Organic compounds -- part of the class 532-570 series – Organic compounds – Nitriles
Reexamination Certificate
2002-06-10
2004-04-06
McKane, Joseph K. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitriles
C435S128000
Reexamination Certificate
active
06717006
ABSTRACT:
Cyanohydrins are of importance, for instance, for the synthesis of alpha-hydroxyacids, alpha-hydroxyketones, beta-aminoalcohols, which are used to produce biologically active substances, for example active pharmaceutical substances, vitamins or pyrethroid compounds.
A cyanohydrin can be produced by addition of hydrocyanic acid (HCN) to the carbonyl group of an aldehyde or of an unsymmetrical ketone, enantiomeric mixtures of unsymmetrical cyanohydrins being formed.
Since in a biologically active enantiomeric mixture usually only one of the two enantiomers is biologically active, there has been no lack of attempts to find a method for producing the (R)-enantiomer of an optically active cyanohydrin in the highest possible optical purity.
Many methods are based on adding HCN to the carbonyl group in the presence of a chiral catalyst, for example an oxynitrilase.
The enantiomeric purity of the cyanohydrin to be synthesized depends to a great extent on how much the competing chemical reaction and racemization can be suppressed.
As is disclosed by J. Am. Chem. Soc. 1991, 113, pp. 6992-6996, particularly in the case of methods employing an aqueous system it is difficult, because of this competing reaction, to achieve high enantioselectivity and enantiomeric purity.
One way of suppressing the competing chemical reaction and racemization is disclosed in EP-A-0 326 063, according to which optically active (R)-cyanohydrins are said to be obtained by reacting aliphatic, aromatic or heteroaromatic aldehydes or ketones in an aqueous environment with hydrocyanic acid in the presence of (R)-oxynitrilase (EC 4.1.2.10) from Prunus amygdalus, by employing acidic conditions, in particular pH≦4.5, at temperatures such that the competing chemical reaction and racemization are negligible compared with the enzymatic synthesis. Reference is made here to the increased activity losses of the biocatalyst under these conditions and the examples show favoring of low temperatures in the range from 5 to 8° C.
Since the enzymes are water-soluble proteins and the substrates, in contrast, are only sparingly water-soluble compounds, the use of water-miscible organic solvents to improve the solubility of the substrate and the product has been proposed.
Thus, for example, Effenberger et al. (Angew. Chem. 99 (1987) pp. 491-492) studied enzymatic cyanohydrin formation in aqueous alcoholic systems varying the pH, temperature and concentration with a view to optimum suppression of the competing reactions. However, the stereochemical purity of the desired end products was frequently unsatisfactory. As an improvement it was proposed to carry out the enzymatic reaction of oxo compounds with hydrocyanic acid in organic water-immiscible solvents in order to suppress the chemical reaction. In this case, preferably ethyl acetate and support-immobilized (R)-oxynitrilase were employed. Although in this manner products of high optical purity were obtained, as a result of the enzyme immobilization, a considerable loss of enzyme activity was observed. In addition, it was found that the non-enzymatic reaction which leads in the aqueous phase, by addition of hydrocyanic acid to the starting compound, to racemic cyanohydrins, causes an unwanted decrease in enantiomeric purity of the product.
In J. Am. Chem. Soc. 1991, 113, pp. 6992-6996 the problems associated with the use of free hydrocyanic acid are avoided by a transcyanation in the presence of hydroxynitrilase using acetone cyanohydrin in a two-phase reaction mixture consisting of an aqueous buffer solution and a water-immiscible solvent. The disadvantage in this case is that the volume of organic solvent, and as a result of the entire reaction mixture, is somewhat large in relation to the amount of aldehyde used. In addition, an extremely long reaction time and a large amount of enzyme are required. Finally, the optical purity of the cyanohydrins is also generally inadequate for enantiospecific synthesis of the target products.
As an improvement, EP-A1-0 547 655 proposes a method in which optically active cyanohydrins are produced from aldehydes or ketones and hydrocyanic acid in a two-phase system consisting of a homogeneous aqueous solution of the hydroxynitrilase and a suitable organic solvent which is at least essentially immiscible with water, the aqueous solution being buffered by an acetate buffer at a concentration of 0.005 to 0.1 mol per liter, and the ratio of organic phase to aqueous phase being between 5:1 and 1:5. The reaction system is stirred during the enzymatic reaction, the two-phase system being maintained.
Despite the reaction at a pH of about 4.5, the chemical reaction, however, cannot be suppressed completely, even in this two-phase system of organic substrate solution and aqueous enzyme solution. A disadvantage with this method is that the ee values of the cyanohydrins could only be improved by using large amounts of enzyme.
It was an object of the invention to find an improved method for the production of optically active cyanohydrins which ensures high enantiomeric purity with at the same time low enzyme and time requirements.
It has now unexpectedly been found that it is possible to react a multiplicity of carbonyl compounds, for instance aliphatic, alicyclic, unsaturated, aromatically substituted aliphatic, aromatic and heteroaromatic aldehydes and ketones, to give the corresponding cyanohydrins with high yield and at high optical purity in a more concentrated procedure, with lower enzyme usage and in with shorter reaction times, compared with the prior art, if the reaction is carried out in an emulsion. Unexpectedly, the enzyme activity remains stable under emulsion conditions which lead, with many proteins, to deactivation, such as in the case of high stirring energy.
The present invention therefore relates to a method for the production of (R)-enantiomers of optically active cyanohydrins by reacting an aldehyde or a ketone with a cyanide group donor in the presence of an (R)-oxynitrilase which is characterized in that a reaction mixture of
a) an aldehyde or ketone dissolved in an organic, water-immiscible or only slightly water-miscible diluent,
b) an aqueous (R)-oxynitrilase solution and
c) a cyanide group donor is stirred in such a manner that an emulsion forms which is maintained up to the end of the enzymatic reaction, whereupon, after the enzymatic reaction is terminated, the corresponding (R)-cyanohydrin is isolated from the reaction mixture.
The starting materials used in the inventive method are an aldehyde or a ketone, a cyanide group donor, an aqueous solution of an (R)-oxynitrilase and an organic water-immiscible or only slightly water-miscible diluent.
Aldehydes are taken to mean here aliphatic, aromatic or heteroaromatic aldehydes. Aliphatic aldehydes are taken to mean saturated or unsaturated, aliphatic, unbranched, branched or cyclic aldehydes. Preferred aliphatic aldehydes are unbranched aldehydes having, in particular, 2 to 30 carbon atoms, preferably 2 to 18 carbon atoms, which are saturated or are monounsaturated or polyunsaturated. The aldehyde can have not only C—C double bonds but also C—C triple bonds. The aliphatic, aromatic or heteroaromatic aldehydes can, in addition, be unsubstituted or be substituted by groups inert under the reaction conditions, for example by unsubstituted or substituted aryl or heteroaryl groups, such as phenyl, phenoxy or indolyl groups, by halogen, hydroxyl, hydroxy-C
1
-C
5
alkyl, C
1
-C
5
alkoxy, C
1
-C
5
alkylthio, ether, alcohol, carboxylic ester, nitro or azido groups.
Examples of aromatic or heteroaromatic aldehydes are benzaldehyde and variously substituted benzaldehydes, for instance 3,4-difluorobenzaldehyde, 3-phenoxybenzaldehyde, 4-fluoro-3-phenoxybenzaldehyde, hydroxybenzaldehyde, methoxybenzaldehyde, in addition furfural, methylfurfural, anthracene-9-carbaldehyde, furan-3-carbaldehyde, indole-3-carbaldehyde, naphthalene-1-carbaldehyde, phthaldialdehyde, pyrazole-3-carbaldehyde, pyrrole-2-carbaldehyde, thiophene-2-carbaldehyde, isophthalaldehyde or pyridinealdehydes, thienylaldehyde
Mayrhofer Herbert
Neuhofer Rudolf
Pöchlauer Peter
Wirth Irma
DSM Fine Chemicals Austria Nfg GmbH & Co KG
Wenderoth Lind & Ponack LLP
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