[SPECIFICATION]
[TITLE OF THE INVENTION]
METHOD FOR PREPARING CHIRAL AMINES [DETAILED DESCRIPTION OF THE INVENTION] [OBJECT OF THE INVENTION] [DESCRIPTION OF THE RELATED ART]
[FIELD OF THE INVENTION]
The present invention relates to a method of preparing chiral
amines, and more preferably, to a method of preparing chiral amines by simple procedures using starting materials which are easy to handle. [BACKGROUND OF THE INVENTION]
The procedures for preparing chiral amines are classified into two categories: chemical procedures using metal catalysts and biochemical procedures using an enzyme catalyst; and the chemical procedure and the biochemical procedures have complementary advantages and shortcomings. Thus, the combination of the two catalysts has been attempted the preparation of chiral amines, but till now, only one method reported by a German group (Reetz, M.T; Schimossek, K. Chimia, 1996, 50. 668) utilized the enzyme-metal combination for preparing chiral amines.
In this method, a chiral amine was prepared as optically pure amide by dynamic kinetic resolution from the mixture of racemic
1-phenylethylamine as a substrate, palladium as a racemization catalyst, and lipase as a selective acylation catalyst. The method uses a racemic mixture of a secondary amine so that one enanitomer of the racemic mixture reacts with an acryl-donating material via the lipase catalyst to convert it into an amide, and another enantiomer converts into a new enantiomer in which enzyme reaction readily occurs via the palladium catalyst, and finally it converts to an amide. The reaction was performed at a temperature of 50 to 55°C for 9 days, and the conversion was 75 to 77%.
However, the method suffers from that it was applicable to only on substrate and required a long reaction time and for a modest yield.
[SUBJECT MATTER OF THE INVENTION]
It is an object of the present invention to provide a method for preparing chiral amines with high yields and excellent optical purities within a shorter reaction time from ketoxime which is readily synthesized from ketone, by the combination of a metal catalyst and a biocatalyst, with a short reaction time, a high yield, and optical purity, and which can be applied to various substrate.
[ELEMENTS AND WORKING EXAMPLES OF THE INVENTION]
These and other objects may be achieved by a method for preparing chiral amines by reacting ketoxime represented by formula I, palladium, lipase, an acyl donor, and a tertiary amine in an organic solvent to prepare an amide represented by formula IV, and then hydrolyzing the amide.
(Formula removed)

(wherein
R1 is hydrogen, an alkyl, an alkoxy, phenyl, or a phenyl substituted with an alkyl;
R2and R3 are each independently, hydrogen or and an alkyl, or R2 and R3 bond together to form a ring, where the alkyl is C1-3 alkyl substituted with hydrogen, oxygen, nitrogen, sulfur, or a halogen, and the ring is represented by -(CH2)n-X-, where n is an integer between 1 to 3;
X is methylene, oxygen, sulfur or nitrogen;
Y is -CH=CH-, -CH=N-, sulfur or oxygen; and
R4 is C1-5 alkyl substituted with oxygen or a halogen.)
The present invention will be illustrated in more detail.
The present invention relates to a method for preparing chiral
amines, which may be useful as an intermediate in the production of medicines from ketoximes, which are easy to make and handle.
In the present invention, ketoxime represented by formula I, palladium as a reduction and racemization catalyst, a lipase as a stereo selective acylation catalyst, an acyl donor, and a tertiary amine react in an organic solvent to provide a chiral amide represented by formula IV.
(Formula removed)

(wherein R1, R2, R3, Y, and R4 are defined as above) In detail procedure, the palladium catalyst is activated in the presence of hydrogen gas at a temperature between 40 to 100°C for 30
minutes to 1 hour. The activated catalyst is then cooled to room
temperature, and ketoxime represented by formula I as a substrate, a
lipase as an acylation catalyst, an acyl donor, a tertiary amine, and an
organic solvent are added. The reaction bath is charged with 1 atm of hydrogen gas. The reaction mixture is preferably performed at a temperature between 40 and 70°C.
The palladium catalyst occurs a reduction of ketoxime and activates racemization reaction of amine from the reduction, and it may be palladium powder, palladium black, or palladium (valence number: 0), supported on carbon, barium sulfate, barium carbonate, or calcium carbonate, and preferably palladium supported on carbon, barium sulfate, barium carbonate or calcium carbonate.
The commercially available supported palladium includes 5 to 10% of palladium. In case that the supported palladium has a palladium content of 5%, the amount of palladium catalyst is preferably 40 to 70 % based on the weight of the ketoxime.
The formulas IIR and IIS represent the enantiomers of racemic amine formed by the reaction.
(Formula removed)

(wherein R1, R2, and R3 are defined as above.)
The lipase catalyzes selective acylation of the enantiomer represented by formula IIR in the presence of the acyl donor, and the compound of formula IIR, on enantiomer, without an additional separation step for isolating the other enantiomer, thereby obtaining to produce the optically pure amide represented by formula IV. The other enantiomer, represented by formula IIS is racemized in situ by the tertiary amine and palladium to form the compound of formula IIR which is continuously converted into an amide represented by formula IV by the enzymatic acylation reaction.
Examples of lipase are immobilized Pseudomonas cepacia lipase (e.g. lipase PS-C immobilized on ceramic, or lipase PS-D immobilized on diatomite (Japan, Amano-Enzymes Inc.), and Candida antarctica lipase (e.g. immobilized on acrylic resin, Novozym 435, Nove Nordisk Korea) are preferable. The amount of the immobilized lipase is preferably 1 to 3 times that of the weight of ketoxime based on weight.
The acyl donor is represented by formula III, and the examples thereof are ethyl acetate, 2,2,2-trifluoroethyl acetate,
2,2,2—trichtoroethyl acetate, and p-chlorophenyl acetate. The amount of the acyl donor is preferably 1.5 to 2 equivalents based on 1 equivalent of ketoxime.
(Formula removed)

R5 is hydrogen, oxygen, nitrogen, sulfur, C1-3 alkyl substituted with a halogen, oxygen, nitrogen or sulfur, C1-3 alkenyl, phenyl or phenyl substituted with a halogen)
The tertiary amine is represented by formula V, and the examples thereof are triethylamine and diisopropylethylamine, and the amount of the tertiary amine is 1 to 5 equivalents based on 1 equivalent of ketoxime.
(Formula removed)

The organic solvent may be benzene, toluene, xylene, tetrahydrofuran, dioxane, methylenechloride, or t—butyl methyl ether. The amount of the organic solvent is preferably controlled between 0.05 to 0.25M based on tne concentration of ketoxime used.
After the complete reaction, the palladium catalyst and lipase
are filtered off, and the optically pure amide was separated by column chromatography.
The amide is hydrolyzed to provide optically pure amine that is useful as an intermediate. The hydrolysis is well known in the related art, so a detailed description thereof will be omitted.
The method for preparing a chiral amine according to the present invention is shown in scheme I.
(Formula removed)

The present invention is further explained in more detail with reference to the following examples, but the examples should not be construed as limiting the scope of the claimed invention.
(Example 1)
Palladium on activated carbon (content of palladium: 5%, 34mg) was activated in the presence of hydrogen gas at a temperature of 40"C for 30 minutes. Acetophenone hydroxime (50mg,0.37mmol) and 100mg of novozym 435 (Nove Nordisk Korea) and 3.6ml of toluene were introduced under an argon atmosphere into the reaction vessel in which activated palladium on activated carbon (content of palladium: 5%, 34mg) was placed. To the resulting mixture, ethyl acetate (72.3/ii,
0.74mmol) and diisopropylethylamind (193µl 1.11mmol))were added,
and deoxygenation occurred under vacuum. The reaction vessel was
charged with 1 atm. of hydrogen gas and stirred at 60°C for 5 days.
After the complete reaction, the reaction mixture was filtered and
subjected to column chromatography to provide
(R)-N-acetyl-l -phenylethylamine. The isolated product was dissolved into 1.2N HCI solution, then refluxed for 9 hours, cooled, and neutralized to obtain a desired amine. The final chemical structure of chiral amine derivative was identified by 1H NMR and 13C-NMR, and the optical purity which were determined with a chiral high-performance liquid chromatography (equipped with Whelk-01 or Chiraldex OD-H column), was 95%ee, and the yield was 80%.
(Examples 2 to 8)
Optically pure amines were prepared by the same procedure as in Example 1, except that oxime as shown in Table 1 was used instead of acetophenone hydroxime.
The yields and optical purities of the chiral amines according to Examples 1 to 8 are shown in Table 1.
(Table removed)

It is evident from Table 1 that the optically pure amines are prepared with high optical purity (94-99%ee) and high yield (70-89%) from the ketoximes using the combination of the palladium catalyst
which catalyzes both reduction of ketoxime and the racemization of the resulting amines, and a lipase which catalyzes enantioselectively the acylation of amine. These results indicate that the present invention provides the methods for the efficient preparation of chiral amines. [Effect of the invention]
The method of the present invention provides the preparation of chiral amines in the form of an amide from achiral ketoximes by the combination of a palladium and a lipase and has advantages that it uses readily available ketoximes as the substrates and provides high yields and excellent enantiopurities.
Since it is applicable for preparing various amines, and the method provides a useful alternative for the conventional chemical or biochemical procedures. The chiral amines prepared by the method of the present invention can be used as chiral building blocks for the synthesis of medicines or fine chemicals.

We claim:
1. A method of preparing chiral amine having a formula IV, said method comprising the steps of:
(a) reacting a ketoxime of formula I in presence of a palladium catalyst in the range of 40-70% based on the weight of ketoxime of formula I, a lipase of 1 to 3 times based on the weight of ketoxime, a 1.5 to 2 equivalent of acyl donor based on 1 equivalent of ketoxime, and 1 to 3 mole tertiary amine based on 1 equivalent of ketoxime in an organic solvent in the range of 0.05 to 0.25 M at a temperature in the range of 40-70°C,
wherein R1 is
(Formula removed)
hydrogen, alkyl, alkoxy, phenyl or phenyl substituted with alkyl; R and R are the same or independently hydrogen or alkyl, or R and R bond together to form a ring, where the alkyl is C1-3 alkyl substituted with hydrogen, oxygen, nitrogen, sulfur or a halogen, and the ring is represented by -(CH2)n-X-, n being an integer between 1 to3; X is methylene, oxygen, sulfur or nitrogen Y is -CH=CH-, -CH=N-, sulfur or oxygen R is a C1-5 alkyl substituted with oxygen or a halogen; and
(b) obtaining an amide of formula IV
(Formula removed)
2. A method as claimed in claim 1, wherein the palladium catalyst is selected from the group consisting of palladium powder, palladium black and palladium supported on carbon, barium sulfate, barium carbonate or calcium carbonate.
3. A method as claimed in claim 1, wherein lipase in step (a) is selected from group consisting of immobilized Pseudomonas cepacia lipase or immobilized Candida antarctica lipase.
4. A method as claimed in claim 1, wherein acyl donor in step (a) is represented by formula III
wherein, R4 is a C 1-5alkyl substituted with oxygen or a halogen; and
R5 is a C 1-3 alkyl substituted with hydrogen, oxygen, nitrogen, sulfur or halogen or
C1-3 alkenyl, phenyl, or phenyl substituted with a halogen.
5. A method as claimed in claim 1, wherein tertiary amine is represented by formula
(Formula removed)

wherein, R6 is C 1-3 alkyl
6. A method for preparing chiral amine substantially as herein described with reference to the foregoing examples and figures.