WO2004054966A1 - Method for the production of optically-active cyanohydrins and the corresponding mandelic acids - Google Patents

Abstract

The invention relates to a method for the production of optically-active cyanohydrins and the corresponding α-hydroxycarboxylic acids, from an aldehyde, a CN source and an optically-active vanadyl-salen catalyst in a biphasic liquid/liquid system, whereby the reaction mixture is reacted at a temperature of 0 to 60 °C. 0.8 to 10 equivalents of cyanide and 0.000005 to 0.05 equivalents of vanadyl-salen catalyst, based on the aldehyde (concentration 0.5 to 4 mol/Liter of solvent) are used. After the reaction the optically-active cyanohydrin, or the corresponding optically-active α-hydroxycarboxylic acid from acid hydrolysis, can be isolated with good enantiomeric excess. The vanadyl-salen catalyst used comprises a salen ligand, whereby the ratio of salen ligand: vanadium (IV) in the catalyst lies in the range 1.4: 1 to 10: 1.

Description

 description

Process for the production of optically active cyanohydrins and their corresponding mandelic acids

The invention relates to a process for the production of optically active cyanohydrins by means of an optically active vanadyl catalyst in a liquid-liquid 2-phase system.

Optically active cyanohydrins and their secondary products, e.g. optically active α-hydroxycarboxylic acids serve as building blocks for the production of biologically active substances, e.g. used in the pharmaceutical or agro industry. Cyanohydrins are accessible through various chemical reactions, such as in Top. Curr. Chem. 1999, 200, 193-226.

A synthesis possibility for optically active cyanohydrins consists in aldehydes in the presence of molecules with "CN" groups (HCN, MCN with M: alkali metal, trimethylsilyl cyanide - also known as TMSCN, cyanohydrins such as acetone cyanohydrin) and an optically active catalyst in (S) - or (R) - to convert cyanohydrins (Compr. Asymmetrie Catal. I-Ill, 1999 (2), Chap. 28).

The enantioselective addition of the CN group to aldehydes is successful with a number of catalysts, but primarily with trimethylsilyl cyanide as the CN source (LP. Holmes, HB Kagan, Tetrahedron Lett. 2000, 41, 7457-7460. Y. Hamashima et al ., Tetrahedron 2001, 57, 805-814. E. Le ere et al., Tetrahedron: Asymmetry, 2000, 11, 3471-3474.).

For example, when using optically active transition metal catalysts, such as titanium-salen complexes, an enantioselective addition of trimethylsilyl cyanide to aldehydes is known (Y. Beiokon, J. Chem. Soc., Perkin Trans. 1 1997, 1293-1295. YN Beiokon et al. J. Am. Chem. Soc. 1999, 121, 3968-3973.).

By YN Beiokon et al. (J. Am. Chem. Soc. 1999, 121, 3970) have been reported that there is no reaction with titanium-salen complexes when using free HCN under the same conditions (at -80 ° C). YN Beiokon et al. also report in Eur. J. Org. Chem. 2000, 2655-2661 that with titanium-salen complexes, when using free HCN, even at room temperature, there is only a very slow reaction compared to using TMSCN. Good sales and

Consequently, enantioselectivities usually require low temperatures (-80 ° C) and TMSCN as the source of cyanide.

Vanadyl salen complexes catalyze the reaction of aldehydes with trimethylsilyl cyanide in principle with higher enantioselectivity than the corresponding titanium salen catalysts (YN Beiokon, M. North, T. Parsons, Org. Lett. 2000, 2, 1617-1619.) However, only the use of TMSCN as a cyanide source is known here.

M. North and Y. N. Beiokon describe the preparation of O-acetylated cyanohydrins in a solid-liquid 2-phase mixture (M. North, Y. N. Beiokon, WO02 / 10095) using an alkali metal cyanide in the form of its salt. The use of free HCN, however, gives poor ee values under the same conditions (0-29%; M. North, Y. N. Beiokon, Chem. Commun. 2002, 244-245.).

A CN source such as trimethylsilyl cyanide is not very suitable for industrial use because it is expensive and also causes large amounts of silicon-containing waste. The implementation of low temperatures such as -80 ° C in technical applications is also expensive and not very practical. Solid alkali metal cyanides are difficult to handle on an industrial scale for safety reasons.

Pure liquid hydrocyanic acid or aqueous solutions of metal cyanides are particularly suitable for use on an industrial scale, since liquids, in particular aqueous solutions, generally allow particularly simple handling.

Therefore, the task was to find a method that would overcome the difficulties associated with the reagents commonly used in the literature and overcomes restrictions with regard to the cyanide source to be used and the reaction temperature and, moreover, also permits the use of pure liquid hydrocyanic acid or an aqueous solution of alkali metal cyanides in a simple manner, without requiring great effort, even technically.

The present invention solves this problem and relates to processes for the preparation of optically active cyanohydrins by reacting an aldehyde with a cyanide source in the presence of an optically active vanadyl catalyst which contains a salen ligand at a temperature in the range from 0 to 60 ° C., the reaction in a liquid-liquid 2-phase system, consisting of an organic solvent and an aqueous phase, and the ratio of salen ligand: vanadium (IV) in the catalyst is in the range from 1.4: 1 to 10: 1

In a preferred embodiment, the invention relates to the preparation of cyanohydrins of the formula (II)

wherein the optically active center * has the absolute configuration (R) or (S), R represents an optionally branched alkyl, alkenyl or alkynyl radical of the chain length Ci to C ₂ o, in particular Ci to Cs, or a radical of the formula (lla)

wherein X, Y and Z are independently the same or different and for H, F, Cl, Br, I, OH, NH ₂ , O (dC ₄ alkyl), OCOCH _3> NHCOCH ₃ , N0 ₂ or dC ₄ alkyl stand. Cyanohydrins of the formula (II) are obtained by reacting an aldehyde of the formula (I)

where R has the meaning given above, in accordance with the aforementioned provisions.

In a further preferred embodiment according to the invention, aldehydes of the formula (Ia) are used.

In the formula (Ia), X preferably represents F, Cl, Br, I, OH, 0 (-C ₄ alkyl), OCOCH ₃ , NHCOCH ₃ , N0 ₂ or CC ₄ alkyl and Y and Z each represent H. or X and Y each for H and Z for OH or X for H and Y and Z each for OH.

Pure hydrocyanic acid, hydrocyanic acid stabilized with acid or an aqueous solution of a metal cyanide, preferably an alkali cyanide, in particular a sodium or potassium cyanide, such as, for example, commercially available aqueous sodium / potassium cyanide solutions with a cyanide content of 13-14%, can be used as the cyanide source.

The cyanohydrin contained in the reaction mixture can optionally be converted directly into the corresponding α-hydroxycarboxylic acid by hydrolysis.

One advantage of the process according to the invention is that it is possible not only to use the aldehydes in comparatively low concentrations, for example 0.1 mol aldehyde / liter, as was customary hitherto, but also to use them Reaction with considerably higher aldehyde concentrations, for example 2.0 mol aldehyde / liter up to 10 mol aldehyde / liter, preferably 2 to 4 mol aldehyde / liter. Accordingly, the space-time yield for stereoselective cyanohydrin reactions is unusually high.

According to the invention, the reaction with the cyanide source is carried out in a liquid-liquid 2-phase mixture. In principle, all organic solvents or solvent mixtures which are inert under the conditions of the reaction are suitable as organic solvents. C _δ- Cio aromatic and C1-C ₁₀ aliphatic, optionally halogenated hydrocarbons or solvent mixtures thereof, and aliphatic ethers with 1-5 carbon atoms per alkyl radical, or cyclic ethers with 4-5 carbon atoms in the ring are particularly suitable as organic solvents. Aromatic optionally substituted Cβ-Cio, preferably Cβ to Cg hydrocarbons, such as toluene, ortho-, meta- and / or para-xylene, chlorinated aliphatic or aromatic hydrocarbons such as methylene chloride, dichloroethane, trichloroethane, chloroform, chlorobenzene, dichlorobenzene are particularly suitable and trichlorobenzene, or ethers, such as. B. diethyl ether, di-n-propyl ether, di-iso-propyl ether, di-n-butyl ether and methyl tert-butyl ether.

Water and aqueous solutions of acids are suitable as the aqueous solvent. Aqueous solutions of mineral acids or of organic compounds with acidic functional groups, such as e.g. Carboxylic acids, sulfonic acids and phosphonic acids. Hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, citric acid or glutamic acid are particularly suitable.

The concentration of the acid in the aqueous solution is preferably 0 to 85%, in particular 0 to 60%. For example, an 85% acid concentration would correspond to the use of pure phosphoric acid, a 37% acid concentration to the use of concentrated hydrochloric acid. Buffers are generally used to prepare 1% solutions. The volume ratio of organic to aqueous phase is usually in the range from 20: 1 to 1:20, in particular in the range from 10: 1 to 1:10. 0.8 to 10.0, in particular 1.0 to 5.0, preferably 1.1 to 3.5, particularly preferably 1.3 to 2.3 mol of cyanide source are used per mol of aldehyde of the formula (I). However, it is also possible to carry out the reaction with 0.5 to 20 mol of cyanide source / mol of aldehyde.

The process according to the invention is carried out at a temperature of 0 to 60 ° C., preferably 10 to 50 ° C., in particular 20 to 40 ° C.

Suitable catalysts are vanadyl-salen complexes consisting of salen ligands of the general formula (III) and vanadium in the oxidation stage (IV).

R, R or S, S enantiomer

The radicals R, R 'and R "of the salen ligand of the general formula (III) can independently of one another be hydrogen, branched or unbranched C ₁ -C ₁₀ alkyl radicals, in particular a methyl or tert-butyl radical, or a group 0 (C * ι-C ₄ alkyl), in particular a methoxy group or halogens, in particular Cl, a substituted aryl group, in particular a phenyl group, or - (CH ₂ ) _m - where m can be an integer between 1 and 8.

The ratio of salen ligand: vanadium (IV) in the catalyst is in the range from 1.4: 1 to 10: 1, preferably in the range from 1.4: 1 to 5: 1, in particular from 1.4: 1 to 3: 1 , Such catalysts are described in the priority German patent application DE-A-101 31 811.1 (internal number 2001 DE309).

The catalyst is prepared by reacting vanadyl sulfate with 1, 4 to 10, in particular with 1, 4 to 5 equivalents of the corresponding salen ligand.

The catalysts contain salen ligands of the formula (III) and vanadium in the oxidation stage (IV) and are preferably synthesized in alcohols in a heterogeneous reaction environment or in a chlorinated hydrocarbon / alcohol mixture in a heterogeneous reaction environment.

To carry out the process according to the invention, the vanadyl salen

Catalyst mixed with the aldehyde in a suitable organic solvent. 0.000005 to 0.05 equivalents of catalyst are preferred

0.00005 to 0.01 equivalents of catalyst, based on the aldehyde.

Water, an aqueous solution of a mineral acid or an aqueous solution of an organic compound with acidic functional groups are then added. The ratio of organic solvent to aqueous phase is 20: 1 to 1:20, preferably 15: 1 to 1:15, in particular 8: 1 to 1: 8.

The pH of the aqueous phase is 1.5 to 7, preferably 2 to 6, particularly preferably 2.5 to 5.5. If necessary, the pH must be adjusted to a value in the range from pH 1.5 to 7, preferably 2 to 6, particularly preferably 2.5 to 5.5 using an alkali salt solution. This is often achieved by adding alkali cyanide solution or HCN.

Instead of the aqueous acid, the use of a buffer solution, such as, for example, phosphoric acid / phosphate buffer, acetic acid / acetate buffer, citric acid / citrate buffer or glutamic acid / glutamate buffer, which has a pH between 1, 5 and 7, is preferred 2 to 6, particularly preferably 2.5 to 5.5, is possible. As mentioned at the beginning, the reaction is carried out at 0 to 60 ° C., in particular at 10 to 50 ° C., preferably at 20 to 40 ° C. In many cases it has proven useful to let the reaction proceed at room temperature.

The aldehyde of the formula (I) is added to the reaction mixture in a concentration of 0.1 to 10.0, in particular 0.5 to 5.0, preferably 1.0 to 4.5 mol, of aldehyde / liter. In a large number of cases, it has proven useful to carry out the reaction with HCN or the aqueous alkali metal cyanide solution with an aldehyde concentration of 2.0 to 4.0 mol / liter.

When the reaction has ended, the optically active cyanohydrin can be isolated from the reaction mixture and, if necessary, cleaned. With toluene as solvent, the optically active cyanohydrin e.g. crystallize in the cold, preferably at temperatures in the range from -20 ° C to 10 ° C.

However, the optically active cyanohydrin, if appropriate in the form of the reaction mixture, can also be converted, for example by acid hydrolysis, into the corresponding optically active α-hydroxycarboxylic acid. Strong acidic acids, such as conc. HCI or aqueous sulfuric acid. If necessary, the aqueous phase must be separated from the reaction mixture before the hydrolysis of the cyanohydrin. During the hydrolysis, the aqueous phase, in which the acid is contained, and the organic phase, in which the optically active cyanohydrin is located, must be thoroughly mixed.

The process according to the invention surprisingly enables aldehydes to be converted into the optically active cyanohydrins of both the (S) and the (R) series in a liquid-liquid 2-phase system with high conversions and good ee values. In particular, substrates which are particularly difficult for, for example, enzymatic processes, such as benzaldehydes substituted in the 2-position, for example 2-chlorobenzaldehyde, can optionally be successfully converted to the corresponding optically active (S) - or (R) -cyanohydrins using the process according to the invention. Examples:

The following examples describe the invention in more detail without restricting it.

After derivatization with acetic anhydride / pyridine, the ee values of the cyanohydrins obtained were determined by gas chromatography on a β-cyclodextrin column.

In the following examples, a VO-salen complex is used to produce a complex of salen ligands of the formula (III) and vanadium in the oxidation state (IV), such as, for example, B. understood vanadyl (IV) sulfate.

Preparation of the VO-Salen complexes using the purple salen ligand as an example

(purple), R, R enantiomer, R = R '= tert-butyl

example 1

Synthesis of VO-salen complex with the salen ligand (purple):

5.46 g (0.01 mol) of (R, R) -2,2 '- [1,2-cyclohexanediyl) bis (nitrilomethylidyn)] to [4,6-di-tert-butyl) phenol] are obtained in 50 ml of ethanol are introduced and 1.14 g (0.0045 mol) of vanadyl sulfate pentahydrate are added. After three hours under reflux and complete conversion (TLC control), the solvent is distilled off, the residue is taken up in 200 ml of dichloromethane and the solution with 100 ml Washed water. After phase separation, drying the solution with sodium sulfate and distilling off the solvent, 5.0 g of light green, amorphous powder are obtained (yield: 96% of theory). The present VaO-Salen complex can be used in the form of the present crude product or, if desired, after purification by chromatography.

Melting point 208 ° C (dec.), [Α] _D ²⁰ = -300 (c = 0.01; CHCI ₃ ), paramagnetic. IR (KBr), v = 2950 (s), 2870 (m), 2350 (w), 2320 (w), 1610 (vs), 1550 (m), 1270 (s) [cm ^"1 ].

Implementation of aldehydes I with the VO-Salen complex from Example 1

Example 2

150 ml of toluene are placed in a flask equipped with a stirrer, internal thermometer, reflux condenser and gas scrubber. 0.2 g (0.17 x 10 ^-3 mol) of (R, R) -VO-salen complex from Examples 1 and 31, 8 g (0.3 mol) of benzaldehyde (freshly dest.) added. Then 69.6 g of 85% phosphoric acid are added. A solution of 32.6 g of KCN in 100 ml of water is added dropwise with ice cooling. The reaction mixture is adjusted to pH 4 by adding 14.0 g of NaOH (50% in water). The dark green reaction mixture is stirred at room temperature for 24 hours. According to the GC, the conversion is 99%; 78% ee for the (S) -mandelic acid cyanohydrin.

saponification:

Before the start of the cyanohydrin hydrolysis, the aqueous phase is separated from the reaction mixture. Then 92.0 g of conc. Hydrochloric acid is added and the hydrolysis mixture is heated to 60 ° C. for 6 hours with vigorous stirring.

Then 200 ml of water are added to the reaction mixture and the organic phase is separated off. The aqueous phase is extracted five times with 100 ml of DIPE. Diisopropyl ether is separated from the combined organic phases by distillation. Crystallized from the remaining toluene

(S) -mandelic acid. The yield is 28.7 g of (S) -mandelic acid (63% of theory based on benzaldehyde; 94% ee). Example 3

150 ml of toluene are placed in a flask equipped with a stirrer, internal thermometer, reflux condenser and gas scrubber. 0.2 g (0.17 x 10 ^"3 mol) of (R, R) -VO-Salen complex from Examples 1 and 31, 8 g (0.3 mol) of benzaldehyde (freshly dest.) 15.0 g of phosphate buffer, 0.1 molar, pH 4 and 12.6 g of HCN (stabilized with about 5% acetic acid) are then added in. The dark green reaction mixture is stirred at room temperature for 24 hours GC: 99%; 80% ee for the (S) -mandelic acid cyanohydrin.

saponification:

92.0 g of conc. Hydrochloric acid is added and the hydrolysis mixture is heated to 60 ° C. for 6 hours with vigorous stirring. Then 200 ml of water are added to the reaction mixture and the organic phase is separated off. The aqueous phase is extracted five times with 100 ml of DIPE. Diisopropyl ether is separated from the combined organic phases by distillation. (S) -mandelic acid crystallizes out of the remaining toluene. The yield is 30.6 g of (S) -mandelic acid (65% of theory with respect to benzaldehyde; 95% ee).

Example 4

150 ml of toluene are placed in a flask equipped with a stirrer, internal thermometer, reflux condenser and gas scrubber. 0.2 g (0.17 x 10 ^"3 mol) of (R, R) -VO-salen complex from Example 1 and 42.5 g (0.3 mol) of 2-chlorobenzaldehyde (freshly distilled water) are added in succession with stirring 69.6 g of phosphoric acid, 85% strength, are added, while a solution of 32.6 g of KCN in 100 ml of water is added dropwise, while cooling with ice, by adding 14.7 g of NaOH (50% in water) The reaction mixture is adjusted to pH 4. The dark green reaction mixture is stirred at room temperature for 24 hours and, according to GC, the conversion is 98% and 73% ee for the (S) -2-chloromandelic acid cyanohydrin.

saponification:

Before the start of the cyanohydrin hydrolysis, the aqueous phase is

Separated reaction mixture. Then 92.0 g of conc. hydrochloric acid added, and the hydrolysis mixture is heated to 60 ° C. for 6 hours with vigorous stirring.

Then 200 ml of water are added to the reaction mixture and the organic phase is separated off. The aqueous phase is extracted twice with 100 ml of DIPE. Diisopropyl ether is separated from the combined organic phases by distillation. (S) -2-Chloromandelic acid crystallizes out of the remaining toluene. The yield is 35.4 g of (S) -2-chloromandelic acid (60% of theory based on 2-chlorobenzaldehyde; 91% ee).

Example 5

150 ml of toluene are placed in a flask equipped with a stirrer, internal thermometer, reflux condenser and gas scrubber. 0.2 g (0.17 x 10 ^"3 mol) of (R, R) -VO-salen complex from Example 1 and 42.5 g (0.3 mol) of 2-chlorobenzaldehyde (freshly distilled water) are added in succession with stirring Then 15.0 g of phosphate buffer, 0.1 molar, pH 4 and 12.6 g of HCN (stabilized with about 5% acetic acid) are added and the dark green reaction mixture is stirred at room temperature for 24 hours according to GC: 98%; 76% ee for the (S) -2-chloromandelic acid cyanohydrin.

Saponification:

92.0 g of conc. Hydrochloric acid is added and the hydrolysis mixture is heated to 60 ° C. for 6 hours with vigorous stirring. Then 200 ml of water are added to the reaction mixture and the organic phase is separated off. The aqueous phase is extracted twice with 100 ml of DIPE. Diisopropyl ether is separated from the combined organic phases by distillation. (S) -2-Chloromandelic acid crystallizes out of the remaining toluene. The yield is 36.6 g of (S) -2-chloromandelic acid (61% of theory in relation to 2-chlorobenzaldehyde; 93% ee).

Example 6

75 ml of toluene are placed in a flask equipped with a stirrer, internal thermometer, reflux condenser and gas scrubber. 0.1 g (0.08 x 10 ^"3 mol) of (R, R) -VO-Salen complex from Examples 1 and 21, 5 g (0.15 mol) are 2-Chlorobenzaldehyde (freshly distilled) added. Then 57.2 g of 85% phosphoric acid are added. A solution of 26.3 g of KCN in 100 ml of water is added dropwise with ice cooling. After the end of the addition, the pH of the reaction mixture is 2.1. The dark green reaction mixture is stirred at room temperature for 24 hours. According to the GC, the turnover is 98%; 72% ee for the (S) -2-chloromandelic acid cyanohydrin.

Example 7

75 ml of toluene are placed in a flask equipped with a stirrer, internal thermometer, reflux condenser and gas scrubber. 0.1 g (0.08 x 10 ^"3 mol) of (R, R) -VO-Salen complex from Example 1 and 21, 5 g (0.15 mol) of 2-chlorobenzaldehyde (freshly dest 45.0 g of 37% hydrochloric acid are then added, while a solution of 26.3 g of KCN in 100 ml of water is added dropwise, while cooling with ice, by adding 2.1 g of NaOH (50% in water) The reaction mixture is adjusted to pH 3.0 The dark green reaction mixture is stirred at room temperature for 24 hours, the conversion according to GC being 96% and 68% ee for the (S) -2-chloromandelic acid cyanohydrin.

Examples 8-9 were carried out analogously to Example 7, in accordance with the information in Table 1.

Table 1 :

Beispiel 10

Example 10

75 ml of toluene are placed in a flask equipped with a stirrer, internal thermometer, reflux condenser and gas scrubber. 0.2 g (0.17 x 10 ^"3 mol) of (R, R) -VO-Salen complex from Examples 1 and 21, 5 g (0.15 mol) of 2-chlorobenzaldehyde (freshly dest Then 25.0 g of citrate buffer, 0.1 molar, pH 4 and 10.1 g of HCN (stabilized with about 5% acetic acid) are added and the dark green reaction mixture is stirred at room temperature for 24 hours according to GC: 100%; 72% ee for the (S) -2-chloromandelic acid cyanohydrin.

Examples 11 to 18 were carried out analogously to Example 10, in accordance with the information in Table 2.

Table 2:

all buffer solutions used had a concentration of 0.1 mol / l

Example 19

75 ml of dichloromethane are placed in a flask equipped with a stirrer, internal thermometer, reflux condenser and gas scrubber. It is stirred in succession 0.1 g (0.08 x 10 ^"3 mol) of (R, R) -VO-salen complex from Examples 1 and 21, 5 g (0.15 mol) of 2-chlorobenzaldehyde (freshly distilled) added. Then 45.0 g of 37% hydrochloric acid are added. A solution of 26.3 g of KCN in 100 ml of water is added dropwise with ice cooling. The reaction mixture is brought to pH 3 by adding 2.2 g of NaOH (50% in water). 0. The dark green

The reaction mixture is stirred at room temperature for 24 hours. According to the GC, the conversion is 99%; 74% ee for the (S) -2-chloromandelic acid cyanohydrin.

Comparative Example 20 75 ml of toluene are placed in a flask equipped with a stirrer, internal thermometer, reflux condenser and gas scrubber. 0.1 g (0.08 x 10 ^"3 mol) of (R, R) -VO-Salen complex from Example 1 and 21, 5 g (0.15 mol) of 2-chlorobenzaldehyde (freshly dest .) Then 52.1 g of hydrochloric acid,

37%, added. A solution of 26.3 g of KCN in 100 ml of water is added dropwise with ice cooling. The reaction mixture has pH 1.0 and is colored blue. The

The reaction mixture is stirred at room temperature for 24 hours. According to the GC, the turnover is 29%; 56% ee for the (S) -2-chloromandelic acid cyanohydrin.

Comparative Example 21 75 ml of toluene are placed in a flask equipped with a stirrer, internal thermometer, reflux condenser and gas scrubber. 0.1 g (0.08 x 10 ^"3 mol) of (R, R) -VO-Salen complex from Example 1 and 21, 5 g (0.15 mol) of 2-chlorobenzaldehyde (freshly dest Then 23.2 g of 85% phosphoric acid are added, while a solution of 26.3 g of KCN in 100 ml of water is added dropwise, while cooling with ice, and after the end of the addition, the pH of the reaction mixture is 7.3. The dark green reaction mixture is stirred at room temperature for 24 hours and, according to GC, the conversion is 100%;

38% ee for the (S) -2-chloromandelic acid cyanohydrin.

Comparative Example 22

75 ml of toluene are placed in a flask equipped with a stirrer, internal thermometer, reflux condenser and gas scrubber. 0.2 g (0.17 x 10 ^-3 mol) of (R, R) -VO-Salen complex from Examples 1 and 21, 5 g (0.15 mol) are 2-Chlorobenzaldehyde (freshly distilled) added. Then 25.0 g hydrochloric acid, 0.1 molar, pH 1, and 10.1 g HCN (stabilized with about 5% acetic acid) are added. The dark green reaction mixture is stirred at room temperature for 24 hours. According to the GC, the turnover is 33%; 24% ee for the (S) -2-chloromandelic acid cyanohydrin.

Comparative Example 23

75 ml of toluene are placed in a flask equipped with a stirrer, internal thermometer, reflux condenser and gas scrubber. 0.2 g (0.17 x 10 ^-3 mol) of (R, R) -VO-Salen complex from Example 1 and 21, 5 g (0.15 mol) of 2-chlorobenzaldehyde (freshly distilled water) .) added. Then 25.0 g of citrate buffer, 0.1 molar, pH 6, and 10.1 g of HCN (stabilized with about 5% acetic acid) are added. The dark green reaction mixture is stirred at room temperature for 24 hours. According to the GC, the turnover is 100%; 63% ee for the (S) -2-chloromandelic acid cyanohydrin.

Claims

claims: 1. A process for the preparation of optically active cyanohydrins by reacting an aldehyde with a cyanide source in the presence of an optically active vanadyl catalyst which contains a salen ligand at a temperature in the range from 0 to 60 ° C., the reaction in a liquid-liquid 2- Phase system consisting of an organic solvent and an aqueous phase is carried out and the ratio of salen ligand: vanadium (IV) in the catalyst is in the range from 1.4: 1 to 10: 1. 2. The method according to claim 1, characterized in that cyanohydrins of the formula (II),

wherein the optically active center * has the absolute configuration (R) or (S), R represents an optionally branched, alkyl, alkenyl or alkynyl radical of chain length Ci to C ₂ o or a radical of the formula (Ila)

wherein X, Y and Z are independently the same or different and for H, F, Cl, Br, I, OH, NH ₂ , 0 (CC ₄ alkyl), OCOCH ₃ , NHCOCH ₃ , N0 ₂ or CC ₄ alkyl, by reacting an aldehyde of the formula (I)

- where R has the meaning given above. 3. The method according to claim 1 and / or 2, characterized in that an aldehyde of the formula (Ia)

used, where X, Y and Z have the meaning given above. 4. The method according to at least one of the preceding claims, characterized in that the cyanide source pure hydrocyanic acid, stabilized with acid hydrocyanic acid or an aqueous solution of a metal cyanide is used. 5. The method according to one or more of the preceding claims, characterized in that the organic solvent is a C ₁ -C ₁₀ aliphatic or Cβ-Cio aromatic optionally halogenated hydrocarbon or an open-chain or cyclic aliphatic ether each having 1-5 carbon atoms per alkyl radical or 4th - 5 carbon atoms per ring or mixtures thereof. 6. The method according to one or more of the preceding claims, characterized in that the concentration of the acid in the aqueous phase is 0 to 85%. 7. The method according to one or more of the preceding claims, characterized in that the pH of the aqueous phase is in the range from 1.5 to 7. 8. The method according to one or more of the preceding claims, characterized in that the volume ratio of organic phase to aqueous phase is in the range from 20: 1 to 1:20. 9. The method according to one or more of the preceding claims, characterized in that the optically active vanadyl catalyst contains salen ligands of the general formula (III) and vanadium in the oxidation stage (IV), where R, R 'and R "independently of one another are hydrogen, branched or unbranched Ci-C-io-alkyl radicals or a group 0 (C * rC alkyl) or halogens or an aryl group or - (CH ₂ ) _m - with m = 1 to 8 mean.

R, R or S, S enantiomer 10. The method according to one or more of the preceding claims, characterized in that 0.8 to 10 equivalents of cyanide source are used per equivalent of aldehyde. 11. The method according to one or more of the preceding claims, characterized in that 0.000005 to 0.05 mol of optically active vanadyl catalyst is used per mole of aldehyde. 12. The method according to one or more of the preceding claims, characterized in that the aldehyde is used in a concentration of 0.1 to 10.0 mol aldehyde / liter of the reaction mixture.