Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Preparing nitrogen-containing organic compound
Reexamination Certificate
2000-11-28
2002-10-15
Saucier, Sandra E. (Department: 1651)
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Preparing nitrogen-containing organic compound
C435S280000
Reexamination Certificate
active
06465222
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to a new process for the stereoselective preparation of substituted cyclohexylcyanohydrins.
It is known that cyanohydrins can be prepared by reaction of ketones with hydrocyanic acid (see, for example, Beyer, Walter, Lehrbuch der Organischen Chemie [Textbook of Organic Chemistry], 21
st
Edition, S. Hirzel Verlag Stuttgart 1988, page 213). In substituted cyclic ketones, however, this reaction does not proceed stereoselectively with sterically less demanding radicals.
Protected cyanohydrins are obtained in the reaction of ketones with trimethylsilyl cyanide (see the reference cited above, Beyer, Walter p. 535 ff., Hiyama, Saito, Synthesis 1985, 645-647). The use of oxynitrilases for the preparation of optically active cyanohydrins is also known (see, for example, EP-A-0 799 894).
It was the object of the present invention to make available a process for the more stereoselective preparation of substituted cyclohexylcyanohydrins.
SUMMARY OF THE INVENTION
The present invention relates to a process for the stereoselective preparation of cyclohexylcyanohydrins of the formula (I)
in which
R represents alkyl, cycloalkyl (in which a methylene group is optionally replaced by oxygen), alkoxy, alkenyloxy, cycloalkyloxy, arylalkyloxy, aryloxy or aryl, in each case optionally substituted,
which is characterized in that cyclohexanones of the formula (II)
in which
R has the abovementioned meanings,
are reacted with a cyanide source in the presence of an oxynitrilase and if appropriate in the presence of a diluent.
DETAILED DESCRIPTION OF THE INVENTION
The wavy line in the formula (I) means that the compounds of the formula (I) are mixtures of cis and trans isomers of the following structure:
Surprisingly, the compounds of the formula (I) are obtained in good yield. Reactions of cycloalkanones with oxynitrilases to give cyanohydrins were not known.
Furthermore, the process according to the invention proceeds more rapidly than the purely chemical process.
The process according to the invention furthermore surprisingly yields, depending on the oxynitrilase employed, an excess of desired isomers (cis or trans).
The process according to the invention can be represented by the following equation if hydrocyanic acid is used as a cyanide source:
Formula (II) provides a general definition of the compounds needed as starting substances for the process according to the invention.
Preferred substituents or ranges of the radical R shown in the formulae mentioned above and below are explained below.
Compounds preferably employed in the process according to the invention are those of the formula (II) in which
R represents C
1
-C
8
-alkyl which is optionally substituted by halogen, C
3
-C
8
-cycloalkyl (in which one methylene group is optionally replaced by oxygen) which is optionally substituted by C
1
-C
6
-alkyl or C
1
-C
6
-alkoxy, C
1
-C
8
-alkoxy which is optionally substituted by halogen, C
3
-C
6
-alkenyloxy which is optionally substituted by halogen, C
2
-C
8
-cycloalkyloxy which is optionally substituted by C
1
-C
6
-alkyl or C
1
-C
6
-alkoxy, or phenyl, phenoxy or benzyloxy, each of which is in each case optionally substituted by halogen, C
1
-C
6
-alkyl, C
1
-C
6
-halogenoalkyl, C
1
-C
6
-alkoxy or C
1
-C
6
-halogenoalkoxy.
Compounds particularly preferably employed are those of the formula (II) in which
R represents C
1
-C
6
-alkyl which is optionally substituted by halogen, C
3
-C
6
-cycloalkyl (in which a methylene group is optionally replaced by oxygen) which is optionally substituted by C
1
-C
4
-alkyl or C
1
-C
4
-alkoxy, C
1
-C
6
-alkoxy which is optionally substituted by halogen, C
3
-C
6
-alkenyloxy which is optionally substituted by halogen, C
3
-C
6
-cycloalkyloxy which is optionally substituted by C
1
-C
4
-alkyl or C
1
-C
4
-alkoxy, or phenyl, phenoxy or benzyloxy, each of which is in each case optionally substituted by halogen, C
1
-C
4
-alkyl, C
1
-C
2
-halogenoalkyl, C
1
-C
4
-alkoxy or C
1
-C
2
-halogenoalkoxy.
Halogen in the above definitions represents fluorine, chlorine, bromine and iodine, particularly fluorine, chlorine and bromine, in particular fluorine and chlorine.
Compounds very particularly preferably employed are those of the formula (II) in which
R is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert-butyl, cyclopentyl, cyclohexyl, allyloxy, 2-butenyloxy, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, phenyl or benzyloxy.
In particular, the following compounds of the formula (II) may be mentioned:
4-methylcyclohexanone
4-methoxycyclohexanone
4-ethylcyclohexanone
4-ethoxycyclohexanone
4-n-propylcyclohexanone
4-n-propoxycyclohexanone
4-isopropylcyclohexanone
4-isopropoxycyclohexanone
4-n-butylcyclohexanone
4-n-butoxycyclohexanone
4-isobutylcyclohexanone
4-isobutoxycyclohexanone
4-tert-butylcyclohexanone
4-tert-butoxycyclohexanone
4-cyclohexylcyclohexanone
4-allyloxycyclohexanone
4-phenylcyclohexanone
4-benzyloxycyclohexanone
The compounds of the formula (I) prepared according to the invention are known in some cases or can be prepared by the processes described in the literature cited at the beginning (M. Mousseron et. Al.; Bull. Soc. Chim. Fr. 4. 1435-39 (1970); P. Geneste et. al.; Bull. Soc. Chim. Fr., II, 187-191 (1980)).
The compounds of the formula (II) needed as starting substances for carrying out the process according to the invention are known in some cases or can be prepared by processes which are known in principle (compare Example II-1 and, for example, J. Org. Chem. 47 3881, 1982).
The process according to the invention is preferably carried out in the presence of a diluent which is inert to the reactants.
Aliphatic or aromatic hydrocarbons, such as benzine, toluene, xylene and tetralin, can preferably be used, in addition aliphatic or aromatic halogenohydrocarbons, such as methylene chloride, chloroform, carbon tetrachloride, chlorobenzene and o-dichlorobenzene, furthermore open-chain or cyclic ethers, such as diethyl ether, methyl tert-butyl ether, diisopropyl ether, tetrahydrofuran and dioxane, in addition carboxylic acid esters, such as ethyl acetate, and also strongly polar solvents, such as dimethyl sulphoxide and sulpholane, or alternatively alcohols such as methanol, ethanol, isopropanol and tert-butanol.
Preferred diluents are ethers (in particular dilsopropyl ether) and carboxylic acid esters (in particular ethyl acetate).
The reaction according to the invention can also be carried out in a two-phase system which consists of water and an organic solvent which is not completely miscible with water. For this, suitable organic solvents are, for example, methyl tert-butyl ether, diisopropyl ether and ethyl acetate. Diisopropyl ether is preferably used.
The process according to the invention can also be carried out in an aqueous system in the absence of an organic solvent at a preferred pH of <5, in particular at a pH of between 3 and 4. The pH is adjusted by means of a buffer. Suitable buffers are, for example, sodium acetate or sodium citrate. Preferably, a 20 to 500 mM sodium citrate buffer is used.
The process according to the invention is carried out in the presence of an oxynitrilase (hydroxynitrile lyase). Oxynitrilases are enzymes which catalyse the cleavage and formation of cyanohydrins. Oxynitrilases have long been known (see, for example, EP-A-0 799 894; Chem. Commun. 1997, 1933; Angew. Chem. 1994, 106, 1609-1619; Angew. Chem. Int. Ed. Engl. 1996, 35, 438; Enantiomer, Vol. 1, pp. 359-363).
For the process according to the invention, the following oxynitrilases are preferably employed: (R)-oxynitrilase from the bitter almond (Prunus amygdalus), (S)-oxy-nitrilase from cassava (Manihot esculenta) and (S)-oxynitrilase from the rubber tree (Hevea brasiliensis). The (R)-oxynitrilase from the bitter almond (Prunus amygdalus) and the (S)-oxynitrilase from cassava (Manihot exculenta) are particularly preferably employed. The (R)-oxynitrilase from the bitter almond (Prunus amygdalus) is very particularly preferably used.
Depending on the typ
Effenberger Franz
Fischer Reiner
Roos Jürgen
Afremova Vera
Bayer Aktiengesellschaft
Gil Joseph C.
Henderson Richard E. L.
Saucier Sandra E.
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