Process for the preparation of rivaroxaban

1. A process for the preparation of Rivaroxaban (I)

comprising:

a) reacting a compound of formula (IV)

 with a compound G-L of formula (V), optionally in the presence of a suitable base to give a compound of formula (VI)

 wherein L is a leaving group and G is a protecting group;

b) converting the compound of formula (VI) to a compound of formula (VII) or salt thereof which may optionally involve isolation of a compound of formula (VII′)

c) reacting the compound of formula (VII) or salt thereof with 5-chloro thiophen-2-carboxylic acid of formula (VIII)

 in the presence of a suitable base to give a compound of formula (IX)

 wherein L 1 is a leaving group; and

d) deprotecting and cyclizing the compound of formula (IX) to provide Rivaroxaban (I).

2. The process of claim 1 , wherein the base used in step (a) is selected from the group consisting of DIPEA (diisopropylethyl amine), TEA (triethyl amine), DEA (diethyl amine), pyridine, DBU (1,8-Diazabicyclo[5.4.0]undec-7-ene), imidazole, N,N-dimethyl aniline, DMAP (4-Dimethylaminopyridine), and mixtures thereof.

3. The process of claim 2 , wherein the base used in step (a) is DIPEA.

4. The process of claim 1 , wherein step (b) involves reaction of compound (VI) with an alkali azide followed by reduction with triphenylphosphine.

5. The process of claim 1 , wherein the base used in step (c) is selected from the group consisting of DIPEA (diisopropylethyl amine), TEA (triethyl amine), DEA (diethyl amine), pyridine, DMAP (4-Dimethylaminopyridine), DBU (1,8-Diazabicyclo[5.4.0]undec-7-ene), N,N-dimethyl aniline, potassium carbonate, sodium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, and mixtures thereof.

6. The process of claim 1 , wherein deprotection and cyclization of step (d) is performed using a phosgene equivalent selected from the group consisting of triphosgene, carbonyl diimidazole (CDI), dicyclohexyl carbodiimide (DCC), and mixtures thereof.

7. The process of claim 6 , wherein deprotection and cyclization of step (d) is performed using triphosgene.

8. A process for the preparation of Rivaroxaban (I)

comprising:

a) reacting (R)-4-[4-(3-chloro-2-hydroxypropylamino)-phenyl]-morpholin-3-one (IVa)

 with benzyl bromide (Va) or benzyl chloride (Va′)

 optionally, in the presence of a suitable base, to give (R)-4-{4-[N-benzyl-(3-chloro-2-hydroxypropyl)amino]phenyl}-morpholin-3-one (VIa)

b) converting (R)-4-{4-[N-benzyl-(3-chloro-2-hydroxypropyl)amino]phenyl}-morpholin-3-one (VIa) to (S)-4-{4-[N-benzyl-(3-amino-2-hydroxypropyl)amino]phenyl}-morpholin-3-one phosphate (VIIaa) which may optionally involve isolation of (R)-4-{4-[N-benzyl-(3-azido-2-hydroxypropyl)amino]-phenyl}-morpholin-3-one (VII′ a)

c) reacting compound of formula (VIIa) with 5-chlorothiophene-2-carbonyl chloride (VIIIa)

 in the presence of a suitable base to give the compound of formula (IXa)

and

d) deprotecting and cyclizing compound of formula (IXa) to provide Rivaroxaban (I).

9. A compound selected from:

wherein G is a protecting group and L is a leaving group.

10. A compound selected from: