Patent Description:
Apixaban is a compound having the chemical name <NUM>-(<NUM>-methoxyphenyl)-<NUM>-oxo-<NUM>-[<NUM>-(<NUM>-oxo-<NUM>-piperidinyl)phenyl]-<NUM>,<NUM>,<NUM>,<NUM>-tetrahydro-<NUM>-pyrazolo[<NUM>,<NUM>-c]pyridine-<NUM>-carboxamide, and has the structure shown below in Formula (V):
<CHM>.

Apixaban is a factor Xa inhibitor and can be used for the treatment or prevention of a thromboembolic disorder. Apixaban is disclosed in <CIT>. Apixaban has been described as a poorly soluble compound.

Approaches for preparing <NUM>,<NUM>-dihydro-pyrazolo[<NUM>,<NUM>-c]pyrid-<NUM>-ones are known in the art. For example, <CIT> discloses procedures for preparing <NUM>,<NUM>-dihydro-pyrazolo[<NUM>,<NUM>-c]pyrid-<NUM>-ones. Furthermore, <CIT> describes a synthesis providing apixaban, and <CIT> discloses a process for the preparation of apixaban and intermediates thereof. Moreover, <NPL>. Still further processes for the preparation and/or purification of apixaban being provided in <CIT>, <CIT>, Research Disclosure database number <NUM> (www. researchdisclosure. com Database with IP. com number IPCOM000240694D, and <CIT>.

The known approaches for preparing apixaban involve numerous preparation steps. In these preparation procedures involving numerous preparation steps each single preparation step is of essential importance for the preparation of the desired final product, and therefore has to provide at least acceptable yields. Furthermore, in every single preparation step, the formation of side products has to be avoided for obtaining the desired final product, apixaban, in particular apixaban in crystalline form, in both high purity and high yields.

Thus, although approaches for preparing apixaban are known in the art, there still remains a need in the art for procedures for preparing apixaban, especially apixaban polymorphic form N-<NUM>, which provide apixaban, in particular apixaban in crystalline form, especially apixaban polymorphic form N-<NUM>, and/or one or more of its intermediates in advantageous yields and high purity. Furthermore, the preparation procedures should apply readily available excipients and/or excipients associated with no or merely low safety risks. Moreover, the procedures for preparing apixaban and its intermediates should allow a large scale production. Furthermore, these procedures should be time-efficient, and should avoid time-extensive preparation procedures, at least during one or several of the preparation steps. Finally, the procedures should avoid the use of materials which are cost-intensive materials, as well as should apply at least in some steps environmentally friendly materials and/or materials associated with low security risk.

The present invention pertains to a process for preparing apixaban of formula (V),
<CHM>
as defined in claim <NUM>.

The aspects, advantageous features and preferred embodiments of the present invention summarized in the following items, respectively alone or in combination, further contribute to solving the problem of the present invention:.

The present invention relates to a process for preparing apixaban of formula (V),
<CHM>
said process comprising:.

Step (ii) of the process for preparing apixaban can comprise:.

Surprisingly, the process of the present invention considerably improves the known approaches for preparing apixaban. Unexpectedly, cyclizing the compound of formula (III) in the presence of potassium carbonate, a first solvent, and a phase transfer catalyst, provides mild reaction conditions, is simple in operation, easy in purification, inexpensive in production costs, environmentally friendly, and suitable for industrial production. Without wishing to be bound to any theory, it is assumed that the presence of potassium carbonate surprisingly reduces the formation of degradation products, and thereby essentially contributes to the preparation of the cyclic intermediate (IV) in high yields and with high purity (e.g. with a purity of more than <NUM>%). Furthermore, potassium carbonate controls the presence of water in the reaction mixture in a highly advantageous and mild manner. Moreover, potassium carbonate is an environmentally friendly compound and can contribute to the provision of a cost-effective provision of apixaban. In addition thereto, cyclizing the compound of formula (III) in the presence of potassium carbonate and a phase transfer catalyst to obtain a compound of formula (IV) provides a time-efficient reaction procedure and therefore contributes to a time-efficient production of apixaban. Finally, the combination of potassium carbonate and a phase transfer catalyst provides the advantage that this combination is effective for cyclizing the compound of formula (III), but at the same time is sufficiently mild for avoiding or minimizing side reactions. The combination of potassium carbonate and a phase transfer catalyst therefore provides the advantage that the formation of impurities can be avoided or minimized and the need for purification procedures, especially the need for complex, material-intensive, and time-intensive purification procedures, such as column chromatography, may be avoided.

In particular, the phase transfer catalyst can be or can comprise a phase transfer catalyst selected from the group of quaternary ammonium salts such as N,N,N,N-tetraalkylammonium halogenides or N-benzyl-N,N,N-trialkylammonium halogenides and mixtures thereof. Especially, the phase transfer catalyst can be or can comprise a phase transfer catalyst selected from the group of N,N,N,N-tetraalkylammonium halogenides or N-benzyl-N,N,N-trialkylammonium halogenides, and mixtures thereof, wherein alkyl can be selected from methyl, ethyl, propyl, butyl, pentyl, (and wherein optionally halogenide can be selected from bromide and chloride).

Preferably, the phase transfer catalyst can be or comprise a phase transfer catalyst selected from the group of N,N,N,N-tetraalkylammonium bromides, and mixtures thereof.

More preferably, the phase transfer catalyst can be or comprise a phase transfer catalyst selected from the group of N,N,N,N-tetraalkylammonium bromides, and mixtures thereof, wherein alkyl can be selected from methyl, ethyl, propyl, butyl, pentyl. More preferably, the phase transfer catalyst can be or comprise N,N,N,N-tetrabutylammonium bromide.

The step of cyclizing the compound of formula (III) in the presence of potassium carbonate, a first solvent, and a phase transfer catalyst can in particular comprise preparing a mixture comprising compound of formula (III), potassium carbonate, a first solvent, and a phase transfer catalyst. This mixture can be subjected to a temperature in the cyclization reaction temperature range, as defined herein.

In particular, step (ii) of cyclizing the compound of formula (III) in the presence of potassium carbonate, a first solvent, and a phase transfer catalyst can be or comprise preparing a mixture (e.g. in a reactor) comprising ethyl <NUM>-(<NUM>-(<NUM>-chloropentanamido)phenyl)-<NUM>-(<NUM>-methoxyphenyl)-<NUM>-oxo-<NUM>,<NUM>,<NUM>,<NUM>-tetrahydro-<NUM>-pyrazolo[<NUM>,<NUM>-c]pyridine-<NUM>-carboxylate (III), and acetonitrile. Potassium carbonate and N,N,N,N-tetrabutylammonium bromide can be added to this mixture.

The suspension can be stirred (e.g. under inert atmosphere, such as nitrogen atmosphere), e.g. at <NUM> ± <NUM>, (e.g. for <NUM> ± <NUM>). Subsequently, salts can be removed by filtration (e.g. hot filtration). Product can be precipitated from the filtrate by solvent exchange with ethyl acetate (e.g. at <NUM>± <NUM>). Solvent exchange with ethyl acetate can be in particular partially evaporating solvent from the filtrate, and adding ethyl acetate after partial evaporation of the solvent from the filtrate. Product can be isolated by filtration. Beige solid can be obtained (e.g. in a yield of <NUM>% or more). The product can be used for the next step without further purification. This process step provides mild reaction conditions, and is furthermore simple in operation, easy in purification, inexpensive in production cost, environmentally friendly, and suitable for industrial production. Water in reaction mixture can be controlled by drying of potassium carbonate and stirring under inert atmosphere.

The first solvent can be an aprotic solvent, especially a polar aprotic solvent. The first solvent can be in particular selected from the group consisting of acetonitrile, acetone, N,N-dimethylformamide, tetrahydrofurane, ethyl acetate, dichloromethane, and mixtures thereof. In particular, the first solvent can be or comprise acetonitrile. The first solvent can for example comprise at least <NUM> wt. %, preferably at least <NUM> wt. % of acetonitrile, based on the total weight of the first solvent.

The term potassium carbonate can be a compound having the formula K<NUM>CO<NUM>. In particular, the term potassium carbonate encompasses all forms of potassium carbonate, including crystalline and amorphous forms thereof, as well as solutions thereof. The term potassium carbonate can comprise solvate(s), especially hydrate(s) thereof; in a preferred embodiment, potassium carbonate is potassium carbonate free of hydrate(s) of potassium carbonate.

In particular, milled, especially fine milled, potassium carbonate can be used, as a small particle size contributes to an advantageous solubility in solvent, especially acetonitrile. For example, potassium carbonate can be used having an average particle size below <NUM>, especially between <NUM> and <NUM>, e.g. between <NUM> and <NUM>. The average particle size can be determined by laser method using a Malvern Mastersizer.

The term "average particle size" as used herein refers to volume mean diameter of particles. The diameter and volume mean diameter can be determined by laser light scattering using e.g. a Malvern Mastersizer Aparatus. Particle sizes are determined by measuring the angular distribution of laser light scattered by a homogeneous suspension of particles. The particles to be subjected to the particle size measurement are first suspended in appropriate non-polar dispersant and then subjected to a size determination in a Malvern Mastersizer instrument.

Compound of formula (III) is a compound known in the art, and can be e.g. prepared as described in the experimental part of the present application.

Step (i) of the process for preparing apixaban can be providing a compound of formula (III) in pure form or as a material containing high amounts of compound of formula (III), such as e.g. a material containing <NUM> wt. % or more, or <NUM> wt. % or more, of compound of formula (III), but can be also providing a mixture, especially a reaction mixture, comprising compound of formula (III).

The second solvent can be in particular selected from the group consisting of esters, alcohols, aromatic hydrocarbons, and mixtures thereof. Esters can be in particular selected from compounds of formula R<NUM>-C(O)-OR<NUM>, wherein R<NUM> can be alkyl having <NUM> or <NUM> or <NUM> or <NUM> or <NUM> or <NUM> carbon atoms, and R<NUM> can be alkyl having <NUM> or <NUM> or <NUM> or <NUM> or <NUM> or <NUM> carbon atoms. Alcohols can be particular selected from compounds of formula R<NUM>-OH, R<NUM> can be alkyl having <NUM> or <NUM> or <NUM> or <NUM> or <NUM> or <NUM> carbon atoms. Aromatic hydrocarbons can be selected from group of compounds that contains one or more aromatic benzene ring, most preferably one benzene ring. Especially, aromatic hydrocarbons can be selected from group of aromatic hydrocarbons having a mono- or bicyclic aromatic ring with <NUM> to <NUM> ring atoms, wherein optionally at one or two or three of the ring atoms -H is substituted with -CH<NUM>, e.g. toluene.

Step (ii) of cyclizing the compound of formula (III) in the presence of potassium carbonate, a first solvent, and a phase transfer catalyst can be carried out at a temperature in the cyclization reaction temperature range. The cyclization reaction temperature range can be the temperature range above <NUM>, e.g. the range of from <NUM> to <NUM>, especially the range of from <NUM> to <NUM>, further especially the range of from <NUM>-<NUM>, further especially the range of from <NUM>-<NUM>.

Step (ii) can be cyclizing the compound of formula (III) in the presence of potassium carbonate, a first solvent, and a phase transfer catalyst, to obtain a compound of formula (IV), compound of formula (III) and potassium carbonate being optionally present in a weight ratio between compound of formula (III) and potassium carbonate (compound of formula (III): potassium carbonate), which can be from <NUM>:<NUM> to <NUM>:<NUM>, preferably <NUM>:<NUM> to <NUM>:<NUM>, especially <NUM>:<NUM> to <NUM>:<NUM>, most preferably about <NUM> : <NUM>.

Step (ii) can be cyclizing the compound of formula (III) in the presence of potassium carbonate, a first solvent, and a phase transfer catalyst, to obtain a compound of formula (IV), phase transfer catalyst and potassium carbonate being optionally present in a weight ratio between phase transfer catalyst and potassium carbonate (phase transfer catalyst: potassium carbonate), which can be from <NUM>:<NUM> to <NUM>:<NUM>, preferably <NUM>:<NUM> to <NUM>:<NUM>, especially <NUM>:<NUM> to <NUM>:<NUM>, most preferably about <NUM> : <NUM>.

Step (iii) of the process for preparing apixaban can be or comprise reacting the compound of formula (IV) with NH<NUM> to obtain apixaban of formula (V), optionally at a temperature of <NUM> or more (e.g. at a temperature of <NUM> to <NUM>), further optionally at a temperature of <NUM> or more (e.g. at a temperature of <NUM> to <NUM>) and in the presence of an organic solvent (which solvent is also referred to hereinafter as organic solvent of step (iii)).

Preferably, the organic solvent of step (iii) can be an organic solvent selected from the group of protic solvents, especially selected from the group of alkyl alcohols, and mixtures thereof.

In particular, the alkyl alcohol can be selected from the group of alkyl alcohols having <NUM> or <NUM> or <NUM> or <NUM> or <NUM> carbon atoms. Especially, the organic solvent of step (iii) can be methanol.

Furthermore, step (iii) can be or comprise reacting the compound of formula (IV) with NH<NUM> in the presence of a solvent to obtain apixaban of formula (V), optionally said solvent being or comprising a protic solvent, especially being or comprising a solvent selected from the group of alkyl alcohols (e.g. containing <NUM> or <NUM> or <NUM> or <NUM> or <NUM> carbon atoms), further optionally said solvent being or comprising methanol.

When reacting the compound of formula (IV) with NH<NUM> in the presence of a solvent, said solvent can be free of water or can contain less than <NUM>. -% of water, preferably not more than <NUM> wt. -% of water, based on the weight of the solvent. Preferably, the reaction mixture comprising compound of formula (IV), NH<NUM>, and a solvent can be free of water or can contain less than <NUM> wt. -% of water, preferably not more than <NUM> wt. -% of water, based on the weight of the reaction mixture.

NH<NUM> can be introduced in gaseous or liquid form into the reaction mixture. This can provide the advantage that the amount of ammonia introduced corresponds to the pressure of the reaction, and thereby influences the conversion of the reaction. Alternatively, NH<NUM> can be introduced in dissolved form, e.g. an organic solution (such as a solution comprising or consisting of NH<NUM> and one or more organic solvent(s)), into the reaction mixture. An organic solvent can be in particular a solvent which comprises at least one carbon atom and is liquid at <NUM> (especially at <NUM> and a pressure of <NUM> atm).

The concentration of starting material (intermediate of formula (IV)) in the reaction mixture, especially in reaction mixtures comprising NH<NUM>, can surprisingly influence the performance of the reaction. Thus, the low solubility of the product at low temperatures provides high yields and an advantageous reaction time period also in more diluted reaction mixtures. Furthermore, carrying out the reaction of step (iii) with methanol and NH<NUM> can advantageously contribute to minimizing impurities, such as in particular:.

In particular, step (iii) of the process for preparing apixaban can be or comprise preparing a reaction mixture comprising an organic solvent (which solvent is also referred to herein as organic solvent of step (iii)) and compound of formula (IV), said organic solvent preferably comprising methanol), adding NH<NUM> (in gaseous form, liquid form and/or dissolved in a solvent capable of dissolving NH<NUM> (e.g. organic solvent(s), such as alkyl alcohols), preferably NH<NUM> in gaseous or liquid form), reacting the compound of formula (IV) with NH<NUM> to obtain apixaban of formula (V), optionally at a temperature of <NUM> or more (e.g. at a temperature of <NUM> to <NUM>), further optionally at a temperature of <NUM> or more (e.g. at a temperature of <NUM> to <NUM>) and in the presence of an organic solvent.

After step (iii), apixaban of high purity, especially apixaban in polymorphic form N-<NUM> can be isolated (directly) from the reaction mixture. Optionally, the reaction mixture obtained after step (iii) can be cooled to a temperature below reaction temperature to induce the precipitation of apixaban, especially of apixaban in crystalline form, further especially of apixaban in polymorphic form N-<NUM>. This provides the advantage that apixaban of high purity can be obtained, as impurities remain dissolved in the reaction mixture, whereas apixaban, especially apixaban in crystalline form, further especially apixaban in polymorphic form N-<NUM>, precipitates. Preferably, the cooling (in particular of the reaction mixture obtained after step (iii) and/or the mixture for crystallizing apixaban during optional step (iv)) can comprise cooling the mixture (especially reaction mixture) at a cooling rate in the range of <NUM> to <NUM>/minute, especially of <NUM> to <NUM>/minute, further especially of <NUM> /min. Especially, the cooling can comprise cooling the reaction mixture at a cooling rate in the range of <NUM> to <NUM>/minute, especially of <NUM> to <NUM>/minute, further especially of <NUM> /min to a temperature in the range of <NUM> to <NUM>, especially in the range of <NUM> to <NUM>, optionally under agitation (e.g. stirring).

In particular, step (iii) can be or comprise preparing a mixture (e.g. in a reactor) comprising ethyl <NUM>-(<NUM>-methoxyphenyl)-<NUM>-oxo-<NUM>-(<NUM>-(<NUM>-oxopiperidin-<NUM>-yl)phenyl)-<NUM>,<NUM>,<NUM>,<NUM>-tetrahydro-<NUM>-pyrazolo[<NUM>,<NUM>-c]pyridine-<NUM>-carboxylate (IV), methanol and ammonia. Ammonia can be added in gas form and/or in liquid form (especially dissolved in alkyl alcohol, such as methanol). The so obtained mixture can be stirred (e.g. at <NUM>± <NUM>), e.g. for <NUM> ± <NUM>), especially at a pressure above ambient pressure (e.g. resulting from the addition of ammonia in gas form and/or in liquid form and reaction temperature higher than boiling point of mixture) and then cooled, e.g. to <NUM>± <NUM>. (Ambient pressure can be e.g. <NUM> atm. ) The suspension can be optionally agitated (e.g. stirred (e.g. at that temperature (<NUM>± <NUM>), e.g. for <NUM>). Product can be isolated by filtration. Apixaban can be obtained as a product with high purity, e.g. all impurities can be HPLC area <<NUM>%, and in crystalline form (N-<NUM> polymorphic form).

Preferably, step (iii) of amidating the compound of formula (IV) to obtain apixaban of formula (V) can be therefore: (iii) amidating the compound of formula (IV) to obtain apixaban of formula (V), said compound of formula (IV) being present in a mixture comprising methanol. In particular, step (iii) of the process for preparing apixaban can be or comprise preparing a reaction mixture comprising methanol and compound of formula (IV), adding NH<NUM> (preferably in gaseous form and/or in liquid form; especially dissolved in alkyl alcohol, such as methanol), and reacting the compound of formula (IV) with NH<NUM> to obtain apixaban of formula (V). Reacting the compound of formula (IV) with NH<NUM> can be preferably at a pressure above <NUM> atm (<NUM><NUM> Pa), further optionally at a pressure in the range of <NUM> kPa to <NUM> kPa. This allows taking advantage of the advantageous properties of methanol for dissolving apixaban, as will be discussed below.

Preferably, the temperature of the reaction mixture obtained after step (iii) of amidating the compound of formula (IV) to obtain apixaban of formula (V) (e.g. said temperature being a temperature of <NUM> or more or a temperature of <NUM> or more; preferably said reaction mixture comprising methanol) is decreased, preferably at a cooling rate in the range of <NUM> to <NUM>/min e.g. of about <NUM>/min, (e.g. to a temperature <NUM> or less, such as <NUM> to <NUM>) for precipitating apixaban in crystalline form, especially apixaban form N-<NUM>.

Furthermore, during the amidation step of the preparation method of the present invention, methanol can be used as solvent. When doing so, a surprisingly good potential of purification is observed, e.g. form N-<NUM> with purity of <NUM>% can be obtained.

The inventors surprisingly discovered that solubility of apixaban in methanol can be improved at high pressure and elevated temperature without formation of additional impurities. This is highly surprising, as methanol is usually considered by the skilled person as antisolvent for apixaban. For example, <NUM> of apixaban can be dissolved in <NUM> of methanol under a pressure of <NUM> kPa and at a temperature of <NUM> while its solubility at atmospheric pressure and reflux temperature is only <NUM> in <NUM>. Apixaban crystallizes upon cooling of the solution, and N-<NUM> form, especially N-<NUM> form of high purity is obtained. Furthermore, N-<NUM> form prepared as described herein can be dried without problems, and achieves usual requirements for residual solvents.

Preferably, step (iii) of amidating the compound of formula (IV) to obtain apixaban of formula (V) can be therefore step (iii) of amidating the compound of formula (IV) to obtain apixaban of formula (V), said compound of formula (IV) being present in a mixture comprising methanol. In particular, step (iii) of process for preparing apixaban can be or comprise preparing a reaction mixture comprising methanol, NH<NUM> and compound of formula (IV), (e.g. by preparing a reaction mixture comprising methanol and compound of formula (IV), adding NH<NUM> (preferably in gaseous form and/or dissolved in methanol)), and reacting the compound of formula (IV) with NH<NUM> to obtain apixaban of formula (V). Preferably, the temperature of the reaction mixture comprising methanol obtained after step (iii) of amidating the compound of formula (IV) to obtain apixaban of formula (V) (e.g. said temperature being a temperature of <NUM> or more or a temperature of <NUM> or more) is decreased, preferably at a cooling rate in the range of <NUM> to <NUM>/min e.g. of about <NUM>/min, (e.g. to a temperature <NUM> or less, such as <NUM> to <NUM>) for precipitating apixaban in crystalline form, especially apixaban form N-<NUM>.

In particular, step (iii) can be or can comprise reacting the compound of formula (IV) with NH<NUM> in the presence of alkyl alcohol to obtain apixaban of formula (V), wherein said reacting of the compound of formula (IV) with NH<NUM> in the presence of alkyl alcohol to obtain apixaban of formula (V) is or comprises:.

optionally, the alkyl alcohol can be selected from the group of methanol, ethanol, propanol (especially straight chain or branched propanol), butanol (especially straight chain or branched butanol), pentanol (especially straight chain or branched pentanol). Preferably, the alkyl alcohol is methanol.

Optionally, step (iii-c. ) is or comprises decreasing the temperature of the mixture obtained in step (iii-b. ), the temperature of the mixture obtained in step (iii-b. ) decreasing less than <NUM> per minute. Further optionally, step (iii-c. ) can be or comprise decreasing the temperature of the mixture obtained in step (iii-b. ) at a rate in the range <NUM> to <NUM>/min, in particular at a rate in the range of <NUM> to <NUM>/min, especially at a rate in the range of <NUM> to <NUM>/min. Optionally, the mixture obtained in step (iii-a. ) can have a content of <NUM> to <NUM> of compound of formula (IV) per milliliter of the reaction mixture, especially a content of <NUM> to <NUM> of compound of formula (IV) per milliliter of the reaction mixture, especially a content of <NUM> to <NUM> of compound of formula (IV) per milliliter of the reaction mixture, in particular a content of <NUM> to <NUM> (e.g. about <NUM>) of compound of formula (IV) per milliliter of the reaction mixture (The volume of the reaction mixture can be determined at <NUM>, especially at a temperature of <NUM> and a pressure of <NUM> atm (<NUM><NUM> Pa)).

Optionally, during step (iii-c. ) the pressure optionally applied during step (iii-b. ) is adapted to ambient pressure. Ambient pressure can be the pressure present at the place where the method is carried out. Ambient pressure can be for example a pressure in the range of <NUM> to <NUM> kPa, especially in the range of <NUM> to 101kPa, further especially in the range of <NUM> to <NUM> kPa.

In one embodiment, polymorph N-<NUM> is obtained by filtration of reaction mixture (e.g. the reaction mixture obtained in step (iii) of amidating the compound of formula (IV) to obtain apixaban of formula (V)), at a temperature higher than <NUM>, and at a pressure between <NUM>-<NUM> bar (<NUM>-<NUM> kPa), and precipitation of product by cooling. This embodiment provides advantageously high yields and polymorph N-<NUM> in high purity.

In particular, the method can comprise a step prior to step (a) comprising: preparing apixaban of formula (V) in the presence of methanol.

Step (i) of providing a compound of formula (III) can comprise:.

In an embodiment, step (C) can be or comprise contacting the compound of formula (II) with <NUM>-bromovaleroyl chloride to obtain a compound of formula (III),
<CHM>
wherein Hal is Br.

In particular, step (A) of contacting <NUM>-chloro-<NUM>-(<NUM>-nitrophenyl)-<NUM>,<NUM>-dihydropyridin-<NUM>(<NUM>)-one and ethyl <NUM>-chloro-<NUM>-(<NUM>-(<NUM>-methoxyphenyl)hydrazono)acetate in the presence of a base to obtain a compound of formula (I) can comprise.

Ethyl <NUM>-chloro-<NUM>-(<NUM>-(<NUM>-methoxyphenyl)hydrazono)acetate can be especially ethyl (Z)-<NUM>-chloro-<NUM>-(<NUM>-(<NUM>-methoxyphenyl)hydrazono)acetate).

Step (A) can in particular comprise preparing a mixture (e.g. in a reactor) comprising toluene, <NUM>-chloro-<NUM>-(<NUM>-nitrophenyl)-<NUM>,<NUM>-dihydropyridin-<NUM>(<NUM>)-one, ethyl (Z)<NUM>-chloro-<NUM>-(<NUM>-(<NUM>-methoxyphenyl)hydrazono)acetate. Triethylamine can then be added (e.g. dropwise) for example e.g. a temperature above <NUM>, such as <NUM>. After the addition, reaction mixture can be stirred (e.g. at <NUM> ± <NUM>), for example for <NUM>. After the reaction is completed, reaction mixture can be cooled (e.g. to <NUM>± <NUM>). The product can be isolated, e.g. by filtration, and slurried in water (e.g. at <NUM>± <NUM>). Yellow solid can be obtained (e.g. at a yield of about <NUM>% or more). The product can be used for the next step without further purification. This procedure provides an uncomplicated approach to the desired intermediate. The product can be obtained with filtration. Salt can be removed by slurrying in water. This process shows a good potential of purification, for example product can be obtained with purity more than <NUM>%. Crude product can be isolated, especially in one phase system. Both isolation and slurrying in water can be made in the same container, e.g. in a filter dryer. Due to the high purity achieved, there is no need for recrystallization or slurrying in organic solvent. Optionally, recrystallization or slurrying in organic solvent can be carried out, if desired.

<NUM>-chloro-<NUM>-(<NUM>-nitrophenyl)-<NUM>,<NUM>-dihydropyridin-<NUM>(<NUM>)-one and ethyl (Z)-<NUM>-chloro-<NUM>-(<NUM>-(<NUM>-methoxyphenyl)hydrazono)acetate are compounds known in the art and are described e.g. in <CIT>.

Step (B) can be in particular reducing the compound of formula (I) in the presence of hydrogen and a hydrogenation catalyst to obtain a compound of formula (II). In particular, the hydrogenation catalyst can be or comprise a hydrogenation catalyst comprising at least one metal selected from the platinum group (e.g. one or more of Pd, Pt) or Ni,
especially the hydrogenation catalyst can be or comprise a hydrogenation catalyst selected from the group of hydrogenation catalysts comprising palladium, and mixtures thereof, further especially the hydrogenation catalyst can be or comprise especially Pd/C, Pd/Al<NUM>O<NUM>, and mixtures thereof.

Especially, step (B) can be reducing the compound of formula (I) in the presence of hydrogen, a hydrogenation catalyst, and a solvent to obtain a compound of formula (II). Furthermore, step (B) can be reducing the compound of formula (I) in the presence of hydrogen, a hydrogenation catalyst, and a solvent to obtain a compound of formula (II), the solvent being or comprising N,N-dimethylformamide (DMF).

Step (B) of reducing the compound of formula (I) in the presence of hydrogen to obtain a compound of formula (II), especially step (B-<NUM>), can in particular be or comprise preparing a mixture comprising ethyl <NUM>-(<NUM>-methoxyphenyl)-<NUM>-(<NUM>-nitrophenyl)-<NUM>-oxo-<NUM>,<NUM>,<NUM>,<NUM>-tetrahydro-<NUM>-pyrazolo[<NUM>,<NUM>-c]pyridine-<NUM>-carboxylate (I), and N,N-Dimethylformamide. Under an inert atmosphere (e.g. the reactor containing the mixture can be inertised), and a catalyst comprising palladium (e.g. <NUM>% Pd/C) is added. Reaction mixture can be stirred under hydrogen (e.g. at <NUM>± <NUM>), for example for <NUM>. After the reaction is completed, catalyst can be removed by filtration. The product can be precipitated from the so obtained filtrate by (e.g. dropwise) addition to water (e.g. at <NUM>± <NUM>). Suspension can be stirred (e.g. at <NUM> ± <NUM>) (e.g. for <NUM>) and then cooled (e.g. to <NUM>± <NUM>). Product can be isolated by filtration (e.g. in a filter dryer), and DMF can be (optionally) removed by slurring in water. Yellow crystalline solid can be obtained. The product can be used for the next step without further purification and drying. Precipitating a product by a dropwise addition of the reaction mixture into warm water at (e.g. at <NUM>± <NUM>), such as at about <NUM>, allows to obtain a product with advantageous crystallinity. Product can be isolated (e.g. on a filter dryer); optionally, the product obtained can be slurried in water to remove residual DMF.

Step (C) of contacting the compound of formula (II) with <NUM>-halogenovaleroyl chloride to obtain a compound of formula (III), can in particular be or comprise preparing a mixture comprising ethyl <NUM>-(<NUM>-aminophenyl)-<NUM>-(<NUM>-methoxyphenyl)-<NUM>-oxo-<NUM>,<NUM>,<NUM>,<NUM>-tetrahydro-<NUM>-pyrazolo[<NUM>,<NUM>-c]pyridine-<NUM>-carboxylate (II), and methylene chloride. The reaction mixture can be stirred (e.g. at RT, such as e.g. at <NUM>± <NUM>, until solid is dissolved. Reaction mixture can then be cooled (e.g. to <NUM> ± <NUM>), and N,N,N-triethylamine can be added, e.g. dropwise. Subsequently, <NUM>-chlorovaleroyl chloride can be added, e.g. dropwise. Reaction mixture can be stirred (e.g. for <NUM> ± <NUM> minutes). Subsequently, temperature can be raised (e.g. to <NUM> ± <NUM>), and the water can be added. Phases can be separated, and the product can be precipitated from the organic phase by addition of ethyl acetate. The so obtained suspension can be stirred (e.g. at <NUM> ± <NUM>) (e.g. for <NUM> ± <NUM> minutes) and cooled (e.g. to -<NUM> ± <NUM>). Product can be isolated by filtration. Beige solid can be obtained in advantageous yields (e.g. a yield <NUM>% or more). The product can be used for the next step without further purification.

During this process step, a solvent exchange can be avoided, as the product can be directly precipitated from the organic phase by addition of alkyl ester (e.g. ethyl acetate), especially alkyl ester (e.g. ethyl acetate) with high purity. This process is time-effective, and contributes to low production costs, as the product can be precipitated from the organic phase.

The present inventors surprisingly discovered that a mixture of DCM (dichloromethane) and MeOH (methanol) considerably increases the solubility of apixaban even at moderate or room temperatures. By addition of methanol, material can be precipitated, and pure form N-<NUM> is obtained. Product can be further slurried in ethanol or other alcohol(s) to stabilize the polymorphic form, as well as to improve the removal of the residual solvents. In particular, the solvent-solute-ratio can be optionally advantageously decreased by subjecting apixaban containing mixtures to increased pressures and increased temperatures.

There is provided a process for preparing apixaban of formula (V), characterized in that step (iv) is: crystallizing apixaban of formula (V)
<CHM>
wherein step (iv) consists of or comprises steps (a) to (f) of a method for the preparation of crystalline apixaban of formula (V), especially apixaban polymorphic form N-<NUM>, said method comprising:.

Preferably, the method for the preparation of crystalline apixaban of formula (V), especially apixaban polymorphic form N-<NUM>, comprises decreasing the second temperature to the third temperature and/or decreasing the temperature of the optionally obtained filtrate to the third temperature at a cooling rate in the range of <NUM> to <NUM>/minute, especially of <NUM> to <NUM>/minute, further especially of <NUM> /min; optionally during said decreasing the mixture or filtrate can be agitated, e.g. stirred.

In particular, the first pressure can be the pressure present at the place where the method is carried out e.g. a pressure of about <NUM> atm (<NUM><NUM> Pa), e.g. a pressure in the range of <NUM> to <NUM> kPa (kilopascal). In particular, the first pressure can be a pressure in the range of <NUM> to <NUM> kPa, especially in the range of <NUM> to 101kPa, further especially in the range of <NUM> to <NUM> kPa.

Furthermore, the first temperature can be a temperature in the range from10 °C to <NUM>, optionally in the range from <NUM> to <NUM>.

In particular, the second pressure can be a pressure in the range from <NUM> kilopascal to <NUM> kilopascal, optionally from <NUM> kilopascal to <NUM> kilopascal.

Especially, the second temperature can be a temperature in the range from <NUM> to <NUM>, optionally in the range from <NUM> to <NUM>.

Especially, the third pressure can be a pressure in the same range as for the first pressure.

In particular, the third temperature can be a temperature in the range from <NUM> to <NUM>, optionally in the range from <NUM> to <NUM>.

Especially, the solvent used in step (a) can be methanol or a solvent mixture comprising or consisting of methanol and dichloromethane.

Furthermore, the solvent used in step (a) can be methanol, dichloromethane, or a solvent mixture comprising or consisting of methanol and dichloromethane, optionally the solvent mixture having a weight ratio (methanol : dichloromethane) in the range of from <NUM> : <NUM> to <NUM> : <NUM>, further optionally <NUM>:<NUM> to <NUM>:<NUM>, preferably <NUM>:<NUM> to <NUM>:<NUM>.

The term "apixaban" as used herein can relate to apixaban in crystalline form, and in amorphous form. Preferably, apixaban prepared by the methods and processes disclosed herein can be or comprise apixaban Form N-<NUM>.

Form N-<NUM> (neat) and Form H2-<NUM> (hydrate) of apixaban are known in the art and may be characterized by unit cell parameters substantially equal to the following shown in the following Table <NUM>, published in <CIT>:
<IMG>.

Furthermore, characteristic X-ray diffraction peak positions (degrees 2θ±<NUM>) at room temperature, based on a pattern (especially a high quality pattern) collected with a diffractometer (CuKα) (with a spinning capillary with 2θ calibrated with a NIST suitable standard), are provided in <CIT> and in <CIT> and are shown in Table <NUM> below for Form N-<NUM> and H2-<NUM>, respectively. Thus, Form N-<NUM> can be characterized by a X-ray diffraction pattern collected with a diffractometer (CuKα) showing the characteristic X-ray diffraction peak positions (degrees 2θ±<NUM>) shown in Table <NUM> below, and Form H2-<NUM> can be characterized by a X-ray diffraction pattern collected with a diffractometer (CuKα) showing the characteristic X-ray diffraction peak positions (degrees 2θ±<NUM>) shown in Table <NUM> below:.

Preferably, step (iv) of optionally crystallizing apixaban of formula (V), especially optionally crystallizing apixaban polymorphic form N-<NUM>, can consist of or can comprise any of the methods for the crystallization and/or purification of apixaban described herein, and in particular can consist of or can comprise steps (a) to (f) of the method(s) for the preparation of crystalline apixaban, especially apixaban Form N-<NUM>, described herein.

The crystalline apixaban of formula (V) obtained after one of or all of steps (d), (e), and (f) can be or can comprise apixaban polymorphic form N-<NUM>.

In particular, the method can comprise a step prior to step (a) comprising: preparing apixaban of formula (V) in the presence of methanol, optionally in the presence of methanol, and ammonia.

There is provided a process for preparing apixaban of formula (V), characterized in that step (iv) is: crystallizing apixaban of formula (V)
<CHM>
wherein step (iv) consists of or comprises steps (a) to (f) of a method for the preparation of crystalline apixaban of formula (V), especially apixaban polymorphic form N-<NUM>, said method comprising.

In particular, the method for the preparation of crystalline apixaban of formula (V), especially apixaban polymorphic form N-<NUM>, can comprise preparing a mixture, usually solution, comprising apixaban, methylene chloride and methanol. The solution can be agitated (e.g.stirred), for example (e.g. at <NUM> ± <NUM>) (e.g. for <NUM> ± <NUM>) and filtered. Apixaban can be precipitated with an addition of methanol (e.g. at room temperature (e.g. at <NUM> ± <NUM>). Suspension can be cooled in (e.g. <NUM> ± <NUM>) (for example to -<NUM> ± <NUM>) and stirred for <NUM> ± <NUM>). Product can be isolated (e.g. on a filter dryer). N-<NUM> polymorphic form, especially in pure form, can be obtained. For stabilizing the polymorphic form and for improving the removal of residual solvents, the isolated product (e.g. in the form of a wet cake) can be slurried in ethanol (e.g. at <NUM> ± <NUM>) (for example for <NUM> hours ± <NUM>). Suspension can then be cooled to room temperature and filtered. The so obtained wet cake can be dried (e.g. at a temperature in the range <NUM>-<NUM>), preferably at a pressure below ambient pressure (e.g. at a pressure p=<NUM>± <NUM>,<NUM> kPa). Pure N-<NUM> form can be obtained, having a purity of more than <NUM> %, as determined by HPLC.

An advantage of the method for the preparation of crystalline apixaban, especially apixaban polymorphic form N-<NUM>, is that the formation of impurities (e.g. dimer impurities, acid impurity and/or H-<NUM> form) can be avoided, as well as that also presence of residual solvents such as <NUM>,<NUM>-propandiol can be avoided. Furthermore, the method(s) and step(s) for the preparation of crystalline apixaban described herein may be carried out at comparatively low temperatures, as well as avoid the use of large quantities of <NUM>,<NUM>-propandiol and/or water.

All described processes ensure filtration (especially GMP filtration) of apixaban solution, especially from small volumes of solvent(s), which solvent(s) can be mixture of DCM and methanol in the range from <NUM>:<NUM> to <NUM>:<NUM> or pure methanol.

In particular, the present inventors developed processes and methods providing apixaban purity ><NUM>%, presence of impurities of not more than <NUM>%; pure polymorphic form N-<NUM>, with average particle size in range <NUM> to <NUM>, preferably <NUM> to <NUM>, most preferably <NUM> to <NUM> is prepared. The process of the present invention furthermore provides the advantage that apixaban can be directly isolated from reaction mixture after amidation; especially with controlled cooling conditions purity ><NUM>%, pure polymorphic form N-<NUM> is obtained. The present inventors surprisingly discovered that particles obtained by this process are very fine elongated rods, and can be easy milled to an average particle size in the range from <NUM> to <NUM>, preferably in the range from <NUM> to <NUM>, most preferably in the range from <NUM> to <NUM>, for example with any type of milling equipment for dry or wet milling, such as jet mill, pin mill, high shear homogeniser. The dried, isolated crystalline apixaban, especially the dried isolated apixaban polymorphic form N-<NUM>, obtained after step (f) of any of the methods for the preparation of crystalline apixaban, can have an average particle size in the range of from <NUM> to <NUM>, preferably from <NUM> to <NUM>, most preferably from <NUM> to <NUM>.

Furthermore, pure polymorphic form N-<NUM> is very well controlled by the process and overcomes problems known from other processes, like residual solvents, and/or H2-<NUM> polymorphic form contamination. From that point of view claimed process is robust on industrial scale.

In particular, the method can comprise a step prior to step (a) comprising:
preparing apixaban of formula (V) in the presence of methanol.

The purity of apixaban in general may be determined with the following HPLC method:
<IMG>.

Accurately weigh about <NUM> of sample into <NUM> volumetric flask, dissolve in <NUM> of DMSO and dilute to volume with diluent.

Use area per cent method. Do not integrate solvent peaks.

Water content may be determined by Karl Fischer method. In particular, water content in the sample can be determined according to European Pharmacopoeia <NUM>, section <NUM>.

The following examples illustrate the invention and are not intended to restrict the scope of the invention in any way.

In a <NUM> reactor is charged <NUM> of toluene, <NUM> of <NUM>-chloro-<NUM>-(<NUM>-nitrophenyl)-<NUM>,<NUM>-dihydropyridin-<NUM>(<NUM>)-one, <NUM> of ethyl (Z)-<NUM>-chloro-<NUM>-(<NUM>-(<NUM>-methoxyphenyl)hydrazono)acetate. Triethylamine <NUM> is added dropwise at <NUM>, after the addition reaction mixture is stirred at <NUM> for <NUM>. After the reaction is completed, reaction mixture is cooled to <NUM>. The product is isolated by filtration in filter dryer and slurried in <NUM> of water at room temperature. Yellow solid is obtained (<NUM> yield <NUM>%). The product is used for the next step without further purification.

In a <NUM> reactor is charged <NUM> of ethyl <NUM>-(<NUM>-methoxyphenyl)-<NUM>-(<NUM>-nitrophenyl)-<NUM>-oxo-<NUM>,<NUM>,<NUM>,<NUM>-tetrahydro-<NUM>-pyrazolo[<NUM>,<NUM>-c]pyridine-<NUM>-carboxylate (I), <NUM> of N, N-Dimethylformamide. Reactor is inertised and a catalyst <NUM>% Pd/C <NUM> is added. Reaction mixture is stirred under hydrogen at <NUM> for <NUM>. After the reaction is completed, catalyst is removed by filtration. The product was precipitated from filtrate by dropwise addition to water at <NUM>. Suspension is stirred at <NUM> for <NUM> and then cooled to <NUM>. Product is isolated by filtration in filter dryer, DMF is removed by slurring in water. Yellow crystalline solid is obtained (<NUM>, LOD=<NUM>%). The product is used for the next step without further purification and drying.

In a <NUM> reactor is charged <NUM> of wet ethyl <NUM>-(<NUM>-aminophenyl)-<NUM>-(<NUM>-methoxyphenyl)-<NUM>-oxo-<NUM>,<NUM>,<NUM>,<NUM>-tetrahydro-<NUM>-pyrazolo[<NUM>,<NUM>-c]pyridine-<NUM>-carboxylate (II), <NUM>,<NUM> methylene chloride. Reaction mixture is stirred at RT until a solid is dissolved. Reaction mixture is cooled to <NUM>, and <NUM> of N,N,N-triethylamine is added dropwise. After the addition <NUM> of <NUM>-chlorovaleroyl chloride is added dropwise. Reaction mixture is stirred for <NUM>. After completion temperature is raised to <NUM> and the water <NUM> is added. Phases are separated, the product is precipitated from organic phase by addition of <NUM> ethyl acetate. Suspension is stirred at <NUM> for <NUM> and cooled to -<NUM>. Product is isolated by filtration. Beige solid is obtained (<NUM>, yield: <NUM>%). The product is used for the next step without further purification.

In a <NUM> reactor is charged <NUM> ethyl <NUM>-(<NUM>-(<NUM>-chloropentanamido)phenyl)-<NUM>-(<NUM>-methoxyphenyl)-<NUM>-oxo-<NUM>,<NUM>,<NUM>,<NUM>-tetrahydro-<NUM>-pyrazolo[<NUM>,<NUM>-c]pyridine-<NUM>-carboxylate (III), <NUM> of acetonitrile. Potassium carbonate (<NUM>) and N,N,N,N-tetrabutylammonium bromide (<NUM>) are added to reaction mixture. Suspension is stirred under nitrogen atmosphere at <NUM> for <NUM>. After a reaction is completed, salts are removed by hot filtration. Product is precipitated from filtrate by solvent exchange with ethyl acetate at <NUM>. Product is isolated by filtration. Beige solid is obtained (<NUM>, yield <NUM>%). The product is used for the next step without further purification.

Solvent exchange in Example <NUM> is performed by evaporation of acetonitrile until LOD of <NUM>-<NUM>% is achieved. Ethyl acetate is than added into reaction mixture (<NUM> vol. Evaporation is continued until LOD (loss of drying) of <NUM>-<NUM>% is achieved. eq of ethyl acetate is added and evaporation is repeated until LOD of <NUM>-<NUM>% is obtained. At the end <NUM> vol. eq of ethyl acetate is added.

For highlighting unexpected and surprising advantageous technical effects of using potassium carbonate in the cyclization step (ii), as identified above, comparative experiments with several other bases were carried out:
When carrying out in a comparative experiment the reaction with trimethylamine, only <NUM>% of product was obtained. When carrying out in a comparative experiment the reaction with potassium tert butoxide, <NUM>% of product was obtained, however (at least) two impurities were obtained in significant amounts (in HPLC area%: <NUM>%).

When carrying out in a comparative experiment the reaction with potassium carbonate in absence of phase transfer catalyst, after <NUM> hours at <NUM> still <NUM>% of unreacted starting material was present. When we added phase transfer catalyst TBAB reaction ended in <NUM> hours. Product was obtained in <NUM>% purity.

Use of potassium carbonate with TBAB phase transfer catalyst significantly reduces industrial costs of API, for approximately <NUM>%. It also reduces time of reaction, it is easy handled, and we obtain product with higher purity.

In a <NUM> reactor is charged <NUM> of ethyl <NUM>-(<NUM>-methoxyphenyl)-<NUM>-oxo-<NUM>-(<NUM>-(<NUM>-oxopiperidin-<NUM>-yl)phenyl)-<NUM>,<NUM>,<NUM>,<NUM>-tetrahydro-<NUM>-pyrazolo[<NUM>,<NUM>-c]pyridine-<NUM>-carboxylate (IV), <NUM> of Methanol and <NUM> ammonia are added. Reaction mixture is stirred at <NUM> for <NUM> under pressure (<NUM>-<NUM> kPa) and then cooled to <NUM>. Suspension is stirred at that temperature for <NUM>. Product is isolated by filtration. With this process of apixaban preparation we obtained a product with high purity, all impurities are HPLC area <<NUM>% and pure N-<NUM> polymorphic form.

Additional experiments concerning the preparation of apixaban by reacting compound of formula (IV) with ammonia in methanol were carried out, wherein several specific parameters were varied:.

As shown in <FIG>, by applying a reaction temperature of <NUM> or more unexpectedly the quantity of unreacted material can be minimized:
When the reaction was performed at <NUM> or <NUM> quantity of unreacted intermediate merely was <NUM>% - <NUM>%.

<FIG> depicts the relationship between unreacted material and temperature.

Synthesizing apixaban by aminolysis with aqueous ammonia can be also carried out. Reacting compound of formula (IV) with ammonia in methanol shows the advantage of contributing to avoiding or reducing the content of acid impurity AXN461.

Presence of a low concentration of starting material (intermediate IV) in the reaction mixture surprisingly contributes to a reduction of the content of acid impurity AXN461 (also referred to herein as APXB461), as may be seen from the following Table and <FIG>.

Impurities AXN <NUM> (the terms AXN <NUM> and APXB461 are used interchangeably herein) and AXN475 referred to herein are:.

From the following Table <NUM>, it is evident that unexpectedly lower concentrations of starting material (dilution mg/mL) in the reaction mixture may contribute to reducing the content of acid impurity AXN461. Lower concentrations of starting material (compound (IV)) can therefore contribute to providing a product with particularly advantageous purity. The relationship between concentration and impurity formation is shown in <FIG>.

The concentration of ammonia (and consequently of the pressure used during reaction) surprisingly influences the reaction conversion. Carrying out the reaction with lower concentration of methanolic ammonia results in lower rate of conversion, and consequently may increase reaction time and formation of acid impurity AXN461 and impurity APXB475.

RRt: relative retention time; APXB: apixaban; AXN461, AXN475, APXB-<NUM> being impurities; Dilution: Dilution of compound (IV) per <NUM> of reaction mixture. The terms APXB461 and AXN461 are used interchangeably herein. The terms APXB475 and AXN475 are used interchangeably herein.

<FIG> shows an unexpected influence of the concentration of ammonia in the reaction mixture on the formation of pure product apixaban (APXB).

In case a reaction mixture with a lower concentration of methanolic ammonia is used, the reaction time can be prolonged and the acid impurity formation can be increased.

The Table supra shows that carrying out the reaction at <NUM>, using anhydrous methanol, anhydrous or essentially anhydrous conditions (water content of the reaction mixture of <NUM>% or below, applying a concentration of starting material (IV) in the reaction mixture of around <NUM>/mL, and a comparatively high concentration of ammonia (about <NUM> - <NUM> (mol/L) NH<NUM> in MeOH) provides particularly advantageous results. Furthermore, surprisingly also the cooling rate and the final temperature of isolation can advantageously contribute.

In reactor after inertization is charged <NUM> of ethyl <NUM>-(<NUM>-methoxyphenyl)-<NUM>-oxo-<NUM>-(<NUM>-(<NUM>-oxopiperidin-<NUM>-yl)phenyl)-<NUM>,<NUM>,<NUM>,<NUM>-tetrahydro-<NUM>-pyrazolo[<NUM>,<NUM>-c]pyridine-<NUM>-carboxylate (IV), and <NUM> of methanol. Suspension is cooled down to <NUM>, <NUM> of ammonia is added in <NUM>. Reaction mixture is stirred at <NUM> rpm, heated in <NUM> to <NUM>, stirred at that temperature for <NUM>. After completion of reaction, reaction mixture is cooled down to <NUM> in <NUM>. Product is isolated by over pressure filtration. Wet cake is washed with <NUM> of cooled methanol. Apixaban of pure polymorphic form N-1is formed, with average particle size <NUM>, milled by pico pin mill at <NUM> rpm to <NUM>.

In <NUM> reactor is charged <NUM> of crude apixaban (V), <NUM> of methylene chloride and <NUM> of methanol are added. Solution is stirred at <NUM> for <NUM> and filtered. Apixaban is precipitated with and addition of <NUM> methanol at room temperature. Suspension is cooled in <NUM> to -<NUM> and stirred for <NUM>. Product is isolated on filter dryer. We obtain pure N-<NUM> polymorphic form. To stabilize polymorphic form and to improve a drying of residual solvents we slurried a wet cake in <NUM> ethanol at <NUM> for <NUM> hours. Suspension is then cooled to room temperature and filtered. Wet cake is dried for <NUM> at <NUM>, <NUM> at <NUM>, and <NUM> at <NUM>, p=<NUM> mbar. Pure N-<NUM> form is obtained, purity more than <NUM> % by HPLC, acid impurity not more than (nmt) <NUM>%, any other nmt <NUM>%. Pure polymorphic form N-<NUM> is obtained, with average particle size <NUM>, milled by pico pin mill with <NUM> rpm to <NUM> which is directly used in formulation studies.

In a cleaned and dried reactor is charged <NUM> of crude apixaban (V), <NUM> of methylene chloride and <NUM> of methanol are added. Solution is stirred at <NUM> for <NUM> with <NUM> rpm and filtered. Apixaban is precipitated with and addition of <NUM> methanol in <NUM> at room temperature. Suspension is cooled in <NUM> to -<NUM> and stirred for <NUM>. Product is isolated by overpressure filtration. We obtain pure N-<NUM> polymorphic form. To stabilize polymorphic form and to improve a drying of residual solvents we slurried a wet cake in <NUM> of ethanol at <NUM> for <NUM> hours with stirring <NUM> rpm. Suspension is than cooled to room temperature in <NUM> and isolated by overpressure filtration. Wet cake is dried for <NUM> at <NUM>, <NUM> at <NUM>, and <NUM> at <NUM>, p=<NUM> mbar. Pure N-<NUM> form is obtained, purity more than <NUM> % by HPLC, acid impurity nmt <NUM>%, any other nmt <NUM>%. Pure polymorphic form N-<NUM> is obtained, with average particle size <NUM>, milled by pico pin mill with <NUM> rpm to <NUM> which is directly used in formulation studies.

A further way to prepare pure polymorph N-<NUM> is by directly over pressure filtration of reaction mixture, at temperature higher than <NUM> and pressure <NUM>-<NUM> kPa and precipitation of product by controlled cooling. With that procedure we increase a yield for more than <NUM>%, we obtain pure product all impurities are under <NUM>% HPLC area. We decrease a quantity of solvent in the last step.

In a <NUM> reactor is charged <NUM> of ethyl <NUM>-(<NUM>-methoxyphenyl)-<NUM>-oxo-<NUM>-(<NUM>-(<NUM>-oxopiperidin-<NUM>-yl)phenyl)-<NUM>,<NUM>,<NUM>,<NUM>-tetrahydro-<NUM>-pyrazolo[<NUM>,<NUM>-c]pyridine-<NUM>-carboxylate (IV), <NUM> of Methanol and <NUM> ammonia are added. Reaction mixture is stirred at <NUM> for <NUM> under pressure and then cooled to <NUM>. Suspension is stirred at that temperature for <NUM>. Product is isolated by filtration. With this process of apixaban preparation, we obtained a product with high purity, all impurities are HPLC area <<NUM>% and pure N-<NUM> polymorphic form.

Claim 1:
A process for preparing apixaban of formula (V),
<CHM>
said process comprising:
(i) providing a compound of formula (III),
<CHM>
<CHM>
wherein Hal is Br or Cl;
(ii) cyclizing the compound of formula (III) in the presence of potassium carbonate, a first solvent, and a phase transfer catalyst, to obtain a compound of formula (IV)
<CHM>
(iii) amidating the compound of formula (IV) to obtain apixaban of formula (V); and
(iv) optionally crystallizing apixaban of formula (V).