FIELD OF THE INVENTION

The present invention refers to a process for obtaining rivaroxaban, as well as the preparation of new acid addition salts of 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1 ,3- oxazolidin-3-yl]phenyl}morpholin-3-one useful for the manufacturing of rivaroxaban and pharmaceutical acceptable salts thereof.

BACKGROUND OF THE INVENTION

Rivaroxaban is an orally-active Factor Xa inhibitor, developed by Bayer for the prevention of venous thromboembolism (VTE) in adult patients undergoing elective hip or knee replacement surgery. Its chemical name is 5-Chloro-N-({(5S)-2-oxo-3-[4- (3-oxomorpholin-4-yl)phenyl]-1 ,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide having the following structure:

Rivaroxaban Rivaroxaban was first disclosed by US patent number US 7,157,456 in which rivaroxaban is prepared by reacting 2-[(2S)-2-oxiranylmethyl]-1 H-isoindole-1 ,3(2H)- dione with 4-(4-aminophenyl)-3-morpholinone to obtain 2-((2R)-2-hydroxy-3-{[4-(3- oxo-4-morpholinyl)phenyl]amino}propyl-1 H-isoindole-1 , 3(2H)-dione (I), as depicted in Scheme 1. The obtained compound was mixed with dimethylaminopyridine, tetrahydrofuran and Ν,Ν'-carbonyldiimidazole to yield 2-({(5S)-2-oxo-3-[4-(3-oxo-4- morpholinyl)phenyl]-1 ,3-oxazolidin-5-yl}methyl)-1 H-isoindole-1 ,3(2H)-dione (la). Elimination of the phthalimide protective group in the following afforded compound (lb), which was used, without further purification in the last step of the synthetic route. Crude rivaroxaban was obtained by addition of 5-chlorothiphene-2-carbonylchloride to a solution of the compound III in pyridine. Purification of rivaroxaban was carried out by means of flash chromatography.

Rivaroxaban

Scheme 1

The process of Scheme 1 has been found to present several disadvantages, such as the presence of unwanted side reactions because of the presence of undesired impurities. As a result of that, the final product is obtained in low purity; forcing to apply chromatographic purification methods that are not feasible processes to industrial scale. Additionally, the use of pyridine, as a solvent, and a base, poses an important issue, as pyridine is a well known carcinogenic compound.

An alternative process for the preparation of rivaroxaban was later disclosed in US 7,351 ,823 B2. The claimed process described the reaction of 4-{4-[(5S)-5- (aminomethyl)-2-oxo-1 ,3-oxazolidin-3-yl]phenyl}morpholin-3-one (lb) hydrochloride with 5-chlorothiophene-2-carbonyl chloride in the presence of a solvent selected from ether, alcohol, ketone and water and an inorganic base to yield rivaroxaban. RIVAROXABAN

Scheme 2

US 7,351 ,823 B2 is silent about the purity of the compound lb-hydrochloride. The inventors of the present application have reproduced the process of scheme 2 and they have observed that compound lb-hydrochloride was obtained with moderate purity, lower than 94%, as desired for industrial applications. Therefore, as compound lb-hydrochloride does not undergo further purification process, the purity of the final rivaroxaban decrease significantly. If rivaroxaban does not comply with pharmaceutical standards then further purification steps are required entailing such further steps a significant decrease in the yield. Worthy of note are the stringent purity requirements which are set by the Drug Agencies. A typical recommendation/requirement for the active pharmaceutical ingredients is that the amount of the unknown impurities should not be more that 0.1 % (See ICH Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients, Q7A, Current Step 4 Version, November 10, 2000).

The wide prevalence of illnesses related to blood coagulation makes rivaroxaban an important active ingredient. As already explained, to date the prio-art provides hazardous, multi-step, complex and expensive methods for obtaining pure rivaroxaban, which may comply with pharmaceutical standards. These facts increase the cost of the final rivaroxaban and the pharmaceutical compositions containing it, which has already resulted in expensive medications. Therefore, there is a need to develop an improved industrially feasible and more economical process for the preparation of rivaroxaban that is more environmentally friendly, and which can yield rivaroxaban in high purity and yield that can be applied to industrial scale.

BRIEF DESCRIPTION OF THE INVENTION The present invention provides a process for manufacturing rivaroxaban with a high purity and good yield, which comprises the use of new acid addition salts of following general formula III:

wherein HA is an organic acid.

Advantageously, the process comprising the use of said above organic acid addition salt results is a straightforward reproducible process, which is more environmentally friendly and applicable at industrial scale. Moreover, the rivaroxaban obtained by the process as herein disclosed has a high purity. Additional advantages of the process as herein disclosed are cycle time, chemical cost, personnel efficiency, reduction in equipment purchases and manufacturing capacity.

It is also provided new acid addition salts of general formula III, wherein HA is an organic acid, as well as their use for the preparation of rivaroxaban.

Various aspects of the present invention are described below.

According to the first aspect of the present invention a process for the manufacturing of rivaroxaban or a pharmaceutically acceptable salt thereof is provided, wherein the process comprises at least the following steps: i) obtaining an acid addition salt of a 4-{4-[(5S))-5-(aminomethyl)-2-oxo-1 ,3- oxozoladine-3-yl]phenyl}morpholin-3-one, wherein the acid used to form the acid addition salt is an organic acid; ii) reacting the acid addition salt of a 4-{4-[(5S))-5-(aminomethyl)-2-oxo-1 ,3- oxozoladine-3-yl]phenyl}morpholin-3-one obtained in step (i) with the suitable reagents to obtain rivaroxaban or a salt thereof.

According to the second aspect of the present invention an acid addition salt of a 4- {4-[(5S))-5-(aminomethyl)-2-oxo-1 ,3-oxozoladine-3-yl]phenyl}morpholin-3-one is provided, wherein the acid used to form the acid addition salt is an organic acid.

According to the third aspect of the present invention a process for the manufacturing of a novel acid addition salt of a 4-{4-[(5S))-5-(aminomethyl)-2-oxo-1 ,3-oxozoladine-3- yl]phenyl}morpholin-3-one is provided, wherein the acid used to form the acid addition salt is an organic acid. According to the fourth aspect of the present invention the use of the acid addition salt of the second aspect, for the preparation of rivaroxaban and pharmaceutically acceptable salts thereof and for the preparation of a pharmaceutical composition comprising rivaroxaban or a pharmaceutically acceptable salt thereof is provided.

According to the fifth aspect of the present invention a pharmaceutical composition comprising a therapeutically effective amount of rivaroxaban prepared according to the first aspect together with appropriate amount of pharmaceutically acceptable excipients or carriers is provided.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 shows powder X-ray diffractogram for the 4-{4-[(5S)-5-(amino methyl)-2-oxo- 1 ,3-oxazolidine-3-yl]phenyl}morpholin-3-one oxalate, obtained by way of Example 6.

Figure 2 shows IR spectra of the 4-{4-[(5S)-5-(amino methyl)-2-oxo-1 ,3-oxazolidine-3- yl]phenyl}morpholin-3-one oxalate, obtained by way of Example 6.

Figure 3 shows the DSC analysis of the 4-{4-[(5S)-5-(amino methyl)-2-oxo-1 ,3- oxazolidine-3-yl]phenyl}morpholin-3-one oxalate, obtained by way of Example 6.

Figure 4 shows the TGA analysis of the 4-{4-[(5S)-5-(amino methyl)-2-oxo-1 ,3- oxazolidine-3-yl]phenyl}morpholin-3-one oxalate, obtained by way of Example 6. Figure 5 shows powder X-ray diffractogram for the 4-{4-[(5S)-5-(amino methyl)-2-oxo- 1 ,3-oxazolidine-3-yl]phenyl}morpholin-3-one malonate, obtained by way of Example 7.

Figure 6 shows IR spectra of the 4-{4-[(5S)-5-(amino methyl)-2-oxo-1 ,3-oxazolidine-3- yl]phenyl}morpholin-3-one malonate, obtained by way of Example 7.

DEFINITIONS

The term "organic acid" as used herein refers to organic compounds which comprises one or more carbon-containing radicals and presents acidic properties. The most common organic acids are the carboxylic acids, whose acidity is associated with their carboxyl group -COOH. The term organic acid, also refers as HA contemplates monoprotic, diprotic or triprotic organic acids. A preferred organic acids are R ₂ COOH compounds, or to mixtures of R ₂ COOH compounds, wherein R ₂ is a linear or branched, saturated or unsaturated alkyl, an aryl or a heteroaryl, said R ₂ group being optionally substituted by one or more halogen, hydroxyl, alkoxyl, carboxyl, carboalkoxyl, aryl or heteraryl groups, and said acid R ₂ COOH having between 1 and 18 carbon atoms. Non-limiting examples of these acids include commercially available oxalic acid, oxalic acid dihydrate, malonic acid, fumaric acid, citric acid, including citric acid monohydrate, maleic acid, tartaric acid, acetic acid, formic acid, trifluoroacetic acid, gluconic acid, lactic acid, malic acid, succinic acid, acetyl salicylic acid, adipic acid, pivalic acid, benzoic acid, phenylacetic acid, p-methoxybenzoic acid, 4-pyridylcarboxylic acid, oleic acid, organosulfur compounds, embonic acid, gentisic acid, glucuronic acid, pyroglutamic acid, glycolic acid, mandelic acid, aspartic acid, hippuric acid, glutaric acid, pimelic acid, palmitic acid and their mixtures.

Particularly, examples of these acids include commercially available organic acids, with the proviso that the organic acid is not oxalic acid, fumaric acid, citric acid, maleic acid, tartaric acid, succinic acid, mandelic acid or benzoic acid.

Particularly, examples of these acids include commercially available oxalic acid dihydrate, malonic acid, citric acid monohydrate, acetic acid, formic acid, trifluoroacetic acid, gluconic acid, lactic acid, malic acid, acetyl salicylic acid, adipic acid, pivalic acid, phenylacetic acid, p-methoxybenzoic acid, 4-pyridylcarboxylic acid, oleic acid, organosulfur compounds, embonic acid, gentisic acid, glucuronic acid, pyroglutamic acid, glycolic acid, aspartic acid, hippuric acid, glutaric acid, pimelic acid, palmitic acid and their mixtures. As used herein, the term "consisting essentially of refers that the entity or process may comprises further features, but those features do not materially any surprising technical affect.

As used herein the term "organic solvent" refers to an organic molecule capable of at least partially dissolving another substance (i.e., the solute). Organic solvents may be liquids at room temperature. Examples of organic solvents that may be used for the present invention include, but are not limited to: hydrocarbon solvents (e.g., n- pentane, n-hexane, n-heptane, n-octane, paraffin, cyclohexane, methylcyclohexane, decahydronaphthalene, mineral oil, crude oils, etc.) which also includes aromatic hydrocarbon solvents (e.g., benzene, toluene, o-xylene, m-xylene, and p-xylene), halogenated hydrocarbon solvents (e.g., carbon tetrachloride, 1 ,2-dichloroethane, dichloromethane, chloroform, etc.), ester solvents (e.g., ethyl formate, methyl acetate, ethyl acetate, ethyl malonate, etc.), ketone solvents (e.g., acetone, methyl ethyl ketone, cyclohexanone, cyclopentanone, etc.), ether solvents (e.g., diethyl ether, dipropyl ether, diphenyl ether, tetrahydrofuran, 1 ,4-dioxane, etc.), amine solvents (e.g., propyl amine, diethylamine, triethylamine, aniline, pyridine), alcohol solvents (e.g., methanol, ethanol, 1 -propanol, 1 -butanol, 1-octanol, benzyl alcohol, phenol, trifluoroethanol, glycerol, ethylene glycol, propylene glycol, m-cresol, etc.), acid solvents (e.g., acetic acid, hexanoic acid, etc.), carbon disulfide, nitrobenzene, N,N- dimethylformamide, Ν,Ν,-dimethylacetamide, dimethyl sulfoxide, N-methyl-2- pyrrolidone, acetonitrile, silicone solvents (e.g., silicone oils, polysiloxanes, cyclosilicones). In some embodiments, the organic solvent may be formed by the combination of two or more organic solvents. The term "polar solvent" as used herein means a solvent that tends to interact with other compounds or itself through acid-base interactions, hydrogen bonding, dipole- dipole interactions, or by dipole-induced dipole interactions. The term "non-polar solvent" as used herein means a solvent that is not a polar solvent. Non-polar solvents interact with other compounds or themselves predominantly through dispersion forces. Non-polar solvents interact with polar solvents mainly through dipole-induced dipole interactions or through dispersion forces. Non-limiting examples of these solvents include toluene, xylene, n-heptane, octane, isooctane, cyclohexane, pentane and 1 ,4-dioxane.

The term "aprotic solvent" as used herein means any molecular solvent which cannot donate H ⁺ . Examples of aprotic solvents that may be used for the present invention include, but are not limited to: tetrahydrofuran (THF), 2-methyl THF, toluene, methyl cyclohexane, acetonitrile, methyl ethyl ketone (MEK), and methyl isobutyl ketone (MIBK).

As used herein, the term "antisolvent" refers to a solvent in which the compound is not fully soluble. Suitable antisolvents for the purification process of rivaroxaban include alcohols, ketones, ethers, esters, hydrocarbons and any mixtures thereof.

For the purposes of this description, the term "alcohol" refers to a hydrocarbon derivative in which one or more hydrogen atoms have been replaced by an -OH group. Suitable alcohols for the present invention include C1-C6 linear, cyclic or branched alcohols and any mixtures thereof. It also includes commercially available alcohols.

The term "amino protecting group" refers to a protecting group for the amino moiety to hinder the reactivity of the amino group. In this instance, the amino group can be attached to an alkyl or aryl moiety or can be present as part of an amide or hydroxamide functional group. Examples of suitable amino protecting groups can be found in, for example Greene's Protective Groups in Organic Synthesis. Non-limiting examples of amino protecting groups are 9-fluorenylmethyl carbamate (Fmoc-NRR'), t-butyl carbamate (Boc-NRR'), benzyl carbamate (Z-NRR', Cbz-NRR'), acetamide, trifluoroacetamide, phthalimide, benzylamine (Bn-NRR'), triphenylmethylamine (Tr- NRR'), benzylideneamine and p-toluenesulfonamide (Ts-NRR'). The preferred amino protecting group is the phthalimide.

As used herein, the term "one-pot process" refers to a process comprising simultaneously or successively adding all reactants into a reactor to have them react together, in which no separation and/or purification of the intermediate state is required before the final product is produced. The term "inorganic base" as used herein refers to a substance that tends to accept a proton. It contains a metal cation and does not contain an organic moiety, as compared to an organic base, which is a substance that contains an organic moiety. The inorganic bases preferred for the present invention are hydroxides of calcium, sodium, magnesium, potassium, lithium and caesium, and carbonates and bicarbonates of calcium, sodium, magnesium, potassium, lithium and caesium. More preferred inorganic bases are carbonates and bicarbonates of sodium, potassium and lithium. Most preferred inorganic base is sodium carbonate. As used herein, the term "organic amine" refers to an organic (i.e., carbon-containing) compound containing at least one primary (i.e., -NH2) or secondary (i.e., -NH-). Examples of organic amines include, but are not limited to: methylamine, ethylamine, propylamine, isopropylamine, butylamine, isobutylamine, sec-butylamine, tert- butylamine, dimethylamine, diethylamine, dipropylamine, and the like.

The term "aminoalcohol" as used herein refers to an organic compound that contains both a primary amine functional group and a primary alcohol functional group. The primary alcohol functional group can be C1-C8 lineal or branched alcohol. Non- limiting examples of aminoalcohols are 2-aminoethanol, 3-aminopropanol, 4- aminobutanol.

As used herein, the term "phosgene equivalent" refers to a compound able to replace phosgene (carbonyl dichloride) as a building block or reagent in organic syntheses, or able to specifically bring about the basic phosgene functions as a (cyclo)carbonylating, chlorocarbonylating, chlorinating or dihydrating agent. Examples of suitable phosgene equivalents can be found in, for example Phogenations- A Handbook. Cotarca L and Eckert H.32-43 (2003).

The term "purification" as used herein refers to the process wherein a purified drug substance can be obtained. The term "industrial purification" refers to purifications, which can be carried out on an industrial scale such as solvent extraction, filtration, slurring, washing, phase separation, evaporation, centrifugation or crystallization.

As used herein, the term, "solvent extraction" refers to the process of separating components of a mixture by using a solvent which possesses greater affinity for one component, and may therefore separate said one component from at least a second component which is less miscible than said one component with said solvent.

The term "filtration" refers to the act of removing solid particles greater than a predetermined size from a feed comprising a mixture of solid particles and liquid. The expression "filtrate" refers to the mixture less the solid particles removed by the filtration process. It will be appreciated that this mixture may contain solid particles smaller than the predetermined particle size. The expression "filter cake" refers to residual solid material remaining on a feed side of a filtration element. As used herein, the term "slurring" refers to any process which employs a solvent to wash or disperse a crude product. As used herein, the term "washing" refers to the process of purifying a solid mass (e.g., crystals) by passing a liquid over and/or through the solid mass, as to remove soluble matter. The process includes passing a solvent, such as distilled water, over and/or through a precipitate obtained from filtering, decanting, or a combination thereof. For example, in one embodiment of the invention, washing includes contacting solids with solvent or solvent mixture, vigorously stirring (e.g., for two hours), and filtering. The solvent can be water, can be an aqueous solvent system, or can be an organic solvent system. Additionally, the washing can be carried out with the solvent having any suitable temperature. For example, the washing can be carried out with the solvent having a temperature between about 0 °C and about 100 °C.

The term "phase separation" refers to a solution or mixture having at least two physically distinct regions. The term "evaporation" refers to the change in state of solvent from liquid to gas and removal of that gas from the reactor. Generally gas is removed by vacuum applied across the membrane. Various solvents may be evaporated during the synthetic route disclosed herein. As known to those of skill in the art, each solvent may have a different evaporation time and/or temperature.

The term "crystallization" refers to any method known to a person skilled in the art such as crystallization from single solvent or combination of solvents by dissolving the compound optionally at elevated temperature and precipitating the compound by cooling the solution or removing solvent from the solution or both. It further includes methods such as solvent antisolvent or precipitation.

The term "pure rivaroxaban" as used herein refers to rivaroxaban of a purity obtained by HPLC of at least 98 % (w/w), preferably of at least 99% (w/w), most preferably of at least 99.5% (w/w).

The term "Dx" as used herein means that x% of the particles in a composition (based on volume) have a diameter below a specified D value. Thus, a D50 of 400 μιη means that 50% of the particles, by volume, have a diameter below 400 μιη. DETAILED DESCRIPTION OF THE INVENTION

The first aspect of the invention relates to a process for the manufacturing of rivaroxaban or a pharmaceutically acceptable salt thereof, wherein the process comprises at least the following steps: i) obtaining an acid addition salt of a 4-{4-[(5S))-5-(aminomethyl)-2-oxo-1 ,3- oxozoladine-3-yl]phenyl}morpholin-3-one (III), wherein the acid used to form the acid addition salt is an organic acid; ii) reacting the acid addition salt of a 4-{4-[(5S))-5-(aminomethyl)-2-oxo-1 ,3- oxozoladine-3-yl]phenyl}morpholin-3-one (III) obtained in step (i) with the suitable reagents to obtain rivaroxaban or a salt thereof.

Scheme 3 depicts obtaining compound (III) from compound (II), and obtaining rivaroxaban from compound (III), wherein P is an amino protecting group and HA is an organic acid as previously defined.

RIVAROXABAN

Scheme 3.

Scheme 4 depicts a preferred embodiment of the process as herein disclosed.

RIVAROXABAN

Scheme 4. P is an amino protecting group and HA is an organic acid as previously defined; and X is a halide.

The acid addition salt of 4-{4-[(5S))-5-(aminomethyl)-2-oxo-1 ,3-oxozoladine-3- yl]phenyl}morpholin-3-one (III), may be obtained by the deprotection of the amino protected precursor (compound II) in the presence of at least one suitable amino deprotecting agent followed by addition of an organic acid. In a preferred embodiment, the amino protecting group P is phthalimide and the amino deprotecting agent is selected from the group consisting of organic amines, ammonia, aminoalcohols, hydrazine, H ₂ , nucleophiles, and mixtures thereof. Preferably the amino deprotecting agent is an organic amine, ammonia or mixtures thereof, more preferably the amino deprotecting agent is methylamine. The deprotection of compound II is typically carried out in the presence of at least one organic solvent or a mixture of organic solvents, preferably a polar organic solvent or a mixture of polar organic solvents, more preferably alcohol or mixtures of alcohols, even more preferably the deprotection is carried out in ethanol, methanol or mixtures thereof. The reaction mixture prepared in this step is normally heated to the reflux temperature of the solvent and stirred until the deprotection of compound II is completed. The reaction may be carried out in one-pot, so, once the deprotection of compound II is completed, an organic acid, as previously defined, is added over the reaction mixture in order to generate compound III. The organic acid can be added in a solid form, or as a dispersion or as a solution. The reaction mixture can be at a temperature between 20 °C up to the reflux temperature of the solvent. In a preferred embodiment, the organic acid is selected from oxalic acid, including oxalic acid dihydrate, fumaric acid, citric acid, including citric acid monohydrate, acetic acid, lactic acid, malic acid, malonic acid, maleic acid, tartaric acid, and formic acid. In addition to the good results obtained with such acids, another further advantage is that they are commercially available. More preferably, the organic acid is oxalic acid, including oxalic acid dihydrate, malonic acid or maleic acid, which allow obtaining acid addition salts of a 4-{4-[(5S))-5-(aminomethyl)-2-oxo-1 ,3-oxozoladine-3- yl]phenyl}morpholin-3-one with a HPLC purity of at least 98.4%. Moreover, the selected organic acid is the same as the one forming the acid addition salt. For example, if the desired addition salt is the malonate, the acid used to obtain it is malonic acid. In another preferred embodiment the organic acid is added in a solution of an organic solvent or mixtures of organic solvents. More preferably, the organic solvent is alcohol or mixtures of alcohols, selected from methanol, ethanol, propanol and butanol. The most preferred alcohols are methanol, ethanol or mixtures thereof. In a more preferred embodiment an alcoholic solution of the organic acid is added dropwise until pH between 1 and 6 is reached, preferably between 1.5 and 5, and more preferably between 1 .5 and 4, leading to the precipitation of the acid addition salt. The organic acid addition can be carried out from about 20 °C up to the reflux temperature of the organic solvent of the deprotection step.

As commented above, in a preferred embodiment of the process as herein disclosed, the deprotection and the addition of the organic acid are carried out in one-pot. Typically, in the one pot process, the molar ratio of compound Ikamino deprotecting agen organic acid is from 1 :3:3.5 to 1 :5.5:6.

In a preferred embodiment, in order to increase the purity of the final crude of rivaroxaban, between step (i) and step (ii) the process may comprise a further step (i'). In step (i') the acid addition salt of 4-{4-[(5S))-5-(aminomethyl)-2-oxo-1 ,3- oxozoladine-3-yl]phenyl}morpholin-3-one obtained in the previous steps is purified.

In step (ii), the acid addition salt (III) is usually mixed with at least one equivalent of an inorganic base, as already defined, in a polar solvent. The reaction mass should be kept at a temperature range between -5 and 15 °C, preferably between 0 and 10 °C. Suitable inorganic bases are selected from hydroxides of calcium, sodium, magnesium, potassium, lithium and caesium, and carbonates and bicarbonates of calcium, sodium, magnesium, potassium, lithium and caesium. Suitable polar solvents are, but not limited, ketones such as acetone, methyl ethyl ketone (MEK), methyl isobutyl ketone (MIBK); ethers such as tetrahydrofuran (THF), dioxane, diisopropyl ether or methyl tert-butyl ether; alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol, sec-butanol or tert-butanol; water or mixtures thereof. Preferably, the solvent is selected from ketones, ethers, water and mixtures thereof and the inorganic base is selected from carbonates and bicarbonates of sodium, potassium and lithium. More preferably, the solvent is an acetone/water mixture and the inorganic base is sodium carbonate. Afterwards, suitable reagents to obtain rivaroxaban such as 5-chlorothiophene-2-carbonyl halide is added to the above reaction mixture and stirred, while the temperature is maintained in order to yield rivaroxaban. Preferably a suitable reagent is 5- chlorothiophene-2-carbonyl chloride.

The molar ratio of the acid addition salt (III) to a suitable reagent such as 5- chlorothiophene-2-carbonyl halide may be from 1 :1 to 1 :3, preferably about 1 :1.5. Afterwards, the reaction mixture is preferably heated to about 50 to 55 °C and further stirred. The resulted crude rivaroxaban may be filtered off and washed with the reaction solvents, when still hot or at room temperature.

Suitable reagents, such as 5-chlorothiophene-2-carbonyl halide may be prepared by mixing 5-chloro-2-thiophenecarboxylic acid with a thionyl halide, preferably thionyl chloride, and an organic solvent or mixtures thereof, preferably N,N- dimethylformamide (DMF), THF, acetone, toluene or mixtures thereof. Afterwards, the reaction mass may be heated to reflux temperature and part of the organic solvent can be distilled out in vacuum at 30-70 °C in order to remove the excess of thionyl chloride.

In a preferred embodiment, the 5-chlorothiophene-2-carbonyl chloride is added as a solution in an organic solvent, preferably toluene. The molar ratio of the acid addition salt (III) to 5-chlorothiophene-2-carbonyl chloride is from 1 :1 to 1 :3, preferably about 1 :1 .5. Afterwards, the reaction mixture is preferably heated from about 50 to 55 °C and further stirred. The resulted crude rivaroxaban may be filtered off and washed with the reaction solvents, when still hot or at room temperature. The 5- chlorothiophene-2-carbonyl chloride solution may be prepared by mixing 5-chloro-2- thiophenecarboxylic acid with a thionyl chloride, and an organic solvent or mixtures thereof, preferably DMF, THF, acetone, toluene or mixtures thereof. Afterwards, the reaction mass is heated to reflux temperature and part of the toluene distilled out in vacuum at 30-70 °C in order to remove the excess of thionyl chloride.

Although the use of an organic acid to form the addition salt is preferred, another possible process to manufacture rivaroxaban could include the use of another inorganic acid instead of HCI.

The second aspect of the invention relates to novel acid addition salts of general formula III:

wherein HA is an organic acid, as already defined, which can be used as intermediates in the preparation process of rivaroxaban. The use of organic acid addition salts affords the manufacturing of rivaroxaban or salts thereof in high purity and high yields by a process that is more environmentally friendly and can be easily applied at industrial scale. These acid addition salts of general formula III are also obtained in high purity and yield and can be easily isolated and purified by using standard industrial methods, avoiding the use of impractical column chromatography, which is a clear advantage, as previously explained. The organic acid HA includes, high purity commercially available monoprotic, diprotic and triprotic acids, as already defined. In a preferred embodiment, the organic acid is oxalic acid, including oxalic acid dihydrate, fumaric acid, citric acid, including citric acid monohydrate, acetic acid, lactic acid, malic acid, maleic acid, malonic acid, tartaric acid or formic acid. In a more preferred embodiment, the organic acid is oxalic acid, including oxalic acid dihydrate, citric acid, including citric acid monohydrate, acetic acid, lactic acid, malic acid, maleic acid or malonic acid.

The third aspect of the invention relates to the process for the preparation of the novel acid addition salts of general formula III, wherein HA is an organic acid, as already defined. The acid addition salts of 4-{4-[(5S))-5-(aminomethyl)-2-oxo-1 ,3- oxozoladine-3-yl]phenyl}morpholin-3-one (III) may be obtained by the deprotection of the amino protected precursor (compound II) in the presence of at least one suitable amino deprotecting agent followed by addition of an organic acid. In a preferred embodiment, the amino protecting group P is phthalimide and the amino deprotecting agent is selected from the group consisting of organic amines, ammonia, aminoalcohols, hydrazine, H ₂ , nucleophiles, and mixtures thereof.

Preferably, the amino deprotecting agent is selected from the group consisting of organic amines, ammonia, aminoalcohols, hydrazine, H ₂ , nucleophiles, and mixtures thereof. Preferably the amino deprotecting agent is an organic amine, ammonia or mixtures thereof, more preferably the amino deprotecting agent is methylamine. The deprotection of compound II is typically carried out in the presence of at least one organic solvent or a mixture of organic solvents, preferably a polar organic solvent or a mixture of polar organic solvents, more preferably alcohol or mixtures of alcohols, even more preferably the deprotection is carried out in ethanol, methanol or mixtures thereof. The reaction mixture prepared in this step is normally heated to the reflux temperature of the solvent and stirred until the deprotection of compound II is completed. The reaction may be carried out in one-pot, so, once the deprotection of compound II is completed, an organic acid, as previously defined, is added over the reaction mixture in order to generate compound III. The organic acid can be added in a solid form, or as a dispersion or as a solution. The reaction mixture can be at a temperature between 20 °C up to the reflux temperature of the solvent. In a preferred embodiment, the organic acid is selected from oxalic acid, including oxalic acid dihydrate, citric acid, including citric acid monohydrate, acetic acid, lactic acid, malic acid, fumaric acid, malonic acid, maleic acid, tartaric acid, and formic acid. In addition to the good results obtained with such acids, another further advantage is that they are commercially available. More preferably, the organic acid is oxalic acid, including oxalic acid dihydrate, malonic acid or maleic acid, which allow obtaining acid addition salts of a 4-{4-[(5S))-5-(aminomethyl)-2-oxo-1 ,3-oxozoladine-3-yl]phenyl}morpholin-3- one with a HPLC purity of at least 98.4%. Moreover, the selected organic acid is the same as the one forming the acid addition salt. For example, if the desired addition salt is the malonate, the acid used to obtain it is malonic acid. In another preferred embodiment the organic acid is added in a solution of an organic solvent or mixtures of organic solvents. More preferably, the organic solvent is alcohol or mixtures of alcohols, selected from methanol, ethanol, propanol and butanol. The most preferred alcohols are methanol, ethanol or mixtures thereof. In a more preferred embodiment an alcoholic solution of the organic acid is added dropwise until pH between 1 and 6 is reached, preferably between 1 .5 and 5, and more preferably between 1 .5 and 4, leading to the precipitation of the acid addition salt. The organic acid addition can be carried out from about 20 °C up to the reflux temperature of the organic solvent of the deprotection step.

As commented above, in a preferred embodiment of the process as herein disclosed, the deprotection and the addition of the organic acid are carried out in one-pot. Typically, in the one pot process, the molar ratio of compound Ikamino deprotecting agen organic acid is from 1 :3:3.5 to 1 :5.5:6.

In a preferred embodiment, the acid addition salt of 4-{4-[(5S))-5-(aminomethyl)-2- oxo-1 ,3-oxozoladine-3-yl]phenyl}morpholin-3-one (III) obtained is isolated and therefore purified by standard industrial purification methods. In this manner, novel salts of 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1 ,3-oxazolidin-3- yl]phenyl}morpholin-3-one (III) having good yield and high HPLC purity are obtained. The HPLC purity is in most of the cases is higher than 95%. In a preferred embodiment, 4-{4-[(5S))-5-(aminomethyl)-2-oxo-1 ,3-oxozoladine-3- yl]phenyl}morpholin-3-one oxalate, 4-{4-[(5S))-5-(aminomethyl)-2-oxo-1 ,3- oxozoladine-3-yl]phenyl}morpholin-3-one citrate, 4-{4-[(5S))-5-(aminomethyl)-2-oxo- 1 ,3-oxozoladine-3-yl]phenyl}morpholin-3-one acetate, 4-{4-[(5S))-5-(aminomethyl)-2- oxo-1 ,3-oxozoladine-3-yl]phenyl}morpholin-3-one lactate, 4-{4-[(5S))-5-

(aminomethyl)-2-oxo-1 ,3-oxozoladine-3-yl]phenyl}morpholin-3-one malate, 4-{4- [(5S))-5-(aminomethyl)-2-oxo-1 ,3-oxozoladine-3-yl]phenyl}morpholin-3-one malonate, 4-{4-[(5S))-5-(aminomethyl)-2-oxo-1 ,3-oxozoladine-3-yl]phenyl}morpholin-3-one fumarate, 4-{4-[(5S))-5-(aminomethyl)-2-oxo-1 ,3-oxozoladine-3-yl]phenyl}morpholin- 3-one maleate, 4-{4-[(5S))-5-(aminomethyl)-2-oxo-1 ,3-oxozoladine-3- yl]phenyl}morpholin-3-one tartrate, or 4-{4-[(5S))-5-(aminomethyl)-2-oxo-1 ,3- oxozoladine-3-yl]phenyl}morpholin-3-one formate are obtained. In a more preferred embodiment, 4-{4-[(5S))-5-(aminomethyl)-2-oxo-1 ,3-oxozoladine-3- yl]phenyl}morpholin-3-one oxalate, 4-{4-[(5S))-5-(aminomethyl)-2-oxo-1 ,3- oxozoladine-3-yl]phenyl}morpholin-3-one malonate or 4-{4-[(5S))-5-(aminomethyl)-2- oxo-1 ,3-oxozoladine-3-yl]phenyl}morpholin-3-one maleate are obtained. Such salts are preferred since they can be obtained with a HPLC purity higher than 98.40%. The acid addition salt obtained is in a solid form, preferably in a crystalline form.

In a preferred embodiment, the amino protected precursor (compound II), wherein P is phthalimide (2-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1 ,3-oxazolidin-5- yl}methyl)-1 H-isoindole-1 ,3(2H)-dione), is used for the preparation of novel acid addition salts of general formula III. The 2-({(5S)-2-oxo-3-[4-(3-oxo-4- morpholinyl)phenyl]-1 ,3-oxazolidin-5-yl}methyl)-1 H-isoindole-1 ,3(2H)-dione is prepared by cyclization of 2-((2R)-2-hydroxy-3-{[4-(3-oxo-4- morpholinyl)phenyl]amino}propyl-1 H-isoindole-1 ,3(2H)-dione in the presence of phosgene or phosgene equivalents, preferably Ν,Ν-carbonyldiimidazole (CDI) in an aprotic solvent, as already defined, and without the need of using a catalyst. The preferred aprotic solvent is selected from tetrahydrofuran (THF), 2-methyl THF, acetonitrile, methyl ethyl ketone (MEK), and methyl isobutyl ketone (MIBK). More preferably, the aprotic solvent is tetrahydrofuran, acetonitrile or MIBK. In a preferred embodiment, the 2-((2R)-2-hydroxy-3-{[4-(3-oxo-4-morpholinyl)phenyl]amino} propyl- 1 H-isoindole-1 ,3(2H)-dione is prepared by reacting 2-[(2S)-2-oxiranylmethyl]-1 H- isoindole-1 ,3(2H)-dione and 4-(4-aminophenyl)-3-morpholinone, using an alcohol, water or mixtures thereof, as a solvent. The preferred solvent is ethanol. The fourth aspect of the invention relates to the use of the acid addition salt of the second aspect, for the preparation of rivaroxaban and pharmaceutically acceptable salts thereof and for the preparation of a pharmaceutical composition comprising rivaroxaban or a pharmaceutically acceptable salt thereof. An additional aspect of the invention relates to the purification of crude rivaroxaban, preferably the crude rivaroxaban obtained by the process as herein disclosed. In a preferred embodiment, rivaroxaban is purified by means of industrial purification techniques such as solvent extraction, filtration, slurring, washing, phase separation, evaporation, centrifugation or crystallization.

In a first preferred embodiment of the process for preparing pure rivaroxaban, the process comprises the following steps: a) heating the mixture of crude rivaroxaban with an organic solvent, wherein the solvent is selected from acetic acid, formic acid, DMF, aqueous mixtures thereof and mixtures thereof to a temperature higher than 50 °C, preferably until a clear solution is obtained; b) obtaining pure rivaroxaban by decreasing to a temperature between 0-30 °C, preferably between 20-30 °C.

The obtained solid is finally filtered off, and, if necessary, washed and dried. The preferred organic solvents are formic acid and aqueous mixtures thereof.

The preferred ratio of crude rivaroxaban to the organic solvent is between 1 :5 and 1 :20. The ratio herein described is mg of crude rivaroxaban to ml of the organic solvent. In more preferred embodiment, the step (a) is carried out at the reflux temperature of the mixture. In an even more preferred embodiment, the pure rivaroxaban of step (b) is obtained in crystalline form. The mixture of step (a) may be obtained by mixing crude rivaroxaban with the organic solvent. In a second preferred embodiment of the process for preparing pure rivaroxaban, the purification process comprises the following steps: a) heating a mixture comprising crude rivaroxaban with at least two organic solvents, wherein one first solvent is selected from acetic acid, formic acid, DMF, aqueous mixtures thereof and mixtures thereof, preferably formic acid and aqueous mixtures thereof; and one second solvent is selected from acetone, acetonitrile, MEK, MIBK and mixtures thereof, preferably acetone, MEK, MIBK and mixtures thereof, to a temperature higher than 50 °C, preferably until a clear solution is obtained; b) obtaining pure rivaroxaban by decreasing the temperature of the mixture obtained in step (a) to a temperature between 0-30 °C, preferably between 20-30 °C. The obtained solid is finally filtered off, and, if necessary, washed and dried. The preferred first solvents are formic acid and aqueous mixtures thereof. The preferred second solvents are acetone, MEK, MIBK and mixtures thereof. The preferred ratio of crude rivaroxaban to the first organic solvent is between 1 :2 and 1 :20. The preferred ratio of crude rivaroxaban to the second organic solvent is between 1 :2 and 1 :20. The ratio herein described is mg of crude rivaroxaban to ml of the first organic solvent or the second organic solvent. In more preferred embodiment, the step (a) is carried out at the reflux temperature of the mixture. In an even more preferred embodiment, the pure rivaroxaban of step (b) is obtained in crystalline form. The mixture comprising crude rivaroxaban with at least two organic solvents may be obtained of different manners. Preferably, it is obtained by mixing crude rivaroxaban with the two organic solvents of step (a). In that case, the crude rivaroxaban may be added to a mixture formed by the two organic solvents. Alternative, firstly the crude rivaroxaban is mixed with one of the organic solvents, secondly such mixture is heated to a temperature higher than 50 °C (e.g. for about 1 hour), and finally the other organic solvent is added.

In a third preferred embodiment of the process for preparing pure rivaroxaban, the process comprises the following steps: a) heating a mixture of crude rivaroxaban with an organic solvent or a mixture of organic solvents selected from acetic acid, formic acid, DMF, aqueous mixtures thereof and mixtures thereof to a temperature higher than 50 °C, preferably until a clear solution is obtained; b) decreasing the temperature to a temperature between 0-30 °C, preferably between 20-30 °C; c) obtaining a suspension of pure rivaroxaban by adding an antisolvent to the rivaroxaban mixture obtained in step (b); d) optionally stirring the rivaroxaban mixture obtained in step (c); e) decreasing the temperature of the rivaroxaban suspension at a temperature from -5 °C to 10 °C; f) optionally stirring the rivaroxaban mixture obtained; g) and isolating pure rivaroxaban, preferably by filtering off, and, if necessary, washed and dried.

The preferred antisolvents of step (c) are selected from acetone, MEK, MIBK, methyl cyclohexane, methanol, ethanol, ethyl acetate, acetonitrile, methyl tertiary butyl ether (MTBE), 2-methyl THF, water, aqueous mixtures thereof, or mixtures thereof. Even more preferred the antisolvent is acetone, MEK, MIBK, acetonitrile, water, or mixtures thereof. The preferred ratio of crude rivaroxaban, organic solvent and antisolvent is between 1 :5:8 and 1 :10:22, respectively (crude rivarobaxan in mg, organic solvent in ml and antisolvent in ml) In more preferred embodiment, the step (a) is carried out at the reflux temperature of the mixture. In an even more preferred embodiment, the pure rivaroxaban of step (b) is obtained in crystalline form. The mixture of step (a) may be obtained by mixing crude rivaroxaban with the organic solvent or the mixture of organic solvents.

These crystallization purification methods allow to obtaining pure rivaroxaban with a HPLC purity of at least 98% (w/w), preferably of at least 99% (w/w), most preferably of at least 99.5% (w/w). Rivaroxaban as prepared and isolated by a process according to the present invention comprises polymorphic Modification I, having a melting point of around 232 °C as defined in US 7,157,456.

Rivaroxaban obtained according to the process of the present invention can be milled or micronised to obtain a D ₅₀ and D ₉₀ particle size of less than about 400 μιη, preferably less than about 200 μιη, more preferably less than about 150 μιη, still more preferably less than about 50 μιη and most preferably less than 15 μιη. Particles of this size are obtained by conventional methods, based on the use of friction to reduce particle size. Such methods include milling, grinding in an air jet mill, hammer and screen mill, fine impact mill, ball mill or vibrator mill. Reduction in particle size may also take place as a result of collision and impact.

Rivaroxaban obtained according to the process of the present invention acts in particular as anticoagulant by means of selective inhibition of the blood coagulation factor Xa, and can be therefore preferably be employed in medicaments for the treatment and/or prevention of thromboembolic disorders. For the purpose of the present invention, "thromboembolic disorders", include, in particular serious disorders such as myocardial infarct, angina pectoris (including unstable angina), reocclusions and restenoses after angioplasty or aortocoronary bypass, stroke, transitory ischemic attacks, peripheral arterial occlusion disorders, pulmonary embolisms, deep venous thrombosis or venous thromboembolism.

The fifth aspect of the invention relates to a pharmaceutical composition comprising a therapeutically effective amount of rivaroxaban prepared according to the first aspect together with appropriate amount of pharmaceutically acceptable excipients or carriers. Administration of said pharmaceutical composition is preferably carried out orally, lingually, sublingually, bucally, rectally, pulmonary, nasally, dermally, transdermally, conjunctivally, optically, parenterally (i.e. bypassing the intestinal tract, that is intravenously, intraarterially, intracardially, intracutaneously, subcutaneously, transdermally, intraperitoneally or intramuscularly) or as an implant or stent. Particularly preferred are oral and parenteral administrations. Particularly preferred is oral administration. In general the pharmaceutical composition of the invention and in the case of intravenous administration, rivaroxaban is administered in amounts from approximately 0.001 to 10 mg/kg, preferably approximately 0.01 to 10 mg/kg, in particular approximately 0.1 to 8 mg/kg, of body weight to achieve effective results. In the case of oral administration, the dose of rivaroxaban is approximately 0.01 to 100 mg/kg, preferably approximately 0.01 to 20 mg/kg, in particular from about 0.1 to 10 mg/kg of body weight.

The pharmaceutical composition of the present invention may take the form of a dosage unit such as a tablet, capsule or a suppository. A preferred pharmaceutical composition is a tablet. Most preferably, the composition is a film-coated tablet.

A dosage unit of the present invention, containing rivaroxaban and suitable for the treatment and/or prevention of "thromboembolic disorders", as defined above, may contain about 0.0005 to 500 mg of the rivaroxaban obtained according to the process of the invention. A preferred dosage unit may contain 1-20 mg of rivaroxaban obtained according to the process of the present invention.

The pharmaceutical compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, powders, granules, and aqueous suspensions and solutions. These dosage forms are prepared according to techniques well-known in the art of pharmaceutical formulation. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavouring and/or colouring agents may be added. The pharmaceutical compositions of this invention may further comprises one or more pharmacologically active ingredients.

Also provided is rivaroxaban or a pharmaceutical composition as defined above, for the use in the treatment or prevention of "thromboembolic disorders", as previously defined.

In addition, the present invention provides a method of treatment or prevention of "thromboembolic disorders", as previously defined, the method comprising the administration, to a subject in need of such treatment or prevention, of rivaroxaban or a pharmaceutical composition as defined above.

In a preferred embodiment, the rivaroxaban or the pharmaceutical composition obtained according to the process described in the present invention is used for the prevention of venous thromboembolism (VTE) in adult patients undergoing elective hip or knee replacement surgery.

In another aspect, the invention provides the use of rivaroxaban of the present invention for the preparation of a medicament for the treatment or prevention of "thromboembolic disorders", as previously defined.

Further aspects/embodiments of the present invention can be found below: Another aspect of the present invention relates to a process for the manufacturing of rivaroxaban or a pharmaceutically acceptable salt thereof, wherein the process comprises at least the following steps: i) obtaining an acid addition salt of a 4-{4-[(5S))-5-(aminomethyl)-2-oxo-1 ,3- oxozoladine-3-yl]phenyl}morpholin-3-one (III), wherein the acid used to form the acid addition salt is an organic acid; ii) reacting the acid addition salt of a 4-{4-[(5S))-5-(aminomethyl)-2-oxo-1 ,3- oxozoladine-3-yl]phenyl}morpholin-3-one (III) obtained in step (i) with the suitable reagents to obtain rivaroxaban or a salt thereof.

Another aspect of the present invention relates to a process for the manufacturing of rivaroxaban or a pharmaceutically acceptable salt thereof, wherein the process comprises at least the following steps: i) obtaining an acid addition salt of a 4-{4-[(5S))-5-(aminomethyl)-2-oxo-1 ,3- oxozoladine-3-yl]phenyl}morpholin-3-one (III), wherein the acid used to form the acid addition salt is an organic acid; ii) reacting the acid addition salt of a 4-{4-[(5S))-5-(aminomethyl)-2-oxo-1 ,3- oxozoladine-3-yl]phenyl}morpholin-3-one (III) obtained in step (i) with the suitable reagents to obtain rivaroxaban or a salt thereof; wherein the acid addition salt obtained in step (i) is isolated in a solid form, preferably in a crystalline form, before carrying step (ii).

Another aspect of the present invention relates to a process for the manufacturing of rivaroxaban or a pharmaceutically acceptable salt thereof, wherein the process comprises at least the following steps: i) obtaining an acid addition salt of a 4-{4-[(5S))-5-(aminomethyl)-2-oxo-1 ,3- oxozoladine-3-yl]phenyl}morpholin-3-one, wherein the acid used to form the acid addition salt is an organic acid, with the proviso that the organic acid is not oxalic acid, fumaric acid, citric acid, maleic acid, tartaric acid, succinic acid, mandelic acid or benzoic acid; ii) reacting the acid addition salt of a 4-{4-[(5S))-5-(aminomethyl)-2-oxo-1 ,3- oxozoladine-3-yl]phenyl}morpholin-3-one obtained in step (i) with the suitable reagents to obtain rivaroxaban or a salt thereof.

Another aspect of the present invention relates to a process for the manufacturing of rivaroxaban or a pharmaceutically acceptable salt thereof, wherein the process comprises at least the following steps: i) obtaining an acid addition salt of a 4-{4-[(5S))-5-(aminomethyl)-2-oxo-1 ,3- oxozoladine-3-yl]phenyl}morpholin-3-one, wherein the acid used to form the acid addition salt is an organic acid selected from oxalic acid dihydrate, malonic acid, citric acid monohydrate, acetic acid, formic acid, trifluoroacetic acid, gluconic acid, lactic acid, malic acid, acetyl salicylic acid, adipic acid, pivalic acid, phenylacetic acid, p-methoxybenzoic acid, 4-pyridylcarboxylic acid, oleic acid, organosulfur compounds, embonic acid, gentisic acid, glucuronic acid, pyroglutamic acid, glycolic acid, aspartic acid, hippuric acid, glutaric acid, pimelic acid, palmitic acid and their mixtures; ii) reacting the acid addition salt of a 4-{4-[(5S))-5-(aminomethyl)-2-oxo-1 ,3- oxozoladine-3-yl]phenyl}morpholin-3-one obtained in step (i) with the suitable reagents to obtain rivaroxaban or a salt thereof.

Another aspect of the present invention relates to a process for the manufacturing of rivaroxaban or a pharmaceutically acceptable salt thereof, wherein the process comprises at least the following steps: i) obtaining an acid addition salt of a 4-{4-[(5S))-5-(aminomethyl)-2-oxo-1 ,3- oxozoladine-3-yl]phenyl}morpholin-3-one (III), wherein the acid used to form the acid addition salt is an organic acid; ii) reacting the acid addition salt of a 4-{4-[(5S))-5-(aminomethyl)-2-oxo-1 ,3- oxozoladine-3-yl]phenyl}morpholin-3-one (III) obtained in step (i) with the suitable reagents to obtain rivaroxaban or a salt thereof, wherein one of the suitable reagents is an inorganic base.

In another embodiment the invention relates to any of the processes defined above, wherein the acid addition salt of a 4-{4-[(5S))-5-(aminomethyl)-2-oxo-1 ,3-oxozoladine- 3-yl]phenyl}morpholin-3-one obtained in step (i) is isolated in a solid form, preferably in a crystalline form, before carrying step (ii). In another embodiment, the invention relates to any of the processes defined above, wherein one of the suitable reagents of step (ii) is an inorganic base, preferably wherein the inorganic base is selected from carbonates and bicarbonates of sodium potassium and lithium, and more preferably wherein the inorganic base is selected from sodium carbonate.

In another embodiment, the invention relates to any of the processes defined above, wherein the organic acid is a R ₂ COOH compound, or to mixtures of R ₂ COOH compounds, wherein R ₂ is a linear or branched, saturated alkyl, unsaturated alkyl, an aryl or a heteroaryl, said R ₂ group being optionally substituted by one or more halogen, hydroxyl, alkoxyl, carboxyl, carboalkoxyl, aryl or heteraryl groups, and said acid R ₂ COOH having between 1 and 18 carbon atoms.

In another embodiment, the invention relates to any of the processes defined above, wherein the organic acid is oxalic acid, including oxalic acid dihydrate, citric acid, including citric acid monohydrate, acetic acid, lactic acid, malic acid, fumaric acid, malonic acid, tartaric acid, formic acid, maleic acid or mixtures thereof, preferably oxalic acid, including oxalic acid dihydrate, citric acid, including citric acid monohydrate, acetic acid, lactic acid, malic acid, maleic acid or malonic acid, more preferably the organic acid is oxalic acid dihydrate, citric acid monohydrate, acetic acid, lactic acid, malic acid, malonic acid or formic acid, and even more preferably the organic acid is oxalic acid dihydrate, malonic acid or maleic acid.

In another embodiment, the invention relates to any of the processes defined above, wherein an acid addition salt consisting essentially of an acid addition salt of a 4-{4- [(5S))-5-(aminomethyl)-2-oxo-1 ,3-oxozoladine-3-yl]phenyl}morpholin-3-one (III) and an organic acid is obtained in the step (i).

In another embodiment, the invention relates to any of the processes defined above, wherein the acid addition salt of the 4-{4-[(5S))-5-(aminomethyl)-2-oxo-1 ,3- oxozoladine-3-yl]phenyl}morpholin-3-one (III) is obtained by reacting the 4-{4-[(5S))- 5-(aminomethyl)-2-oxo-1 ,3-oxozoladine-3-yl]phenyl}morpholin-3-one with a suitable acid or a suitable acid precursor to obtain the acid addition salt. In another embodiment, the invention relates to any of the processes defined above, wherein the suitable acid is the same acid as the one forming the acid addition salt.

In another embodiment, the invention relates to any of the processes defined above, wherein the organic acid is added to a solution formed by the 4-{4-[(5S))-5- (aminomethyl)-2-oxo-1 ,3-oxozoladine-3-yl]phenyl}morpholin-3-one and a first solvent. In another embodiment, the first solvent is an organic solvent or a mixture of organic solvents, wherein the first solvent comprises at least an alcohol or mixtures of alcohols, preferably methanol, ethanol or mixtures thereof. In another embodiment, the first solvent consists essentially of at least an alcohol, or mixtures of alcohols, preferably, the first solvent is an alcohol. In another embodiment, the first solvent consists essentially of an alcohol, or mixtures of alcohols, preferably, the first solvent is an alcohol. In a preferred embodiment, the alcohol is selected from the group consisting of methanol, ethanol, propanol, butanol and mixtures thereof, preferably methanol, ethanol or mixtures thereof.

In another embodiment, the invention relates to any of the processes defined above, wherein the organic acid is added in a solid form, in dispersion or in a solution of a second solvent.

In another embodiment, the invention relates to any of the processes defined above, wherein the organic acid is added in a solution of a second solvent, and the second solvent comprises, preferably consists essentially of, an organic solvent or mixtures of organic solvents In another embodiment, the second solvent is an alcohol, or a mixture of alcohols. In a preferred embodiment, the alcohol is methanol, ethanol, propanol, butanol and mixtures thereof, preferably methanol, ethanol or mixtures thereof.

In another embodiment, the invention relates to any of the processes defined above, wherein during the addition of the organic acid the temperature of the solution comprising the 4-{4-[(5S))-5-(aminomethyl)-2-oxo-1 ,3-oxozoladine-3- yl]phenyl}morpholin-3-one is from 20 °C to reflux temperature of the first solvent.

In another embodiment, the invention relates to any of the processes defined above, wherein the organic acid is added until a pH between 1 and 6 is reached, preferably between 1 .5 and 5, and more preferably between 1 .5 and 4.

In another embodiment, the invention relates to any of the processes defined above, wherein the 4-{4-[(5S))-5-(aminomethyl)-2-oxo-1 ,3-oxozoladine-3- yl]phenyl}morpholin-3-one is obtained by the deprotection of an amino protected precursor.

In another embodiment, the invention relates to any of the processes defined above, wherein the amine is protected by an amino protecting group and the amino protecting group is selected from the group consisting of 9-fluorenylmethyl carbamate t-butyl carbamate, benzyl carbamate, acetamide, trifluoroacetamide, phthalimide, benzylamine, triphenylmethylamine, benzylideneamine and p-toluenesulfonamide, preferably phthalimide. In another embodiment, the invention relates any of the processes defined above, wherein the amino protected precursor is deprotected in the presence of at least one suitable amino deprotecting agent. In another embodiment, the invention relates to any of the processes defined above, wherein the amino protecting group is phthalimide and the deprotecting agent is selected from the group consisting of organic amines, ammonia, hydrazine, H ₂ , nucleophiles, and mixtures thereof, preferably the deprotecting agent is an organic amine, ammonia or mixtures thereof, more preferably the deprotecting agent is methylamine.

In another embodiment, the invention relates to any of the processes defined above, wherein the deprotection is carried out in at least one organic solvent, preferably a polar organic solvent, more preferably alcohol.

In another embodiment, the invention relates to any of the processes defined above, wherein the deprotection is carried out in the presence of at least one organic solvent or a mixture of organic solvents, preferably a polar organic solvent or a mixture of polar organic solvents, more preferably alcohol or mixtures thereof, the most preferably ethanol, methanol or mixtures thereof.

In another embodiment, the invention relates to any of the processes defined above, wherein the amino protecting group is phthalimide and the deprotection is carried out in the presence of a polar organic solvent, preferably alcohol, more preferably ethanol, methanol or mixtures thereof.

In another embodiment, the invention relates to any of the processes defined above, wherein the deprotection is carried out in the presence of ethanol, methanol or mixtures thereof as a solvent.

In another embodiment, the invention relates to any of the processes defined above, wherein the deprotection and the step (i) is carried out in one-pot. In another embodiment, the invention relates to any of the processes defined above, which further comprises a step (i'), wherein in such step (i') the salt obtained in the previous step (i) is purified before step (ii).

In another embodiment, the invention relates to any of the processes defined above, wherein the step (ii) comprises reacting the acid addition salt with a 5- chlorothiophene-2-carbonyl halide, preferably 5-chlorothiophene-2-carbonyl chloride.

In another embodiment, the invention relates to any of the processes defined above, wherein the step (ii) comprises reacting the acid addition salt with a 5- chlorothiophene-2-carbonyl halide, preferably 5-chlorothiophene-2-carbonyl chloride, and at least one base, preferably at least about one equivalent of a base.

In another embodiment, the invention relates to any of the processes defined above, wherein the step (ii) comprises reacting the acid addition salt with a 5- chlorothiophene-2-carbonyl halide, preferably 5-chlorothiophene-2-carbonyl chloride, and at least one inorganic base, preferably at least about one equivalent of an inorganic base. In another embodiment, the invention relates to any of the processes defined above, wherein the step (ii) is carried out in a polar solvent, preferably a ketone, an ether, an alcohol, water or mixtures thereof.

In another embodiment, the invention relates to any of the processes defined above, wherein the step (ii) comprises reacting the acid addition salt with a 5- chlorothiophene-2-carbonyl halide, preferably 5-chlorothiophene-2-carbonyl chloride; and at least one inorganic base, preferably at least about one equivalent of an inorganic base, wherein the inorganic base is selected from hydroxides of calcium, sodium, magnesium, potassium, lithium and caesium, and carbonates and bicarbonates of calcium, sodium, magnesium, potassium, lithium and caesium, preferably, the inorganic base is selected from carbonates and bicarbonates of sodium, potassium and lithium, and even more preferably, the inorganic base is sodium carbonate; and wherein the process is carried out in a polar solvent, preferably a ketone, an ether, an alcohol, water or mixtures thereof, more preferably, the solvent is a ketone/water mixture, and most preferably, the solvent is an acetone/water mixture.

Another aspect of the present invention relates to a process for the manufacturing of rivaroxaban or a pharmaceutically acceptable salt thereof, wherein the process comprises at least the following steps: i) obtaining an acid addition salt of a 4-{4-[(5S))-5-(aminomethyl)-2-oxo-1 ,3- oxozoladine-3-yl]phenyl}morpholin-3-one, wherein the acid used to form the acid addition salt is an inorganic acid with the proviso that the inorganic acid is not hydrochloric acid; ii) reacting the acid addition salt of a 4-{4-[(5S))-5-(aminomethyl)-2-oxo-1 ,3- oxozoladine-3-yl]phenyl}morpholin-3-one obtained in step (i) with the suitable reagents to obtain rivaroxaban or a salt thereof, wherein the acid used to form the acid addition salt is an inorganic acid with the proviso that the inorganic acid is not hydrochloric acid, obtained in the step (i) with the suitable reagents to obtain rivaroxaban or a salt thereof.

Another aspect of the present invention relates to a process for preparing pure rivaroxaban, wherein the process comprises the following steps: a) heating the mixture of crude rivaroxaban with an organic solvent, wherein the solvent is selected from acetic acid, formic acid, DMF, aqueous mixtures thereof and mixtures thereof to a temperature higher than 50 °C, preferably until a clear solution is obtained; b) obtaining pure rivaroxaban by decreasing the temperature to a temperature between 0-30 °C, preferably between 20-30 °C.

In another embodiment the invention relates to the process as defined above, wherein the ratio of crude rivaroxaban to the organic solvent is preferably between 1 :5 and 1 :20. The ratio herein described is mg of crude rivaroxaban to ml of the organic solvent.

In another embodiment the invention relates to the process as defined above, wherein the step (a) is carried out at the reflux temperature of the mixture. In another embodiment the invention relates to the process as defined above, wherein the pure rivaroxaban of step (b) is obtained in crystalline form.

In another embodiment the invention relates to the process as defined above, wherein the mixture of step (a) is obtained by mixing crude rivaroxaban with the organic solvent.

Another aspect of the present invention relates to a process for preparing pure rivaroxaban, wherein the process comprises the following steps: a) heating a mixture comprising crude rivaroxaban with at least two organic solvents, wherein one first solvent is selected from acetic acid, formic acid, DMF, aqueous mixtures thereof and mixtures thereof, preferably formic acid and aqueous mixtures thereof; and one second solvent is selected from acetone, acetonitrile, MEK, MIBK and mixtures thereof, preferably acetone, MEK, MIBK and mixtures thereof, to a temperature higher than 50 °C; b) obtaining pure rivaroxaban by decreasing the temperature of the mixture obtained in step (a) to a temperature between 0-30 °C, preferably between 20-30 °C.

In another embodiment the invention relates to the process as defined above, wherein the ratio of crude rivaroxaban to the first organic solvent is between 1 :2 and 1 :20 and the ratio of crude rivaroxaban to the second organic solvent is between 1 :2 and 1 :20. The ratio herein described is mg of crude rivaroxaban to ml of the first organic solvent or the second organic solvent.

In another embodiment the invention relates to the process as defined above, wherein the step (a) is carried out at the reflux temperature of the mixture. In another embodiment the invention relates to the process as defined above, wherein the pure rivaroxaban of step (b) is obtained in crystalline form.

In another embodiment the invention relates to the process as defined above, wherein the mixture of step (a) is obtained by mixing crude rivaroxaban with the two organic solvents of step (a).

In another embodiment the invention relates to the process as defined above, wherein the crude rivaroxaban is added to a mixture formed by the two organic solvents.

In another embodiment the invention relates to the process as defined above, wherein firstly the crude rivaroxaban is mixed with one of the organic solvents, secondly such mixture is heated to a temperature higher than 50 °C, and finally the other organic solvent is added.

Another aspect of the present invention relates to a process for preparing pure rivaroxaban, wherein the process comprises the following steps: a) heating a mixture of crude rivaroxaban with an organic solvent or a mixture of organic solvents selected from acetic acid, formic acid, DMF, aqueous mixtures thereof and mixtures thereof to a temperature higher than 50 °C; b) decreasing the temperature of the rivaroxaban mixture obtained to a temperature between 0-30 °C, preferably between 20-30 °C; c) obtaining a suspension pure rivaroxaban by adding an antisolvent to the rivaroxaban mixture obtained in step (b); d) optionally stirring the rivaroxaban mixture obtained in step (c); e) decreasing the temperature of the rivaroxaban suspension at a temperature from -5 °C to 10 °C; f) optionally stirring the rivaroxaban mixture obtained; g) and isolating pure rivaroxaban, preferably by filtering off, and, if necessary, washed and dried.

In another embodiment the invention relates to the process as defined above, wherein the antisolvent of step (c) is selected from acetone, MEK, MIBK, methyl cyclohexane, methanol, ethanol, ethyl acetate, acetonitrile, methyl tertiary butyl ether (MTBE), 2-methyl THF, water or mixtures thereof, preferably acetone, MEK, MIBK, acetonitrile, water, and mixtures thereof. In another embodiment the invention relates to the process as defined above, wherein the ratio of crude rivaroxaban, organic solvent and antisolvent is between 1 :5:8 and 1 :10:22, respectively (crude rivarobaxan in mg, organic solvent in ml and antisolvent in ml)

In another embodiment the invention relates to the process as defined above, wherein the step (a) is carried out at the reflux temperature of the mixture. In another embodiment the invention relates to the process as defined above, wherein the pure rivaroxaban is obtained in crystalline form.

In another embodiment the invention relates to the process as defined above, wherein the mixture is obtained by mixing crude rivaroxaban with the organic solvent or the mixture of organic solvents.

Another aspect of the present invention relates to an acid addition salt of a 4-{4- [(5S))-5-(aminomethyl)-2-oxo-1 ,3-oxozoladine-3-yl]phenyl}morpholin-3-one, wherein the acid used to form the acid addition salt is an organic acid.

Another aspect of the present invention relates to an acid addition salt of a 4-{4- [(5S))-5-(aminomethyl)-2-oxo-1 ,3-oxozoladine-3-yl]phenyl}morpholin-3-one, wherein the acid used to form the acid addition salt is an organic acid, with the proviso that the organic acid is not oxalic acid, fumaric acid, citric acid, maleic acid, tartaric acid, succinic acid, mandelic acid or benzoic acid.

Another aspect of the present invention relates to an acid addition salt of a 4-{4- [(5S))-5-(aminomethyl)-2-oxo-1 ,3-oxozoladine-3-yl]phenyl}morpholin-3-one, wherein the acid used to form the acid addition salt is an organic acid, selected from oxalic acid dihydrate, malonic acid, citric acid monohydrate, acetic acid, formic acid, trifluoroacetic acid, gluconic acid, lactic acid, malic acid, acetyl salicylic acid, adipic acid, pivalic acid, phenylacetic acid, p-methoxybenzoic acid, 4-pyridylcarboxylic acid, oleic acid, organosulfur compounds, embonic acid, gentisic acid, glucuronic acid, pyroglutamic acid, glycolic acid, aspartic acid, hippuric acid, glutaric acid, pimelic acid, palmitic acid and their mixtures. In a preferred embodiment, the organic acid used to form the acid addition salt is oxalic acid dihydrate, malonic acid, citric acid monohydrate, acetic acid, formic acid, lactic acid, malic acid or mixtures thereof, more preferably oxalic acid dihydrate, malonic acid, citric acid monohydrate, acetic acid, formic acid, lactic acid or malic acid. The most preferably organic acid is malonic acid or formic acid.

Another aspect of the present invention relates to an acid addition salt of a 4-{4- [(5S))-5-(aminomethyl)-2-oxo-1 ,3-oxozoladine-3-yl]phenyl}morpholin-3-one, wherein the acid used to form the acid addition salt is an organic acid, preferably the acid addition salt is 4-{4-[(5S))-5-(aminomethyl)-2-oxo-1 ,3-oxozoladine-3- yl]phenyl}morpholin-3-one oxalate, 4-{4-[(5S))-5-(aminomethyl)-2-oxo-1 ,3- oxozoladine-3-yl]phenyl}morpholin-3-one citrate, 4-{4-[(5S))-5-(aminomethyl)-2-oxo- 1 ,3-oxozoladine-3-yl]phenyl}morpholin-3-one acetate, 4-{4-[(5S))-5-(aminomethyl)-2- oxo-1 ,3-oxozoladine-3-yl]phenyl}morpholin-3-one lactate, 4-{4-[(5S))-5-

(aminomethyl)-2-oxo-1 ,3-oxozoladine-3-yl]phenyl}morpholin-3-one malate, 4-{4- [(5S))-5-(aminomethyl)-2-oxo-1 ,3-oxozoladine-3-yl]phenyl}morpholin-3-one malonate, 4-{4-[(5S))-5-(aminomethyl)-2-oxo-1 ,3-oxozoladine-3-yl]phenyl}morpholin-3-one fumarate, 4-{4-[(5S))-5-(aminomethyl)-2-oxo-1 ,3-oxozoladine-3-yl]phenyl}morpholin- 3-one maleate, 4-{4-[(5S))-5-(aminomethyl)-2-oxo-1 ,3-oxozoladine-3- yl]phenyl}morpholin-3-one tartrate, 4-{4-[(5S))-5-(aminomethyl)-2-oxo-1 ,3- oxozoladine-3-yl]phenyl}morpholin-3-one formate, more preferably 4-{4-[(5S))-5- (aminomethyl)-2-oxo-1 ,3-oxozoladine-3-yl]phenyl}morpholin-3-one oxalate or 4-{4- [(5S))-5-(aminomethyl)-2-oxo-1 ,3-oxozoladine-3-yl]phenyl}morpholin-3-one malonate.

In another embodiment, the invention relates to the acid addition salt, as defined above, which is selected from 4-{4-[(5S))-5-(aminomethyl)-2-oxo-1 ,3-oxozoladine-3- yl]phenyl}morpholin-3-one malonate and 4-{4-[(5S))-5-(aminomethyl)-2-oxo-1 ,3- oxozoladine-3-yl]phenyl}morpholin-3-one formate.

In another embodiment the invention relates to the acid addition salt, according to any of the aspects defined above, wherein the organic acid addition salt is in a solid form, preferably in a crystalline form. Another aspect of the present invention relates to an acid addition salt of a 4-{4- [(5S))-5-(aminomethyl)-2-oxo-1 ,3-oxozoladine-3-yl]phenyl}morpholin-3-one, wherein the acid used to form the acid addition salt is an organic acid and the salt is in a solid form, preferably in a crystalline form. Another aspect of the present invention relates to the use of an acid addition salt of a 4-{4-[(5S))-5-(aminomethyl)-2-oxo-1 ,3-oxozoladine-3-yl]phenyl}morpholin-3-one, for the preparation of rivaroxaban and pharmaceutically acceptable salts thereof.

In another embodiment, the invention relates to the use of an acid addition salt of a 4- {4-[(5S))-5-(aminomethyl)-2-oxo-1 ,3-oxozoladine-3-yl]phenyl}morpholin-3-one as defined above, for the preparation of a pharmaceutical composition comprising rivaroxaban or a pharmaceutically acceptable salt thereof.

Another aspect of the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of rivaroxaban prepared according to any of the processes defined above together with appropriate amount of pharmaceutically acceptable excipients or carriers. In another embodiment, the invention relates to the pharmaceutical composition as defined above, further comprising one or more pharmacologically active ingredients.

In another embodiment the invention relates to the pharmaceutical composition defined above for the prevention of venous thromboembolism (VTE) in adult patients undergoing elective hip or knee replacement surgery.

In the following, the present invention is further illustrated by examples. They should in no case be interpreted as a limitation of the scope of the invention as defined in the claims. Unless indicated otherwise, all indications of percentage are by weight and temperatures are in degrees Celsius.

EXAMPLES Example 1. Preparation of 2-((2R)-2-hydroxy-3-{[4-(3-oxo-4- morpholinyl)phenyl]amino} propyl)-1 H-isoindole-1 ,3(2H)-dione.

238.50 g (1.174 mol) of 2-[(2S)-2-oxiranylmethyl]-1 H-isoindole-1 , 3(2H)-dione (I), 150 g (0.781 mol) of 4-(4-amino phenyl)-3-morpholinone and 3L of ethanol were charged in a 5L flask and the reaction mass was heated at 80 °C for 9 hours. Afterwards the reaction mass was cooled down to 30 °C, and the resulting solid was filtered off and dried under vacuum at 70 °C.

Yield: 249 g. Molar yield: 80.68%. HPLC purity 96.90%. M.P.: 214 °C. Specific Optical Rotation (S.O.R.): [a ]D25 = +6.24° (c = 1 ,DMSO) Example 2. Preparation of 2-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1 ,3- oxazolidin-5-yl}methyl)-1 H-isoindole-1 ,3(2H)-dione.

142.5 g (0.360 mol) of 2-((2R)-2-hydroxy-3-{[4-(3-oxo-4-morpholinyl)phenyl]amino} propyl)-1 H-isoindole-1 , 3(2H)-dione (I), 175.32 g (1 .082 mol) of N,N- carbonyldiimidazole and 1425 mL of tetrahydrofuran were charged in a 3L flask and the reaction mass was heated to reflux for 4 hours. Then, the reaction mass was cooled down to 0 °C for 1 hour and the resulting solid was filtered off and dried under vacuum at 70 °C.

Yield: 137.8 g. Molar yield: 90.73%. HPLC purity: 99.74%. M.P.: 223 °C. S.O.R.: [a ] _D ²⁵ = -75.26° (c = 1 ,DMSO)

Example 3. Preparation of 2-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1 ,3- oxazolidin-5-yl}methyl)-1 H-isoindole-1 ,3(2H)-dione.

100 g (0.253 mol) of 2-((2R)-2-hydroxy-3-{[4-(3-oxo-4-morpholinyl)phenyl]amino} propyl)-1 H-isoindole-1 ,3(2H)-dione (I), 123 g (0.759 mol) of N,N-carbonyldiimidazole and 1 L of acetonitrile were charged in a 3 L flask and the reaction mass was heated to reflux for 4 hours. Afterwards, the reaction mass was cooled down to 0 °C for 1 hour and the resulting solid was filtered off and dried under vacuum at 70 °C.

Yield: 92 g. Molar yield: 86.79%. HPLC purity: 99.98%. M.P.: 223 °C Example 4. Preparation of 2-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1 ,3- oxazolidin-5-yl}methyl)-1 H-isoindole-1 ,3(2H)-dione.

250 g (0.632 mol) of 2-((2R)-2-hydroxy-3-{[4-(3-oxo-4-morpholinyl)phenyl]amino} propyl)-1 H-isoindole-1 , 3(2H)-dione, 205 g (1 .265 mol) of N,N-carbonyldiimidazole and 2500 mL of MIBK were charged in a flask and the reaction mass was heated to reflux for 3 hours. Then, the reaction mass was allowed to cool at 0°C for 1 hour. Afterwards, the solid was filtered off, washed with 500 mL of methanol and the wet cake was sucked dried (LOD~5%) (Dry weight: 244.0 g). The wet cake as such was carried forward without drying.

Molar yield: 91.57%. HPLC purity: 99.68%

Example 5. Preparation of 4-{4-[(5S)-5-(amino methyl)-2-oxo-1 ,3-oxazolidine-3- yl]phenyl}morpholin-3-one oxalate.

50 g (0.1 10 mol) of 2-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1 ,3-oxazolidin-5- yl}methyl)-1 H-isoindole-1 ,3(2H)-dione (II), 45.81 mL of methylamine (40% aqueous solution, 0.53 mol) and 1250 mL of methanol were charged in a 3 L flask and the reaction mixture was heated to 65 °C for 1 hour. Afterwards, 77.81 g (0.610 mol) of oxalic acid dihydrate in 233 mL of methanol were added dropwise until pH 2-3 was reached, at which the solid started to precipitate, and heated the reaction mass to reflux for 1 hour. After cooling to 25 °C for 1 h, the product was filtered off, washed with methanol and dried under vacuum at 50 °C.

Yield: 37 g. Molar yield: 82.22%. HPLC purity: 99.91 %. M.P.: 195.90 °C (DSC).

Example 6. Preparation of 4-{4-[(5S)-5-(amino methyl)-2-oxo-1 ,3-oxazolidine-3- yl]phenyl}morpholin-3-one oxalate.

10 g (0.024 mol) of 2-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1 ,3-oxazolidin-5- yl}methyl)-1 H-isoindole-1 ,3(2H)-dione (II), 7.12 mL of methylamine (40% aqueous solution, 0.083 mol) and 150 mL of methanol were charged in a 1 L autoclave and heated to reflux temperature (65 °C) for 1 hour. Afterwards, the reaction mass was cooled to 25-30°C and transferred to another flask. The reaction mass was heated again to 65.0°C and 14.25 g (0.095 mol) of oxalic acid dihydrate in 50 mL of methanol were added dropwise within 30 min. Then, the reaction mass was heated to reflux for another 5 hours. After allowing cooling to 0-5 °C, the solid was filtered off and dried under vacuum at 50 °C.

Yield: 6.87 g. Molar yield: 76%. HPLC purity: 99.78%. M.P.: 195.90 °C (DSC).

XRD (°2Th): 5.2, 15.6, 16.7, 16.9, 18.2, 19.6, 19.9, 20.0, 20.3, 20.5, 23.5, 25.7, 27.0 and 28.8 as shown in figure 1 .

IR (cm ^"1 ): 3003.7, 1910.3, 1740.3, 1698.3, 1651 .2, 1605.7, 1522.6, 1483.3, 1428.9, 141 1.6, 1380.0, 1345.0, 1328.8, 1316.4, 1293.0, 1223.5, 1 139.1 , 1 127.0, 1 103.2, 1068.2, 1032.9, 999.9, 940.9, 923.7, 887.8, 867.6, 828.7, 782.6, 754.3, 709.5, 616.7, 576.8, 556.7, 547.6, 525.9, 505.1 , 495.0, 486.7, 475.5, 465.5 and 454.8 as shown in figure 2. Example 7. Preparation of 4-{4-[(5S)-5-(amino methyl)-2-oxo-1 ,3-oxazolidine-3- yl]phenyl}morpholin-3-one malonate.

10 g (0.024 mol) of 2-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1 ,3-oxazolidin-5- yl}methyl)-1 H-isoindole-1 ,3(2H)-dione (II), 7.12 mL of methylamine (40% aqueous solution, 0.083 mol) and 150 mL of methanol were charged in a 1 L autoclave and heated to reflux temperature (65.0°C) for 1 hour. Afterwards, the reaction mass was cooled to 25-30°C and transferred to another flask. Then, 9.9 g (0.095 mol) of malonic acid in 50 mL of methanol were added dropwise within 30 min. Then, the reaction mass was stirred to 25-30 °C for 24 hours. The solid obtained after filtration was stirred in 100 mL of ethanol at 25 °C for 1 hour. Finally, the solid obtained was filtered off and dried under vacuum at 50 °C.

Yield: 5.9 g. Molar yield: 62.89%. HPLC purity: 99.15%. MP.: 189.14 °C (DSC).

XRD (°2Th): 18.0, 20.1 , 21 .6, 23.0, 24.0, 24.1 , 24.3, and 27.6 as shown in figure 5. IR (cm ^"1 ): 3473.0, 2912.5, 2691.9, 1745.6, 1661 .6, 1598.7, 1519.5, 1459.3, 1475.5, 1434.8, 1409.9, 1378.0, 1343.0, 1328.9, 131 1.1 , 1288.9, 1263.3, 1227.1 , 1 162.2, 1 136.7, 1 125.3, 1060.4, 1037.9, 1002.6, 982.6, 919.5, 858.4, 833.0, 777.3, 752.5, 710.8, 689.0, 671.8, 597.5, 556.5, 547.3, 526.1 , 516.0, 505.8, 495.9, 486.1 , 475.3, 465.5 and 455.6 as shown in figure 6. Example 8. Preparation of 4-{4-[(5S)-5-(amino methyl)-2-oxo-1 ,3-oxazolidine-3- yl]phenyl}morpholin-3-one malonate.

50 g (0.1 19 mol) of 2-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1 ,3-oxazolidin-5- yl}methyl)-1 H-isoindole-1 ,3(2H)-dione (II), 35.63 mL of methylamine (40% aqueous solution, 0.416 mol) and 750 mL of methanol were charged in a 1 L autoclave and heated to reflux temperature (65.0°C) for 1 hour. Afterwards, the reaction mass was cooled to 25-30°C and transferred to another flask. Then, 49.43 g (0.475 mol) of malonic acid in 250 mL of methanol were added dropwise within 30 min. Then, the reaction mass was stirred to 25-30 °C for 24 hours, followed by seeding and stirring at 25-30 °C for 3 hours. Finally, the solid obtained was filtered off, washed and dried under vacuum at 50 °C.

Yield: 30.8 g. Molar yield: 65.65%. HPLC purity: 98.92%. M.P.: 189.14 °C (DSC).

Example 9. Preparation of 4-{4-[(5S)-5-(Amino amino methyl)-2-oxo-1 ,3- oxazolidine-3- yl-3-yl]phenyl}morpholin-3-one hydrochloride

9 g (0.021 mol) of 2-({(5S)-2-Oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1 ,3-oxazolidin-5- yl}methyl)-1 H-isoindole-1 ,3(2H)-dione (II), 8.06 mL of methylamineamine (40% aqueous solution, 0.235 mol) and 80 mL of ethanol were charged in a 100 mL flask and the reaction mixture was heated to 65 °C for 2h. Then, 10 mL of a 20% HCI solution was added until the pH of the reaction mass was adjusted to 2.7. The reaction mass was cooled to 30 °C and the resulting solid was filtered off, washed with ethanol and dried under vacuum at 60 °C.

Yield: 5.3 g. Molar yield: 75.7%. HPLC purity: 93.9% Example 10. Preparation of 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4- morpholinyl)phenyl]-1 ,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide (crude rivaroxaban).

a) 5-chlorothiophene-2-carbonyl chloride

38.38 g (0.236 mol) of 5-chloro-2-thiophenecarboxylic acid, 230 mL of toluene, 0.3 mL of DMF and 20.6 mL of thionyl chloride were charged in a 500 mL flask and the reaction mass was heated to 1 10 °C for 2 hours. Then, 50% of toluene (1 15 mL) was distilled out in vacuum at 65-70 °C in order to remove the excess of thionyl chloride. Finally, the mixture is cooled to 25 °C under nitrogen.

b) 5-Chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1 ,3-oxazolidin-5- yl}methyl)-2-thiophenecarboxamide (crude rivaroxaban).

15.52 g (0.146 mol) of sodium carbonate, 200 mL of water and 360 mL of acetone were charged in a 1 L flask and the reaction mass cooled to 0-5 °C under stirring. Then, 45 g of 4-{4-[(5S)-5-(amino methyl)-2-oxo-1 ,3-oxazolidine-3- yl]phenyl}morpholin-3-one oxalate (0.1 18 mol) was added and stirred for 30 minutes at the same temperature. 1 15 mL of the 5-chlorothiphene-2-carbonyl chloride solution (50% toluene, about 42-43% chloride) was then charged dropwise into the reaction mass at 0-5 °C within 15 minutes and stirred for 30 minutes. After reaching room temperature (25-30 °C), the reaction mass was stirred for 1 hour and 225 mL of water were added. The mixture was subsequently heated at 50 °C and stirred for 1 hour. After filtration at identical temperature, the solid product was washed with water and acetone and dried.

Yield: 47 g. Molar yield: 91 .22%. HPLC purity 98.12%. M.P.: 232 °C. S.O.R.: [a ] _D ²⁵ = -39° (c=0.2983, DMSO)

Example 11. Preparation of crude rivaroxaban.

8 g (0.021 mol) of 4-{4-[(5S)-5-(amino methyl)-2-oxo-1 ,3-oxazolidine-3- yl]phenyl}morpholin-3-one oxalate, 2.75 g of sodium carbonate (0.026 mol), 35 mL of water and 60 mL of acetone were charged in a 1 L flask. After cooling the reaction mass to 8-10 °C, a solution of 7.60 g of 5-chlorothiophene-2-carbonyl chloride (0.042 mol) in 24 mL of toluene were added maintaining the same temperature. Then, the reaction mass was heated to 50-55 °C and stirred for 1 hour. The resulting product was allowed to cool at 25-30 °C, filtered off and dried under vacuum at 80 °C.

Yield: 8.2 g. Molar yield: 89.90%. HPLC purity 98.84%. S.O.R.: [a ] _D ²⁵ = -39.7° (c=0.2983, DMSO)

Example 12. Preparation of crude rivaroxaban

300 g (0.787 mol) of 4-{4-[(5S)-5-(amino methyl)-2-oxo-1 ,3-oxazolidine-3- yl]phenyl}morpholin-3-one oxalate, 103 g (0.972 mol) of sodium carbonate, 131 1 mL of water and 2250 mL of acetone were charged in a 5 L flask. After cooling the reaction mass to 8-10 °C, 213.75 g (1 .181 mol) of 5-chlorothiophene-2-carbonyl chloride in 1000 mL of toluene were added maintaining the same temperature. Then, the reaction mass was heated to 50-55 °C and stirred for 1 hour. The resulting product was allowed to cool at 25-30 °C, filtered off and dried under vacuum at 80 °C. Yield: 300 g. Molar yield: 87.71 %. HPLC purity 97.59%. Example 13. Preparation of crude rivaroxaban

25 g (0.0633 mol) of 4-{4-[(5S)-5-(amino methyl)-2-oxo-1 ,3-oxazolidine-3- yl]phenyl}morpholin-3-one malonate, 8.31 g (0.784 mol) of sodium carbonate, 1 12 mL of water and 250 mL of acetone were charged in a 5 L flask. After cooling the reaction mass to 8-10 °C, 17.18 g (0.095 mol) of 5-chlorothiophene-2-carbonyl chloride in 85 mL of toluene were added maintaining the same temperature. Then, the reaction mass was heated to 50-55 °C and stirred for 1 hour. The resulting product was allowed to cool at 25-30 °C, filtered off and dried under vacuum at 80 °C. Yield: 20 g. Molar yield: 72.57%. HPLC purity 98.22%.

Example 14. Preparation of crude rivaroxaban

25 g (0.012 mol) of 2-({(5S)-2-Oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1 ,3-oxazolidin- 5-yl}methyl)-1 H-isoindole-1 ,3(2H)-dione (II), 1 1.2 mL of methylamine (40% aqueous solution, 0.058 mol) and 125 mL of methanol were charged in a 500 mL flask. Then, the reaction mass was heated to reflux for 1 hour and concentrated under reduced pressure. The crude product was slurried in 125 mL of toluene and 16.5 mL of triethylamine were added to the reaction mass at 25 °C. Afterwards, 17.81 g (0.098 mol) of 5-chlorothiophene-2-carbonyl chloride in 100 mL of toluene were added dropwise and the reaction mass was stirred for 1 hour at 25 °C. At this stage, the reaction mass was heated at 50 °C for 1 hour and 75 ml of water was added at the same temperature. Finally, the resulting product was filtered off, washed with water and dried under vacuum at 50 °C.

Yield: 15 g. Molar yield: 52.63%. HPLC purity 81.82%

Example 15. Preparation of crude rivaroxaban

25 g (0.012 mol) of 2-({(5S)-2-Oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1 ,3-oxazolidin- 5-yl}methyl)-1 H-isoindole-1 ,3(2H)-dione (II), 1 1.2 mL of methylamine (40% aqueous solution, 0.058 mol) and 125 mL of methanol were charged in a 500 mL flask. Then, the reaction mass was heated to reflux for 1 hour and concentrated under reduced pressure. The crude product was slurried in 125 mL of acetone and 16.5 mL of triethylamine were added to the reaction mass at 25 °C. Afterwards, 17.81 g (0.098 mol) of 5-chlorothiophene-2-carbonyl chloride in 100 mL of toluene were added dropwise and the reaction mass was stirred for 1 hour at 25 °C. At this stage, the reaction mass was heated at 50 °C for 1 hour and 75 mL of water was added at the same temperature. Finally, the resulting product was filtered off, washed with water and dried under vacuum at 50 °C.

Yield: 15 g. Molar yield: 52.63%. HPLC purity 77.71 %

Example 16. Purification of crude rivaroxaban.

5 g (0.01 1 mol) of crude rivaroxaban, with a HPLC purity of 98.69%, and 50 mL of formic acid (85% aqueous solution) were charged in a 250 mL flask. Then, the reaction mass was heated to reflux for 1 hour. After cooling to 25 °C, the resulting product was filtered off, and dried under vacuum at 80 °C.

Yield: 4 g. Molar yield: 80%. HPLC purity 99.65%. M.P.: 232 °C (DSC). S.O.R.: [a ] _D ²⁵ = -39.7° (C=0.2983,DMSO)

Example 17. Purification of crude rivaroxaban.

5 g (0.01 1 mol) of crude rivaroxaban, with a HPLC purity of 98.69%, and 50 mL of formic acid (70% aqueous solution) were charged in a 250 mL flask and the reaction mass was heated to reflux for 1 hour. After cooling to 25 °C, the resulting product was filtered off, and dried under vacuum at 80 °C.

Yield: 4.5 g. Molar yield: 90%. HPLC purity 99.68%. M.P.: 232 °C (DSC). S.O.R.: [a ] _D ²⁵ = -39.7° (C=0.2983,DMSO)

Example 18. Purification of crude rivaroxaban.

5 g (0.01 1 mol) of crude rivaroxaban, with a HPLC purity of 98.69 and 40 mL of dimethylformamide were charged in a 250 mL flask and the reaction mass was heated to reflux for 1 hour. After cooling to 25 °C, the resulting product was filtered off, and dried under vacuum at 80 °C.

Yield: 2.5 g. Molar yield: 50%. HPLC purity 99.52%

Example 19. Purification of crude rivaroxaban.

10 g (0.023 mol) of crude rivaroxaban prepared according to example 12 and 70 mL of formic acid (98% aqueous solution) were charged in a 500 mL flask and the reaction mass was heated to 60 °C for 1 hour, until a clear solution is obtained. Afterwards, the reaction mass was cooled to 25 °C within 45 min, and 150 mL of acetone were added, at which point the solid started to precipitate. The reaction mass was then stirred at 25-30 °C for 15 minutes, allowed to cool at 0-5 °C within 30 min, followed by stirring at this temperature for 1 hour. Afterwards, the solid was filtered off and washed with 20 mL of acetone. The wet cake obtained (HPLC purity: 99.06%) was further purified by the same procedure. The resulting product was dried under vacuum at 80.0°C.

Yield: 8 g. Overall recovery: 80%. HPLC purity: 99.74%. M.P.: 233 °C (DSC)

Example 20. Purification of crude rivaroxaban.

10 g (0.023 mol) of crude rivaroxaban prepared according to example 12 and 70 mL of formic acid (98% aqueous solution) were charged in a 500 mL flask and the reaction mass was heated to 60 °C for 1 hour. Afterwards, the reaction mass was cooled to 25 °C within 45 min and 200 mL of MEK were added, at which point the solid started to precipitate. The reaction mass was then stirred at 25-30 °C for 15 minutes and allowed to cool at 0-5 °C within 30 min, followed by stirring at this temperature for 1 hour. Afterwards, the solid was filtered off and washed with 20 mL of MEK. The wet cake obtained (HPLC purity: 99.42%) was further purified by the same procedure. The resulting product was dried under vacuum at 80.0°C.

Yield: 8.5 g. Overall recovery: 85%. HPLC purity: 99.70 %. M.P.: 232 °C (DSC). XRD (°2Th): 22.5.

Example 21. Purification of crude rivaroxaban.

10 g (0.023 mol) of crude rivaroxaban prepared according to example 12 and 70 mL of formic acid (98% aqueous solution) were charged in a 500 mL flask and the reaction mass was heated to 60 °C for 1 hour. Afterwards, the reaction mass was cooled to 25 °C within 45 min and 200 mL of MIBK were added, at which point the solid started to precipitate. The reaction mass was then stirred at 25-30 °C for 15 minutes and allowed to cool at 0-5 °C within 30 min, followed by stirring at this temperature for 1 hour. Afterwards, the solid was filtered off and washed with 20 mL of MIBK. The wet cake obtained (HPLC purity: 98.98%) was further purified by the same procedure. The resulting product was dried under vacuum at 80.0°C.

Yield: 8 g. Overall recovery: 80%. HPLC purity: 99.57 %. M.P.: 232.2 °C (DSC) Example 22. Purification of crude rivaroxaban.

10 g (0.023 mol) of crude rivaroxaban prepared according to example 12 and 70 mL of formic acid (98% aqueous solution) were charged in a 500 mL flask and the reaction mass was heated to 60 °C for 1 hour. Afterwards, the reaction mass was cooled to 25 °C within 45 min and 100 mL of ethanol were added, at which point the solid started to precipitate. The reaction mass was then stirred at 25-30 °C for 15 minutes and allowed to cool at 0-5 °C within 30 min, followed by stirring at this temperature for 1 hour. Afterwards, the solid was filtered off and washed with 20 mL of ethanol. The wet cake obtained (HPLC purity: 99.04%) was further purified by the same procedure. The resulting product was dried under vacuum at 80.0°C.

Yield: 8 g. Overall recovery: 80%. HPLC purity: 99.66 %

Example 23. Purification of crude rivaroxaban.

10 g (0.023 mol) of crude rivaroxaban prepared according to example 12 and 70 mL of formic acid (98% aqueous solution) were charged in a 500 mL flask and the reaction mass was heated to 60 °C for 1 hour. Afterwards, the reaction mass was cooled to 25 °C within 45 min and 100 mL of acetonitrile were added, at which point the solid started to precipitate. The reaction mass was then stirred at 25-30 °C for 15 minutes and allowed to cool at 0-5 °C within 30 min, followed by stirring at this temperature for 1 hour. Afterwards, the solid was filtered off and washed with 20 mL of acetonitrile. The wet cake obtained (HPLC purity: 99.72%) was further purified by the same procedure. The resulting product was dried under vacuum at 80.0°C.

Yield: 7 g. Overall recovery: 70%. HPLC purity: 99.94 %. M.P.: 232.7 °C (DSC)

Example 24. Purification of crude rivaroxaban.

10 g (0.023 mol) of crude rivaroxaban prepared according to example 12 and 70 mL of formic acid (98% aqueous solution) were charged in a 500 mL flask and the reaction mass was heated to 60 °C for 1 hour. Afterwards, the reaction mass was cooled to 25 °C within 45 min and 150 mL of ethyl acetate were added, at which point the solid started to precipitate. The reaction mass was then stirred at 25-30 °C for 15 minutes and allowed to cool at 0-5 °C within 30 min, followed by stirring at this temperature for 1 hour. Afterwards, the solid was filtered off and washed with 20 mL of ethyl acetate. The wet cake obtained (HPLC purity: 99.42%) was further purified by the same procedure. The resulting product was dried under vacuum at 80.0°C.

Yield: 8 g. Overall recovery: 80%. HPLC purity: 99.69 %

Example 25. Purification of crude rivaroxaban.

5 g (0.01 1 mol) of crude rivaroxaban prepared according to example 12 and

50 mL of MEK were charged in a 500 mL flask and the reaction mass was heated to 80 °C for 1 hour. Afterwards, 40 mL of formic acid (98% aqueous solution) were added dropwise until the solution was clear, followed by heating to 80 °C for 1 hour. The reaction mass was then cooled to 25 °C within 45 min, being 55 °C the temperature at which the solid started to precipitate. Afterwards, the reaction mass was stirred at 25 °C for 1 hour, followed by filtering off and washing with 20 mL of MEK. The resulting product was dried under vacuum at 80.0°C.

Yield: 3.7 g. Overall recovery: 74%. HPLC purity: 99.75 %. M.P.: 232.2 °C (DSC)

Example 26. Purification of crude rivaroxaban.

5 g (0.01 1 mol) of crude rivaroxaban prepared according to example 12 and 50 mL of MIBK were charged in a 500 mL flask and the reaction mass was heated to 1 16 °C for 1 hour. Afterwards, 15 mL of formic acid (98% aqueous solution) were added dropwise until the solution was clear, followed by heating to 80 °C for 1 hour. The reaction mass was then cooled to 25 °C within 45 min, being 94 °C the temperature at which the solid started to precipitate. Afterwards, the reaction mass was stirred at 25 °C for 1 hour, followed by filtering off and washing with 20 mL of MIBK. The resulting product was dried under vacuum at 80.0°C.

Yield: 4.8 g. Overall recovery: 96%. HPLC purity: 99.51 %

Example 27. Purification of crude rivaroxaban.

25 g (0.057 mol) of crude rivaroxaban prepared according to example 12,

375 mL of MEK and 175 mL of formic acid (98% aqueous solution) were charged in a 1 L flask and the reaction mass was heated to 80 °C for 1 hour. Afterwards, the reaction mass was allowed to cool to 25 °C, being 55-58 °C the temperature at which the solid started to precipitate. The reaction mass was then cooled to 0-5 °C within 30 min, followed by stirring at this temperature for 1 hour. The solid was then filtered off and washed with 50 mL of MEK. The wet cake obtained (HPLC purity: 99.66%) was further purified by the same procedure. The resulting product was dried under vacuum at 80.0°C.

Yield: 20 g. Overall recovery: 80%. HPLC purity: 99.91 %. M.P.: 232.2 °C (DSC). XRD (°2Th): 22.5 and 26.7.

Example 28. Purification of crude rivaroxaban.

15 g (0.344 mol) of crude rivaroxaban prepared according to example 13, 225 mL of MEK and 105 mL of formic acid (98% aqueous solution) were charged in a 500 mL flask and the reaction mass was heated to 80 °C for 1 hour. Afterwards, the reaction mass was allowed to cool to 25 °C, being 55-58 °C the temperature at which the solid started to precipitate. The reaction mass was then cooled to 0-5 °C within 30 min, followed by stirring at this temperature for 1 hour. The solid was then filtered off and washed with MEK and dried under vacuum at 80.0°C. The solid obtained (HPLC purity: 99.70%) was further purified by the same procedure.

Yield: 1 1.8 g. Overall recovery: 90%. HPLC purity: 99.93 %