WO2016113415A1 - Procédé de préparation de riociguat essentiellement exempt d'impuretés génotoxiques - Google Patents

Procédé de préparation de riociguat essentiellement exempt d'impuretés génotoxiques Download PDF

Info

Publication number
WO2016113415A1
WO2016113415A1 PCT/EP2016/050825 EP2016050825W WO2016113415A1 WO 2016113415 A1 WO2016113415 A1 WO 2016113415A1 EP 2016050825 W EP2016050825 W EP 2016050825W WO 2016113415 A1 WO2016113415 A1 WO 2016113415A1
Authority
WO
WIPO (PCT)
Prior art keywords
riociguat
solvate
solvent
temperature
ray powder
Prior art date
Application number
PCT/EP2016/050825
Other languages
English (en)
Inventor
Marijan STEFINOVIC
Frank Richter
Ulrich Griesser
Christoph Langes
Original Assignee
Sandoz Ag
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sandoz Ag filed Critical Sandoz Ag
Publication of WO2016113415A1 publication Critical patent/WO2016113415A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to a process for the preparation of riociguat which removes the major genotoxic impurities and/or alkylating agents.
  • the present invention relates to solvates which are useful as intermediates for the preparation of pure riociguat.
  • Riociguat (BAY 63-2521 ), having the chemical name N-[4,6-Diamino-2-[1-(2-fluorobenzyl)- 1 H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl]-N-methylcarbamic acid methyl ester, or sometimes also called or also sometimes called Methyl-(4,6-diamino-2-(1-(2-fluorobenzyl)- 1 H-pyrazolo[3, 4-b]pyridin-3-yl)-5-pyrimidinyl)(methyl)carbamate is a stimulator of the soluble guanylate cyclase.
  • Riociguat has been approved for the treatment of inoperable, or persistent, recurrent chronic thromboembolic pulmonary hypertension (CTEPH) after surgery in adult patients and for the treatment of pulmonary arterial hypertension and is in development for the treatment of systemic sclerosis and Raynaud's phenomenon.
  • CTEPH chronic thromboembolic pulmonary hypertension
  • the compound of formula VIII is further reacted with a methyl chloroformate or with a dimethyl carbonate derivative to form a compound of formula VI.
  • the compound of formula VI is then methylated to form crude riociguat of formula (I).
  • Crude riociguat of formula (I) is then purified by a process comprising the intermediate isolation of a riociguat DMSO solvate of formula (II).
  • the solvent DMSO has to be removed.
  • the compound of formula (II) is boiled in pharmaceutically acceptable solvents such as ketones, esters, ethers or alcohols.
  • the riociguat obtained in this manner contains detectable amounts of DMSO.
  • DMSO is an active pharmaceutical ingredient by itself. It is used as an active pharmaceutical ingredient in the treatment of interstitial cystitis. DMSO removal is difficult to achieve by the published processes. It is thus a further object of the invention to provide riociguat essentially free from DMSO and suitable for pharmaceutical use.
  • WO 2014/128109 discloses forms of riociguat, such as polymorphs and solvates, and describes a 1 ⁇ 4 ethyl acetate solvate of riociguat in example 6.
  • diffractogram in Tab.3 and figure 4 comprises reflexes at °2Theta positions of 9.1 and 25.6.
  • the present invention relates to riociguat - the compound of formula (I) - which is essentially free from potential genotoxic impurities and/or alkylating agents.
  • the present invention enables preparation of riociguat which is essentially free from genotoxic impurities by providing a new process.
  • the present inventors have invented a process for the preparation of riociguat, wherein crude riociguat is dissolved in a water-soluble aprotic solvent, then an anti-solvent is added such that the addition leads to the precipitation of a solid form of riociguat and then said precipitated solid-form of riociguat is isolated.
  • the present invention also relates to several crystalline solvates of riociguat which are useful for the purification of riociguat, such as riociguat methylacetate solvate, riociguat ethylacetate solvate and riociguat butan-2-one solvate.
  • the present invention also relates to the use of the process of the present invention for enriching riociguat from a mixture comprising riociguat and compound of formula III.
  • the present invention also relates to the use of a riociguat solvate of the present invention for enriching riociguat from a mixture comprising riociguat and compound of formula III.
  • Figure 1 X-ray powder diffraction pattern of Hemi-ethyl acetate solvate of Riociguat
  • Figure 2 X-ray powder diffraction pattern of Hemi-butan-2-one (Methyl-Ethyl-Ketone) solvate of Riociguat
  • X-ray powder diffraction patterns were obtained with a X'Pert PRO diffracto meter (PANalytical, Almelo, The Netherlands) equipped with a theta/theta coupled goniometer in transmission geometry, programmable XYZ stage with well plate holder, Cu-Ka1 , 2 radiation source (wavelength 0.15419 nm) with a focusing mirror, a 0.5° divergence slit, a 0.02° soller slit collimator and a 0.5° anti-scattering slit on the incident beam side, a 2 mm anti-scattering slit, a 0.02° soller slit collimator, a Ni-filter and a solid state PIXcel detector on the diffracted beam side.
  • the patterns were recorded at a tube voltage of 40 kV, tube current of 40 mA, applying a step size of 0.013° 2 theta with 40s per step in the angular range of 2°
  • HPLC and MS analysis was carried out using a Waters Alliance 2795 HPLC system equipped with a Waters Micromass Quattro Micro API mass spectrometer running
  • Detection was done at 254nm. Purity was calculated based on the integrated peak sizes of the elution profile. MS spectra of the relevant impurities were recorded.
  • “Pure” riociguat in the context of the present invention refers to riociguat having a chemical purity of at least 98% when analyzed by HPLC-UV at 254nm, for example by the HPLC-UV- MS method described above.
  • riociguat in the context of the present invention, refers to riociguat having a chemical purity of at most 95% when analyzed by HPLC-UV at 254nm, for example by the HPLC-UV- MS method described above.
  • an antisolvent is a solvent in which riociguat has a low solubility at 70°C and ambient pressure, such as a solubility of at most 30 mg/ml.
  • a "water soluble” solvent is a solvent characterized by a water solubility of at least 2g solvent /100 ml distilled water 20°C. Water soluble solvents include solvents which are freely miscible with water.
  • a "polar” solvent is a solvent characterized by a dielectricity constant of at least 5 at 20°C
  • polymorphs refers to crystalline forms having the same chemical composition but different spatial arrangements of the molecules, atoms, and/or ions forming the crystal.
  • solvate refers to a crystalline form of a molecule, atom, and/or ions that further comprises molecules of a solvent or solvents incorporated into the crystalline lattice structure.
  • the solvent molecules in the solvate may be present in a regular arrangement and/or a non-ordered arrangement.
  • the solvate may comprise either a stoichiometric or nonstoichiometric amount of the solvent molecules.
  • a solvate with a nonstoichiometric amount of solvent molecules may result from partial loss of solvent from the solvate.
  • Solvates may occur as dimers or oligomers comprising more than one molecule of riociguat within the crystalline lattice structure.
  • amorphous form refers to a solid form of a molecule, atom, and/or ions that is not crystalline. An amorphous solid does not display a definitive X-ray diffraction pattern.
  • X-ray diffraction peak positions means that typical peak position and intensity variability are taken into account.
  • peak positions (2 ⁇ ) will show some inter-apparatus variability, typically as much as 0.2 °.
  • relative peak intensities will show inter-apparatus variability as well as variability due to degree of crystallinity, preferred orientation, prepared sample surface, and other factors known to those skilled in the art, and should be taken as qualitative measure only.
  • riociguat form I is a crystalline form of riociguat free base which may be characterized by having an x-ray powder diffraction pattern (XRPD) comprising four or more peaks at 2theta values of the group 6.7 ⁇ 0.2°, 9.0 ⁇ 0.2°, 17.8 ⁇ 0.2°, 25.6 ⁇ 0.2°, 25.6 ⁇ 0.2° and 27, 4 ⁇ 0.2° wherein X-ray powder diffraction is measured at a temperature of 22°C using CuKa radiation.
  • XRPD x-ray powder diffraction pattern
  • the present invention relates to riociguat comprising less than 600ppm of the compound of formula III, preferably less than 50ppm, such as less than 10ppm and more preferably less than 2ppm, based on the total weight of riociguat.
  • the present invention also relates to riociguat comprising less than 600 ppm of DMSO, preferably less than 200ppm, more preferably less than 50ppm, and most preferably no detectable traces of DMSO.
  • the present invention also relates to pure riociguat comprising less than 600ppm of the compound of formula III, preferably less than 50ppm, such as less than 10ppm and more preferably less than 2ppm, based on the total weight of riociguat.
  • the present invention also relates to pure riociguat comprising less than 600 ppm of DMSO, preferably less than 200ppm, more preferably less than 50ppm, and most preferably no detectable traces of DMSO.
  • the present invention also relates to pure riociguat comprising less than 600ppm of the compound of formula III and less than 600 ppm of DMSO, preferably less than 200ppm DMSO, more preferably less than 50ppm DMSO, and most preferably no detectable traces of DMSO.
  • the present invention also relates to pure riociguat comprising less than 50ppm of the compound of formula III and less than 600 ppm of DMSO, preferably less than 200 ppm DMSO, more preferably less than 50 ppm DMSO, and most preferably no detectable traces of DMSO.
  • the present invention also relates to pure riociguat comprising less than 10ppm of the compound of formula III and less than 600 ppm of DMSO, preferably less than 200 ppm DMSO, more preferably less than 50 ppm DMSO, and most preferably no detectable traces of DMSO.
  • the present invention also relates to pure riociguat comprising less than 2ppm of the compound of formula III and less than 600 ppm of DMSO, preferably less than 200 ppm DMSO, more preferably less than 50 ppm DMSO, and most preferably no detectable traces of DMSO.
  • the process of the present invention enables the preparation of such highly pure riociguat.
  • the present invention thus also relates to a process for the purification of riociguat. Briefly, a) crude riociguat is dissolved in a water-soluble aprotic solvent, then b) an anti-solvent is added such that the addition leads to the precipitation of a solid form of riociguat, and then c) said solid form of riociguat is isolated.
  • the crude riociguat to be used for the purification process typically has a chemical purity of at most 95%, and preferably a chemical purity of at least 20%, at least 40%, at least 60% or at least 80%.
  • Preferred ranges for the chemical purity of the starting material to be used in the purification process of the invention are 20% to 95%, 50% to 95%, 60% to 95%, 60% to 92%, 70% to 95%, 70% to 92%, 80% to 95% and 80% to 92%.
  • the water-soluble aprotic solvent which is used for the dissolution of crude riociguat in step a) can be any water-soluble aprotic solvent wherein riociguat has a sufficient solubility at 70°C and ambient pressure, such as a solubility of at least 20 mg/ml, more preferably of at least 40 mg/ml.
  • a water-soluble aprotic solvent has a solubility in distilled water at 20°C of at least 2g solvent / 100 ml distilled water, such as at least 10g solvent / 100ml distilled water, and preferably at least 25g solvent / 100 ml distilled water.
  • polar aprotic solvents are preferred, in particular polar aprotic solvents having a dielectricity constant of at least 15 at 20°C, such as at least 20 at 20°C.
  • polar aprotic solvent a polar aprotic solvent having a boiling point at a pressure of 1013mbar of below 165°C, in particular of below 155°C, are preferred.
  • polar aprotic solvent having a melting point at a pressure of 1013mbar of below 15°C, in particular of below 13°C, are preferred.
  • polar aprotic solvent a polar aprotic solvent having density at a temperature of 20°C and a pressure of 1013mbar of below 1.05g/cm 3 are preferred.
  • Suitable water-soluble aprotic solvents are dimethylformamide (DMF), dioxane, and tetrahydrofurane.
  • DMF is a particularly preferred water-soluble aprotic solvent for dissolution of crude riociguat in step a).
  • a suitable amount of crude riociguat can be added to the water-soluble aprotic solvent. It is preferable to produce a solution of riociguat in the water soluble aprotic solvent which is fairly concentrated, for example a solution where the concentration of riociguat is at least 50%, such as at least 75% of the solubility of riociguat in the respective water-soluble aprotic solvent.
  • the examples provide further guidance for suitable concentrations of riociguat in the solvent of step a). Sufficient time is allowed so that at least part of the crude riociguat, preferably most of the riociguat, dissolves in the solvent.
  • Dissolution can be aided by heating, such as bringing the solvent / riociguat mixture to a temperature of from 50°C to just below the boiling point of the solvent, for example from 70°C to 2K below the boiling point of the respective solvent. If the solvent for dissolution of crude riociguat is dimethylformamide a temperature of around 100°C can be used for that step.
  • the obtained solution which may still have some undissolved solids at this stage, can be filtered prior to addition of the antisolvent, for example in the same or a similar fashion as described in the exemplifying section.
  • Anti-solvent is then added to the obtained solution. It is preferred that this step is done at temperatures above ambient temperature, such as from 50°C to 10K below the boiling point of the respective solvent of step a), for example at a temperature of from 50°C to 90°C, such as at around 70°C.
  • Anti-solvent is added in an amount sufficient to cause formation of a solid form of riociguat, such as crystalline riociguat form I or a crystalline solvate of riociguat.
  • Typical volume ratios of antisolvent / water-soluble aprotic solvent are at least 1 :2, such as at least 1 :1 , for example at least 2:1 , at least 3:1 , at least 4:1 or at least 5:1 .
  • the skilled person will appreciate that for an industrial scale precipitation process the amount of antisolvent to be added will be determined experimentally, so as to minimize costs by avoiding the addition of unnecessarily antisolvent.
  • the anti-solvent for step b) is preferably a solvent in which riociguat has a solubility at 70°C and ambient pressure of at most 30 mg/ml, more preferably of at most 20 mg/ml, such as at most 15 mg/ml or at most 10 mg/ml.
  • Preferred anti-solvents are aprotic.
  • suitable anti-solvents are organic esters or organic ketones having a molecular weight of at most 200Da, and preferably of at most 150 Da, such as at most 100 Da.
  • Particularly preferred anti- solvents are organic esters having at most 6 carbon atoms, such as at most 5 carbon atoms. Examples are ethylacetate or methylacetate.
  • organic ketones having at most 6 carbon atoms, such as at most 5 carbon atoms.
  • examples are butan-2-one (methyl-ethyl-ketone) and propanone (acetone).
  • acetone methyl-ethyl-ketone
  • a process where acetone is used in step b) is most preferred, as the final product is highly pure and produced in a very good yield (as described in example 4).
  • a preferred combination of a water-soluble aprotic solvent in step a) and an anti-solvent in step b) is a) dimethylformamide / b) acetone.
  • a further preferred combination of a water-soluble aprotic solvent in step a) and an anti- solvent in step b) is a) dimethylformamide / b) methylacetate.
  • a further preferred combination of a water-soluble aprotic solvent in step a) and an anti- solvent in step b) is a) dimethylformamide / b) ethylacetate.
  • a further preferred combination of a water-soluble aprotic solvent in step a) and an anti- solvent in step b) is a) dimethylformamide / b) butan-2-one.
  • a further combination of a water-soluble aprotic solvent in step a) and an anti-solvent in step b) is a) dioxane / b) acetone.
  • a further combination of a water-soluble aprotic solvent in step a) and an anti-solvent in step b) is a) dioxane / b) methylacetate.
  • a further combination of a water-soluble aprotic solvent in step a) and an anti-solvent in step b) is a) dioxane / b) ethylacetate.
  • a further combination of a water-soluble aprotic solvent in step a) and an anti-solvent in step b) is a) dioxane / b) butan-2-one.
  • a further combination of a water-soluble aprotic solvent in step a) and an anti-solvent in step b) is a) tetrahydrofuran / b) acetone.
  • a further combination of a water-soluble aprotic solvent in step a) and an anti-solvent in step b) is a) tetrahydrofuran / b) methylacetate.
  • a further combination of a water-soluble aprotic solvent in step a) and an anti-solvent in step b) is a) tetrahydrofuran / b) ethylacetate.
  • a further combination of a water-soluble aprotic solvent in step a) and an anti-solvent in step b) is a) tetrahydrofuran / b) butan-2-onebutan-2-one.
  • the solid form of riociguat can be a crystalline solvate, such as a methylecetate solvate, an ethylacetate solvate or a butan-2- onebutan-2-one solvate, or it can be a crystalline solid form of riociguat itself.
  • a crystalline solvate such as a methylecetate solvate, an ethylacetate solvate or a butan-2- onebutan-2-one solvate
  • riociguat form I forms and can be isolated.
  • step b) Even more surprising was that the use of acetone as the antisolvent in step b) led to the direct preparation of riociguat form I in high yield and purity.
  • the present invention also relates to several crystalline solvates of riociguat which are useful for the purification of riociguat, such as riociguat methylacetate solvate, riociguat ethylacetate solvate and riociguat butanon solvate. It has been found that these solvates unexpectedly allow production of riociguat with advantageous properties.
  • Riociguat methylacetate solvate is crystalline and has as an advantage that it allows for an easy desolvation process to yield pure riociguat. Moreover, only methylacetate, a harmless solvent, is present in small amounts in the riociguat obtained from and by the process of the invention which uses riociguat methylacetate solvate as an intermediate.
  • Riociguat ethylacetate solvate is crystalline and has as an advantage that it allows for an easy desolvation process to yield pure riociguat. Moreover, only ethylacetate, a harmless solvent, is present in small amounts in the riociguat obtained from and by the process of the invention which uses riociguat ethylacetate solvate as an intermediate.
  • the riociguat ethylacetate solvate of the invention shows an about 2:1 stoichiometry of riociguat to ethylacetate and is thus best described as being a riociguat hemi-ethylacetate.
  • the present invention preferably relates to riociguat ethylacetate solvate wherein the molar ratio of riociguat to ethylacetate is 1 .8 to 2.2 molecules of riociguat per 1.0 molecule of ethylacetate.
  • Crystalline riociguat ethylacetate solvate of the present invention may be characterized by having an x-ray powder diffraction pattern (XRPD) comprising four or more peaks at 2theta values of the group 8.3 ⁇ 0.2°, 8.7 ⁇ 0.2°, 10.9 ⁇ 0.2°, 13.3 ⁇ 0.2°, 19.4 ⁇ 0.2° and 25.2 ⁇ 0.2° wherein X-ray powder diffraction is measured at a temperature of 22°C using CuKa radiation.
  • XRPD x-ray powder diffraction pattern
  • Crystalline riociguat ethylacetate solvate of the present invention may alternatively be characterized by having an x-ray powder diffraction pattern (XRPD) comprising at least 6, preferably at least 8 or at least 10 peaks at 2theta values selected from peaks indicated in the left hand column of table 1 below.
  • XRPD x-ray powder diffraction pattern
  • Crystalline riociguat ethylacetate solvate of the present invention may also be characterized by having an x-ray powder diffraction pattern (XRPD) comprising four or more peaks at 2theta values of the group 8.3 ⁇ 0.2°, 8.7 ⁇ 0.2°, 10.9 ⁇ 0.2°, 13.3 ⁇ 0.2°, 19.4 ⁇ 0.2° and 25.2 ⁇ 0.2° wherein X-ray powder diffraction is measured at a temperature of 22°C using CuKa radiation, but not having a peak at 9.1 ⁇ 0.2°.
  • XRPD x-ray powder diffraction pattern
  • Crystalline riociguat ethylacetate solvate of the present invention may also be characterized by having an x-ray powder diffraction pattern (XRPD) comprising four or more peaks at 2theta values of the group 8.3 ⁇ 0.2°, 8.7 ⁇ 0.2°, 10.9 ⁇ 0.2°, 13.3 ⁇ 0.2°, 19.4 ⁇ 0.2° and 25.2 ⁇ 0.2° wherein X-ray powder diffraction is measured at a temperature of 22°C using CuKa radiation, but not having a peak at 25.6 ⁇ 0.2°.
  • XRPD x-ray powder diffraction pattern
  • Crystalline riociguat ethylacetate solvate of the present invention may also be characterized by having an x-ray powder diffraction pattern (XRPD) comprising four or more peaks at 2theta values of the group 8.3 ⁇ 0.2°, 8.7 ⁇ 0.2°, 10.9 ⁇ 0.2°, 13.3 ⁇ 0.2°, 19.4 ⁇ 0.2° and 25.2 ⁇ 0.2° wherein X-ray powder diffraction is measured at a temperature of 22°C using CuKa radiation, but not having peaks at 9.1 ⁇ 0.2° and 25.6 ⁇ 0.2°.
  • XRPD x-ray powder diffraction pattern
  • Riociguat butan-2-onebutan-2-one solvate is crystalline and has as an advantage that it allows for an easy desolvation process to yield pure riociguat. Moreover, only butan-2- onebutan-2-one (methyl-ethyl-ketone), a harmless class 3 solvent, is present in small amounts in the riociguat obtained from and by the process of the invention which uses riociguat butan-2-onebutan-2-one solvate as an intermediate.
  • Crystalline riociguat butan-2-one solvate may be characterized by having an x-ray powder diffraction pattern (XRPD) comprising four or more peaks at 2theta values seleted from the group 8.3 ⁇ 0.2°, 1 1 .4 ⁇ 0.2°, 14.7 ⁇ 0.2°, 20.1 ⁇ 0.2°, 24.9 ⁇ 0.2° and 26.5 ⁇ 0.2°, wherein X-ray powder diffraction is measured at a temperature of 22°C using CuKa radiation.
  • XRPD x-ray powder diffraction pattern
  • Crystalline riociguat butan-2-one solvate may alternatively be characterized by having an x- ray powder diffraction pattern (XRPD) comprising at least 6, preferably at least 8 or at least 10 peaks at 2theta values seleted from peaks indicated in the left hand column of table 2 below.
  • XRPD x- ray powder diffraction pattern
  • methylacetate solvate, riociguat ethylecetate solvate and riociguat butan-2-one solvate can be converted to crystal form I of riociguat under mild conditions.
  • the conversion of the riociguat butan-2-one solvate to form I of riociguat can be effected by drying in vacuo , e.g. at about 10 to 20 mbar at a temperature of preferably about 60°C for several hours, e.g. for about 4 to 24 hours.
  • desolvation can be effected by refluxing the above mentioned riociguat solvates in ethylacetate, also yielding riociguat form I.
  • riociguat form I obtained by the conversion of the above- mentioned riociguat solvates has a decreased level of residual solvents compared to the previously available riociguat form I obtained via the riociguat DMSO solvate.
  • Residual solvent determination such as explained below for the measurement of residual DMSO content in riociguat form I of the present invention, can be measured by techniques known in art, e.g. such as gas chromatography.
  • Blank 1 ml internal standard solution in a HS-vial
  • Reference stock solution Weigh about 45 mg- 55 mg from each of MEK, DMF, EE,DMSO in 50 ml internal standard solution.
  • Reference solution Pipette 5 ml Reference stock solution in a 20ml volumetric flask and fill with internal standard solution to the mark. From this solution pipette 1 ml in a HS- vial.
  • Detection limit solution Pipette 0.4ml from the Reference solution in a 10 ml volumetric flask and fill with internal standard solution to the mark.
  • Test solution Weigh about 50 mg-55 mg of the substance in a HS-vial and dissolve in 1 ml internal standard solution.
  • the present invention relates to riociguat crystal form I wherein at most 5000 ppm of DMSO is present.
  • at most 2000 ppm such as at most 1500 ppm, such as at most 1000 ppm, such as at most 90 ppm, at most 80 ppm, at most 70 ppm, at most 60 ppm, at most 50 ppm, at most 40 ppm, at most 30 ppm, at most 20 ppm and most preferably at most 10 ppm residual DMSO is present, in particular when measured according to the above-described residual solvent method.
  • the present invention also relates to riociguat form I, which is essentially free from DMSO (dimethylsulfoxide).
  • DMSO dimethylsulfoxide
  • the obtained riociguat form I of the present invention has an overall organic volatile impurity content of up to l OOOppm, and being essentially free from DMSO.
  • the present invention is further illustrated by the following embodiments and combinations of embodiments resulting from the given dependencies and back-references: Riociguat comprising less than 0.06 wt.% of compound of formula III, based on the total weight of Riociguat.
  • Riociguat according to embodiment 1 comprising less than 10 ppm of compound of formula III.
  • Riociguat according to embodiment 1 comprising less than 2 ppm of compound of formula III.
  • step a) has a solubility in distilled water at 20°C of at least 10g solvent / 100 ml distilled water.
  • step a) has a solubility in distilled water at 20°C of at least 25g solvent / 100 ml distilled water.
  • step a) has a boiling point at a pressure of 1013mbar of below 165°C, in particular of below 155°C.
  • step a) has a melting point at a pressure of 1013mbar of below 15°C, in particular of below 13°C.
  • any one of the embodiments 9 to 44 wherein the water soluble aprotic solvent for step a) is dimethylformamide and wherein the anti-solvent for step b) is selected from methylacetate, ethylacetate, butan-2-one and aceton.
  • Riociguate ethylacetate solvate of embodiment 49, characterized by having a X-ray powder diffraction pattern comprising four or more peaks at 2theta values of the group 8.3 ⁇ 0.2°, 8.7 ⁇ 0.2°, 10.9 ⁇ 0.2°, 13.3 ⁇ 0.2°, 19.4 ⁇ 0.2° and 25.2 ⁇ 0.2° wherein X-ray powder diffraction is measured at a temperature of 22°C using CuKa radiation.
  • Riociguat butan-2-one solvate characterized by having a X-ray powder diffraction pattern comprising four or more peaks at 2theta values of the group 8.3 ⁇ 0.2°, 8.7 ⁇ 0.2°, 10.9 ⁇ 0.2°, 13.3 ⁇ 0.2°, 19.4 ⁇ 0.2° and 25.2 ⁇ 0.2° wherein X-ray powder diffraction is measured at a temperature of 22°C using CuKa radiation.
  • Riociguat butan-2-one solvate of embodiment 51 characterized by having a X-ray powder diffraction pattern comprising four or more peaks at 2theta values of the group 8.3 ⁇ 0.2°, 1 1 .4 ⁇ 0.2°, 14.7 ⁇ 0.2°, 20.1 ⁇ 0.2°, 24.9 ⁇ 0.2° and 26.5 ⁇ 0.2° wherein X-ray powder diffraction is measured at a temperature of 22°C using CuKa radiation.
  • the process of embodiment 43, wherein the isolated solid form of riociguat from step c) is further heated to a temperature of from 50°C to 100°C at a pressure below 900mbar.
  • Riociguat was prepared as disclosed in example 7 of WO 201 1/064171 and had a chemical purity of 91.7% by the area of the riociguat peak in the HPLC-UV elution profile.
  • Both the solvates from examples 1 and 2 can be converted to riociguat Form I by heating the material to 150°C under vacuum for an appropriate amount of time.
  • Example 4 Direct preparation of riociguat form I from crude riociguat using DMF-Acetone Crude Riociguat (200 mg; Form I; 91 .7% percentage area purity) was dissolved in 1.0 ml DMF at 100 °C to obtain a clear solution. After filtration through a 0.44 micron filter, 5 ml acetone was added. The hot solution (water bath 70 °C) was allowed to stand. Crystallisation occurred while the temperature was slowly decreased to ambient temperature. After 24 hours the precipitate was filtered off and dried at ambient conditions to obtain form I. Yield 78% ; 97.6% purity

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne un nouveau procédé pour la purification de riociguat et de nouveaux solvates cristallins qui sont des intermédiaires utiles dans la purification de riociguat.
PCT/EP2016/050825 2015-01-16 2016-01-15 Procédé de préparation de riociguat essentiellement exempt d'impuretés génotoxiques WO2016113415A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP15151499 2015-01-16
EP15151499.9 2015-01-16

Publications (1)

Publication Number Publication Date
WO2016113415A1 true WO2016113415A1 (fr) 2016-07-21

Family

ID=52350024

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2016/050825 WO2016113415A1 (fr) 2015-01-16 2016-01-15 Procédé de préparation de riociguat essentiellement exempt d'impuretés génotoxiques

Country Status (1)

Country Link
WO (1) WO2016113415A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9884859B2 (en) 2013-10-17 2018-02-06 Sunshine Lake Pharma Co., Ltd. Solid form of pyrazolopyridine compound
US20220048907A1 (en) * 2018-12-17 2022-02-17 Adverio Pharma Gmbh Methyl {4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1h-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamate active compound product having improved properties, production and formulation thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003095451A1 (fr) 2002-05-08 2003-11-20 Bayer Healthcare Ag Pyrazolopyridines a substitution carbamate
WO2011064171A2 (fr) 2009-11-27 2011-06-03 Bayer Schering Pharma Aktiengesellschaft Procédé de préparation de méthyl-{4,6-diamino-2-[1-(2-fluorobenzyl)-1h-pyrazolo[3,4-b]pyridino-3-yl]pyrimidino-5-yl}méthylcarbamate et d'épuration de ce composé pour son utilisation en tant qu'agent pharmaceutique
WO2014128109A1 (fr) 2013-02-21 2014-08-28 Bayer Pharma Aktiengesellschaft Formes du {4,6-diamino-2-[1-(2-fluorobenzyl)-1h-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}méthylcarbamate de méthyle

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003095451A1 (fr) 2002-05-08 2003-11-20 Bayer Healthcare Ag Pyrazolopyridines a substitution carbamate
WO2011064171A2 (fr) 2009-11-27 2011-06-03 Bayer Schering Pharma Aktiengesellschaft Procédé de préparation de méthyl-{4,6-diamino-2-[1-(2-fluorobenzyl)-1h-pyrazolo[3,4-b]pyridino-3-yl]pyrimidino-5-yl}méthylcarbamate et d'épuration de ce composé pour son utilisation en tant qu'agent pharmaceutique
WO2014128109A1 (fr) 2013-02-21 2014-08-28 Bayer Pharma Aktiengesellschaft Formes du {4,6-diamino-2-[1-(2-fluorobenzyl)-1h-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}méthylcarbamate de méthyle

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHEM. MED. CHEM, vol. 4, 2009, pages 853 - 865

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9884859B2 (en) 2013-10-17 2018-02-06 Sunshine Lake Pharma Co., Ltd. Solid form of pyrazolopyridine compound
US20220048907A1 (en) * 2018-12-17 2022-02-17 Adverio Pharma Gmbh Methyl {4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1h-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamate active compound product having improved properties, production and formulation thereof

Similar Documents

Publication Publication Date Title
US20100240667A1 (en) Crystalline forms of (6r)-l-erythro-tetrahydrobiopterin dihydrochloride
WO2007013086A1 (fr) Nouveaux polymorphes de tenofovir disoproxil fumarate
AU2021277593A1 (en) Solid forms of [(1 S)-1 -[(2S,4R,5R)-5-(5-amino-2-oxo-thiazolo[4,5-d]pyrimidin-3-yl)-4-hydroxy-te trahydrofuran-2-yl]propyl] acetate
WO2016127960A1 (fr) Sel de sulfate ibrutinib
CA2965716C (fr) Forme cristalline de bisulfate inhibiteur de kinase jak et procede de preparation correspondant
KR20070072891A (ko) 타달라필 결정형 및 이의 제조 방법
WO2016113415A1 (fr) Procédé de préparation de riociguat essentiellement exempt d'impuretés génotoxiques
KR20180113822A (ko) 1-[(4-메틸-퀴나졸린-2-일)메틸]-3-메틸-7-(2-부틴-1-일)-8-(3-(r)-아미노-피페리딘-1-일)-크산틴의 신규한 결정형 및 그의 제조방법
US12012421B2 (en) Solid forms of [(1S)-1-[(2S,4R,5R)-5-(5-amino-2-oxo-thiazolo[4,5-d]pyrimidin-3-yl)-4-hydroxy-tetrahydrofuran-2-yl]propyl] acetate
US12012420B2 (en) Solid forms of [(1S)-1-[(2S,4R,5R)-5-(5-amino-2-oxo-thiazolo[4,5-d]pyrimidin-3-yl)-4-hydroxy-tetrahydrofuran-2-yl]propyl] acetate
EP2189461B1 (fr) Hydrochlorure crystalline d'irinotecan et procédés pour sa préparation
JP6538711B2 (ja) アモルファス形状のチオコルヒチン誘導体
UA67875C2 (uk) Напівгідрохлорид 8-ціано-1-циклопропіл-7-(1s,6s-2,8-діазабіцикло[4.3.0]нонан-8-іл)-6-фтор-1,4-дигідро-4-оксо-3-хінолінкарбонової кислоти та лікарський засіб на його основі
JP7330180B2 (ja) チピラシル塩酸塩結晶ｉｉｉ型の製造方法
CN106957311B (zh) 雷替曲塞的溶剂化物及其制备方法
KR20070014164A (ko) 5,11-디하이드로-11-에틸-5-메틸-8-｛2-｛(1-옥시도-4-퀴놀리닐)옥시｝에틸｝-6Ｈ-디피리도［3,2-ｂ：2',3'-ｅ]［1,4］디아제핀-6-온의 결정 형태
JP2006111561A (ja) 抗菌薬の１／２水和物の製造方法
RU2393162C2 (ru) ЗАМЕЩЕННЫЕ 2Н,8Н-1,4-ДИОКСА-9b-АЗАФЕНАЛЕН-2,8-ДИОНЫ И СПОСОБ ИХ ПОЛУЧЕНИЯ
RO133946B1 (ro) Procedee de preparare şi utilizare ale noilor forme cristaline ale 6-(3-metil-5-nitroimidazol-4-il)sulfanil-9h-pu rinei
US20150290199A1 (en) Linagliptin solid dispersion
WO2017009333A1 (fr) Procédé de purification de l'idélalisib
AU2004259056A1 (en) Method for purification of amlodipine free base

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 16700653

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 16700653

Country of ref document: EP

Kind code of ref document: A1