Process for the preparation of enantiomerically and diastereomerically enriched cyclobutane amines and amides

1. A process for the preparation of enantiomerically and diastereomerically enriched cyclobutane amides comprising

(a) reducing the nitrile moiety of a compound of formula (I) to an aldehyde

wherein A is selected from aryl, heteroaryl, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl and C 3 -C 7 -cycloalkyl, which aryl, heteroaryl, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl and C 3 -C 7 -cycloalkyl are unsubstituted or substituted with one or more substituents independently selected from halogen, cyano, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkoxy, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 1 -C 6 -alkylsulfanyl, C 1 -C 6 -haloalkylsulfanyl, C 1 -C 6 -alkylsulfinyl, C 1 -C 6 -haloalkylsulfinyl, C 1 -C 6 -alkylsulfonyl, C 1 -C 6 -haloalkylsulfonyl, C 2 -C 6 -haloalkenyl and C 2 -C 6 -haloalkynyl;

wherein the reduction of the nitrile moiety of the compound of formula (I) is carried out via partial hydrogenation to the corresponding intermediate imine applying H 2 and a metal hydrogenation catalyst, followed by subsequent hydrolysis to the compound of formula (II)

then

(b) reacting the compound of formula (II) in the presence of a suitable Lewis acid to obtain a compound of formula (III)

wherein * indicates a stereocentre, then

(c) reacting a compound of formula (III) with an ammonium salt and H 2 in presence of a chiral transition metal catalyst to obtain an enantiomerically and diastereomerically enriched amine of formula (IV)

wherein * indicates a stereocentre, and then

further reacting the amine of formula (IV) with a compound of formula (X)

wherein Y is a suitable leaving group selected from OH, OR or halogen, R is C 1 -C 6 -alkyl, and E is selected from aryl, heteroaryl, hydrogen, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl and C 3 -C 7 -cycloalkyl which aryl, heteroaryl, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl and C 3 -C 7 -cycloalkyl are unsubstituted or substituted with one or more substituents independently selected from halogen, cyano, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkoxy, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 1 -C 6 -alkylsulfanyl, C 1 -C 6 -haloalkylsulfanyl, C 1 -C 6 -alkylsulfinyl, C 1 -C 6 -haloalkylsulfinyl, C 1 -C 6 -alkylsulfonyl, C 1 -C 6 -haloalkylsulfonyl, C 2 -C 6 -haloalkenyl and C 2 -C 6 -haloalkynyl;

so as to form the enantiomerically and diastereomerically enriched amide of formula (VII)

2. The process according to claim 1 , wherein

A and E are selected from aryl and heteroaryl, which aryl and heteroaryl are unsubstituted or substituted with one or more substituents independently selected from halogen, cyano, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkoxy and C 1 -C 6 -haloalkoxy.

3. The process according to claim 1 , wherein

A is phenyl and E is heteroaryl, which phenyl and heteroaryl are unsubstituted or substituted with one or more substituents independently selected from halogen, cyano, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkoxy and C 1 -C 6 -haloalkoxy.

4. The process according to claim 1 , wherein the compound of formula (II) is reacted in step (b) in the presence of a Lewis acid selected from AlCl 3 and GaCl 3 .

5. The process according to claim 4 , wherein

1.0-1.5 mole equivalents of AlCl 3 or GaCl 3 relative to the compound of formula (II) are added in step (b).

6. The process according to claim 1 , wherein the chiral transition metal catalyst in step (c) comprises a transition metal selected from Ru, Rh, Ir and Pd, and a chiral ligand with a bidentate phosphor of the general formula (VIII)

wherein Z is a linking group and R 1 , R 2 , R 3 and R 4 are independently selected from aryl, heteroaryl, C1-C6-alkyl and C 3 -C 6 -cycloalkyl, each of which is unsubstituted or substituted with one or more substituents independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl and halogen.

7. The process according to claim 6 , wherein

the linking group Z is selected from (R and S)-1,1′-binaphthyl, (R and S)-4,4′-bi-1, 3-benzodioxole, (R and S)-2, 2′, 6,6′-tetramethoxy-3, 3′-bipyridine, (R and S)-6,6′-dimethoxy-1, 1′-biphenyl, (R and S)-4,4′, 6,6′ tetramethoxy-1, 1′-biphenyl, 2, 2′-bis-[(R)-cx-(dimethylamino)benzyl]ferrocene, ferrocenyl methyl, ferrocene, benzene and ethyl.

8. The process according to claim 6 , wherein the chiral ligand is selected from

(R)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl,

(R)-2,2′-bis(di-p-tolylphosphino)-1,1′-binaphthyl,

(R)-2,2′-bis[di(3,5-xylyl)phosphino]-1,1′-binaphthyl,

(R)-5,5′-bis(diphenylphosphino)-4,4′-bi-1,3-benzodioxole,

(R)-5,5′-bis(di[3,5-xylyl]phosphino)-4,4′-bi-1,3-benzodioxole,

(R)-5,5′-bis[di(3,5-di-tert-butyl-4-methoxyphenyl)phosphino]-4,4′-bi-1,3-benzodioxole,

(S)-1,13-bis(diphenylphosphino)-7,8-dihydro-6H-dibenzo[f,h][1,5]dioxin,

(R)-2,2′,6,6′-tetramethoxy-4,4′-bis(di(3,5-xylyl)phosphino)-3,3′-bipyridine,

(R)-2,2′-bis(diphenylphosphino)-6,6′-dimethoxy-1,1′-biphenyl,

(R)-2,2′-bis(diphenylphosphino)-4,4′,6,6′-tetramethoxy-1,1′-biphenyl,

(R)-6,6′-bis(diphenylphosphino)-2,2′,3,3′-tetrahydro-5,5′-bi-1,4-benzodioxin,

(R)-(+)-2,2′-bis(diphenylphosphino)-5,5′,6,6′,7,7′,8,8′-octahydro-1,1′-binaphthyl,

(R)-(+)-2,2′-bis(di-3,5-xylylphosphino)-5,5′,6,6′,7,7′,8,8′-octahydro-1,1′-binaphthyl,

(R)-5,5′-bis(diphenylphosphino)-2,2,2′,2′-tetrafluoro-4,4′-bi-1,3-benzodioxole,

(S)-1-[(S)-1-[di(3,5-xylyl)phosphino]ethyl]-2-[2-[di(3,5-xylyl)phosphino]phenyl]ferrocene, and

(S)-1-[(S)-1-[bis[3,5-bis(trifluoromethyl)phenyl]phosphino]ethyl]-2-[2-(diphenylphosphino)phenyl]ferrocene.

9. The process according to claim 6 , wherein

the chiral transition metal catalyst is selected from [RuCl(p-cymene)((S)-DM-SEGPHOS)]Cl, [RuCl(p-cymene)((R)-DM-SEGPHOS)]Cl, [NH 2 Me 2 ][(RuCl((R)-xylbinap)) 2 (u-Cl) 3 ], [NH 2 Me 2 ][(RuCl((S)-xylbinap)) 2 (u-Cl) 3 ], Ru(OAc) 2 [(R)-binap], Ru(OAc) 2 [(S)-binap], Ru(OAc) 2 [(R)-xylbinap], Ru(OAc) 2 [(S)-xylbinap], RuCl 2 [(R)-xylbinap][(R)-daipen], RuCl 2 [(S)-xylbinap][(S)-daipen], RuCl 2 [(R)-xylbinap][(R,R)-dpen] and RuCl 2 [(S)-xylbinap][(S,S)-dpen].

10. A process for the preparation of a compound of formula (III)

wherein A is as defined in claim 1 and * indicates a stereocentre, comprising reacting a compound of formula (II)

with a suitable Lewis acid.

11. A process for the preparation of a compound of formula (III)

wherein A is as defined in claim 1 and * indicates a stereocentre, comprising reacting a compound of formula (II)

with a Lewis acid selected from AlCl 3 and GaCl 3 .

12. The process according to claim 11 , wherein 1.0-1.5 mole equivalents of AlCl 3 or GaCl 3 relative to the compound of formula (II) is added.

13. The process according to claim 10 , wherein the compound of formula (III)

wherein A is selected from aryl, heteroaryl, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl and C 3 -C 7 -cycloalkyl, which aryl, heteroaryl, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl and C 3 -C 7 -cycloalkyl are unsubstituted or substituted with one or more substituents independently selected from halogen, cyano, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkoxy, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 1 -C 6 -alkylsulfanyl, C 1 -C 6 -haloalkylsulfanyl, C 1 -C 6 -alkylsulfinyl, C 1 -C 6 -haloalkylsulfinyl, C 1 -C 6 -alkylsulfonyl, C 1 -C 6 -haloalkylsulfonyl, C 2 -C 6 -haloalkenyl and C 2 -C 6 -haloalkynyl and * indicates a stereocentre,

is further reacted with an ammonium salt and H 2 in presence of a chiral transition metal catalyst to obtain an enantiomerically and diastereomerically enriched amine of formula (IV)

wherein * indicates a stereocentre, and then

further reacting the amine of formula (IV) with a compound of formula (X)

wherein Y is a suitable leaving group selected from OH, OR or halogen, R is C 1 -C 6 -alkyl, and E is selected from aryl, heteroaryl, hydrogen, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl and C 3 -C 7 -cycloalkyl which aryl, heteroaryl, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl and C 3 -C 7 -cycloalkyl are unsubstituted or substituted with one or more substituents independently selected from halogen, cyano, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkoxy, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 1 -C 6 -alkylsulfanyl, C 1 -C 6 -haloalkylsulfanyl, C 1 -C 6 -alkylsulfinyl, C 1 -C 6 -haloalkylsulfinyl, C 1 -C 6 -alkylsulfonyl, C 1 -C 6 -haloalkylsulfonyl, C 2 -C 6 -haloalkenyl and C 2 -C 6 -haloalkynyl;

so as to form the enantiomerically and diastereomerically enriched amide of formula (VII)

14. The process according to claim 13 , wherein the chiral transition metal catalyst comprises a transition metal selected from Ru, Rh, Ir and Pd, and a chiral ligand with a bidentate phosphor of the general formula (VIII)

wherein Z is a linking group and R 1 , R 2 , R 3 and R 4 are independently selected from aryl, heteroaryl, C 1 -C 6 -alkyl and C 3 -C 6 -cycloalkyl, each of which is unsubstituted or substituted with one or more substituents independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl and halogen.

15. A process for the preparation of a compound of formula (V)

wherein A is as defined in claim 1 , which comprises reacting a compound of formula (II)

in the presence of a Lewis acid selected from AlCl 3 and GaCl 3 to obtain a compound of formula (III)

and further reacting the compound of formula (III) with acetonitrile and a suitable additive, wherein the additive is selected from acyl chlorides, anhydrides or esters.

16. The process according to claim 1 , wherein Y is chloro.

17. The process according to claim 4 , wherein the Lewis acid is AlCl 3 .

18. The process according to claim 6 , wherein the transition metal is Ru.

19. The process according to claim 7 , wherein the linking group Z is (R and S)-1,1′-binaphthyl.

20. The process according to claim 11 , wherein the Lewis acid is AlCl 3 .

21. The process according to claim 13 , wherein Y is chloro.

22. The process according to claim 15 , wherein the Lewis acid is AlCl 3 .

23. The process according to claim 15 , wherein the additive is selected from acetyl chloride, isopropenyl acetate, 4-methoxybenzoyl chloride and p-anisic anhydride.