PRIORITY

This application claims the benefit of Indian Provisional Application with no. 1667/CHE/201 1 filed on 16 May 201 1 the contents of each of which are incorporated by reference herein.

BACKGROUND OF THE INVENTION

1. Technical Field

The present invention relates to processes for the preparation of 5-chloro-N-({(5S)-2- oxo-3 - [4-(3 -oxo-4-morpholinyl)phenyl] - 1 ,3 -oxazolidin-5 -yl } methyl)-2-thiophene-carboxamide.

2. Description of the Related Art

Rivaroxaban is a novel anticoagulant used for the prevention of venous thromboembolism in adult patients undergoing elective hip or knee replacement surgery and is under review in US and approved in several countries of Europe. Rivaroxaban is structurally related to the antibacterial compound Linezolid (Zyvox) is enantiomerically pure. Rivaroxaban is available in the market under the brand name Xarelto® as 10 mg tablets in Europe. Rivaroxaban is chemically described as 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4- morpholinyl)phenyl] -1,3 -oxazolidin-5 -yl } methyl)-2-thiophene-carboxamide (herein after referred as rivaroxaban) and is r hown below:

U.S. Patent No. US 7,585,860 describes morpholinyl oxazolidinone thiophene carboxamides including rivaroxaban or pharmaceutically acceptable acid addition salts thereof, a pharmaceutical composition and a method of treatment. The US '860 patent also discloses a process for the preparation of rivaroxaban which

illustrated by s

U.S. Publication application US2007/0149522A1 and Drugs of the future 2006, 31(6), 484-493 discloses a e below:

U.S. Patent No. US 7,816,355 Bl describes a process for the preparation of rivaroxaban which is illustrated by below scheme:

The process disclosed in the patent US '860 patent exhibits various disadvantages in the reaction management which has particularly unfavourable effects for preparation of the compound of the formula (I) on the industrial scale.

The alternate process disclosed in the U.S. Publication application US '522A1 involves the usage of toxic solvents or reagents. This is disadvantageous per se, and in addition these toxic substances must be removed from the final product (I) until below the maximum limit permissible in each case in the product for regulatory reasons, may require additional process steps which make the process expensive.

The reported processes aforementioned involves hazardous and expensive reagents, has more scope for the formation of impurities, intricate to handle on commercial scale, requires additional purification steps thus ending up with low yields and purities of the final product thus rendering the process not viable on commercial scale.

Hence there is a need to provide an improved process for the preparation of rivaroxaban, which avoids the use of potentially hazardous, expensive chemicals, the formation of isomeric and other process related impurities, while affording the desired product rivaroxaban or a pharmaceutically acceptable salt resulting in high yield and purity. The reaction steps of the present invention involving the reaction of compound of formula III or V with the compound of formula II of the present invention have not been reported in the literature.

The processes of the present invention are simple, eco-friendly, economic, reproducible, robust and are well amenable on industrial scale.

SUMMARY OF THE INVENTION

The present invention relates to processes for the preparation of 5-chloro-N-({(5S)-2- oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]- 1, 3-oxazolidin-5-yl} methyl)-2-thiophene- carboxamide.

In one aspect, the present invention provides a process for the preparation of 5-chloro-N- ({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]-l , 3-oxazolidin-5-yl} methyl)-2-thiophene- carboxamide of formula (I),

comprising:

a) reacting the compound 5-Chloro-thio hene-2-carboxylic acid of formula (IV)

(IV)

with a suitable reagent in the presence of a base to ive the compound of formula (III)

(III)

Where Rl is C i _-8 alkyl straight or branched chain like methyl, ethyl, propyl, isopropyl, butyl, isobutyl, arylalkyl, sub/unsub. phenyl;

b) reacting the compound of formula (III) with a compound 4-{4-[(5S)-5-(Aminomethyl)-2- oxo-l ,3-oxazolidin-3-yl]phenyl}morpholin-3-one of formula II or a salt thereof

(Π)

in the presence of suitable base to give the compound of formula I.

In another aspect, the present invention provides an alternate process for the preparation of 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]- 1, 3-oxazolidin-5-yl} methyl)- 2-thiophene-carboxamide (I

(I)

comprising:

reacting the compound substituted 5-Chloro-thiophene-2-carboxylic acid ester of formula (V)

(V)

Where R is C i _-8 alkyl straight chain or branched like methyl, ethyl, propyl, isopropyl, butyl, isobutyl, aryl alkyl, substituted or unsubstituted phenyl;

with a compound 4-{4-[(5S)-5-(Aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl} - morpholin-3-one of formula II or a salt thereof

optionally in the presence of suitable base to give the compound of formula I. In another aspect, the present invention provides rivaroxaban (I) having the compound of structural formula III

III

Where Rl is C i _-8 alkyl straight or branched chain like methyl, ethyl, propyl, isopropyl, butyl, isobutyl, arylalkyl, sub/unsub. phenyl;

in an amount less than or equal to 0.1 area % as determined by HPLC.

In yet another aspect, the present invention provides rivaroxaban (I) having the compound of structural formula Ilia

Ilia

Where Rl is C i.g alkyl straight or branched chain like methyl, ethyl, propyl, isopropyl, butyl, isobutyl, arylalkyl, sub/unsub. phenyl;

in an amount less than or equal to 0.1 area % as determined by HPLC.

In yet further aspect, the present invention provides rivaroxaban (I) having the compound of structural formula II

II

in an amount less than or equal to 0.1 area % as determined by HPLC.

In a still further aspect, the present invention provides rivaroxaban (I) having the compound of structural formula V

V Where R is C i _-8 alkyl straight chain or branched like methyl, ethyl, propyl, isopropyl, butyl, isobutyl, aryl alkyl, substituted or unsubstituted phenyl;

in an amount less than or equal to 0.1 area % as determined by HPLC.

BRIEF DESCRIPTION OF THE DRAWING

Fig. 1 : is a schematic representation of the processes of present invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to processes for the preparation of 5-chloro-N-({(5S)-2- oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]-l,3-oxazolidin-5-yl}methyl)-2-thiophene-carboxamide.

In one embodiment of the present invention, there is provided a process for the preparation of 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]-l, 3-oxazolidin-5- yl } methyl)-2-thiophene-carboxamide of formula (I),

(I)

comprising: ^'

a) reacting the compound 5-chloro-thio hene-2-carboxylic acid of formula (IV)

(IV)

with a suitable reagent in the presence of a base to give the compound of formula (III)

(iii)

Where Rl is C i _-8 alkyl straight or branched chain like methyl, ethyl, propyl, isopropyl, butyl, isobutyl, arylalkyl, sub/unsub. phenyl; b) reacting the compound of formula (III) with a compound 4-{4-[(5S)-5-

(aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl}morpholin- 3-one of formula II or a salt thereof

in the presence of suitable base to give the compound of formula I.

The reaction step (a) comprising the reaction of compound of formula IV with suitable reagent selected from alkyl chloro formates like ethyl chloro formate, isobutyl chloro formate; sub. or unsub. phenyl chloroformates like phenyl chloroformate, 4-nitrophenyl chloroformate; aryl alkyl chloroformate like benzyl chloroformate and the like. Preferably ethyl chloro formate.

The bases that can be used in the reaction steps (a) and (b) are organic bases such as triethylamine, tripropylamine, pyridine, diisopropylamine, diisopropylethylamine, tributylamine;

Inorganic bases such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, and the like; or a mixture thereof, preferably organic base. Most preferably tri ethyl amine is being used.

The solvents that can be used in step (a) and (b) include but are not limited to halogenated solvents such as dichloromethane, ethylene dichloride, chloroform, chlorobenzene and the like; esters such as ethyl acetate, propyl acetate, isopropyl acetate, tertiary butyl acetate and the like; ethers such as tetrahydrofuran, 1 ,4-dioxane and the like; hydrocarbons such as toluene, xylene and the like; aprotic polar solvents such as Ν,Ν-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), N-methyl-2-pyrrolidinone (NMP) and the like; or a mixture thereof. Preferably dichloromethane is being used.

Optionally the reaction steps (a) and b) are performed separately or can be carried out by single pot.

The reaction temperature in reaction steps (a) and b) can range from about -10°C to about 30°C, preferably from about -5°C to about 10°C.

The time period required for the completion of the reaction step (a) can range from about 30 minutes to about 5 hours, preferably about 30 minutes. The time period required for the completion of the reaction step (b) can range from about 30 minutes to about 20 hours, preferably 10 hours.

Optionally the intermediate compound of formula III is being isolated.

In another embodiment of the present invention, there is provided an alternate process for the preparation of 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]-l , 3- oxazolidin-5-yl} methyl)- -thiophene-carboxamide of formula (I),

comprising:

reacting the compound substituted 5-Chlo -thio hene-2-carboxylic acid ester of formula (V)

Where R is C i _-8 alkyl straight chain or branched like methyl, ethyl, propyl, isopropyl, butyl, isobutyl, aryl alkyl, substituted or unsubstituted phenyl;

with a compound 4-{4-[(5S)-5-(Aminomethyl)-2-oxo-l ,3-oxazolidin-3-yl]phenyl}-morpholin-3- one of formula II or a salt thereof

in the presence of organic solvent and optionally in the presence of a base to give the compound of formula I.

The solvent(s) that can be used is selected from the group consisting of alcohols such as methanol, ethanol, isopropanol, ethylene glycol and the like; alkyl ethers such as tetrahydrofuran, dioxane and the like; esters such as ethyl acetate, isopropyl acetate and the like; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; hydrocarbons such as toluene, xylene and the like; nitriles such as acetonitrile and the like; N,N-dialkylamides such as Ν,Ν-dimethylformamide (DMF), Ν,Ν-dimethylacetamide, sulfoxides and sulfones (e.g. dimethyl sulfoxide and sulfolane); halogenated hydrocarbons such as dichloromethane, chloroform and the like; water or a mixture thereof. Preferably ethylene glycol is being used.

Optionally the reaction is performed in the absence of solvents.

The reaction temperature can be in the range of about 25°C to about 150°C or the boiling point of the solvent(s) used, preferably about 65°C.

When the reaction is performed in the absence of solvents the preferred reaction temperature can range from about 100°C to about 150°C, preferably about 120°C.

The time required for the reaction to complete may vary depending on the reaction temperature and the nature of the reagents and solvents employed. The time period required can range from about 30 minutes to about 48 hours, preferably about 10 hours.

The bases that can be used optionally include are organic bases or inorganic bases. The organic bases that can be used include, but are not limited to triethylamine, pyridine and the like; Inorganic bases include one or more of alkali metal carbonates, such as sodium carbonate or potassium carbonate, sodium hydrogen carbonate; and alkali metal hydroxides, such as sodium hydroxide or potassium hydroxide and the like or mixtures thereof, preferably organic base.

As used herein, the term "alkyl" by itself or as part of another substituent, means, unless otherwise stated, a saturated straight or branched chain, or cyclic hydrocarbon radical, Examples of saturated hydrocarbon radicals include, but are not limited to groups such as methyl, ethyl, n- propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl)methyl, cyclopropylme hyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.

As used herein, the term "aryl" by itself or as part of another substituent, means, unless otherwise stated, a polyunsaturated, aromatic, hydrocarbon substituent which can be a single ring or multiple rings (often from 1 to 3 rings) which are fused together or linked covalently. "Aryl" includes, but is not limited to, "heteroaryl" groups.

After completion of the reaction, the desired compounds can be obtained from the reaction mixture by conventional means known in the art. For example, the working-up of reaction mixtures, especially in order to isolate desired compounds, follows customary procedures, known to the organic chemists skilled in the norms of the art and steps, e.g. selected from the group comprising but not limited to extraction, neutralization, crystallization, chromatography, evaporation, drying, filtration, centriiugation and the like.

Optionally the process steps of present invention can be carried out by one pot synthesis.

Advantageously the intermediates or their salts used here in the processes of the present invention may exist in either crystalline or amorphous or mixtures thereof.

Advantageously the intermediate compound aminomethyloxazolidinone (II) can be used in any salt form and morph.

In this way it is possible firstly to avoid the carcinogenic pyridine which is used as solvent and base in the process described in US '860. It is additionally possible according to the invention to avoid the complicated chromatographic purification of the product (I).

The process disclosed in US' 860, in which the aminomethyloxazolidinone (II) crude product obtained after concentration of the reaction mixture is directly employed in the further reaction with chlorothiophenecarbonyl chloride, has by contrast the disadvantage that the secondary components of this reaction, which are present in the aminomethyloxazolidinone (II) crude product, impede the subsequent preparation of the final product (I) and additionally contaminate the product (I). In contrast thereto, the use of aminomethyloxazolidinone (II) isolated salt form like hydrochloride in pure form or purified form of its free base makes improved reaction management possible in the following reaction with chlorothiophenecarbonyl compound with unwanted side reactions being avoided and a purer product being obtained, so that the elaborate chromatographic purification can be avoided.

The compound of formula I obtained by the processes of present invention is optionally purified by making slurry in polar solvents at ambient or mild temperatures or recrystallization using solvents or by acid base or carbon treatment.

Preferably by recrystallization using acetic acid or mixture with water in any proportion without limitation.

In yet another embodiment of the present invention, there is provided rivaroxaban (I) having the compound of structural formula III

III

Where Rl is C i _-8 alkyl straight or branched chain like methyl, ethyl, propyl, isopropyl, butyl, isobutyl, arylalkyl, sub/unsub. phenyl;

in an amount less than or equal to 0.1 area % as determined by HPLC.

In yet further embodiment of the present invention, there is provided rivaroxaban (I) having the compound of structural formula Ilia Ilia

Where Rl is C i _-8 alkyl straight or branched chain like methyl, ethyl, propyl, isopropyl, butyl, isobutyl, arylalkyl, sub/unsub. phenyl;

in an amount less than or equal to 0.1 area % as determined by HPLC.

In a still further embodiment of the present invention, there is provided rivaroxaban (I) having the compound of structur l formula II

II

in an amount less than or equal to 0.1 area % as determined by HPLC.

In yet another embodiment of the present invention, there is provided rivaroxaban (I) having the compound of structural formula V

V

Where R is C i.g alkyl straight chain or branched like methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and aryl alkyl, substituted or unsubstituted phenyl;

in an amount less than or equal to 0.1 area % as determined by HPLC. The processes of present invention are especially valuable for the following reasons: it makes it possible to obtain the compound of formula (I) on an industrial scale in excellent yields, starting from a simple, low-cost starting materials and reagents.

The processes reported for the preparation of rivaroxaban or its intermediates in the art results in the formation of various impurities and bye products leading to include additional purification steps at several stages thus resulting in very poor yields and purities of the final product.

Advantageously, the processes of present invention does not involve purification steps thus provides the final product rivaroxaban with higher yields and purities.

Preferably, the yield of the intermediates and the final product is about 80%, or more, more preferably, the yield is about 80% to about 90%, most preferably, the yield is about 90% to about 95%, or more, by weight.

The product obtained by the processes described above can have high enantiomeric excess. Preferably, the amount of R-enantiomer is less than about 1% as measured by area percentage by chiral HPLC, more preferably less than about 0.5%, and most preferably less than about 0.15% by chiral HPLC.

The processes according to the present invention preferably yields (+)-rivaroxaban or a pharmaceutically acceptable salt thereof in substantially pure enantiomeric form. Thus the ratio of (+) : (-) as obtained by the process of present invention may be at least about 99: 1 , such as at least about 99.8:0.2, or more preferably at least about 99.9 : 0.1. Preferably (+)-rivaroxaban or salt thereof prepared by a processes according to the present invention has an enantiomeric purity of at least about 99.7%, or more preferably at least about 99.9%.

As referred above (+) rivaroxaban is commonly called as rivaroxaban thus can be referred here in either way.

The intermediate compounds of (II), (IV) and (V) are known per se to the person skilled in the art or can be prepared by customary methods. For ex. US 7,585,860 which is herein incorporated for reference.

Furthermore, compound of formula (I) can be present in tautomeric forms. This is known to the person skilled in the art, and such compounds are likewise within the scope of the invention. The rivaroxaban (I) obtained by the processes of the present invention preferably has an average particle size greater than 300 μιτι. The term "average particle size" or "particle size" as used herein refers to the volume mean diameter of particles.

Rivaroxaban (I) can be further micronized to obtain particles with dc>o >60 μηι, more preferably dc>o > 40 μηι, and most preferably d%> 30 μι ^η . As used herein dg ₀ > x means that at least 90 % by volume of the particles have a particle size above x.

The particle size can be determined by laser light scattering for instance using a Malvern Mastersizer Apparatus MS 2000 equipped with a Hydro S dispersion unit using purified water as the dilution medium. Micronized rivaroxaban can be obtained for instance by single or multistage micronization in the dry state using dry mills, such as cutting mills, pin/cage mills, hammer mills, jet mills, fluidized bed jet mills, ball mills and roller mills.

In yet another embodiment, rivaroxaban or its pharmaceutically acceptable salts obtained by the processes described above has residual organic solvents or organic volatile impurities comprises less than the amount recommended for pharmaceutical products, as set forth for example in ICH guidelines and U.S. pharmacopoeia; less than about 500ppm of N- methylpyrolidine (NMP), less than about 700ppm of tetrahydrofuran, less than about 600ppm of dichloromethane, less than about 400ppm of acetonitrile, ethylene glycol, less than lOOOppm of methanol, ethanol, ethyl acetate, isopropyl alcohol, acetone, acetic acid, n-hexane, n-heptane, less than 800ppm of Ν,Ν-dimethyl formamide (DMF), less tha lOOOppm of dimethyl acetamide (DMA).

The present invention provides simple, ecofriendly, inexpensive, reproducible, robust processes for preparation of rivaroxaban (I) which are well adaptable on a commercial scale.

The invention is further defined by reference to the following examples describing in detail the preparation of the composition and methods of use of the invention. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.

EXAMPLES

Example 1: Preparation of Rivaroxaban (I)

16.25 gms of 5-chlorothiophene-2-carboxylic acid and 162.5 ml of dichloromethane were charged into a clean and dry 1 lit. 4 neck R.B. Flask. 12.12 gms of triethyl amine was charged at about 30°C followed by stirring for about 15 mins. to get homogenous solution. The resultant reaction solution was cooled to about -5°C and 11.935 gms of ethyl chloro formate was added at about -5°C over about 15 mins. Then reaction temperature was raised to about 0°C and was stirred for about 30mins. After completion of the reaction, a mixture of 32.75 gms of 4-{4-[(5S)-5-(Aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl} -morpholin-3-one

hydrochloride, 10.1 gms of triethyl amine and 100ml of dichloromethane was added at about - 5°C over about 30mins. The resultant reaction mixture was stirred at about -5°C for about 1 hr. The reaction temperature was raised to about 30°C and was stirred overnight. After completion of the reaction, the solvent was distilled completely at about 40°C to afford 98 gms of the title compound as solid, the solid obtained was recry stall ized from water to afford of the title compound in pure form.

Yield : 36 gms.; Purity by HPLC: 99.85%.

Purification of Rivaroxaban (I)

35 gms of rivaroxaban obtained from example 1 and 1 6ml of acetic acid were charged into a clean and dry 500ml of R.B. Flask. The reaction suspension was heated to about 1 10°C to get homogenous solution. 2.5 gms of charcoal carbon was charged and was stirred for about 15 mins.The reaction suspension was filtered on celite and the celite was washed with 20ml of acetic acid. The filtrate obtained was cooled to about 30 ⁹ C and further cooled to about 20°C and was stirred for about 1 hr.The solid separated was filtered and the solid obtained was washed with 30ml of acetic acid followed by 60ml of water to afford title compound in pure form.

Yield: 32 gms.: Purity by HPLC: 99.94%.

Example - 2: Alternate process for the preparation of Rivaroxaban (I)

20 gms of 4-{4-[(5S)-5-(Aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl} -morpholin- 3-one, 25 ml of ethylene glycol and 12.13 gms of methyl-5-chlorothiophene-2-carboxylic acid were charged into a clean and dry 500ml. 4 neck R.B. Flask. The reaction mixture was heated to about 65°C for about 48 hours. After completion of the reaction, the reaction mass was decomposed by addition of 200ml of water. The solid separated was filtered and the solid obtained was dried and recrystallized from acetic acid to afford the title compound in pure form. Yield : 26gms.; Purity by HPLC: 99.8%.

Example - 3: Preparation of Rivaroxaban (I) in neat conditions

20 gms of 4-{4-[(5S)-5-(Aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl} -morpholin- 3-one, and 12.13 gms of methyl-5-chlorothiophene-2-carboxylic acid were charged into a clean and dry 500ml. 4 neck R.B. Flask. The reaction mixture was heated to about 120°C for about 48 hours under nitrogen. After completion of the reaction, the reaction mass was cooled to about 30°C, 180ml of acetic acid was added. The resultant reaction suspension was heated to about 110°C, 2.5 gms of charcoal carbon was added. The suspension was filtered and the filtrate was cooled to about 20°C for about 15 mins. The solid separated was filtered and the solid was washed with water afford the title compound in pure form.

Yield : 26gms.; Purity by HPLC: 99.96%.