CLIAMS:We claim:
1. A process for preparation of oxazolidinone derivative compounds of formula (Compound-8)

comprising the steps of:
(i). reacting (S)-epichlorohydrin with a metal azide in an aqueous organic solvent to give an
azido alcohol compound of formula (1);

(ii). cyclizing the azido alcohol compound-1 obtained in step (i) above to an oxirane
compound of formula (2) in an organic solvent in presence of an inorganic base;

(iii). reacting oxirane compound-2 obtained in step (ii) above with a compound of formula (3)



in presence of a solvent to give an azido alcohol compound of formula (4);

(iv). converting azido alcohol compound-4 obtained in step (iii) above to an
oxazolidinone compound of formula (5);

(v). reducing the compound-5 obtained in step (iv) above to an amine compound of
formula (6);

(vi). reacting the amine compound-6 obtained in step (v) above with a compound of
formula (7)

to obtain the desired oxazolidinone derivative compound of formula (8).

2. A process as claimed in claim 1, wherein said metal azide in step (i) is selected from the group consisting of lithium azide (LiN3), sodium azide (NaN3) and potassium azide (KN3).

3. A process as claimed in claim 1, wherein said organic solvent in step (i) is selected from the group consisting of methanol, ethanol, propanol, acetone, dimethyl formamide and butanol.

4. A process as claimed in claim 1, wherein said organic solvent in step (ii) is selected from ketonic solvent, alcoholic solvent or a mixture thereof.

5. A process as claimed in claim 4, wherein said ketonic solvent is selected from the group consisting of acetone, methyl isobutyl ketone and methyl isopropyl ketone.

6. A process as claimed in claim 4, wherein said alcoholic solvent is selected from the group consisting of methanol, ethanol, isopropyl alcohol, n-propanol and tert-butyl alcohol.

7. A process as claimed in claim 1, wherein said inorganic base in step (ii) is selected from the group consisting of potassium carbonate, sodium carbonate, potassium bicarbonate and sodium bicarbonate.

8. A process as claimed in claim 1, wherein the solvent in step (iii) is selected from the group consisting of isopropyl alcohol (IPA), methanol, ethanol, n-propanol and butanol.

9. A process as claimed in claim 1, wherein said azido alcohol compound (4) is converted into oxazolidinone compound (5) by a carbonylating reagent selected from carbonyldiimidazole, diethyl carbonate, methyl chloroformate, benzyl chloroformate, phenyl chloroformate and triphosgene.

10. A process as claimed in claim 9, 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 (5) is reduced to said amine compound (6) 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 reduction is done in presence of a protic or aprotic solvent.

13. A process as claimed in claim 12, wherein said solvent is selected from toluene, tetrahydrofuran, methanol, ethanol, IPA, water and mixture thereof.

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

the obtained oxazolidinone derivative is Linezolid compound (Compound-8a)

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

the obtained oxazolidinone derivative is Rivaroxaban compound (Compound-8b).

16. A process for preparation of Linezolid comprising the steps of:
(i). reacting (S)-epichlorohydrin with a metal azide in an aqueous organic solvent to give (S)-
1-azido-3-chloro- propan-2-ol (Compound-1)

(ii). cyclizing compound-1 obtained in step (i) above to (S)-2-azidomethyl-oxirane
(Compound-2) in an organic solvent in presence of an inorganic base;

(iii). Reacting oxirane compound-2 obtained in step (ii) with 3-fluoro-4-morpholin-4-yl-
phenylamine (Compound-3a)

in presence of a solvent to obtain (R)-1-azido-3-(3-fluoro-4-morpholin-4-yl-phenylamino)- propan-2-ol (Compound-4a);

(iv). converting compound-4a obtained in step (iii) to (R)-5-azidomethyl-3-
(3-fluoro-4-morpholin-4-yl-phenyl)-oxazolidin-2-one (Compund-5a);

(v). reducing compound-5a obtained in step (iv) to (S)-5-aminomethyl-3-(3-
fluoro-4-morpholin-4-yl-phenyl)-oxazolidin-2-one (Compound-6a);

(vi) reacting compound-6a obtained in step (v) above with acetic anhydride (compound-7a)
to obtain Linezolid (Compound-8a).

17. A process as claimed in claim 16, wherein said metal azide in step (i) is selected from the group consisting of lithium azide (LiN3), sodium azide (NaN3) and potassium azide (KN3).

18. A process as claimed in claim 16, wherein said organic solvent in step (i) is selected from the group consisting of methanol, ethanol, propanol, acetone, dimethyl formamide and butanol.

19. A process as claimed in claim 16, wherein said organic solvent in step (ii) is selected from ketonic solvent, alcoholic solvent or a mixture thereof.

20. A process as claimed in claim 19, wherein said ketonic solvent is selected from the group consisting of acetone, methyl isobutyl ketone and methyl isopropyl ketone.

21. A process as claimed in claim 19, wherein said alcoholic solvent is selected from the group consisting of methanol, ethanol, isopropyl alcohol, n-propanol and tert-butyl alcohol.

22. A process as claimed in claim 16, wherein said inorganic base in step (ii) is selected from the group consisting of potassium carbonate, sodium carbonate, potassium bicarbonate and sodium bicarbonate.

23. A process as claimed in claim 16, wherein the solvent in step (iii) is selected from the group consisting of isopropyl alcohol (IPA), methanol, ethanol, n-propanol and butanol.

24. A process as claimed in claim 16, wherein said azido alcohol compound (4a) is converted into oxazolidinone compound (5a) by a carbonylating reagent selected from carbonyldiimidazole, diethyl carbonate, methyl chloroformate, benzyl chloroformate, phenyl chloroformate and triphosgene.

25. A process as claimed in claim 24, 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.

26. A process as claimed in claim 16, wherein said compound (5a) is reduced to said amine compound (6a) in presence of a reducing agent selected from Pd-C/H2, trialkyl and triaryl phosphine.

27. A process as claimed in claim 26, wherein said reduction is done in presence of a protic or aprotic solvent.

28. A process as claimed in claim 27, wherein said solvent is selected from toluene, tetrahydrofuran, methanol, ethanol, IPA, water and mixture thereof.

29. A process for preparation of Linezolid

from (R)-5-azidomethyl-3-(3-fluoro-4-morpholin-4-yl-phenyl)-oxazolidin-2-one (Compund-5a) in one step without isolation of the intermediates, the process comprising:
dissolving (R)-5-azidomethyl-3-(3-fluoro-4-morpholin-4-yl-phenyl)-oxazolidin-2-one (Compund-5a) in toluene or THF and adding triphenyl phosphine followed by acetic anhydride; filtering the solid and recrystallizing in suitable solvent to obtain the purified Linezolid.

30. A process for preparation of Rivaroxaban comprising the steps of:

(i) reacting (S)-epichlorohydrin with a metal azide in an aqueous organic solvent to give (S)-1-azido-3-chloro propan-2-ol (Compound-1)

(ii) cyclizing compound-1 obtained in step (i) above to (S)-azidomethyl-oxirane
(Compound-2) in an organic solvent in presence of an inorganic base;

(iii) reacting compound-2 obtained in step (ii) above with 4-(4-aminophenyl)-3-morpholinone (Compound-3b)

in presence of a solvent to give (R)-4-[4-(3-azido-2-hydroxy-propylamino)phenyl]-morpholin-3-one (Compound-4b);

(iv) converting compound-4b obtained in step (iii) to (R)-4-[4-(5-azidomethyl-2-oxo-oxazolidin-3-yl)-phenyl]-morpholin-3-one (Compund-5b);

(v) reducing compound-5b obtained in step (iv) to (S)-4-[4-(5aminomethyl-2-oxo-oxazolidin-3-yl)-phenyl]-morpholin-3-one (Compound-6b);

(vi) reacting compound-6b obtained in step (v) above with a compound of formula
(Compound-7b)

to obtain Rivaroxaban (Compound-8b).

31. A process as claimed in claim 30, wherein said metal azide in step (i) is selected from the group consisting of lithium azide (LiN3), sodium azide (NaN3) and potassium azide (KN3).

32. A process as claimed in claim 30, wherein said organic solvent in step (i) is selected from the group consisting of methanol, ethanol, propanol, acetone, dimethyl formamide and butanol.

33. A process as claimed in claim 30, wherein said organic solvent in step (ii) is selected from ketonic solvent, alcoholic solvent or a mixture thereof.

34. A process as claimed in claim 33, wherein said ketonic solvent is selected from the group consisting of acetone, methyl isobutyl ketone and methyl isopropyl ketone.

35. A process as claimed in claim 33, wherein said alcoholic solvent is selected from the group consisting of methanol, ethanol, isopropyl alcohol, n-propanol and tert-butyl alcohol.
36. A process as claimed in claim 30, wherein said inorganic base in step (ii) is selected from the group consisting of potassium carbonate, sodium carbonate, potassium bicarbonate and sodium bicarbonate.

37. A process as claimed in claim 30, wherein the solvent in step (iii) is selected from the group consisting of isopropyl alcohol (IPA), methanol, ethanol, n-propanol and butanol.

38. A process as claimed in claim 30, wherein said azido alcohol compound (4b) is converted into oxazolidinone compound (5b) by a carbonylating reagent selected from carbonyldiimidazole, diethyl carbonate, methyl chloroformate, benzyl chloroformate, phenyl chloroformate and triphosgene.

39. A process as claimed in claim 38, 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.

40. A process as claimed in claim 30, wherein said compound (5a) is reduced to said amine compound (6a) in presence of a reducing agent selected from Pd-C/H2, trialkyl and triaryl phosphine.
41. A process as claimed in claim 40, wherein said reduction is done in presence of a protic or aprotic solvent.

42. A process as claimed in claim 41, wherein said solvent is selected from toluene, tetrahydrofuran, methanol, water and mixture thereof.

43. A process for preparation of Rivaroxaban

From (R)-4-[4-(5-azidomethyl-2-oxo-oxazolidin-3-yl)-phenyl]-morpholin-3-one Compund-5b) in one step without isolation of the intermediates, the process comprising:
dissolving (R)-4-[4-(5-azidomethyl-2-oxo-oxazolidin-3-yl)-phenyl]-morpholin-3-one (Compund-5b) in toluene or THF and adding triphenyl phosphine followed by addition of water and vaccume distillation to obtain thick residue; dissolving the residue in methylene dichloride and adding to a pre-prepared suspension of 5-chlorothiophene-2-carboxylic acid (compound 7b) in dichloromethane and cabonyldiimidazole; stirring at reflux temperature and distilling the organic layer; adding isopropyl alcohol and filtering the solid as Rivaroxaban and recrystallizing in suitable solvent to obtain the purified Rivaroxaban.
,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 using (S)-Epichlorohydrin.

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 show 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
Applicant’s pending Indian Patent Application No. 1715/CHE/2013 describes a combined process for preparation of Linezolid and Rivaroxaban using (R)-Epichlorohydrin as starting material as illustrated below as Scheme-VI.

Scheme-VI
(R)-Epichlorohydrin has been conventionally used as starting material for preparation of oxazolidinone derivatives like Linezolid and Rivaroxaban. In the above referred patents/patent applications, wherever, Epichlorohydrin is used in the process, it is always the (R)-Epichlorohydrin.
Madhusudhan Gutta et. al., ARKIVOC 2012 (vi) 45-56 describes synthesis of Linezolid utilizing (S)-1-azido-3-chloropropan-2-yl chloroformate (3a) or (S)-1- phthalimido-3- chloropropan-2-yl chloroformate (3b) as a key starting material, which reacts with 3-Fluoro-4-morpholin-4-yl-phenylamine in presence of potassium carbonate in acetone to give corresponding 2-oxazolidinone (6a or 6b). Reduction of compound 6a and treating with acetic anhydride or treating compound 6b with hydrazine hydrate followed by treating with acetic anhydride results Linezolid.

The staring materials are prepared by reaction of (S)-Epicholorohydrin with NaN3 in presence of AcOH and H2O, in ambient temperature for 5 h or with Phthalimide in presence of K2CO3 (cat.), IPA, with reflux for 5 h and further treating the corresponding product with triphosgene in presence of Et3N and THF.

Below scheme-VII gives the outline of the above described process for Linezolid.

Reagents and conditions: (a) NaN3, AcOH, H2O, ambient temperature, 5 h, 80%; (b)
Phthalimide, K2CO3 (cat.), IPA, reflux, 5 h, 75%; (c) Triphosgene, Et3N, THF, 0 °C to r.t.,
2-3 h,72-89%.

Scheme-VII
Reagents and conditions: (a) K2CO3, Acetone, r.t., overnight, 82-86%; (b) H2, Pd/C, Ac2O, MeOH, 20 psi, r.t., 3 h, 85%; (c) (i) Hydrazine hydrate, MeOH, reflux, 1 h; (ii) Ac2O, Toluene, r.t., 1 h, 70%.

Chinese publication No. CN 102321041 describes a reaction of (S)-epichlorohydrin and sodium azide to obtain 1-azido-3-chloro-2-propanol; cyclizing 1-azido-3-chloro-2-propanol with N-(3-fluoro-4-morpholinophenyl)amine; and finally, reducing and acetylizing to obtain the linezolid as shown below in scheme-VIII:

Scheme-VIII

G. Madhusudhan et. al., Der Pharma Chemia, 2011, 3 (5): 168-175 describes preparation of 2-((R)-3-(3-fluoro-4-morpholinophenylamino)-2-hydroxypropyl)isoindoline-1,3-dione as a key intermediate for synthesis of Linezolid, starting from (S)-epichlorohydrin and phthalimide in presence of isopropanol (IPA) and potassium carbonate (K2CO3).

International Publication WO 2007/116284 describes preparation of Linezolid by reacting (S)-(+)-Epichlorohydrin with a mixture of substituted benzaldehyde derivative and aqueous ammonia in presence of solvents such as alcohols, ethers and methylene chloride to form the key starting material and further to Linezolid as outlined below in scheme-IX:

Scheme-IX

International Publication WO 2012/159992 relates to a process for preparation of Rivaroxaban using (S)-Epichlorohydrin as shown below in scheme- X:

Leaving group L= OR2, wherein R2 is (C1-C15)alkyl, aryl, aryl (C1-C4) alkyl, hetroaryl or heteroaryl-(C1-C4)alkyl.
Scheme-X
In the above scheme 4-(4-Amino-phenyl)-morpholin-3-one (1) reacts with benzyl chloro formate (18a) or dodecyl chloroformate (18b) to give benzyl (4-(3-oxomorpholin)phenyl)- carbamate (19a) dodecyl (4-(3-oxomorpholin)phenyl)carbamate (19b) respectively. (S)-(+)-Epichlorohydrin reacts with 4-chlorobenzaldehyde (21a) or benzaldehyde (21b) in presence of aqueous ammonia to give (S)-1-chloro-3-[(4-chlorobenzylidine)-amino]-propan-2-ol (22a) or (S)-3-(benzylidineamino)-1-chloro-propan-2-ol (22b) respectively. Reaction of compounds 19a with 22a or 19b with 22b gives intermediate (S)-4-[4-(5{[4-chlorobenzylidine)-amino]-methyl}-2-oxo-oxazolidin-3-yl)-phenyl]-morpholin-3-one (23a) or (S)-4-[4-(5{[benzylidine)-amino]-methyl}-2-oxo-oxazolidin-3-yl)-phenyl]-morpholin-3-one (23b) respectively. Further fragmentation of N=C bond of the intermediate compound 23a or 23b , followed by acylation of resulting intermediate with 5-chloro-thiophene-2-carbonyl chloride in a solvent medium in presence of a base gives Rivaroxaban.
US20110275805 discloses a method for preparation of Linezolid starting from (S)-Epichlorohydrin wich reacts with dibenzyl amine as described in below scheme-XI:-

Scheme-XI
It is apparent from the above that conventionally (R)- Epichlorohydrin has been the preferred choice for preparation of Linezolid or Rivaroxaban. However, some prior arts have also disclosed using (S)-Epichlorohydrin as starting material for preparation of Linozolid or Rivaroxaban. But, in addition to lacking in commercial viability, none of the prior arts discloses a process using (S)-Epichlorohydrin 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 using (S)- Epichlorohydrin.

Another object of the invention is to provide a novel combined process for preparation of Linezolid and Rivaroxaban using (S)- Epichlorohydrin.

Another object of the invention is to provide a novel process for preparation of Linezolid compounds using (S)- Epichlorohydrin.

Another object of the invention is to provide a novel process for preparation of Rivaroxaban compounds using (S)- Epichlorohydrin .

SUMMARY OF THE INVENTION

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

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

The novel process uses (S)-Epichlorohydrin as the starting material which reacts with a metal azide to give an azido alcohol compound (Compound-1), subsequently cyclizing compound-I to an oxirane compound (Compound-2) in presence of an inorganic base as follows:

The novel process comprises the steps of:

(i) reacting (S)-Epichlorohydrin with a metal azide to give an azido alcohol compound-1

(ii) cyclizing the azido alcohol compound-1 obtained in step (i) above to an oxirane compound-2 in organic solvents in presence of an inorganic base;

(iii) reacting oxirane compound-2 obtained in step (ii) above with a compound-3 in presence of solvents;

to give an azido alcohol compound of formula (Compound-4);

(iv) converting azido alcohol compound-4 obtained in step (iii) above to an oxazolidinone compound of formula (Compund-5);

(v) reducing the compound-5 obtained in step (iv) above to an amine compound of formula (Compound-6);

(vi) reacting the amine compound-6 obtained in step (v) above with a (Compound-7)

to obtain the desired oxazolidinone derivative compound of formula (Compound-8).

R1 is as described above in step (iii).

In one embodiment of the invention, when-

the obtained oxazolidinone derivative is Linezolid compound (Compound-8a).

In another embodiment of the invention, when-

the obtained oxazolidinone derivative is Rivaroxaban compound (Compound-8b).

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 using (S)-Epichlorohydrin. More particularly, the invention specifically provides a process which can be used for the preparation of Linezolid as well as Rivaroxaban compounds using (S)-Epichlorohydrin.

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 starting from reaction of (S)-Epichlorohydrin and a metal azide as follows:

Scheme-A

In an exemplary embodiment, the process comprises the steps of:

Step-I: -Reacting (S)-Epichlorohydrin with a metal azide to give an azido alcohol
compound of formula (Compound-1)

This step comprises dissolving metal azide in water at room temperature and adding (S)-Epichlorohydrin in a suitable organic solvent. Stir the reaction mixture at 5-10°C for 1hour and allowing the reaction mixture to reach to room temperature for 3-4 hrs.

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 suitable organic solvent may be selected from methanol, ethanol, propanol, acetone , dimethyl formamide and butanol. In one preferred embodiment the organic solvent is methanol.

Step-II: -Cyclizing the azido alcohol compound-1 obtained in Step-(I) above to an oxirane compound-2 in presence of an inorganic base

This step comprises cyclizing the compound-1 in presence of an inorganic base in a suitable organic solvent . In one preferred embodiment the inorganic base is potassium carbonate.

Step-III: Reacting the oxirane compound-2 obtained in Step-II above with a compound-3


to give an azido alcohol compound of formula (Compound-4);

This step involves addition of compound-3 to a solution of compound-2 in alcoholic solvent at room temperature.

The reaction can be carried out in any suitable alcoholic solvent selected from methanol, ethanol, isopropyl alcohol (IPA), propanol and butanol. In one preferred embodiment, isopropyl alcohol is used.

Step-IV: -Converting azido alcohol compound-4 obtained in Step-III above to an
oxazolidinone compound-5

The step-IV comprises dissolving azide compound-4 in a suitable organic solvent and carbonylating using carbonylating reagents to obtain compound-5. The carbonylation reaction is carried out by using any carbonylating reagents such as carbonyldiimidazole (CDI), 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.
In one embodiment the inorganic base is metal carbonate selected from potassium carbonate and sodium carbonate. Preferably in one embodiment the metal carbonate is potassium carbonate.

Step-V: -Reducing the compound-5 obtained in Step-IV above to an amine compound-6

The compound-5 is dissolved in an organic solvent and reduced to amine compound-6 using a reducing agent. The reducing agent may be selected from Pd-C/H2 and triphenyl phosphine (TPP). In one preferred embodiment, triphenyl phosphine (TPP) is used as reducing agent.

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

Step-VI:-reacting the amine compound-6 obtained in Step-V above with a compound-7

to obtain the desired oxazolidinone derivative compound of formula (Compound-8).

R1 is as described above in step (iii).
This step comprises reacting compound (6) with compound (7) in an organic solvent under suitable conditions to get the crude oxazolidinone derivative compound (8). Crystallizing the crude compound (8) in suitable solvent to get pure compound (8).

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 compound-8.

In an exemplary embodiment, the oxazolidinone derivatives compound of formula (Compound-8) 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:

Step-I. Reacting (S)-Epichlorohydrin with a metal azide to give (S)-1-azido-3-chloro-
propan-2-ol (Compound-1);

Step-II. Cyclizing the compound-1 obtained in step (I) above to (S)-2- azidomethyl-oxirane (Compound-2) in presence of an inorganic base;

Step-III. Reacting compound-2 obtained in step (II) above with 3-fluoro-4-morpholin-4-
yl-phenylamine (Compound-3a) in presence of organic solvents;

to give (R)-1-azido-3-(3-fluoro-4-morpholin-4-yl-phenylamino)-propan-2-ol (Compound-4a);

Step-IV. Converting compound-4a obtained in step (III) above to (R)-5-azidomethyl-3-(3-
fluoro-4-morpholin-4-yl-phenyl)-oxazolidin-2-one (Compund-5a);

Step-V. Reducing compound-5a obtained in step (IV) above to (S)-5-aminomethyl-3-(3-
fluoro-4-morpholin-4-yl-phenyl)-oxazolidin-2-one (Compound-6a);

Step-VI. Reacting compound-6a obtained in step (V) above with acetic anhydride
(Compound-7a) to obtain Linezolid (Compound-8a).

The Step (I) in above described Scheme-B comprises reacting (S)-Epichlorohydrin with a metal azide in a suitable organic solvent at ambient temperature to give (S)-1-azido-3-chloro-propan-2-ol (Compound-1), wherein 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 suitable organic solvent may be selected from methanol, ethanol, propanol, acetone , dimethyl formamide and butanol. In one preferred embodiment the organic solvent is methanol.

The step-II in above Scheme-B comprises dissolving (S)-1-azido-3-chloro-propan-2-ol (Compound-1) in suitable organic solvent in presence of an inorganic base and refluxing for 3-4 hr at reflux temperature. Distilling and dissolving the residue in water and ethyl acetate at room temperature with stir for 5-10 minutes and separating and distill out organic solvent to get crude (S)-2-azidomethyl-oxirane (Compound-2).

The organic solvent may be ketonic solvent, alcoholic solvent or a mixture thereof. The ketonic solvent may be selected from acetone, methyl isobutyl ketone, methyl isopropyl ketone . The alcohlic solvent may be selected from methanol, ethanol, propanol, isopropanol, n-butanol.

In one preferred embodiment the ketonic solvent is acetone and alcohlic solvent is isopropyl alcohol.

The inorganic base may be selected from potassium carbonate, sodium carbonate, potassium bicarbonate and sodium bicarbonate In one preferred embodiment the inorganic base is potassium carbonate.

The step-III in above described scheme-B involves addition of 3-fluoro-4-morpholin-4 yl-phenylamine (Compound-3a) to a solution of (S)-2-azidomethyl-oxirane compound-2 in an alcoholic solvent at room temperature. Heating the reaction mass to reflux temperature for 10-12 hrs, distilling the solvent under vacuum to obtain the crude (R)-1-azido-3-(3-fluoro-4-morpholin-4-yl-phenylamino)-propan-2-ol (Compound-4a). Further treating with dichloromethane and water; separating and extracting with dichloromethane and distilling under vacuum to get (R)-1-azido-3-(3-fluoro-4-morpholin-4-yl-phenylamino)-propan-2-ol (Compound-4a).

The reaction can be carried out in any suitable alcoholic solvent selected from isopropyl alcohol (IPA), methanol, ethanol, propanol and butanol. In one preferred embodiment, isopropyl alcohol is used.
The step-IV in above described scheme-B comprises dissolving (R)-1-azido-3-(3-fluoro-4-morpholin-4-yl-phenylamino)-propan-2-ol (Compound-4a) in a suitable organic solvent and carbonylating using carbonylating reagents to obtain (R)-5-azidomethyl-3-(3-fluoro-4-morpholin-4-yl-phenyl)-oxazolidin-2-one (Compund-5a). 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.
In one embodiment the inorganic base is metal carbonate selected from potassium carbonate and sodium carbonate. Preferably in one embodiment the metal carbonate is potassium carbonate.

The step-V in above described scheme-B comprises dissolving (R)-5-azidomethyl-3-(3-fluoro-4-morpholin-4-yl-phenyl)-oxazolidin-2-one (Compund-5a) in an organic solvent and reduced to (S)-5-aminomethyl-3-(3-fluoro-4-morpholin-4-yl-phenyl)-oxazolidin-2-one (Compound-6a) using a reducing agent. The reducing agent may be selected from Pd-C/H2 and triphenyl phosphine. In one preferred embodiment, triphenyl phosphine (TPP) is used as reducing agent.

The reduction reaction is carried out in solvent selected from protic and aprotic solvents or mixtures thereof. In one preferred embodiment, the solvents are toluene,tetrahydrofuran, isopropyl alcohol (IPA) and mixture thereof.

The step-VI in above described scheme-B comprises adding acetic anhydride (compound-7a) at 0-5°C to a solution of (S)-5-aminomethyl-3-(3-fluoro-4-morpholin-4-yl-phenyl)-oxazolidin-2-one (Compound-6a) 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 70°C based on choosen solvent and stirring for 1-2 hrs. Cooling the reaction mass to room temperature, filtering and washing the mass to get crude oxazolidinone derivative Linezolid (compound-8a). Crystallizing the crude Linezolid (compound-8a) in suitable solvent selected from acetic acid, methanol, ethanol, propanol, isopropanol and butanol to get pure Linezolid (compound-8a). In preferred embodiment the suitable solvent is used methanol.

The organic solvent may be selected from methylene dichloride (MDC), toluene, tetrahydrofuran, acetonitrile, chloroform . In one preferred embodiment the organic solvent
methylene dichloride is used.

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:

Step-I: Reacting (S)-epichlorohydrin with a metal azide to give (S)-1-azido-3-chloro-
propan-2-ol (Compound-1)

Step-II: Converting compound-1 obtained in step (I) above to (S)-Azidomethyl-oxirane
(Compound-2) in presence of an inorganic base;

Step-III: Reacting compound-2 obtained in step (II) above with 4-(4-aminophenyl)-3-
morpholinone (Compound-3b) in presence of alcoholic solvents;

to give (R)-4-[4-(3-azido-2-hydroxy-propylamino) phenyl]-morpholin-3-one (Compound-4b);

Step-IV: Converting compound-4b obtained in step (III) above to (R)-4-[4-(5-azidomethyl-
2-oxo-oxazolidin-3-yl)-phenyl]-morpholin-3-one (Compund-5b);

Step-V: Reducing compound-5b obtained in step (IV) above to (S)-4-[4-(5-aminomethyl-
2-oxo-oxazolidin-3-yl)-phenyl]-morpholin-3-one (Compound-6b);

Step-VI: Reacting compound-6b obtained in step (v) above with a compound of formula
(Compound-7b)

to obtain Rivaroxaban (Compound-8b).

The Step (I) in above described Scheme-B comprises reacting (S)-Epichlorohydrin with a metal azide in a suitable organic solvent at ambient temperature to give (S)-1-azido-3-chloro-propan-2-ol (Compound-1), wherein 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 suitable organic solvent may be selected from methanol, ethanol, propanol, acetone , dimethyl formamide and butanol. In one preferred embodiment the organic solvent is methanol.

The step-II in above Scheme-B comprises dissolving (S)-1-azido-3-chloro-propan-2-ol (Compound-1) in suitable organic solvent in presence of an inorganic base and refluxing for 3-4 hr at reflux temperature. Distilling and dissolving the residue in water and ethyl acetate at room temperature with stir for 5-10 minutes and separating and distill out organic solvent to get crude (S)-2-azidomethyl-oxirane (Compound-2).

The organic solvent may be ketonic solvent, alcoholic solvent or a mixture thereof. The ketonic solvent may be selected from acetone, methyl isobutyl ketone, methyl isopropyl ketone . The alcohlic solvent may be selected from methanol, ethanol, propanol, isopropanol, n-butanol.

In one preferred embodiment the ketonic solvent is acetone and alcohlic solvent is isopropyl alcohol.
The inorganic base may be selected from potassium carbonate, sodium carbonate, potassium bicarbonate and sodium bicarbonate In one preferred embodiment the inorganic base is potassium carbonate.

Step-III in the above described scheme-C comprises addition of 4-(4-aminophenyl)-3-morpholinone (Compound-3b) to a solution of (S)-azidomethyl-oxirane compound-2 in alcoholic solvent at room temperature. Heating the reaction mass to reflux temperature for 10-12 hrs, distilling the solvent under vacuum to obtain the crude (R)-4-[4-(3-azido-2-hydroxy-propylamino) phenyl]-morpholin-3-one (Compound-4b).

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

The step-IV in above described scheme-C comprises dissolving (R)-4-[4-(3-azido-2-hydroxy-propylamino) phenyl]-morpholin-3-one (Compound-4b) in a suitable organic solvent and carbonylating using carbonylating reagents to obtain (R)-4-[4-(5-azidomethyl-2-oxo-oxazolidin-3-yl)-phenyl]-morpholin-3-one (Compund-5b). 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.

In one embodiment the inorganic base is metal carbonate selected from potassium carbonate and sodium carbonate. Preferably in one embodiment the metal carbonate is potassium carbonate.

The step-V in above described scheme-C comprises dissolving (R)-4-[4-(5-azidomethyl-2-oxo-oxazolidin-3-yl)-phenyl]-morpholin-3-one (Compund-5b) in an organic solvent and reduced to (S)-4-[4-(5-aminomethyl-2-oxo-oxazolidin-3-yl)-phenyl]-morpholin-3-one (Compound-6b) using a reducing agent. The reducing agent may be selected from Pd-C/H2 and triphenyl phosphine. In one preferred embodiment, triphenyl phosphine (TPP) is used as reducing agent.

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

The step-VI in above described scheme-C comprises dissolving the (S)-4-[4-(5-aminomethyl-2-oxo-oxazolidin-3-yl)-phenyl]-morpholin-3-one (Compound-6b) in an organic solvent reacted with 5-chlorothiophene-2-carboxylic acid (compound-7b) using CDI and base or with 5-chlorothiophene-2-carbonyl chloride (compound-7b) in presence of base at suitable temperature. Followed by simple an aqueous workup to get the crude Rivaroxaban (compound-8b) . Crystallizing the crude Rivaroxaban (compound-8b) in suitable solvent to get pure Rivaroxaban (compound-8b).

EXAMPLES:
The invention is further described in more detailed way in the following examples.

(I). Preparation of Linezolid

Example-1:- Preparation of (S)-1-azido-3-chloro-propan-2-ol (compound-1)

Sodium azide (85.0 gr, 1.3 mol) was dissolved in water (400.0 mL) at room temperature, cool to 5-10°C then add ammonium chloride (70.0 gr, 1.3 mol) and (S)-Epichlorohydrin (100.0 gr, 1.08 mol) in methanol (100.0 mL) was added. The reaction mixture was stirred for 1 hr at 5-10°C, and then allowed to reach the temp up to RT for 3-4 hrs. Reaction mass extracted with ethyl acetate (2 x 200.0 mL). The combined extracts were washed with water. The organic layer dried over anhydrous Na2SO4 and distill out to get (S)-1-azido-3-chloro-propan-2-ol (compound 1).

Example-2:- Preparation of (S)-2-azidomethyl oxirane (compound 2)

To a solution of (S)-1-azido-3-chloropropan-2-ol (compound 1) (100.0 gr, 0.738 mol), acetone (400.0 mL) and potassium carbonate (200.0 gr, 1.45 mol) was added at room temperature. The reaction mixture was stirred at reflux temperature for 3-4 hr. The progress of the reaction was monitored by GC. After completion of reaction filter the solids and proceeded to distillation under vacuum to get the residue. The residue dissolve in water (100.0 mL) and ethyl acetate (300.0 mL) then stir for 5 to 10 min at RT. Separate the organic layer and distill out under vacuum to get the (S)-2-azidomethyl oxirane (compound 2).

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

(S)-2-azidomethyl oxirane (compound 2) (50.0 gr, 0.5 mol) was taken in isopropyl alcohol (375.0 mL) and 3-fluoro-4-morpholin-4-yl-phenylamine (compound 3a) (74.3 gr, 0.378 mol) was added at room temperature. The whole reaction mass was heated to reflux temperature for 10-12 hrs. The progress of the reaction was monitored by TLC. After completion of reaction distil off the solvent under vacuum to get residue. Followed by simple an aqueous work up, the residue was dissolved in dichloromethane (400.0 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 (150.0 mL). The combined organic phase was washed with water (150.0 mL) and dried with anhydrous Na2SO4. The organic layer was distilled under vacuum to get residue .

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.

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

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

A. Using carbonyldiimidazole (CDI)
To a solution of (R)-1-azido-3-(3-fluoro-4-morpholin-4-yl-phenylamino)-propan-2-ol (compound 4a) (10.0 gr, 0.033 mol) in dichloromethane (50.0 mL) under nitrogen atmosphere and stirred for 10 min for complete dissolution, followed by carbonyldiimidazole (6.58 gr, 0.04 mol) 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 (25.0 mL) was added and stirred for 10 minutes and organic layer was separated. Aqueous layer was extracted with dichloromethane (15.0 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 (10.0 mL) to get the very thick residue. To the residue methanol (20.0 mL) was added 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 (compound 5a) (8.6 gr).

B. Using diethyl carbonate
(R)-1-azido-3-(3-fluoro-4-morpholin-4-yl-phenylamino)-propan-2-ol (compound 4a) (20.0 gr, 0.067 mol) in diethyl carbonate (50.0 mL) and potassium carbonate (23.36 gr, 0.169 mol) 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, distil off the solvent under vacuum to get residue. The residue was dissolved in dichloromethane (100.0 mL) and water (100.0 mL) then stirred for 10 min at room temperature. The layers were separated and aqueous layer was extracted with dichloromethane (40.0 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) followed by methanol (40.0 mL) was added and the reaction mass 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 (10.0 mL) and dried to get pure compound (compound 5a) (16.0 gr).

Example-5:- Preparation of (R)-1-azido-3-(3-fluoro-4-morpholin-4-yl-phenylamino) propan-2-ol (compound 4a) from (S)-1-azido-3-chloro-propan-2-ol (compound-1) in single step:

(S)-1-azido-3-chloropropan-2-ol (compound-1) (100.0 gr, 0.738 mol) dissolved in isopropyl alcohol (500.0 mL) and potassium carbonate (200.0 gr, 1.45 mol) was added at room temperature. The reaction mixture was heated to reflux and maintained at reflux temperature for 3-4 hr. The insoluble materials was filtered and proceeded to next step. 3-fluoro-4-morpholin-4-yl-phenylamine (compound 3a) (108.6 gr, 0.553 mol) was added to the above isopropyl alcohol reaction mass. The whole reaction mass was heated to reflux temperature for 10-12 hrs. The progress of the reaction was monitored either by TLC or HPLC. After completion of reaction distil off the solvent to get residue. 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 (200.0 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. 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.

Example-6:- Preparation of (R)-5-azidomethyl-3-(3-fluoro-4-morpholin-4-yl-phenyl)-oxazolidin-2-one (compound 5a) from (S)-1-azido-3-chloro-propan-2-ol (compound-1) in single step:

A solution of (S)-1-azido-3-chloropropan-2-ol (compound-1) (100.0 gr, 0.738 mol) in isopropyl alcohol (500.0 mL) and potassium carbonate (200.0 gr, 1.45 mol) was added at room temperature. The reaction mixture was heated to reflux and maintained at 1-2 hr then cool to RT then 3-fluoro-4-morpholin-4-yl-phenylamine (compound 3a) (108.6 gr, 0.553 mol) was added to the above isopropyl alcohol reaction mass at room temperature. The whole reaction mass was heated to reflux temperature for 10-12 hrs. The progress of the reaction was monitored by TLC. After completion of reaction filter the insoluble materials and distil off the solvent to get residue (compound 4a). The residue was dissolved in dichloromethane (500.0 mL) under nitrogen atmosphere and stirred for 10 min for complete dissolution, followed by carbonyldiimidazole (107.7 gr, 0.664 mol) 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 (500 .0 mL) was added and stirred for 10 minutes and organic layer was separated. Aqueous layer was extracted with dichloromethane (200.0 mL). Both the organic layers were combined and add water (400.0 mL) and PH of the reaction mass adjusted to 1.0 with hydrochloric acid. Separate the aqueous layer and organic layer, followed by add water to the organic layer and reaction mass PH adjusted to 8.0-8.5 with sodium hydroxide solution. Separate the organic layer and extract the aqueous layer with methylene dichloride (100.0 mL). Combine both the organic layers and dried with anhydrous Na2SO4. The organic layer was distilled under vacuum, followed by co-distilled with methanol (100.0 mL) to get the residue. Followed by methanol (200.0 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 compound (compound 5a).

Example-7:- Preparation of (S)-5-aminomethyl-3-(3-fluoro-4-morpholin-4-yl-phenyl)
-oxazolidin-2-one (compound 6a)

(R)-5-azidomethyl-3-(3-fluoro-4-morpholin-4-yl-phenyl)-oxazolidin-2-one (compound 5a) (20.0 gr, 0.062 mol) in toluene (120.0 mL) and cooled to 10-15°C then slowly added triphenyl phosphine (16.32 gr, 0.062 mol) 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 60-65°C. 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 methylene dichloride (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 methylene dichloride (50.0 mL). Organic layers were combined and washed with water (40.0 mL) and organic layer was dried with anhydrous. Na2SO4 and distilled the solvent completely under vacuum and product isolated in isopropyl ether and dried to obtain (compound 6a) (14.0 gr).

Example-8: Preparation of Linezolid (8a) from compound (6a)

To a solution of (S)-5-aminomethyl-3-(3-fluoro-4-morpholin-4-yl-phenyl)-oxazolidin-2-one (compound 6a) (10.0 gr, 0.033 mol) in methylene dichloride (25.0 mL), acetic anhydride (compound 7a) (6.0 mL) was added at 0-5°C. Slowly temperature was raised to room temperature and heated reflux temperature and stirred for 1-2 hrs. The reaction mass was distilled and add methanol (20.0 mL) then stirred at room temperature for 10-15 min, filtered and wash with methanol to get crude Linezolid. The crude compound was crystallized in methanol to get pure Linezolid (compound 8a) (8.5 gr).

Example-9: Preparation of Linezolid (8a) from compound (5a) in single step:

(R)-5-azidomethyl-3-(3-fluoro-4-morpholin-4-yl-phenyl)-oxazolidin-2-one (compound 5a) (25.0 gr, 0.077 mol) was dissolved in toluene (125.0 mL) and cooled to 10-15°C then slowly triphenyl phosphine (20.05 gr, 0.077 mol) 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 (10.0 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 anhydrous Na2SO4. To the organic layer acetic anhydride (compound 7a) (12.5 mL) was added at 0-5°C. The whole reaction mass was stirred at 65-70°C for 1-2 hrs. The reaction mass was cooled to room temperature, precipitated product was filtered and washed with methanol to get crude Linezolid. The crude compound was crystallized in methanol to get pure Linezolid (compound 8a) (18.0gr).

Example-10: Preparation of Linezolid (8a) from 5a in a single pot process:

(R)-5-azidomethyl-3-(3-fluoro-4-morpholin-4-yl-phenyl)-oxazolidin-2-one (5a) (25.0 gr, 0.077 mol) was dissolved in toluene (100.0 mL) and cooled to 0-5°C then slowly triphenyl phosphine (20.05 gr, 0.077 mol) and acetic anhydride (25.0 mL) was added and stirred for 45-50 minutes at the same temperature. Slowly temperature was brought to room temperature and stirred for 2-3 hrs. The progress of the reaction was monitored by TLC. After completion of reaction, separated solid was filtered and washed with toluene and water, followed by drying at 60-70°C. The crude compound was crystallized in methanol to get pure Linezolid (8a) (17.5 gr).

(II). Preparation of Rivaroxaban

Example-11: Preparation of (R)-4-[4-(3-azido-2-hydroxy-propylamino) phenyl]-morpholin-3-one (4b) from (S)-2-Azidomethyl oxirane (compound 2)

Compound (1) and compound (2) were prepared according to Example-1 and Example-2 respectively, as described above.

(S)-2-Azidomethyl oxirane (compound 2) (25.0 gr, 0.25 mol) was dissolved in isopropyl alcohol (180.0 mL) and 4-(4-aminophenyl)-3-morpholinone (compound 3b) (36.5 gr, 0.19 mol) was added at room temperature. The whole reaction mass was heated to reflux temperature for 10-12 hrs. The progress of the reaction was monitored by TLC. After completion of reaction and distil off the solvent to get residue. The residue was dissolved in dichloromethane (150.0 mL) and water (100.0 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 to get residue .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.

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

A. Using carbonyldiimidazole (CDI)
To a solution of (R)-4-[4-(3-azido-2-hydroxy-propylamino)phenyl]-morpholin-3-one (compound 4b) (20.0 gr, 0.068 mol) in dichloromethane (100.0 mL) under nitrogen atmosphere and stirred for 10 min for complete dissolution, followed by carbonyldiimidazole (13.36 gr, 0.082 mol) was added with stirring. The whole reaction mass was stirred for 3-4 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 (100 .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 (30.0 mL) to get the very thick residue. To the residue methanol (60.0 mL) was added 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 and it was filtered washed with methanol to get pure compound (5b) (17.0 gr).

B. Using diethyl carbonate
(R)-4-[4-(3-azido-2-hydroxy-propylamino) phenyl]-morpholin-3-one (compound 4b) (10.0 gr, 0.034 mol) in diethyl carbonate (25.0 mL) and potassium carbonate (9.5 gr, 0.068 mol) 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, distil off the solvent under vacuum to get residue. The residue was dissolved in dichloromethane (60.0 mL) and water (30.0 mL) then stirred for 10 min at room temperature. The layers were separated and aqueous layer was extracted with dichloromethane (30.0 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) followed by methanol (30.0 mL) was added and the reaction mass heated to reflux for 30 minutes and then cooled to room temperature. Solid product was thrown out from reaction mass and stirred for 30 minutes. Precipitated solid was filtered and washed with methanol (5.0 mL) and dried to get pure compound (5b) (7.5 gr).

Example-13: Preparation of (R)-4-[4-(3-azido-2-hydroxy-propylamino) phenyl]-morpholin-3-one (compound 4b) from (S)-1-azido-3-chloro-propan-2-ol (compound 1) in single step:

(S)-1-azido-3-chloropropan-2-ol (compound 1) (50.0 gr, 0.369 mol) dissolved in isopropyl alcohol (250.0 mL) and potassium carbonate (100.0 gr, 0.724 mol) was added at room temperature. The reaction mixture was heated to reflux and maintained at reflux temperature for 3-4 hr. The insoluble materials was filtered and proceeded to next step. 4-(4-aminophenyl)-3-morpholinone (compound 3b) (53.2 gr, 0.276 mol) was added to the above isopropyl alcohol reaction mass. The whole reaction mass was heated to reflux temperature for 10-12 hrs. The progress of the reaction was monitored by TLC. After completion of reaction distil off the solvent to get residue. Followed by simple an aqueous work up, the residue was dissolved in dichloromethane (300.0 mL) and water (200.0 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 product. 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 methanol.

Example-14: Preparation of (S)-4-[4-(5-aminomethyl-2-oxo-oxazolidin-3-yl)-phenyl]-morpholin-3-one (compound 6b)

(R)-4-[4-(5-azidomethyl-2-oxo-oxazolidin-3-yl)-phenyl]-morpholin-3-one (compound 5b)
(25.0 gr,0.078 mol) in tetrahydrofuran (125.0 mL) and cooled to 10-15°C then slowly added triphenyl phosphine (20.66 gr, 0.078 mol) 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 (10.0 mL) was added and stirred for 2-3 hrs at 60-65°C. 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 (18.0 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 methylene dichloride (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 methylene dichloride (50.0 mL). Organic layers were combined and washed with water (40.0 mL) and organic layer was dried with anhydrous. Na2SO4 and distilled the solvent completely under vacuum and product isolated in isopropyl ether and dried to obtain compound (6b) (18.0 gr).

Example-15: Preparation of Rivaroxaban (8b) from compound (6b)

Carbonyldiimidazole (12.0 gr, 0.074 mol) was added slowly to a suspension of 5-chlorothiophene-2-carboxylic acid (compound 7b) (10.0 gr, 0.055 mol) in methylenedichloride (60.0 mL) at 0-5°C, and stirred for 1.0 hr at room temperature, then triethyl amine (7.5 gr, 0.074 mol) 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 (compound 6b) (18.0gr, 0.061 mol) 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 (compound 8b).

Example-16: Preparation of Rivaroxaban (8b) from compound (5b) in single step:

(R)-4-[4-(5-azidomethyl-2-oxo-oxazolidin-3-yl)-phenyl]-morpholin-3-one (compound 5b) (25.0 gr, 0.078 mol) was dissolved in tetrahydrofuran (150.0 mL) and cooled to 10-15°C then slowly triphenyl phosphine (20.7 gr, 0.078 mol) 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 60-65°C for 2-3 hrs. After completion of reaction, distilled off the solvent under vacuum to get thick residue. In the mean time carbonyldiimidazole (15.0 gr, 0.092 mol) was added slowly to a suspension of 5-chlorothiophene-2-carboxylic acid (compound 7b) (12.8 gr, 0.070 mol) in dichloromethane (125.0 mL) at 0-5°C under nitrogen atmosphere and stirred for 1 hr at same temperature. To this reaction mass add the above residue (dissolve the residue in methylenedichloride) at 0-5°C.The slowly reaction mass 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 to obtained Rivaroxaban (compound 8b).