Process for the preparation of optically pure fesoterodine derivatives

1. A compound of formula (IV) or (IV′)

wherein, R 2 and R 3 , independently of one another, are selected from H and C 1 -C 6 alkyl, or together form a ring of 3 to 7 members with the nitrogen to which they are bound; R 4 is hydrogen or a hydroxyl protecting group; and R 6 is a chiral group;

or a solvate or salt thereof.

2. A compound according to claim 1 , wherein R 6 is the residue of (+)-menthol or (−)-menthol.

3. A compound according to claim 1 selected from the group formed by

or a solvate thereof.

4. A compound according to claim 3 selected from the group formed by

or a solvate thereof.

5. A process for preparing a compound of formula (IV) or (IV′) as defined in claim 1 , or a solvate or salt thereof, the process comprising reacting a compound of formula (II), or a solvate or salt thereof,

wherein

R 2 , R 3 and R 4 are as defined in claim 1 ; and

R 5 is selected from —C(O)Cl, —C(O)Br, —C(O)OH, —C(O)OR′, —C(O)OCOR′ and CN, wherein R′ is selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, aryl and arylalkyl;

with an optically active chiral alcohol of formula (III)

R 6 —OH  (III)

wherein R 6 is as defined in claim 1 .

6. The process according to claim 5 , wherein the compound of formula (IV) or (IV′), or the solvate or salt thereof, is further (b) separated; and (c) converted into a compound of formula (I) or (I′), respectively, or a solvate or salt thereof

wherein

R 1 is C 1 -C 6 alkyl; and

R 2 and R 3 as defined in claim 5 .

7. The process according to claim 6 , wherein the chiral alcohol of formula (III) is a chiral secondary alcohol wherein the hydroxyl group is attached directly to a chiral centre.

8. The process according to claim 7 , wherein the chiral alcohol of formula (III) is selected from (D)-(+)-menthol, (L)-(−)-menthol and (S)-1-phenylethanol.

9. The process according to claim 8 , wherein the chiral alcohol of formula (III) is selected from (D)-(+)-menthol and (L)-(−)-menthol.

10. The process according to claim 6 , wherein R 2 and R 3 are independently selected from C 1 -C 6 alkyl.

11. The process according to claim 9 , wherein R 1 , R 2 and R 3 are isopropyl.

12. The process according to claim 6 , wherein R 4 is hydrogen.

13. The process according to claim 6 , wherein R 5 is selected from —C(O)Cl and —C(O)Br.

14. The process according to claim 6 , wherein the compound of formula (IV) or (IV′), or a solvate or salt thereof, is converted into a compound of formula (I) or (I′), or a solvate or salt thereof, by a process comprising:

(a) subjecting compound of formula (IV) or (IV′), or a solvate or salt thereof, to a reduction reaction to obtain a compound of formula (V) or (V′), respectively, or a solvate or salt thereof,

wherein R 2 , R 3 and R 4 are as defined in claim 5 ;

(b) if R 4 is a hydroxyl protecting group, deprotecting it either before or after step (a); and

(c) subjecting a compound of formula (V) or (V′), or a solvate or salt thereof, wherein R 4 is hydrogen to an esterification reaction with a compound of formula (VI)

wherein

R 1 is as defined in claim 6 , and

X is selected from Cl, Br, OH, OR″ and OCOR″, wherein R″ is selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, aryl and arylalkyl;

to obtain a compound of formula (I) or (I′), or a solvate or salt thereof;

or by a process comprising:

(a) subjecting compound of formula (IV) or (IV′), or a solvate or salt thereof, to a hydrolysis reaction to obtain a compound of formula (VII) or (VII′), or a solvate or salt thereof,

wherein R 2 , R 3 and R 4 are as defined in claim 5 ;

(b) if R 4 is a hydroxyl protecting group, deprotecting it either before or after step (a);

(c) subjecting a compound of formula (VII) or (VII′), or a solvate or salt thereof, wherein R 4 is hydrogen to an esterification reaction with a compound of formula (VI)

wherein

R 1 is as defined in claim 6 , and

X is selected from Cl, Br, OH, OR″ and OCOR″, wherein R″ is selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, aryl and arylalkyl,

to obtain a compound of formula (VIII) or (VIII′), or a solvate or salt thereof,

wherein R 1 , R 2 and R 3 are as defined in claim 5 ; and

(d) subjecting compound of formula (VIII) or (VIII′), or a solvate or salt thereof, to a chemoselective reduction to obtain a compound of formula (I) or (I′) or a solvate or salt thereof.

15. The process according to claim 6 , wherein the compound of formula (I) or (I′) in the free amine form is further converted into a salt thereof by treatment with an acid.

16. The process according to claim 6 , wherein the compound of formula (I) or a salt or solvate thereof is selected from the group consisting of Fesoterodine, Fesoterodine fumarate, Fesoterodine hydrochloride, and a solvate thereof.

17. The process according to claim 6 , wherein the compound of formula (I) or a salt or solvate thereof is selected from the group consisting of Fesoterodine, and an enantiomer, solvate or salt thereof, which comprises:

(a) reacting a compound of formula (IIa), or a solvate or salt thereof,

with an optically active chiral alcohol of formula (III)

R 6 —OH  (III)

to yield a compound of formula (IVa) and the diastereoisomer, or a solvate or salt thereof,

wherein R 6 is as defined in claim 5 ;

(b) separating the compound of formula (IVa) or the diastereoisomer, or a salt or solvate thereof; and

(c) converting the compound of formula (IVa), or the diastereoisomer, solvate or salt thereof, into a compound of formula (I), or an enantiomer, solvate or salt thereof.

18. The process according to claim 17 , wherein the compound of formula (IVa), or a diastereoisomer, solvate or salt thereof, is converted into Fesoterodine, or an enantiomer, solvate or salt thereof, by a process comprising:

(a) subjecting compound of formula (IVa), or a diastereoisomer, solvate or salt thereof, to a reduction reaction to obtain a compound of formula (Va), or an enantiomer, solvate or salt thereof,

(b) subjecting compound of formula (Va), or an enantiomer, solvate or salt thereof, to an esterification reaction with a compound of formula (VIa)

wherein X is selected from Cl, Br, OH, OR″ and OCOR″, wherein R″ is selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, aryl and arylalkyl;

or by a process comprising:

(a) subjecting compound of formula (IVa), or a diastereoisomer, solvate or salt thereof, to a hydrolysis reaction to obtain a compound of formula (VIIa), or an enantiomer, solvate or salt thereof,

(b) subjecting compound of formula (VIIa), or an enantiomer, solvate or salt thereof, to an esterification reaction with a compound of formula (VIa)

wherein X is selected from Cl, Br, OH, OR″ and OCOR″, wherein R″ is selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, aryl and arylalkyl,

to obtain a compound of formula (VIIIa), or an enantiomer, solvate or salt thereof,

(c) subjecting compound of formula (VIIIa), or an enantiomer, solvate or salt thereof, to a chemoselective reduction.

19. The process according to claim 17 , wherein Fesoterodine in the free amine form is further converted into a salt thereof.

20. The process according to claim 19 , wherein Fesoterodine is further converted into Fesoterodine fumarate, Fesoterodine hydrochloride, or a solvate thereof.

21. A compound of formula (IIa)

or a solvate or salt thereof.

22. The process according to claim 6 , wherein the compound of formula (I) or a salt or solvate thereof is selected from a group consisting of Fesoterodine hydrochloride monohydrate and a solvate thereof.

23. The process according to claim 19 , wherein Fesoterodine is further converted into Fesoterodine hydrochloride monohydrate, or a solvate thereof.