Process for the preparation of deuterated compounds containing N-alkyl groups

1. A process for preparing a deuterated compound (II) containing at least one structural element of the formula N—C—C, which is not part of an aromatic ring system, and wherein the amount of deuterium at the carbon atom in the alpha position and/or the carbon atom in the beta position of the structural element is at least 1%,

comprising reacting a compound (I) comprising a residue which contains at least one structural element N—C—C, wherein at least one H atom is at each carbon atom of the structural element and the N—C—C element is not part of an aromatic ring system,

with a deuterium source in the presence of a catalyst of formula (2)

1-UH-tetra-Z-cyclopentadienyl-(tetra-Z-2,4-cyclopentadien-1-U)-μ-hydro-tetra-L-diruthenium(II)  (2),

wherein

UH is OH, NHR 5 , or SH;

U is O, NR 5 or S;

R 5 is (C 1 -C 6 )alkyl, phenyl or —CH 2 -phenyl;

Z is, independently of each other, (C 1 -C 6 )alkyl or phenyl, wherein each phenyl is optionally substituted by (C 1 -C 6 )alkyl or phenyl, wherein phenyl is optionally substituted 1 or more times by halogen, and

L is CO, CN or COD.

2. The process according to claim 1 , wherein the structural element in a compound (I) is N—C(H) m —C(H) n wherein m is 1 or 2 and n is 1, 2 or 3.

3. The process according to claim 1 , wherein the structural element in a compound (I) is N—CH 2 —CH 2 .

4. The process according to claim 1 , wherein the residue containing the structural element in compound (I) is —N(C 2-12 )alkylene, —NH(C 2 -C 12 )alkyl, —N((C 1 -C 12 )alkyl)((C 2 -C 12 )alkyl), —(C 2 -C 12 )alkylene-N((C 1 -C 12 )alkyl) 2 , —(C 1 -C 12 )alkylene-N((C 1 -C 12 )alkyl)((C 2 -C 12 )alkyl)) or (C 3 -C 15 )heterocycloalkyl.

5. The process according to claim 1 , wherein compound (I) is a compound of formula (I)

R 1 -L 1 -V-L 2 -W-L 3 -X-L 4 -Y  (I)

wherein

R 1 is

H,

OH,

C(O)—(C 1 -C 6 )alkyl,

C(O)—V,

C(O)OR 8 ,

OC(O)—(C 1 -C 6 )alkyl,

OC(O)NR7R8

OC(O)—V,

C(O)NR 7 R 8 ,

Si—R 7 ,

OSiR 7 ,

NR 7 —C(O)—(C 1 -C 6 )alkyl,

NR 7 —C(O)O(C 1 -C 6 )alkyl,

NR 7 —C(O)—V,

C(O) 2 R 8 ,

NR 7 —C(O)—NR 7 R 8 ,

NR 7 R 8 ,

SR 8 ,

S(O)—(C 1 -C 6 )alkyl,

S(O)—V,

S(O) 2 NR 7 R 8 ,

NR 7 —SO 2 —(C 1 -C 6 )alkyl,

NR 7 —SO 2 —(C 1 -C 6 )alkylene-V,

NR7—SO 2 —V,

S(O) 2 —(C 1 -C 6 )alkyl,

S(O) 2 —OR 8 , or

OS(O) 2 —R 8 ;

R 7 is H, (C 1 -C 12 )alkyl, or phenyl;

R 8 is H, (C 1 -C 12 )alkyl;

L 1 is

a bond,

(C 1 -C 12 )alkylene,

(C 1 -C 6 )alkenylene, or

(C 2 -C 6 )alkynylene;

L 2 , L 3 , or L 4 is independently of each other a group R 2 —R 3 —R 4 wherein

R 2 and R 4 are independently of each other selected from

a bond,

O,

C(O),

C(O)CO,

C(O)NR 7 ,

NR 7 C(O),

N(C(O)R7),

C(O)O,

OC(O),

NR 7 ,

S,

S(O),

S(O) 2 ,

S(O) 2 —O,

OS(O) 2 ,

S(O) 2 NR 7 , or

NR 7 S(O) 2 ;

R 3 is

a bond,

(C 1 -C 12 )alkylene,

(C 1 -C 6 )alkenylene, or

(C 2 -C 6 )alkynylene;

with the proviso that R 2 or R 4 is a bond if R 3 is a bond;

V, W, X and Y are

a bond,

(C 3 -C 8 )cycloalkyl,

(C 5 -C 15 )heteroaryl,

(C 6 -C 10 )aryl, or

(C 3 -C 15 )heterocycloalkyl,

wherein said (C 6 -C 10 )aryl, (C 5 -C 14 )heteroaryl, (C 3 -C 15 )heterocycloalkyl or (C 3 -C 8 )cycloalkyl is optionally substituted one, two, three or four times by a group independently of each other selected from R 9 ;

and wherein Y may also be H,

R 9 is

halogen,

oxo,

OH,

NO 2 ,

CN,

SO 2 —N═CH—N[(C 1 -C 6 )alkyl] 2 ,

SF 5 ,

CF 3 ,

C(NH)(NH 2 ),

PO 3 (R 7 ) 1-3 ,

R 1 ,

L 1 -R 1 ,

O-L 1 -R 1 ,

V,

L1-V, or

O-L 1 -V;

and a V substituent in R 9 may not be further substituted by a V substituent;

wherein in any alkyl or alkylene residue one or more carbon atoms are optionally replaced by O, provided that two oxygens are not directly connected to each other, and wherein any alkyl or alkylene is optionally substituted by one, two or three residues independently of each other selected from

halogen, cyano, hydroxyl, O(C 1 -C 6 )Alkyl, S(C 1 -C 6 )alkyl, phenyl, O-phenyl, benzyl, OC(O)(C 1 -C 6 )alkyl, C(O)(C 1 -C 6 )alkyl, C(O)O(C 1 -C 6 )alkyl or C(O)OH.

6. The process according to claim 5 , wherein R 1 is NR 7 R 8 .

7. The process according to claim 5 , wherein R 7 and R 8 are (C 1 -C 12 )alkyl.

8. The process according to claim 5 , wherein L 1 is a bond or (C 1 -C 6 )alkylene.

9. The process according to claim 5 , wherein R 1 -L 1 is (C 1 -C 12 )alkyl.

10. The process according to claim 5 , wherein one or more of V, W, X or Y contains the structural element N—C—C.

11. The process according to claim 10 , wherein one or more of V, W, X or Y is (C 3 -C 15 )heterocycloalkyl.

12. The process according to claims 10 , wherein one or more of V, W, X or Y is, independently of each other, selected from

13. The process according to claim 5 , wherein R 2 is a bond, O, CO, C(O)O, NH, N(C(O)R 7 ), C(O)NH or NHC(O).

14. The process according to claim 5 , wherein R 3 is a bond, (C 1 -C 6 )alkenylene or (C 1 -C 6 )alkylene optionally substituted, independently of each other, one, two or three times by OH, halogen, C(O)O(C 1 -C 6 )alkyl, OC(O)(C 1 -C 6 )alkyl or optionally substituted phenyl.

15. The process according to claim 5 , wherein R 4 is a bond, O, C(O), C(O)O, OC(O), S(O) 2 , NH, NHC(O) or C(O)NH.

16. The process according to claim 5 , wherein

R1 is H, OH or NR 7 R 8 ;

L1 is a bond or (C 1 -C 6 )alkylene;

V is a bond, (C 6 -C 10 )aryl preferably phenyl, (C 3 -C 8 )cycloalkyl, (C 5 -C 15 )heteroaryl or (C 3 -C 15 )heterocycloalkyl, preferably

each of L2, L3 and L4 is R2-R3-R4, wherein

R2 is a bond, O, S(O)2, C(O), C(O)O, OC(O), NH, NHC(O), N(C(O)R 7 ) or C(O)NH;

R3 is a bond, (C1-C6)alkenylene or (C 1 -C 6 )alkylene optionally substituted one, two or three times by a group selected from (C 1 -C 6 )alkyl, C(O)—(C 1 -C 6 )alkyl, OH, OC(O)—(C 1 -C 6 )alkyl, or (C 6 -C 10 )aryl preferably phenyl, wherein (C 6 -C 10 )aryl is optionally substituted one, two three times by R9;

R4 is a bond, O, S(O) 2 , NH, NHC(O), C(O)NH, C(O) or C(O)O, provided that R2 or R4 is a bond if R3 is a bond;

W and X is, independently of each other, a bond, (C 6 -C 10 )aryl preferably phenyl, (C 3 -C 8 )cycloalkyl, (C 5 -C 15 )heteroaryl or (C 3 -C 15 )heterocycloalkyl, and

Y is H, (C 6 -C 10 )aryl preferably phenyl, (C 3 -C 8 )cycloalkyl, (C 5 -C 15 )heteroaryl or (C 3 -C 15 )heterocycloalkyl;

and any (C 1 -C 6 )alkylene in L1 and R3 is optionally substituted one, two or three times by a group selected from halogen, (C 1 -C 6 )alkyl, C(O)—(C 1 -C 6 )alkyl, C(O)O(C 1 -C 6 )alkyl, OH, OC(O)—(C 1 -C 6 )alkyl, or phenyl, and/or one or more carbon atoms are optionally replaced by O;

and in L1, R3, V, W, X and Y any (C 6 -C 10 )aryl, (C 5 -C 15 )heteroaryl or (C 3 -C 15 )heterocycloalkyl is optionally substituted one, two, or three times by R9.

17. The process according to claim 1 , wherein the catalyst is 1-Hydroxy-tetraphenylcyclopentadienyl-(tetraphenyl-2,4-cyclopentadien-1-one)-μ-hydrotetracarbonyldiruthenium(II).

18. The process according to claim 1 , wherein the catalyst is used in an amount of 1 to 50 mol %.

19. The process according to claim 1 , wherein the amount of deuterium at each carbon atom in the N—C—C structural element is at least 10%.