WO2014170908A1

WO2014170908A1 - Process for preparation of oxazolidinone derivatives

Info

Publication number: WO2014170908A1
Application number: PCT/IN2013/000761
Authority: WO
Inventors: Satyanarayana Reddy BHEMIREDDY; V. Vara Prasada Reddy PAIDIMARLA; Venkat Reddy YARAPATHI
Original assignee: NOSCH LABS PRIVATE Ltd
Current assignee: NOSCH LABS PRIVATE Ltd
Priority date: 2013-04-18
Filing date: 2013-12-09
Publication date: 2014-10-23
Anticipated expiration: 2015-10-18

Abstract

A process for preparation of oxazolidinone derivatives such as Linezolid and Rivaroxaban using (S)-Epichlorohydrin.

Description

PROCESS FOR PREPARATION OF OXAZOLIDINONE DERIVATIVES

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 Linezoiid and Rivaroxaban using (5)-Epich.lorohydrin.

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 Linezoiid, Torezolid, Radezolid, Eperezolid and Rivaroxaban.

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

Linezoiid is chemically known as (5)-N-[[3-[3-fIuoro-4-(4-morpholinyl)phenyl]-2-oxo-5- oxazo!idinyl] methyl] acetamide and is a synthetic antibacterial agent of oxazolidinone class. Linezoiid 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 muliocida. 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]-l,3-oxazolidin-5-yl}-methyl)-2-thiophene carboxainide and is an orally active anticoagu lant 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 95/0727 1 , EP07 1 7738) first disclosed Linezol id and related compounds, its therapeutic uses as well as a process for its preparation and is represented by fol lowing structure (I).

(I)

The process for preparation of Linezol id described in U .S Patent No. 5,688,792 is given in the below scheme-1.

H₂ ^■

2) Pyridine, Acetic anhydride

Linezolid

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

O

Reducing agent

Acetylating agent Λ

Solvent

Linezolid O

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 (^J-N-(4-morpholinyl-3-flurophenyl)-2-oxo-5-oxazolidinyI-methyIazide with thioacetic acid without mentioning the isolation process. WO 2001/4791 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]-lH-isoindole-l,3(2H)-dione, 4-(4-aminophenyl)-3- morpholinone and 5-chlorothiophene-2-carbonyl chloride as given in Scheme-Ill below:

o

Scheme-Ill

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-({55)-2-oxo-3-[4-(3-oxo-4- · morpholinyl)-phenyl]-l,3-oxazolidin-5-yl}-methyl)-2-thiophenecarboxamide involving starting compound 5-chlorothiophene-2-carbonyl chloride, (2₁S -3ⁱamino-p!Opane-l,2-diol and 4-(4-amtnophenyl)-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.

Sc eme-IV

Scheme-V

Applicant's pending Indian Patent Application No. 1715/CHE/2013 describes a combined process for preparation of Linezolid and Rivaroxaban using (T^-Epichlorohydrin as starting material as illustrated below as Scheme-Vi.

R—

Scheme-VI

(.Rj-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 (/^-Epichlorohydrin. adhusudhan Gutta et. a!;, ARKIVOC 2012 (vi) 45-56 describes synthesis of Linezolid utilizing (5)- l -azido-3-chloropropan-2-yl chloroformate (3a) or (S)- \ - 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 fol lowed by treating with acetic anhydride results Linezolid.

The staring materials are prepared by reaction of (5)-Epicholorohydrin with NaN₃ in presence of AcOH and H₂0, in ambient temperature for 5 h or with Phthal imide in presence of K₂C0₃ (cat.), !PA, with reflux for 5 h and further treating the corresponding product with triphosgene in presence of Et₃N and THF.

Below scheme-Vl I gives the outline of the above described process .

Epichlorohydri 2a = -N₃ 3a R = -N₃

2b R - -NPhth 3b R = -NPhth

Reagents and conditions: (a) NaN₃, AcOH, H₂0, ambient temperature, 5 h, 80%; (b) Phthalimide, ₂C0₃ (cat.), I PA, reflux, 5 h, 75%; (c) Triphosgene, Et₃N, THF, 0 °C to r.t. 2-3 h,72-89%. ^'

3a : X = -CI, R = -N_:,- 3b : X = -C1, = -NPhth 5a : R = -N

5b : R = -NPhth

6a : R = -N-s

Linezolid, 1

6b : R = -NPhth

Scheme- VII Reagents and conditions: (a) K₂C0₃, Acetone, r.t., overnight, 82-86%; (b) H₂, Pd/C, Ac₂0, MeOH, 20 psi, r.t., 3 h, 85%; (c) (i) Hydrazine hydrate, MeOH, reflux, 1 h; (ii) Ac₂0, Toluene, r.t., 1 h, 70%. Chinese publication No. CN 102321041 describes a reaction of (S')-epichloiOhydrin and sodium azide to obtain l-azido-3-chloro-2-propanol; cyclizing l-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-Vlll:

Scheme- VIII

G. Madhusudhan et. al., Der Pharma Chernia, 201 3 (5): 168-175 describes preparation of 2-((/?)-3-(3-fluoro-4-morpholinophenylamino)-2-hydroxypiOpyl)isoindoline-l,3-dione as a key intermediate for synthesis of Linezolid, starting from (5 -epichlorohydrin and phthalimide in presence of isopropanol (IPA) and potassium carbonate (K.2CO3).

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:

(S)

-Epichlorohydrin (Key starting material)

X = Ch

R = be

Linezolid

Scheme-IX

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

20

HQ CI

CI CI

Ri= H or4-Chloro O' λ\_/

6

RVX

Leaving group L= OR₂, wherein R₂ is (Ci-Cis)alkyl, aryl, aryl (C1-C4) alkyl, hetroaryl or heteroaryl-(Ci-Ci)alkyl.

Scheme-X In the above scheme 4-(4-Amino-phenyl)-morpholin-3-one (I) reacts with benzyl chloro formate (18a) or dodecyl chloroform ate (18b) to give benzyl (4-(3-oxomorpholin)phenyl)- carbamate (19a) dodecyl (4-(3-oxomorpholiii)phenyl)carbamate (1 b) respectively. (S)-(+)- Epichlorohydrin reacts with 4-ch)orobenzaldehyde (21 a) or benzaldehyde (2 lb) in presence of aqueous ammonia to give (5)-l-chloro-3-[(4-chlorobenzy!idine)-amino]-propan-2-ol (22a) or (S 3-(benzylidtneamino)-l-chloro-propan-2-ol (22b) respectively. Reaction of compounds 1 a with 22a or 1 b with 22b gives intermediate (5)-4-[4-(5{[4-chlorobenzylidine)-amino]- methyl}-2-oxo-oxazolidin-3-yl)-phenyl]-morpholin-3-one (23a) or (5)-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 , fol lowed 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-Xl:-

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 (Sj-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 (5)- Epichlorohydrin .

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

Another object of the invention is to provide a novel process for preparation of Linezol id compounds using (S)- Epich lorohydrin.

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

SUMMARY OF THE INVENTION

Accordingly there is provided a process for preparation of more than one oxazol idinone derivatives using (S)- Epich lorohydrin. More particularly, the i nvention specifical ly discloses a process using (S)- Epichlorohydrin wh ich can be used for the preparation of Linezol id as wel l as Rivaroxaban.

The novel process of the invention is suitable for preparation of more than one oxazolid inone derivatives, more particularly Linezol id compounds and Rivaroxaban compounds.

The novel process uses (S)-Epich!orohydrin as the starting material which reacts with a metal azide to give an azido alcohol compound (Compound- 1 ), subsequently cycl izing compound-I to an oxirane compound (Compound-2) in presence of an inorgan ic base as fol lows:

Organic solvent Organic solvent

Compound-1 Compound-2 The novel process comprises the steps of: reacting (5)-Epich lorohydrin with a metal azide to give an azido alcohol compound- 1

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

Com pound-2

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

R|-NH₂

Compound-3 to give an azido alcohol compound of formula (Compound-4);

'^"if T ^'N

OH

Compound-4 wherein, |

(iv) converting azido alcohol compound-4 obtained in step (i i i) above to an xazol idinone com pound of formula (Compund-5);

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

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

O

R-C-R₂

Compound-7 to obtain the desired oxazolidinone derivative compound of formula (Compound-8).

Compound-8

Wherein. R₂ = -CH₃ or R₇

O

II

and R = -o-e-cn₃ o R = -OH or -CI

Ri is as described above in step (iii)

In one embodiment of the invention, vvhen-

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

0

N

0

Linezolid

Compound-8a In another embodiment of the invention, when-

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

Rivaroxaban

Compound-8b

DETAILED DESCRIPTION OF THE INVENTION

Detai led em bod iments of the present invention are disclosed herein below. However, it is to be understood that the disclosed embod iments are merely exemplary of the invention, which can be embodied in various forms. The scope of the invention is not l im ited to the d isclosed embodiments and terms and phrases used herein are not intended to be l im iting 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 oxazol id i none derivatives using (5)-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)-Epich lorohydrin.

The process is illustrated below in scheme-A. The scheme-A i l lustrates a common process for preparation of oxazolidinone derivatives, more specifical ly, Linezolid and Rivaroxaban starting from reaction of (S)-Epich lorohydrin and a metal azide as fol lows: — NH,

Metal azide

0, OH Inorganic base Q, Compouncl-3 _

.CI Organic solvent

Or^ganic solvent Alcoholic solvent

Compound-2 Reflux

Compound-

O O

CD1/MDC

or Pd-C/H, or

R-C-R₂

¹ H ^N3 Diethyl carbonate* ^Ri^— N p Λ

Compotind-7 inoraaiuc base TPP

Solvent

Organic solvent

Compound-4 Compound-5 ~ Compound-6

Compound-8

Linezolid / Riva roxaban

') . R = -0- R₂ = -CHj Linezolid

ii) R =-O R, = CI Rivnroxaban

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) on

N

CI

Compound-1

This step comprises dissolving metal azide in water at room temperature and adding (5)- Epichlorohydrin in a suitable organic solvent. Stir the reaction mixture at 5- 10°C for l hour and allowing the reaction mixture to reach to room'temperature for 3-4 hrs. In an exem plary embodiment the metal azide may be selected from l ithium azide (LiNj_j, sodium azide (NaN₃) and potassium azide (K.N₃). In one preferred embodiment the metal azide is sodium azide (NaN₃).

The su itable organ ic solvent may be selected from methanol, ethanol, propano l, 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 o,

Compound-2

Th is step com prises cyclizing the compound- 1 in presence of an inorganic base in a suitabl organic solvent . In one preferred embodiment the inorgan ic base is potassium carbonate.

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

R |— NH₂

Compound-3

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

-N ^'

H

OH

Compound-4 wherein,

Th is 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 alcohol ic solvent selected from methanol, ethanol, isopropyl alcohol (1 PA), propanol and butanol. I n one preferred embodiment, isopropyl alcohol is used. Step-IV: -Converting azido alcohol compound-4 obtained in Step-III above to an

oxazolidinone compound-5

Compound-5 The step-I V comprises d issolving azide compound-4 in a su itable organic solvent and carbonylating using carbonylating reagents to obtain compound-5. The carbonylation reaction is carried out by using any carbonylating reagents such as carbonyldii m idazole (CD1), diethyl carbonate, methyl chloroformate, benzyl chloroformate, phenyl chloroformate and triphosgene, preferably carbonyldi im idazole or d iethyl carbonate. In the case.of dialkyi carbonates and alkyl/aralkyl ch loroformates the carbony lation should be carried out in presence of inorgan ic bases such as metal carbonates, metal bicarbonates and metal hydroxides.

I n one embod iment the inorgan ic base is metal carbonate selected from potassium carbonate and sod ium 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

Com pound-6

The compound-5 is dissolved in an organic solvent and reduced to am ine compound-6 using a reducing agent. The reducing agent may be selected from Pd-C/H and triphenyl phosph ine (TPP). In one preferred embod iment, triphenyl phosph ine (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 compoii

0

R-C- ₂

Compound-7

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

Compound-8

Wherein, R-> = -CH-,

O

II

and R = -0-C-CH-, or R =-OH or, -CI

Ri 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, vvhen-

R = -O-C-CH3 . , = R₂ = _-CH _.

the obtained oxazolidinone derivative is Linezolid compound.

Linezolid

Compound-8a In another embodiment of the invention vvhen-

The-obtained oxazolidinone derivative is Rivaroxaban com ound.

Rivaroxaban

Compound-8b

The above described process under Scheme-A is a general process for preparation of oxazolidinone derivatives of formula compound-8.

In an exemplary em bodiment, the oxazol idinone derivatives compound of formula (Com pound-8) is Linezol id or Rivaroxaban.

The general scheme-A is further described herein after separately for Linezol id as scheme-B and for Rivaroxaban as scheme-C.

The below scheme-B i l lustrates the process for preparation of Linezol id fol lowing the steps as described in general scheme-A.

o NaN, / NH₄CI OH

LA. XI Water Acetone or I PA / \

N, O N- -NH,

CS Epiclilorohydrin Mthanol _jCO-,

(S)- l -Azido-3-chloro- (5 2-Azidoniethyl

propan-2-ol -oxirane 3-FIiioro-4-morpholin-4- yl-phenylamine

Compound- 1 Com pound-2

Compound-3a

(tf)- l -Azido-3-(3-fUioro-4-morpholin-4- (/?)-5-Azidomethyl-3-(3- rlLioro-4-morpholin- yl-plienylamino)-propaii-2-ol 4-yl-plienyl)-oxazolidirt-2-orte

Compound-4a Compound-5a

Compound-6a Compound-8a

Scheme-B The process for preparation of Linezolid il lustrated in Scheme-B comprises the steps of.

Step-I. Reacting (5 -Epichlorohydrin with a metal azide to give (S)- \ -azido-3-chloro- propan-2-ol (Compound- 1 );

OH 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;

0 C mpound-2

Step-III. Reacting compound-2 obtained in step (I I) above with 3-fluoro-4-morpholin-4- yl-pheny!amine (Compou of organic solvents;

Compound-3a to give (/?)- ! -azido-3-(3-fluoro-4-morpholin-4-yl-phenylamino)-propan-2-ol (Compound-4a);

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

Compound-5a

Step-V. Reducing compound-5a obtained in step (IV) above to (5)-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).

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 (5)- l -azido-3-chloro- propan-2-ol (Compound- ! ), wherein the metal azide may be selected from lithium azide (LiN₃₎, sodium azide (NaN₃) and potassium azide ( N₃). 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-ll in above Scheme-B comprises dissolving (Syi-azido^-chloro-propan^-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 (5)-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 alcohiic solvent may be selected from methanol, ethanol, propanol, isopropanol, n-butanol.

In one preferred embodiment the ketonic solvent is acetone and alcohiic 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-Ill in above described scheme-B involves addition of 3-fluoro-4-morpholin-4 yl- phenylamine (Compound-3a) to a solution of (5")-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)-l -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 (?)-I-azido-3-(3-fluoro-4-morpholin-4-yI-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 d issolving (7?)- l -azido-3-(3-fIuoro-4- morpholin-4-yl-phenylam ino)-propan-2-ol (Compound-4a) in a suitable organic solvent and carbonylati ng using carbonylating reagents to obtain (./?)-5-azidomethyl-3-(3-fl uoro-4- morpholin-4-y)-phenyl)-oxazol idin-2-one (Compund-5a). The carbonylation reaction is carried out by using any carbonylating reagents such as carbonyldiimidazole, diethyl carbonate, methyl ch loro formate, benzyl ch loroform ate, phenyl chloroformate and triphosgene, preferably carbonyldiimidazole_, or diethyl carbonate.

In the case of d ialkyl carbonates and alky 1/aralkyl ch loroformates the carbonylation should. be carried out in presence of inorgan ic bases such as metal carbonates, metal bicarbonates and metal hydroxides. In one embodiment the inorganic base is metal carbonate selected from potassium carbonate and sod ium carbonate. Preferably in one embodiment the metal carbonate is potassium carbonate. The step-V in above described scheme-B comprises dissolving (7?)-5-azidomethyl-3-(3- fluoro-4-morphol in-4-yl-phenyl)-oxazol idin-2-one (Compund-5a) in an organic solvent and reduced to (5)-5-am inomethyl-3-(3-fluoro-4-morphol in-4-yl-phenyl)-oxazol id in-2-one (Compound-6a) using a reducing agent. The reducing agent may be selected from Pd-C/H₂ and triphenyl phosphine. I n one preferred embodiment, triphenyl phosph ine (TPP) is used as reducing agent.

The reduction reaction is carried out in solvent selected from protic and aprotic solvents or m ixtures thereof. I n one preferred embodiment, the solvents are toluene,tetrahydrofuran, isopropyl alcohol (IP A) and mixture thereof.

The step-VI in above described scheme-B comprises adding acetic anhydride (com pound-7a) at 0-5°C to a solution of (5)-5-am inomethyl-3-(3-fluoro-4-morphol in-4-yl-phenyl)- oxazol idin-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, fi ltering and washi ng the mass to get crude oxazol idinone derivative Linezol id (compound- 8a). Crystal l izing the crude Linezolid (compound-8a) in su itable 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.

(

Com ound-1 Compound-2 Compound-3b

IPA

Reflux

(/?)-4-[4-(3-Azido-2-hydroxy-propylamino

ph

enyl ]-morpholin-3-one one

Compound-6b Compound-8b

Scheme-C

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

Step-I: Reacting (5)-epichlorohydrin with a metal azide to give (5)-l -azido-3-chloro- propan-2-ol (Compound- 1 )

Compound- 1 Step-Π: Converting compound- 1 obtained in step (1) above to (S)-Azidomethyl-oxirane

(Compound-2) in presence of an inorganic base;

O ^{' ■}

Com pound-2

Step-III: Reacting compound-2 obtained in step (I I) above with 4-(4-am inophenyI)-3- morphol inone (Compou of alcohol ic solvents;

Compou nd-3b

(/?)-4-[4-(3-azido-2-hydroxy-propylam ino) phenyl]-morphol i n-3-one (Com pound-4b);

Com poiind-4b

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

Com poii nd-5b

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

Com pound-6b

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

(Compound-7b) . ^'

R= CI or OH

(Com ound-7b)

to obtain Rivaroxaban (Compound-8b).

Rivaroxaban

Compound-8b The Step (I) in above described Scheme-B comprises reacting (5)-Epich lorohydrin with a metal azide in a suitable organ ic solvent at am bient temperature to give (S - l -azido-3-chloro- propan-2-ol (Compound- 1 ), vvherein the metal azide may be selected from lithium azide (LiN₃₎, sod ium azide ( aN₃) and potassi um azide ( N₃). In one preferred embodiment the metal azide is sodium azide (MaN₃).

The suitable organic solvent may be selected from methanol, ethanol, propanol, acetone , dimethyl formam ide and butanol. In one preferred embod iment the organic solvent is methanol. The step- l l in above Scheme-B comprises d issolvi ng (5)- 1 -azido-3-ch loro-propan-2-ol (Compound- 1 ) in suitable organic solvent in presence of an inorganic base and refluxing for 3-4 hr at reflux temperature. Disti l l ing and dissolving the residue in water and ethyl acetate at room temperature with stir for 5- 1 0 m in utes and separating and disti ll out organ ic solvent to get crude (S)-2-azidomethyl-oxirane (Comp,ound-2).

The organic solvent may be ketonic solvent, alcohol ic solvent or a mixture thereof. The ketonic solvent may be selected from acetone, methyl isobutyl ketone, methyl isopropyl ketone . The alcohl ic 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, sod ium carbonate, potassium bicarbonate and sodium bicarbonate In one preferred embod iment the inorganic base is potassium carbonate. Step-Ill in the above described scheme-C com prises add ition of 4-(4-am inophenyl)-3- morpho!inone (Compound-3b) to a solution of (5)-azidomethyl-oxirane compound-2 in alcoholic solvent at room temperature. Heating the reaction mass to reflux temperature for 1 0- 12 hrs, distil l ing the solvent under vacuum . to obtain the crude (/?)-4-[4-(3-azido-2- hydroxy-propylam ino) phenyl]-morphol in-3-one (Compound-4b).

The reaction can be carried out in any suitable solvent selected from isopropyl alcohol (I PA), methanol, ethanol, propanol and butanol . In one preferred embodiment, isopropyl alcohol is used. The step-I V in above descri bed scheme-C com prises d issolving (/?)-4-[4-(3-azido-2-hydroxy- propylam ino) phenyl]-morpholin-3-one (Compound-4b) in a su itable organic solvent and carbonylating using carbonylating reagents to obtain (/?)-4-[4-(5-azidomethyl-2-oxo- oxazol idin-3-y!)-phenyl]-morpholin-3-one (Compund-5b). The carbonylation reaction is carried out by using any carbonylating reagents such as carbonyld i i m idazole, diethyl carbonate, methyl chloroformate, benzyl chloroformate, phenyl chloroformate and triphosgene, preferably carbonyldi im idazole or diethyl carbonate.

I n the case of dialkyl carbonates and alky l/aralkyl chloroformates the carbonylation shou ld be carried out in presence of inorgan ic bases such as metal carbonates, metal bicarbonates and metal hydroxides.

I n one embod iment the inorgan ic base is metal carbonate selected from potassium carbonate and sodium carbonate. Preferably in one embodiment the metal carbonate is potassi um carbonate.

The step-V in above described scheme-C comprises dissolving (,R)-4-[4-(5-azidomethyl-2- oxo-oxazol idin-3-yl)-phenyl]-morpholin-3-one (Compund-5b) in an organ ic solvent and reduced to (5)-4-[4-(5-aminomethyl-2-oxo-oxazol idin-3-yl)-phenyl]-morphol in-3-one (Compound-6b) using a reducing agent. The reducing agent may be selected from Pd-C/H₂ and tripheny! 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 m ixtures thereof. In one preferred em bodiment, the solvents are tetrahydrofuran, toluene, isopropyl alcohol (I A), water and mixture thereof.

The step-Vl in above described scheme-C comprises dissolving the ( -4-[4-(5-aminomethyl- 2-oxo-oxazo!idin-3-yl)-phenyl]-morpholin-3-one (Compound-6b) in an organic solvent reacted with 5-chlorothiophene-2-carboxylic acid (compotind-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 (5)-l-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 (5)-Epichlorohydrin ( 100.0 gr, 1 .08 mol) in methanol ( 100.0 mL) was added. The reaction mixture was stirred for I 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 a₂S04 and distill out to get (5)- I -azido-3-chloro-propan-2-ol (compound I ).

Example-2:- Preparation of (5 -2-azidomethyl oxirane (compound 2)

To a solution of (S)- l -azido-3-chloropropan-2-ol (compound I ) ( 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 (5 2-azidomethyl oxirane (compound 2).

Example-3:- Preparation of (?)-l-azido-3-(3-fluoro-4-morpholin-4-yl-phenyIamino)- 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-morphoIin-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 Na₂S0₄. 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.

The novel azide compound (/?)-l-azido-3-(3-fIuoro-4-morpholin-4-yl-phenylamino)-propan- 2-ol (4a) 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 ± 0.2° 2Θ. Ή-NMR: (400 MHz, DMSO-d6) δ 2.79-2.8 l (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, 1 H), 5.3 1 -5.32 (d, I H), 5.54-5.57 (t, 1 H), 6.3 1 -6.34 (dd, 1 H), 6.38-6.42 (dd, 1 H), 6.79-6.83 (t, 1 H). Mass (M⁺+ 1 ) = 296.3 Example-4:- Preparation of (/?)-5-azidomethyl-3-(3-fluoro-4-morpholin-4-yl-phenyl)- oxazolidin-2-one (compound 5a)

A. Using carbonyldiimidazole (CDI)

To a solution of (/?)- l -azido-3-(3-fl Lioro-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 ( 1 5.0 mL). Both the organic layers were combined and dried with anhydrous a₂S0₄. The organic layer was disti lled under vacuum, followed by co-distil led 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 m inutes, then slowly cooled to room temperature and stirred for 25-30 min. Solid compound was thrown out from the reaction mass was fi ltered and washed with methanol to get pure compound (compound 5a) (8.6 gr).

B. Using diethyl carbonate

(/?)- l -azido-3-(3 fluoi -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- 1 6 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 ( 1 00.0 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 a2SC>4. 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 m inutes 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 ( 1 0.0 mL) and dried to get pure compound (compound 5a) ( 16.0 gr).

Example-5:- Preparation of (/?)-l-azido-3-(3-fluoro-4-morpholin-4-yl-phenyIamino) propan-2-ol (compound 4a) from (5)-l-azido-3-chloro-propan-2-ol (compound-1) in single step: (S)- l -azido-3-ch loropropan-2-ol (compound- 1 ) ( 1 00.0 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- morphol in-4-yl-phenylam ine (compound 3a) ( 1 08.6 gr, 0.553 mol) was added to the above isopropyl alcohol reaction mass. The whole reaction mass was heated to reflux tem perature for 1 0- 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 d ichloromethane (400.0 m L) and water (300.0 mL) and stirred for 1 0 minutes at room temperature. Two layers were separated and aqueous layer was extracted with- dichloromethane (200.0 mL). The organ ic layers were combined and washed with brine •solution ( 100.0 mL) and organic layer was dried with anhydrous a₂SC>4 and distilled under vacuum to get the crude residue. The resultant crude product was purified by column chromatography using si l ica 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.

ExampIe-6:- Preparation of (/?)-5-azidomethyi-3-(3-fluoro-4-morpholin-4-yl-phenyi)- oxazolidin-2-one (compound 5a) from (5)-l-azido-3-chloro-propan-2-ol (compound-1) in single step:

,

A solution of (5)- l -azido-3-chloropropan-2-ol (compound- 1 ) ( 1 00.0 gr, 0.738 mol) in isopropyl alcohol (500.0 m L) and potassium carbonate (200.0 gr, 1 .45 mol) was added at room temperature. The reaction m ixture was heated to reflux and maintained at 1 -2 hr then cool to RT then 3-fluoro-4-morpholin-4-yl-phenylam ine (compound 3a) ( 1 08.6 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 fi lter 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 carbonyldiimidazo!e ( 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 1 0 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 P^H of the reaction mass adj usted to 1 .0 with hydrochloric acid. Separate the aqueous layer and organic layer, followed by add water to the organic layer and reaction mass P^H 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 Na₂S0₄. 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 (5 -5-aminomethyl-3-(3-fluoro-4-morpholin-4-yl-phenyI)

-oxazolidin-2-one (compound 6a) (7?)-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- 1 5°C then slowly added triphenyl phosphine ( 16.32 gr, 0.062 mol) and stirred for 10- 1 5 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 10-1 5°C, followed by IPA.HCI ( 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 P^H adjusted to 9.0 to 1 0.0 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. Na2S0₄ and distilled the solvent completely under vacuum and product isolated in isopropyl ether and dried to obtain (compound 6a) ( 1 .0 gr).

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

To a solution of (5)-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- 1 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 1 0- 1 5°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 a₂S04. 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) ( 1 8. Ogr). Example-10: Preparation of Linezolid (8a) from 5a in a single pot process:

(7?)-5-azidomethyl-3-(3-fluoro-4-morpholin-4-yl-phenyl)-oxazol idin-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) ( 1 7.5 gr).

(II). Preparation of Rivaroxaban

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

Compound ( 1 ) and compound (2) were prepared according to Example- ] and Example-2 respectively as described above. (S)-2-Azidomethyl oxirane (compound 2) (25.0 gr, 0.25 mol) was dissolved in isppropyl 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 ( 1 50.0 mL) and water ( 100.0 mL) then stirred for 1 0 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 a₂S04. 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 ( ?)-4-[4-(5-azidomet yI-2-oxo-oxazolidin-3-yl)-phenyI]- morpholin-3-one (5b)

A. Using carbonyldiimidazole (CDI)

To a solution of (y?)-4-[4-('3-azido-2-hydroxy-propylamino)phenyI]-morpholin-3-one

(compound 4b) (20.0 gr, 0.068 mol) in dichloromethane ( 100.0 mL) under nitrogen atmosphere and stirred for 1 0 min for complete dissolution, followed by carbonyldiimidazole ( 1.3.36 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 Na?SC>4. 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 m L) 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 fi ltered washed with methanol to get pure compound (5b) ( 1 7.0 gr).

B. Using diethyl carbonate

(/?)-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 m L) and dried with anhydrous Na₂S04. 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. Sol id 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 (/?)-4-[4-(3-azido-2-hydroxy-propyIamino) phenylj- morpholin-3-one (compound 4b) from (5 -l-azido-3-chloro-propan-2-ol (compound 1) in single step: (.S)- l -azido-3-chloropiOpan-2-ol (compound 1 ) (50.0 gr, ^s0.369 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 a₂S04 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.

Exam pie- 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-I5°C, followed by IPA.HCI (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 P^H 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. Na₂S0₄ 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 (5)-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:

(?)-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 triphen l 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).

Claims

We claim:

I. A process for preparation of oxazolidinone derivative compounds of formula (Compound-8)

Compound-8

Wherein,

Wherein, ₂ = -CH or R₂ = '\ ^^-_C(

comprising the steps of:

(i) . reacting (5)-epich!orohydrin with a metal azide in an aqueous organic solvent to give an azido alcohol compound of formula (1);

OH

Compound-1

(ii) . cyclizing the azido alcohol compound-1 obtained in step (i) above to an oxirane

1 compound of formula (2) in an organic solvent in presence of an inorganic base;

Compound-2

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

R -NH,

Compound-3 in presence of a solvent to give an azido alcohol compound of formula (4); OH

Compound-4 wherein, ^| =

(iv) . converting azido alcohol compound-4 obtained in step (iii) above to an

oxazolidinone compound of formula (5);

Compound-5

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

formula (6);

Compound-6

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

O

R-C-R₂

Compound-7

Wherein, _{R =} ._Q_^__CH3 or R =-OH or -CI

Wherein, R, = -CH₃ or R, =

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 ( N₃). 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, d imethyl formam ide and butanol.

A process as claimed i n claim 1 , wherein said organ ic solvent in step (i i) is selected from ketonic solvent, alcohol ic solvent or. a m ixture thereof.

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

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

A process as claimed in claim I , wherei n said inorgan ic base in step (i i) is selected from the group consisting of potassium carbonate, sodium carbonate, potassium bicarbonate and sodium bicarbonate.

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

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

-A- process as claimed in claim- ⁽).- u hereiir w hen d ial ky l carbonates ^" or alkyl ^'aralk l 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.

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 1 1 , wherein said reduction is done in presence of a protic or aprotic solvent.

1 3. ' 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

Linezolid

Compound-

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

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

Rivaroxaban

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)- l -azido-3-chloro- propan-2-ol (Compound- 1 ) (i i). cycl izing compound- 1 obtained in step (i) above to (^-2-azidomethyl-oxirane

(Compound-2) in an organic solvent in presence of an inorganic base;

O

Compound-2

(iii). Reacting oxirane compound-2 obtained in step (ii) with 3-fluoro-4-morphol in-4-yl- pheny!amine (Compound-3a)

Compound-3a in presence of a solvent to obtain (/?)- l -azido-3 -(3-fluoro-4-morphol in-4-yl-phenylam ino)- propan-2-ol (Compound-4a);

Compound-4a (iv). converting compound-4a obtained in step (i i i) to (7?)-5-azidomethyl-3- (3-fluoro-4-morphol in-4-yl-phenyl)-oxazol idin-2-one (Com pund-5a);

Compound-5a

(v). reducing compound-5a obtained in step (iv) to (S)-5-am inomethyl-3-(3- fluoro-4-morph01 in-4-yl-phenyl)-oxazol idin-2-one (Compound-6a);

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

Linezolid

Compound-8a

1 7. A process as claimed in claim 1 6, wherein said metal azide in step (i) is selected from the group consisting of lithium azide (LiN₃), sodium azide (NaN₃) and potassium azide ( N₃).

1 8. A process as claimed in claim 1 6, wherein said organ ic solvent in step (i) is selected from the group consisting of methanol, ethanol, propanol, acetone, dimethyl formamide and butanol. -

1 9. A process as claimed in claim 1 6, wherein said organic solvent in step (i i) is selected from ketonic solvent, alcohol ic solvent or a m ixture 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.

2 1 . 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 1 6, wherein said inorgan ic base in step (i i) is selected from the group consisting of potassium carbonate, sod ium carbonate, potassium bicarbonate and sodium bicarbonate. 23. A process as claimed in claim 1 6, wherein the solvent in step (i i i) is selected from the group consisting of isopropyl alcohol (I PA), methanol, ethanol, n-propanol and butanol.

24. A process as claimed in claim 1 6, wherein said azido alcohol compound (4a) is converted into oxazol idinone compound (5a) by a carbonylating reagent selected from carbonyld i imidazole, d iethyl carbonate, methyl chloroformate, benzyl chloroformate, phenyl chloroformate and triphosgene.

25. A process as claimed in claim 24, wherein when d ialkyl 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 1 6, 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

Linezolid

Compound-8a from (^)-5-azidomethyl-3-(3-fl uoro-4-morphol in-4-yl-phenyl)-oxazolidin-2-one (Compund- 5a) in one step without isolation of the intermediates, the process comprising: dissolving ( ?)-5-azidomethyl-3-(3-fluoro-4-morphol in-4-yl-phenyl)-oxazolidi n-2-one (Compund-5a) in toluene or TH F and adding triphenyl phosphine fol lowed by acetic anhydride; filtering the sol id and recrystal l izing in su itable solvent to obtain the purified Linezolid.

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

(i) reacting (5)-epich lorohydrin with a metal azide in an aqueous organic solvent to give (5)- l -azido-3-ch loro propan-2-ol (Compound- 1 ) Compound-1

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

Compound-2

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

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

OH

Compound-4b

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

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

Compound-6b

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

R= CI or OH

(Compound-7b) to obtain Rivaroxaban (Compound-8b).

Rivaroxaban

Compound-8b

3 1 . A process as claimed in clai m 30, wherein said metal azide in step (i) is selected from the group consisting of l ithium azide (LiN₃₎, sod ium azide (NaN₃) and potassium azide ( N₃).

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 formam ide and butanol.

33. A process as claimed in claim 30, wherein said organ ic solvent in step (ii) is selected from ketonic solvent, alcohol ic 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.

3^'5. A process as claimed in claim 33, wherein said alcohol ic 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, sod ium carbonate, potassium bicarbonate and sodium bicarbonate.

37. A process as claimed in claim 30, wherein the solvent in step (ii i) is selected from the group consisting of isopropyl alcohol (I PA), 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 carbonyldi imidazole, 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 inorgan ic 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 am ine compound (6a) in presence of a reducing agent selected from Pd-C/H2, trialkyl and triaryl phosphine.

4 1 . 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 4 1 , wherein said sol vent is selected from tol uene, tetrahydrofuran, methanol, water and m ixture thereof.

A process for preparation of Rivaroxa

Compound-8b

From ( ?)-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 (/?)-4-[4-(5-azidomethyl-2-oxo-oxazol id in-3-yl)-phenyl]-morphol in-3-one (Compund-5 b) in toluene or TH F and add ing triphenyl phosphine fol lowed by add ition of water and vaccume distillation to obtain thick residue; dissolving the residue in methylene dich loride and adding to a pre-prepared suspension of 5-ch lorothiophene-2-carboxyl ic acid (compound 7b) in dichloromethane and cabonyld i im idazole; stirring at refl ux 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.

44. A novel azide compound, (?)-l-azido-3-(3-fluoro-4-morpholin-4-yl phenylamino)- propan-2-ol of formula (4a).

Compound-4a

45. A novel azide compound as claimed in 44 which is characterized by X-ray power diffraction spectrum with peaks at peaks about 7.016, 10.33, 15.20, 15.73, 16.35, 1.8.15, 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 ±0.2029 and

1H-NMR: (400 MHz, DMSO-d6) δ 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, 1 H), 5.31-5.32 (d, I H), 5.54-5.57 (t, 1H), 6.31 -6.34 (dd, 1 H), 6.38-6.42 (dd, 1 H), 6.79-6.83 (t, 1 H). Mass (M++1 ) = 296.3.