Process for preparing optically active cyanohydrins and...

Details Process for preparing optically active cyanohydrins and... Process for preparing optically active cyanohydrins and...

2001-11-01

2003-11-25

McKane, Joseph K. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Nitriles

C435S128000

Reexamination Certificate

active

06653498

ABSTRACT:

BACKGROUND OF THE INVENTION
The invention relates to a process for preparing optically active cyanohydrins using a highly active (R)-hydroxynitrile lyase extract.
Optically active cyanohydrins and their secondary products, for example optically active &agr;-hydroxycarboxylic acids, serve as building blocks for producing biologically active substances which are used in the pharmaceutical or agricultural industries, for example, as described in F. Effenberger: Hydroxynitrile Lyases in Stereoselective Synthesis (in Stereoselective Biocatalysis edited by R. N. Patel; Marcel Dekker Inc. New York—Basle 2000, pages 321 to 342).
A possible method for synthesizing optically active cyanohydrins is the use of hydroxynitrile lyase produced from natural products which, depending on the natural product, can be produced in the R or S form and converts aldehydes, in the presence of prussic acid, into the corresponding (R)- or (S)-cyanohydrins. The substrate spectrum of the enzyme differs depending on the natural product.
(R)-Hydroxynitrile lyase is most simply, and therefore most frequently, produced from almond flour.
In the sequence of aromatic aldehydes, benzaldehyde and 3- and 4-substituted benzaldehydes are included among the substrates which may be converted to optically active cyanohydrins with great success using (R)-hydroxynitrile lyase produced from almond flour as the natural product or from other natural products. In contrast, 4-hydroxybenzaldehyde and 3,4-dihydroxybenzaldehyde are among the starting materials which, using (R)-hydroxynitrile lyase produced from almond flour or other natural products may only be converted into the corresponding optically active cyanohydrins with difficulty. 2-substituted benzaldehydes are not very suitable as substrates for the reaction using (R)-hydroxynitrile lyases.
SUMMARY OF THE INVENTION
A disadvantage of the known processes is that in the reaction of the aldehydes with HCN or KCN in the presence of (R)-hydroxynitrile lyase to give the corresponding optically active cyanohydrins, the aldehydes are usually used in the form of dilute solutions of low concentration. Accordingly, the space-time yield, based on the aldehydes used, is decreased.
In view of the above-described restrictions with respect to the aldehydes to be used and the disadvantages of low space-time yields, there is a need for a process which avoids these restrictions and disadvantages and, furthermore, may also be implemented industrially in a simple manner without requiring great expenditure.
This object is surprisingly achieved by a process for preparing optically active cyanohydrins of the formula (II)
DETAILED DESCRIPTION OF THE INVENTION
It comprises reacting an aldehyde of the formula (I)
with HCN in a water-immiscible organic solvent in the presence of water, in the absence or presence of a buffer, in the presence of a (R)-hydroxynitrile lyase, where X, Y and Z in formula (II) have the same meaning as in formula (I), independently of one another are identical or different, and are H, F, Cl, Br, I, OH, O(C
1
-C
4
-alkyl), OCOCH
3
, NHCOCH
3
, NO
2
or C
1
-C
4
-alkyl.
During the entire reaction with HCN, usually a pH of 0 to 8, in particular 2 to 7, preferably 3 to 6, is maintained. In a number of cases it has proved to be advantageous to maintain a pH of 3.3 to 5.5, in particular 4.0 to 5.5, preferably 4.5 to 5.3.
The reaction is usually carried out at 0 to 60° C. and intensive mixing is employed. The cyanohydrin of the formula (II) may if appropriate be converted into the corresponding carboxylic acid by hydrolysis.
The details hereinafter which also relate to a procedure using an aqueous R-hydroxynitrile lyase extract, also relate to the abovementioned procedure in the presence of an R-hydroxynitrile lyase. The procedure in the presence of the aqueous R-hydroxynitrile lyase extract mentioned below represents a special variant of the inventive process in the presence of an R-hydroxynitrile lyase. The R-hydroxynitrile lyase can be used in pure form or in the form of an extract. The R-hydroxynitrile lyase is commercially available, for example, in pure form or purified form.
The reaction is usually carried out in the presence of 20 to 1000 units of R-hydroxynitrile lyase/mmol aldehyde, in particular 50 to 500 units of R-hydroxynitrile lyase/mmol of aldehyde, preferably 80 to 400 units of R-hydroxynitrile lyase/mmol of aldehyde. The number of units of R-hydroxynitrile lyase required for reaction of the aldehyde also depends on the type of aldehyde. Readily reactive aldehydes may be reacted with relatively low numbers of units of R-hydroxynitrile lyase/mmol of aldehyde, whereas less reactive aldehydes require higher numbers of units of R-hydroxynitrile lyase/mmol of aldehyde. The units (abbreviation U) are a measure of the activity of R-hydroxynitrile lyase.
As already mentioned, the reaction is carried out in the absence or presence of a buffer. The reaction in the absence of a buffer is a particularly simple variant of the inventive process.
In a number of cases it can be advantageous to carry out the inventive reaction of the aldehyde with HCN in the presence of a buffer. Particularly suitable buffers or buffer mixtures are those which develop their buffer action in the specified pH range and maintain the pH in this range during the reaction. If the buffering action of the buffer is insufficient to maintain the pH in the predetermined range during the reaction, if necessary, the pH must be adjusted by addition of acid or addition of base.
Suitable buffers are, for example, glutamic acid-glutamate, phosphoric acid-phosphate, acetic acid-acetate and citric acid-citrate buffers, in particular acetic acid-acetate and citric acid-citrate buffer.
It has proved to be useful to carry out the reaction in the presence of 20 to 500 mmol of buffer/liter, in particular 40 to 300 mmol of buffer/liter, preferably 80 to 160 mmol of buffer/liter. Usually the buffer is dissolved in water and used in the form of an aqueous solution comprising 20 to 500, in particular 40 to 300, preferably 80 to 160, mmol of buffer per liter.
The invention, according to a particular embodiment, relates to a process for preparing optically active cyanohydrins of the formula (II)
It comprises reacting, with intense mixing at 0 to 60°C., an aldehyde of the formula (I)
with HCN in a water-immiscible organic solvent in the presence of a (R)-hydroxynitrile lyase extract prepared by extracting a (R)-hydroxynitrile-lyase-containing natural product at pH 3.3 to 5.5 with water in the absence or presence of a buffer, separating the organic phase from the aqueous phase and if appropriate converting the cyanohydrin of the formula (II) by hydrolysis into the corresponding carboxylic acid, where X, Y and Z in formula (II) have the same meaning as in formula (I), independently of one another are identical or different and are H, F, Cl, Br, I, OH, O(C
1
-C
4
-alkyl), OCOCH
3
, NHCOCH
3
, NO
2
or C
1
-C
4
-alkyl.
The inventive process makes it possible, surprisingly, to convert even less readily reactive aldehydes, such as 4-hydroxybenzaldehyde and 3,4-dihydroxy-benzaldehyde, into the optically active cyanohydrins with high yields and good ee values. Furthermore, 2-substituted benzaldehydes, for example
2-chlorobenzaldehyde, may also be highly successfully reacted by means of the inventive process to give the corresponding optically active cyanohydrins. In view of the fact that considerable difficulties would certainly be expected during a reaction of 2-substituted benzaldehydes to give optically active cyanohydrins because of the steric conditions, it is considered highly surprising that even 2-substituted benzaldehydes can be converted into the optically active cyanohydrins.
A further advantage of the inventive process is that it is possible to use the aldehydes, not only as is customary to date at comparatively low concentrations, for example 0.1 mol of aldehyde/liter, but also to carry out the reaction with considerably higher aldehyde concentrations, for example 1.0 mol of aldehyde/liter and above. Therefore, the s

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