Process for the preparation of chiral 2-aryl morpholines

Patent metadata

Field	Value
Publication number	US-2016289718-A1
Application number	US-201615175779-A
Country	US
Kind code	A1
Filing date	Jun 7, 2016
Priority date	Dec 11, 2013
Publication date	Oct 6, 2016
Grant date	—

Abstract

The invention relates to a novel process for the preparation of chiral 2-(4-aminophenyl) morpholines of the formula

wherein R 1 is hydrogen an amino protecting group.

The chiral 2-(4-aminophenyl) morpholines of the formula I are key intermediates for the preparation of compounds that have a good affinity to the trace amine associated receptors (TAARs).

First claim

We claim:

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

(I) wherein R 1 is hydrogen or an amino protecting group (PG) said process comprising the steps of:
(b) reducing a ketone of the formula II wherein X is a halogen atom with an

oxidoreductase 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

(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 PG is Boc or benzyl.

4 . The process of claim 1 , wherein the enzymatic reduction in step (a) is performed with an oxidoreductase that 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 co-substrate 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 has the (R) or the (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 Mb 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

oxidoreductase enzyme to afford the chiral alcohol of the formula (Ma);
(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 i

Assignees

• Hoffmann La Roche

Inventors

• Trussardi Rene
• Iding Hans

Classifications

• A61K31/5375

  1,4-Oxazines, e.g. morpholine · CPC title

• C12P7/02

  containing a hydroxy group · CPC title

• C12P13/008

  containing a N-O bond, e.g. nitro (-NO2), nitroso (-NO) · CPC title

• Y02P20/55

  Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups · CPC title

• C12P41/00

  Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture · CPC title