Reaction of (di)amines in the presence of a lysine oxidase and of a reducing agent
The invention relates to methods for reacting (di)amines as substrates in the presence of a lysine oxidase arid a reducing agent, resulting in alcohols, diols or cyclic secondary amines. In a particular embodiment, the invention is directed to methods of preparing cyclic secondary amines suitable for ultimately synthesizing piperidine-2-carboxylic acid and proline derivatives, useful, for example as thrombin inhibitors.
1. A method for reacting amines of the general formula (I)
with A- meaning
to give compounds of the general formula (II) or (III)
with B- meaning HO—CH 2 —R 3 — or R 4 —
comprising the following steps:
a) oxidation of at least one
group of an amine of the general formula (I) to a carbonyl group in the presence of a lysine oxidase as catalyst;
b) where appropriate reaction of the second NH 2 group of an amine of the general formula (I) with
with the carbonyl group resulting from a) to give an enamine or imine by cyclization;
c) reduction of the carbonyl group(s) resulting from a), or of the anamine or imine resulting where appropriate from b), with a reducing agent respectively to hydroxymethyl groups or to a cyclic secondary amine of the general formula (II),
where R 1 is NR 5 or a linear bivalent C 2 –C 6 hydrocarbon radical which is optionally substituted by CO 2 H, C 2 R 6 , OH, SH and/or N(R 5 ) 2 and/or contains nonadjacent O, S and/or N atoms,
where R 5 is H or linear C 1 –C 6 -alkyl and R 6 is linear C 1 –C 6 -alkyl or branched C 3 –C 6 -alkyl or C 6 –C 10 -aryl,
and R 2 is H, CO 2 H, C 2 R 6 or CN,
where the method is carried out as a one-pot method, lysine oxidise and reducing agent are present together, and
in the definition of A in the general formula (I)
R 3 is a bivalent C 0 –C 1 or C 5 –C 18 hydrocarbon radical which is optionally substituted by linear C 1 –C 6 -alkyl or branched C 3 –C 6 -alkyl, C 6 –C 10 -aryl, C 4 –C 10 -heteroaryl and/or CO 2 R 6 and/or contains nonadjacent O, S and/or N atoms, and
R 4 is a linear C 1 –C 20 hydrocarbon radical which is optionally substituted by functional groups CO 2 H and/or CO 2 R 6 and/or contains nonadjacent O, S and/or N atoms.
2. A method for preparing cyclic secondary amines of the general formula (II) from diamines of the general formula (Ia)
where R 1 is NR 5 or a linear bivalent hydrocarbon radical with 2 to 6 C atoms, which is optionally substituted by functional groups CO 2 H, C 2 R 6, OH, SH and/or N(R 5 ) 2, and/or contains nonadjacent heteroatoms O, S and/or N, p 1 where R 5 is H or linear C 1 –C 6 -alkyl and R 6 is linear C 1 –C 6 -alkyl or branched C 3 –C 6 -alkyl or C 6 –C 10 -aryl, and R 2 is H, CO 2 H, C 2 R 6 or CN,
comprising the following steps:
oxidation of one of the two
groups of a dimaine of the general formula (Ia) to a carbonyl group in the presence of a lysine oxidase as catalyst;
b) reaction of the second NH 2 group of the diamine of the general formula (Ia) with the carbonyl group resulting from step a) to give an enamine or imine by cyclization;
c) reduction of the enamine or imine resulting from b) with a reducing agent to give a cyclic secondary amine of the general formula (II);
wherein the method is carried out as one-pot method, and lysine oxidase and reducing agent are present together.
3. A method as claimed in claim 2 , wherein the diamine of the general formula (Ia) is selected from the group consisting of lysine, omithine and 1,6-diaminohexane.
4. A method for preparing diols of the general formula (IIIa) from diamines of the general formula (Tb)
comprising the following steps:
a) oxidation of the two aminomethyl groups of a diamine of the general formula Ib) to formyl groups in the presence of a lysine oxidizase as catalyst;
b) reduction of the formyl groups resulting from a) with a reducing agent to hydroxymethyl groups to form a diol of the general formula (IIIa);
wherein the method is carried out as one-pot method, lysine oxidize and reducing agent are present together, and
R 3 is a bivalent C 0 –C 1 or C 5 –C 18 hydrocarbon radical which is optionally substituted by linear C 1 –C 6 -alkyl or branched C 3 –C 6 -alkyl, C 6 –C 10 -aryl, C 4 –C 10 -heteroaryl and/or CO 2 R 6, and/or contains nonadjacent O, S and/or N atoms, wherein R 6 is linear C 1 –C 6 -alkyl or branched C 3 –C 6 -alkyl or C 6 –C 10 -aryl.
5. A method for preparing primary alcohols R 4 —CH 2 —OH from amines R 4 —CH 2 —NH 2 comprising the following steps:
a) oxidation of the aminomethyl group of an amine R 4 —CH 2 —NH2 to a formyl group in the presence of a lysine oxidase as catalyst;
b) reduction of the formyl group resulting from a) with a reducing agent to a hydroxylmethyl group to form a primary alcohol R 4 —CH 2 —OH;
wherein the method is carried out as one-pot method, lysine oxidase and reducing agent are present together, and
R 4 is a linear C 1 –C 20 hydrocarbon radical which is optionally substituted by functional groups CO 2 H and/or CO 2 R 6 and/or contains nonadjacent O, S and/or N atoms, wherein R 6 is linear C 1 –C 6 -alkyl or branched C 3 –C 6 -alkyl or C 6 –C 10 -aryl.
6. A method as claimed in claim 1 , wherein a lysine oxidase from a yeast is employed.
7. A method as claimed in claim 2 , wherein a lysine oxidase from a yeast is employed.
8. A method as claimed in claim 3 , wherein a lysine oxidase from a yeast is employed.
9. A method as claimed in claim 4 , wherein a lysine oxidase from a yeast is employed.
10. A method as claimed in claim 5 , wherein a lysine oxidase from a yeast is employed.
11. The method of any of claims 6 , 7 , 8 , 9 , or 10 , wherein said yeast is Pichia pastoris.