WO2014104904A1

WO2014104904A1 - Process for preparation of bosentan monohydrate of pharmaceutical purity

Info

Publication number: WO2014104904A1
Application number: PCT/PL2013/000173
Authority: WO
Inventors: Katarzyna Sidoryk; Wojciech ŁUNIEWSKI; Maria PUCHALSKA; Marta ŁASZCZ; Wioleta Maruszak; Marta KOŚCIUCH
Original assignee: Instytut Farmaceutiyczny
Current assignee: Instytut Farmaceutiyczny
Priority date: 2012-12-30
Filing date: 2013-12-30
Publication date: 2014-07-03
Anticipated expiration: 2015-06-30
Also published as: PL402305A1

Abstract

A process for the preparation of bosentan monohydrate of pharmaceutical purity is characterized by that crude bosentan is suspended in methyl alcohol / dichloromethane mixture at a volume ratio from 8:1 to 1:2, the mixture is stirred at room temperature, crystalline bosentan monohydrate is isolated, dried to constant weight and optionally crystallized to obtain appropriate crystal shape.

Description

Process for preparation of bosentan monohydrate of pharmaceutical purity

Field of the invention The present invention relates to the process for preparation of bosentan monohydrate of pharmaceutical purity.

Background of the invention

Bosentan, 4-tert-butyl-N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2- (pyrimidin-2-y l)pyrimidin-4-yl] benzene- 1 -sulfonamide, is an orally active dual endothelin-A and -B receptor (ETA/ETB) antagonist. Bosentan is indicated in Europe for the treatment of pulmonary arterial hypertension (PAH) to improve exercise capacity and symptoms in patients with WHO functional class III (with efficacy shown in primary (idiopathic and heritable) PAH, PAH secondary to scleroderma without significant interstitial pulmonary disease, and PAH associated with congenital systemic- to-pulmonary shunts and Eisenmenger's physiology), and also indicated to reduce the number of new digital ulcers in patients with systemic sclerosis and ongoing digital ulcer disease [Mealy, N. E. et al., Drugs Future 2001, 26, 1149; Thomson Reuters Cortellis].

Both bosentan as well as the syntheses thereof have been described in the European Patent Application EP 0526708 Al. The key steps of one of the synthetic variants, depicted in Scheme 1 below, are the condensation of dichloropyrimidine derivative (1) and tert-butyl benzenesulfonamide (2) to block susceptible to substitution chlorine atom. The resulting monochloro derivative of N-pyrimidinesulfonamide (3) is subsequently transformed into bosentan due to condensation with ethylene glycol in the presence of metallic sodium.

Numerous modifications of the aforementioned method have been disclosed in some publications and patent applications. Condensation of dichloropyrimidine derivative (1) and tert-butyl benzenesulfonamide (2) carried out in the presence of different bases, eg. K₂C0₃ and either BnNEt₃Cl or Bv^NBr in toluene under reflux, K₂C0₃ in the absence of phase transfer catalyst in toluene or MeCN, or in DMSO either in the presence or absence of K₂C0₃, have been disclosed in EP 0526708 Al. Substitution with ethylene glycol anion was also carried out by means of the bases such as NaOH in boiling THF, optionally in the presence of 18-crown-6, or t-BuONa, t- BuOK, NaOMe or NaH in THF under reflux. One of the drawbacks of this synthetic approach is that said synthesis leads to the formation of abundant reaction by-products such as bis-sulfonamide derivative (6), i.e. the product of the reaction between two molecules of sulfonamidic derivative and one molecule of ethylene glycol. Said by-product, named 'dimer', is difficult to remove. In addition, following the synthetic pathway disclosed in EP 0526708 Al (temperature range between 100-110°C, excess of ethylene glycol, metallic sodium) bosentan of low chemical purity is obtained. According to the Inventors of International Patent Application published as WO 2009/004374, purity of synthesized bosentan was assessed at the level of barely 69-73%, and the attempts of its purification by means of column chromatography led to further decrease of total yield to 30-40%. Such a dramatic yield drop under the employed conditions resulted from degradation of bosentan to the so called 'deshydroxyethyl bosentan' (7), the by-product which has been disclosed in WO 2009/093127 description.

Bosentan obtained according to the procedure disclosed in EP 0526708 A requires multiple and elaborate crystallization processes. Authors of "Research and Development of a Second-Generation Process for Bosentan, an Endothelin Receptor Antagonist" in Org. Proc. Res. Dev., 2002, 6 (2), 120-124 report, to decrease the amount of impurities, such as dimer and pyrimidinon to the level accepted for active pharmaceutical ingredient, three subsequent crystallizations are necessary to be carried out, two of them in methyl alcohol : isopropyl acetate and one in ethyl alcohol : water mixtures. Unfortunately, none analytical data concerning reduction of impurities level can be found in the said publication. The authors claim, purity of the product obtained under disclosed protocol accounts for 99.3% (HPLC), except for identified impurities it contains also unidentified ones up to 0.2%. This purity is too low for the compound to be accepted as the active pharmaceutical ingredient. According to European Medicines Agency guidelines (European Medicines

Agency) authorized by International Conference on Harmonisation, Harmonised Tripartite Guideline. Q3A(R2), Impurities in new drug substances, and Q3C(R4), Impurities: Guideline for Residual Solvents, approved in Geneva in 2006, active pharmaceutical ingredient must fall into line with the particular recommendations regarding purity, which means, the content of impurities and residual solvents cannot exceed acceptable limits. For the pharmaceutical substances, which are not disclosed in monographs of European Pharmacopoeia, acceptable content of a single identified impurity is <0.15% and of an unidentified impurity is <0.10%.

In the International Patent Application WO 2009/093127 modified synthetic approach has been disclosed. To reduce the level of bosentan impurities, the substitution of N-pyrimidinylsulfonamide monochloro derivative (3) with ethylene glycol was carried out in the presence of NaOH at 92-97°C for 5 h. This process yielded crude bosentan of as high purity as 99.11% (Impurity 7 - 0.35%, Impurity 6 - 0.2%). Owing to subsequent crystallization in methyl alcohol / ethyl acetate, bosentan of 99.94% purity was obtained. The main drawback of this methodology is low yield of the final product in comparison with yield of the process disclosed in EP 0526708 Al. In addition, as has been reported in the International Patent Application WO 2011/024056, bosentan synthesized in the presence of sodium hydroxide contained higher amount of dimer (6) by-product, reaching up to 0.34%.

In the process described in WO 2010/032261, substitution reaction was carried out under similar conditions to those revealed in EP 0526708 Al, except the amount of metallic sodium used was reduced from about 10 to 2.4 equivalents in relation to the amount of the substrate. The synthesis was performed at 100°C for 27-30 h to furnish the product of 95.66% purity. Subsequent crystallization in methyl alcohol / isopropyl acetate mixture (1 : 1) yielded bosentan of 97.8% purity, and the subsequent crystallization in ethyl alcohol / water mixture yielded the product of 99.13% purity. The level of impurities in such a way purified compound still exceeds limits acceptable for pharmaceutical substance.

Bosentan purification to remove the aforementioned impurities is also the subject of International Patent Application published as WO 2011/021216. Said process comprises multiple crystallization of crude bosentan in the mixtures of solvents including, among others, methyl alcohol / ethyl acetate, and methyl alcohol / ethyl acetate / water. The final product of 99.85% purity is obtained, but in only 40% yield of crystallization process.

According to the alternate approach, referred to as second generation synthesis, bosentan is obtained by condensation of N-pyrimidinylsulfonamide monochloro derivative (3) with tert-butyl ethylene glycol ether in the presence of NaOH in toluene, followed by treatment of tert-butyl bosentan ether, as an intermediate, with formic acid at 85-90°C in toluene and subsequent hydrolysis of the formate derivative (NaOH in H₂0) (Org. Proc. Res. Dev., 2002, 6 (2), 120-124).

In this process, after one crystallization in ethyl alcohol-water mixture, the final product is obtained in 99.7% yield, but deprotection of bosentan formate makes the total synthesis one step longer in comparison with the first generation one.

Thus, there is still a need in the art for a technological process based on simple and effective purification methods, which will provide bosentan of purity accepted by the demands approved for active pharmaceutical ingredients. Description of the invention

The present invention relates to the process for preparation of bosentan of pharmaceutical purity due to purification of crude bosentan, obtained from dichloro pyrimidine . in the two-step synthesis, comprising formation of N- pyrimidinylsulfonamide monochloro derivative, transforming the intermediate into bosentan in the reaction with ethylene glycol anion generated in presence of metallic sodium.

Crude bosentan, synthesized under said protocol, is contaminated with three main impurities of identified chemical structures. They are known as, 'deshydroxy ethyl bosentan' (7), 'dimer' (6) and the substrate of the last synthetic step - N- pyrimidinylsulfonamide monochloro derivative (3). In particular, both first mentioned by-products appear to hamper purification of the final product and obtaining bosentan of pharmaceutical purity.

Excess of sodium, temperature and reaction time are the key reaction parameters, which quantitatively influence formation of the by-product (7). The impurity (7) is the degradation product of bosentan, which forms under basic conditions. Sudden increase of this impurity is detected after completion of the reaction, when bosentan molecule decomposition occurs. The formation of the other impurity, ie. 'dimer', is influenced mainly by excess of glycol and sodium used in the reaction.

The term 'crude' when used herein, refers to bosentan of purity higher than 97%, containing less than 1% of any single impurity assessed by HPLC analysis.

To obtain crude bosentan of the said purity profile, the reaction parameters such as the amount of metallic sodium, temperature and reaction time were optimized by means of HPLC monitoring of the last synthetic step. To find optimal reaction conditions, low level of the impurities as well as reaction time were mainly considered.

In the preferred embodiment of the invention, crude bosentan of demanded purity is obtained in the reaction of 4-(tert-butyl)-N-(6-chloro-5-(2-methoyphenoxy)- [2,2'-bipyrimidin]-4-yl)-benzenesulfonamide and sodium glycolate, which is generated from ethylene glycol and 10-fold molar excess of sodium, at 70-75°C for 3-5 h. More preferably, at first sodium glycolate is generated at room temperature, then 4-(tert- butyl)-N-(6-chloro-5-(2-methoxyphenoxy)-[2,2'-bipyrimidin]-4-yl)-benzenesulfonamide is added and the resulting mixture is heated at reaction temperature.

Process for preparation of bosentan monohydrate of pharmaceutical purity according to the present invention is characterized by that crude bosentan is suspended in methyl alcohol : dichloromethane mixture at volume ratio from 8: 1 to 1 :2, the suspension is stirred at room temperature, crystalline bosentan monohydrate is isolated, dried to constant weight and optionally subjected to additional crystallization step to obtain appropriate crystal shape.

The term 'room temperature' relates to the temperature ranging from 15 to 30°C, for example from 20 to 25°C.

In the preferred embodiment of the invention, crude bosentan is suspended in methyl alcohol : dichloromethane mixture at volume ratio 5:1. Stirring the suspension, so called 'maceration' process, is continued at room temperature for 24 h.

The ratio of the solvents mixture volume in relation to the amount of crude bosentan subjected to maceration ranges from 2: 1 to 10:1, preferably is about 6: 1 (v/w), which is far less in comparison with the amounts of solvents used under standard crystallization protocols.

Maceration process is carried out once or, preferably, twice. The best mode of realization of the present invention involves the different variants.

According to one variant of the invention, crude bosentan as a solid is treated with previously prepared mixture of solvents.

According to another variant of the invention, crude bosentan as a solid is added into previously prepared mixture of solvents.

According to another variant of the invention, crude bosentan as a solid is treated with methyl alcohol, the resulting mixture is stirred for a short period of time, for example for ca. 1 h, to this mixture dichloromethane is added to obtain the mixture of solvents of appropriate ratio, and then stirring is continued for a certain period of time, for example for ca. 23 h.

Bosentan, the reaction product of 4-(tert-butyl)-N-(6-chloro-5-(2- methoxyphenoxy)-[2,2'-bipyrimidin]-4-yl)-benzenesulfonamide and sodium glycolate, crystallizes in form of monohydrate, forming monoclinic lattice system, with crystals belonging to P2_!/c space group. The basic parameters of bosentan monohydrate crystalline structure are collected in Table 1, and its crystalline structure is depicted on Fig. 2.

Table 1. X-ray structural data collected for bosentan monohydrate

Molecular formula C₂₇H₂₉N₅0₆S'H₂0

Molecular weight 569,63

Temperature of measurement, 100(2)

Wave length, A 0,71073

Lattice system Monoclinic

Space group P 2i/c

Parameters of the unit cell, A a = 12,3442(12); b = 15,1329(14);

c = 14,6450(14),

α = γ = 90°, β = 95,215(2)° Unit cell volume, A³ 2724,4(6)

Number of molecules in the unit cell, Z 4

Density (calculated), Mg/m³ 1 ,389

Bosentan monohydrate molecules are joined together, forming chains propagated along c axis. Water molecule is joined with two bosentan molecules through three hydrogen bonds: N(1)-H(1)...0(1S), 0(1S)-H(1S)...N(5)#2, 0(1S)-H(2S)...0(2). In two first mentioned bonds, water is the proton donor, but in the third one water is the proton acceptor. There are two other hydrogen bonds joining two bosentan molecules 0(3)- H(3)...N(7)#1, 0(3)-H(3)...N(5)#l, which are longer and account for respectively 3,3144(16) and 3,1354(15). The data of hydrogen bonding geometry are collected in Table 2. Table 2. Hydrogen bounding geometry of bosentan monohydrate, (A)

Symmetry code: #1 -x,-y+l,-z+l #2 x,-y+l/2,z-l/2

It turned out that purification of crude bosentan by maceration according to the present invention does not affect crystalline structure of bosentan monohydrate, but it influences the shape of the obtained crystals. The analysis of crystal shape and particle size distribution by laser diffraction technique proves that particles formed due to maceration of crude bosentan monohydrate in methyl alcohol / dichloromethane system tend to be smaller in size than in case of crystallization under standard conditions in ethyl alcohol / water. The comparison analysis of volume particle size distribution is presented in Table 3.

Table 3. Volume particle size distribution of bosentan monohydrate

Particle size distribution of bosentan monohydrate obtained by the process according to the present invention is depicted on Fig. 4.

Bosentan monohydrate obtained by maceration has volume moment mean D[4,3] at range 50 - 60 μη , median particle size d(0.5) about 35 μπι, wherein 10% of particles have diameter below 15 μπι, and 90% below 100 μπι.

Bosentan monohydrate of small particles size enhances its bioavailability in vivo, and also facilitates manufacturing process of solid dosage forms, allowing to avoid additional operations such as grinding or micronization of active pharmaceutical ingredient. Depending on a type of a dosage form to be produced, bosentan monohydrate purified by maceration can be optionally subjected to micronization. Both grinding and micronization techniques as well as crystal size analysis are well known to those skilled in the art. Upon grinding in a ball mill for instance, particles of size not smaller than 30-40 μιη are usually obtained. When micronizing in a conical mill or in a mill with fluidal beads, in a ball mill, colloidal or jet mill or by spray drying, reduction of particle size to less than 10 μπι can be achieved.

In the preferred variant of the invention, bosentan monohydrate of purity and particle size distribution meeting the requirements for active pharmaceutical ingredients is obtained directly by maceration, air drying to constant weight at room temperature, preferably at 22 ± 2°C. Optionally, if required, bosentan monohydrate can be crystallized in ethyl alcohol / water mixture. It has been proved experimentally that additional crystallization does not increase purity of the product, and only influences formation of crystals of different shape comparing with those obtained by maceration.

Bosentan monohydrate obtained by maceration according to the present invention is characterized by X-ray powder diffraction pattern (XRPD) measured on diffractometer equipped with the copper anode of Kot λ = 1,54056 A wave length, represented as relative intensities of diffraction peaks I I₀, diffraction angles 2Θ and interplanar distances d, with scanning range from 3 to 40°, scanning rate 0,5°/min and step size 0,02°. The data are collected in Table 4.

Table 4. X-Ray powder diffraction pattern of bosentan monohydrate

3.656 24.32 25

3.582 24.83 23

3.461 25.72 18

3.350 26.58 24

3.260 27.33 22

3.191 27.94 21

Exemplary XRPD pattern of bosentan monohydrate obtained according to the present invention is depicted on Fig. 5.

Infrared spectrum of bosentan mono ydrate obtained according to the present invention, determined in KBr tablet, is depicted on Fig. 6.

On Fig. 7, TG curve obtained from thermogravimetric (TGA) analysis (TGA, full line) under dynamic heating regime ranging from 30°C to 180°C at heating rate 10°C/min, and SDTA curve (Single Differential Thermal Analysis, broken line) are depicted. On TGA the effect of mass loss at temperature range from 30°C to about 170°C is observed. Comparison of the effects shown on TGA and SDTA curves indicates, the first effect is attributed to evaporation of superficially absorbed solvent and the base line sloping down reflects melting and concomitant decomposition of the sample. Loss of mass accounts for about 3,13%, this result 3,31% was confirmed by coulometric titration with an oven evaporator and theoretical calculations of water content in the sample. Melting point 104,35°C was determined from SDTA curve.

The present invention provides the method for preparation of bosentan monohydrate in the stable crystalline form, having particles of relatively small diameters and narrow particle size distribution in one simple technological process. Bosentan monohydrate obtained according to the present invention has impurity profile that meets the standards established for active pharmaceutical ingredients. The advantage of purification by maceration in comparison with crystallization is significant reduction of solvents consumption, and thus diminished output of wastes.

The present invention is further illustrated by the following examples. Examples

Analytical methods

> Single-crystal X-ray diffraction Single-crystal structure was determined by X-ray diffraction technique using

BRUKER KAPPA APEXII ULTRA diffractometer equipped with the rotating anode ΜοΚα, (λ = 0.71073 A, 50.0 kV, 22.0 mA), APEX-II CC detector, Oxford Cryostream cooler, at temperature 100 K. Indexing, integration and initial scaling was performed using SAINT and SADABS software. A single crystal was centered 50 mm from CCD camera. 560 Frames were collected in 1° increment, at 20 s per frame exposure time. Crystal structure was elucidated and refined using SHELXS-97 software.

• X-Ray powder diffraction (XRPD) X-Ray powder diffraction pattern was measured on Rigaku MiniFlex diffractometer, with the following parameters:

• Radiation: CuKal , λ=1 ,54056 A

• Scanning range 2D : from 3 to 40°

• Step size: 0,02°

· Scanning rate: 0,5°/min

• Detector: scintillating counter.

• Infrared spectroscopy (IR) IR spectra were performed in pressed KBr tablets, containing about 1,5 mg of tested substance and about 200 mg of KBr, on Nicolet Impact 410 spectrometer at measurement range from 4000 to 400 cm^"1 and 4 cm^"1 resolution.

• Thermogravimetry (TGA) TGA measurements were performed in the furnace sample chamber TGA/SDTA851^e by Mettler Toledo, under following conditions:

Melting pot: aluminum, 40 μΐ. capacity,

Purge gas: N₂, flow rate 60 mL/min,

Measurement conditions: the samples were heated under dynamic regime ranging from 30 to 180 °C at heating rate 10 °C/min,

Samples preparation: the crystalline substances weighting from 5 to 10 mg were placed in the melting pots without prior preparation. The melting pots were air-tight pressed and punctured before the measurement. The empty pot correction was included in the measurements.

On each thermogram the following curves are depicted: TGA (full line) and SDTA (broken line). TGA curve represents the changes of a sample mass as a function of temperature or time. On the differential SDTA curve the effects of solvent evaporation and a substance melting are shown.

• Microscopic and particle size analysis

Particle size distribution was measured by laser diffraction method with particle size distribution analyzer Mastersizer 2000, Malvern and dispersion adapter Hydro 2000S, Malvern. Microscopic visualization was performed with automated microscopic analyzer Morphologi G3s Malvern in diascopic light.

Measurement conditions: Measurement conditions:

Laser diffractions

Device/dispersion adapter Mastersizer 2000 / Hydro 2000S

Malvern

Ultrasound (us) 0% Stirring speed 2100 rounds/min

Dispersion medium Isooctanol

Single measurement time 0.5 s

Background measurement time 10 s

Refraction coefficient of tested particles 1.52

Refraction coefficient of dispersant 1.391

Absorption coefficient 0.01

Obscuration 5-25%

Microscopic analysis

Device/dispersion adapter Morphologi G3S / -, Malvern

Dispersion medium Isooctan

Example 1

Synthesis of 4-(iert-butyi)-N-(6-chloro-5-(2-methoxyphenoxy)-[2,2'-bipyrimidine]- 4-yl)-benzenesulfonamide (3)

349,17 g/mol 213,30 g/mol 526,01 g/mol In a flask equipped with mechanical stirrer, thermometer, reflux condenser, dropping funnel and heating mantle, 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'- bipyrimidine 1 (105 g), 4-(ter/-butyl)benzenesulfonamide 2 (64.1 g, 0.30 mol) in DMSO (525 mL) are placed. To this suspension potassium carbonate (83 g, 0.60 mol) is added. The resulting mixture is heated at 100 - 105°C for 3 - 4 h upon stirring. Reaction progress is monitored by HPLC. The solution is cooled down to 20 -25°C. Water (875 mL) is added dropwise within 10 - 15 min. and stirring is continued for 1 h. Precipitated solid is filtered off, washed with water (2 x 350 mL), then transferred into flask. After addition of water (800 mL) and concentrated hydrochloric acid (50 mL) the solution is stirred for 30 min. The precipitated solid is filtered off , washed with water (2 x 200 mL) and acetone (2 x 175 mL). The solid is dried at 40 ± 2°C for 16 - 24 h under atmospheric pressure. The product is obtained in 157.8 - 158.7 g (100%) yield as cream- colored solid. Example 2

Synthesis of 4-(tert-butyl)-N-(6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-[2,2'- bipy rimidine] -4-y l)benzenesulfonamide (5)

In a 6 L capacity flask equipped with mechanical stirrer, thermometer and reflux condenser ethylene glycol (2.325 L, 41.60 mol) is placed. Metallic sodium (67.8 g, 2.95 mol) is added portionwise upon stirring and maintaining temperature below 40°C. 4- (tert-Butyl)-N-(6-chloro-5-(2-methoyphenoxy)-[2,2'-bipyrimidine]-4-yl)- benzenesulfonamide (3) (155 g, 0.29 mol) obtained in the prior step is added. The mixture is heated at 70-75°C and stirred for 4 - 5 h. Reaction progress is monitored by HPLC. Heating is stopped and the solution is left to cool down to 22 ± 2°C.The solution is transferred into separatory funnel, water (4 L) and acetic acid (320 mL) are added to adjust pH to 5. While stirring the solution for 30 min. suspension is formed. Dichloromethane (1 L) is added and stirring is continued for 15 min. Organic phase is separated and water layer is extracted with dichloromethane (2 x 1 L). Combined organic extracts are condensed under vacuum evaporator. The product is obtained as pale yellow foam, which is dissolved in ethanol (500 mL) at 40 - 45 °C. The clear solution is transferred into 2 L capacity flask, equipped with mechanical stirrer and dropping funnel. After addition of water (500 mL) within 15 min., the resulting mixture is stirred for 60 min. Precipitated solid is filtered off and washed with the mixture of ethanol : water 1 : 1 (2 x 100 mL). The solid is air dried to constant weight at 22 ± 2°C. The product is obtained in 143.6 - 146.8 g (ca. 87%) yield. Example 3. Influence of reaction conditions on the level of crude bosentan purity

An influence of reaction conditions on the crude bosentan purity was investigated. Synthesis was carried out under conditions described in Example 2.

8. 5 70-75 24 97.70 0.90 0.05

9. 5 70-75 22 97.89 0.71 0.15

Example 4

Purification of 4-(icrt-butyl)-N-(6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-[2,2'- bipyrimidine]-4-yI)benzenesuIfonamide (5)

A. First maceration in methanol : dichloromethane 5:1 (v/v) (previously prepared mixture of solvents is added to the solid)

In a 2 L capacity flask equipped with mechanical stirrer, 4-(tert-butyl)-N-(6-(2- hydroxyethoxy)-5-(2-methoxyphenoxy)-[2,2'-bipyrimidine]-4-yl)benzenesulfonamide 5 (146.0 g) obtained in prior step is placed. To this solid, previously prepared mixture of methanol : dichloromethane 5: 1 (876 mL) is added. The resulting mixture is stirred at 22 ± 2°C for 24 h. Precipitated solid is filtered off and washed with methanol (2 x 40 mL). It is air dried at 22 ± 2°C to constant weight. The product is obtained in 115.1 - 128.5 g (79 - 88%) yield as fine-crystalline, yellowish solid.

B. Second maceration in methanol : dichloromethane 5:1 (v/v) (the solid is added into previously prepared solvents mixture)

Methanol (575 mL) and dichloromethane (115 mL) are placed in a 2 L capacity flask equipped with mechanical stirrer. 4-(tert-Butyl)-N-(6-(2-hydroxyethoxy)-5-(2- methoxyphenoxy)-[2,2'-bipyrimidine]-4-yl)benzenesulfonamide 5 (115.0 g) within 10 - 15 min. is added portionwise. The solution is stirred at 22 ± 2 °C for 24 h. The solid is filtered off and washed with methanol (2 x 30 mL). The solid is air dried at 22 ± 2°C to constant weight. The product is obtained in 91.3 - 100.1 g (79 - 87%) yield as fine- crystalline, pale yellow solid.

C. Crystallization in ethanol : water 1:1 (v/v).

4-(tert-Butyl)-N-(6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-[2,2'-bipyrimidine]- 4-yl)benzenesulfonamide 5 (91.0 g) in ethanol (260 mL) is paced in a 500 mL capacity flask equipped with mechanical stirrer, reflux condenser and thermometer. The solution is heated at reflux, until the solid is completely dissolved. Hot solution is filtered, the residue is washed out from the flask with ethanol (2 x 20 mL). The solution is transferred into a 1 L capacity flask equipped with mechanical stirrer and dropping funnel. To the hot mixture water (300 mL) is added dropwise within 15 min., resulting solution is stirred at 22 ± 2°C for 2 h. Precipitated solid is filtered off and washed with ethanol : water 1 :1 (2 x 40 mL). It is air dried at 22 ± 2°C to constant weight. The product is obtained in 87.4 - 90.1 g ( 96 - 99%) yield as white solid.

Claims

1. A process for the preparation of bosentan monohydrate of pharmaceutical purity, characterized by that crude bosentan is suspended in methyl alcohol / dichloromethane mixture at a volume ratio from 8: 1 to 1 :2, the mixture is stirred at room temperature, crystalline bosentan monohydrate is isolated, dried to constant weight and optionally crystallized to obtain appropriate crystal shape.

2. The process according to claim 1 wherein the step of maceration is performed once or twice.

3. The process according to claim 1 wherein crude bosentan is suspended in methyl alcohol / dichloromethane mixture at volume ratio about 5: 1.

4. The process according to claim 1 wherein the volume of solvents mixture in relation to crude bosentan weight is from 2:1 to 10: 1 (v/w).

5. The process according to claim 4 wherein the volume of solvents mixture in relation to crude bosentan weight is about 6: 1 (v/w).

6. The process according to claim 1 wherein the mixture is stirred for ca. 24 h.

7. The process according to any one of claims 1-6 wherein crude bosentan as a solid is treated with the previously prepared mixture of solvents

8. The process according to any one of claims 1-6 wherein crude bosentan as a solid is added to the previously prepared solvents mixture.

8. The process according to any one of claims 1-6 wherein crude bosentan as a solid is treated with methyl alcohol, the resulting suspension is stirred for ca. 1 h, to this mixture dichloromethane is added to achieve said proportions of solvents and stirring is continued for ca. 23 h.

9. The process according to any one of claims 1-8 wherein crude bosentan is obtained in the reaction of 4-(tert-butyl)-N-(6-chloro-5-(2-methoxyphenoxy)-[2,2'- bipyrimidine]-4-yl)benzenesulfonamide and sodium glycolate generated using 10-fold molar excess of metallic sodium.

10. The process according to any one of claims 1-9 wherein crude bosentan is obtained in the reaction of 4-(tert-butyl)-N-(6-chloro-5-(2-methoxyphenoxy)-[2,2'- bipyrimidine]-4-yl)benzenesulfonamide and sodium glycolate carried out at 70-75°C for 3-5 h.

11. The process according to any one of claims 9 or 10 wherein sodium glycolate is generated at room temperature, then 4-(tert-butyl)-N-(6-chloro-5-(2- methoxyphenoxy)-[2,2'-bipyrimidine]-4-yl)-benzenesulfonamide is added and the resulting mixture is heated up to 70-75°C.