WO2001096277A1 - Method for producing 2,3,4,6-tetramethyl mandelic acid and 2,3,4,6-tetramethyl mandelic acid acetate - Google Patents

Abstract

The invention relates to a novel method for producing 2,3,4,6-tetramethyl mandelic acid and acetate, by reacting a mixture of 1,2,3,5-tetramethylbenzene (isodurol) and 1,2,4,5-tetramethylbenzene (durol) with 0.5 to 1.75 mol glyoxylic acid or glyoxylic acid hydrate per mol of 1,2,3,5-tetramethylbenzene (isodurol), at a temperature ranging between 0 and 100 DEG C.

Description

Process for the preparation of 2,3,4,6-tetramethylmethane acid and 2,3,4,6-tetramethylmandelic acid acetate

The present invention relates to a new process for the preparation of 2,3,4,6-

Tetramethylmandelic acid and acetate.

2,3,4,6-tetramethylmandelic acid is known (Chem. Ber. 20 (1887) 3097-3104; J. Amer. Chem. Soc. 61 (1939) 3246-3249). They are produced either by Friedel-Crafts acylation of 1,2,3,5-tetramethylbenzene (isodurol) to give 2,3,4,6-

Tetramethylacetophenone, its oxidation to isodurylglyoxylic acid with potassium permanganate and subsequent reduction with sodium amalgam (Chem. Ber. 20 (1887) 3097-3104); or by Friedel-Crafts acylation of 1,2,3,5-tetramethylbenzene (isodurol) to 2,3,4,6-tetramethylacetophenone, its oxidation to the isodurylglyoxal with selenium dioxide and conversion to 2,3,4,6- Tetramethylmandelic acid with

Potassium hydroxide (J. Amer. Chem. Soc. 61 (1939) 3246-3249). These syntheses are multi-stage and require toxic or difficult to handle compounds (sodium amalgam; selenium dioxide). They are therefore not suitable for the production of large amounts of 2,3,4,6-tetramethylmandelic acid.

It is also known that mandelic acids substituted on the aromatic can be prepared in such a way that the aromatic is reacted with glyoxylic acid or glyoxylic acid hydrate in the presence of a base or acid. The reactions are preferably carried out in the presence of a base when a phenol is reacted with glyoxylic acid or glyoxylic acid hydrate as the substituted aromatic. For example, it is known from EP-A-023 459 that the reaction of 4-methylphenol (p-cresol) with glyoxylic acid in dilute aqueous sodium hydroxide solution leads to 2-hydroxy-5-methyl-mandanic acid. It is also known that the reaction of, for example, 1,3,5-triisopropylbenzene with glyoxylic acid hydrate and sulfuric acid in glacial acetic acid gives 2,4,6-triisopropylmandelic acid (Organic Process Research &

Development 1, (1997) 137-148). 2,3,4,6-tetramethylmandelic acid can thus be prepared by an analogous reaction of 1,2,3,5-tetramethylbenzene (isodurol) with glyoxylic acid or glyoxylic acid hydrate.

However, it is of great economic disadvantage that pure 1,2,3,5-tetramethylbenzene (isodurol) is not commercially available in large (technically relevant) quantities. Technically, 1,2,3,5-tetramethylbenzene (isodurol) is only available in a mixture with 1,2,4,5-tetramethylbenzene (Durol). Depending on the origin of the 1,2,3,5-tetramethylbenzene, other alkyl aromatics may also be present in a mixture; called his here for example dimethyl ethyl benzenes. The properties of these various alkyl aromatics (boiling point; melting point) are so similar to one another that separation is not possible or is possible only with disproportionate effort.

In the reaction of a mixture of isodurol and durol, which may also contain other alkyl aromatics (such as, for example, dimethylethylbenzenes), under the typical conditions known in the prior art, mixtures of 2,3,4 are thus difficult to separate , 6-tetramethyl- and 2,3,5,6-tetra-methyl-mandelic acid, possibly further contaminated by dimethyl-ethyl-mandelic acids (cf. Preparation Examples: Comparative Experiments 1 and 2).

It was found that 2,3,4,6-tetramethylmandelic acids of the formula (I)

in which R represents hydrogen or a radical -CO-R,

in which

R ^{2 represents} methyl, ethyl or propyl,

gets

by mixing a mixture of 1,2,3,5-tetramethylbenzene (isodurol) and 1,2,4,5-

Tetramethylbenzene (durol), which may contain other alkyl aromatics such as dimethyl ethyl benzenes, optionally in the presence of a solvent and a catalyst at a temperature between 0 and 100 ° C with 0.5 to 1.75 mol of glyoxylic acid or glyoxylic acid hydrate per mole of 1,2,3,5-tetramethylbenzene (isodurol).

Surprisingly, the 2,3,4,6-tetramethylmandelic acids of the formula (I) mentioned above can be prepared in a simpler manner, with high selectivity and in better yield by the process according to the invention.

Compounds of formula (I). in which

R represents a radical -CO-R ² ,

in which

R 2 represents methyl, ethyl or propyl,

are new.

Preferred compounds of the formula (I) are the compounds of the formula (Ia)

in which

R represents hydrogen or a radical -CO-CH ₃ ,

which by reacting a mixture of 1,2,3,5-tetramethylbenzene and 1,2,4,5-tetramethylbenzene, which may contain other alkyl aromatics such as dimethylethylbenzenes, in the presence of acetic acid as solvent and an acid as Reacts catalyst at temperatures between 0 and 100 ° C with 0.5 to 1.75 mol of glyoxylic acid or glyoxylic acid hydrate per mole of 1,2,3,5-tetramethylbenzene (isodurol).

Glyoxylic acid for selective alkylation by the process according to the invention can be used, for example, as a commercially available 50% aqueous solution or as a glyoxylic acid hydrate. If a 50% aqueous solution of glyoxylic acid is used, enough water can be distilled off, if necessary, with a suitable solvent so that the residual water content corresponds to that of the monohydrate. However, it is also possible to use the 50% aqueous solution.

The amount of glyoxylic acid or glyoxylic acid hydrate to be used by the process according to the invention is based on the amount of 1,2,3,5-tetramethylbenzene (isodurol), which, such as for example, dimethyl ethyl benzene is calculated. 0.5 to 1.75 mol of glyoxylic acid or glyoxylic acid hydrate are used per mol of 1,2,3,5-tetramethylbenzene (isodurol). The inventive method can be carried out at temperatures between 0 and 100 ° C.

The amount of glyoxylic acid or glyoxylic acid hydrate to be used by the process according to the invention per mole of 1,2,3,5-tetramethylbenzene can depend on the reaction temperature and the following preferred combinations result: 1.4 to 1.75 moles of glyoxylic acid or glyoxylic acid hydrate per mole 1, 2,3,5-tetramethylbenzene at 30 to 50 ° C, or 0.8 to 1.3 moles of glyoxylic acid or glyoxylic acid hydrate per mole of 1,2,3,5-tetramethylbenzene at 10 to 90 ° C. Particularly preferred combinations are 1.45 to 1.75 mol of glyoxylic acid or glyoxylic acid hydrate per mole of 1,2,3,5-tetramethylbenzene at 35 to 50 ° C., or 0.9 to 1.25 mol of glyoxylic acid or glyoxylic acid hydrate per mole 1, 2,3,5-tetramethylbenzene at 20 to 60 ° C. At high molar ratios, the dependence on the temperature is therefore more pronounced.

Acids can typically be used as catalysts for the reaction of 1,2,3,5-tetramethylbenzene (isodurol), which is present in a mixture with 1,2,4,5-tetramethylbenzene (durol) and optionally further alkyl aromatics such as dimethyl ethyl benzene such as sulfuric acid, hydrochloric acid or p-toluenesulfonic acid can be used. The acids can be used in amounts of 0.1 to 200 mole percent, based on the amount of glyoxylic acid or glyoxylic acid hydrate used. Amounts of 1 to 180 mole percent are preferred; Amounts of 5 to 150 mole percent are particularly preferred.

Examples of suitable solvents for the process according to the invention are carboxylic acids such as formic acid, acetic acid, propionic acid, etc., mixtures of these solvents or mixtures of these solvents with water. Acetic acid or propionic acid are preferred; acetic acid is particularly preferred. The reaction usually takes place under normal pressure, but in principle it can also be carried out under elevated or reduced pressure.

The reaction times of the process according to the invention are between 1 and 24 hours.

The mixture of 1,2,3,5-tetramethylbenzene and 1,2,4,5-tetramethylbenzene is known and commercially available. All other reagents are also known and commercially available.

Compounds of the formula (I) can be converted in a known manner to 2,3,4,6-tetramethylphenylacetic acid. Phenylacetic acid derivatives, in turn, are important precursors for active substances in crop protection or are used as pharmaceutical active substances (cf. WO 97/36868).

The preparation of the compounds of the formula (I) is to be illustrated by the following preparation examples.

Preparation Examples

example 1

To a solution of 7.8 g [85 mmol] glyoxylic acid hydrate and 13.45 g techn.

Isodurol (81.9% isodurol = 11.02 g = 82 mmol; 16.8% Durol = 2.26 g = 17 mmol) in 100 ml glacial acetic acid, 8.2 g 97% sulfuric acid are added dropwise at room temperature. The reaction mixture is heated and stirred at 45 to 50 ° C for 16 hours. The reaction mixture is then mixed with 170 ml of ice water and extracted three times with 35 ml of methylene chloride. The combined organic phases are dried over sodium sulfate and concentrated in vacuo. 23.8 g of a viscous oil are obtained which, according to GC / MS (after silylation), has the following composition (area%):

0.4% 2,3,5,6-tetramethylmandelic acid

7.8% 2,3,4,6-tetrimethylmandelic acid 0.7% 2,3,5,6-tetramethylmandelic acid acetate 71.1% 2,3,4,6-tetramethylmandelic acid acetate

Example 2

To a solution of 33.4 g [363 mmol] glyoxylic acid hydrate and 57.25 g technical. Isodurol (58.6% Isodurol = 33.55 g = 250 mmol; 22.4% Durol = 12.82 g = 95.5 mmol; 11.4% Dimethyl-ethyl-benzene = 6.53 g = 48.7 mmol) in 400 ml of glacial acetic acid, 35 g of 97% sulfuric acid are added dropwise at room temperature. The reaction mixture is heated and stirred at 35 to 40 ° C for 16 hours. The reaction mixture is then mixed with 700 ml of ice water and extracted three times with 150 ml of methylene chloride. The combined organic phases are dried over sodium sulfate and concentrated in vacuo. 74.5 g of a viscous oil are obtained which, according to GC / MS (after silylation), has the following composition (area%): 0.6% 2,3,5,6-tetramethylmandelic acid 9.5% 2,3,4,6-tetramethylmandelic acid 1.9% 2,3,5,6-tetramethylmandelic acid acetate 65.8% 2,3,4 , 6-tetramethyl-mandelic acid acetate

Example 3

To a solution of 23.9 g [250 mmol] glyoxylic acid hydrate and 57.25 g technical. Isodurol (58.6% Isodurol = 33.55 g = 250 mmol; 22.4% Durol = 12.82 g = 95.5 mmol; 11.4% Dimethyl-ethyl-benzene = 6.53 g = 48.7 mmol) in 400 ml of glacial acetic acid, 35 g of 97% sulfuric acid are added dropwise at room temperature. The reaction mixture is heated and stirred at 45 to 50 ° C for 16 hours. The reaction mixture is then mixed with 700 ml of ice water and extracted three times with 150 ml of methylene chloride. The combined organic phases are over

Dried sodium sulfate and concentrated in vacuo. The residue is dissolved in 250 ml of water and 120 ml of 10% sodium hydroxide solution. It is shaken twice with 250 ml of methyl tert-butyl ether (MTBE), the aqueous phase is then adjusted to pH 1-2 with hydrochloric acid, shaken three times with 100 ml of MTBE, the ether phase is dried over sodium sulfate and concentrated in vacuo. 59.1 g of a viscous oil result, which according to GC / MS (after silylation) has the following composition (area%):

0.7% 2,3,5,6-tetramethylmandelic acid 37.8% 2,3,4,6-tetramethylmandelic acid

1.1% 2,3,5,6-tetramethylmandelic acid acetate 51.3% 2,3,4,6-tetramethylmandelic acid acetate Example 4

To a solution of 4.78 g [52 mmol] glyoxylic acid hydrate and 11.45 g techn. Isodurol (58.6% isodurol = 6.71 g = 50 mmol; 22.4% Durol = 2.56 g = 19 mmol; 11.4% dimethyl ethyl benzene = 1.3 g - 9.1 mmol) in 80 ml of glacial acetic acid

0.25 g of 97% sulfuric acid was added dropwise. The reaction mixture is heated and stirred at 45 to 50 ° C for 16 hours. The reaction mixture is then mixed with 140 ml of ice water and extracted three times with 30 ml of methylene chloride. The combined organic phases are dried over sodium sulfate and concentrated in vacuo. This gives 10.5 g of an oily product which, according to GC / MS (after silylation), has the following composition (area%):

0.2% 2,3,5,6-tetramethylmandelic acid 43.7% 2,3,4,6-tetramethylmandelic acid

2.1% 2,3,4,6-tetramethylmandelic acid acetate

Example 5

To a solution of 7.7 g [52 mmol] 50% aqueous. Glyoxylic acid and 11.45 g techn. Isodurol (58.6% isodurol = 6.71 g = 50 mmol; 22.4% Durol = 2.56 g = 19 mmol; 11.4% dimethyl ethyl benzene = 1.3 g = 9.7 mmol) 7 g of 97% sulfuric acid are added dropwise to 80 ml of glacial acetic acid at room temperature. The reaction mixture is heated and stirred at 45 to 50 ° C for 16 hours. The reaction mixture is then mixed with 140 ml of ice water and shaken out three times with 30 ml of methylene chloride each. The combined organic phases are dried over sodium sulfate and concentrated in vacuo. 14.1 g of an oily product are obtained which, according to GC / MS (after silylation), has the following composition (area%): 0.3% 2,3,5,6-tetramethylmandelic acid 12.8% 2,3,4,6-tetramethylmandelic acid 0.8% 2,3,5,6-tetramethylmandelic acid acetate

52.1% 2,3,4,6-tetramethylmandelic acid acetate

Example 6

To a solution of 4.78 g [52 mmol] glyoxylic acid hydrate and 11.45 g techn. Isodurol (58.6% isodurol = 6.71 g = 50 mmol; 22.4% Durol = 2.56 g = 19 mmol; 11.4% dimethyl ethyl benzene = 1.3 g = 9.7 mmol) in 80 ml of glacial acetic acid

7.35 g of 36% hydrochloric acid were added dropwise. The reaction mixture is heated and stirred at 45 to 50 ° C for 16 hours. The reaction mixture is then mixed with 140 ml of ice water and extracted three times with 30 ml of methylene chloride. The combined organic phases are dried over sodium sulfate and concentrated in vacuo. 12.4 g of an oily product are obtained which, according to GC / MS (after silylation), has the following composition (area%):

0.2% 2,3,5,6-tetramethylmandelic acid 16.5% 2,3,4,6-tetramethylmandelic acid 0.3% 2,3,5,6-tetramethylmandelic acid acetate

25.2% 2,3,4,6-tetramethylmandelic acid acetate

Comparative example 1

To a solution of 54.3 g [590 mmol] glyoxylic acid hydrate and 33.6 g technical. Isodurol (81.9% isodurol = 17.52 g = 205 mmol; 16.8% Durol = 5.64 g = 42 mmol) in 400 ml glacial acetic acid, 24 g of 97% sulfuric acid are added dropwise at room temperature.

The reaction mixture is heated and stirred at 105 to 110 ° C for 15 hours. The reaction mixture is then mixed with 500 ml of ice water and extracted once with 200 ml and three times with 100 ml of methylene chloride. The combined organic phases are dried over sodium sulfate and concentrated in vacuo. This gives 67.6 g of a viscous oil which, according to GC / MS (after silylation), has the following composition (area%):

3.6% 2,3,5,6-tetramethylmandelic acid 4.8% 2,3,4,6-tetramethylmandelic acid 15.3% 2,3,5,6-tetramethylmandelic acid acetate

20.6% 2,3,4,6-tetramethylmandelic acid acetate

Comparative example 2

To a solution of 13.8 g [150 mmol] glyoxylic acid hydrate and 13.45 g technical.

Isodurol (81.9% isodurol = 11.02 g = 82 mmol; 16.8% Durol - 2.26 g = 16.8 mmol) in 160 ml glacial acetic acid, 9.6 g 97% sulfuric acid are added dropwise at room temperature. The reaction mixture is heated and stirred at 110 to 115 ° C for 17 hours. The reaction mixture is then mixed with 200 ml of ice water and extracted three times with 40 ml of methylene chloride. The united organic

Phases are dried over sodium sulfate and concentrated in vacuo. 24.6 g of a viscous oil are obtained which, according to GC (after silylation), has the following composition (area%): 2.0% 2,3,5,6-tetramethylmandelic acid

6.1% 2,3,4,6-tetramethylmandelic acid 14.0% 2,3,5,6-tetramethylmandelic acid acetate 43.5% 2,3,4,6-tetramethylmandelic acid acetate

Claims

Patentansprflche Process for the preparation of compounds of formula (I)

in which R represents hydrogen or a radical -CO-R 2, in which R> 2 represents methyl, ethyl or propyl, characterized in that a mixture of 1,2,3,5-tetramethylbenzene (isodurol) and 1,2,4,5-tetramethylbenzene (durol), which may contain other alkyl aromatics, optionally in the presence of a solvent and a catalyst at a temperature between 0 and 100 ° C with 0.5 to 1.75 moles of glyoxylic acid or glyoxylic acid hydrate per mole of 1,2,3,5-tetramethylbenzene (isodurol). A process for the preparation of compounds of formula (I) according to claim 1, in which R represents hydrogen or a radical -CO-CH ₃ , characterized in that a mixture of 1,2,3,5-tetramethylbenzene and 1,2,4,5-tetramethylbenzene, which may also contain other alkyl aromatics, in the presence of acetic acid as solvent and an acid as catalyst at temperatures between 0 and 100 ° C. with 0.5 to 1.75 mol of glyoxylic acid or glyoxylic acid hydrate per mole 1, 2,3,5-tetramethylbenzene (isodurol). 3. Compounds of formula (I)

in which R represents a radical -CO-R ² , in which R represents methyl, ethyl or propyl. 4. The method according to claim 1 and 2, characterized in that one uses 1.4 to 1.75 mol of glyoxylic acid or glyoxylic acid hydrate per mole of 1,2,3,5-tetramethylbenzene at 30 to 50 ° C. 5. The method according to claim 1 and 2, characterized in that one uses 0.8 to 1.3 moles of glyoxylic acid or glyoxylic acid hydrate per mole of 1,2,3,5-tetra-methylbenzene at 10 to 90 ° C. 6. The method according to claim 1 and 2, characterized in that 1.45 to 1.75 mol of glyoxylic acid or glyoxylic acid hydrate per mol of 1,2,3,5-tetramethylbenzene is used at 35 to 50 ° C. 7. The method according to claim 1 and 2, characterized in that 0.9 to 1.25 mol of glyoxylic acid or glyoxylic acid hydrate per mole of 1,2,3,5-tetra-methylbenzene at 20 to 60 ° C is used.