Process for the preparation of chiral 2-aryl morpholines

1. A process for the preparation of a chiral 2-(4-aminophenyl) morpholine of formula (I)

wherein R 1 is hydrogen or an amino protecting group (PG) said process comprising the steps of:

(a) reducing a ketone of the formula II wherein X is a halogen atom with an

ketoreductase enzyme to afford the chiral alcohol of the formula IIIa;

(b) displacing the halogen intramolecularly followed by in situ ring opening

of the resulting epoxide IIIb with ethanolamine to afford IVb;

(c) introducing a protecting group to afford IVa wherein PG is an amino protecting group;

(d) contacting IVa with R 3 SO 2 X wherein X is a halogen to afford VI;

(e) cyclizing VI to afford the chiral morpholine V wherein PG is as defined

above;

(f) reducing the nitro group to afford chiral 2-(4-aminophenyl) morpholine of the formula I wherein R 1 is an amino PG; and,

(g) optionally removing the amino protecting group PG to afford a compound of formula I wherein R 1 is a H.

2. The process of claim 1 , wherein the amino protecting group is selected from Boc (t-butoxycarbonyl), benzyl, 4-methoxybenzyl, benzhydryl, Fmoc (fluorenylmethoxycarbonyl), Cbz (benzyloxycarbonyl), Moz (p-methoxybenzyl carbonyl), Troc (2,2,2-trichloroethoxycarbonyl), Teoc (2-(trimethylsilyl)ethoxycarbonyl), Adoc (adamantoxycarbonyl), formyl, acetyl or cyclobutoxycarbonyl.

3. The process of claim 2 , wherein the amino protecting group is Boc or benzyl.

4. The process of claim 1 , wherein said ketoreductase converts the ketone of formula II into the chiral alcohol of formula IIIa with an enantiomeric excess of at least 98%.

5. The process of claim 1 , wherein the enzymatic reduction in step a) is performed in the presence of NADH or NADPH as co-factor.

6. The process of claim 5 , wherein the co-factor is regenerated with a cosubstrate selected from a secondary alcohol or from an additional enzyme selected from alcohol dehydrogenase, glucose dehydrogenase, formate dehydrogenase, glucose-6-phosphate dehydrogenase, phosphite dehydrogenase or hydrogenase.

7. The process of claim 6 , wherein the enzymatic reduction is performed in an aqueous medium in the presence of an organic co-solvent at temperatures of 1° C. to 50° C.

8. The process of claim 7 , wherein a homogeneous suspension is formed.

9. The process of claim 1 , wherein the chiral carbon is either the (R) or (S) configuration with an enantiomeric excess of at least 98%.

10. The process of claim 1 wherein the intermediate epoxide in step (b) is isolated, converted to ethanolamine IVb which is isolated and the protecting group is introduced in a third step to afford IVa.

11. The process of claim 10 , wherein:

(i) the epoxide is formed using an alkali hydroxide as base;

(ii) the ethanolamine IVb is formed in an organic solvent at a temperature of 0° C. to 60° C. using an excess of 2 to 30 equivalents of ethanolamine,

(iii) the protecting group is Boc and which is introduced in the presence of an organic solvent at a temperature of 0° C. to 40° C.

12. The process of claim 1 wherein the alcohol Ma is converted to ethanolamine IVb in situ without isolation of the epoxide and IVb is isolated and the protecting group is introduced in a second step to afford IVa.

13. The process of claim 12 wherein:

(i) the first step is performed in the presence of an organic solvent at a temperature of 0° C. to 60° C. using an excess of 2 to 30 equivalents of ethanolamine,

(ii) the second step is introduction of the Boc amino protecting group PG in the presence of an organic solvent at a temperature of 0° C. to 40° C.

14. The process of claim 1 wherein the alcohol Ma is converted to the N-protected ethanolamine IVa in situ without isolation of the epoxide by contacting IIIb with an N-protected ethanolamine of the formula

wherein PG stands for an amino protecting group.

15. The process of claim 14 , wherein to the N-protected ethanolamine IVa is N-benzylethanolamine and is introduced in the presence of an organic base, an organic solvent, at a temperature of between 40° C. and the reflux temperature of the solvent.

16. The process of claim 1 , wherein (i) step (d) is carried out by reacting the N-protected ethanolamine compound of formula IVb with a sulfonyl chloride of the formula R 3 —SO 2 Cl in the presence of an organic base and an organic solvent at a temperature of 0° C. to 40° C. to form an sulfonate of the formula VI

wherein PG is as defined above and R 3 is C 1-4 alkyl or phenyl optionally substituted with a C 1-4 alkyl group, with a nitro group or with a halogen atom; and (ii) the subsequent cyclization of VI is accomplished with a non-nucleophilic base at a temperature of 0° C. to 40° C.

17. The process of claim 1 , wherein the reduction of the nitro group in step (f) is performed with hydrogen in the presence of a metal hydrogenation catalyst and an organic solvent.

18. A process for the preparation of a compound of formula XX

wherein:

R 2 is aryl or heteroaryl, wherein the aromatic rings are optionally substituted by one or two substituents, selected from C 1-7 -alkyl, halogen, CF 3 , OCF 3 , OCH 2 CF 3 , C 1-7 -alkoxy or cyano; or a pharmaceutically suitable acid addition salt thereof, comprising the steps of:

(a) reducing a ketone of the formula (II) wherein X is a halogen atom with an

ketoreductase enzyme to afford the chiral alcohol of the formula (IIIa);

(b) displacing the halogen intramolecularly followed by in situ ring opening of the resulting epoxide IIIb with ethanolamine to afford IVb

(c) introducing a protecting group to afford IVa wherein PG is an amino protecting group;

(d) contacting IVa with R 3 SO 2 X wherein X is a halogen to afford VI

(e) cyclizing VI to afford the morpholine V wherein PG is as defined above

(f) reducing the nitro group to form the chiral 2-(4-aminophenyl) morpholine of the formula I wherein R 1 is a PG;

(g) removing the amino protecting group PG to afford a compound of formula I wherein R 1 is a H; and,

(h) treating I with an ester of formula R 2 COOR 4 wherein R 2 is as above and R 4 is C 1-7 -alkyl or with a carboxylic acid of the formula R 2 COOH to afford a compound of formula XX.

19. A process for the preparation of a compound of formula XXX comprising

wherein:

R 2 is aryl or heteroaryl, wherein the aromatic rings are optionally substituted by one or two substituents, selected from C 1-7 -alkyl, halogen, CF 3 , OCF 3 , OCH 2 CF 3 , C 1-7 -alkoxy or cyano; or a pharmaceutically suitable acid addition salt thereof, comprising the steps of:

(a) reducing a ketone of formula II wherein X is a halogen atom with an

ketoreductase enzyme to afford the chiral alcohol of the formula IIIa;

(b) displacing the halogen intramolecularly followed by in situ ring opening of the

resulting epoxide IIIb with ethanolamine to afford IVb;

(c) introducing a protecting group to afford IVa wherein PG is an amino protecting group;

(d) contacting IVa with R 3 SO 2 X wherein X is a halogen to afford VI

(e) cyclizing VI to afford the morpholine V wherein PG is as defined above

(f) reducing the nitro group to form the chiral 2-(4-aminophenyl) morpholine of the formula I wherein R 1 is a PG;

(g) removing of the amino protecting group PG to afford a compound of formula I wherein R 1 is a H; and,

(h) treating I with R 2 X wherein R 2 is as above and X is halogen to afford a compound of formula XXX.