WO2023111797A1

WO2023111797A1 - Pyrimidine sulfamide derivatives and process for manufacturing them

Info

Publication number: WO2023111797A1
Application number: PCT/IB2022/062016
Authority: WO
Inventors: Alain Collas; Thierry JOUSSEAUME; Christopher James Nichols; Christopher Paul DE DOBBELAERE
Original assignee: Janssen Biotech, Inc.
Priority date: 2021-12-17
Filing date: 2022-12-09
Publication date: 2023-06-22

Abstract

The present invention relates to a solid form of potassium (5-(4-bromophenyl)-6-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin-4-yl)(sulfamoyl)amide of formula (Ia), a crystalline form thereof, a process for manufacturing each of them, and a process for manufacturing {5-(4-bromo-phenyl)-6-[2-(5 bromo-pyrimidin-2 yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamide of formula (Ib).

Description

PYRIMIDINE SULFAMIDE DERIVATIVES AND PROCESS FOR MANUFACTURING THEM

CROSS REFERENCE TO RELATED APPLICATION

This application claims priority to U.S. Provisional Application No. 63/290,938, filed

December 17, 2021. The disclosure is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to a solid form of potassium (5-(4-bromophenyl)-6-(2-((5- bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin-4-yl)(sulfamoyl)amide of formula (la),

a crystalline form thereof, a process for manufacturing each of them, and a process for manufacturing {5-(4-bromo-phenyl)-6-[2-(5 bromo-pyrimidin-2 yloxy)-ethoxy]-pyrimidin- 4-yl}- sulf amide of formula (lb)

BACKGROUND

Aprocitentan, {5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin- 4-yl}- sulfamide has the formula lb, and is also known under the name ACT- 132577. It is an endothelin receptor inhibitor and useful as endothelin receptor antagonist. The compound of formula lb is a member of a structural family that was previously generically disclosed in WO 02/053557. In particular, the compound of formula lb, while showing endothelin receptor antagonist activity, exhibits in vivo a much longer half-life and a much shorter clearance in comparison to corresponding alkylated derivatives. This makes the compound of formula lb particularly suitable for long-acting pharmaceutical compositions, as disclosed in WO 2009/024906. Certain manufacturing processes relating to aprocitentan are disclosed in W02009/024906 and WO2015/121397. W02018/154101 discloses crystalline forms of aprocitentan, as well as processes to prepare them.

Because of its ability to inhibit the endothelin binding, aprocitentan can be used for the treatment of endothelin related diseases which are associated with an increase in vasoconstriction, proliferation or inflammation due to endothelin. Examples of such endothelin related diseases are hypertension, pulmonary hypertension, coronary diseases, cardiac insufficiency, renal and myocardial ischemia, renal failure, cerebral ischemia, dementia, migraine, subarachnoidal hemorrhage, Raynaud’s syndrome, digital ulcers and portal hypertension. They can also be used in the treatment or prevention of chronic kidney disease (CKD), diabetes, diabetic nephropathy, diabetic retinopathy, diabetic vasculopathy, chronic heart failure and diastolic dysfunction. They can further be used in the treatment or prevention of atherosclerosis, restenosis after balloon or stent angioplasty, inflammation, stomach and duodenal ulcer, cancer, melanoma, prostate cancer, prostatic hypertrophy, erectile dysfunction, hearing loss, amaurosis, chronic bronchitis, asthma, pulmonary fibrosis, gram negative septicemia, shock, sickle cell anemia, glomerulonephritis, renal colic, glaucoma, connective tissue diseases, therapy and prophylaxis of diabetic complications, complications of vascular or cardiac surgery or after organ transplantation, complications of cyclosporin treatment, pain, hyperlipidemia as well as other diseases, presently known to be related to endothelin.

According to WO2015/121397, the compound of formula (lb) is prepared by the following one -pot process:

^b

Thereby, the halide of formula (a) or (b) is reacted with sulfamide in a polar aprotic organic solvent or a polar mixture of aprotic organic solvents in the presence of a base, whereby the base is selected from the group consisting of NaOH, KOH, 1,8- diazabicyclo[5.4.0]undec-7-ene, triethylamine, potassium /erZ-butylate, Na2COs, K2CO3 and CS2CO3. The polar aprotic organic solvent is selected from the group consisting of MeCN, chlorobenzene, iPrOAc, THF, NMP, dioxane, DMAC, DME, DMF, DMSO, sulfolane or a mixture of two solvents. The temperatures for the sulfamidation preferably range from 60°C to 80°C and are exemplified in ranges of 70°C to 75°C. Workup is achieved under acidic conditions using 20% to 40% citric acid or IM H2SO4 for obtaining aprocitentan (lb), or by adding citric acid. W02018/154101 in particular describes multiple crystalline forms of aprocitentan, i.e. the compound of formula (lb). The processes disclosed therein are similar to the one-pot reaction of WO2015/121397, including a process applicable for the production of aprocitentan in multi-kilogram scale. As may be seen from W02018/154101, many different solid forms such as different crystal forms or solvate forms of aprocitentan are known. It is important however to control the process for obtaining the desired specific crystal form, which is not trivial. Moreover, aprocitentan has a high tendency to form solvates. Therefore, the choice of solvents in the manufacturing process is very difficult in order to avoid undesired solvates. Besides this, the manufacturing process faces an important safety aspect because if DMSO is used as solvent, it can decompose under basic conditions, which results in a narrow safety margin for temperatures of 70 to 75°C as used in the multi-kilogram process known from W02018/154101. In particular large scale processes require the possibility to control crystal form and solvate form of the product. If such control is insufficient, a complete production batch may require expensive and time consuming additional workup, or may even be discarded. Moreover, the safety aspect becomes more and more important, the larger the scale of the production becomes.

SUMMARY OF THE INVENTION

It is therefore the object of the present invention to provide a robust, safe and efficient process for the manufacturing of aprocitentan. In particular, it is an object to provide a process for the manufacturing of aprocitentan which robustly leads to the desired crystalline form of aprocitentan. Moreover, the occurance of undesired side products should be avoided, i.e. a high purity is achieved.

In a first aspect, the invention relates to a solid form of potassium (5-(4-bromophenyl)-6-(2- ((5-bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin-4-yl)(sulfamoyl)amide of formula (la):

In a second aspect, the invention relates to crystalline forms thereof.

In a third aspect, the invention relates to a process for manufacturing the solid form of potassium (5-(4-bromophenyl)-6-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin-4- yl)(sulfamoyl)amide of formula (la), said process comprising the reaction of 5-(4- bromophenyl)-4-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)-6-fluoropyrimidine of formula (a)

with sulfamide, in the presence of K2CO3, and isolating the compound of formula (la) in solid form.

In a fourth aspect, the invention relates to the use of the solid form of potassium (5-(4- bromophenyl)-6-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin-4-yl)(sulfamoyl)amide of formula (la) for the manufacture of aprocitentan, i.e. {5-(4-bromo-phenyl)-6 [2 (5 bromo- pyrimidin-2 yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamide of formula (lb)

lb. In a fifth aspect, the invention relates to a process for manufacturing aprocitentan, comprising the step of reacting the solid form of potassium (5-(4-bromophenyl)-6-(2-((5- bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin-4-yl)(sulfamoyl)amide of formula (la) with acid in a mixture of water and an organic solvent.

CERTAIN EMBODIMENTS

1. A solid form of potassium (5-(4-bromophenyl)-6-(2-((5-bromopyrimidin-2- yl)oxy)ethoxy)pyrimidin-4-yl)(sulfamoyl)amide of formula (la):

2. The solid form of potassium (5-(4-bromophenyl)-6-(2-((5-bromopyrimidin-2- yl)oxy)ethoxy)pyrimidin-4-yl)(sulfamoyl)amide of formula (la) according to Embodiment

1, which is a crystalline form.

3. The solid form of potassium (5-(4-bromophenyl)-6-(2-((5-bromopyrimidin-2- yl)oxy)ethoxy)pyrimidin-4-yl)(sulfamoyl)amide of formula (la) according to Embodiment

2, which is characterized by an X-ray powder diffraction pattern with at least four peaks, or at least six peaks, or at least eight peaks having an angle of refraction 29 (2theta) values selected from: 9.3°, 9.6°, 10.6°, 15.6°, 16.0°, 18.2°, 19.3°, 20.7°, 21.3°, 21.8°, 22.9°, 24.1°, or 24.4° 2theta; wherein said X-ray powder diffraction diagram is obtained by using Cu Ka radiation; and the accuracy of the 29 (2theta) values is in the range of 29 +/- 0.2° (2theta +/- 0.2°).

4. The solid form of potassium (5-(4-bromophenyl)-6-(2-((5-bromopyrimidin-2- yl)oxy)ethoxy)pyrimidin-4-yl)(sulfamoyl)amide of formula (la) according to Embodiment 2, which is characterized by an X-ray powder diffraction pattern with at least four peaks, or at least six peaks, or at least eight peaks having angle of refraction 29 (2theta) values selected from: 8.0°, 10.4°, 12.0°, 15.1°, 17.5°, 18.4°, 21.5°, 22.6°, 24.8°, 26.4°, or 28.7° 2theta; wherein said X-ray powder diffraction diagram is obtained by using Cu Ka radiation; and the accuracy of the 29 (2theta) values is in the range of 29 +/- 0.2° (2theta +/- 0.2°).

5. Process for manufacturing a solid form of potassium (5-(4-bromophenyl)-6-(2-((5- bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin-4-yl)(sulfamoyl)amide of formula (la)

la , said process comprising the reaction of 5-(4-bromophenyl)-4-(2-((5-bromopyrimidin-2- yl)oxy)ethoxy)-6-fluoropyrimidine of formula (a)

with sulfamide, in the presence of K2CO3, and optionally water, in a polar aprotic organic solvent, at a temperature below 80°C, and isolating the compound of formula la in solid form.

6. The process according to Embodiment 5, wherein the polar aprotic organic solvent is DMSO.

7. The process according to Embodiments 5 or 6, wherein seed crystals of the crystalline form of potassium (5-(4-bromophenyl)-6-(2-((5-bromopyrimidin-2- yl)oxy)ethoxy)pyrimidin-4-yl)(sulfamoyl)amide according to Embodiment 3 or Embodiment 4 are added.

8. Potassium (5-(4-bromophenyl)-6-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)- pyrimidin-4-yl)(sulfamoyl)amide of formula (la) obtainable by the process steps of any one of Embodiments 5 to 7.

9. Use of the solid form of potassium (5-(4-bromophenyl)-6-(2-((5-bromopyrimidin-2- yl)oxy)ethoxy)pyrimidin-4-yl)(sulfamoyl)amide of formula (la) according to any one of Embodiments 1 to 4 in a process for manufacturing {5-(4-bromo-phenyl)-6 [2 (5 bromo- pyrimidin-2 yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamide of formula (lb)

lb.

10. A process for manufacturing {5-(4-bromo-phenyl)-6 [2 (5 bromo-pyrimidin-2 yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamide of formula (lb)

lb wherein the solid form of potassium (5-(4-bromophenyl)-6-(2-((5-bromopyrimidin-2- yl)oxy)ethoxy)pyrimidin-4-yl)(sulfamoyl)amide of formula (la) according to any one of Embodiments 1 to 4 is reacted with acid in a mixture of water and an organic solvent.

11. The manufacturing process according to Embodiment 10, wherein the acid is hydrochloric acid.

12. The manufacturing process according to Embodiment 11, wherein hydrochloric acid is added in amount of 1.02 to 1.5 equivalents (calculated in mol/mol, based on amout of potassium (5-(4-bromophenyl)-6-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)-pyrimidin-4- yl)(sulfamoyl)amide), preferably from 1.05 to 1.2 equivalents.

13. The manufacturing process according to any one of Embodiments 10 to 12, wherein the organic solvent is methyl-ethyl ketone.

14. The manufacturing process according to any one of Embodiments 10 to 13, wherein seed crystals of {5-(4-bromo-phenyl)-6 [2 (5 bromo-pyrimidin-2 yloxy)-ethoxy]-pyrimidin- 4-yl}- sulf amide of formula (lb) are added, characterized by an X-ray powder diffraction pattern with at least four peaks, or at least six peaks, or at least eight peaks having an angle of refraction 29 (2theta) values selected from: 9.8°, 9.9°, 11.7°, 14.5°, 15.4°, 15.6°, 16.9°, 17.2°, 17.8°, 18.6°, 19.9°, 20.0°, 21.5°, 21.9°, 22.8°, 23.2°, 23.5°, 24.9°, 25.1°, 25.3°, 25.6°, 25.9°, 27.1°, 27.3°, 28.5°, 29.0°, 29.4°, 30.1° and 30.6°; wherein said X-ray powder diffraction diagram is obtained by using combined Cu Kai and Ka2 radiation, without Ka2 stripping; and the accuracy of the 29 values is in the range of 29 +/- 0.2°.

BRIEF DESCRIPTION OF THE FIGURES

Description of the Figures:

Figure 1 shows the X-ray powder diffraction diagram of crystalline Form A of potassium (5-(4-bromophenyl)-6-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin-4- yl)(sulfamoyl)amide of formula (la).

Figure 2 shows the TGA and DSC of crystalline Form A of potassium (5-(4- bromophenyl)-6-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin-4-yl)(sulfamoyl)amide of formula (la).

Figure 3 shows the X-ray powder diffraction diagram of crystalline Form B of potassium (5-(4-bromophenyl)-6-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin-4- yl)(sulfamoyl)amide of formula (la).

Figure 4 shows the TGA and DSC of crystalline Form B of potassium (5-(4- bromophenyl)-6-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin-4-yl)(sulfamoyl)amide of formula (la).

Figure 5 shows the X-ray powder diffraction diagram of crystalline Form A of aprocitentant, i.e. {5-(4-bromo-phenyl)-6 [2 (5 bromo-pyrimidin-2 yloxy)-ethoxy]- pyrimidin-4-yl} -sulfamide of formula (lb).

DETAIEED DESCRIPTION

The present inventors have surprisingly found process conditions that could increase the safety margin without lowering efficieny of the manufacturing process. The occurance of undesired side -products could be reduced. Moreover, a significant advantage of splitting the final process step into two steps resulted in a better control of the desired form of the end product aprocitentan in respect of crystal form and avoding solvates, as well as less residual solvent content.

Various embodiments of the invention are presented hereafter.

The invention firstly relates to a solid form of potassium (5-(4-bromophenyl)-6-(2-((5- bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin-4-yl)(sulfamoyl)amide of formula (la):

It is understood that the solid form of potassium (5-(4-bromophenyl)-6-(2-((5- bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin-4-yl)(sulfamoyl)amide of formula (la) may comprise non-coordinated and / or coordinated solvent. Coordinated solvent is used herein as term for a crystalline solvate. Likewise, non-coordinated solvent is used herein as term for physiosorbed or physically entrapped solvent (definitions according to Polymorphism in the Pharmaceutical Industry (Ed. R. Hilfiker, VCH, 2006), Chapter 8: U.J. Griesser: The Importance of Solvates).

In one embodiment, the solid form of potassium (5-(4-bromophenyl)-6-(2-((5- bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin-4-yl)(sulfamoyl)amide of formula (la) is a crystalline form.

In one embodiment, the solid or crystalline form of potassium (5-(4-bromophenyl)-6-(2- ((5-bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin-4-yl)(sulfamoyl)amide of formula (la) is a solvate, for instance a solvate with water or DMSO. Preferably, the solid form of potassium (5-(4-bromophenyl)-6-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin-4- yl)(sulfamoyl)amide of formula (la) is a solvate with water, more preferably a monohydrate.

In one embodiment, the crystalline form of potassium (5-(4-bromophenyl)-6-(2-((5- bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin-4-yl)(sulfamoyl)amide of formula (la) relates to Form A having an X-ray powder diffraction pattern with at least four peaks, or at least six peaks, or at least eight peaks having angle of refraction 29 (2theta) values selected from: 9.3°, 9.6°, 10.6°, 15.6°, 16.0°, 18.2°, 19.3°, 20.7°, 21.3°, 21.8°, 22.9°, 24.1°, or 24.4° 2theta; wherein said X-ray powder diffraction diagram is obtained by using Cu Ka radiation; and the accuracy of the 29 (2theta) values is in the range of 29 +/- 0.2° (2theta +/- 0.2°). In certain embodiments, crystalline Form A is characterized as comprising the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 29: 10.6°, 16.0°, and 24.4°; or in certain embodiments 10.6°, 16.0°, 20.7°, 24.1°, and 24.4°.

Specifically, crystalline Form A shows an X-ray powder diffraction diagram with the following peaks and their relative intensity given in parenthesis: 9.3° (6.8%), 9.6°(18.9%), 10.6° (86.0%), 15.6° (27.2%), 16.0° (72.7%), 18.2° (18.6%), 19.3° (25.5%), 20.7° (64.2%), 21.3° (49.6%), 21.8° (33.3%), 22.9° (17.4%), 24.1° (52.3%), or 24.4° (100%) 2theta, wherein said X-ray powder diffraction diagram is obtained by using Cu Ka radiation; and the accuracy of the 29 (2theta) values is in the range of 29 +/- 0.2° (2theta +/- 0.2°). The X-ray powder diffraction diagram is shown in Figure 1.

The present data show peaks having a relative intensity, as compared to the most intense peak in the diagram, of the following percentages (relative peak intensitites given in parentheses) at the indicated angles of refraction 2theta (selected peaks from the range 2-42° 2theta with relative intensity larger then 6% are reported).

Crystalline Form A in particular is a monohydrate. The TGA and DSC are shown in Figure 2. Karl Fischer titration confirmed that Form A is a monohydrate.

In one embodiment, the crystalline form of potassium (5-(4-bromophenyl)-6-(2-((5- bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin-4-yl)(sulfamoyl)amide of formula (la) relates to Form B having an X-ray powder diffraction pattern with at least four peaks, or at least six peaks, or at least eight peaks having angle of refraction 29 (2theta) values selected from: 8.0°, 10.4°, 12.0°, 15.1°, 17.5°, 18.4°, 21.5°, 22.6°, 24.8°, 26.4°, or 28.7° 2theta; wherein said X-ray powder diffraction diagram is obtained by using Cu Ka radiation; and the accuracy of the 29 (2theta) values is in the range of 29 +/- 0.2° (2theta +/- 0.2°). In certain embodiments, crystalline Form B is characterized as comprising the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 29: 8.0°, 22.6°, and 24.8°; or in certain embodiments 8.0°, 18.4°, 22.6°, 24.8°, and 28.7°. Specifically, crystalline Form B shows an X-ray powder diffraction diagram with the following peaks and their relative intensity given in parenthesis: 8.0° (59.1%), 10.4° (15.4%), 12.0° (9.3%), 15.1° (12.1%), 17.5° (42.6%), 18.4° (47.4%), 21.5° (21.7%), 22.6° (55.6%), 24.8° (100%), 26.4° (40.4%), or 28.7° (44.8%) 2theta, wherein said X-ray powder diffraction diagram is obtained by using Cu Ka radiation; and the accuracy of the 29 (2theta) values is in the range of 29 +/- 0.2° (2theta +/- 0.2°). The X-ray powder diffraction diagram is shown in Figure 3.

The present data show peaks having a relative intensity, as compared to the most intense peak in the diagram, of the following percentages (relative peak intensitites given in parentheses) at the indicated angles of refraction 2theta (selected peaks from the range 2- 42° 2theta with relative intensity larger then 9% are reported).

Crystalline Form B in particular is a DMSO solvate. The TGA and DSC are shown in Figure 4.

A preferred crystalline form of potassium (5-(4-bromophenyl)-6-(2-((5-bromopyrimidin-2- yl)oxy)ethoxy)pyrimidin-4-yl)(sulfamoyl)amide of formula (la) is Form A.

Moreover, the invention relates to a process for manufacturing a solid form of potassium (5-(4-bromophenyl)-6-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin-4- yl)(sulfamoyl)amide of formula (la)

la said process comprising the reaction of 5-(4-bromophenyl)-4-(2-((5-bromopyrimidin-2- yl)oxy)ethoxy)-6-fluoropyrimidine of formula (a)

with sulfamide (H2NSO2NH2), in the presence of K2CO3, and optionally water, in a polar aprotic organic solvent, at a temperature below 80°C, and isolating the compound of formula la in solid form. The obtained solid form of the compound of formula la may be dried. The polar aprotic organic solvent is selected from the group consisting of MeCN, chlorobenzene, iPrOAc, THF, NMP, dioxane, DMAC, DME, DMF, DMSO, sulfolane or a mixture of two or more of said solvents.

In one embodiment of this manufacturing process, the reactor is charged first with the polar aprotic organic solvent, sulfamide is added, followed by K2CO3, optionally water is added, and finally the compound of formula (a).

In one embodiment, the polar aprotic organic solvent is DMSO.

It is preferred to set the reaction temperature below 50°C in order to obtain a good safety window, in particular when using DMSO as a polar organic solvent. Preferably, the temperature is from 40°C to <50°C, more preferably 45°C ±3°C, or 45°C ±2°C.

In one embodiment of the manufacturing process, sulfamide (H2NSO2NH2) may be used in an amount of 1.7 to 2.3 equivalents (calculated in mol/mol, based on amout of starting material 5-(4-bromophenyl)-4-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)-6- fluoropyrimidine as reference), preferably in an amount of 1.8 to 2.2 equivalents, and more preferably in an amount of 2 equivalents ±5% per equivalent of the compound of formula (a) (mol/mol).

The amount of K2CO3 used in the manufacturing process is not particularly limited, in particular the upper limit is not particularly limited. In one embodiment of the manufacturing process, K2CO3 is used in an amount of 2 to 15 equivaltens, of 2 to 10 equivaltens, or of 2.5 to 7.5 equivalents based on K2CO3 anhydride (calculated in mol/mol, based on amout of starting material 5-(4-bromophenyl)-4-(2-((5-bromopyrimidin-2- yl)oxy)ethoxy)-6-fluoropyrimidine as reference), preferably in an amount of 3 to 7 equivalents, in an amount of 3 to 6 equivalents, in an amount of 4 to 6 equivalents and more preferably in an amount of 5 equivalents ±10%, even more preferably 5 equivalents ±5% per equivalent of the compound of formula (a) (mol/mol). The use of more than 4 equivalents, for instance 4 to 15 equivalents, or 4 to 10 equivalents, or 4 to 6 equivalents, and more preferably in an amount of 5 equivalents ±10%, even more preferably 5 equivalents ±5% per equivalent of the compound of formula (a) (mol/mol) may improve filterability in large scale synthesis, e.g. at scales higher than 1 mol of the compound of formula (a).

In one embodiment of the manufacturing process, water may be added in an amount of 0.5 to 1.5 equivalents (calculated in mol/mol, based on amout of starting material 5-(4- bromophenyl)-4-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)-6-fluoropyrimidine as reference), preferably in an amount of 0.6 to 1.4 equivalents, in an amount of 0.7 to 1.3 equivalents, in an amount of of 0.8 to 1.2 equivalents, more preferably in an amount of 1 equivalent ±5% per equivalent weight of the compound of formula (a) (mol/mol).

In one embodiment of the manufacturing process, DMSO may be used in an amount of 5 to 6 kg per kg of the compound of formula (a), preferably in an amount of 5.1 to 5.9 kg per kg of the compound of formula (a), more preferably in an amount of 5.2 to 5.8 kg per kg of the compound of formula (a), for example 5.5 kg per kg of the compound of formula (a) ±5% (wt/wt).

Thereby, the reaction time ranges from 18 to 30 h, preferably 18 to 25 h, for example from 18 to 22 h, preferably at a temperature from 40°C to <50°C, more preferably 45°C ±3°C, or45°C ±2°C.

The reaction time in the above process may be controlled by in-process control (IPC) via HPLC for reaction conversion. Preferably, the conversion is regarded as completed at < 1.0 %area of compound (a). HPLC conditions may be chosen as indicated in the experimental part below. After completion of the reaction, the precipitated inorganic salts are filtered off the reaction mixture, rinsed with organic solvent, for instance a mixture of EtOAc and DMSO (preferably 50:50 wt/wt), or EtOAc.

The product-containing mother liquor is further worked up by adding organic solvent and water, mixing and separating the phases, and crystallising potassium (5-(4-bromophenyl)- 6-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin-4-yl)(sulfamoyl)amide of formula (la) from the aqueous phase. Thereby, seed crystals may optionally be used for promoting and facilitating crystallisation of the desired crystal form.

For instance, during work-up further organic solvent, for example EtOAc, is added to the obtained liquid phase containing the product, followed by water. After mixing, the water phase is separated and again washed with organic solvent, for instance with EtOAc. Finally, the water phase containing the product is collected.

The solid form of potassium (5-(4-bromophenyl)-6-(2-((5-bromopyrimidin-2- yl)oxy)ethoxy)pyrimidin-4-yl)(sulfamoyl)amide of formula (la) is obtained by precipitation, preferably by crystallisation, from the separated aqueous layer.

Preferably, the precipitation or crystallisation occurs at a temperature of 27 to -KFC, preferably 25°C to -9°C. Preferably, the precipitation or crystallisation is completed at a temperature below 5°C, preferably below 0°C, more preferably below -5°C, for instance at -5°C to -KFC, -6°C to -KFC, or -8°C ± 1°C.

The crystallisation process is optionally supported by adding seed crystals of potassium (5- (4-bromophenyl)-6-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin-4- yl)(sulfamoyl)amide of formula (la). Thereby, crystalline Form A or crystalline Form B may serve as seed crystals. Preferred is crystaline Form A of potassium (5-(4- bromophenyl)-6-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin-4-yl)(sulfamoyl)amide of formula (la), preferably added as a slurry in an organic solvent, such as EtOAc. That means, that preferably, the seeding material comprises crystalline Form A, but also mixtures of Form A and Form B are possible. The amount of seeding crystals is not particularly limited, in particular not with respect to an upper limit. The amount may be at least 0.005 equ., for instance ranging from 0.005 to 0.2 equ., or from 0.005 to 0.15 equ. of seed crystals may be used (calculated in mol/mol, based on amout of starting material 5-(4- bromophenyl)-4-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)-6-fluoropyrimidine as reference). Crystallisation conditions are the same as described above.

The solid form of potassium (5-(4-bromophenyl)-6-(2-((5-bromopyrimidin-2- yl)oxy)ethoxy)pyrimidin-4-yl)(sulfamoyl)amide of formula (la), preferably Form A thereof, is isolated by filtration and washing with an appropriate solvent, for instance IPA or a mixture of IPA/water. Preferably, the solvent is pre-cooled. The obtained product is then dried.

In one embodiment, the process for manufacturing a solid form of potassium (5-(4- bromophenyl)-6-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin-4-yl)(sulfamoyl)amide of formula (la) is performed under inert atmosphere, e.g. under nitrogen.

It is understood that one embodiment of the present invention realtes to a solid form of potassium (5-(4-bromophenyl)-6-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin-4- yl)(sulfamoyl)amide of formula (la) obtainable by the process described above, i.e. by reacting 5-(4-bromophenyl)-4-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)-6- fluoropyrimidine of formula (a) with with sulfamide, in the presence of K2CO3, in a polar aprotic organic solvent, preferably DMSO, and optionally water, at a temperature below 80°C, and isolating the compound in solid form. This includes all reaction conditions as described above.

One aspect of the present invention relates to the use of the solid form potassium (5-(4- bromophenyl)-6-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin-4-yl)(sulfamoyl)amide of formula (la), or a crystalline form thereof, in a process for manufacturing {5-(4-bromo- phenyl)-6 [2 (5 bromo-pyrimidin-2 yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamide of formula (lb)

One aspect relates to a process for manufacturing {5-(4-bromo-phenyl)-6 [2 (5 bromo- pyrimidin-2 yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamide of formula (lb)

lb wherein the solid form of potassium (5-(4-bromophenyl)-6-(2-((5-bromopyrimidin-2- yl)oxy)ethoxy)-pyrimidin-4-yl)(sulfamoyl)amide of formula (la) is reacted with acid, in a mixture of water and an organic solvent.

In a preferred embodiment, the solid form of potassium (5-(4-bromophenyl)-6-(2-((5- bromopyrimidin-2-yl)oxy)ethoxy)-pyrimidin-4-yl)(sulfamoyl)amide of formula (la) is a crystalline form, for instance Form A or Form B as described above, or a mixture thereof, most preferably crystalline Form A thereof.

In a preferred embodiment, the acid is hydrochloric acid. In a further preferred embodiment, the organic solvent is an alkyl ketone, for example methyl ethyl ketone (MEK).

In one embodiment of this manufacturing process, crystalline Form A or crystalline Form B of potassium (5-(4-bromophenyl)-6-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)-pyrimidin- 4-yl)(sulfamoyl)amide of formula (la) (or a mixture of Form A and Form B) as described above is reacted with hydrochloric acid in a mixture of water and methyl ethyl ketone to obtain {5-(4-bromo-phenyl)-6 [2 (5 bromo-pyrimidin-2 yloxy)-ethoxy]-pyrimidin-4-yl}- sulf amide of formula (lb).

Thereby, the hydrochloric acid may be added in amount of 1.02 to 1.5 equivalents, preferably from 1.05 to 1.2 equivalents (calculated in mol/mol, based on amout of starting material potassium (5-(4-bromophenyl)-6-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)- pyrimidin-4-yl)(sulfamoyl)amide as reference). The HC1 preferably has a concentration of 0.7 to 1.3 M in water. In one embodiment of this manufacturing process, the ratio of water / methyl ethyl ketone is 70:30 (wt/wt) ± 10%, preferably 70:30 (wt/wt) ± 7%, more preferably 70:30 (wt/wt) ± 5%.

In one embodiment of this manufacturing process, the reaction temperature during and after HC1 addition is in a range from 15 °C to 25 °C.

In one embodiment of this manufacturing process, the reaction time is 10 to 25 h, preferably 15 to 23 h.

The crystallisation of the final product aprocitentan, i.e. 5-(4-bromo-phenyl)-6 [2 (5 bromo-pyrimidin-2 yloxy)-ethoxy]-pyrimidin-4-yl}- sulfamide of formula (lb), may optionally be supported by addition of seed crystals.

In a preferred embodiment, the crystallisation of {5-(4-bromo-phenyl)-6 [2 (5 bromo- pyrimidin-2 yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamide of formula (lb) is supported by seeding with a desired crystalline form of the product, i.e. aprocitentan. Preferably, Form A of {5-(4-bromo-phenyl)-6 [2 (5 bromo-pyrimidin-2 yloxy)-ethoxy]-pyrimidin-4-yl}- sulfamide of formula (lb) is used as seed crystals.

The amount of seeding material, in particular seed crystals of Form A of aprocitentan, is not particularly limited, in particular not with respect to an upper limit. The amount may be at least 0.005 equ., for instance ranging from 0.005 to 0.2 equ., or from 0.005 to 0.1 equ. based on starting material potassium salt of formula (la) in mol/mol, preferably from 0.01 to 0.05 equ, for example 0.02 equ. ± 10%.

Hence, the desired product {5-(4-bromo-phenyl)-6 [2 (5 bromo-pyrimidin-2 yloxy)- ethoxy]-pyrimidin-4-yl}- sulfamide of formula (lb), i.e. aprocitentan, is obtained in crystalline form during the manufacturing process, wherein the solid form of potassium (5- (4-bromophenyl)-6-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin-4- yl)(sulfamoyl)amide of formula (la) is used as starting material. Preferably, aprocitentan is obtained in crystalline Form A.

The crystalline form of aprocitentan as preferred herein, namely crystalline Form A, is known from W02018/154101A1 and can be prepared according to Example 1 disclosed therein. Form A of aprocitentan is characterized as described below. In one embodiment of the process for manufacturing {5-(4-bromo-phenyl)-6 [2 (5 bromo- pyrimidin-2 yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamide of formula (lb), in a first reactor, water is added to the solid or crystalline form (for instance Form A or Form B, preferably Form A) of potassium (5-(4-bromophenyl)-6-(2-((5-bromopyrimidin-2- yl)oxy)ethoxy)pyrimidin-4-yl)(sulfamoyl)amide of formula (la), followed by methyl ethyl ketone. In a second reactor, HC1 is added to water, preferably, seeds of crystalline Form A of aprocitentan are added. Then, the content of the first reactor is dosed to the second reactor, preferably at a temperature below 25°C, more preferably at 20°C±3°C. The temperature of the obtained reaction mixture is then maintained as described above for a time period as described above. Thereafter, the obtained product is filtered off, optionally rinsed with water, and dried.

In one embodiment, the process for manufacturing {5-(4-bromo-phenyl)-6 [2 (5 bromo- pyrimidin-2 yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamide of formula (lb) as described above is performed under inert atmosphere, e.g. under nitrogen.

Crystalline form A of {5-(4-bromo-phenyl)-6 [2 (5 bromo-pyrimidin-2 yloxy)-ethoxy]- pyrimidin-4-yl} -sulfamide of formula (lb), i.e. aprocitentan, is characterized by an X-ray powder diffraction pattern with at least four peaks, or at least six peaks, or at least eight peaks having an angle of refraction 29 (2theta) values selected from: 9.8°, 9.9°, 11.7°, 14.5°, 15.4°, 15.6°, 16.9°, 17.2°, 17.8°, 18.6°, 19.9°, 20.0°, 21.5°, 21.9°, 22.8°, 23.2°, 23.5°, 24.9°, 25.1°, 25.3°, 25.6°, 25.9°, 27.1°, 27.3°, 28.5°, 29.0°, 29.4°, 30.1° and 30.6°; wherein said X-ray powder diffraction diagram is obtained by using combined Cu Kai and Ka2 radiation, without Ka2 stripping; and the accuracy of the 29 values is in the range of 29 +/- 0.2°.

The relative intensities of the peaks are as follows: 9.8° (18%), 9.9° (18%), 11.7° (14%), 14.5° (10%), 15.4° (14%), 15.6° (29%), 16.9° (19%), 17.2° (16%), 17.8° (100%), 18.6° (50%), 19.9° (54%), 20.0° (67%), 21.5° (24%), 21.9° (10%), 22.8° (18%), 23.2° (49%), 23.5° (83%), 24.9° (32%), 25.1° (20%), 25.3° (24%), 25.6° (33%), 25.9° (16%), 27.1° (23%), 27.3° (39%), 28.5° (13%), 29.0° (23%), 29.4° (15%), 30.1° (12%) and 30.6° (10%), wherein said X-ray powder diffraction diagram is obtained by using combined Cu Kai and Ka2 radiation, without Ka2 stripping; and the accuracy of the 29 values is in the range of 29 +/- 0.2°. The present data show peaks having a relative intensity, as compared to the most intense peak in the diagram, of the following percentages (relative peak intensitites given in parentheses) at the indicated angles of refraction 2theta (selected peaks from the range 3- 33° 2theta with relative intensity larger then 10% are reported).

Moreover, crystalline form A essentially show the X-rai powder diffraction pattern as depicted in Figure 5.

EXPERIMENTAL PART

ABBREVIATIONS AND TERMS USED IN THIS TEXT

The following abbreviations are used throughout the specification and the examples:

Ac acetyl aq. aqueous

DCM dichloromethane

DMAC dimethylacetamide

DME 1,2-dimethoxy ethane

DMF dimethylformamide

DMSO dimethylsulfoxide

DSC Differential Scanning Calorimetry

EtOAc ethyl acetate equ. equivalent(s) (same as eq., equiv.)

Hept heptane

IPA isopropyl alcohole / isopropanol

IPC in-process control iPrOAc isopropyl acetate

IT internal temperature

MeCN acetonitrile

MEK methyl ethyl ketone

NLT not less than

NMP A-methyl-2-pyrrolidone org. organic

RT room temperature % a/a percent determined by area ratio

TFA trifluoroacetic acid

THF tetrahydrofuran

TGA Thermo-Gravimetric Analysis tR retention time

Tr reactor temperature wt/wt weight/weight (same as w/w)

XR(P)D X-ray (powder) diffraction

Definitions of particular terms used in this text:

The following paragraphs provide definitions of the various chemical moieties for the compounds according to the invention as well as other particular terms used in this text and are intended to apply uniformly throughout the specification and claims, unless an otherwise expressly set out definition provides a broader or narrower definition:

♦♦♦ The expression “polar aprotic solvent” refers to a solvent which does not have an acidic hydrogen and has an electric dipole moment of at least 1.5 Debye. Representative examples of polar aprotic solvents include MeCN, chlorobenzene, EA, iPrOAc, THF, NMP, dioxane, DMAC, DME, DMF, DMSO or sulfolane.

♦♦♦ The expression “polar mixture of aprotic solvents” refers to a mixture of solvents which do not have an acidic hydrogen, whereby said mixture has an electric dipole moment of at least 1.5 Debye. Representative examples of mixtures of aprotic solvents include, but are not limited to: a mixture of two solvents, whereby the first of these solvents is selected from the group consisting of toluene and DCM and the second of these solvents is selected from the group consisting of MeCN, chlorobenzene, EA, iPrOAc, THF, NMP, dioxane, DMAC, DME, DMF, DMSO and sulfolane; or a mixture of toluene, DCM and a solvent selected from the group consisting of MeCN, chlorobenzene, EA, iPrOAc, THF, NMP, dioxane, DMAC, DME, DMF, DMSO and sulfolane.

The expression “room temperature” as used herein refers to a temperature of from 20 to 30°C, and preferably 25°C. Particular embodiments of the invention are described in the following Examples, which serve to illustrate the invention in more detail without limiting its scope in any way.

EXAMPLES

All temperatures given are internal temperatures, unless stated otherwise, and are stated in °C.

Parameters of the HPLC method:

X-ray Powder Diffraction (XRPD)

XRPD diffractograms were collected on a Bruker AXS D8 Advance diffractometer using Cu Ka radiation (40 kV, 40 mA) and a 9-29 goniometer fitted with a Ge monochromator.

The incident beam passes through a 2.0 mm divergence slit followed by a 0.2 mm antiscatter slit and knife edge. The diffracted beam passes through an 8.0 mm receiving slit with 2.5° Soller slits followed by the Lynxeye Detector. The software used for data collection and analysis was Diffrac Plus XRD Commander and Diffrac Plus EVA respectively. Samples were run under ambient conditions as flat plate specimens using powder. The sample was prepared on a polished, zero-background (510) silicon wafer by gently pressing onto the flat surface or packed into a cut cavity. The sample was rotated in its own plane. Details:

Angular range: 4 to 42° 29

Step size: 0.05° 29

Collection time: 0.5 s/step (total collection time: 6.40 min)

Thermo- Gravimetric Analysis (TGA)

TGA data were collected on a TA Instruments Q500 TGA, equipped with a 16 position autosampler. Typically, 5-10 mg of each sample was loaded onto a pre-tared aluminium DSC pan and heated at 10°C/min from ambient temperature to 350°C. A nitrogen purge at 60 ml/min was maintained over the sample.

The instrument control software was Advantage for Q Series and Thermal Advantage and the data were analysed using Universal Analysis or TRIOS.

Differential Scanning Calorimetry (DSC)

DSC data were collected on a TA Instruments Q2000 equipped with a 50 position autosampler. Typically, 0.5 - 5 mg of each sample, in a pin-holed aluminium pan, was heated at 10 °C/min from 25 °C to 330 °C. A purge of dry nitrogen at 50 ml/min was maintained over the sample.

Modulated temperature DSC was carried out using an underlying heating rate of 2 °C/min and temperature modulation parameters of ±0.318 °C (amplitude) every 60 seconds (period).

Water Determination by Karl Fischer Titration (KF)

The water content was measured on a Metrohm 874 Oven Sample Processor at 150 °C with 851 Titrano Coulometer using Hydranal Coulomat AG oven reagent and nitrogen purge. Weighed solid samples were introduced into a sealed sample vial. Approximately 10 mg of sample was used per titration and duplicate determinations were made. An average of these results is presented unless otherwise stated. Data collection and analysis were performed using Tiamo software.

Synthesis:

Example 1: Preparation of seed crystals of potassium (5-(4-bromophenyl)-6-(2-((5- bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin-4-yl)(sulfamoyl)amide

1.1: potassium (5-(4-bromophenyl)-6-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin- 4-yl)(sulfamoyl)amide

In a 100 mL reactor at 25 °C was charged {5-(4-bromo-phenyl)-6 [2 (5 bromo-pyrimidin-2 yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamide (10 g, 1 equiv). Then, THF (88.6 g, 10 V) was added to obtain a solution. Then, potassium tert-butoxide (2.05 g, 1 equiv) in THF (8.86 g, IV) was slowly added at 20 °C. The resulting suspension was vigorously stirred for 7h and then cooled down to 0 °C over 6h and to -1 °C (as fast as possible). The reaction mixture was filtered off to give a solid which was dried at 50 °C overnight to deliver a beige solid (10.94 g, 102.3 %).

XRD analysis showed an amorphous solid.

1.2: potassium (5-(4-bromophenyl)-6-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin- 4-yl)(sulfamoyl)amide

In a 400 mL reactor at 25 °C was charged DMSO (150 mL). Then, the starting material (5- (4-bromophenyl)-4-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)-6-fluoropyrimidine) (30 g, 1 equiv.) and sulfamide (12.39 g, 2 equiv.) were charged. The reaction mixture was stirred at 300 rpm and potassium carbonate 325 Mesh (44.54 g, 5 equiv.) and water (0.6 g, 0.52 equiv) were successively added. The reaction was then stirred at 60 °C (Tr) for 6h. After completion of the reaction, the mixture was cooled to 25 °C and stirred overnight. The salts were filtered off and washed with EtOAc (135 g). The filtrate was transferred into a 400 mL reactor and cooled down to 10 °C. Then, water (150 g) was added and the temperature adjusted to 25 °C. The layers were allowed to settle and the organic layer (top layer) was discarded. The aqueous layer was washed with EtOAc (135 g) and the organic layer discarded. The aqueous layer was stirred at 25 °C and then cooled to 5 °C over 1 hour. Then, seeds of potassium (5-(4-bromophenyl)-6-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin-4- yl)(sulfamoyl)amide (300 mg, amorphous material from 1.1) were added. The mixture was cooled down to -5°C over 6h. The solid was filtered off and washed with water (10 g) (melting of the solid) and IPA (7.9g). All the mother liquors and the solid filtered off were combined and evaporated in vacuo to deliver 38 g of material (Yield 79%).

XRPD analysis showed peaks at 8.0°, 10.4°, 12.0°, 15.1°, 17.5°, 18.4°, 21.5°, 22.6°, 24.8°, 26.4°, or 28.7° 2theta; wherein said X-ray powder diffraction diagram is obtained by using Cu Ka radiation; and the accuracy of the 29 (2theta) values is in the range of 29 +/- 0.2° (2theta +/- 0.2°) (see Figure 3). The compound is a DMSO solvate, indicated herein as

Form B of potassium (5-(4-bromophenyl)-6-(2-((5-bromopyrimidin-2- yl)oxy)ethoxy)pyrimidin-4-yl)(sulfamoyl)amide.

1.3: potassium (5-(4-bromophenyl)-6-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin- 4-yl)(sulfamoyl)amide

In a 400 mL reactor at 25 °C was charged DMSO (150 mL). Then, starting material (5-(4- bromophenyl)-4-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)-6-fluoropyrimidine) (30 g, 1 equiv.) and sulfamide (12.39 g, 2 equiv.) were charged. The reaction mixture was stirred at 300 rpm and potassium carbonate 325 Mesh (44.54 g, 5 equiv.) and water (0.6 g, 0.52 equiv) were successively added. The reaction was then stirred at 60 °C (Tr) for 6h. After completion of the reaction, the mixture was cooled to 25 °C and stirred overnight. The salts were filtered off and washed with EtOAc (135 g). The filtrate was transferred into a 400 mL reactor and cooled down to 10 °C. Then, water (150 g) was added and the temperature adjusted to 25 °C. The layers were allowed to settle and the organic layer (top layer) was discarded. The aqueous layer was washed with EtOAc (135 g) and the organic layer discarded.

The aqueous layer was stirred at 25 °C and then cooled to 5 °C over 1 hour. Then, seeds of potassium (5-(4-bromophenyl)-6-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin-4- yl)(sulfamoyl)amide (300 mg, DMSO solvate from 1.2) were added. The mixture was cooled down to -5°C over 4h and to -8 °C over 4 hours and stirred at -12 °C for 2.5 hours. The solid was filtered off and washed with IPA (16 g). The potassium salt was dried at 40 °C under vacuum to deliver 31.24 g of material (Yield 84%).

XRD analysis showed a mixture of DMSO solvate and hydrate.

1.4: potassium (5-(4-bromophenyl)-6-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin- 4-yl)(sulfamoyl)amide

In a IL reactor at 25 °C was charged DMSO (75 mL). Then, the temperature was increased to Tr 60 °C over 15 min and starting material (5-(4-bromophenyl)-4-(2-((5-bromopyrimidin- 2-yl)oxy)ethoxy)-6-fluoropyrimidine) (30 g, 1 equiv.) was charged. The reaction mixture was cooled down to 25 °C and sulfamide (12.39 g, 2 equiv.) and potassium carbonate sesquihydrate (52.73 g, 5 equiv.) were successively added. The reaction was then stirred at 60 °C (Tr) for 6h. After completion of the reaction, the mixture was cooled to 20 °C and the salts were filtered off and washed with EtOAc (135 g). The filtrate was transferred into a 400 mL reactor and cooled down to 10 °C. Then, water (225 g) was added and the temperature adjusted to 25 °C. The layers were allowed to settle and the organic layer (top layer) was discarded. The aqueous layer was washed with EtOAc (135 g) and the organic layer discarded.

The aqueous layer was heated to 45 °C to dissolve any solid and cooled down to 20 °C over 30 min. Then, seeds of potassium salt (300 mg, product obtained from batch 1.3, i.e. a mixture of DMSO solvate and hydrate) were added. The mixture was cooled down to -5°C over 6h and stirred overnight. The solid was filtered off and washed with IPA (30 g). The potassium salt was dried at RT under vacuum to deliver 28.83 g of material (Yield 83%).

XRPD analysis showed peaks at 9.3°, 9.6°, 10.6°, 15.6°, 16.0°, 18.2°, 19.3°, 20.7°, 21.3°, 21.8°, 22.9°, 24.1°, or 24.4° 2theta; wherein said X-ray powder diffraction diagram is obtained by using Cu Ka radiation; and the accuracy of the 29 (2theta) values is in the range of 29 +/- 0.2° (2theta +/- 0.2°) (see Figure 1). The compound is a monohydrate.. The compound is indicated herein as Form A of potassium (5-(4-bromophenyl)-6-(2-((5- bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin-4-yl)(sulfamoyl)amide.

Water determination by Karl Fischer Titration (KF) showed that a monohydrate was obtained.

Example 2: potassium (5-(4-bromophenyl)-6-(2-((5-bromopyrimidin-2- yl)oxy)ethoxy)pyrimidin-4-yl)(sulfamoyl)amide:

All process activities are performed under nitrogen.

Into a reactor at 25 °C were successively charged DMSO (2.64 kg), sulfamide (0.204 kg, 2.127 M, 2 equ.), potassium carbonate (0.441 kg, 3.191 M, 3 equ.) and then water (19.2 g).

Then, the starting material (5-(4-bromophenyl)-4-(2-((5-bromopyrimidin-2- yl)oxy)ethoxy)-6-fluoropyrimidine) (0.5 kg; 1.064 M, lequ.) was added. The reaction mixture was stirred 45 °C for 20h and then cooled down to 25 °C. The solids were filtered off and the cake was rinsed with a mixture of EtOAc/DMSO (50:50 wt/ wt) (2 x 0.5 kg) and EtOAc (1.76 kg). To the mother liquor was added water (2.5 kg) and the temperature was adjusted to 35°C. The agitation was stopped and the layers allowed to settle. The aqueous layer was separated and washed with EtOAc (2.26 kg). The agitation was stopped and the layers allowed to settle. The aqueous layer was separated and heated up to 40°C. Then, the aqu. layer was cooled to 25°C and the aqu. layer was seeded with potassium (5- (4-bromophenyl)-6-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin-4- yl)(sulfamoyl)amide of Form A (0.01 equiv., 6.2 g) in EtOAc. The batch was stirred at 25°C for 2h and then, cooled down to -8°C over 6h. After aging the batch at -8 °C for 6h, the product was filtered off and washed with IPA (1 kg) and IPA/H2O (90:10 wt/wt) (1 kg). Then solid was then dried at 25°C for 18h to deliver potassium (5-(4-bromophenyl)-6- (2-((5-bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin-4-yl)(sulfamoyl)amide as a white powder (0.505 kg, 81% yield). XRPD confirmed that Form A of potassium (5-(4- bromophenyl)-6-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin-4-yl)(sulfamoyl)amide was obtained.

Example 3: {5-(4-bromo-phenyl)-6 [2 (5 bromo-pyrimidin-2 yloxy) -ethoxy] - pyrimidin-4-yl}-sulfamide

All process activities are performed under nitrogen.

Into a reactor at 24°C were successively added potassium (5-(4-bromophenyl)-6-(2-((5- bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin-4-yl)(sulfamoyl)amide (0.45kg, 0.7702 mol, 1 equ.) as obtained in Example 2, water (1.755 kg) and MEK (0.747 kg). In another reactor were added water ( 3.596kg), cone. HC1 (35-37 wt%, 1.107 equiv.) and seed crystals of {5- (4-bromo-phenyl)-6 [2 (5 bromo-pyrimidin-2 yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamide of Form A (9 g; 0.01648 mol; 0.02 equ.). The content of the first reactor was dosed to the second reactor at 20°C over 3h. The reaction mixture was stirred at 20°C for 16.5h. The solid was then filtered off and washed with water/MEK (90:10 wt:wt) (2.604 kg) and water (2.655 kg ). Then solid was then dried at 25°C for 18h to deliver {5-(4-bromo-phenyl)-6 [2 (5 bromo-pyrimidin-2 yloxy)-ethoxy]-pyrimidin-4-yl} -sulfamide as a white powder (0.404 kg, 96% yield). XRPD confirmed that Form A of aprocientan was obtained. Example 4: {5-(4-bromo-phenyl)-6 [2 (5 bromo-pyrimidin-2 yloxy) -ethoxy] - pyrimidin-4-yl}-sulfamide

Into a reactor at 24°C were successively added water (29.15 g) and MEK (12.5 g). The temperature (internal temperature) was adjusted to 15 °C. Then potassium (5-(4- bromophenyl)-6-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin-4-yl)(sulfamoyl)amide (5g, 8.557 mmol, 1 equ.) (DMSO solvate; Form B) was added. In another reactor were added water (83.45g), cone. HC1 (36.5 wt%, 1.107 equiv.) and seed crystals of { 5-(4- bromo-phenyl)-6 [2 (5 bromo-pyrimidin-2 yloxy)-ethoxy]-pyrimidin-4-yl} -sulfamide of Form A (0.1 g; 0.1831 mmol; 0.02 equ.). The content of the first reactor was dosed to the second reactor at 20°C over 3h. The reaction mixture was stirred at 20°C for 16.5h. The solid was then filtered off and washed with water/MEK (90:10 wt:wt) (11.995 g) and water (24.47 g). Then solid was then dried at 25°C for 18h to deliver {5-(4-bromo-phenyl)-6 [2 (5 bromo-pyrimidin-2 yloxy)-ethoxy]-pyrimidin-4-yl} -sulfamide as a white powder (3.75 g, 96% yield). XRPD confirmed that Form A of aprocitentan was obtained.

Claims

2. Process for manufacturing a solid form of potassium (5-(4-bromophenyl)-6-(2-((5- bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin-4-yl)(sulfamoyl)amide of formula (la)