substances and intermediates. The intermediates obtained during the synthesis should advantageously be usable for the production of menthane carboxylic acid derivatives without requiring complex purification operations.

[0015] This problem is solved by a process for the production of menthane carbaldehyde, menthane carboxylic acid or a derivative of menthane carboxylic acid, comprising the following step: – Conversion of an ester of menthane glycidic acid (IV) to menthane carbaldehyde (V). Compare the reaction schemes below.

[0016] Preferably, the method according to the invention comprises the following steps: – Reaction of menthone (II) with a haloacetic acid ester to form the ester of menthane glycidic acid (IV), – Conversion of the ester of menthane glycidic acid thus prepared to menthane carbaldehyde (V).

[0017] Preferred embodiments of the invention will become apparent from the detailed description of the invention below.

[0018] The process according to the invention comprises, as a principal step, the reaction of the menthane glycidic acid ester (IV), preferably by hydrolysis followed by decarboxylation, yielding menthane carbaldehyde (V). The preparation of menthane carbaldehyde (V) from the glycidic acid ester (IV) has not previously been described in the literature. The hydrolysis of the glycidic acid ester (IV) is preferably carried out in the presence of a strong base in a protic solvent, preferably water. The conditions are selected such that hydrolysis occurs. The strong base, preferably an aqueous strong base, is preferably used in equimolar or superstoichiometric amounts. The reaction is preferably carried out either with aqueous alkali solution or with alkali alkoxide and water (aqueous alkali alkoxide), each in equimolar or superstoichiometric amounts.The reaction is preferably carried out with (i) alkali alkoxide and (ii) water, preferably using alkoxide and water in equimolar amounts based on the glycidic acid ester. The reaction can be carried out at room temperature (22°C) or above or below this temperature, with carrying it out at room temperature being preferred for practical reasons. The hydrolysis product obtained (menthane glycidic acid) can be isolated, for example, in the form of the alkali salt or the glycidic acid itself. Decarboxylation follows the isolation. Preferably, however, the alkali salt is used for decarboxylation without isolation.

[0019] Decarboxylation is preferably achieved by the application of heat and / or under acidic conditions (i.e., by reaction with acid).

[0020] Preferably, an aqueous solution of the alkali salt of menthane glycidic acid is mixed with aqueous acid at an elevated temperature of at least 50°C, preferably at least 70°C. Aqueous mineral or carboxylic acids known to those skilled in the art are generally used, preferably aqueous sulfuric acid, hydrochloric acid, or acetic acid. In this embodiment, it has proven advantageous to use a water separator for heavy solvents and to carry out the reaction under reflux with heating. The aldehyde formed is obtained as an organic distillate.

[0021] In summary, to convert the prepared ester of menthane glycidic acid to menthane carbaldehyde, the ester is preferably hydrolyzed and the hydrolysis product as menthane glycidic acid or as a salt of menthane glycidic acid, after intermediate isolation or without intermediate isolation, is decarboxylated.

[0022] The following implementation sequence is preferred: – Reacting the ester of menthane glycidic acid with a strong base, preferably aqueous alkali hydroxide or aqueous alkali alkoxide, such that the ester hydrolyzes, wherein preferably the ester of menthane glycidic acid is reacted with (i) an equimolar amount of alkali alkoxide and (ii) water and / or – Decarboxylation of the hydrolysis product as the alkali salt of menthane glycidic acid, after or without intermediate isolation of the alkali salt, and / or – Decarboxylation of the hydrolysis product by adding heat and / or by reacting with acid, preferably by reacting with aqueous acid at a temperature of at least 50°C, preferably at least 70°C.

[0023] The process according to the invention preferably comprises, in addition to the hydrolysis / decarboxylation of the menthane glycidyl ester to menthane carbaldehyde, the further step of synthesizing menthane glycidyl esters (IV) from menthone (II). This is preferably carried out by reacting menthone (II) with a haloacetic acid ester (III) in the presence of a base, preferably in an inert solvent. Preferred bases are alkali alkoxides, preferably sodium or potassium alkoxide. The reaction is generally carried out at temperatures in the range of -10 to 30°C, preferably -5 to 10°C. Examples of preferred inert solvents include organic ethers, preferably tetrahydrofuran or tert-butyl methyl ether. The haloacetic acid ester and the base, preferably the alkali alkoxide, can be used in equimolar amounts or superstoichiometrically with respect to the menthone; superstoichiometric use is preferred.The resulting crude product is preferably purified by distillation, whereby unreacted menthone is first distilled off in the foreshots and then the product is distilled off from the residue.

[0024] The present invention relates in a preferred embodiment to a process for the production of menthanecarbaldehyde starting from menthone (II) comprising the following steps: – Reaction of menthone (II) with a haloacetic acid ester (III) to form the ester of menthane glycidic acid, – Conversion of the ester of menthane glycidic acid (IV) thus prepared to menthane carbaldehyde (V).

[0025] In a preferred embodiment of the present invention, the menthanecarbaldehyde obtained according to the invention is oxidized to menthanecarboxylic acid (I) in an additional step. Preferably, one or more oxidizing agents are used, selected from the group consisting of air, oxygen, hydrogen peroxide, and tert-butyl peroxide. Preferably, air, more preferably in the presence of a manganese(II) or cobalt(II) salt, or hydrogen peroxide is used as the oxidizing agent. Alternatively, and preferably when using the aforementioned oxidizing agents, the oxidation is carried out at a temperature of at least 40°C.

[0026] The oxidation of menthanecarbaldehyde (V) is thus carried out by oxidizing agents known to those skilled in the art. Examples of suitable oxidizing agents include air, oxygen, hydrogen peroxide, and tert-butyl peroxide. Preferably, hydrogen peroxide or air is used as the oxidizing agent, the latter optionally with the addition of a metal salt, preferably a manganese(II) or cobalt(II) salt. In all variants, the oxidation is preferably carried out at an elevated temperature, which is at least approximately 40°C. For example, oxidation at 50–60°C is typically complete after 26 hours. For product isolation, extraction into the aqueous phase is preferably carried out in an alkaline solution in an aqueous-organic system, and after acidification of the aqueous phase, extraction is performed with an organic solvent.

[0027] In a preferred embodiment, the inventive method comprises all of the following steps described above, as summarized in the reaction scheme below:

[0028] This means X Halogen, preferably chlorine or bromine R = organic residue, preferably aliphatic group, preferably C1-C 10 -Alkyl, C1-C 10 -Alkenyl, C1-C 10 -Alkynyl, optionally substituted, preferably methyl and ethyl.

[0029] Crucial to the invention is the step from the ester of menthane glycidic acid (IV) to menthane carbaldehyde (V), see above. The configurations at the stereocenters are not shown in the reaction scheme; in practice, a mixture of stereoisomers is regularly present.

[0030] The mixture of menthane carboxylic acid stereoisomers obtained according to the invention can be converted into a mixture of menthane carboxylic acid stereoisomers (preferably menthane carboxylic acid halides, menthane carboxylic acid esters, or menthane carboxylic acid amides) by known methods. Advantageous changes in the stereoisomeric composition can be selectively induced in this process. The stereoisomers of interest can be isolated by suitable methods, such as chromatography, distillation, or crystallization.

[0031] The present invention therefore also relates to a process for the production of a derivative of menthane carboxylic acid, comprising the following additional step: – Conversion of menthane carboxylic acid (I) (with a suitable halogenating agent) to a menthane carboxylic acid halide (VI).

[0032] The menthane carboxylic acid used is produced according to a process according to the invention.

[0033] As mentioned, the produced menthane carboxylic acid is usually present in a mixture with stereoisomers of menthane carboxylic acid (stereoisomeric mixture of carboxylic acids). Preferably, the conditions for the conversion of the menthane carboxylic acid to the menthane carboxylic acid halide are chosen such that a configuration inversion occurs at one or more stereogenic centers and the proportion of the menthane carboxylic acid halide in the stereoisomeric mixture of carboxylic acid halides is greater than the proportion of the menthane carboxylic acid in the stereoisomeric mixture of carboxylic acids.

[0034] The present invention also relates to a process for the production of a menthane carboxylic acid halide or a reaction product of a menthane carboxylic acid halide, comprising the following steps: – Production or provision of menthane carboxylic acid in mixture with stereoisomers of menthane carboxylic acid and – Reacting the mixture with a halogenating agent to form a mixture comprising menthane carboxylic acid halide and stereoisomers of menthane carboxylic acid halide, wherein the conditions during the reaction are chosen such that a configuration inversion takes place at one or more stereogenic centers, so that the proportion of the menthane carboxylic acid halide in the stereoisomeric mixture of the carboxylic acid halides is greater than the proportion of the menthane carboxylic acid in the stereoisomeric mixture of the carboxylic acids.

[0035] Preferably, the isomer ratio is controlled by the choice of halogenating agent. Suitable halogenating agents are thionyl chloride, phosphorus trichloride, and phosphorus pentachloride. Surprisingly, the reaction with thionyl chloride results in a partial configuration reversal, particularly of the neomenthyl isomer to the menthy isomer. It has been found that a carboxylic acid mixture with 65% neomenthyl and 16% menthy isomers yields a carboxylic acid chloride mixture with 10% neomenthyl and 68% menthy isomer content. See also the more detailed embodiments below.

[0036] A preferred process according to the invention for the production of a derivative of menthane carboxylic acid, in particular for the production of a menthane carboxylic acid halide, comprises the following steps: – Reaction of menthone (II) with a haloacetic acid ester to form the ester of menthane glycidic acid, – Conversion of the ester of menthane glycidic acid thus produced to menthane carbaldehyde, wherein the ester of menthane glycitic acid is reacted with a strong base, preferably aqueous alkali hydroxide or aqueous alkali alkoxide, such that the ester is hydrolyzed, wherein preferably the ester of menthane glycitic acid is reacted with (i) an equimolar amount of alkali alkoxide and (ii) water, and wherein the hydrolysis product as the alkali salt of menthane glycidic acid, after intermediate isolation or without intermediate isolation of the alkali salt, is decarboxylated by the addition of heat and / or by reaction with acid, preferably by reaction with aqueous acid at a temperature of at least 50°C, preferably at least 70°C, – Oxidation of the produced menthane carbaldehyde to menthane carboxylic acid, wherein one or more oxidizing agents selected from the group consisting of air, oxygen, hydrogen peroxide and tert-butyl peroxide are preferably used to oxidize the produced menthanecarbaldehyde. and / or the oxidation is carried out at a temperature of at least 40°C, – Conversion of the produced menthane carboxylic acid to a menthane carboxylic acid halide.

[0037] Menthane carboxylic acid chlorides are suitable as starting materials for the synthesis of various other menthane derivatives. For example, the corresponding menthane carboxylic acid amides can be obtained by reaction with amines, or the corresponding menthane carboxylic acid esters can be obtained by reaction with alcohols (possibly in the form of the corresponding alkoxide).

[0038] The present invention thus also includes a process for the production of a derivative of menthane carboxylic acid, with the additional step of converting the menthane carboxylic acid halide to a derivative selected from the group consisting of menthane carboxylic acid amides and menthane carboxylic acid esters.

[0039] In this process step, the menthane carboxylic acid halide used is typically present in a mixture with stereoisomers of the menthane carboxylic acid halide. The reaction conditions for converting the menthane carboxylic acid halide to the menthane carboxylic acid amide or to the menthane carboxylic acid ester are preferably selected such that a configuration inversion occurs at one or more stereogenic centers, resulting in a greater proportion of the menthane carboxylic acid amide or menthane carboxylic acid ester in the stereoisomeric mixture of the carboxylic acid amides than the proportion of the menthane carboxylic acid halide in the stereoisomeric mixture of the carboxylic acid halides. See the more detailed explanations below.

[0040] In the production of a menthane carboxylic acid amide according to the invention, the menthane carboxylic acid halide is typically reacted with an amine. In a preferred embodiment, the amine is selected from the group consisting of p-anisidine, ethylamine, tert-butylamine, cyclopropylamine, ethyl aminoacetic acid ester, 2-(4-aminophenyl)acetamide, (4-aminophenyl)acetonitrile, 2-pyridin-2-ylethylamine, 1-methyl-2-pyridin-3-ylethylamine, benzo[1,3]dioxole-5-ylamine, 2-(2-methylindol-1-yl)ethylamine, and 1-methyl-2-thiophen-3-ylethylamine.

[0041] A preferred method according to the invention for the production of a menthane carboxylic acid amide or menthane carboxylic acid ester comprises the following steps: – Production or provision of menthane carboxylic acid halide in mixture with stereoisomers of menthane carboxylic acid halide and – Reacting to the mixture with an amine or alcohol (possibly in the form of the alcoholate) to form a mixture comprising menthane carboxylic acid amide and stereoisomers of menthane carboxylic acid amide or menthane carboxylic acid ester and stereoisomers of menthane carboxylic acid ester.

[0042] As explained above, the reaction of a stereoisomeric mixture comprising menthane carboxylic acid, as well as the reaction of the resulting mixture of stereoisomers of the menthane carboxylic acid halo mixture, can result in a configuration inversion at one or more stereogenic centers. For example, menthane carboxylic acid chloride VI can be obtained from the stereoisomeric mixture of menthane carboxylic acids with phosphorus trichloride, phosphorus pentachloride, or thionyl chloride. Surprisingly, the reaction with thionyl chloride, for instance, leads to a configuration inversion of the neomenthyl isomer to the menthy isomer. According to GC analysis, a carboxylic acid mixture with 65% neomenthyl and 16% menthy isomers yields a carboxylic acid chloride mixture with 10% neomenthyl and 68% menthy isomers. From this, a stereoisomeric mixture of the corresponding menthane carboxylic acid amides can be obtained by reaction with amines.For example, when reacted with p-anisidine VII, a mixture of the corresponding menthane carboxylic acid anilides VIII results, with a further configuration inversion occurring. Thus, the resulting reaction product contains only 8% neomenthane and 75% menthane carboxylic acid N-(4-methoxyphenyl)-amide (trade name: Frescolat SC-1 or WS-12).

[0043] The respective content of the isomers in the individual reaction stages is shown in the following table as an example; see the corresponding examples 3, 4 and 5 below. Content [GC-Fl.-%] Carboxylic acid carboxylic acid chloride carboxylic acid amide Neomenthan- 65 10 8 Menthane- 16 68 75 Isomenthane 5,7 12 13 Neoisomenthan- 10 0,8 1,2

[0044] Both menthane and neomenthanecarboxylic acid N-(4-methoxyphenyl)-amide can be isolated from the crude product by crystallization and / or chromatography.

[0045] Further aspects and preferred embodiments of the present invention will become apparent from the following examples and the accompanying claims. In the examples, unless otherwise indicated by the context, the percentages refer to weight. Examples

[0046] The “menthone” used is a stereoisomeric mixture comprising 93.3% (–)-menthone and 5.9% (+)-isomenthone. Example 1: Methyl menthane glycidyl ester (4-Isopropyl-7-methyl-1-oxa-spiro[2.5]octane-2-carboxylic acid methyl ester) (compare formula IV)

[0047] 220 g of sodium methylate are placed in 800 ml of tetrahydrofuran and cooled to -5°C. 308 g of menthone are added. Then, 434 g of methyl chloroacetic acid are added over 4 hours at a temperature of no more than 0°C. After addition, the mixture is stirred for 2 hours at 0–5°C. 700 g of water are added and the mixture is stirred for 1 hour at 10°C. After phase separation, the aqueous phase is extracted with tetrahydrofuran, and the combined organic phases are washed with water. After concentration of the organic phase, the mixture is distilled in a 10 cm packed column. This yields 350 g of product (Kp). 1,1mbar = 106°C) with a content of 98.4% (sum of stereoisomers). This corresponds to a theoretical yield of 76%. Isomer 1 (content: 89.6%) 1H-NMR data 400 MHz CDCl3 (ppm): 3.78 s 3H; 3.62 s 1H; 1.98–1.62 m 4H; 1.65 d,d,d 13.4 Hz, 4.3 Hz, 1.6 Hz 1H; 1.50 d,d,d 10.5 Hz, 10.2 Hz, 3.3 Hz 1H; 1.43 d,d,d 10.6 Hz, 5.0 Hz, 3.0 Hz 1H; 1.31 d,d 13.5 Hz, 10.0 Hz 1H; 1.07 m 1H; 0.94 d 6.8 Hz 3H; 0.90 d 6.7 Hz 3H; 0.81 d 6.8 Hz 3H 13C-NMR data (ppm): 169.5 s; 67.1 seconds; 56.7 days; 52.1 q; 45.9 days; 36.8 tons; 32.8 tons; 30.5 days; 26.0 days; 24.0 t; 22.7 q; 21.3 q; 18.5 sq Mass spectrum: 211(61), 121(99), 95(100), 93(70), 81(98), 69(48), 67(57), 55(63), 43(45), 41(63) Isomer 2 (content: 6.0%) Mass spectrum: 211(56), 121(89), 95(98), 93(69), 81(100), 69(44), 67(58), 55(70), 43(44), 41(63) Isomer 3 (content: 2.8%) Mass spectrum: 211(47), 121(85), 95(94), 93(64), 81(100), 69(42), 67(51), 55(67), 43(43), 41(57) Example 2 Menthanecarbaldehyde (2-isopropyl-5-methyl-cyclohexanecarbaldehyde) (compare formula V)

[0048] 231 g of menthane glycidyl ester from Example 1 were added to a solution of 64.8 g sodium methylate in 480 g methanol and cooled to 10°C. 21.6 g of water were added, and the mixture was stirred for 2 hours at room temperature. The methanol was then distilled off under reduced pressure, and 370 g of water were added to the remaining residue. The resulting sodium salt solution of menthane glycidyl was then decarboxylated as follows.

[0049] 120 g of acetic acid and 250 g of water were heated under reflux in a 1 L three-necked flask equipped with a heavy solvent water separator. The sodium salt solution of menthane glycidic acid was added over 3 hours and then heated under reflux for a further 30 minutes. The separated organic distillate was treated with tert-butyl methyl ether and water, and the phases were separated. The organic phase was washed with water, dried with sodium sulfate, and concentrated. 72.5 g of product were obtained with a purity of 96% (sum of stereoisomers). This corresponds to a theoretical yield of 41.3%.

[0050] The isomers were isolated by preparative gas chromatography. However, during subsequent spectroscopic measurements, they had already been oxidized to the carboxylic acids. From the structure of the carboxylic acids, the presence of the corresponding menthanecarbaldehyde was deduced for each isomer. Isomer 1 (content: 67%) Mass spectrum: 168(8.3), 109(69), 107(55), 97(51), 95(43), 83(56), 81(83), 69(96), 55(100), 43(48), 41(80)

[0051] The presence of neomenthanecarbaldehyde was inferred for this isomer from the structure of the carboxylic acid. Isomer 2 (content: 13%) Mass spectrum: 168(9.6), 135(54), 109(90), 107(39), 97(56), 95(46), 83(70), 81(65), 69(99), 55(100), 41(73)

[0052] The presence of menthanecarbaldehyde was inferred for this isomer from the structure of the carboxylic acid. Isomer 3 (content: 6%) Mass spectrum: 168(7,9), 125(42), 109(54), 107(52), 97(42), 83(62), 81(80), 69(83), 55(100), 43(46), 41(73)

[0053] The presence of isomenthanecarbaldehyde was inferred for this isomer from the structure of the carboxylic acid. Isomer 4 (content: 5.7%) Mass spectrum: 168(7.3), 135(45), 109(70), 97(48), 95(50), 83(72), 81(73), 69(89), 55(100), 43(42), 41(72)

[0054] The presence of neoisomenthanecarbaldehyde was inferred for this isomer from the structure of the carboxylic acid. Example 3 Menthanecarboxylic acid (2-Isopropyl-5-methyl-cyclohexanecarboxylic acid) (compare formula I) Method A: Oxidation with atmospheric oxygen

[0055] Air was passed through 53 g of menthanecarbaldehyde, prepared according to Example 2, for 26 hours at a temperature of 50°C. The mixture was first treated with 10% sodium hydroxide solution and then with tert-butyl methyl ether. After phase separation, the aqueous phase was adjusted to pH 1 with dilute hydrochloric acid and extracted twice with tert-butyl methyl ether. The combined organic phases were washed with water, dried with sodium sulfate, and concentrated. 36 g of product were obtained with a purity of 97% (sum of stereoisomers). This corresponds to a theoretical yield of 62.5%. Isomer 1 (content: 65%) 1H (400 MHz, CDCl3) ppm: 11.10 (br, 1H) 2.92 (m, 1H), 2.02 (t,d,d 2.4 Hz, 3.5 KHz, 13.6 Hz; 1H) 1.56–1.80 (m, 5H), 1.17 (d,d,d 5.3 Hz, 12.2 Hz, 13.6 Hz; 1H), 0.85–1.05 (m, 2H), 0.93 (d 6.6 Hz; 3H), 0.91 (d 6.6 Hz; 3H), 0.86 (d 6.4 Hz, 3H) 13C (100 MHz, CDCl3) ppm: 181.7 s, 46.4 d, 41.9 d, 38.0 t, 35.4 t, 30.3 d, 27.5 d, 25.5 t, 22.4 q, 21.5 q, 21.3 q. Massenspektrum: 184(7.3), 115(60), 114(71), 95(88), 73(54), 70(96), 69(100), 56(47), 55(81), 43(51), 41(70), Isomer 2 (Gehalt: 16%) 1 H (400 MHz, CDCl3) ppm: 2.31 (d, t 3.4 Hz 11.7 Hz; 1H), 1.92 (d,t,d 2.3 Hz, 3.9 Hz, 12,6 Hz; 1H), 1.76 (d,q,q 2.8 Hz, 7.0 Hz, 7.0 Hz; 1H) 1.65–1.78 (m, 2H), 1.51 (t,t 3.1 Hz, 11.6 Hz; 1H), 1.38 (m, 1H), 1.21 (q 12.1 Hz; 1H), 1.03 (m, 2H), 0.92 (d, 6.9 Hz; 3H), 0.91 (d, 6.5 Hz; 3H), 0.81 (d 7.0 Hz; 3H) 13 C (100 MHz, CDCl3) 183.2 s, 47.7 d, 44.2 d, 38.8 t, 34.5 t, 32.0 d, 29.3 d, 23.8 t, 22.3 q, 21.3 q, 16.0 q. Massenspektrum: 184(6,6), 114(79), 95(68), 81(38), 73(43), 70(51), 69(100), 56(44), 55(73), 43(42), 41(64), Isomer 3 (Gehalt: 5,7%) 1H (400 MHz, CDCl3) ppm: 2.60 (d,t 4.0 Hz, 9.1 Hz; 1H), 1.92 (m, 1H), 1.34–1.86 (m, 8H), 0.94 (d 7.2 Hz; 3H) 0.92 (d 6.9 Hz; 3H), 0.87 (d 6.9 Hz; 3H) 13 C (100 MHz, CDCl3) ppm: 183,6 s, 43.8 d, 41.8 d, 34.5 t, 30.5 t, 28.9 d, 27.6 d, 21.2 q, 19.9 t, 19.3 q, 17.6 Massenspektrum: 184(5), 115(46), 114(67), 95(100), 81(41), 73(41), 70(82), 69(93), 55(74), 43(47), 41(66), Isomer 4 (Gehalt: 10%) 1 H (400 MHz, CDCl3) ppm: 2.51 (t,d 3.3 Hz, 11.9 Hz; 1H), 1.77–1.95 (m, 4H), 1.25–1.50 (m, 4H), 1.09 (m, 1H) 0.94 (d, 6.2 Hz; 3H) 0.92 (d, 6.2 Hz, 3H), 0.88 (d, 6.3 Hz; 3 Hz) 13 C (100 MHz, CDCl3) ppm: 183,3 s, 46.0 d, 42.3 d, 32.2 d, 31.0 t, 29.5 t, 29.2 t, 26.1 d, 22.2 q, 22.0 q, 21.3 q. Massenspektrum: 184(2), 114(90), 95(89), 83(49), 73(53), 70(75), 69(100), 56(48), 55(87), 43(48), 41(79), Methode B: Oxidation mit Wasserstoffperoxid

[0056] 100 g of 30% hydrogen peroxide, 7.7 g of acetic acid, and 0.42 g of iodine were added, along with 25 g of menthanecarbaldehyde prepared according to Example 2. The mixture was then stirred at 60°C for 24 hours. After the reaction was complete, the phases were separated. The upper phase was adjusted to pH 11 with 10% sodium hydroxide solution and stirred for 2 hours. It was extracted with methyl tert-butyl ether, and the aqueous phase was subsequently acidified with 10% sulfuric acid. For product separation, the organic phase was extracted twice with methyl tert-butyl ether, washed neutrally with water, dried with sodium sulfate, and concentrated on a rotary evaporator. 21.1 g of product were obtained with a content of 96.7% (sum of stereoisomers). This corresponds to a theoretical yield of 75%. Example 4 Menthanecarboxylic acid chloride (2-Isopropyl-5-methyl-cyclohexanecarboxylic acid chloride) (compare formula VI)

[0057] 35 g of menthanecarboxylic acid, prepared according to Example 3, were placed in 300 ml of toluene. 45.2 g of thionyl chloride, dissolved in 200 ml of toluene, were added over 30 minutes at room temperature. After addition, the mixture was heated under reflux for 5 hours. Upon concentration under reduced pressure, 39 g of menthanecarboxylic acid chloride were obtained with a purity of 90% (sum of stereoisomers). This corresponds to a theoretical yield of 91%. Isomer 1 (content: 10%): 1 H (400 MHz, C6D6) ppm: 3.10 (m, 1H), 2.13 (t,d,d 2.4 Hz, 3.3 Hz, 14.1 Hz; 1H), 1.64 (m, 1H), 1.62 (d,q,q, 9.7 Hz, 6.5 Hz, 6.5 Hz; 1H), 1.43–1.54 (m, 2H), 1.30 (m, 1H), 0.79 (m, 1H), 0.75 (d, 6.5 Hz; 3H), 0.74 (d 6.4 Hz; 3H) 0.67 (d 6.6 Hz; 3H), 0.59 (m, 2H) 13 C (100 MHz, C6D6) ppm: 173.6 s, 56.1 d, 47.6 d, 37.0 t, 34.9 t, 30.3 d, 27.9 d, 26.0 t, 21.9 q, 20.9 q, 20.9 q. Massenspektrum: 202(0,5), 123(78), 112(50), 95(93), 83(72), 81(81), 70(65), 69(69), 67(60), 55(100), 41(75) Isomer 2 (Gehalt: 68%) 1 H (400 MHz, C6D6) ppm: 2.50 (d,t 3.5 Hz, 11.5 Hz; 1H), 1.80 (d,q,q 3.0 Hz, 6,9 Hz, 6.9 Hz; 1H), 1.70 (d,t,d 2.1 Hz, 3.5 Hz, 12.5 Hz; 1H) 1.50 (t,t 3.2 Hz, 11.6 Hz; 1H) 1.35 (m, 2H), 1.02 (q 12.1 Hz; 1H), 0.85 (m, 1H), 0.76 (d 6.8 Hz; 3H), 0,67 (d 6.8; 3H), 0.66 (d 6.3 Hz; 3H), 0.51–0.69 (m, 2H) 13 C (100 MHz, C6D6) ppm: 176,1 s, 59.1 d, 44.8 d, 38.2 t, 34.2 t, 31.9 d, 29.2 d, 23.6 t, 21.9 q, 20.9 q, 15.6 q. Massenspektrum: 202(0,7), 123(43), 122(55), 112(61), 95(59), 83(79), 81(70), 70(53), 69(65), 55(100), 41(63) Isomer 3 (Gehalt: 12%) 1 H (400 MHz, C6D6) ppm: 2.81 (d,d,d 4.1 Hz, 7.2 Hz, 8.0 Hz; 1H), 1.68 (m, 1H), 1.61 (m, 3H), 1.30 (m, 1H), 1.10–1.25 (m, 3H), 0.98 (m, 1H), 0.83 (d 6.9 Hz; 6H), 0.66 (d 6.9 Hz, 3H) 13C (100 HZ, C6D6) ppm: 176.9 s, 54.6 d, 44.2 d, 34.1 t, 30.0 t, 28.4 d, 27.6 d, 21.1 q, 20.0 t, 19.3 q, 18.1 q. Mass spectrum: 202(0.5), 123(44), 112(40), 95(81), 83(81), 81(70), 70(82), 69(63), 67(41), 55(100), 41(66) Isomer 4 (content: 0.8%) Mass spectrum: 202(0.4), 112(38), 95(100), 83(60), 81(89), 69(48), 67(69), 55(88), 43(43), 41(74) Example 5 Menthanecarboxylic acid-N-(4-methoxyphenyl)-amide (compare formula VIII)

[0058] 39 g of menthanecarboxylic acid chloride from Example 3 were dissolved in 30 ml of methylene chloride and added to a solution of 23.4 g of p-anisidine and 18.7 g of triethylamine in 220 ml of methylene chloride. The reaction mixture was stirred at room temperature for 24 hours. After completion of the reaction, the mixture was washed with water, acidified with dilute hydrochloric acid, and washed again with water. After drying and concentration of the organic phase, 49 g of crude product were obtained. This product contained 75% menthane, 8% neomenthane, 13% isomenthane, and 1.2% neoisomenthanecarboxylic acid N-(4-methoxyphenyl)amide.

[0059] Menthanecarboxylic acid N-(4-methoxyphenyl) amide was isolated by recrystallization of the crude product with a cyclohexane / ethanol mixture containing 99%. [α] D 20 = (c 1,0, EtOH) = –58.6° Fp = 178°C 1H NMR data, 400 MHz, CDCl3 (ppm): 7.42 m 2H; 7.02 s(br) 1H; 6.85m2H; 3.79s 3H; 2.12 d,d,d, 11.4 H, 11.4 Hz, 3.6 Hz 1H, 1.89 m 1H; 1.82d,q,q, 2.6Hz, 6.8Hz, 6.8Hz 1H; 1.69–1.79m2H; 1.62t,t, 11.2Hz, 2.8Hz 1H; 1.38m 1H; 1.31 d,d,d 11.9 Hz, 11.9 Hz, 11.9 Hz; 0.95–1.12 m2H; 0.92d 6.9Hz 3H; 0.92d 6.3Hz 3H; 0.83d 6.9Hz 3H. 13 C-NMR data 100 MHz CDCl3 (ppm): 174.0 s; 156.3s 131.1s; 121.7d; 121.7d; 114.1d; 114.1d; 55.5q; 50.7d; 44.6d; 39.5t; 34.5t; 32.3d; 28.8d; 24.0t; 22.3q; 21.4q; 16.3 q. Mass spectrum: 289(16), 124(9), 123(100), 122(9), 108(12), 83(25), 69(10), 57(7), 55(17), 41(10)

[0060] Neomenthane carboxylic acid N-(4-methoxyphenyl) amide with a content of 99.8% was isolated from the mother liquor by chromatography on silica gel with the eluent cyclohexane / acetic ester (95 / 5). [α] p 20 = (c 1,0, EtOH) = 16.4° Fp = 151°C 1H NMR data, 400 MHz, CDCl3 (ppm): 7.39 m 2H; 7.03 s(br) 1H; 6.84m2H; 3.78s 3H; 2.68m 1H; 1.1.86–2.02 m 3H; 1.82d 12.9Hz 1H; 1.65–1.76 m2H; 1.24 d,d,d 5.2 Hz, 12.8 Hz, 13.8 Hz 1H; 1.08 d,d,d 4.2 Hz, 8.9 Hz, 12.8 Hz 1H; 0.95d 6.7Hz 3H; 0.91d 6.6Hz 3H; 0.88m 1H; 0.84 d 6.4 Hz 3H. 13 C-NMR data 100 MHz CDCl3 (ppm): 173.4 s; 156.3s; 131.3s; 121.7d; 121.7d, 114.1d; 114.1d; 55.5q; 46.8d; 44.4d; 39.3t; 35.3t; 30.5d; 27.d; 25.5t, 22.5q; 21.7q; 21.3 q. Mass spectrum: 289(12), 124(9), 123(100), 122(5), 108(11), 83(15), 69(7), 57(4), 55(12), 41(6)

[0061] The isomethane and neoisomenthane isomers could be isolated from the mother liquor by preparative gas chromatography. Isomenthanecarboxylic acid N-(4-methoxyphenyl)amide: 1H-NMR-Daten, 400 MHz, CDCl3 (ppm): 7.43 m 2H; 7.01 s(br) 1H; 6.85 m 2H; 3.79 s 3H; 2.33 d,d,d 3.8 Hz, 10.9 Hz, 10.9 Hz 1H; 2.06 m 1H; 1.86 d,d,d 4.7 Hz, 11.6 Hz; 13.3 Hz; 1H; 1.80 d,q,q, 3.5 Hz, 6.9 Hz, 6.9 Hz; 1.45–1.70 m 5H; 1.31 m 1H; 0.99 d 7.1 Hz 3H; 0.93 d 6.9 Hz 3H; 0.86 d 6.9 Hz 3H. 13 C-NMR-Daten 100 MHz CDCl3 (ppm): 174.3 s; 156.3 s; 131.1 s; 121.7 d; 121.7 d; 114.1 d; 114.1 d; 55.5 q; 44.9 d; 44.7 d; 36.1 t; 30.9 t; 28.8 d; 27.1 d; 21.3 q; 18.4 q; 16.8 q. Massenspektrum: 289(13), 124(9), 123(100), 108(12), 83(25), 69(11), 57(7), 55(17), 43(6), 41(8) Neoisomenthancarbonsäure-N-(4-methoxyphenyl)-amid: Massenspektrum: 289(9), 124(9), 123(100), 122(6), 108(13), 83(11), 69(7), 55(13), 43(6), 41(8) ZITATE ENTHALTEN IN DER BESCHREIBUNG

[0062] This list of documents cited by the applicant was automatically generated and is included solely for the reader's convenience. The list is not part of the German patent or utility model application. The DPMA accepts no liability for any errors or omissions. Cited patent literature

[0063] WO 2005 / 002582

[0002] US 2005 / 054651

[0002] WO 2010 / 019730 [0002, 0011] GB 1392907

[0004] WO 2004 / 031128

[0012] WO 2007 / 096074

[0013] Cited non-patent literature

[0064] AK Bose et al. Journal of Organic Chemistry, 1963, 28, 1223

[0004] H.-P. Pfeiffer et al. Liebigs Annalen der Chemie, 1987, 725

[0004] JG Smith, GF Wright, Journal of Organic Chemistry, 1952, 17, 1116

[0004] D. Cunningham et al. Journal of the Chemical Society, Perkin Transactions 1, 2002, 2692

[0004] C. Spino, C. Gobdout, Journal American Chemical Society, 2003, 125, 1206

[0005] A. Kato et al.

[0006] N. Yang et al., Jingxi Huagong 2010, 27, 622 (CA 153: 643682)

[0007] M. Botton, Bulletin De La Societe Chimique France, 1973, 2472–2478

[0008] C. Spino, C. Gobdout, Journal American Chemical Society, 2003, 125, 1206

[0010]

Claims

[1] A process for the production of menthane carbaldehyde, menthane carboxylic acid or a derivative of menthane carboxylic acid, comprising the following step: – Conversion of an ester of menthane glycidic acid to menthane carbaldehyde. [2] Method according to claim 1, comprising the following steps: – Reaction of menthone with a haloacetic acid ester to form the ester of menthane glycidic acid, – Conversion of the ester of menthane glycidic acid thus produced to menthane carbaldehyde. [3] Method according to claim 1 or 2, wherein to convert the prepared ester of menthane glycidic acid to menthane carbaldehyde the ester is hydrolyzed and the hydrolysis product is decarboxylated as menthane glycidic acid or as a salt of menthane glycidic acid, after intermediate isolation or without intermediate isolation. [4] Method according to claim 3, wherein – the ester of menthane glycidic acid is reacted with a strong base, preferably aqueous alkali hydroxide or aqueous alkali alkoxide, such that the ester is hydrolyzed, wherein preferably the ester of menthane glycidic acid is reacted with (i) an equimolar amount of alkali alkoxide and (ii) water and / or – the hydrolysis product is decarboxylated as the alkali salt of menthane glycidic acid, after intermediate isolation or without intermediate isolation of the alkali salt, and / or – the hydrolysis product is decarboxylated by the addition of heat and / or by reaction with acid, preferably by reaction with aqueous acid at a temperature of at least 50°C, preferably at least 70°C. [5] A process according to any one of claims 1 to 4 for the production of menthane carboxylic acid or a derivative of menthane carboxylic acid, comprising the following additional step: – Oxidation of the produced menthanecarbaldehyde to menthanecarboxylic acid. [6] The method of claim 5, wherein the produced menthanecarbaldehyde is oxidized – one or more oxidizing agents are used, selected from the group consisting of air, oxygen, hydrogen peroxide and tert-butyl peroxide wherein air, preferably in the presence of a manganese(II) or a cobalt(II) salt, or hydrogen peroxide is preferably used as the oxidizing agent. and / or – the oxidation is carried out at a temperature of at least 40°C. [7] A process according to any of the preceding claims for the production of a derivative of menthane carboxylic acid, comprising the following additional step: – Conversion of the produced menthane carboxylic acid to a menthane carboxylic acid halide. [8] Method according to claim 7, wherein the produced menthane carboxylic acid exists in a mixture with stereoisomers of menthane carboxylic acid and The reaction conditions for the conversion of the prepared menthane carboxylic acid to the menthane carboxylic acid halide are chosen such that a configuration inversion takes place at one or more stereogenic centers, so that the proportion of the menthane carboxylic acid halide in the stereoisomeric mixture of the carboxylic acid halides is greater than the proportion of the menthane carboxylic acid in the stereoisomeric mixture of the carboxylic acids. [9] Method according to claim 7 or 8 for the production of a derivative of menthane carboxylic acid, comprising the following additional step: – Conversion of the menthane carboxylic acid halide to a subsequent product selected from the group consisting of menthane carboxylic acid amides and menthane carboxylic acid esters. [10] Method according to any one of claims 7 to 9 for the production of a menthane carboxylic acid amide or menthane carboxylic acid ester, wherein the menthane carboxylic acid halide is present in a mixture with stereoisomers of the menthane carboxylic acid halide. [11] A process according to any one of claims 7 to 10 for the preparation of a menthane carboxylic acid amide, wherein the menthane carboxylic acid halide is reacted with an amine selected from the group consisting of p-anisidine, ethylamine, tert-butylamine, cyclopropylamine, ethyl aminoacetic acid ester, 2-(4-aminophenyl)acetamide, (4-aminophenyl)acetonitrile, 2-pyridin-2-ylethylamine, 1-methyl-2-pyridin-3-ylethylamine, benzo[1,3]dioxol-5-ylamine, 2-(2-methylindol-1-yl)ethylamine, 1-methyl-2-thiophen-3-ylethylamine. [12] Method according to any one of claims 7 to 10 comprising the following steps: – Reaction of menthone with a haloacetic acid ester to form the ester of menthane glycidic acid, – Conversion of the ester of menthane glycidic acid thus produced to menthane carbaldehyde, wherein the ester of menthane glycitic acid is reacted with a strong base, preferably aqueous alkali hydroxide or aqueous alkali alkoxide, such that the ester is hydrolyzed, wherein preferably the ester of menthane glycitic acid is reacted with (i) an equimolar amount of alkali alkoxide and (ii) water, and wherein the hydrolysis product as the alkali salt of menthane glycidic acid, after intermediate isolation or without intermediate isolation of the alkali salt, is decarboxylated by the addition of heat and / or by reaction with acid, preferably by reaction with aqueous acid at a temperature of at least 50°C, preferably at least 70°C, – Oxidation of the produced menthane carbaldehyde to menthane carboxylic acid, wherein one or more oxidizing agents selected from the group consisting of air, oxygen, hydrogen peroxide and tert-butyl peroxide are preferably used to oxidize the produced menthanecarbaldehyde. and / or the oxidation is carried out at a temperature of at least 40°C, – Conversion of the produced menthane carboxylic acid to a menthane carboxylic acid halide. [13] A process, preferably according to claim 7, for the production of a menthane carboxylic acid halide or a reaction product of a menthane carboxylic acid halide, comprising the following steps: – Production or provision of menthane carboxylic acid in mixture with stereoisomers of menthane carboxylic acid and – Reacting the mixture with a halogenating agent to form a mixture comprising menthane carboxylic acid halide and stereoisomers of menthane carboxylic acid halide, wherein the conditions during the reaction are chosen such that a configuration inversion takes place at one or more stereogenic centers, so that the proportion of the menthane carboxylic acid halide in the stereoisomeric mixture of the carboxylic acid halides is greater than the proportion of the menthane carboxylic acid in the stereoisomeric mixture of the carboxylic acids. [14] A process, preferably according to one of claims 7 to 13, for the production of a menthane carboxylic acid amide or menthane carboxylic acid ester, comprising the following steps: – Production or provision of menthane carboxylic acid halide in mixture with stereoisomers of menthane carboxylic acid halide and – Reacting to the mixture with an amine or alcohol to form a mixture comprising menthane carboxylic acid amide and stereoisomers of menthane carboxylic acid amide or menthane carboxylic acid ester and stereoisomers of menthane carboxylic acid ester.