WO2013120464A1

WO2013120464A1 - A process for the preparation of rivaroxaban based on saving of 1,1'-carbonyl diimidazole.

Info

Publication number: WO2013120464A1
Application number: PCT/CZ2013/000014
Authority: WO
Inventors: Ales Halama; Radim Krulis; Jiri BRICHAC
Original assignee: Zentiva KS
Current assignee: Zentiva KS
Priority date: 2012-02-17
Filing date: 2013-02-12
Publication date: 2013-08-22
Anticipated expiration: 2014-08-17
Also published as: CZ2012114A3

Description

A process for the preparation of rivaroxaban based on saving of U'-carbonyl

diimidazole.

Technical Field

The invention relates a new method of performing of the cyclization reaction providing the 2- oxo- 1 , 3 -oxazoli dine heterocycle during the chemical synthesis of rivaroxaban, which is an active pharmaceutical substance used for preparation of a drug from the therapeutic group of anticoagulants.

Background Art

Rivaroxaban, chemically (_lS)-5-chloro-N-({2-oxo-3-[4-(3-oxomo holin-4-yl)phenyl]-l ,3- oxazolidin-5-yl}methyl)thiophene-2-carboxamide, described by formula (1), was developed by the company Bayer Healthcare (WOO 1/47919, 2001). Rivaroxaban is applied in the clinical practice as the active ingredient of an orally available anticoagulant that is commercially marketed as Xarelto and is used in the prevention and treatment of arterial or venous thromboembolic disorders. In its effect, rivaroxaban is characterized by direct selective inhibition of the FXa coagulation enzyme {Drugs of the Future 2006, 31(6): 484-493).

H₂

For the preparation of rivaroxaban (1) four key structures referred to as building blocks can be used as advanced intermediates. All the so far described syntheses are using two virtually equal building blocks. The first one are derivatives of 4-(4-aminophenyl)morpholin-3-one (2, G=H), where it may be the case of an unsubstituted amine or a derivative alkylated on nitrogen or a carbamate derived from this compound. The other general and commonly used building block for the rivaroxaban molecule are derivatives of 5-chlorothiophene-2-carboxylic acid (3, X=OH), or its functional derivatives such as the chloride or amide. Two more types of starting compounds are specific for either process. They include chiral building blocks, e.g. (iS)-glycidyl phtalimide (4), (Sy3-aminopropane-l ,2-diol (5), (i?)-epichlorohydrin (6) and (i?)-glycidyl butyrate (7), as well as carbonylation agents, e.g. Ι , Γ-carbonyldiimidazole (8, abbreviated CDI), alkyl chloroformates 9) and phosgene (10). chiral building blocks:

(4) (5) (6)

carbonylation agents:

(8) (9) (10)

Up to now three synthetic methods have been described for chemical synthesis of rivaroxaban (1) based on the use of CDI as the carbonylation agent, which are distinguished from each other especially in the chiral building blocks used. The individual methods are described in a more detailed way in the following sources (reference source, chiral block):

(a) WO 01/47919, US 7 157 456B2, J.Med. Chem. (2005), 48(19), 5900-5908, (^-glycidyl phthalimide,

(b) WO 2004060887,

(5)-3-aminopropane-l ,2-diol,

(c) WO 2009/023233 Al ,

(i?)-epichlorohydrin.

A substantial structural feature of rivaroxaban (1) is represented by the 3, 5 -substituted 2-oxo- 1 ,3-oxazolidine heterocycle described by the general chemical formula (11), wherein Ri means a substituted aryl and R₂ means a substituted alkyl. In the chemical synthesis of 3,5- substituted 2-oxo- l ,3-oxazolidines (11) carbonylation agents of general formula (12) are used, wherein both X and Y mean a suitable leaving group, e.g. a halogen, alcoxy group or 1H- imidazol- l -yl. The carboxylation agents, which may be e.g. CDI (8), alkyl chloroformates (9) or phosgene (10), are the source of the carbonyl group in the target heterocycle. The starting compounds for the preparation of 3, 5 -substituted 2-oxo- l ,3-oxazolidines include variously substituted l -alkyl-2-(arylamino)ethanols of formula (13), wherein R_\ means a substituted aryl and R₂ means a substituted alkyl; see Scheme 1.

(12) (8) (9) (10)

Scheme 1

In the case of cyclization performed in the synthesis of rivaroxaban (according to Scheme 2, stage (b)) four equivalents of CDI are consumed per one equivalent of the starting compound (WO 01/47919, J.Med. Chem. (2005), 48(19), 5900-5908). The consumption of CDI in case of this synthesis of rivaroxaban is unusually high. Compared to other carbonylation agents (phosgene, alkylchloroformates) the use of CDI brings a number of advantages as alternative agents are toxic, harmful for the environment and release highly corrosive hydrogen chloride during the reaction. On the other hand, CDI is considerably more expensive than the alternative agents. Thus, from the economical point of view it is convenient to minimize the

Scheme 2 The present invention relates to a new and industrially applicable method of carrying out the carbonylation reaction in the preparation of intermediates of rivaroxaban, which is characterized by saving of the expensive carboxylation agent (CDI), which makes it possible to reduce costs of commercial production of rivaroxaban.

Disclosure of Invention

The invention provides a convenient method of performing the cyclization reaction in the preparation of rivaroxaban intermediates that is characterized by a reduced consumption of the expensive carboxylation agent CDI.

The invention consists in a method of cyclizing 2-((2i?)-2-hydroxy-3- { [4-(3-oxomorpholin-4- yl)phenyl]amino}propyl)-l H-isoindol-l,3(2H)-dione of formula (14) to 2-({(55)-2-oxo-3-[4- (3-oxomorpholin-4-yl)phenyl]- l ,3-oxazolidin-5-yl}methyl)- l H-isoindol- l ,3(2H)-dione of formula (15), characterized by a process consisting of the following steps:

(a) reaction of compound (14) carried out in a suitable solvent with 1 to 1.5 equivalents of Ι , -carbonyldiimidazole of formula (8), yielding a mixture of the non-cyclic intermediate 2-((2/?)-2-hydroxy-3-(N-(4-(3-oxomorpholin-4-yl)phenyl)-lH-imidazol- l - yl-carbox-amido)propyl)- lH-isoindol-l ,3(2H)-dione of formula (16) and the cyclic product of formula (15), which contains more than 50% of compound (16);

(b) cyclization of the mixture of the compounds obtained in step (a) in a solvent or a mixture of solvents suitable for cyclization in the presence of a suitable base as the catalyst;

(c) isolation of the cyclic compound (15). A C₄ to C§ ether, polyethylene glycol, a Ci to C6 chlorinated solvent or their mixtures in any proportions can be used as a suitable solvent for the preparation of the compound (15) in step (a), preferably a solvent selected from the group of tetrahydrofuran, 2-methyltetrahydrofuran, 1 ,4-dioxane, ierf-butylmethylether, diie i-butylether, polyethylene glycol PEG-200 to PEG- 800, dichloromethane, chloroform, 1 ,1 ,2-trichloroethylene, chlorobenzene or their mixtures in any proportions. A metal alkoxide of formula (17), wherein R means a linear or branched C i to Cs alkyl and M means an alkali metal, can be used as a suitable base for preparation of the compound (15) in step (b).

R-O-M

(17)

An alkoxide selected from the group of sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium isopropoxide, sodium tert-butoxide, potassium tert- butoxide, lithium ferf-butoxide can be used as a suitable metal alkoxide in step (b). Besides a metal alkoxide, a suitable base can also be used in step (b), selected from the group of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium hydride, methyllithium, n-butyllithium, lithium diisopropylamide or lithium hexamethyldisilazide. Potassium tert- butoxide or its solution in an organic solvent, e.g. a solution in tetrahydrofuran, is preferably used as the base in step (b). A solvent selected from the group of a C4 to C8 ether, polyethylene glycol, a C I to C6 chlorinated solvent or their mixtures in any proportions can be used as suitable solvents for the preparation of the compound (15) in step (b). The preparation of the compound (15) is also characterized in that the cyclization in step (b) is carried out at a temperature in the range of from 40°C to the boiling point of the solvent.

The process of preparation of the compound (15) is finalized by its isolation from the reaction mixture, which is characterized in that the isolation in step (c) is carried out in such a way that the separated product is filtered off from the reaction mixture, washed with a C_\ to C5 alcohol and/or water and the isolated product is dried.

The present invention relates to a method of carrying out the cyclization of 2-((2 ?)-2-hydroxy- 3 - { [4-(3 -oxomorpholin-4-yl)phenyl]amino } propyl)- 1 H-isoindol- 1 ,3(2H)-dione of formula (14) to 2-({(55)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]- l ,3-oxazolidin-5-yl}methyl)-lH- isoindol- l ,3(2H)-dione of formula (15), see Scheme 3. The method according to the invention is characterized by making use of the possibility of cyclization of the reaction intermediate, 2- ((2^)-2-hydroxy-3-(N-(4-(3-oxomorpholin-4-yl)phenyl)- lH-imidazol-yl- l - carboxamido)propyl)- l H-isoindol- l ,3(2H)-dione of formula (16), by treatment with bases or with heat during its melting, see path (b) in Scheme 4. Compared to the prior process, see path (a) in Scheme 3, the consumption of the expensive carbonylation agent is saved. When the cyclization method according to the invention is used, only 1 to 1.5 equivalents of CDI per 1 equivalent of the starting compound (14) are consumed, while 4 CDI equivalents were consumed in the original method.

Scheme 3

The invention is based on the surprising finding that in the reaction of the compound (14) with CDI, the reaction intermediate (16) is formed very quickly, which is unexpectedly stable and can even be isolated from the reaction mixture in the solid state. Due to relatively high stability of the reaction intermediate (16) the conversion of the compound (14) to the target cyclic product (15) only proceeds very slowly and under treatment with an unusually big excess of the carbonylation agent (CDI). The observed phenomenon is surprising as very similar reactions of related compounds run easily and with the use of just one CDI equivalent per one equivalent of the compound cyclized (US2007032472). A high consumption of CDI (ca. 4 equivalents) during cyclization of the compound (14) to the cyclic product (15) was also confirmed by a comparative experiment, see Example 1. Conversely, when 2 to 3 equivalents of CDI were used (Examples 2, 5 and 6), a mixture of the compounds (16) and (15) was obtained where the compound (16) predominated with contents over 60%. When 1 CDI equivalent was used, the non-cyclic intermediate (16) was obtained, see Example 4 and Fig. 3.

It has been found out in investigating the properties of the isolated intermediate (16) that it could be cyclized without the need of using an excessive amount of CDI. Two principally different methods of conversion of the compound (16) to the compound (15) have been found. The first method consists in heat-induced cyclization that occurs spontaneously during melting of the isolated compound. This way, the target product was prepared with in a 77% yield, see Example 3. The cyclization method based on melting of the compound (16) features high energy demands and is not suitable for application in the production scale. Melting of the compound (16) and its conversion to the compound (15) only occurs at temperatures over 150°C, which precludes the use of common solvents. The use of a suitable base that can, moreover, be used in significantly lower amounts than the equivalent of the cyclized compound (e.g. 0.2 eq. according to Example 8) has turned out to be more convenient for cyclization of the compound (16). Using this method the target product (15) was obtained from the isolated compound (16) by the action of a suitable base with the yield of 78% (calculated on the starting compound (14)), see Example 7. The method, wherein first a mixture of the compounds (16) and (15) is prepared from the compound (14) by treatment with 1 to 1.5 equivalents of CDI and subsequently a suitable base is added to the mixture to finalize the cyclization of the compound (16) to the cyclic product (15), has proved to be still more convenient. Using this approach to the cyclization reaction there is no need to isolate the compound (16) from the reaction environment, which saves the solvents used and time required for production of the compound (15). The method of cyclization without isolation of the compound (16) and with the use of a suitable base provided the cyclic product (15) with the yield of 84% (calculated on the starting compound (14)); see Example 8.

The process of cyclization of the compound (14) makes it possible to reproducibly obtain the cyclic product (15), characterized by the chemical purity of 99.8% and higher. The compound (15) prepared by the method of the invention can be further used for synthesis of rivaroxaban (1), which is the active substance in an anticoagulant drug. A convenient and distinguishing feature from the former method of cyclization of the compound (14) to the compound (15) consists in the use of a lower amount of the expensive carbonylation agent. The reduced amount of the carbonylation agent used is compensated by use of a cheap base. Brief Description of Drawings

Fig. 1 presents the record of an LC MS analysis of the product (mixture of (15) and (16)) in accordance with Example 2. Fig. 2 presents the record of an LC MS analysis of the product (mixture of (15) and (16)) in accordance with Example 6. Fig. 3 presents the record of an LC MS analysis of the product (16) in accordance with Example 4.

Fig. 4 presents the record of an LC MS analysis of the product (15) in accordance with Example 7.

Fig. 5 presents the MS spectrum of the compound (16) prepared by the process in accordance with Example 4.

Examples

The subject of the invention will be clarified in more detail by the examples below, which, however, do not affect the scope of the invention defined in the claims in any way.

EXAMPLE 1 (preparation of 2-({(55)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]- l ,3- oxazolidin-5-yl}methyl)- lH-isoindol- l ,3(2H)-dione (15))

300 ml of THF were added to 20 g of 2-((2i?)-2-hydroxy-3-{ [4-(3-oxomorpholin-4- yl)phenyl]amino}propyl)- lH-isoindol-l ,3(2H)-dione (14, 0.0506 mol), 16 g of Ι , Γ- carbonyldiimidazole (0.09869 mol) and 0.1 g of 4-dimethylamino)pyridine. The suspension was stirred and heated to boiling for 7 hours, then slightly cooled and another portion of Ι , Γ-carbonyldiimidazole (0,09869 mol) was added. Then, the suspension was stirred under boiling for 14 hours. After that the mixture was cooled to 25°C, which was followed by filtration, washing of the cake with THF, with an ethanol/water mixture (9: 1) and drying. 15.6 kg of an off-white powder was obtained that melted at the temperature of 216 to 217°C; HPLC 99.9%, content of the (R)- isomer below 0.03%, yield 73%.

EXAMPLE 2 (preparation of a mixture of the compounds (15) and (16))

400 ml of THF were added to 30 g of 2-((2^)-2-hydroxy-3-{[4-(3-oxomorpholin-4- yl)phenyl]amino}propyl)-lH-isoindol-l ,3(2H)-dione (14, 0.0759 mol), 25 g of 1 , 1 '- karbonyldiimidazole (0.1542 mol) and 0.1 g of 4-dimethylamino)pyridine. The obtained suspension was stirred and heated to boiling. After ca. 15 minutes from the beginning of boiling the suspension got dissolved, and conversely, after another 15 minutes of boiling a solid substance was formed. Then the suspension was stirred under boiling for 15 hours. After that the mixture was cooled to 25°C, which was followed by filtration, washing of the cake with THF (2x50 ml), with ethanol (2x50 ml) and drying. 32 g of an off-white powder was obtained. The measurement of the melting point showed that this powder first melts at 170- 175°C, then re-crystallizes and melts again at 215 to 216 °C; according to HPLC the isolated product was a mixture of 20.7% of the compound (15) and 78.8% of the compound (16), see Fig. 1.

EXAMPLE 3 (preparation of 2-({(55 2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-l ,3- oxazolidin-5-yl}methyl)-lH-isoindol- l ,3(2H)-dione (15) by melting of the compound (16))

(15) (16) (15)

HPLC: 20,7 % 78,8 % 99,8 %

The mixture of the compounds (15) and (16), prepared by the process of Example 2 was heated in a sand bath. The solid substance started to melt when the bath temperature exceeded 150°C; the temperature was gradually increased to 180°C and the mixture was heated at this temperature for 30 minutes. After cooling the re-melted material was suspended in 75 ml of ethanol and the suspension was thoroughly stirred up. This was followed by filtration, washing of the cake with 25 ml of ethanol and vacuum drying at 120°C. 25.6 g of a white powder with the melt, point of 216 to 218°C was obtained; HPLC 99.8%; the yield, calculated on to starting material (14) from Example 2 was 77%.

EXAMPLE 4 (2-((2^)-2-hydroxy-3-(N-(4-(3-oxomorpholin-4-yl)phenyl)-lH-imidazol-yl- l - carboxamido)propyl)-lH-isoindol-l ,3(2H)-dione (16))

400 ml of THF were added to 31 .2 g of 2-((2 )-2-hydroxy-3-{ [4-(3-oxomorpholin-4- yl)phenyl]amino}propyl)-lH-isoindol-l,3(2H)-dione (14, 0.0789 mol), 14.5 g of Ι , Γ- carbonyldiimidazole (0.0894 mol) and 0.1 g of 4-dimethylamino)pyridine. The suspension was stirred and heated to boiling. After ca. 20 minutes from the beginning of boiling the suspension got dissolved, and conversely, after another 5 minutes of boiling a solid substance was formed. Then, the mixture was boiled for another 15 minutes and after that cooled to ca. 40 °C, which was followed by filtration, washing of the cake with THF (2x25 ml) and drying. 35.8 g of white powder that melted at 191 to 193°C was obtained; HPLC 96.8 %, MS (M+ l ) 490.1 , yield 92 %, see Fig. 3 (LC MS) and Fig. 5 (MS). EXAMPLE 5 (preparation of a mixture of the compounds (15) and (16))

200 ml of THF were added to 15.5 g of 2-((2 ?)-2-hydroxy-3-{[4-(3-oxomorpholin-4- yl)phenyl]amino}propyl)-lH-isoindol-l ,3(2H)-dione (14, 0.0392 mol), 14.5 g of 1 ,1 '- carbonyldiimidazole (0.0894 mol) and 0.05 g of 4-dimethylamino)pyridine. The suspension was stirred and heated to boiling. After ca. 20 minutes from the beginning of boiling the suspension got dissolved, and conversely, after another 5 minutes of boiling a solid substance was formed. Then, the mixture was boiled for another 15 minutes and after that cooled to ca. 40°C, which was followed by filtration, washing of the cake with THF (25 ml) and drying. 18.3 g of an off-white powder that melted at 185- 188°C was obtained; according to HPLC the isolated product was a mixture of 14.8% of the compound (15) and 85.2% of the compound (16). EXAMPLE 6 (preparation of a mixture of the compounds of (15) and (16))

200 ml of THF were added to 15.5 g of 2-((2 ?)-2-hydroxy-3-{[4-(3-oxomorpholin-4- yl)phenyl]amino}propyl)- l H-isoindol- l ,3(2H)-dione (14, 0.0392 mol), 19.0 g of Ι , Γ- carbonyldiimidazole (0.1 176 mol) and 0.05 g of 4-dimethylamino)pyridine. The suspension was stirred and heated to boiling. After ca. 20 minutes from the beginning of boiling the suspension got dissolved, and conversely, after another 5 minutes of boiling a solid substance was formed. Then, the mixture was boiled for another 15 minutes and after that cooled to ca. 40°C, which was followed by filtration, washing of the cake with THF (25 ml) and drying. 17.8 of an off-white powder that first melts at 165-175°C, then re-crystallizes and melts again at 215 to 217°C was obtained. According to HPLC the isolated product was a mixture of 39.6% of the compound (15) and 60.4% of the compound (16), see Fig. 2.

EXAMPLE 7 (preparation of 2-({(55 2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-l,3- oxazolidin-5-yl} methyl)- lH-isoindol- l ,3(2H)-dione (15) by treatment of the compound (16)) with a base

25 g of 2-((2i?)-2-hydroxy-3-(N-(4-(3-oxomorpholin-4-yl)phenyl)-lH-imidazol-yl-l - carboxamido)propyl)- lH-isoindol-l ,3(2H)-dione (16, 51 mmol) prepared according to Example 4 were suspended in 350 ml of THF, 5.5 ml of a solution of tert-BuOK (20% by weight, 9.1 mmol) was added dropwise under stirring, which was diluted with 20 ml of THF before adding. The suspension was stirred and heated to boiling for 19 hours, then 400 ml of ethanol were added and the boiling continued for 2 hours. Cooling of the mixture to 35°C was followed by filtration, washing of the cake with ethanol, water and ethanol again. After drying, 16.8 g of an off-white powder that melted at 215-217°C was obtained; HPLC 99.8%, content of the (R isomer below 0.03%, yield 78%, see Fig. 4.

EXAMPLE 8 (preparation of 2-({(5S 2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]- l ,3- oxazolidin-5-yl}methyl)-lH-isoindol- l ,3(2H)-dione (15) by treatment of the compound (16)) with a base

400 ml of THF were added to 30 g of 2-((2i?)-2-hydroxy-3-{[4-(3-oxomorpholin-4- yl)phenyl]amino}propyl)- lH-isoindol- l ,3(2H)-dione (14, 0.0759 mol), 13.5 g of 1 , 1 '- carbonyldiimidazole (0.0832 mol) and 0.1 g of 4-dimethylamino)pyridine. The suspension was stirred and heated to boiling. After ca. 20 minutes from the beginning of boiling the suspension got dissolved, and conversely, after another 5 minutes of boiling a solid substance was formed. Then the mixture was boiled for another 15 minutes and after that 9.6 ml of a solution of iert-BuOK in THF (20% by weight, 9.1 mmol) diluted with 35 ml of THF were added dropwise. The suspension was stirred and heated to boiling for 10 hours, then 600 ml of ethanol were added and boiling continued for 2 hours. Cooling of the mixture to 3 °C was followed by filtration, washing of the cake with ethanol, water and ethanol again. After vacuum drying, 18.2 g of an off-white powder that melted at 216-217°C was obtained; HPLC 99.8%, content of the (R)- isomer below 0.03%, yield 84%. ANALYTIC METHODS (A-C): Below, the analytic methods used for characterization of the compounds prepared in accordance with the invention are described.

A Mass spectroscopy combined with liquid chromatography (LC-MS)

The mass spectra were obtained with the use of an API 3000 mass spectrometer based on triple quadrupole (AB Sciex, USA), which was connected to an HPLC 200 series liquid chromatograph (Perkin-Elmer, USA). 10 μΐ, of the sample was sprayed onto a inetex column, 150 x 4.6 mm; 2.6μ (Phenomenex, USA). The mobile phase consisted of a mixture of ACN - 10 mM ammonium formate, pH 6.3. The gradient program was as follows: isocratically 30% ACN up to 4 min, then gradient to 100% ACN up to 18 min. The flow rate of the mobile phase was 600 μΐ/min. An APCI ion source in the positive full scan mode was used for detection in the mass spectrometer. The temperature of the ion source was 300°C, the scanning range was from m/z 50 to m/z 1000 and nitrogen with the flow of 12 arbitrary units was used as the nebulization gas. The wavelength of 230 nm was used for detection in the PDA detector. The Analyst 1.4.1. software (AB Sciex, USA) was used for data acquisition.

B Melting point

Melting points of the prepared substances were measured on a Kofler block with the sample heating rate of 10°C/min (up to 120°C) and 4°C/min (over 120°C). The measured values of melting points or melting intervals, respectively, are given in the respective Examples.

C High-Performance Liquid Chromatography (HPLC)

Related substances and optical purity of substances were measured in a Waters Alliance 2695/2695XC liquid chromatograph with a W2996/W2998 PDA detector.

For determination of related substances of the products (15) and (16), a Discovery RP Amide C 16 column, 1 0 x 4.0 mm, 5 μιη was used at 10°C. Gradient elution with a three-component mobile phase (component A: 10 mM aqueous solution of ammonium acetate, pH = 5.0; component B: acetonitrile; component C: methanol) in accordance with the table below was used: Component A Component B Component C

Time (min) Flow (ml/min)

(%) (%) (%)

0 1.0 90 10 0

1 1.0 90 10 0

1 1 1 .0 65 20 15

16 1.0 65 20 15

25 1.0 40 60 0

35 1.0 40 60 0

36 1.0 90 10 0

40 1.0 90 10 0

The wavelength used for the detection was 260 nm

For determination of the optical purity of the product (15), a Chiralpak AD-RH column, 150 x 4.6 mm, 5 μπι was used at 35°C. Isocratic elution with a two-component mobile phase with the following composition: component A: 0.01 M aqueous solution of potassium hydrogen phosphate pH = 7.5; component B: acetonitrile was used. The analysis was performed at the flow rate of 1 .0 ml/min and the proportion of the A:B components = 40:60 (V/V); the substances were detected at the wavelength of 240 nm.

Claims

1. A process for the preparation of 2-({(5£)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]- 1 ,3 -oxazolidin-5-yl} methyl)- lH-isoindol- 1 ,3 (2H)-dione of formula (15), characterized in that 2-((2i^)-2-hydroxy-3-{ [4-(3-oxomorpholin-4-yl)phenyl]amino}propyl)- l H- isoindol- l ,3(2H)-dione of formula (14) is cyclized by a process, which consists of the following steps:

(a) reaction of the compound (14) performed in a suitable solvent with 1 to 1.5 equivalents of 1 , 1 '-carbonyldiimidazole of formula (8), producing a mixture of the non-cyclic intermediate 2-((2^)-2-hydroxy-3-(N-(4-(3-oxomorpholin-4-yl)phenyl)- l //-imidazol- l-yl-carboxamido)propyl)-lH-isoindol-l ,3(2H)-dione of formula (16) and the cyclic product of formula (15) that contains more than 50% of the compound (16);

(b) cyclization of the mixture of compounds from step (a) in a solvent or a mixture of solvents suitable for cyclization in the presence of a suitable base as the catalyst;

(c) isolation of the cyclic compound (15).

2. A process for the preparation of the compound (15) according to claim 1 , characterized in that said suitable solvent in step (a) is selected from the group comprising a C to Cs ether, polyethylene glycol, a Ci to C chlorinated solvent or their mixtures in any proportion.

3. A process for the preparation of the compound (15) according to claims 1 and 2, characterized in that said suitable solvent in step (a) is selected from the group comprising tetrahydrofuran, 2-methyltetrahydrofuran, 1 ,4-dioxane, tert- butylmethylether, diterf-butylether, polyethylene glycol PEG-200 to PEG-800, dichloromethane, chloroform, 1 ,1 ,2-trichloroethylene, chlorobenzene or their mixtures in any proportion.

4. A process for the preparation of the compound (15) according to claim 1 , characterized in that said suitable base in step (b) is a metal alkoxide of formula (17),

R-O-M

(17)

wherein R means a linear or branched C_\ to C$ alkyl and M means an alkali metal.

5. A process for the preparation of the compound (15) according to claim 4, characterized in that said suitable base in step (b) is a metal alkoxide selected from the group of sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium isopropoxide, sodium ier/-butoxide, potassium tert-butoxide, lithium tert-butoxide.

6. A process for the preparation of the compound (15) according to claim 1 , characterized in that said suitable base in step (b) is a base selected from the group of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium hydride, methyllithium, n-butyllithium, lithium diisopropylamide or lithium hexamethyldisilazide.

7. A process for the preparation of the compound (15) according to claim 5, characterized in that said suitable base is potassium ter/-butoxide or its solution in an organic solvent, preferably a solution in tetrahydrofuran.

8. A process for the preparation of the compound (15) according to claim 1 , characterized in that said suitable solvent for cyclization in step (b) is selected from the group comprising a C₄ to C₈ ether, polyethylene glycol, a Ci to C6 chlorinated solvent or their mixtures in any proportion.

9. A process for the preparation of the compound (15) according to claim 1 , characterized in that the cyclization in step (b) is carried out at a temperature of from 40°C to the boiling point of the solvent.

10. A process for the preparation of the compound (15) according to claim 1 , characterized in that the isolation in step (c) is carried out by filtering the product from the reaction mixture, washing with a Ci to C5 alcohol and/or water and drying the isolated product.

1 1. Use of the compound (15), prepared by a process according to any one of claims 1 to 10, for the preparation of rivaroxaban (1).