Processes for the preparation of rivaroxaban and intermediates thereof

1. A process for the preparation of (S)- or (R)-Rivaroxaban comprising reacting a primary amine formation agent with a compound of Formula 13′:

wherein

G 1 is OR 1 , NR 2 R 3 or CQ 3 ;

R 1 is alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl or substituted arylalkyl;

R 2 and R 3 are either (a) two independent groups or (b) together form a single ring group with the N to which they are bonded;

R 2 and R 3 , when independent groups, are independently selected from the group consisting of: H, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl and substituted arylalkyl;

R 2 and R 3 , when together form a single ring group with the N to which they are bonded, are a heteroaryl ring;

Q is halogen; and

G 2 is a primary amine precursor.

2. The process of claim 1 wherein the suitable primary amine formation agent is selected from the group consisting of: hydrogen, hydride based reducing agents, metal catalyzed reducing agents, acids and R—NR 4 R 5 wherein R is hydrogen, —OH, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl or substituted arylalkyl; R 4 and R 5 are either two independent groups or together form a single ring group with the N to which they are bonded; R 4 and R 5 , when independent groups, are independently selected from the group consisting of: H, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, amine and substituted amino; and R 4 and R 5 , when together form a single ring group with the N to which they are bonded, are a heteroaryl ring.

3. The process of claim 1 further comprising reacting a compound of Formula 11′:

with a compound of Formula 12:

thereby forming the compound of Formula 13′

wherein

G 1 is OR 1 , NR 2 R 3 or CQ 3 ;

R 1 is alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl or substituted arylalkyl;

R 2 and R 3 are either (a) two independent groups or (b) together form a single ring group with the N to which they are bonded;

R 2 and R 3 , when independent groups, are independently selected from the group consisting of: H, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl and substituted arylalkyl;

R 2 and R 3 , when together form a single ring group with the N to which they are bonded, are a heteroaryl ring;

Q is halogen;

G 2 is a primary amine precursor; and

X 1 is a leaving group selected from the group consisting of halogen, sulfonyloxy, imidazole, ester, C 1 -C 4 alkoxy, substituted C 1 -C 4 alkoxy, trihalomethoxy, N-hydroxysuccinimide, p-nitrophenol, N-hydroxyphthalimide, and N-hydroxybenzotriazole.

4. The process of claim 3 further comprising reacting a compound of Formula 9:

with a compound of Formula 10′:

thereby forming the compound of Formula 11′

wherein

G 2 is OR 1 , NR 2 R 3 or CQ 3 ;

R 1 is alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl or substituted arylalkyl;

R 2 and R 3 are either (a) two independent groups or (b) together form a single ring group with the N to which they are bonded;

R 2 and R 3 , when independent groups, are independently selected from the group consisting of: H, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl and substituted arylalkyl;

R 2 and R 3 , when together form a single ring group with the N to which they are bonded, are a heteroaryl ring;

Q is halogen;

X and Y are either i) separate groups or ii) together form a single ring group with the two carbons to which they are bonded; and when: i) X and Y are separate groups, X is a halogen and Y is —OH; or ii) X and Y together form a single ring group with the two carbons to which they are bonded, they are an oxygen atom; and

G 2 is a primary amine precursor.

5. The process of claim 3 further comprising reacting a compound of Formula 7′:

with a compound of Formula 8:

thereby forming the compound of Formula 11′

wherein

L 1 is a leaving group selected from the group consisting of: halogen, imidazole, ester, C 1 -C 4 alkoxy, trihalomethoxy, N-hydroxysuccinimide, p-nitrophenol, N-hydroxyphthalimide, and N-hydroxybenzotriazole;

G 1 is OR 1 , NR 2 R 3 or CQ 3 ;

R 1 is alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl or substituted arylalkyl;

R 2 and R 3 are either (a) two independent groups or (b) together form a single ring group with the N to which they are bonded;

R 2 and R 3 , when independent groups, are independently selected from the group consisting of: H, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl and substituted arylalkyl;

R 2 and R 3 , when together form a single ring group with the N to which they are bonded, are a heteroaryl ring;

Q is halogen; and

G 2 is a primary amine precursor.

6. The process of claim 4 further comprising, reacting a compound of Formula 2:

with a compound of Formula 8:

thereby forming the compound of Formula 9

wherein

L 1 is a leaving group selected from the group consisting of: halogen, imidazole, ester, C 1 -C 4 alkoxy, trihalomethoxy, N-hydroxysuccinimide, p-nitrophenol, N-hydroxyphthalimide, and N-hydroxybenzotriazole;

G 1 is OR 1 , NR 2 R 3 or CQ 3 ;

R 1 is alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl or substituted arylalkyl;

R 2 and R 3 are either (a) two independent groups or (b) together form a single ring group with the N to which they are bonded;

R 2 and R 3 , when independent groups, are independently selected from the group consisting of: H, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl and substituted arylalkyl;

R 2 and R 3 , when together form a single ring group with the N to which they are bonded, are a heteroaryl ring; and

Q is halogen.

7. The process of claim 5 further comprising reacting a compound of Formula 2:

with a compound of Formula 10′:

thereby forming the compound of Formula 7′

wherein

X and Y are either i) separate groups or ii) together form a single ring group with the two carbons to which they are bonded; and when: i) X and Y are separate groups, X is a halogen and Y is —OH; or ii) X and Y together form a single ring group with the two carbons to which they are bonded, they are an oxygen atom; and

G 2 is a primary amine precursor.

8. The process of claim 5 further comprising reacting either:

i) a compound of Formula 4′:

ii) a compound of Formula 6′:

with a compound of Formula 5:

thereby forming the compound of Formula 7′

wherein

L 2 is a halogen or sulfonyloxy group;

M is H or a metal selected from the group consisting of Li, Na and K; and

G 2 is a primary amine precursor.

9. The process of claim 8 wherein the compound of Formula 4′ is reacted with the compound of Formula 5 and further comprising reacting a compound of Formula 2:

with a compound of Formula 3′:

thereby forming the compound of Formula 4′

wherein

X and Y are either i) separate groups or ii) together form a single ring group with the two carbons to which they are bonded; and when: i) X and Y are separate groups, X is a halogen and Y is —OH; or ii) X and Y together form a single ring group with the two carbons to which they are bonded, they are an oxygen atom; and

L 2 is a halogen or sulfonyloxy group.

10. The process of claim 8 wherein the compound of Formula 6′ is reacted with the compound of Formula 5 and further comprising reacting a compound of Formula 4′:

with a sixth base selected from the group consisting of: metal hydroxides, carbonates, phosphates, tertiary amines, aryl amines, and mixtures thereof,

thereby forming the compound of Formula 6′

wherein L 2 is a halogen or sulfonyloxy group.

11. The process of claim 1 wherein G 1 is OR 1 and G 2 is an azide or NR 2 ′R 3 ′, wherein R 2 ′ and R 3 ′ are either two independent groups or together form a single ring group with the N to which they are bonded; R 2 ′ and R 3 ′, when independent groups, are independently selected from the group consisting of: hydrogen and a suitable amine protecting group, provided that both R 2 ′ and R 3 ′ are not both hydrogen; R 2 ′ and R 3 ′, when together, form a single ring group with the N to which they are bonded, are a heterocyclic ring, a substituted heterocyclic ring, phthalimide or saccharin.

12. The process of claim 1 wherein G 1 is OR 1 and G 2 is an azide, heterocyclic or substituted heterocyclic ring.

13. The process of claim 12 wherein R 1 is an alkyl and G 2 is a heterocyclic ring or a substituted heterocyclic ring.

14. The process of claim 3 wherein G 1 is OR 1 and G 2 is an azide, heterocyclic or substituted heterocyclic ring.

15. The process of claim 3 wherein X 1 is halogen.

16. The process of claim 5 wherein G 2 is an azide, heterocyclic or substituted heterocyclic ring.

17. The process of claim 5 wherein G 2 is phthalimide.

18. The process of claim 5 wherein L 1 is halogen and G 1 is OR 1 .

19. The process of claim 8 wherein M is a metal and G 2 is an azide, heterocyclic or substituted heterocyclic ring.

20. The process of claim 8 wherein M is potassium and G 2 is a phthalimide.