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WO2023111797A1 - Dérivés de pyrimidinsulfamides et procédé de fabrication associé - Google Patents

Dérivés de pyrimidinsulfamides et procédé de fabrication associé Download PDF

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Publication number
WO2023111797A1
WO2023111797A1 PCT/IB2022/062016 IB2022062016W WO2023111797A1 WO 2023111797 A1 WO2023111797 A1 WO 2023111797A1 IB 2022062016 W IB2022062016 W IB 2022062016W WO 2023111797 A1 WO2023111797 A1 WO 2023111797A1
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WO
WIPO (PCT)
Prior art keywords
pyrimidin
ethoxy
formula
bromopyrimidin
bromophenyl
Prior art date
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PCT/IB2022/062016
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English (en)
Inventor
Alain Collas
Thierry JOUSSEAUME
Christopher James Nichols
Christopher Paul DE DOBBELAERE
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Janssen Biotech, Inc.
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Application filed by Janssen Biotech, Inc. filed Critical Janssen Biotech, Inc.
Publication of WO2023111797A1 publication Critical patent/WO2023111797A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine

Definitions

  • 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)
  • 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.
  • 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.
  • 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.
  • CKD chronic kidney disease
  • 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.
  • the compound of formula (lb) is prepared by the following one -pot process:
  • 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 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.
  • 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.
  • the safety aspect becomes more and more important, the larger the scale of the production becomes.
  • the occurance of undesired side products should be avoided, i.e. a high purity is achieved.
  • 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):
  • the invention in a second aspect, relates to crystalline forms thereof.
  • the invention in a third aspect, 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.
  • 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.
  • 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.
  • 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).
  • 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.
  • 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):
  • 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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°).
  • 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°.
  • 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.
  • 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°).
  • 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°.
  • 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.
  • 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.
  • sulfamide H2NSO2NH2
  • 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.
  • 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).
  • the polar aprotic organic solvent is DMSO.
  • reaction temperature is from 40°C to ⁇ 50°C, more preferably 45°C ⁇ 3°C, or 45°C ⁇ 2°C.
  • sulfamide H2NSO2NH2
  • H2NSO2NH2 sulfamide
  • sulfamide 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).
  • K2CO3 used in the manufacturing process is not particularly limited, in particular the upper limit is not particularly limited.
  • 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).
  • 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).
  • 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).
  • 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.
  • IPC in-process control
  • HPLC conditions may be chosen as indicated in the experimental part below.
  • 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.
  • seed crystals may optionally be used for promoting and facilitating crystallisation of the desired crystal form.
  • organic solvent for example EtOAc
  • 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.
  • the precipitation or crystallisation occurs at a temperature of 27 to -KFC, preferably 25°C to -9°C.
  • 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).
  • seed crystals of potassium 5- (4-bromophenyl)-6-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin-4- yl)(sulfamoyl)amide of formula (la).
  • crystalline Form A or crystalline Form B may serve as seed crystals.
  • 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.
  • 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.
  • an appropriate solvent for instance IPA or a mixture of IPA/water.
  • 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.
  • 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.
  • 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
  • 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.
  • the acid is hydrochloric acid.
  • the organic solvent is an alkyl ketone, for example methyl ethyl ketone (MEK).
  • 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).
  • 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.
  • 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%.
  • reaction temperature during and after HC1 addition is in a range from 15 °C to 25 °C.
  • 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.
  • 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.
  • a desired crystalline form of the product i.e. aprocitentan.
  • 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%.
  • 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.
  • aprocitentan is obtained in crystalline Form A.
  • crystalline form of aprocitentan as preferred herein namely crystalline Form A
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 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).
  • crystalline form A essentially show the X-rai powder diffraction pattern as depicted in Figure 5.
  • 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.
  • 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.
  • 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.
  • room temperature 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.
  • 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:
  • 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.
  • 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).
  • the instrument control software was Advantage for Q Series and Thermal Advantage and the data were analysed using Universal Analysis or TRIOS.
  • 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.
  • Form B of potassium (5-(4-bromophenyl)-6-(2-((5-bromopyrimidin-2- yl)oxy)ethoxy)pyrimidin-4-yl)(sulfamoyl)amide.
  • 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%).
  • 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%).
  • 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.
  • 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).
  • EtOAc/DMSO 50:50 wt/ wt
  • EtOAc (1.76 kg
  • 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.

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Abstract

La présente invention concerne une forme solide de (5-(4-bromophényl)-6-(2-((5-bromopyrimidin-2-yl)oxy)éthoxy)pyrimidin-4-yl)(sulfamoyl)amidure de potassium de formule (Ia), une forme cristalline de ce dernier, un procédé de fabrication de chacun d'eux et un procédé de fabrication de {5-(4-bromo-phényl)-6-[2-(5 bromo-pyrimidin-2 yloxy)-éthoxy]-pyrimidin-4-yl}-sulfamide de formule (Ib).
PCT/IB2022/062016 2021-12-17 2022-12-09 Dérivés de pyrimidinsulfamides et procédé de fabrication associé WO2023111797A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120142716A1 (en) * 2007-08-17 2012-06-07 Martin Bolli 4-pyrimidinesulfamide derivative
US20160368882A1 (en) * 2014-02-14 2016-12-22 Actelion Pharmaceuticals Ltd Process for manufacturing pyrimidine sulfamide derivatives
US20200002317A1 (en) * 2017-02-27 2020-01-02 Idorsia Pharmaceuticals Ltd Crystalline forms of a 4-pyrimidinesulfamide derivative aprocitentan

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120142716A1 (en) * 2007-08-17 2012-06-07 Martin Bolli 4-pyrimidinesulfamide derivative
US20160368882A1 (en) * 2014-02-14 2016-12-22 Actelion Pharmaceuticals Ltd Process for manufacturing pyrimidine sulfamide derivatives
US20200002317A1 (en) * 2017-02-27 2020-01-02 Idorsia Pharmaceuticals Ltd Crystalline forms of a 4-pyrimidinesulfamide derivative aprocitentan

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