"PROCESS FOR THE SYNTHESIS OF RIVAROXABAN AND INTERMEDIATE FOR THE PRODUCTION THEREOF"

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DESCRIPTION

Field of the invention

The present invention relates to a process for the synthesis of Rivaroxaban, and to a salt that forms as an intermediate in said synthesis.

Background of the invention

Rivaroxaban is an active substance developed by Bayer Pharma AG is marketed under the name Xarelto ^® in the form of tablets for oral administration. The substance acts as a direct and highly selective inhibitor of factor Xa, interrupting the sequence of blood coagulation steps and consequently inhibiting the formation of thrombin and the development of thrombi; is used as an anticoagulant, for example for the prevention of strokes in patients with atrial fibrillation or blood clots in the veins (deep vein thrombosis) that may form following surgical procedures.

Rivaroxaban is the INN name of the compound with lUPAC name (S)-5- chloro-A/-{[2-oxo-3-[4-(3-oxomorpholine4-yl)phenyl]-oxazolid ine-5-yl]- methyl}thiophene-2-carboxamide, havin the following structural formula:

varoxa an

The family of compounds of which Rivaroxaban is a part was described for the first time in patent WO 01/47919 A1 , which also reports possible synthesis pathways.

Other patent documents, such as for example WO 201 1 /012321 A1 , describe the preparation and isolation of polymorphs of the compound.

The aim of the invention is to provide an alternative process for the preparation of Rivaroxaban. Summary of the invention

These aims are achieved with the present invention, which, in a first aspect thereof, relates to a process for the production of Rivaroxaban, comprising the following steps:

a) reacting 4-(4-aminophenyl)morpholine-3-one (I) with (S)-(+)-N(2,3- epoxypropyl)phthalimide (II) to form the compound 2-{(R)-2-hydroxy-3-[4- (3-oxo-morpholine-4-yl)phenylamino ropyl} isoindole-1 ,3-dione

(I) (ll)

reacting the compound (III) with Ν,Ν-carbonyldiimidazole (CDI) to form the compound 2-{(S)-2-oxo-3-[4-(3-oxo-morpholine-4-yl)phenyl]- oxazolidine-5-yl-methyl}-isoindole-1 ,3-dione (IV):

c) reacting the compound (IV) with methylamine and then adding nitric acid to form the compound (V), (5S)-4-{4-[5-(aminomethyl)-2-oxo-1 ,3- oxazolidine-3-yl henyl}mor holine-3-one nitrate:

(V)

reacting the compound (V) with 5-chlorothiophen-2-carbonyl chloride to ield Rivaroxaban:

In a second aspect thereof, the invention relates to the compound (5S)-4-{4- [5-(aminomethyl)-2-oxo-1 ,3-oxazolidine-3-yl]-phenyl}morpholine-3-one nitrate, compound (V), intermediate of the process described above.

Detailed description of the invention

The present invention originates from having identified that it is possible to obtain high purity Rivaroxaban from a specific intermediate compound consisting of the nitrate salt of (5S)-4-{4-[5-(aminomethyl)-2-oxo-1 ,3-oxazolidine-3-yl]- phenyl}morpholine-3-one (Compound V).

It has been surprisingly found that the intermediate V, salified with nitric acid, which nitrate anion is substantially not nucleophilic, has a high purity greater than that of corresponding salts with halohydric acids (hydrochloride, hydrobromide, etc.), thus the end product obtained from the process of the invention has an improved impurity profile with respect to the processes of the prior art.

The first aspect of the invention relates to a novel process for the synthesis of Rivaroxaban comprising the steps a) to d) reported above.

In step a), compound 4-(4-aminophenyl)morpholine-3-one (I) is reacted with compound (S)-(+)-N(2,3-epoxypropyl)phthalimide (II); compounds (I) and (II) are both commercially available. The reaction is carried out using as solvent an alcohol having a low number of carbon atoms, preferably methanol, and preferably with a slight stoichiometric excess of the compound (II), for example with a molar ratio of the compound (II) and the compound (I) of between 1 .2 and 1 .3; the reaction temperature is preferably between 50 °C and the boiling temperature of the solvent (65 °C in the case of methanol). The reaction time is between about 15- 25 hours. The compound (III) produced in the reaction is insoluble in the reaction solvent from which it precipitates as a solid and is recovered by means known to those skilled in the art, by filtration for example, preferably washing it with a solvent like the one used for the reaction and subsequent drying. In step b) the compound (III) obtained in the previous step is reacted with Ν,Ν-carbonyldiimidazole (CDI), a product that is commonly available commercially. The CDI causes the formation of the cyclic carbamate between the alcohol and the secondary amine of the compound (III), leading to the formation of the compound (IV). The CDI is used in slight stoichiometric excess, in a molar ratio with respect to the compound (III) of between 1 .2 and 1 .3, for example. For the purposes of carrying out the reaction, the compounds (III) and CDI are suspended in a suitable solvent, an halogenated aliphatic or aromatic hydrocarbon for example (chlorobenzene is preferred), the solution is brought to a temperature of between about 80 °C and maintained at this temperature for a period of several hours. At the end of the reaction, the mass is brought to room temperature and the product obtained is filtered and lastly dried.

Step c) is carried out in two phases, wherein in the first phase, the phthalimide group is removed from the compound (IV) with formation of the corresponding amine, and in the second phase, the salt of the amine forms with nitric acid.

In the first phase (phthalimide removal), the compound (IV) is reacted with methylamine. Methylamine, CH3-NH2, is a gas, and is preferably used in aqueous solution. Methylamine is used in high stoichiometric excess with respect to the compound (IV). After having loaded the reactants, its inside temperature is brought to a value of about 60 °C, for a period of several hours. At the end of the reaction, the mass is distilled until a dense residue containing the compound (5S)-4-{4-[5- (aminomethyl)-2-oxo-1 ,3-oxazolidine-3-yl]-phenyl}morpholine-3-one is obtained, wherein the phthalimido radical of the compound (IV) is replaced by a primary amine. The residue is typically dissolved with water and alcohol.

In the second phase of step c) to the mixture thus obtained nitric acid in aqueous solution is added, typically at a temperature of about 25 °C, causing salification of the amine produced in the previous phase. The intermediate thus precipitated is filtered and washed with a lower alcohol (C1-C5) and dried thus recovering the compound (V).

In the last step of process d), the compound (V) is reacted with 5- chlorothiophene-2-carbonyl chloride to give the desired Rivaroxaban compound.

Due to its instability, the 5-chlorothiophene-2-carbonyl chloride is not a commercial product and must be prepared shortly before use. As is well known to the synthesis chemist, the corresponding carboxylic acid (5-chloro-2- thiophenecarboxylic acid) and a chlorinating reagent such as phosphorus trichloride (PC ), phosphorus pentachloride (PCI5) or, preferably, thionyl chloride (SOCI2) are used to produce this reagent, working in a suitable solvent, such as a halogenated hydrocarbon for example; the reaction occurs in the presence of N,N- dimethylformamide with reaction catalyst function.

The reaction between the compound (V) and 5-chlorothiophene-2-carbonyl chloride is carried out in a suitable reactor, in the presence of triethylamine with the function of neutralising the hydrochloric acid that is freed.

The reaction is carried out at a temperature of between -5 and 35 °C, while slowly adding a solution of 5-chlorothiophene-2-carbonylchloride to the compound (V) suspended in a solvent, preferably an halogenated hydrocarbon. The reaction is relatively fast, and requires a timeframe of about one hour for its completion. At the end of the reaction, water is added to the reaction mass, obtaining a heterogeneous biphasic system, wherein the product is the insoluble part, while in the aqueous phase the salts present in the reaction remain dissolved. The desired product can be recovered by known methods, for example by means of centrifugation, washing the solid mass obtained with solvent and then with water and final drying. On a diffractometric analysis of the powders (XRPD), the Rivaroxaban thus obtained has the same polymorphic form, form I, as the product obtained in example 44 of patent application WO 01 /47919 A1 , in which the compound was described for the first time.

The crude Rivaroxaban obtained in step d) can then be subjected to purification operations, as is well known in the field, in view of its use in the pharmaceutical sector.

The compound (V), (5S)-4-{4-[5-(aminomethyl)-2-oxo-1 ,3-oxazolidine-3-yl]- phenyl}morpholine-3-one nitrate, obtained in isolated form at the end of phase c) described above, is a further aspect of the present invention.

The invention will be further illustrated by the following examples. In the examples, all reagent amounts, even when liquid or gaseous, and solvent amounts, are reported in mass, to avoid having to take changes in volume due to the different process temperatures into account; similarly, the reported percentages are to be understood as being by weight unless otherwise indicated (and with the exception of data relating to reaction yields).

These examples are to be considered illustrative but non-limiting examples of the claims object of the patent.

EXAMPLE 1

This example relates to the preparation of 2-{(fl)-2-hydroxy-3-[4-(3-oxo- morpholine-4-yl)-phenylamino]-propyl}isoindol-1 ,3-dione, step a) of the process.

10.0 kg of 4-(4-aminophenyl)morpholine-3-one, 13.0 kg of (S)-(+)-N-(2,3- epoxypropyl)phthalimide and 170 kg of methanol are loaded into a reactor as a single solvent.

The mass is heated to around 60 °C and maintained at this temperature for 20 hours, then cooled to 0-10 °C. There is precipitation of the desired product, which is filtered and washed with 30.0 kg of methanol. The product obtained is oven-dried, obtaining 17.0 kg of the desired compound (III), with a reaction yield equal to 82.7%.

EXAMPLE 2

This example relates to the preparation of 2-{(S)-2-oxo-3-[4-(3-oxo- morpholine-4-yl)phenyl]-oxazolidine-5-yl-methyl}-isoindol-1 ,3-dione, step b) of the process.

17.0 kg of the compound (III) obtained in example 1 , 170 kg of chlorobenzene and 8.5 kg of Ν,Ν-carbonyldiimidazole are loaded into a reactor. The mass is brought to about 100 °C and maintained at this temperature for 4 hours. At the end of the reaction, the mass is cooled to 0-10 °C then filtered by washing it with 34.0 kg of chlorobenzene and lastly oven-dried. 17.0 kg of the desired compound (IV) are obtained, with a reaction yield equal to 93.8%.

EXAMPLE 3

This example relates to preparation of the compound (5S)-4-{4-[5- (aminomethyl)-2-oxo-1 ,3-oxazolidine-3-yl]phenyl}morpholine-3-one nitrate, step c) of the process. 17.0 kg of the compound (IV) obtained in example 2, 170 kg of ethanol and

20.4 kg of methylamine in aqueous solution at 40% by weight, are loaded into a reactor. The temperature of the reactant system is then brought to about 60 °C and maintained at this value for 3 hours.

At the end of the reaction, the mass obtained is distilled under vacuum until a dense residue is obtained; 170 kg of ethanol and 34.0 kg of water are added to the residue.

4.47 kg of an aqueous solution at 65% by weight of nitric acid, are slowly added to the mixture thus obtained, maintained at a temperature of about 30 °C. At the end of the addition of the acid, the precipitate is filtered and washed with

25.5 kg of ethanol and lastly oven-dried. 1 1 .0 kg of the desired compound (V) are obtained, with a reaction yield equal to 76.9%.

EXAMPLE 4

This example relates to the preparation of 5-chlorothiophene-2-carbonyl chloride, to be used in step d) of the process.

6.6 kg of 5-chloro-2-thiophenecarboxylic acid, 33.0 kg of methylene chloride and 0.33 kg of Ν,Ν-dimethylformamide are loaded into a reactor. The mass is heated to reflux (about 43 °C) and 6.15 kg of thionyl chloride are slowly added while maintaining this temperature. The system is reacted to reflux for about 3 hours, after which the mass obtained is distilled until an oily residue is obtained. 16.0 kg of methylene chloride are added to this residue, the solution is brought to a temperature of between 10 and 30 °C and stored for use in step d).

EXAMPLE 5

This example relates to the preparation of Rivaroxaban.

1 1 .0 kg of the compound (V) obtained in example 3, 88.0 kg of methylene chloride and 1 1 .0 kg of triethylamine are loaded into an glass-lined reactor. The solution containing the 5-chlorothiophene-2-carbonyl chloride obtained in example 4 is added to the suspension which has been maintained at a temperature between 10-20 °C. The mass, maintained at a temperature of between 10-20 °C, is reacted for about one hour then 55.0 kg of water are added. A suspension is obtained that is centrifuged to separate the solid; this is then washed with 16.5 kg of water. The recovered solid is dried, obtaining 12.2 kg of crude Rivaroxaban, with a yield equal to 90.2%.

EXAMPLE 6

This example refers to the purification of Rivaroxaban.

The 12.2 kg of crude Rivaroxaban obtained in example 5 and 122 Kg of acetic acid are loaded into an glass-lined reactor.

The mass is heated to solution at about 90 °C to be filtered and thus allow elimination of any mechanical impurities present, then the solvent used to dissolve the crude product (the acetic acid) is almost completely eliminated by vacuum distillation, without going below 90 °C, thus reobtaining the solid product in the form of almost dry residue.

The practically dry residue thus obtained is then dissolved with 50 kg of acetone; the undissolved mass is heated to about 62 °C for about 30' (there is no solubilisation therefore it is not to be considered a crystallization but merely a slurry in acetone), then cooled to 10-20 °C and filtered.

The product thus obtained is dried at 80-90 °C.

1 1 .0 kg of pure Rivaroxaban are recovered, with a purification yield equal to 90.0%, having HPLC purity greater than 99.85% and enantiomeric purity greater than 99.9%.