Racemization of optically active amines

Details Racemization of optically active amines Racemization of optically active amines

2002-10-01

2003-06-10

Davis, Brian (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Amino nitrogen containing

Reexamination Certificate

active

06576795

ABSTRACT:

The present invention relates to a process for racemizing optically active amines of the formula I
where R
1
and R
2
are different and R
1
, R
2
, R
3
are alkyl, cycloalkyl, arylalkyl, aryl, heteroaryl and heterocyclic radicals and R
3
may also be hydrogen (H), with the radicals being able to bear substituents selected from the group consisting of alkyl, cycloalkyl, alkoxy, aryloxy, amino, alkylamino and dialkylamino, by reacting the optically active amine I in the presence of hydrogen and a hydrogenation or dehydrogenation catalyst at elevated temperature.
Optically active amines of the formula I are, for example, valuable pharmaceuticals and intermediates for the preparation of active compounds (cf., for example: DEA29 03 589, page 2, lines 17 to 26). Since frequently only one of the two enantiomers (based on the asymmetric carbon atom shown in the formula I) is active, or is more active than the other enantiomer, processes are required for racemizing the less active enantiomer which is obtained, for example, in resolution of the corresponding racemic amine by known methods because the more active enantiomer can once again be obtained from the racemized amine by known methods (e.g. resolution).
Chem. Abstracts 110: 192247v (IN-A-162 213) discloses a process for preparing racemic 2-aminobutanol by treating 1-2-aminobutanol with ammonia in the presence of Rh/Al
2
O
3
.
U.S. Pat. No. 4,096,186 describes a process for racemizing optically active amino alcohols in which the amino alcohol is brought into contact with ammonia and hydrogen in the presence of a hydrogenation catalyst which preferably comprises cobalt. In the reaction of optically active 2-amino-1-butanol, a degree of racemization of only 63% is achieved at a racemate yield of at most 97.6%. At a degree of racemization of 99%, on the other hand, a racemate yield of only 75.1%, is achieved.
U.S. Pat. No. 4,990,666 discloses a process for racemizing optically active amino alcohols in which the amino alcohol is brought into contact with Raney cobalt in the presence of hydrogen. It is stated that high temperatures, e.g. above 160° C., reduce the racemate yield.
Derwent Abstract No. 94-197043/24 (Chem. Abstracts 121: 179093z; JP-A-06 135 906) describes a process for racemizing optically active vicinal primary diamines in the presence of hydrogen and a hydrogenation catalyst such as Raney nickel and Raney cobalt.
Patent Abstracts of Japan, Vol. 12, No, 467 (C-550), (JP-A-63 185 943), describes the racemization of optically active 1-methyl-3-phenylpropylamine in the presence of Raney nickel or Raney cobalt and hydrogen at 50-200° C.
U.S. Pat. No. 3,954,870 discloses a method of racemizing certain optically active alpha, beta-diphenylethylamines by heating in the presence of dry Raney nickel.
DE-A-28 51 039 describes a process for preparing racemic mixtures from optically active 1-arylamines in which the optically active 1-arylamines are treated with hydrogen in the presence of a hydrogenation catalyst, in particular Raney cobalt.
DE-A-29 03 589 describes a process for preparing racemic mixtures from optically active amines by treating the optically active amines with hydrogen at elevated temperature in the presence of a hydrogenation catalyst, in particular Raney cobalt or Raney nickel. The reaction of optically active 2amino-1-phenylpropane over a Raney cobalt catalyst for a reaction time of 12 hours leads, at a degree of racemization of at most 98%, to a racemate yield of only 91.1%.
WO 00/29357 relates to a process for racemizing optically active amines by reaction of the optically active amine in the gas phase in the presence of hydrogen and a hydrogenation or dehydrogenation catalyst at elevated temperature.
WO 00/47546 discloses a process for racemizing optically active amines by reaction of the optically active amine in the presence of hydrogen and a hydrogenation or dehydrogenation catalyst at elevated temperature, in which the reaction is carried out in the liquid phase and the catalyst comprises the catalytically active constituents copper, silver, iron, cobalt, nickel, ruthenium, rhodium, palladium, osmium, iridium and/or platinum and a support material selected from the group consisting of aluminum oxide, zirconium dioxide, titanium dioxide, carbon and oxygen-containing compounds of silicon.
WO 00/47545 (equivalent: U.S. Pat. No. 6,049,007) describes a process for preparing racemic amines by simultaneously reacting a corresponding optically active amine and a corresponding secondary alcohol and/or a corresponding unsymmetrical ketone and a particular amine in situ in the presence of hydrogen and a hydrogenation or dehydrogenation catalyst at elevated temperature.
U.S. Pat. No. 6,060,624 relates to a process for racemizing particular optically active primary &bgr;-alkoxyalkylamines by reaction over a nickel or cobalt catalyst in the presence of hydrogen and ammonia.
Another disadvantage of some processes of the prior art is that expensive noble metal catalysts are used.
It is an object of the present invention to discover an improved economical process for racemizing optically active amines in which the process product is obtained with a high degree of racemization at a simultaneously high racemization yield (racemate yield) and a high space-time yield.
We have found that this object is achieved by a process for racemizing optically active amines of the formula I
where R
1
and R
2
are different and R
1
, R
2
, R
3
are alkyl, cycloalkyl, arylalkyl, aryl, heteroaryl and heterocyclic radicals and R
3
may also be hydrogen (H), with the radicals being able to bear substituents selected from the group consisting of alkyl, cycloalkyl, alkoxy, aryloxy, amino, alkylamino and dialkylalmino, by reacting the optically active amine I in the presence of hydrogen and a hydrogenation or dehydrogenation catalyst at elevated temperature, wherein the catalyst comprises the active components copper and zinc oxide and a support material.
In a particular embodiment, the catalyst comprises an oxidic support material selected from the group consisting of aluminum oxide, silicon dioxide, titanium dioxide, zirconium dioxide, magnesium oxide, iron oxide and cerium dioxide or carbon or mixtures thereof.
Aluminum oxide is preferred as support material.
The process of the present invention can be carried out in the liquid phase or preferably in the gas phase, batchwise or preferably continuously, as follows, with the catalyst preferably being present in the reactor as a fixed bed.
The process of the present invention can be carried out in the absence or preferably the presence of the amine of the formula R
3
NH
2
in which the radical R
3
corresponds to the radical R
3
of the optically active amine I (e.g. the amine ammonia in the case of racemization of optically active amines I in which R
3
=H)
If the process is carried out in the presence of the amine R
3
NH
2
, the molar ratio of R
3
NH
2
to amine I is generally from 1:1 to 50:1, preferably from 1.5:1 to 30:1, particularly preferably from 2:1 to 20:1, very particularly preferably from 2:1 to 10:1. The R
3
NH
2
excess based on the amine I can also be greater than 50:1.
The hydrogen is generally fed into the reaction in an amount of from 5 to 400 l, preferably from 10 to 200 l, per mole of amine component I, with the number of liters quoted being based on S.T.P. in each case.
When the process of the present invention is carried out in the gas phase, the optically active amine I is continuously passed in gaseous form in a gas stream which is sufficiently large for vaporization and comprises hydrogen and advantageously the amine R
3
NH
2
, preferably consists of hydrogen and the amine R
3
NH
2
, over the catalyst at pressures of generally from 0.1 to 30 MPa, in particular from 0.1 to 10 MPa, preferably from 0.1 to 5 MPa, particularly preferably from 0.1 to 3 MPa, in a reactor, e.g. an externally heated tube reactor.
The gaseous mixture can be passed through the fixed catalyst bed either from the top or from the bottom. The gas stream required is preferably obtained by mea

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