Process for preparing heterocyclic (R)- and (S)-cyanohydrins
View Patent ↗A process for preparing enantiomer-enriched heterocyclic (R)- and (S)-cyanohydrins of the formula (I), where R1, R2, R3, R4 independently of one another are H, an unsubstituted or substituted C 1 –C 24 -alkyl, alkenyl or alkynyl radical, where one or more carbon atoms in the chain can be replaced by an oxygen atom, a nitrogen atom, a sulfur atom, an SO or an SO 2 group, an unsubstituted or substituted aryl or heteroaryl radical or heterocyclic radical or halogen, hydroxyl, NR5R6, acetyl, oxo, C 1 –C 6 -carbalkoxy, C 1 –C 6 -carbalkoxyamino, COOR7, cyano, amide, benzoylamino or NO 2 , R5 and R6 are H, C 1 –C 6 -alkyl radical, phenyl radical, benzyl radical or COOR7, or together form a C 2 –C 8 -alkylene or heteroalkylene radical, R7 is H or C 1 –C 6 -alkyl, n is 0, 1, 2 or 3, X, Y and Z can be an unsubstituted or substituted carbon atom or a radical selected from the group consisting of N, O, S or NR5R6, where R5 and R6 are as defined above, SO or SO 2 , and at least one of the radicals X, Y and Z is not a carbon atom, where the compounds of the formula (I) can have one or more double bonds in the ring, with the proviso that in a 5-membered ring the double bond is not conjugated with the —C(OH)CN-group, and/or can be anellated and/or bridged, by reacting a ketone of the formula (II), where R1, R2, R3, R4, X, Y, Z and n have the meanings above, with an (R)- or (S)-hydroxynitrile lyase in an organic, aqueous or two-phase system, or in emulsion, in the presence of a cyanide group donor.
1. A process for preparing enantiomer-enriched heterocyclic (R)- and (S)-cyanohydrins of the formula (I),
where R1, R2, R3, R4 independently of one another are H, an unbranched, branched or cyclic C 1 –C 24 , alkyl, alkenyl or alkynyl radical which can be unsubstituted, mono substituted or polysubstituted by substituents inert under the reaction conditions, where one or more carbon atoms in the chain can be replaced by an oxygen atom, a nitrogen atom, a sulfur atom, an SO or an SO 2 group, an aryl or heteroaryl or heterocyclic radical which can be unsubstituted, monosubstituted or polysubstituted by substituents inert under the reaction conditions, or halogen, hydroxyl, NR5R6, acetyl, oxo, C 1 –C 6 -carbalkoxy, C 1 –C 6 -carbalkoxyamino, COOR7, cyano, amide, benzoylamino or NO 2 ,
R5 and R6 independently of one another can be H, unbranched, branched or cyclic C 1 –C 6 -alkyl radical, phenyl radical, benzyl radical, COOR7, or together form a C 2 –C 8 -alkylene or -heteroalkylene radical,
R7 is H or C 1 –C 6 -alkyl,
X and Y independently of one another can be a carbon atom which can be unsubstituted, monosubstituted or disubstituted by substituents inert under the reaction conditions, or a radical selected from the group consisting of N, O, S, or NR5R6, where R5 and R6 are as defined above, SO or SO 2 ,
n is 0, 1, 2 or 3,
Z is a carbon atom which can be unsubstituted, monosubstituted or disubstituted by substituents inert under the reaction conditions, or a radical selected from the group consisting of N, O, S, or NR5R6, where R5 and R6 are as defined above, SO or SO 2 ,
and at least one of the radicals X, Y and Z is not a carbon atom,
where the compounds of the formula (I), depending on the ring size, can have one or more double bonds in the ring, with the proviso that in the 5-membered ring the double bond is not conjugated with the —C(OH)CN-group,
and/or can be monoanellated or polyanellated by 5-membered, 6-membered or 7-membered rings containing 0 to 3 heteroatoms,
and/or can be bridged by an unbranched or branched C 1 –C 6 -alkylene radical, the alkyl chain of which can be interrupted by one or more heteroatoms and/or can have a double bond, which comprises reacting ketones of the formula (II),
where R1, R2, R3, R4, X, Y, Z and n have the meanings given above, using a non-immobilized (R)- or (S)-hydroxynitrile lyase in the organic, aqueous or two-phase system or in emulsion in the presence of a cyanide-group donor to give the desired (R)- and (S)-cyanohydrins.
2. The process as claimed in claim 1 , wherein ketones of the formula (II) are used as starting materials, where R1, R2, R3 and R4 independently of one another are H, a saturated or monounsaturated, unbranched, branched or cyclic C 1 –C 12 -alkyl radical in which a carbon atom in the chain can be replaced by an oxygen atom, a nitrogen atom or a sulfur atom, a phenyl, biphenyl or naphthyl radical, where the radicals can be substituted by one or more substituents selected from the group consisting of C 1 –C 6 -alkyl, C 1 –C 6 -alkoxy, C 1 –C 12 -alkylalkoxy, C 1 –C 20 -aryloxy, halogen, hydroxyl, oxo, carboxyl, phenyl which can be unsubstituted or monosubstituted or disubstituted by halogen, hydroxyl, C 1 –C4-alkyl or C 1 –C 4 -alkoxy, or halogen, hydroxyl, oxo, C 1 –C 6 -carbalkoxy, C 1 –C 6 -carbalkoxyamino, NR5R6, acetyl, COOR7, cyano, amide, benzoylamino or NO 2 ,
R5 and R6 independently of one another can be H or an unbranched, cyclic or branched C 1 –C 6 -alkyl radical or together form a C 2 –C 8 -alkylene radical,
R7 is H or C 1 –C 6 -alkyl,
n is 0, 1 or 2,
X, Y and Z independently of one another are a carbon atom which can be unsubstituted or monosubstituted or disubstituted by C 1 –C 6 -alkyl, C 1 –C 6 -alkoxy, C 1 –C 12 -alkylalkoxy, C 1 –C 20 -aryloxy halogen, hydroxyl, oxo, carboxyl, phenyl which can be unsubstituted or monosubstituted or disubstituted by halogen, hydroxyl, C 1 –C 4 -alkyl or C 1 –C 4 -alkoxy, or a radical selected from the group consisting of N, O, S or NR5R6, where one or two of the radicals X, Y or Z is not a carbon atom, where the ketones of the formula (II) when n=0 do not contain a double bond, when n=1 do not contain a double bond, or contain one double bond and when n=2 contain zero to two double bonds and/or can be anellated by a 5-membered or 6-membered ring containing 0 to 1 heteroatoms, and/or can be be bridged by an unbranched or branched C 1 –C 6 -alkylene radical which can have a double bond.
3. The process as claimed in claim 1 , wherein the organic diluents used for the reaction in the organic system are water-immiscible or slightly water-miscible aliphatic or aromatic hydrocarbons which may be halogenated, alcohols, ethers or esters or mixtures.
4. The process as claimed in claim 1 , wherein the reaction is performed in emulsion.
5. The process as claimed in claim 1 , wherein the enantioselective reaction is carried out in an aqueous system, where a solution or acetate buffer, borate butter, phthalate buffer, citrate buffer or phosphate buffer solution containing the corresponding hydroxynitrile lyase or mixtures of these buffer solutions serves as reaction medium.
6. The process as claimed in claim 1 , wherein the hydroxynitrile lyase used is a native or recombinant (R)- or (S)-hydroxynitrile lyase.
7. The process as claimed in claim 6 , where the hydroxynitrile lyase used is a native (S)-hydroxynitrile lyase from manioc or Hevea brasiliensis , recombinant (S)-hydroxynitrile lyase from genetically modified microorganisms selected from the group consisting of Pichia pastoris, E. coli or Saccharomyces cerevisiae , native (R)-hydroxynitrile lyases from Prunus amygdalus, Prunus laurocerasus or Prunus serotina , or recombinant (R)-hydroxynitrile lyases.
8. The process as claimed in claim 1 , wherein the cyanide group donor is prussic acid, alkali metal cyanide or cyanohydrins of the general formula (III),
R7R8C(OH)(CN)
where R7 and R8 independently of one another are hydrogen or an unsubstituted hydrocarbon group, or R7 and R8 together form an alkylene group having 4 or 5 carbon atoms, where R7 and R8 are not simultaneously hydrogen.