CLIAMS:We claim:
1. A process for preparation of oxazolidinone derivative compounds of formula (7)


comprising the steps of:

i). reacting a compound of formula (1)

With (R)-epichlorohydrin of formula (L)

to give a compound of formula (2);

ii). converting compound (2) obtained in above step (i) to an azide compound of
formula (3) in presence of a solvent;

iii). converting azide compound (3) obtained in above step (ii) to an oxazolidinone
compound of formula (4);

iv). reducing the compound (4) obtained in above step (iii) to an amine compound of
formula(5);

v). reacting the amine compound (5) obtained in above step (iv) with a compound of
formula (6)

to obtain the desired oxazolidinone derivative compound of formula (7).

2. A process as claimed in claim 1, wherein said azide compound (3) is obtained by reacting compound (2) with a metal azide selected from lithium azide (LiN3), sodium azide (NaN3) and potassium azide (KN3).

3. A process as claimed in claim 2 wherein said metal azide is sodium azide (NaN3).

4. A process as claimed in claim 2, wherein said compound (2) is reacted with alkali metal azide in presence of metal iodides selected from sodium iodide (NaI) and
potassium iodide (KI).
5. A process as claimed in claim 4, wherein said metal iodide is sodium iodide (NaI).

6. A process as claimed in claim 1, wherein said solvent in step (ii) is selected from tetrahydrofuran, acetonitrile, dimethylformamide (DMF), N-methyl-2-pyrrolidinone and dimethylsulfoxide.

7. A process as claimed in claim 6, wherein said solvent is DMF.

8. A process as claimed in claim 1, wherein said azide compound (3) is converted into oxazolidinone compound (4) by a carbonylating reagent selected from carbonyldiimidazole, diethyl carbonate, methyl chloroformate, benzyl chloroformate, phenyl chloroformate and triphosgene.

9. A process as claimed in claim 8, wherein said carbonylating reagent is carbonyldiimidazole or diethyl carbonate.

10. A process as claimed in claim 8, wherein when dialkyl carbonates or alkyl/aralkyl chloroformates are selected as carbonylating reagent, the carbonylation is carried out in presence of inorganic bases such as metal carbonates, metal bicarbonates and metal hydroxides.

11. A process as claimed in claim 1, wherein said compound (4) is reduced to said compound (5) in presence of a reducing agent selected from Pd-C/H2, trialkyl and triaryl phosphine.

12. A process as claimed in claim 11, wherein said reducing agent is triphenyl phosphine.

13. A process as claimed in claim 11, wherein said reduction is done in presence of a protic or aprotic solvent.

14. A process as claimed in claim 13, wherein said solvent is selected from toluene, tetrahydrofuran, methanol, water and mixture thereof.

15. A process as claimed in claim 1, wherein when –

the obtained oxazolidinone derivative is Linezolid compound.

16. A process as claimed in claim 1, wherein when-

the obtained oxazolidinone derivative is Rivaroxaban compound.

17. An oxazolidinone compound (7) obtained from the process as claimed in claim 1.

18. A process for preparation of Linezolid comprising the steps of:

i). reacting 3-fluoro-4-morpholin-4-yl-phenylamine compound of formula (1a)

with (R)-epichlorohydrin compound of formula (L)

to give (R)-1-chloro-3-(3-fluoro-4-morpholin-4-yl-phenylamino)-propan-2-ol
compound of formula (2a);

ii). converting compound (2a) to a novel azide compound (R)-1-azido-3-(3-fluoro-4-
morpholin-4-yl phenylamino)-propan-2-ol compound of formula (3a) in presence
of a solvent;

iii). converting compound (3a) to an oxazolidinone, (R)-5-azido methyl-3-(3-fluoro-4-
morpholin-4-yl-phenyl)-oxazolidin-2-one compound of formula (4a);

iv). reducing compound (4a) to (S)-5-aminomethyl-3-(3-fluoro-4-morpholin-4-yl-
phenyl)-oxazolidin-2-one compound of formula (5a);

v). reacting the amine compound (5a) with acetic anhydride to obtain Linezolid
compound of formula (7a).

19. A process as claimed in claim 18, wherein said compound (2a) is converted to (R)-1-azido-3-(3-fluoro-4-morpholin-4-yl phenylamino)-propan-2-ol, azide compound (3a) by a metal azide selected from lithium azide (LiN3), sodium azide (NaN3) and potassium azide (KN3).

20. A process as claimed in claim 19, wherein said metal azide is sodium azide (NaN3).

21. A process as claimed in claim 19, wherein said compound (2a) is converted to (R)-1-azido-3-(3-fluoro-4-morpholin-4-yl phenylamino)-propan-2-ol, azide compound (3a) in presence of metal iodides selected from sodium iodide (NaI) and potassium iodide (KI).

22. A process as claimed in claim 21, wherein said metal iodide is sodium iodide (NaI).

23. A process as claimed in claim 18, wherein said solvent in step (ii) is selected from tetrahydrofuran, acetonitrile, dimethylformamide (DMF), N-methyl-2-pyrrolidinone and dimethylsulfoxide.

24. A process as claimed in claim 23, wherein said solvent is DMF.

25. A process as claimed in claim 18, wherein said azide compound (3a) is converted into (R)-5-azidomethyl-3-(3-fluoro-4-morpholin-4-yl-phenyl)-oxazolidin-2-one compound (4a) by a carbonylating reagent selected from carbonyldiimidazole, diethyl carbonate, methyl chloroformate, benzyl chloroformate, phenyl chloroformate and triphosgene.

26. A process as claimed in claim 25, wherein said carbonylating agent is carbonyldiimidazole or diethyl carbonate.

27. A process as claimed in claim 25, wherein when dialkyl carbonates or alkyl/aralkyl chloroformates are selected as carbonylating agent, the carbonylation is carried out in presence of inorganic bases such as metal carbonates, metal bicarbonates and metal hydroxides.

28. A process as claimed in claim 18, wherein said compound (4a) is reduced to (S)-5-aminomethyl-3-(3-fluoro-4-morpholin-4-yl-phenyl)-oxazolidin-2-one compound (5a) in presence of a reducing agent selected from Pd-C/H2, trialkyl and triaryl phosphine.

29. A process as claimed in claim 28, wherein said reducing agent is triphenyl phosphine.

30. A process as claimed in claim 28, wherein said reduction is done in presence of a protic or aprotic solvent.

31. A process as claimed in claim 30, wherein said solvent is selected from toluene, tetrahydrofuran, methanol, water and mixture thereof.

32. A Linezolid compound obtained from the process as claimed in claim 18.

33. A novel azide compound, (R)-1-azido-3-(3-fluoro-4-morpholin-4-yl phenylamino)-propan-2-ol of formula (3a).

34. A novel azide compound as claimed in 33 which is characterized by X-ray power diffraction spectrum with peaks at peaks about 7.016, 10.33, 15.20, 15.73, 16.35, 18.15, 18.59, 20.09, 20.70, 21.04, 21.34, 22.17, 22.97, 23.36, 24.06, 27.49, 28.45, 28.81, 29.58, 29.95, 32.00 ± 0.20 2? and
1H-NMR: (400 MHz, DMSO-d6) d 2.79-2.81(m, 4H), 2.91-3.05(m, 2H), 3.20-3.31
(m, 2H), 3.66-3.68 (m, 4H), 3.77-3.78 (bs, 1H), 5.31-5.32 (d, 1H), 5.54-5.57 (t, 1H),
6.31-6.34 (dd, 1H), 6.38-6.42 (dd, 1H), 6.79-6.83 (t, 1H). Mass (M++1) = 296.3.

35. A process for preparation of (R)-1-azido-3-(3-fluoro-4-morpholin-4-yl phenylamino)-propan-2-ol compound (3a) as claimed in claim 33 or 34, comprising converting (R)-1-chloro-3-(3-fluoro-4-morpholin-4-yl-phenylamino)-propan-2-ol compound (2a) into azide compound (3a) by a metal azide in presence a metal iodide.

36. A process as claimed in claim 35, wherein said metal azide is selected from lithium azide (LiN3), sodium azide (NaN3) and potassium azide (KN3)

37. A process as claimed in claim 36, wherein said metal azide is sodium azide (Na N3)

38. A process as claimed in claim 35, wherein said metal iodide is selected from sodium iodide (NaI) and potassium iodide (KI).

39. A process as claimed in claim 38, wherein said metal iodide is sodium iodide (NaI).

40. A process as claimed in claim 35, wherein said azide compound (3a) is isolated and purified.
41. A process for preparation of Rivaroxaban comprising the steps of:

i). reacting 4-(4-amino-phenyl)-morpholin-3-one compound of formula (1b)

with (R)-epichlorohydrin of formula (L)

to obtain 4-[4-(3-chloro-2R-hydroxy-propylamino)-phenyl]-morpholin-3-one
compound of formula (2b);

ii). converting 4-[4-(3-chloro-2R-hydroxy-propylamino)-phenyl]-morpholin-3-one
(compound 2b) to 4-[4-(3-azido-2R-hydroxy-propylamino)-phenyl]-morpholin-3-
one, an azide compound (3b) in a solvent;

iii). converting azide compound (3b) to an oxazolidinone compound, (R)-4-[4-(5-
azidomethyl-2-oxo-oxazolidin-3-yl)-phenyl]-morpholin-3-one compound (4b);

iv). reducing compound (4b) to (S)-4-[4-(5-Aminomethyl-2-oxo-oxazolidin-3-yl)-
phenyl]- morpholin-3-one compound of formula (5b);

v). reacting the amine compound (5b) with a compound of formula (6b)

to obtain Rivaroxaban compound of formula (7b).

42. A process as claimed in claim 41, wherein said compound (2b) is converted to 4-[4-(3-azido-2R-hydroxy-propylamino)-phenyl]-morpholin-3-one, an azide compound (3b) by a metal azide selected from lithium azide (LiN3), sodium azide (NaN3) and potassium azide (KN3).

43. A process as claimed in claim 42, wherein said metal azide is sodium azide (NaN3).

44. A process as claimed in claim 41, wherein said compound (2b) is converted to 4-[4-(3-azido-2R-hydroxy-propylamino)-phenyl]-morpholin-3-one, an azide compound (3b) in presence of metal iodides selected from sodium iodide (NaI) and potassium iodide (KI).

45. A process as claimed in claim 44, wherein said metal iodide is sodium iodide (NaI).

46. A process as claimed in claim 41, wherein said solvent in step (ii) is selected from tetrahydrofuran, acetonitrile, dimethylformamide (DMF), N-methyl-2-pyrrolidinone and dimethylsulfoxide.
47. A process as claimed in claim 46, wherein said solvent is DMF.

48. A process as claimed in claim 41, wherein said compound (3b) is converted into (R)-4-[4-(5-azidomethyl-2-oxo-oxazolidin-3-yl)-phenyl]-morpholin-3-one, compound (4b) by a carbonylating reagent selected from carbonyldiimidazole, diethyl carbonate, methyl chloroformate, benzyl chloroformate, phenyl chloroformate and triphosgene.

49. A process as claimed in claim 41, wherein said carbonylating agent is carbonyldiimidazole or diethyl carbonate.

50. A process as claimed in claim 48, wherein when dialkyl carbonates or alkyl/aralkyl chloroformates are selected as carbonylating agent, the carbonylation is carried out in presence of inorganic bases such as metal carbonates, metal bicarbonates and metal hydroxides.

51. A process as claimed in claim 41, wherein said compound (4b) is reduced to (S)-4-[4-(5-aminomethyl-2-oxo-oxazolidin-3-yl)-phenyl]-morpholin-3-one compound (5b) in presence of a reducing agent selected from Pd-C/H2, trialkyl and triaryl phosphine.

52. A process as claimed in claim 51, wherein said reducing agent is triphenyl phosphine.

53. A process as claimed in claim 51, wherein said reduction is done in presence of a protic or aprotic solvent.

54. A process as claimed in claim 53, wherein said, wherein said reduction is done in presence of a solvent selected from toluene, tetrahydrofuran, methanol, water and mixture thereof.

55. A Rivaroxaban compound obtained from the process as claimed in claim 41.
,TagSPECI:FIELD OF THE INVENTION

The invention relates to a process for preparation of oxazolidinone derivatives. More particularly, the invention relates to a novel combined process for preparation of Linezolid and Rivaroxaban. The invention also relates to novel intermediates for preparation of Oxazolidinone derivatives.

BACKGROUND OF THE INVENTION

Oxazolidinones are a class of compounds containing 2-oxazolidone in the structure. The general structure of oxazolidinone is given below:-

It has been reported that oxazolidinone derivatives shows a number of biological activities such as antibacterial, anticoagulant, anti-tubercular, antidepressant, anti-thyroid, agriculture fungicide etc. Some of the oxazolidinone derivatives include Linezolid, Torezolid, Radezolid, Eperezolid and Rivaroxaban.

Among these, the Linezolid is a potent antibacterial agent whereas; Rivaroxaban is an important antithrombotic agent. Structurally, both Linezolid and Rivaroxaban are oxazolidinone derivatives but both exhibit different biological activities and different pharmaceutical use.

Linezolid is chemically known as (S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl] methyl] acetamide and is a synthetic antibacterial agent of oxazolidinone class. Linezolid is used for the treatment of serious infections caused by Gram positive bacteria that are resistant to other antibiotics and also gram-negative microorganism such as Pasteurella multocida. It is mostly active against streptococci, methicillin- resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE).

Rivaroxaban has chemical formula of (5-chloro-N-({5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)-phenyl]-1,3-oxazolidin-5-yl}-methyl)-2-thiophene carboxamide and is an orally active anticoagulant used for prophylaxis and/or treatment of thromboembolic disorders especially angina pectoris, myocardial infarction, stroke, ischemic attacks, pulmonary embolism (PE) and deep vein thrombosis (VTE).

U.S Patent No. 5,688,792 (WO 95/07271, EP0717738) first disclosed Linezolid and related compounds, its therapeutic uses as well as a process for its preparation and is represented by following structure (I).

(I)
The process for preparation of Linezolid described in U.S Patent No. 5,688,792 is given in the below scheme-I.

Scheme-I
The PCT publication WO 2011/114210 describes a process for preparation of Linezolid as shown below in scheme-II:

Scheme-II

Further processes for preparation of Linezolid are also described in U.S Patent No. 5,837,870, 6887995,7291614,7429661,7307163, PCT Publication No. WO 99/24393, WO 2007/116284, Journal of Med. Chem. 39(3), 673-679, 1996 and Tetrahedron Lett. 40(26), 4855, 1999.

Tetrahedron Lett. 40(26), 4855, 1999 describes a process for the preparation of Linezolid by treating (R)-N-(4-morpholinyl-3-flurophenyl)-2-oxo-5-oxazolidinyl-methylazide with thioacetic acid without mentioning the isolation process.

WO 2001/47919 first disclosed Rivaroxaban having the following structure (II).

WO 2001/47919 also describes a process for preparation of Rivaroxaban from the starting compounds 2-[(2S)-2-oxiranylmethyl]-1H-isoindole-1,3(2H)-dione, 4-(4-aminophenyl)-3-morpholinone and 5-chlorothiophene-2-carbonyl chloride as given in Scheme-III below:

Scheme-III

US 2005/0182055 describe a process for preparation of Rivaroxaban taking the same starting material as described above in WO 01/47919.

WO 2004/060887 relates to a method producing 5-chloro-N-({5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)-phenyl]-1,3-oxazolidin-5-yl}-methyl)-2-thiophenecarboxamide involving starting compound 5-chlorothiophene-2-carbonyl chloride, (2S)-3-amino-propane-1,2-diol and 4-(4-aminophenyl)-3-morpholinone.

US 2007/006611 describe a process for preparation of 4-(4-aminophenyl)-3-morpholinone by reacting 4-(4-nitrophenyl)-3-morpholinone with hydrogen in presence of a hydrogenation catalyst, characterized in that the reaction is effected in an aliphatic alcohol.
PCT publication WO2012/051692 describes processes for preparation of Rivaroxaban as represented below in scheme-IV and Scheme-V.

Scheme-IV

Scheme-V

It is apparent from the above that preparation processes described in the prior arts either disclose a process for Linezolid or disclose a process for Rivaroxaban. In addition to lacking the commercial viability, none of the prior art discloses a process which can be used for preparation of more than one oxazolidinone.

OBJECT OF THE INVENTION

The primary object of the invention is to provide a combined process for preparation of more than one oxazolidinone derivative compounds.

Another object of the invention is to provide a novel combined process for preparation of Linezolid and Rivaroxaban.

Another object of the invention is to provide a novel process for preparation of Linezolid compounds.

Another object of the invention is to provide a novel process for preparation of Rivaroxaban compounds.

Another object of the invention is to provide novel intermediates for preparation of oxazolidinone derivatives.

Another object of the invention is to provide novel intermediates for preparation of Linezolid compounds.

A further object of the invention is to provide a process for preparation of novel intermediates of Linezolid preparation.

SUMMARY OF THE INVENTION

Accordingly there is provided a process for preparation of more than one oxazolidinone derivatives. More particularly, the invention specifically discloses a process which can be used for the preparation of Linezolid as well as Rivaroxaban.

The novel process of the invention suitable for preparation of more than one oxazolidinone derivatives, more particularly Linezolid compounds and Rivaroxaban compounds, comprises the steps of:

i). reacting a compound of formula (1);

With (R)-epichlorohydrin of formula (L);


to give a compound of formula (2);



ii). converting compound (2) obtained in above step (i) to an azide compound of formula (3)
in presence of a solvent;

iii). converting azide compound (3) obtained in above step (ii) to an oxazolidinone compound
of formula (4);

iv). reducing the compound (4) obtained in above step (iii) to an amine compound of
formula (5);

v). reacting the amine compound (5) obtained in above step (iv) with a compound of
formula (6)


to obtain the desired oxazolidinone derivative compound of formula (7).


In one embodiment of the invention, when-

the obtained oxazolidinone derivative is Linezolid compound.

In another embodiment of the invention, when-

The obtained oxazolidinone derivative is Rivaroxaban compound.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure1: Figure -1 represents DSC thermogram of the novel Linezolid intermediate azide compound (R)-1-azido-3-(3-fluoro-4-morpholin-4-yl phenylamino)- propan-2-ol.

Figure2: Figure-2 represents X-ray powder diffractogram of the novel Linezolid intermediate azide compound (R)-1-azido-3-(3-fluoro-4-morpholin-4-ylphenylamino)-propan-2-ol

DETAILED DESCRIPTION OF THE INVENTION

Detailed embodiments of the present invention are disclosed herein below. However, it is to be understood that the disclosed embodiments are merely exemplary of the invention, which can be embodied in various forms. The scope of the invention is not limited to the disclosed embodiments and terms and phrases used herein are not intended to be limiting but rather to provide an understandable description of the invention. The invention is defined by claims appended hereto.

The invention provides a process for preparation of more than one oxazolidinone derivatives. More particularly, the invention specifically provides a process which can be used for the preparation of Linezolid as well as Rivaroxaban compounds.

The process is illustrated below in scheme-A. The scheme-A illustrates a common process for preparation of oxazolidinone derivatives, more specifically, Linezolid and Rivaroxaban.

Scheme-A
In an exemplary embodiment, the process comprises the steps of:

Step-I: - Reacting a compound of formula (1)

With (R)-epichlorohydrin of formula (L)

to give a compound of formula (2);

This step comprises dissolving the compound (1) in a suitable solvent and adding (R)-epichlorohydrin in the solution at room temperature. Reaction mass heated to reflux temperature for 12-16 hrs, distilling the solvent under vacuum to obtain the crude compound (2).

The reaction can be carried out in any suitable solvent selected from methanol, ethanol, propanol, isopropanol and butanol. In one preferred embodiment, methanol is used.

Step-II:- converting compound (2) obtained in step (I) to an azide compound of formula (3) in presence of a solvent;

Wherein, R1 = as described in step (I)

The step comprises dissolving compound (2) in a suitable solvent selected from protic and aprotic solvents or a mixture thereof. Treating with metal iodides such as sodium iodide (NaI) or potassium iodide (KI) at a suitable temperature which may be 25-100°C, preferably 35-40 °C. To the reaction mass metal azide is adding at 35-40°C.

In an exemplary embodiment the solvent may be selected from tetrahydrofuran, acetonitrile, dimethylformamide (DMF), N-methyl-2-pyrrolidinone and dimethylsulfoxide. In one preferred embodiment, the solvent is DMF.

In an exemplary embodiment the metal azide may be selected from lithium azide (LiN3), sodium azide (NaN3) and potassium azide (KN3). In one preferred embodiment the metal azide is sodium azide (NaN3).

The quantity of metal iodide is 0.1 to 1.0 equivalents, preferably 0.1 to 0.5 equivalents, more preferably 0.1 to 0.2 equivalents to the per mole equivalent of formula 1.

The quantity of metal azides is 1.0 to 5.0 equivalents, preferably 1.0 to 2.5 equivalents, more preferably 1.0 to 1.2 equivalents to the per mole equivalent of formula 1.

The whole reaction is performed at 25°C to boiling temperature of the solvent used.

Step-III:- converting azide compound (3) obtained in step (II) to an oxazolidinone compound of formula (4);

Wherein, R1 = as described in step (I)

The step comprises dissolving azide compound (3) in a suitable organic solvent and carbonylating using carbonylating reagents to obtain compound (4). The carbonylation reaction is carried out by using any carbonylating reagents such as carbonyldiimidazole, diethyl carbonate, methyl chloroformate, benzyl chloroformate, phenyl chloroformate and triphosgene, preferably carbonyldiimidazole or diethyl carbonate.
In the case of dialkyl carbonates and alkyl/aralkyl chloroformates the carbonylation should be carried out in presence of inorganic bases such as metal carbonates, metal bicarbonates and metal hydroxides.
Step-IV:- reducing the compound (4) obtained in step (III) to an amine compound of formula (5);

Wherein, R1 = as described in step (I)

The compound (4) is reduced to amine compound (5) using a reducing agents. The reducing agent may be selected from Pd-C/H2 and triphenyl phosphine. In preferred embodiment, triphenyl phosphine (TPP) is used as reducing agent.

The reduction reaction is carried out in a solvent selected from protic and aprotic solvents or mixtures thereof. In one preferred embodiment, the solvents are toluene, tetrahydrofuran, methanol, water and mixture thereof.

Step-V:- reacting the amine compound (5) obtained in step (IV) with a compound of formula (6)

to obtain the desired oxazolidinone derivative compound of formula (7).

This step comprises adding compound (6) at 0-5°C to a solution of compound (5) in an organic solvent either using base or in absence of the base and slowly raising the temperature to room temperature and heating up to 65-70°C and stirring for 1-2 hrs. Cooling the reaction mass to room temperature, filtering and washing the mass to get crude oxazolidinone derivative compound (7). Crystallizing the crude compound (7) in suitable solvent to get pure compound (7).
In one embodiment of the invention, when-

the obtained oxazolidinone derivative is Linezolid compound.

In another embodiment of the invention, when-

The obtained oxazolidinone derivative is Rivaroxaban compound.

The above described process under Scheme-A is a general process for preparation of oxazolidinone derivatives of formula (7).

In an exemplary embodiment, the oxazolidinone derivatives compound of formula (7) is Linezolid or Rivaroxaban.

The general scheme-A is further described herein after separately for Linezolid as scheme-B and for Rivaroxaban as scheme-C.
The below scheme-B illustrates the process for preparation of Linezolid following the steps as described in general scheme-A.

Scheme-B

The process for preparation of Linezolid illustrated in Scheme-B comprises the steps of:

i). reacting 3-fluoro-4-morpholin-4-yl-phenylamine compound of formula (1a)

with (R)-epichlorohydrin compound of formula (L)

to give (R)-1-chloro-3-(3-fluoro-4-morpholin-4-yl-phenylamino)-propan-2-ol compound of formula (2a);

ii). converting compound (2a) to a novel azide compound (R)-1-azido-3-(3-fluoro-4-morpholin-4-yl phenyl amino)-propan-2-ol compound of formula (3a) in presence of a solvent;

iii). converting compound (3a) to an oxazolidinone, (R)-5-azido methyl-3-(3-fluoro-4-morpholin-4-yl-phenyl)-oxazolidin-2-one compound of formula (4a);

iv). reducing compound (4a) to (S)-5-Aminomethyl-3-(3-fluoro-4-morpholin-4-yl-phenyl)-oxazolidin-2-one compound of formula (5a);

v). reacting the amine compound (5a) with acetic anhydride to obtain Linezolid compound of formula (7a).

The step (i) in above described scheme-B comprises dissolving 3-fluoro-4-morpholin-4-yl-phenylamine compound (1a) in a suitable solvent and adding (R)-epichlorohydrin at room temperature. Heating the reaction mass to reflux temperature for 12-16 hrs, distilling the solvent under vacuum to obtain the crude (R)-1-chloro-3-(3-fluoro-4-morpholin-4-yl-phenylamino)-propan-2-ol (compound 2a).

The solvent used in above in step (i) for dissolving the compound (1a) may be selected from alcohols such as methanol, ethanol, propanol, isopropanol and butanol. In one preferred embodiment, methanol is used.
The step (ii) in above described scheme-B comprises dissolving (R)-1-chloro-3-(3-fluoro-4-morpholin-4-yl-phenylamino)-propan-2-ol (compound 2a) in suitable solvent selected from protic and aprotic solvents or a mixture thereof. Treating with metal iodides such as sodium iodide (NaI) or potassium iodide (KI) at a suitable temperature which may be 25-100°C, preferably 35-40°C. To the reaction mass metal azide is adding at 35-40°C.

In an exemplary embodiment the solvent may be selected from tetrahydrofuran, acetonitrile, dimethylformamide (DMF), N-methyl-2-pyrrolidinone and dimethylsulfoxide. In one preferred embodiment, the solvent is DMF.

In an exemplary embodiment the metal azide may be selected from lithium azide (LiN3), sodium azide (NaN3) and potassium azide (KN3). In one preferred embodiment the metal azide is sodium azide (NaN3).

The quantity of metal iodide is 0.1 to 1.0 equivalents, preferably 0.1 to 0.5 equivalents, more preferably 0.1 to 0.2 equivalents to the per mole equivalent of formula 1.

The quantity of metal azides is 1.0 to 5.0 equivalents, preferably 1.0 to 2.5 equivalents, more preferably 1.0 to 1.2 equivalents to the per mole equivalent of formula 1.

The whole reaction is performed at 25°C to boiling temperature of the solvent used.

The step (iii) in above described scheme-B comprises dissolving (R)-1-azido-3-(3-fluoro-4-morpholin-4-yl phenylamino)-propan-2-ol (compound 3a) in a suitable organic solvent and carbonylating using carbonylating reagents to obtain compound (4a). The carbonylation reaction is carried out by using any carbonylating reagents such as carbonyldiimidazole, diethyl carbonate, methyl chloroformate, benzyl chloroformate, phenyl chloroformate and triphosgene, preferably carbonyldiimidazole or diethyl carbonate.
In the case of dialkyl carbonates and alkyl/aralkyl chloroformates the carbonylation should be carried out in presence of inorganic bases such as metal carbonates, metal bicarbonates and metal hydroxides.
The step (iv) of the scheme-B comprises reducing (R)-5-azido methyl-3-(3-fluoro-4-morpholin-4-yl-phenyl)-oxazolidin-2-one (compound 4a) to (S)-5-aminomethyl-3-(3-fluoro-4-morpholin-4-yl-phenyl)-oxazolidin-2-one (compound 5a) in presence of reducing agent selected from Pd-C/ H2, trialkyl and triaryl phosphine, preferably triphenyl phosphine (TPP).

The reduction reaction is carried out in a solvent selected from protic and aprotic solvents or mixtures thereof. In one preferred embodiment, the solvents are toluene, tetrahydrofuran, methanol, water and mixture thereof.

The step (v) of the scheme-B comprises dissolving the (S)-5-aminomethyl-3-(3-fluoro-4-morpholin-4-yl-phenyl)-oxazolidin-2-one (compound 5a) in toluene at 0-5°C and adding acetic anhydride at the same temperature to obtain Linezolid compound of formula (7a). This step comprises adding compound (6) at 0-5°C to a solution of compound (5) in toluene and slowly raising the temperature to room temperature and heating up to 65-70°C and stirring for 1-2 hrs. The reaction mass is cooling to room temperature, filtering and washing with toluene to get crude Linezolid compound (7a). The crude Linezolid crystallizing in methanol to obtain pure Linezolid.

The below scheme-C illustrates the process for preparation of Rivaroxaban following the steps as described in general scheme-A.

Scheme-C

The process for preparation of Rivaroxaban illustrated in Scheme-C comprises the steps of:

i). reacting 4-(4-amino-phenyl)-morpholin-3-one compound of formula (1b);

with (R)-epichlorohydrin of formula (L);

to obtain 4-[4-(3-chloro-2R-hydroxy-propylamino)-phenyl]-morpholin-3-one compound of formula (2b);

ii). converting 4-[4-(3-chloro-2R-hydroxy-propylamino)-phenyl]-morpholin-3-one (compound 2b) to (R)-4-[4-(3-azido-2-hydroxy-propylamino)-phenyl]-morpholin-3-one an azide compound (3b) in presence of a solvent;

iii). converting compound (3b) to an oxazolidinone compound, (R)-4-[4-(5-azidomethyl-2-oxo-oxazolidin-3-yl)-phenyl]-morpholin-3-one compound (4b);

iv). reducing compound (4b) to (S)-4-[4-(5-aminomethyl-2-oxo-oxazolidin-3-yl)-phenyl]-morpholin-3-one compound of formula (5b);

v). reacting the amine compound (5b) with a compound of formula (6b);

to obtain Rivaroxaban compound of formula (7b).

The step (i) in above described scheme-C comprises dissolving 4-(4-aminophenyl)-3-morpholinone compound (1b) in a suitable solvent and adding (R)-epichlorohydrin at room temperature. Heating the whole reaction mass to reflux temperature for 12-16 hrs, distilling the solvent under vacuum and isolated in suitable solvent to obtain 4-[4-(N-(3-chloro-2R-hydroxy-1-propyl) amino) phenyl] morpholin-3-one (compound 2b).

The reaction can be carried out in any suitable solvent selected from methanol, ethanol, propanol, isopropanol and butanol. In one preferred embodiment, methanol is used.

The step (ii) in above described scheme-C comprises dissolving 4-[4-(N-(3-chloro-2R-hydroxy-1-propyl)amino)phenyl]morpholin-3-one (compound 2b) in suitable solvent selected from protic and aprotic solvents or a mixture thereof. Treating with metal iodides such as sodium iodide (NaI) or potassium iodide (KI) at a suitable temperature which may be 25-100°C, preferably 35-40°C. To the reaction mass metal azide is adding at 35-40°C.

In an exemplary embodiment the solvent may be selected from tetrahydrofuran, acetonitrile, dimethylformamide (DMF), N-methyl-2-pyrrolidinone and dimethylsulfoxide. In one preferred embodiment, the solvent is DMF.
In an exemplary embodiment the metal azide may be selected from lithium azide (LiN3), sodium azide (NaN3) and potassium azide (KN3). In one preferred embodiment the metal azide is sodium azide (NaN3).

The quantity of metal iodide is 0.1 to 1.0 equivalents, preferably 0.1 to 0.5 equivalents, more preferably 0.1 to 0.2 equivalents to the per mole equivalent of formula 1.

The quantity of metal azides is 1.0 to 5.0 equivalents, preferably 1.0 to 2.5 equivalents, more preferably 1.0 to 1.2 equivalents to the per mole equivalent of formula 1.

The whole reaction is performed at 25°C to boiling temperature of the solvent used.

The step (iii) in above described scheme-C comprises dissolving 4-[4-(3-azido-2-hydroxy-propylamino)-phenyl]-morpholin-3-one (compound 3b) in a suitable organic solvent and carbonylating using carbonylating reagents to obtain compound (R)-4-[4-(5-azidomethyl-2-oxo-oxazolidin-3-yl)-phenyl]-morpholin-3-one compound (4b).
The carbonylation reaction is carried out by using any carbonylating reagents such as carbonyldiimidazole, diethyl carbonate, methyl chloroformate, benzyl chloroformate, phenyl chloroformate and triphosgene, preferably carbonyldiimidazole or diethyl carbonate.
In the case of dialkyl carbonates and alkyl/aralkyl chloroformates the carbonylation should be carried out in presence of inorganic bases such as metal carbonates, metal bicarbonates and metal hydroxides.
The step (iv) of the scheme-C comprises reducing (R)-4-[4-(5-azidomethyl-2-oxo-oxazolidin-3-yl)-phenyl]-morpholin-3-one compound (4b) to (S)-4-[4-(5-aminomethyl-2-oxo-oxazolidin-3-yl)-phenyl]-morpholin-3-one (compound 5b) in presence of reducing agent selected from Pd-C/H2, trialkyl and triaryl phosphine, preferably triphenyl phosphine (TPP).

The reduction reaction is carried out in a solvent selected from protic and aprotic solvents or mixtures thereof. In one preferred embodiment, the solvents are toluene, tetrahydrofuran, methanol, water and mixture thereof.

The step (v) of the scheme-C comprises preparing a suspension of 5-chlorothiophene-2-carboxylic acid (compound 6b) in methylenedichloride at 0-5°C under nitrogen atmosphere , slowly adding carbonyldiimidazole and stirring for about 1 hour at room temperature, adding triethyl amine at 0-5°C, followed by addition of a solution of (S)-4-[4-(5-aminomethyl-2-oxo-oxazolidin-3-yl)-phenyl]-morpholin-3-one (compound 5b) in methylenedichloride at 0-5°C over a period of 30 min. Stirring the whole reaction mass at reflux temperature for about 3 hours, separating the organic layer from aqueous layer distilling the solvent under vacuum and isolated in a suitable organic solvent to obtain the Rivaroxaban.

EXAMPLES:
The invention is further described in following examples.

(I). Preparation of Linezolid

Example-1: Preparation of (R)-1-chloro-3-(3-fluoro-4-morpholin-4-yl-phenylamino)-propan-2-ol (2a)

3-Fluoro-4-morpholin-4-yl-phenylamine (100.0 gr) was dissolved in methanol (500.0 mL) at room temperature and (R)-epichlorohydrin (50.0 gr) was added. The whole reaction mass was heated to reflux temperature for 14 hrs. The solvent was distilled under vacuum to get residue of (R)-1-chloro-3-(3-fluoro-4-morpholin-4-yl-phenylamino)-propan-2-ol (145.0 gr). The obtained residue was preceded to next step without purification.

Example-2: Preparation of (R)-1-azido-3-(3-fluoro-4-morpholin-4-yl-phenylamino)-propan-2-ol (3a)

To a solution of (R)-1-chloro-3-(3-fluoro-4-morpholin-4-yl-phenylamino)-propan-2-ol (145.0 g) in dimethylformamide (1500.0 mL) sodium iodide (10.0 gr) was added at 35-40°C. The mixture was stirred at 35-400C for 45 minutes followed by adding sodium azide (40.0 gr) at the same temperature. The whole reaction mass was stirred at 95-100°C for 4-5 hrs. The progress of the reaction was monitored by TLC. After completion of reaction, solvent was distilled out under vacuum below 100°C. The residue was dissolved in dichloromethane (400.0 mL) and water (300.0 mL) and stirred for 10 minutes at room temperature. Two layers were separated and aqueous layer was extracted with dichloromethane (100.0 mL). The organic layers were combined and washed with brine solution (100.0 mL) and organic layer was dried with anhydrous Na2SO4 and distilled under vacuum to get the crude residue (148.0 gr).

The resultant crude product was purified by column chromatography using silica gel eluted with ethyl acetate in petroleum ether. The fractions containing the title compound were combined and concentrated under vacuum; the resulted solid was isolated in isopropyl ether (3a).

This stage was purified only for compound identification purpose otherwise without purification it can be converted to next stage.

The novel azide compound (R)-1-azido-3-(3-fluoro-4-morpholin-4-yl-phenylamino)-propan-2-ol (3a) is characterized by X-ray power diffraction spectrum with peaks at peaks about 7.016, 10.33, 15.20, 15.73, 16.35, 18.15, 18.59, 20.09, 20.70, 21.04, 21.34, 22.17, 22.97, 23.36, 24.06, 27.49, 28.45, 28.81, 29.58, 29.95, 32.00 ± 0.20 2? as depicted in Figure2.
1H-NMR: (400 MHz, DMSO-d6) d 2.79-2.81(m, 4H), 2.91-3.05(m, 2H), 3.20-3.31(m, 2H), 3.66-3.68 (m, 4H), 3.77-3.78 (bs, 1H), 5.31-5.32 (d, 1H), 5.54-5.57 (t, 1H), 6.31-6.34 (dd, 1H), 6.38-6.42 (dd, 1H), 6.79-6.83 (t, 1H). Mass (M++1) = 296.3.

Example-3: Preparation of (R)-5-azidomethyl-3-(3-fluoro-4-morpholin-4-yl-phenyl)-oxazolidin-2-one (4a)

A. Using carbonyldiimidazole (CDI)

A solution of crude (R)-1-azido-3-(3-fluoro-4-morpholin-4-yl-phenylamino)-propan-2-ol (76.0 gr) in dichloromethane (250.0 mL) was placed under nitrogen atmosphere and stirred for 10 min for complete dissolution, carbonyldiimidazole (45.5 gr) was added with stirring. The whole reaction mass was stirred for 4-5 hrs at reflux temperature. The progress of the reaction mass was monitored by TLC analysis. After completion of reaction, the reaction mass was cooled to room temperature and water (150.0 mL) was added and stirred for 10 minutes and organic layer was separated. Aqueous layer was extracted with dichloromethane (50.0 mL). Both the organic layers were combined and dried with anhydrous Na2SO4. The organic layer was distilled under vacuum, followed by co-distilled with methanol (50.0 mL) to get the very thick residue. Methanol (100.0 mL) was added to the whole residue and heated to reflux for 30 minutes, then slowly cooled to room temperature and stirred for 25-30 min. Solid compound was thrown out from the reaction mass was filtered and washed with methanol to get pure compound (4a) (36.0 gr).

Example-4: Preparation of (R)-5-azidomethyl-3-(3-fluoro-4-morpholin-4-yl-phenyl)-oxazolidin-2-one (4a)

B. Using diethyl carbonate

A solution of crude (R)-1-azido-3-(3-fluoro-4-morpholin-4-yl-phenylamino)-propan-2-ol (76.0 gr) in diethyl carbonate (250.0 mL) was prepared and potassium carbonate (70.0 gr) was added with stirring. The whole reaction mass was stirred for 14-16 hrs at reflux temperature. Progress of the reaction mass was monitored by TLC analysis. After completion of reaction, distilled the solvent under vacuum to get residue. The residue was dissolved in dichloromethane (200.0 mL) and water (200.0 mL) then stirred for 10 min at room temperature. The layers were separated and aqueous layer was extracted with dichloromethane (100.0 mL). The combined organic phase was washed with water (100.0 mL) and dried with anhydrous Na2SO4. The organic layer was distilled under vacuum and co-distilled with methanol (50.0 mL) to get the crude mass. Methanol (100.0 mL) was added to the crude and heated to reflux for 30 minutes and then cooled to room temperature. While cooling the reaction mass solid product was thrown out from reaction mass and stirred for 30 minutes. Precipitated solid was filtered and washed with methanol (25.0 mL) and dried to get pure compound (4a) (32.0 gr).

Example-5: Preparation of (S)-5-aminomethyl-3-(3-fluoro-4-morpholin-4-yl-phenyl)-oxazolidin-2-one (5a)

(R)-5-azidomethyl-3-(3-fluoro-4-morpholin-4-yl-phenyl)-oxazolidin-2-one (25.0 gr) was dissolved in toluene (125.0 mL) and cooled to 10-15°C then slowly triphenyl phosphine (20.5 gr) was added and stirred for 10-15 min at same temperature. Slowly temperature was raised to room temperature and stirred for 2-3 hrs, followed by adding water (10.0 mL) and heating to 60-65°C for 2-3 hrs. After completion of reaction, separate the water layer and organic layer dried with anhyd.Na2SO4. Organic layer cooled to 10-15°C followed by IPA.HCl (15.0 mL) was added and stirred for 2-3 hrs at 25-30°C. The precipitated solid was filtered and washed with toluene. The wet compound was dissolved in a water (100.0 mL) and ethyl acetate (100.0 mL), and then PH adjusted to 9.0 to 10.0 with lye solution. Organic layer was separated and aqueous layer extracted with ethyl acetate (50.0 mL). Organic layers were combined and washed with water (50.0 mL) and organic layer was dried with anhyd. Na2SO4 and distilled the solvent completely under vacuum, finally compound was isolated in isopropyl ether and dried to obtain (5a) (19.8 gr).

Example-6: Preparation of Linezolid (7a) from amine intermediate (compound 5a)

To a solution of (S)-5-aminomethyl-3-(3-fluoro-4-morpholin-4-yl-phenyl)-oxazolidin-2-one (25.0 gr) in toluene (125.0 mL), acetic anhydride (14.0 mL) was added at 0-5°C. Slowly temperature was raised to room temperature and heated up to 65-70°C and stirred for 1-2 hrs. The reaction mass was cooled to room temperature, filtered and wash with toluene to get crude Linezolid. The crude compound was crystallized in methanol to get pure Linezolid (7a) (22.5 gr).

Example-7: Preparation of Linezolid (7a) from oxazolidinone intermediate (compound
4a)

(R)-5-azidomethyl-3-(3-fluoro-4-morpholin-4-yl-phenyl)-oxazolidin-2-one (50.0 gr) was dissolved in toluene (250.0 mL) and cooled to 10-15°C then slowly triphenyl phosphine (40.1 gr) was added and stirred for 10-15 minutes at the same temperature. Slowly temperature was brought to room temperature and stirred for 2-3 hrs, followed by water (20.0 mL) was added and stirred for 2-3 hrs at 60-65°C. After completion of reaction, separated the water layer and organic layer was dried with anhyd.Na2SO4. To the organic layer acetic anhydride (25.0 mL) was added at 0-50C. The whole reaction mass temperature was slowly brought to room temperature and then temperature raised to 65-70°C and stirred for 1-2 hrs. The reaction mass was cooled to room temperature, filtered and washed with toluene to get crude Linezolid. The crude compound was crystallized in methanol to get pure Linezolid (38.0 gr).

(II). Preparation of Rivaroxaban

Example-8: Preparation of 4-[4-(N-(3-chloro-2R-hydroxy-1-propyl) amino) phenyl] morpholin-3-one (2b)

4-(4-Aminophenyl)-3-morpholinone (100.0 gr) was dissolved in methanol (500.0 mL) at room temperature and (R)-(-) epichlorohydrin (52.7 gr) was added. The whole reaction mass was heated to reflux temperature for 12 hrs. The solvent was distilled under vacuum and isopropyl alcohol (300.0 mL) was added, heated to reflux for 1.0 hr followed by cool to room temperature and stirred for 30 minutes. The separated solid was filtered and dried (2b).

Example-9: Preparation of 4-[4-(3-azido-2R-hydroxy-propylamino)-phenyl]-morpholin-3-one (3b)

To a solution of 4-[4-(N-(3-chloro-2R-hydroxy-1-propyl) amino) phenyl] morpholin-3-one (50.0 gr) in dimethylformamide (250.0 mL) sodium iodide (3.15 gr) was added at 40-45°C. The mixture was stirred at 40-45°C for 45 minutes followed by sodium azide (13.7 gr) was added at same temperature. The whole reaction mass was stirred at 95-100°C for 3-4 hrs. The progress of the reaction was monitored by TLC. After completion of reaction the solvent was distilled out under vacuum below 100°C. The residue was dissolved in dichloromethane (200.0 mL) and water (100.0 mL) and stirred for 10 minutes at room temperature. Two layers were separated and aqueous layer was extracted with dichloromethane (100.0 mL). The organic layers were combined and washed with brine solution (100.0 mL) and organic layer was dried with anhyd. Na2SO4 and distilled under vacuum and added isopropyl ether at room temperature and stirred for 30 minutes, solid product filtered and dried to obtain (3b).

Example-10: Preparation of (R)-4-[4-(5-azido-2-oxo-oxazolidin-3-yl)-phenyl]-morpholin-3-one (4b)

A. Using carbonyldiimidazole (CDI)

A solution of (R)-4-[4-(3-azido-2-hydroxy-propylamino)-phenyl]-morpholin-3-one (3b) (20.0 gr) in dichloromethane (120.0 mL) was placed under nitrogen atmosphere and stirred for 10 minutes for complete dissolution. Carbonyldiimidazole (12.0 gr) was added with stirring. The whole reaction mass was stirred for 4-5 hrs at reflux temperature. The progress of the reaction mass was monitored by TLC analysis. After completion of reaction, the reaction mass was cooled to room temperature and water (50.0 mL) was added and stirred for 10 minutes. Separated the organic layer and aqueous layer extract with dichloromethane (20.0 mL). Both the organic layers were combined and dried with anhydrous Na2SO4. The organic layer was distilled under vacuum, followed by co-distilled with methanol (20.0 mL) and added methanol (50.0 mL) to the whole residue and heated to reflux for 30 minutes, then slowly cool to room temperature and stirred for 25-30 minutes. Solid product separated from the reaction mass was filtered and washed with methanol and dried to get pure compound 4b (18.2 gr).

Example-11: Preparation of (R)-4-[4-(5-azido-2-oxo-oxazolidin-3-yl)-phenyl]-morpholin-3-one (4b)

B. Using diethyl carbonate

A solution of 4-[4-(3-azido-2R-hydroxy-propylamino)-phenyl]-morpholin-3-one (3b) (25.0 gr) in diethyl carbonate (150.0 mL) was prepared and potassium carbonate (25.0 gr) was added with stirring. The whole reaction mass was stirred for 13-14 hrs at reflux temperature. Progress of the reaction mass was monitored by TLC analysis. The reaction mass was distilled under vacuum to get residue. The residue was dissolved in dichloromethane (125.0 mL) and water (100.0 mL) then stirred for 10 minutes at room temperature. The layers were separated and aqueous layer was extracted with dichloromethane (50.0 mL). The combined organic phase was washed with water (50.0 mL) and dried with anhydrous Na2SO4. The organic layer was distilled under vacuum and co-distilled with methanol (20.0 mL) to get the crude mass. Methanol (100.0 mL) was added to the crude and heated to reflux for 30 minutes and then cooled to room temperature and stirred for 20-30 minutes. Separated product was filtered and washed with methanol and dried to obtain compound (4b) (19.6 gr).

Example-12: Preparation of (S)-4-[4-(5-aminomethyl-2-oxo-oxazolidin-3-yl)-phenyl]-morpholin-3-one (5b)

(R)-4-[4-(5-azido-2-oxo-oxazolidin-3-yl)-phenyl]-morpholin-3-one (20.0 gr) dissolved in tetrahydrofuran (120.0 mL) and cooled to 10-150C then slowly added triphenyl phosphine (16.5 gr) and stirred for 10-15 minutes at same temperature. Slowly temperature was raised to room temperature and stirred for 2-3 hrs followed by water (5.0 mL) was added and stirred for 2-3 hrs at 60-650C. After completion of reaction by TLC analysis, distil out the solvent and co-distilled with isopropyl alcohol. Isopropyl alcohol (100.0 mL) was added to the reaction mass and cooled to 10-15°C, followed by IPA.HCl (15.0 mL) was added and stirred for 2-3 hrs at 25-30°C. The precipitated solid was filtered and washed with isopropyl alcohol. The wet compound was dissolved in a water (75.0 mL) and ethyl acetate (100.0 mL), and then PH adjusted to 9.0 to 10.0 with lye solution. Organic layer was separated and aqueous layer extracted with ethyl acetate (40.0 mL). Organic layers were combined and washed with water (40.0 mL) and organic layer was dried with anhyd. Na2SO4 and distilled the solvent completely under vacuum and product isolated in isopropyl ether and dried to obtain (5a) (15.5 gr).

Example-13: Preparation of Rivaroxaban (7b) from oxazolidinone intermediate (compound 4b):
Part-1:
(R)-4-[4-(5-azido-2-oxo-oxazolidin-3-yl)-phenyl]-morpholin-3-one (25.0 gr) was dissolved in tetrahydrofuran (150.0 mL) and cooled to 10-150C then slowly triphenylphosphine (20.7 gr) was added and stirred for 10-15 minutes at same temperature. Slowly temperature was brought to room temperature and stirred for 2-3 hrs. Followed by water (6.0 mL) was added and heat to 60-650 C for 2-3 hrs. After completion of reaction, distilled off the solvent under vacuum to get thick residue and the residue was dissolved in methylenedichloride to precede next step.

Part-2:
Carbonyldiimidazole (15.0 gr) was added slowly to a suspension of 5-chlorothiophene-2-carboxylic acid (12.8 gr) in dichloromethane (125.0 mL) at 0-5°C under nitrogen atmosphere and stirred for 1 hr at room temperature and triethyl amine (TEA) (10.0 gr) was added to the mixture at 0°C and part-1 organic solution was added over a period of 30 minutes at 0-5°C. Slowly temperature was raised to room temperature and stirred for 4-5 hrs at reflux temperature. Water (100.0 mL) was added and stirred for 10 minutes, separated the organic layer and distilled under vacuum. Then isopropyl alcohol (100.0 mL) was added and heated to reflux for 30 minutes, slowly cooled to room temperature, stirred for 20 minutes filtered and dried the solid product to obtained Rivaroxaban (7b).
Example-14: Preparation of Rivaroxaban (7b) from amine intermediate (compound 5b):

Carbonyldiimidazole (12.0 gr) was added slowly to a suspension of 5-chlorothiophene-2-carboxylic acid (10.0 gr) in methylenedichloride (60.0 mL) at 0-5°C, and stirred for 1.0 hr at room temperature, then triethyl amine (7.5 gr) was added to the reaction mixture at 0-5°C followed by adding a solution of (S)-4-[4-(5-aminomethyl-2-oxo-oxazolidin-3-yl)-phenyl]-morpholin-3-one (18.0 gr) in methylenedichloride (100.0 mL) at 0-5°C over a period of 30 minutes. The whole reaction mass was stirred at reflux temperature for 3.0 hrs. Water (100.0 mL) was added, stirred for 20 minutes and separated the organic layer and aqueous layer extract with methylenedichloride (100.0 mL). The organic layers were combined and washed with water, distilled off the organic solvent under vacuum, followed by adding methanol and stirred for 30 minutes. The separated product was filtered and washed with methanol to get the Rivaroxaban (7b).