Process For Dynamic Kinetic Resolution (DKR) Of Racemic Compounds In (Hydro) Fluorocarbon Solvents
A process for preparing a third compound stereo-selectively which process comprises reacting a substrate comprising a first enantiomeric compound with a racemisation catalyst to give a second enantiomeric compound, and concurrently reacting the second enantiomeric compound in the presence of a biological catalyst to give the third compound, wherein the process is performed in a solvent comprising at least one (hydro) fluorocarbon. The biological catalyst is preferably an enzyme. The substrate preferably comprises a racemate of the first and second enantiomeric compounds. The second enantiomeric compound may be reacted with a reagent, such as acyl donor, to form the third compound in the presence of the biological catalyst.
1 . A process for preparing a third compound stereo-selectively which process comprises:
reacting a substrate comprising a first enantiomeric compound with a racemisation catalyst to give a second enantiomeric compound, and concurrently reacting the second enantiomeric compound in the presence of a biological catalyst to give the third compound, wherein the process is performed in a solvent comprising at least one (hydro) fluorocarbon.
2 . A process according to claim 1 wherein the biological catalyst is an enzyme.
3 . A process according to claim 2 wherein the enzyme is a hydrolase.
4 . A process according to claim 3 wherein the enzyme is selected from the proteases and lipases.
5 . A process according to claim 2 wherein the enzyme is part of a whole cell culture.
6 . A process according to claim 1 wherein the biological catalyst is an abzyme.
7 . A process according to claim 1 wherein the first and second enantiomeric compounds are R and S isomers of a compound.
8 . A process according to claim 1 wherein the substrate comprises a racemate of the first and second enantiomeric compounds.
9 . A process according to claim 1 wherein the substrate is not a racemate of the first and second enantiomeric compounds.
10 . A process according to claim 1 wherein the first and second enantiomeric compounds are selected from alcohols, carboxylic acids, carboxylic acid esters, amino acid esters, amines, thiols and amides.
11 . A process according to claim 1 wherein the solvent comprises at least one C 1-10 (hydro)fluorocarbon.
12 . A process according to claim 11 wherein the at least one C 1-10 hydrofluorocarbon is selected from the group consisting of difluoromethane (R-32), pentafluoroethane (R-125), 1,1,1-trifluoroethane (R-143a), 1,1,2,2-tetrafluoroethane (R-134), 1,1,1,2-tetrafluoroethane (R-134a), 1,1-difluoroethane (R-152a), 1,1,1,3,3-pentafluoropropane (R-245fa), 1,1,1,2,3,3-hexafluoropropane (R-236ea) and 1,1,1,2,3,3,3-heptafluoropropane (R-227ea), 2,3,3,3-tetrafluoropropene (R-1234yf), 1,3,3,3-tetrafluoropropene (R-1234ze) and (Z)-1,2,3,3,3-pentafluoropropene (R-1225ye).
13 . A process according to claim 12 wherein the solvent comprises at least one of 1,1,1,2,3,3,3-heptafluoropropane (R-227ea) and 1,1,1,2 tetrafluoroethane (R-134a).
14 . A process according to claim 11 wherein the solvent comprises iodotrifluoromethane (CF 3 I).
15 . A process according to claim 1 wherein the at least one (hydro)fluorocarbon is used in combination with a co-solvent.
16 . A process according to claim 14 wherein the co-solvent is halogen free.
17 . A process according to claim 1 wherein the solvent is in the liquid state.
18 . A process according to claim 1 which is conducted in the presence of water at a level which is less than that required for the water to form a separate aqueous phase in the reaction system.
19 . A process according to claim 18 wherein the amount of water is used is below the saturation level for the solvent.
20 . A process according to claim 18 wherein the amount of water that is used is less than 1% by weight of water based on the total weight of the solvent.
21 . A process according to claim 1 wherein the biological catalyst is selected from Novozym 435 and Subtilisin Carlsberg.
22 . A process according to claim 1 wherein the racemisation catalyst comprises a metal.
23 . A process according to claim 22 wherein the racemisation catalyst comprises a metal complex.
24 . A process according to claim 22 wherein the metal is palladium.
25 . A process according to claim 22 wherein the racemisation catalyst comprises palladium on carbon.
26 . A process according to claim 22 wherein the metal is ruthenium.
27 . A process according to claim 25 wherein the racemisation catalyst comprises a complex of ruthenium (II) and at least one aromatic or heteroaromatic ligand.
28 . A process according to claim 27 wherein the racemisation catalyst comprises chlorodicarbonyl[1-(i-propylamino)-2,3,4,5 tetraphenylcyclopentadienyl]ruthenium (II), 1-hydroxytetraphenylcyclopentadienyl(tetraphenyl-2,4-cyclopentadien-1-one)-mu-hydrotetracarbonyldiruthenium (H) 3 or dichloro(p-cymene)ruthenium(II) dimer.
29 . A process according to any of claim 1 wherein the racemisation catalyst comprises a biological catalyst.
30 . A process according to claim 29 wherein the racemisation catalyst comprises a racemase enzyme or an epimerase enzyme.
31 . A process according to claim 1 wherein the second enantiomeric compound is reacted with a reagent in the presence of the biological catalyst to form the third compound.
32 . A process according to claim 31 wherein the reagent is an acyl donor.
33 . A process according to claim 31 wherein, the reagent is a vinyl alkanoate or an isopropenyl alkanoate.
34 . A process according to claim 33 wherein the reagent is vinyl acetate.
35 . A process according to claim 1 wherein the third compound is formed in an enantiomeric excess of at least 50%.
36 . A process according to claim 1 wherein the third compound is formed in an enantiomeric excess of at least 70%.
37 . A process according to claim 1 wherein the third compound is formed in an enantiomeric excess of at least 90%.
38 . (canceled)