PROCESS FOR PREPARING BICYCLIC AMINE DERIVATIVES

1 . A process for preparing a bicyclic amine derivative of the formula (Ia) or (Ib),

wherein

A is a 5- or 6-membered ring;

R is hydrogen, halogen, —CN, hydroxyl which optionally carries a protecting group, a group Y′-A 2 -X 1 —, or a group R 1 —W-A 1 -Q-Y-A 2 -X 1 —;

R 1 is hydrogen, C 1 -C 6 -alkyl, C 3 -C 12 -cycloalkyl-C 1 -C 4 -alkyl, halogenated C 1 -C 6 -alkyl, tri-(C 1 -C 4 -alkyl)-silyl-C 1 -C 4 -alkyl, hydroxy-C 1 -C 4 -alkyl, C 1 -C 6 -alkoxy-C 1 -C 4 -alkyl, amino-C 1 -C 4 -alkyl, C 1 -C 6 -alkylamino-C 1 -C 4 -alkyl, di-C 1 -C 6 -alkylamino-C 1 -C 4 -alkyl, C 1 -C 6 -alkylcarbonylamino-C 1 -C 4 -alkyl, C 1 -C 6 -alkyloxycarbonylamino-C 1 -C 4 -alkyl, C 1 -C 6 -alkylaminocarbonylamino-C 1 -C 4 -alkyl, di-C 1 -C 6 -alkylaminocarbonylamino-C 1 -C 4 -alkyl, C 1 -C 6 -alkylsulfonylamino-C 1 -C 4 -alkyl, (optionally substituted C 6 -C 12 -aryl-C 1 -C 6 -alkyl)amino-C 1 -C 4 -alkyl, optionally substituted C 6 -C 12 -aryl-C 1 -C 4 -alkyl, optionally substituted C 3 -C 12 -heterocyclyl-C 1 -C 4 -alkyl, C 3 -C 12 -cycloalkyl, C 1 -C 6 -alkylcarbonyl, C 1 -C 6 -alkoxycarbonyl, halogenated C 1 -C 6 -alkoxycarbonyl, C 6 -C 12 -aryloxycarbonyl, aminocarbonyl, C 1 -C 6 -alkylaminocarbonyl, (halogenated C 1 -C 4 -alkyl)aminocarbonyl, C 6 -C 12 -arylaminocarbonyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, optionally substituted C 6 -C 12 -aryl, hydroxy, C 1 -C 6 -alkoxy, halogenated C 1 -C 6 -alkoxy, C 1 -C 6 -hydroxyalkoxy, C 1 -C 6 -alkoxy-C 1 -C 4 -alkoxy, amino-C 1 -C 4 -alkoxy, C 1 -C 6 -alkylamino-C 1 -C 4 -alkoxy, di-C 1 -C 6 -alkylamino-C 1 -C 4 -alkoxy, C 1 -C 6 -alkylcarbonylamino-C 1 -C 4 -alkoxy, C 6 -C 12 -arylcarbonylamino-C 1 -C 4 -alkoxy, C 1 -C 6 -alkoxycarbonylamino-C 1 -C 4 -alkoxy, C 6 -C 12 -aryl-C 1 -C 4 -alkoxy, C 1 -C 6 -alkylsulfonylamino-C 1 -C 4 -alkoxy, (halogenated C 1 -C 6 -alkyl)sulfonylamino-C 1 -C 4 -alkoxy, C 6 -C 12 -arylsulfonylamino-C 1 -C 4 -alkoxy, (C 6 -C 12 -aryl-C 1 -C 6 -alkyl)sulfonylamino-C 1 -C 4 -alkoxy, C 3 -C 12 -heterocyclylsulfonylamino-C 1 -C 4 -alkoxy, C 3 -C 12 -heterocyclyl-C 1 -C 4 -alkoxy, C 6 -C 12 -aryloxy, C 3 -C 12 -heterocyclyloxy, C 1 -C 6 -alkylthio, halogenated C 1 -C 6 -alkylthio, C 1 -C 6 -alkylamino, (halogenated C 1 -C 6 -alkyl)amino, di-C 1 -C 6 -alkylamino, di-(halogenated C 1 -C 6 -alkyl)amino, C 1 -C 6 -alkylcarbonylamino, (halogenated C 1 -C 6 -alkyl)carbonylamino, C 6 -C 12 -arylcarbonylamino, C 1 -C 6 -alkylsulfonylamino, (halogenated C 1 -C 6 -alkyl)sulfonylamino, C 6 -C 12 -arylsulfonylamino or optionally substituted C 3 -C 12 -heterocyclyl;

W is —NR 8 — or a bond;

A 1 is optionally substituted C 1 -C 4 -alkylene or a bond;

Q is —S(O) 2 — or —C(O)—;

Y is —NR 9 — or a bond;

Y′ is Y which optionally carries a protecting group;

A 2 is optionally substituted C 1 -C 4 -alkylene, C 1 -C 4 -alkylene-CO—, —CO—C 1 -C 4 -alkylene, C 1 -C 4 -alkylene-O—C 1 -C 4 -alkylene, C 1 -C 4 -alkylene-NR 10 —C 1 -C 4 -alkylene, optionally substituted C 2 -C 4 -alkenylene, optionally substituted C 2 -C 4 -alkynylene, optionally substituted C 6 -C 12 -arylene, optionally substituted C 6 -C 12 -heteroarylene or a bond;

X 1 is —O—, —NR 11 —, —S—, optionally substituted C 1 -C 4 -alkylene, optionally substituted C 2 -C 4 -alkenylene, optionally substituted C 2 -C 4 -alkynylene;

R 2 is hydrogen, halogen, C 1 -C 6 -alkyl, halogenated C 1 -C 4 -alkyl, hydroxy-C 1 -C 4 -alkyl, —CN, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, optionally substituted C 6 -C 12 -aryl, hydroxy, C 1 -C 6 -alkoxy, halogenated C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxycarbonyl, C 2 -C 6 -alkenyloxy, C 6 -C 12 -aryl-C 1 -C 4 -alkoxy, C 1 -C 6 -alkylcarbonyloxy, C 1 -C 6 -alkylthio, C 1 -C 6 -alkylsulfinyl, C 1 -C 6 -alkylsulfonyl, aminosulfonyl, amino, C 1 -C 6 -alkylamino, C 2 -C 6 -alkenylamino, nitro or optionally substituted C 3 -C 12 -heterocyclyl, or two radicals R 2 together with the ring atoms of A to which they are bound form a 5- or 6-membered ring;

A 3 is —O—, —S—, —NR 16 —, a bond or C 1 -C 2 -alkylene;

R 3 is hydrogen, halogen, C 1 -C 6 -alkyl or C 1 -C 6 -alkoxy, or two radicals R 3 together with the carbon atom to which they are attached form a carbonyl group;

R 4a is C 1 -C 4 -alkylcarbonyl, (halogenated C 1 -C 4 -alkyl)carbonyl or C 6 -C 12 -arylcarbonyl;

R 4b is hydrogen or C 1 -C 6 -alkyl; or

R 4a , R 4b

together are C 2 -C 10 -alkylenecarbonyl;

X 2 is —O—, —NR 6 —, >CR 12a R 12b or a bond;

X 3 is —O—, —NR 7 —, —S—, >CR 13a R 13b or a bond;

R 5 is optionally substituted C 6 -C 12 -aryl, optionally substituted C 3 -C 12 -cycloalkyl or optionally substituted C 3 -C 12 -heterocyclyl;

R 6 is hydrogen or C 1 -C 6 -alkyl;

R 7 is hydrogen or C 1 -C 6 -alkyl;

R 8 is hydrogen or C 1 -C 6 -alkyl;

R 9 is hydrogen, C 1 -C 6 -alkyl, C 3 -C 12 -cycloalkyl, amino-C 1 -C 6 -alkyl, optionally substituted C 6 -C 12 -aryl-C 1 -C 4 -alkyl or C 3 -C 12 -heterocyclyl; or

R 9 , R 1

together are C 1 -C 4 -alkylene; or

R 9 is C 1 -C 4 -alkylene that is bound to a carbon atom in A 2 and A 2 is C 1 -C 4 -alkylene or to a carbon atom in X 1 and X 1 is C 1 -C 4 -alkylene;

R 10 is hydrogen, C 1 -C 6 -alkyl or C 1 -C 6 -alkylsulfonyl;

R 11 is hydrogen or C 1 -C 6 -alkyl, or

R 9 , R 11

together are C 1 -C 4 -alkylene,

R 12a is hydrogen, optionally substituted C 1 -C 6 -alkyl, C 1 -C 6 -alkylamino-C 1 -C 4 -alkyl, di-C 1 -C 6 -alkylamino-C 1 -C 4 -alkyl, C 3 -C 12 -heterocyclyl-C 1 -C 6 -alkyl, optionally substituted C 6 -C 12 -aryl or hydroxy;

R 12b is hydrogen or C 1 -C 6 -alkyl, or

R 12a , R 12b

together are carbonyl or optionally substituted C 1 -C 4 -alkylene, wherein one —CH 2 — of C 1 -C 4 -alkylene may be replaced by an oxygen atom or —NR 14 —;

R 13a is hydrogen, optionally substituted C 1 -C 6 -alkyl, C 1 -C 6 -alkylamino-C 1 -C 4 -alkyl, di-C 1 -C 6 -alkylamino-C 1 -C 4 -alkyl, C 3 -C 12 -heterocyclyl-C 1 -C 6 -alkyl, optionally substituted C 6 -C 12 -aryl or hydroxy;

R 13b is hydrogen or C 1 -C 6 -alkyl, or

R 13a , R 13b

together are carbonyl or optionally substituted C 1 -C 4 -alkylene, wherein one —CH 2 — of C 1 -C 4 -alkylene may be replaced by an oxygen atom or —NR 15 —;

R 14 is hydrogen or C 1 -C 6 -alkyl;

R 15 is hydrogen or C 1 -C 6 -alkyl; and

R 16 is hydrogen, C 1 -C 6 -alkyl, C 3 -C 12 -cycloalkyl-C 1 -C 4 -alkyl, halogenated C 1 -C 4 -alkyl, hydroxy-C 1 -C 4 -alkyl, C 1 -C 6 -alkoxy-C 1 -C 4 -alkyl, amino-C 1 -C 4 -alkyl, CH 2 CN, C 6 -C 12 -aryl-C 1 -C 4 -alkyl, C 3 -C 12 -cycloalkyl, —CHO, C 1 -C 4 -alkylcarbonyl, (halogenated C 1 -C 4 -alkyl)carbonyl, C 6 -C 12 -arylcarbonyl, C 1 -C 4 -alkoxycarbonyl, C 6 -C 12 -aryloxycarbonyl, C 1 -C 6 -alkylaminocarbonyl, C 2 -C 6 -alkenyl, —C(═NH)NH 2 , —C(═NH)NHCN, C 1 -C 6 -alkylsulfonyl, C 8 -C 12 -arylsulfonyl, amino, —NO or C 3 -C 12 -heterocyclyl,

or a salt thereof;

comprising the rhodium-catalyzed asymmetric hydrogenation of an enamine of the formula (II),

wherein A, A 3 , R, R 2 , R 3 , R 4a , R 4b , R 5 , X 2 and X 3 are as defined above,

or of a salt thereof;

in the presence of a chiral ligand, wherein the chiral ligand is a chiral phosphine ligand.

2 . The process as claims in claim 1 , wherein the rhodium catalyst is a rhodium(I) compound.

3 . The process as claimed in claim 2 , wherein the rhodium(I) compound is of formula (IIIa), (IIIb) or (IIIc),

[RhLi 1 An] 2   (IIIa)

[RhLi 2 2 An] n   (IIIb)

[RhLi 1 2 An]  (IIIc)

wherein

Li 1 is C 5 -C 12 -alkadiene, C 5 -C 12 -cycloalkadiene or C 5 -C 12 -bicycloalkadiene;

Li 2 is C 2 -C 12 -alkene or C 5 -C 8 -cycloalkene;

n is 1 or 2; and

An is halide, tetrafluoroborate, trifluoromethanesulfonate or acetylacetonate.

4 . The process as claimed in claim 3 , wherein the rhodium(I) compound is of formula (IIIa) with Li 1 being C 6 -C 10 -cycloalkadiene or C 5 -C 12 -bicycloalkadiene, in particular 1,5-cyclooctadiene or norbornadiene, and An being chloride.

5 . The process as claimed in claim 1 , wherein the chiral phosphine ligand is a chiral diphosphine ligand.

6 . The process as claimed in claim 5 , wherein the diphosphine ligand comprises a ferrocene moiety.

7 . The process as claimed in claim 6 , wherein the diphosphine ligand is of the formula (IVa), (IVb), (IVc) or (IVd),

wherein

R 18 , R 19 , R 21 , and R 21 , independently of each other, are selected from the group consisting of C 1 -C 12 -alkyl, C 5 -C 7 -cycloalkyl, C 3 -C 6 -hetaryl and C 6 -C 12 -aryl, wherein C 3 -C 6 -hetaryl and C 6 -C 12 -aryl are unsubstituted or carry 1, 2, 3, 4 or 5 substituents selected from the group consisting of C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy and di-C 1 -C 4 -alkylamine.

8 . The process as claimed in claim 7 , wherein the diphosphine ligand is of the formula (IVa) or (IVb) with R 18 and R 19 having the same meaning and R 20 and R 21 having the same meaning.

9 . The process as claimed in claim 8 , wherein R 18 and R 19 are both C 1 -C 12 -alkyl and R 20 and R 21 are both optionally substituted C 3 -C 5 -hetaryl or optionally substituted C 6 -C 10 -aryl.

10 . The process as claimed in claim 9 , wherein R 18 and R 19 are both tert-butyl and R 20 and R 21 are both 1-naphthyl or 2-furyl.

11 . The process as claimed in claim 1 , which further comprises:

(a) providing a ketone of the formula (V),

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

and

(b) converting the ketone of the formula (V) into the enamine of the formula (II), wherein A, A 3 , R, R 2 , R 3 , R 4a , R 4b , R 5 , X 1 , and X 2 are as defined in claim 1 .

12 . The process as claimed in claim 1 , wherein the bicyclic amine derivative is a compound of the formula (Ia) and the chiral phosphine ligand is the diphosphine of formula (IVa), as defined in claim 1 .

13 . (canceled)

14 . (canceled)

15 . The process as claimed in claim 1 , wherein, in formulae (Ia), (Ib) and (II), R 4a is C 1 -C 4 -alkylcarbonyl or (halogenated C 1 -C 4 -alkyl)carbonyl and R 4b is hydrogen or C 1 -C 6 -alkyl;

or R 4a , R 4b together are C 2 -C 6 -alkylenecarbonyl.

16 . The process as claimed in claim 1 , further comprising crystallizing from heptane, methanol or a mixture of heptane and methanol the compound of formula (Ia) or (Ib), wherein A is a benzene ring, R is —OCH 3 , R 2 is hydrogen, A 3 is R 3 is hydrogen, R 4a is ethoxycarbonyl, R 4b is hydrogen, X 2 is X 3 is a bond, and R 5 is phenyl.

17 . A bicyclic amine derivative of the formula (Ia) or the formula (Ib),

wherein

A, A 3 , R, R 2 , R 3 , R 4a , R 4b , R 5 , X 2 and X 3 are as defined in claim 1 .

18 . An enamine of the formula (II),

wherein A, A 3 , R, R 2 , R 3 , R 4a , R 4b , R 5 , X 2 and X 3 are as defined in claim 1 .

19 . A ketone of the formula (V′),

wherein A, A 3 , R 2 , R 3 , R 5 , X 2 and X 3 are as defined in claim 1 , and R is halogen, methoxymethoxy, methoxyethoxymethoxy, tert-butyloxy, allyloxy, 2-tetrapyranyloxy, benzyloxy, acetyloxy, pivaloyloxy, benzoyloxy, tert-butyldimethylsilyloxy or tert-butyldiphenylsilyloxy, preferably halogen and in particular bromine.

20 . The ketone of claim 19 having the formula (V′-1),

21 . The bicyclic amine derivative of claim 17 having the formula (Ia′) or the formula (Ib′),

wherein

R a is halogen, in particular bromine, or C 1 -C 4 -alkoxy, in particular methoxy;

R 4a is C 1 -C 4 -alkylcarbonyl, in particular ethylcarbonyl;

R 4b is hydrogen; or

R 4a , R 4b together are C 2 -C 6 -alkylenecarbonyl.

22 . The enamine of claim 18 having the formula (II′),