EP1989176A1

EP1989176A1 - Process for preparing menthyl amides

Info

Publication number: EP1989176A1
Application number: EP07722804A
Authority: EP
Inventors: Andreas Job; Uwe Westeppe; Lars Rodefeld
Original assignee: Saltigo GmbH
Current assignee: Saltigo GmbH
Priority date: 2006-02-21
Filing date: 2007-02-13
Publication date: 2008-11-12
Also published as: US20090171119A1; DE102006007883A1; CN101384546A; JP2009527516A; WO2007096074A1

Abstract

An improved process is provided for preparing menthyl amides by reacting menthyl halides with magnesium or lithium and subsequently reacting with an isocyanate, a heterocycle or a carbamoyl chloride.

Description

Process for the preparation of menthylamides

The present invention relates to an improved process for the preparation of menthylamides.

Menthol is known for its physiological cooling effect on the skin and mucosal membranes of the mouth and is widely used as a flavor in foods, drinks, toothpaste, mouthwash, as well as a component in a variety of toiletries, ointments and lotions for topical application. This cooling effect is a physiological effect due to the direct

Effect of menthol on the nerve endings of the human body, which are responsible for the perception of heat or cold, and is not based on the latent heat of vaporization. It is believed that menthol has a direct stimulating effect on the cold receptors on the nerve endings, which in turn stimulate the central nervous system.

However, the use of menthol is limited because of its strong peppermint odor and its relatively high volatility.

In DE-A-24 136 39 and DE-A-22 052 55 special menthylamides were described for the first time, which also have a strong physiological cooling effect on the skin and on the

Own mucosal membranes of the body, especially those of the nose, mouth, throat and gastrointestinal tract. In many cases, this cooling effect is much more durable than that obtained with menthol without the strong odor at the same time. The compounds also have a lower volatility than menthol and are used as so-called cooling agents in the food industry. Their economic production is thus of great interest.

DE-A-22 052 55 and DE-A-24 136 39 disclose a process for the preparation of menthyl amides in which, starting from menthyl chloride, first a Grignard reagent is formed, which is reacted with carbon dioxide to give menthylcarboxylic acid in a subsequent step. This intermediate is then reacted with a chlorinating agent such as thionyl chloride to give the corresponding menthyl chloride, which reacts with a suitable mono- or disubstituted amine in a further step in the presence of a hydrogen chloride acceptor such as sodium hydroxide to give the desired menthyl amide. This procedure is disadvantageous in that, starting from menthyl chloride, it requires four chemical synthesis steps up to the target molecule. Due to the widespread use of menthylamides and their derivatives in the food industry, there was therefore a need for a technically simple and economical process for the preparation of these menthylamides.

Surprisingly, it has been found that the reaction of a menthyl halide with

Magnesium or lithium and then with an isocyanate, a heterocycle or a carbamoyl chloride leads directly to the desired menthyl amide. This method represents a significant reduction of the previous synthetic route.

The invention relates to a process for the preparation of compounds of the general formula (I)

in which

R ¹ Ci-C ₃₀ -alkyl, C ₂ -C ₂₀ alkenyl, C ₂ -C ₂ o-alkynyl, C ₃ -C ₂₀ cycloalkyl, C ₃ -C ₂₀ cycloalkenyl, C ₃ -C ₂₀ cycloalkynyl, C -C ₂₀ -hydroxyalkyl, C ₃ -C ₂₀ -acyloxyalkyl, C _r

C ₂₀ alkoxy, C ₂ -C ₂₀ alkoxyalkyl, C ₂ -C ₂₀ alkylthioalkyl, C ₂ -C ₂₀ aminoalkyl, CrC ₂₀ -

Acylaminoalkyl, C ₂ -C ₂ o-carboxyalkyl, a radical -C _n H _2n C (= O) R ⁴ or a radical -

C _n H _2n COOR ⁴ , where -C _n H _{2n is} a straight-chain or branched

Alkylengruppe is, in which n is an integer from 1 to 10 and R ^{4 is} hydrogen, Q-C _1O -Al IyCyI, Ci-C ₈ hydroxyalkyl, C ₁ -C ₈ alkoxyalkyl or CC ₈ acyloxyalkyl,

R ^{2 may have} the same meanings as R ¹ , furthermore may denote hydrogen or a radical --X-OH, where X represents a straight-chain or branched C 1 -C ₂₀ -alkylene group which is optionally interrupted by one or more heteroatoms, or

R ¹ and R ² together form an alkylene chain optionally interrupted by one or more heteroatoms, taken together with the nitrogen atom to which R ¹ and R ^{2 are} bonded, forming a maximum 10-membered ring,

R ^{3 is} hydrogen, C, -C _3o- alkyl or C ₆ -C ₂₄ -arylalkyl, and the methyl and the isopropyl radical on all available carbon atoms of the

Cyclohexyl rings, but not both radicals are located on the same carbon atom, by first preparing a compound of general formula (II)

in which

Hal is chlorine, bromine or iodine, R ^{3 has} the meanings given for general formula (I) and the methyl and isopropyl radicals can be located on all available carbon atoms of the cyclohexyl ring, but not both radicals are located on the same carbon atom, with magnesium or lithium and optionally elemental iodine or an alkyl halide, and then either with an isocyanate of the general

Formula (III),

where R ^{1 has} the meanings given for the general formula (I) or with a heterocycle of the general formula (IV),

where R ¹ and X have the meanings given for the general formula (I), or with a carbamoyl chloride of the general formula (V),

wherein R ¹ and R ^{2 have} the meanings given for the general formula (I).

In the compounds of the general formulas (I) and (II), the methyl and the isopropyl radicals can be present on all available carbon atoms of the cyclohexyl ring, but not both radicals are located on the same carbon atom. Simplified, the compounds of general formula (I) are also referred to as menthylamides.

Preference is given to the following compounds of the formula (II) which have a 2-isopropyl-5-methylcyclohexyl, 4-isopropyl-3-methylcyclohexyl or 2-isopropyl-4-methylcyclohexyl radical.

The use leads to correspondingly substituted compounds of general formula (I).

In the general formulas (I) and (II) R ³ are hydrogen, C ₃ -alkyl or C ₆ -C ₂ -T arylalkyl, preferably hydrogen, Ci-Ci _o alkyl or C _ö -Cπ arylalkyl, in particular methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neo-pentyl, 1-ethylpropyl , or benzyl.

The preparation of the educt of the general formula (II) is possible by methods familiar to the person skilled in the art. For example, the preparation of the particular menthol chloride from menthol is extensively described in the literature, e.g. in J. Org. Chem. 2000, 65, 2337.

The reaction of the starting material of the general formula (II) with the Grignard reagent can be carried out in various solvents (see, for example, J. Org. Chem. 2000, 65, 2337 for possible solvents for the Grignard reagent preparation). Suitable solvents are THF, dioxane, methyl THF, Cylcopentylmethylether or mixtures of the aforementioned solvents with aromatic solvents such as toluene or xylene.

As isocyanates it is possible to use isocyanates of the general formula (III) which have the following general, preferred or particularly preferred meanings for R ¹ . There are thus obtained compounds of the general formula (I) which have the corresponding general, preferred or particularly preferred meaning of R ¹ , and in which R ^{2 is} hydrogen. In general formulas (I) and (III), R ¹

C, -C _3o alkyl, C ₂ -C ₂₀ alkenyl, C ₂ -C 2 -C ₀ alkynyl, C _r C ₂ o-cycloalkyl, C ₃ -C ₂₀

Cycloalkenyl, C ₃ -C ₂ o-cycloalkynyl, C ₂₀ hydroxyalkyl, C ₃ -C ₂ o-acyloxyalkyl, C, - C ₂₀ alkoxy, C ₂ -C ₂₀ alkoxyalkyl, C ₂ -C ₂₀ alkylthioalkyl , C ₂ -C ₂₀ -aminoalkyl, C ₃ -C ₂₀ -

Acylaminoalkyl, C ₂ -C ₂₀ carboxyalkyl, a radical -C _n H _2n C (= O) R ⁴ or a radical -

C _n H _2n COOR ⁴ , where -C _n H _{2n is} a straight-chain or branched

Alkylengruppe is, in which n is an integer from 1 to 10 and R ^{4 is} hydrogen, C _r

C _lo alkyl, Ci-Q-hydroxyalkyl, Ci-Cg alkoxyalkyl or C | -C ₈ -Acyloxyalkyl represents

All the abovementioned meanings for the radical R ¹ which have alkyl, alkenyl, alkynyl radicals can each be branched or unbranched.

R ¹ in the general formulas (I) or (III) is preferably

Ci-C ₄ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₀ alkynyl, C ₅ -C ₁₀ cycloalkyl, C ₅ -C ₁₀ cycloalkenyl, C ₅ -C ₀ cycloalkynyl, C _r ci ₀ hydroxyalkyl, C ₃ -C ₀ -Acyloxyalky-, C, - Cio-alkoxy, C ₂ -C ₀ alkoxyalkyl, C ₂ -C ₁₀ alkylthioalkyl, C ₂ -C _lo aminoalkyl, C ₃ -C ₀ - acylaminoalkyl, C ₂ -C ₀ carboxyalkyl, a radical -C _n H _2n C (= O) R ⁴ or a radical - C _n H _2n COOR ^4, wherein -C _n H _2n is a straight or branched Alkylengrupppe in which n is an integer from 1 to 6 and R ⁴ is hydrogen C _r Ci ₀ alkyl, Ci-C ₈ - hydroxyalkyl, Ci-C ₈ alkoxyalkyl or C ₈ represents -Acyloxyalkyl.

Particularly preferred R ¹ in the general formulas (I) or (III), _R represents a linear or branched Ci C ₀ -alkyl radical such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-

Butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neo-pentyl, 1

Ethylpropyl, cyclohexyl, cyclopentyl, n-hexyl, 1, 1-dimethylpropyl, 1, 2-dimethylpropyl,

1, 2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-

Dimethylbutyl, 1, 2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1, 1, 2-trimethylpropyl, 1, 2,2-trimethyl-propyl,

1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, n-hexyl, n-heptyl, n-octyl, n-nonyl or n-decyl.

As an alternative to the isocyanates of the general formula (III) it is also possible to use heterocycles of the general formula (IV) in which R ¹ can assume all general, preferred or particularly preferred meanings which R ^{1 can have} in the general formula (II), and X is a straight-chain or branched C ₁ -C ₂₀ -alkylene group, preferably one straight-chain or branched C 1 -C ₈ -alkylene group, more preferably a methylene, ethylene, n-propylene, n-butylene or n-pentylene group, these general, preferred or particularly preferred alkylene groups being optionally substituted by one or more Heteroatoms, preferably oxygen or sulfur, are interrupted.

If, instead of the isocyanate of the general formula (III), a heterocycle of the general formula (IV) is used, hydroxy-functionalized amides are thus obtained.

Alternatively to the isocyanates of the general formula (III) and the heterocycles of the general formula (IV), it is also possible to use carbamoyl chlorides of the general formula (V)

where R ¹ and R ^{2 may have} all the general, preferred and particularly preferred meanings mentioned above for the general formula (I).

The compounds of the general formula (I) have both geometric isomers and optical isomers and can be isomerically pure, ie consist of only one geometric or optical isomer, or be mixtures of isomers, both in the geometric as well as the starting materials and methods used in their preparation in the optical sense. The cyclohexyl ring is in its basic structure a chair-shaped molecule which can be present in the cis-form or trans-form relative to the methyl and isopropyl radical. The example of 2-isopropyl-5-methylcyclohexyl-carboxamide, this means that the substitution of the cyclohexyl ring by the carboxamide group -CONHR ¹ in 1-position leads to four configuration or geometric isomers, depending on whether the

Substitution is axial or equatorial with the cis or trans isomer. Furthermore, optical isomers result for each of the aforementioned geometric isomers. The general formula (I) is thus intended to include all possible stereoisomers as well as all possible diastereomers and enantiomers.

The process according to the invention is usually carried out by introducing magnesium or lithium under inert gas and adding a solvent. Subsequently, optionally elemental iodine or an alkyl halide such as ethyl bromide, 1, 2-dichloroethane or 1, 2-dibromoethane, preferably ethyl bromide, are added. The addition of elemental iodine or an alkyl halide has proven especially in the use of magnesium. The temperature is maintained in a range of 2O ⁰ C to 80 ⁰ C and adjusted depending on the solvent used. Subsequently, the compound of general formula (II) is added. It has been found useful to solve this compound of the general formula (II) in the same solvent as that presented.

Usually, the molar ratio of magnesium or lithium to the compound of the general formula (II) is (0.9-1.6): 1, preferably (1.0-1.4): 1. The addition is carried out in such a way that the temperature of the reaction mixture in a range of 20 ⁰ C to 80 ⁰ C moves. Again, an adaptation to the solvent used can be done. Subsequently, it is usually stirred for a certain period, the

Reaction mixture cooled to a temperature of 20 ⁰ C to 5O ⁰ C and filtered off or decanted.

Subsequently, the reaction with the further reagent takes place in the form of the isocyanate of the general formula (III), the heterocycle of the general formula (IV) or of

Carbamoyl chloride of the general formula (V). These compounds may be either as such, i. be used in substance or diluted in an organic solvent.

A variant of the procedure is to add the further reagent to the reaction mixture, which is obtained in the reaction of the compound of general formula (II) with magnesium or lithium. It is also possible, however, to reverse the order of addition, i. the reaction mixture from the reaction of the compound of the general formula (II) with magnesium or lithium is added to the further reagent of the formula (III), (IV) or (V).

Usually, the molar ratio of the compound of general formula (III), (IV) or (V) to the compound of general formula (IT) (0.95-1.4): 1, preferably (1.0-1.2 ): 1. It is also possible to partially distill off the solvent used for the reaction with magnesium or lithium before adding these reagents. In this case, the reagent to be added is then advantageously used dissolved in an organic solvent, for example toluene or xylene. After the reaction, the still present, originally used for the reaction with magnesium or lithium and lower boiling solvent can be further distilled off and optionally recycled. After the reaction, the reaction mixture is treated with aqueous acid and the mixture is worked up, for example by phase separation or extraction with an organic solvent. The desired compound of general formula (I) is removed via the organic phases, dried and isolated.

The above-mentioned steps of the reaction and the work-up can be carried out not only batchwise but also continuously.

If a continuous operation is used, the solution obtained after the reaction of the compound of the general formula (II) with magnesium or lithium is advantageously transferred via an overflow device into the next reaction vessel, thereby separating off the magnesium or lithium excess.

Examples: Example 1

Magnesium turnings (0.87 g) introduced under nitrogen were placed in a heated flask and treated with 7.6 ml of THF. At 50 ^° C., about 92 mg of ethyl bromide were added to start the reaction. Thereafter, a solution of 5 g of menthyl chloride in 10.2 ml of THF at 55 ⁰ C in 3.5 h was added to the mixture. Subsequently, stirring was continued at 70 ^° C. for a further 1.3 hours. After cooling the mixture to 22 ° C, this was filtered and transferred to another flask. To the filtered reaction solution was added 3.05 g of butyl isocyanate and stirring was continued for one hour. While cooling and stirring, this mixture was added to 127 g of 2% hydrochloric acid. The mixture was washed three times with 20 ml each

Extracted dichloromethane. The combined organic phases were dried over magnesium sulfate and concentrated.

Was obtained 5.70 g of pale yellow oil, which according to gas chromatographic analysis contains 53% product. This corresponds to a yield of 45% of theory.

Example 2:

Magnesium turnings (0.87 g) introduced under nitrogen were placed in a heated flask and treated with 7.6 ml of THF. At 5O ⁰ C to start the reaction, approximately 92 mg of ethyl bromide added. Then a solution of 5 g of menthyl chloride in 10.2 ml of THF was added

55 ° C in 3.5 h to the mixture. Subsequently, stirring was continued at 70 ^° C. for a further 1.3 hours. After cooling the mixture to 22 ° C, this was filtered and transferred to another flask. To the filtered reaction solution was added 2.23 g of ethyl isocyanate and stirring was continued for one hour. While cooling and stirring, this mixture was added to 127 g of 2% hydrochloric acid. The mixture was washed three times with 20 ml each

Obtained were 5.30 g pale yellow oil, which according to gas chromatographic analysis contains 43% product. This corresponds to a yield of 39% of theory.

Claims

claims:

1. Process for the preparation of compounds of the general formula (I)

in which

R ¹ is C, -C ₃ -alkyl, C ₂ -C ₂₀ alkenyl, C ₂ -C ₂ o-alkynyl, C ₃ -C ₂₀ cycloalkyl, C ₃ -C ₂₀ cycloalkenyl, C ₃ -C ₂₀ cycloalkynyl , Ci -C ₂₀ -Hy droxyalkyl, C ₃ -C ₂₀ - acyloxyalkyl, C, -C ₂₀ alkoxy, C ₂ -C ₂₀ alkoxyalkyl, C ₂ -C ₂₀ alkylthioalkyl, C ₂ -C _2NC aminoalkyl, C C ₃ -C ₂₀ acylaminoalkyl, C ₂ -C ₂₀ carboxyalkyl, a radical -C _n H _2n C (= O) R ⁴ or a radical -C _n H _2n COOR ⁴ , where -C _n H _{2n is} a straight-chain or branched Alkylengrupppe is and in which n is a whole number from 1 to 10 R ⁴ is hydrogen, C, -C _o alkyl, C, -C ₈ hydroxyalkyl, C ₁ -C ₈ - alkoxyalkyl or C | -C ₈ - Represents acyloxyalkyl,

R ^{2 may have} the same meanings as R ¹ , may also denote hydrogen or a radical -X-OH, where X is a straight-chain or branched C _r

C _{20 represents} alkylene group which is optionally interrupted by one or more heteroatoms, or

R ¹ and R ² together form an alkylene chain which is optionally interrupted by one or more heteroatoms and which, taken together with the nitrogen atom to which R ¹ and R ^{2 are} bonded, forms a maximally 10-membered ring,

R ^{3 is} hydrogen, C, -C ₃₀ alkyl or C ₆ -C ₂₄ arylalkyl, and the methyl and the isopropyl radical can sit on all available carbon atoms of the cyclohexyl ring, but not both radicals are located on the same carbon atom by first a compound of general formula (II)

in which Hal is chlorine, bromine or iodine,

R? has the meanings given for the general formula (I) and the methyl and the isopropyl radical can sit on all available carbon atoms of the cyclohexyl ring, but not both radicals on the same

Carbon atom are arranged with magnesium or lithium and optionally elemental iodine or a

Reacting alkyl halide, and then

Either with an isocyanate of the general formula (III),

wherein R ^{1 has} the meanings given for the general formula (I)

Or with a heterocycle of the general formula (IV),

wherein R ¹ and R ^{2 have} the meanings given for the general formula (I).

Process according to claim 1, wherein as compounds of the general formula (II) either

be used.

3. The method according to claim 1 or 2, wherein R ³ in the general formulas (I) and (II) is hydrogen, C | -C ₆ means, arylalkyl -C _O-alkyl or C, preferably methyl, ethyl, n-propyl , isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl,

2-methylbutyl, 3-methylbutyl, neo-pentyl, 1-ethylpropyl or benzyl.

4. The method according to one or more of claims 1 to 3, wherein isocyanates of the general formula (III) are used, wherein R ¹ is CPCU alkyl, C ₂ -CiO- alkenyl, C ₂ -C ₀ alkynyl, C ₅ - Ci _{0-cycloalkyl,} C ₅ -C, ₀ cycloalkenyl, C ₅ -C ₀ -

Cycloalkynyl, Ci-Cio-hydroxyalkyl, C ₃ -Cio-acyloxyalkyl, C _r Cio-alkoxy, C ₂ -CiO- alkoxyalkyl, C ₂ -C ₀ alkylthioalkyl, C ₂ -C ₀ aminoalkyl, Ca-Cio-acylaminoalkyl, C ₂ - C, o-carboxyalkyl, a radical -C _n H _2n C (=) OR ⁴ or a radical -C _n H _2n COOR ⁴ , where -C _n H _{2n is} a straight-chain or branched Alkylengrupppe, in the n is an integer from 1 to 6 and R ⁴ is hydrogen C _r Ci ₀ alkyl, C | -C ₈ hydroxyalkyl,

Ci-Cg-alkoxyalkyl or Ci-C ₈ acyloxyalkyl.

5. The method according to one or more of claims 1 to 4, wherein isocyanates of the general formula (III) are used, wherein R ^{1 is} methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert Butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl,

3-methylbutyl, neo-pentyl, 1-ethylpropyl, cyclohexyl, cyclopentyl, n-hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1, 1, 2-trimethylpropyl, 1, 2,2-

Trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, n-hexyl, n-heptyl, n-octyl, n-nonyl or n-decyl.

6. The method according to one or more of claims 1 to 3, wherein heterocycles of the general formula (FV) are used, wherein R ¹ can assume all meanings which are mentioned for R ¹ in claims 1 to 5 and X is a straight-chain or branched CpCg alkylene group, more preferably methylene, ethylene, n-propylene, n-butylene, n-pentylene, wherein these alkylene groups optionally interrupted by one or more heteroatoms, preferably oxygen or sulfur.

7. The method according to one or more of claims 1 to 3, wherein carbamoyl chlorides of the general formula (V) are used, wherein R ¹ and R ² can assume all meanings which are mentioned for R ¹ and R ² in claims 1 to 5 ,

8. The method according to one or more of claims 1 to 7, characterized in that initially introduced under inert gas magnesium or lithium and mixed with a solvent, then optionally elemental iodine or an alkyl halide, preferably ethyl bromide, 1,2-dichloroethane or 1,2 -Dibromethan added, the temperature is maintained in a range of 2O ⁰ C to 8O ⁰ C, then the

Compound of the general formula (II) is added, and with the isocyanate of the general formula (III), the heterocycle of the general formula (IV) or the carbamoyl chloride of the general formula (V) is reacted.