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WO2024209391A1 - Procédé de préparation de pralsetinib, et intermédiaires de celui-ci sous forme cristalline - Google Patents

Procédé de préparation de pralsetinib, et intermédiaires de celui-ci sous forme cristalline Download PDF

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Publication number
WO2024209391A1
WO2024209391A1 PCT/IB2024/053300 IB2024053300W WO2024209391A1 WO 2024209391 A1 WO2024209391 A1 WO 2024209391A1 IB 2024053300 W IB2024053300 W IB 2024053300W WO 2024209391 A1 WO2024209391 A1 WO 2024209391A1
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Prior art keywords
pralsetinib
formula
solvent
process according
compound containing
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PCT/IB2024/053300
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English (en)
Inventor
Balasaheb Jadhav
Madhu SADASHIVAIAH
Vijay KUMBHAR
Makarand Gore
Sachin DEVADHE
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Olon S.P.A.
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Publication of WO2024209391A1 publication Critical patent/WO2024209391A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B63/00—Purification; Separation; Stabilisation; Use of additives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention relates to a process for preparing Pralsetinib.
  • the present invention also relates to intermediates thereof in crystalline form. Background of the invention
  • FDA Food and Drug Administration granted accelerated approval for Pralsetinib on September 4th, 2020 for non-small cell lung cancer (NSCLC) and on December 1st, 2020 for thyroid cancer, for: (i) adult patients with metastatic RET fusion-positive NSCLC, (ii) adult and paediatric patients >12 years of age with advanced or metastatic RET-mutant medullary thyroid cancer who require systemic therapy, and (iii) adult and paediatric patients >12 years of age with advanced or metastatic RET fusion-positive thyroid cancer who require systemic therapy and who are radioactive iodine refractory (if radioactive iodine is appropriate) .
  • Pralsetinib The synthesis of Pralsetinib and its intermediates is disclosed in WO 2017/079140 Al and WO 2022/120136 Al by Blueprint Medicines Corporation.
  • WO 2021/243192 Al describes crystalline forms A, B, C, F, G, J, K, L, M, N, P, 5-A, 5-B, and 5-C of Pralsetinib.
  • WO 2022/086899 Al describes Pralsetinib crystalline Forms I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII.
  • Forms CM-I, CM-II, CM-III, CM-IV, CM- V, CM-VI, CM-VII and CM-VIII are described in CN111777595A.
  • crystalline Form-II and HyB of Pralsetinib are mentioned.
  • WO 2021/243192 Al describes also different Pralsetinib salts with other acids, such as benzene sulfonic acid, methane sulfonic acid, hydrochloric acid, hydrobromic acid, nitric acid, pyruvic acid, citric acid, fumaric acid, maleic acid, salicylic acid, glutaric acid, sulphuric acid, tartaric acid, phosphoric acid and succinic acid.
  • acids such as benzene sulfonic acid, methane sulfonic acid, hydrochloric acid, hydrobromic acid, nitric acid, pyruvic acid, citric acid, fumaric acid, maleic acid, salicylic acid, glutaric acid, sulphuric acid, tartaric acid, phosphoric acid and succinic acid.
  • Pralsetinib co-crystals are disclosed in WO 2021/243192 Al.
  • co-crystals are reported with 4-amino benzoic acid, 4-hydroxy benzoic acid, benzoic acid, vanillic acid, quercetin dihydrate, gentisic acid, saccharin and urea.
  • Pralsetinib solvates are known.
  • solvates with tetrahydrofuran (THF) , chloroform, cyclohexane, methanol are described in WO 2021/243192 Al and a solvate with dimethyl sulfoxide (DMSO) is described in WO2022117448A1.
  • WO 2021/243192 Al As regards the amorphous form of Pralsetinib, its preparation process by chloroform distillation is described in WO 2021/243192 Al. This process results in the formation of the amorphous form of Pralsetinib, however a substantial amount of chloroform remains trapped . For this reason, controlling residual chloroform within 60 ppm as per ICH limit could be challenging . Moreover, the process according to WO 2021 /243192 Al is not an industrially feasible process .
  • the present invention regards a process for preparing Pralsetinib, which involves the use of Pralsetinib salts or co-crystals as crystalline intermediates .
  • the present invention relates to a process for the preparation of Pralsetinib of Formula I : Formula I as defined in claim 1 .
  • the present invention relates to crystalline compounds containing Pralsetinib with an acid selected from : ( IS ) — ( + ) — 10— camphorsul fonic acid ( CSA) , tri fluoroacetic acid ( TFA) and pyroglutamic acid (PGA) , as defined in the appended claims .
  • an acid selected from : ( IS ) — ( + ) — 10— camphorsul fonic acid ( CSA) , tri fluoroacetic acid ( TFA) and pyroglutamic acid ( PGA)
  • the Applicant has found that the reaction for obtaining the crystalline compounds containing Pralsetinib with the above acids is faster than the reaction for obtaining other salts and requires low temperatures , thus resulting in very good yields and quality of the crystalline intermediates obtained .
  • these crystalline compounds containing Pralsetinib are isolated as solids and for this reason are easier to handle on a large scale .
  • the use of these intermediates allows to obtain Pralsetinib as Active Pharmaceutical Ingredient (API ) of very high quality .
  • the process according to the present invention is advantageous under various aspects .
  • the process of the invention allows to obtain a product free of solvents , therefore it is much easier to meet the requirements of the ICH regulation .
  • Figure 1 XRPD pattern of the crystalline form o f Pralsetinib salt with CSA of Formula V .
  • Figure 2 TGA of the crystalline form of Pralsetinib salt with CSA of Formula V .
  • Figure 3 XRPD pattern of the crystalline form o f Pralsetinib salt with TFA of Formula VI .
  • Figure 4 TGA of the crystalline form of Pralsetinib salt with TFA of Formula VI .
  • Figure 5 XRPD pattern of the crystalline form o f Pralsetinib co-crystal with PGA of Formula VII.
  • Figure 7 XRPD pattern of Pralsetinib of Formula I in amorphous form.
  • the present invention relates to a process for preparing Pralsetinib of Formula I Formula I, said process comprising: a) reacting a compound of Formula II
  • Formula III wherein the solvent is selected from an organic solvent, water or a combination thereof; b) isolating the compound of Formula III at a pH ranging from 2 to 9; c) reacting the isolated compound of Formula III with a compound of Formula IV
  • Formula IV in the presence of a coupling agent, a base and a polar aprotic solvent to obtain Pralsetinib in the form of a solution; d) isolating a crystalline compound containing Pralsetinib by reacting Pralsetinib in the form of a solution obtained in step c) with an acid selected from: ( IS ) - (+ ) -1 O-camphorsulf onic acid (CSA) , trifluoroacetic acid (TFA) and pyroglutamic acid (PGA) ; e) dissolving the isolated crystalline compound containing Pralsetinib obtained in step d) in a solvent selected from alcohols, esters, aromatic hydrocarbons, chlorinated solvents, or mixtures thereof, and adding to the so obtained solution a basic solution to obtain a solution of Pralsetinib as free base; f) isolating Pralsetinib from the solution of Pralsetinib as free base obtained in step e) .
  • the base is preferably selected from: sodium hydroxide (NaOH) , lithium hydroxide (LiOH) and potassium hydroxide (KOH) .
  • the organic solvent used in step a) is preferably selected from: alcohols, ethers.
  • the solvent is an alcohol, it is selected from methyl alcohol (MeOH) , ethyl alcohol (EtOH) .
  • EtOH ethyl alcohol
  • THF tetrahydrofuran
  • Mixtures of solvents are preferably selected from: THF/water, THF/EtOH/water , EtOH/water, and MeOH/water.
  • the mixture of solvents is THF/EtOH/water.
  • the solvent is selected from: alcohols, preferably methyl alcohol (MeOH) or ethyl alcohol (EtOH) ; ethers, preferably tetrahydrofuran (THE) ; and water, or mixtures thereof.
  • alcohols preferably methyl alcohol (MeOH) or ethyl alcohol (EtOH)
  • EtOH ethyl alcohol
  • ethers preferably tetrahydrofuran (THE)
  • water or mixtures thereof.
  • the compound of the Formula II is reacted in step a) with a base at a temperature from 25°C to 70°C, preferably from 50°C to 60°C.
  • the pH is preferably from 2 to 5.
  • the pH value can be obtained by adding an acid, preferably hydrochloric acid (HC1) .
  • step b) isolation of the compound of Formula III is preferably carried out by crystallization or precipitation.
  • a solvent is added, which is preferably selected from alcohols and ketones.
  • the solvent is an alcohol, it is selected from MeOH, EtOH or isopropyl alcohol (IPA)
  • IPA isopropyl alcohol
  • step b) isolation is carried out by crystallization or precipitation, by adding a solvent selected from: alcohols, preferably MeOH, EtOH or isopropyl alcohol (IPA) ; and ketones, preferably acetone; or mixtures thereof .
  • the coupling agent is preferably selected from benzotriazole-l-yl-oxy-tris- pyrrolidino-phosphonium hexafluorophosphate (PyBOP) , N, N, N ' , N ' -tetramet hyl-O- ( IH-benzotriazol-l-yl ) uronium hexafluorophosphate (HBTU) , 2- ( IH-benzotriazole-l-yl ) - 1 , 1 , 3 , 3-tetramethylaminium tetrafluoroborate (TBTU) , N- ethyl-N'- ( 3-dimethylaminopropyl ) carbodiimide hydrochloride (EDC.HC1) and 1-
  • the coupling agent is PyBOP.
  • the base of step c) is preferably selected from N, N-diisopropylethylamine (DIPEA) or triethylamine (TEA) .
  • DIPEA N, N-diisopropylethylamine
  • TEA triethylamine
  • the base is DIPEA.
  • the polar aprotic solvent of step c) is preferably selected from: N,N- dimethylacetamide (DMAc) , dimethyl sulfoxide (DMSO) , N, N-dimethylformamide (DMF) or mixtures thereof.
  • DMAc N,N- dimethylacetamide
  • DMSO dimethyl sulfoxide
  • DMF N, N-dimethylformamide
  • the polar aprotic solvent is DMAc.
  • the compound of the Formula III is reacted with compound of Formula IV in step c) by using PyBOP as coupling agent, DMAc as polar aprotic solvent and DIPEA as base.
  • the crystalline compound containing Pralsetinib of step d) that may be used as intermediate in the above process , can be represented by one of the following formulas : wherein the intermediate of Formula V is
  • Pralsetinib/TFA salt and the intermediate of Formula VI I is Pralsetinib/PGA co-crystal .
  • the acid is preferably tri fluoroacetic acid ( TFA) to obtain the crystalline compound containing Pralsetinib of Formula VI .
  • the isolation according to step d) is obtained by adding a solvent selected from: esters, nitriles, ethers, chlorinated solvents, and water, or mixtures thereof.
  • a solvent selected from: esters, nitriles, ethers, chlorinated solvents, and water, or mixtures thereof.
  • the solvent is an ester, it is preferably ethyl acetate (EtOAc) .
  • EtOAc ethyl acetate
  • the solvent is a nitrile, it is preferably ACN.
  • the solvent is a chlorinated solvent, it is preferably dichloromethane (DCM) .
  • the solvent is an ether, it is preferably tert-butyl methyl ether (MTBE) .
  • the mixture of solvents is EtOAc/MTBE or DCM/MTBE .
  • the isolation according to step d) is obtained by adding a solvent selected from: esters, nitriles, chlorinated solvents, and water, or mixtures thereof.
  • a solvent selected from: esters, nitriles, chlorinated solvents, and water, or mixtures thereof.
  • the solvent is an ester, it is preferably EtOAc.
  • the solvent is a nitrile, it is preferably ACN.
  • the solvent is a chlorinated solvent, it is preferably dichloromethane (DCM) .
  • the mixture of solvents is ACN/water .
  • the compounds of Formula V, VI and VII are isolated according to step d) at a temperature from 25°C to 70°C, more preferably from 25°C to 30°C.
  • the basic solution is preferably an aqueous solution of a base selected from: LiOH, NaOH, KOH, or mixtures thereof.
  • the solvent used in step e) is selected from alcohols, esters, chlorinated solvents, aromatic hydrocarbons, or mixtures thereof.
  • the solvent when the solvent is an ester, it is EtOAc.
  • the solvent when the solvent is an aromatic hydrocarbon, it is toluene.
  • the solvent when the solvent is an alcohol, it is selected from EtOH, MeOH, tert-butanol (t-BuOH) .
  • the solvent is a chlorinated solvent, it is dichloromethane.
  • the mixture of solvents is selected from EtOH/DCM, MeOH/DCM, t- BuOH/DCM. More preferably, the mixture of solvent is EtOH/DCM.
  • the mixture of solvents is a mixture of alcohol/DCM in an amount of from 10/90 % to 50/50 % v/v.
  • Pralsetinib With reference to the isolation of Pralsetinib according to step f ) , it is preferably carried out by distillation, lyophilization or spray-drying.
  • the so obtained Pralsetinib can be in crystalline form or, preferably, in amorphous form.
  • distillation it is performed at a temperature from 25°C to 100°C, preferably from 70°C to 80°C.
  • an antisolvent is added.
  • This antisolvent is preferably selected from alkanes, ethers.
  • the antisolvent is an alkane, it is preferably selected from cyclohexane, n-heptane, n- hexane .
  • the antisolvent is an ether, it is preferably MTBE .
  • the invention also relates to crystalline compounds containing
  • Pralsetinib having formulas: .
  • the crystalline compound containing Pralsetinib of Formula V is the Pralsetinib/CSA salt, and it has an X- ray powder diffraction pattern comprising at least one of the characteristic peaks, expressed in 2-theta values (26) , at 5.7° ⁇ 0.2°, 10.8° ⁇ 0.2°, 13.8° ⁇ 0.2°, 17.0° ⁇ 0.2°, 19.4° ⁇ 0.2°.
  • the crystalline compound containing Pralsetinib of Formula V has an X- ray powder diffraction pattern comprising at least two of the characteristic peaks, expressed in 2-theta values (26) , at 5.7° ⁇ 0.2°, 10.8° ⁇ 0.2°, 13.8° ⁇ 0.2°, 17.0° ⁇ 0.2°, 19.4° ⁇ 0.2°.
  • the crystalline compound containing Pralsetinib of Formula V has an X-ray powder diffraction pattern comprising at least three of the characteristic peaks, expressed in 2-theta values (26) , at 5.7° ⁇ 0.2°, 10.8° ⁇ 0.2°, 13.8° ⁇ 0.2°, 17.0° ⁇ 0.2°, 19.4° ⁇ 0.2°. Even more preferably, the crystalline compound containing Pralsetinib of Formula V has an X-ray powder diffraction pattern comprising at least four of the characteristic peaks, expressed in 2-theta values (20) , at 5.7° ⁇ 0.2°, 10.8° ⁇ 0.2°, 13.8° ⁇ 0.2°, 17.0° ⁇ 0.2°, 19.4° ⁇ 0.2°. According to a preferred embodiment, the crystalline compound containing Pralsetinib of Formula
  • V has an X-ray powder diffraction pattern comprising or consisting of the characteristic peaks, expressed in 2- theta values (26) , at 5.7° ⁇ 0.2°, 10.8° ⁇ 0.2°, 13.8° ⁇ 0.2°, 17.0° ⁇ 0.2°, 19.4° ⁇ 0.2°.
  • the crystalline Pralsetinib/CSA salt of Formula V further has at least one of the characteristic peaks, expressed in 2-theta values (20) , at 20.0° ⁇ 0.2° , 21.8° ⁇ 0.2°, 22.1° ⁇ 0.2°.
  • the crystalline Pralsetinib/CSA salt of Formula V shows the TGA of Figure 2.
  • VI is in the form of a Pralsetinib/TFA salt, and it has an X-ray powder diffraction pattern comprising at least one of the characteristic peaks, expressed in 2-theta values (26) , at 6.1° ⁇ 0.2°, 7.8° ⁇ 0.2°, 14.3° ⁇ 0.2°, 15.6° ⁇ 0.2°, 17.7° ⁇ 0.2°, 17.9° ⁇ 0.2°, 22.1° ⁇ 0.2°.
  • the crystalline compound containing Pralsetinib of Formula VI has an X-ray powder diffraction pattern comprising at least two of the characteristic peaks, expressed in 2-theta values (26) , at 6.1° ⁇ 0.2°, 7.8° ⁇ 0.2°, 14.3° ⁇ 0.2°, 15.6° ⁇ 0.2°, 17.7° ⁇ 0.2°, 17.9° ⁇ 0.2°, 22.1° ⁇ 0.2°.
  • the crystalline compound containing Pralsetinib of Formula VI has an X-ray powder diffraction pattern comprising at least three of the characteristic peaks, expressed in 2-theta values (26) , at 6.1° ⁇ 0.2°, 7.8° ⁇ 0.2°, 14.3° ⁇ 0.2°, 15.6° ⁇ 0.2°, 17.7° ⁇ 0.2°, 17.9° ⁇ 0.2°, 22.1° ⁇ 0.2°.
  • the crystalline compound containing Pralsetinib of Formula VI has an X- ray powder diffraction pattern comprising at least four of the characteristic peaks, expressed in 2-theta values (26) , at 6.1° ⁇ 0.2°, 7.8° ⁇ 0.2°, 14.3° ⁇ 0.2°, 15.6° ⁇ 0.2°, 17.7° ⁇ 0.2°, 17.9° ⁇ 0.2°, 22.1° ⁇ 0.2°.
  • the crystalline compound containing Pralsetinib of Formula VI has an X- ray powder diffraction pattern comprising or consisting of the characteristic peaks, expressed in 2-theta values (26) , at 6.1° ⁇ 0.2°, 7.8° ⁇ 0.2°, 14.3° ⁇ 0.2°, 15.6° ⁇ 0.2°, 17.7° ⁇ 0.2°, 17.9° ⁇ 0.2°, 22.1° ⁇ 0.2°.
  • the crystalline Pralsetinib/TFA salt of Formula VI further has a characteristic peak, expressed in 2-theta values (26) , at 11.5° ⁇ 0.2°.
  • the crystalline Pralsetinib/TFA salt of Formula VI shows the TGA of Figure 4.
  • the invention also relates to a crystalline compound containing Pralsetinib having Formula VII:
  • the crystalline compound containing Pralsetinib of Formula VII is a Pralsetinib/PGA co-crystal, and it has an X-ray powder diffraction pattern comprising at least one of the characteristic peaks, expressed in 2-theta values (26) , at 6.4° ⁇ 0.2°, 8.5° ⁇ 0.2°, 13.3° ⁇ 0.2°, 14.9° ⁇ 0.2°, 18.2° ⁇ 0.2°.
  • the crystalline compound containing Pralsetinib of Formula VII has an X-ray powder diffraction pattern comprising at least two of the characteristic peaks, expressed in 2-theta values (26) , at 6.4° ⁇ 0.2°, 8.5° ⁇ 0.2°, 13.3° ⁇ 0.2°,
  • the crystalline compound containing Pralsetinib of Formula VII has an X-ray powder diffraction pattern comprising at least three of the characteristic peaks, expressed in 2-theta values (26) , at 6.4° ⁇ 0.2°, 8.5° ⁇ 0.2°, 13.3° ⁇ 0.2°,
  • the crystalline compound containing Pralsetinib of Formula VII has an X-ray powder diffraction pattern comprising at least four of the characteristic peaks, expressed in 2-theta values (26) , at 6.4° ⁇ 0.2°, 8.5° ⁇ 0.2°, 13.3° ⁇ 0.2°, 14.9° ⁇ 0.2°, 18.2° ⁇ 0.2°.
  • the crystalline compound containing Pralsetinib of Formula VII has an X-ray powder diffraction pattern comprising or consisting of the characteristic peaks, expressed in 2-theta values (26) , at 6.4° ⁇ 0.2°, 8.5° ⁇ 0.2°, 13.3° ⁇ 0.2°, 14.9° ⁇ 0.2°, 18.2° ⁇ 0.2° .
  • the crystalline Pralsetinib/PGA cocrystal of Formula VII further has at least one of the characteristic peaks, expressed in 2-theta values (20) , at 19.1° ⁇ 0.2°, 22.8° ⁇ 0.2°, 23.7° ⁇ 0.2°, 27.2° ⁇ 0.2°.
  • the crystalline Pralsetinib/PGA cocrystal of Formula VII shows the TGA of Figure 6.
  • DIPEA N, N-Diisopropylethylamine
  • Example 1 Synthesis of the compound of Formula III (cyclohexanecarboxylic acid, l-methoxy-4- [ 4-methyl- 6- [ (5-methyl-lH -pyrazol-3-yl ) amino] -2-pyrimidinyl ] ) .
  • Example 2 Synthesis of the compound of Formula III (cyclohexanecarboxylic acid, l-methoxy-4- [ 4-methyl- 6- [ (5-methyl-lH -pyrazol-3-yl ) amino] -2-pyrimidinyl] ) .
  • the suspension was stirred for 30 min, then PyBOP was added (11.30 g, 21.71 mmol) .
  • the reaction mixture was stirred for 2 hours and the end of the reaction was monitored by HPLC .
  • the reaction mixture was diluted with H2O (200 mL) and the product was extracted with EtOAc (200 mL) .
  • the organic layer was washed with 9.0% aqueous NaHCCL followed by 15.0% brine solution.
  • the organic layer was distilled to get an oily residue to which EtOAc (50 mL) was added and stirred to get clear solution.
  • TFA was added (2.14 g, 18.79 mmol) to the solution and stirred for 2-3 hours until precipitation occurred.
  • the suspension was stirred for 30 mins and PyBOP (4.52 g, 8.68 mmol) was added.
  • the reaction mixture was stirred for 2 hours and the end of the reaction was monitored by HPLC.
  • the reaction mixture was diluted with H2O (80 mL) and the product extracted with ethyl acetate (80 mL) .
  • the organic layer was washed with 9.0% aqueous NaHCCh followed by 15.0% brine solution.
  • the organic layer was distilled to get an oily residue to which EtOAc (20 mL) was added and stirred to get clear solution.
  • Pyroglutamic acid (0.97 g, 7.5 mmol) was added and the reaction mixture was stirred for 12 hours.
  • Pralsetinib/CSA salt (Formula V) was dissolved in DCM (10 volumes) The obtained solution was washed with 10% aqueous NaOH solution (10 volumes) . The organic layer was distilled to get foamy and amorphous solid which was dissolved in DCM (10 volumes) with 10-50% of EtOH to get clear solution. The solution was filtered to remove particles and distilled under vacuum at the temperature of 25-80°C with or without agitation to remove the solvents completely, then cooled to 25-30°C and added cyclohexane (10 volumes) , stirred for 2 hours. The product was filtered and dried in VTD to obtain Pralsetinib in amorphous form (Formula I) with yield > 90.0%.
  • Example 9 Pralsetinib (Formula I) in amorphous form from Pralsetinib/TFA salt (Formula VI) .
  • Pralsetinib/TFA salt (Formula VI) (5.0 g, 7.73 mmol) was dissolved in DCM (50 ml) . The obtained solution was washed with 10% aqueous NaOH solution (50 ml) . The organic layer was distilled to get foamy and amorphous solid which was dissolved in DCM (50 ml) with 10-50% EtOH to get clear solution. The solution was filtered to remove particles and distilled under vacuum at temperature 25-80°C with or without agitation to remove the solvents completely, then cooled to 25°-30°C and added cyclohexane (50 ml) , stirred for 2 hours. The product was filtered and dried in VTD to obtain Pralsetinib amorphous form (Formula I) with yield > 90.0%.
  • Example 10 Pralsetinib Amorphous form (Formula I) from Pralsetinib/PGA co-crystal (Formula VII) .
  • Pralsetinib/PGA co-crystal (Formula VII) was dissolved in DCM (10 volumes) . The obtained solution was washed with 10% aqueous NaOH solution (10 volumes) . The organic layer was distilled to get foamy and amorphous solid which was dissolved in DCM (10 volumes) with 10-50% EtOH to get clear solution. The solution was filtered to remove particles and distilled under vacuum at temperature 25-80°C with or without agitation to get a foamy solid. Cooled to 25-30°C then cyclohexane (10 volumes) was added, stirred for 2 hours. The product was filtered and dried in VTD to obtain Pralsetinib (Formula I) in amorphous form with yield > 90.0%.

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Abstract

La présente invention concerne un procédé de préparation de Pralsetinib. La présente invention concerne également des intermédiaires de ceux-ci sous forme cristalline.
PCT/IB2024/053300 2023-04-06 2024-04-04 Procédé de préparation de pralsetinib, et intermédiaires de celui-ci sous forme cristalline WO2024209391A1 (fr)

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IT102023000006819A IT202300006819A1 (it) 2023-04-06 2023-04-06 Processo per preparare pralsetinib in forma amorfa, e relativi intermedi in forma cristallina.

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WO2021243186A1 (fr) * 2020-05-29 2021-12-02 Blueprint Medicines Corporation Compositions pharmaceutiques de pralsetinib
WO2021243192A1 (fr) * 2020-05-29 2021-12-02 Blueprint Medicines Corporation Formes solide de pralsetinib
WO2022086899A1 (fr) * 2020-10-19 2022-04-28 Teva Pharmaceuticals International Gmbh Formes à l'état solide de pralsetinib et leur procédé de préparation
WO2022120136A1 (fr) * 2020-12-04 2022-06-09 Blueprint Medicines Corporation Procédé de préparation de pralsétinib

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