Process for the preparation of enantiomerically enriched indoline-2-carboxylic acid

1. Process for the preparation of an enantiomerically enriched optionally substituted indoline-2-carboxylic acid according to formula (1)

or a salt thereof, in which Y is an hydroxyl group, a substituted or non-substituted alkoxy group with 1-10 carbon atoms, a substituted or non-substituted aryloxy group or an amine residue, and in which Z represents one or more substituents on an aromatic group that are chosen from the group consisting of hydrogen, an hydroxyl group, an optionally substituted cyclic or acyclic aliphatic group with 1-10 carbon atoms, an optionally substituted aliphatic heterocyclic group with 1-10 carbon atoms, an optionally substituted (hetero)aryl group, an optionally substituted alkoxy group with 1-10 carbon atoms, a halogen atom, an amine group, a nitro group, a carboxylic acid, a carboxylic ester, a carboxylic amide, nitril and trifluoromethyl group, wherein an enantiomerically enriched chiral ortho-X-substituted phenylalanine compound according to formula (2)

or a salt thereof, in which Y and Z are as defined above and X is a leaving group, is subjected to cyclisation at a temperature of below about 140° C., upon formation of the enantiomerically enriched indoline-2-carboxylic acid compound according to formula (1).

2. Process according to claim 1 , wherein X is chosen from the group consisting of chloride, bromide, iodide, and a mesylate group.

3. Process according to claim 1 , wherein Z is hydrogen, Y is hydroxyl and the indoline-2-carboxylic acid according to formula (1) is enantiomerically enriched in the (S)-enantiomer.

4. Process according to claim 1 , wherein the process is carried out in the presence of a metal catalyst comprising a transition metal atom or ion selected from the groups 8 to 11 of the Periodic Table of Elements.

5. Process according to claim 1 , wherein the metal catalyst comprises at least a copper metal atom or salt.

6. Process according to claim 1 , wherein the process is carried out in the absence of a ligand.

7. Process according to claim 1 , wherein the cyclisation reaction is carried out in an organic solvent, in water, in an ionic liquid or in a mixture of two or more thereof.

8. Process according to claim 1 , wherein the cyclisation reaction is carried out in the presence of a base.

9. Process according to claim 1 , wherein the enantiomerically enriched compound (2) is prepared from the corresponding ortho-X-substituted cinnamic acid derivative of formula (3)

or a salt thereof, wherein X, Y and Z are as defined above, by reacting the compound of formula (3) with an amino group donor in the presence of a stereoselective phenylalanine ammonia lyase (PAL) [Process (A)].

10. Process according to claim 1 , wherein the enantiomerically enriched compound (2) is prepared by contacting a compound according to formula (6)

or a salt thereof, in which X, Y and Z are as defined above and B is a COR1 group in which R1 is an optionally substituted cyclic or acyclic aliphatic group with 1-10 carbon atoms, an optionally substituted aliphatic heterocyclic group with 1-10 carbon atoms, an optionally substituted (hetero)aryl group, or an optionally substituted alkoxy group with 1-10 carbon atoms,

with a hydrogen donor in the presence of a chiral catalyst comprising a transition metal upon formation of a compound according to formula (7)

or a salt thereof, in which X, Y, Z and B are as defined above, and subjecting said compound (7) to an hydrolysis reaction upon formation of a compound according to formula (2) [Process (B)].