Functionalized pyridine N-oxides and processes for the preparation of the same

1. A process for the preparation of a 2-substituted-5-(1-alkylthio)alkyl-pyridine N-oxide according to formula (I),

wherein

L represents a single bond or R 1 , S and L taken together represent a 4-, 5- or 6-membered ring;

R 1 represents (C 1 -C 4 ) alkyl;

R 2 and R 3 individually represent hydrogen, methyl, ethyl, fluoro, chloro or bromo;

n is an integer from 0-3; and

Y represents (C 1 -C 4 ) haloalkyl;

in which:

i) an enamine according to formula (II)

wherein

R 1 , R 2 , R 3 , L, and n are as previously defined, and R 4 and R 5 independently represent C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 1 -C 8 arylalkyl, C 1 -C 8 haloalkyl, C 1 -C 8 alkoxyalkyl, C 1 -C 8 alkylaminoalkyl, aryl or heteroaryl or R 4 and R 5 taken together with N represent a 5- or 6-membered saturated or unsaturated ring is condensed with an α,β-unsaturated ketone according to formula (III)

wherein

Y is as previously defined; and

X 1 represents halogen, OR 6 , OSO 2 R 6 , SR 6 , SOR 6 , SO 2 R 6 or NR 7 R 8 , where R 6 represents hydrogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 1 -C 8 arylalkyl, C 1 -C 8 haloalkyl, C 1 -C 8 alkoxyalkyl, C 1 -C 8 alkylaminoalkyl, aryl or heteroaryl, and R 7 and R 8 independently represent hydrogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 1 -C 8 arylalkyl, C 1 -C 8 haloalkyl, C 1 -C 8 alkoxyalkyl, C 1 -C 8 alkylaminoalkyl, aryl or heteroaryl or R 7 and R 8 taken together with N represent a 5- or 6-membered saturated or unsaturated ring;

to provide an intermediate compound according to formula (IV)

wherein

R 1 , R 2 , R 3 , R 4 , R 5 , L and n are as previously defined; and

ii) the intermediate compound according to formula (IV) is cyclized using an amine nucleophile according to formula (V)

H 2 N—X 2   (V)

wherein X 2 represents hydroxyl.

2. The process of claim 1 , wherein cyclization of the intermediate compound according to formula (IV) is performed under refluxing conditions.

3. The process of claim 2 , wherein the refluxing conditions include a temperature in the range of 50° C. to 90° C.

4. The process of claim 1 , wherein the amine nucleophile is hydroxylamine.

5. The process of claim 4 , wherein the hydroxylamine is in the form hydroxylamine hydrochloride.

6. The process of claim 5 , wherein the cyclization further includes using a non-nucleophilic base.

7. The process of claim 6 , wherein the non-nucleophilic base is triethylamine.

8. The process of claim of claim 1 , wherein the enamine according to formula (II) is condensed with the α,β-unsaturated ketone according to formula (III) at a temperature from −20° C. to 35° C.

9. The process of claim 1 , wherein the enamine according to formula (II) is condensed with the α,β-unsaturated ketone according to formula (III) at a temperature from −5° C. to 20° C.

10. The process of claim 1 , where the enamine according to formula (II) is condensed with the α,β-unsaturated ketone according to formula (III) in a non-polar solvent.

11. The process of claim 10 , wherein the non-polar solvent is toluene.

12. The process of claim 1 , wherein Y is CF 3 .

13. The process of claim 1 , wherein R 2 and R 3 independently represent hydrogen, methyl or ethyl.

14. The process of claim 1 , wherein R 2 , R 3 , n, and Y are as previously defined, R 1 represents CH 3 , L represents a single bond and the compound of formula (I) has the structure

wherein n=1-3.

15. The process of claim 14 , wherein Y represents (C 1 -C 4 ) haloalkyl, R 2 and R 3 individually represent hydrogen, methyl, ethyl, fluoro, chloro or bromo, and n is an integer from 1-3.

16. The process of claim 15 , wherein Y represents CF 3 , R 2 and R 3 individually represent hydrogen, methyl or ethyl, and n is an integer from 1-3.

17. The process of claim 1 , which further includes the preparation of a compound according to formula (VI)

wherein

R 1 , R 2 , R 3 , L, n and Y are as previously defined;

X 3 is optional and represents O when present;

X 4 represents NNO 2 , NCN, NCOOR 9 or NCONH 2 ; and

R 9 represents (C 1 -C 3 ) alkyl;

in which:

a compound according to formula (I) is reacted with one or more reactants suitable for the addition of X 4 and optionally X 3 .

18. A process for the preparation of a compound according to formula (VI)

wherein

L represents a single bond or R 1 , S and L taken together represent a 4-, 5- or 6-membered ring;

R 1 represents (C 1 -C 4 ) alkyl;

R 2 and R 3 individually represent hydrogen, methyl, ethyl, fluoro, chloro or bromo;

n is an integer from 0-3; and

Y represents (C 1 -C 4 ) haloalkyl;

X 3 is optional and represents O when present;

X 4 represents NNO 2 , NCN, NCOOR 9 or NCONH 2 ; and

R 9 represents (C 1 -C 3 ) alkyl;

in which:

a compound according to formula (I)

wherein R 1 , R 2 , R 3 , L, n and Y are as previously defined is reacted with one or more reactants suitable for the addition of X 4 and optionally X 3 .

19. A process for the preparation of a 2-substituted-5-(1-alkylthio)alkyl-pyridine N-oxide according to formula (I),

wherein

L represents a single bond or R 1 , S and L taken together represent a 4-, 5- or 6-membered ring;

R 1 represents (C 1 -C 4 ) alkyl;

R 2 and R 3 individually represent hydrogen, methyl, ethyl, fluoro, chloro or bromo;

n is an integer from 0-3; and

Y represents (C 1 -C 4 ) haloalkyl;

in which a compound according to formula (IV)

wherein Y, R 1 , R 2 , R 3 , R 4 , R 5 , L and n are as previously defined is cyclized using an amine nucleophile according to formula (V)

H 2 N—X 2   (V),

wherein X 2 represents hydroxyl.

20. The process of claim 19 , in which:

an enamine according to formula (II)

wherein

R 1 , R 2 , R 3 , L, and n are as previously defined, and

R 4 and R 5 independently represent C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 1 -C 8 arylalkyl, C 1 -C 8 haloalkyl, C 1 -C 8 alkoxyalkyl, C 1 -C 8 alkylaminoalkyl, aryl or heteroaryl or R 4 and R 5 taken together with N represent a 5- or 6-membered saturated or unsaturated ring;

is condensed with an α,β-unsaturated ketone according to formula (III)

wherein

Y is as previously defined; and

X 1 represents halogen, OR 6 , OSO 2 R 6 , SR 6 , SOR E , SO 2 R 6 or NR 7 R 8 , where R 6 represents hydrogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 1 -C 8 arylalkyl, C 1 -C 8 haloalkyl, C 1 -C 8 alkoxyalkyl, C 1 -C 8 alkylaminoalkyl, aryl or heteroaryl, and R 7 and R 8 independently represent hydrogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 1 -C 8 arylalkyl, C 1 -C 8 haloalkyl, C 1 -C 8 alkoxyalkyl, C 1 -C 8 alkylaminoalkyl, aryl or heteroaryl or R 7 and R 8 taken together with N represent a 5- or 6-membered saturated or unsaturated ring to provide the compound according to formula (IV).

21. The process of claim 19 , in which:

an acetyl chloride compound according to formula (VII)

wherein Y represents C 1 -C 4 haloalkyl is reacted with an alkyl vinyl ether according to formula (VIII)

wherein R 10 represents C 1 -C 4 alkyl to provide an intermediate compound according to formula (IX)

and the intermediate compound according to formula (IX) is condensed with an enamine according to formula (II)

wherein

R 1 , R 2 , R 3 , L, and n are as previously defined, and

R 4 and R 5 independently represent C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 1 -C 8 arylalkyl, C 1 -C 8 haloalkyl, C 1 -C 8 alkoxyalkyl, C 1 -C 8 alkylaminoalkyl, aryl or heteroaryl or R 4 and R 5 taken together with N represent a 5- or 6-membered saturated or unsaturated ring to provide the compound according to formula (IV).