WO2021140525A1 - Nouvelle forme cristalline de 1-(2,2-difluoro-2h-1,3-benzodioxol-5-yl)-n-{1-[(2r)-2,3-dihydroxypropyl]-6-fluoro-2-(1-hydroxy-2-méthylpropan-2-yl)-1h-indol-5-yl}cyclopropane-1-carboxamide et son procédé de préparation - Google Patents

Nouvelle forme cristalline de 1-(2,2-difluoro-2h-1,3-benzodioxol-5-yl)-n-{1-[(2r)-2,3-dihydroxypropyl]-6-fluoro-2-(1-hydroxy-2-méthylpropan-2-yl)-1h-indol-5-yl}cyclopropane-1-carboxamide et son procédé de préparation Download PDF

Info

Publication number
WO2021140525A1
WO2021140525A1 PCT/IN2021/050021 IN2021050021W WO2021140525A1 WO 2021140525 A1 WO2021140525 A1 WO 2021140525A1 IN 2021050021 W IN2021050021 W IN 2021050021W WO 2021140525 A1 WO2021140525 A1 WO 2021140525A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
solvents
palladium
process according
tezacaftor
Prior art date
Application number
PCT/IN2021/050021
Other languages
English (en)
Inventor
Thirumalai Rajan Srinivasan
Eswaraiah Sajja
Vijayavitthal T MATHAD
Venkata Narasayya SALADI
Satyanarayana Revu
Suresh Challa
Original Assignee
Msn Laboratories Private Limited, R&D Center
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 Msn Laboratories Private Limited, R&D Center filed Critical Msn Laboratories Private Limited, R&D Center
Publication of WO2021140525A1 publication Critical patent/WO2021140525A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present application relates to a novel crystalline form of 1-(2,2-difluoro- 2H- 1 ,3-benzodioxol-5-yl)-N- ⁇ 1-[(2R)-2,3-dihydroxypropyl]-6-fluoro-2-(1-hydroxy- 2-methylpropan-2-yl)-1H-indol-5-yl ⁇ cyclopropane- 1 -carboxamide compound of formula- 1 and its process for the preparation thereof.
  • Structure of formula- 1 is shown as follows and which is referred to as Tezacaftor.
  • the present application also relates to the novel process for the preparation of
  • Tezacaftor is approved by USFDA as a combination drug with Ivacaftor under the brand name of SYMDEKO and another combination with Ivacaftor and Elexacaftor under the brand name of TRIKAFTA for the treatment of cystic fibrosis in aged 12 years and older who are homozygous for the F508del mutation or who are heterozygous for the F508del mutation and have one of the following mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.
  • CFTR cystic fibrosis transmembrane conductance regulator
  • Tezacaftor and its process for the preparation was disclosed in US7645789B2.
  • This patent discloses the purification of Tezacaftor residue by the column chromatography (50-100 % ethyl acetate and hexanes) to obtain the cream-colored foamy solid.
  • US8802868B2 discloses the crystalline Form-A of Tezacaftor and amorphous solid dispersions of Tezacaftor and co-polymer.
  • Polymorphic forms of a compound can be distinguished in a laboratory by X- ray diffraction spectroscopy and by other methods such as, infrared spectrometry. Additionally, polymorphic forms of the same drug substance or active pharmaceutical ingredient, can be administered by itself or formulated as a drug product (also known as the final or finished dosage form), and are well known in the pharmaceutical art to affect, for example, the solubility, stability, flowability, tractability and impressibility of drug substances and the safety and efficacy of drug products. The present inventors developed a process for the preparation of Tezacaftor using novel key starting materials.
  • the first embodiment of the present invention provides a novel crystalline form of Tezacaftor of formula- 1, herein after designated as crystalline form-M.
  • the second embodiment of the present invention provides a process for the preparation of crystalline form-M of Tezacaftor of formula- 1.
  • Third embodiment of the present invention provides a processes for preparation of Tezacaftor of formula- 1.
  • Fourth embodiment of the present invention provides a process for the preparation of(R)-2-( 1 -(benzyloxy)-2-methylpropan-2-yl)- 1 -((2,2-dimethyl- 1,3- dioxolan-4-yl) methyl)-6-fluoro-5-nitro-1H-indole of formula-7.
  • Seventh embodiment of the present invention provides another process for the preparation of Tezacaftor.
  • Ninth embodiment of present invention provides one or more novel intermediates of Tezacaftor selected from compound of formula-4, compound of formula-7, compound of formula-9, compound of formula- 11 and compound of formula-13.
  • Figure-1 Illustrates the PXRD pattern of crystalline Form-M of Tezacaftor.
  • Figure-2 Illustrates the PXRD pattern of crystalline Form-M of Tezacaftor obtained according to the example-2.
  • suitable solvent used in the present invention can be selected from but not limited to “hydrocarbon solvents” such as n-pentane, n-hexane, n-heptane, cyclohexane, petroleum ether, benzene, toluene, xylene and mixtures thereof; “ether solvents” such as dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, tetrahydrofuran, 1,4-dioxane and mixtures thereof; “ester solvents” such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n- butyl acetate, isobutyl acetate, tert-butyl acetate and mixtures thereof; “polar-aprotic solvents” such as dimethylacetamide, dimethylformamide,
  • base used in the present invention refers to inorganic bases selected from “alkali metal carbonates” such as sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate and the like; “alkali metal bicarbonates” such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate and the like; “alkali metal hydroxides” such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; “alkyl metals” such as n-butyl lithium and like; “metal hydrides” such as lithium hydride, sodium hydride, potassium hydride and the like; “alkali metal phosphates” such as disodium hydrogen phosphate, dipotassiumhydrogen phosphate; ammonia such as aqueous ammonia, ammonia gas, methanolic ammonia and like and “organic bases” selected from but not limited to methyl amine, ethyl amine, diisopropyl amine, diisopropy
  • the term “deprotecting agent” is selected "acids” such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, acetic acid, trifluoro acetic acid, formic acid, benzene sulfonic acid, trifluoromethane sulfonic acid, toluene sulfonic acid, pyridinium p-toluene sulfonic acid etc; and "hydrogen fluoride (HF) sources” such as ammonium fluoride, tetrabutyl ammonium fluoride, pyridine-HF, Et3N-3HF etc; Zn/Acetic acid, DDQ; titanium reagents such as titanium tetrachloride; "base” such as alkali metal carbonate and alkali metal hydroxides, sodium in liquid ammonia, organic base etc.; metal catalysts in presence of hydrogen source.
  • HF hydrogen fluoride
  • the first aspect of first embodiment provides the crystalline form-M of Tezacaftor of formula- 1 characterized by its powder X-Ray difffactogram illustrated in figure- 1 or figure-2.
  • the second aspect of the first embodiment provides the use of crystalline form-M of Tezacaftor for the preparation of pharmaceutical formulations.
  • the third aspect of the first embodiment provides pharmaceutical composition comprising crystalline form-M of Tezacaftor and at least one pharmaceutically acceptable excipient.
  • pharmaceutical compositions or “pharmaceutical formulations” include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.
  • Second embodiment of the present invention provides process for the preparation of crystalline form-M of Tezacaftor of formula- 1, comprising: a) dissolving Tezacaftor in a solvent, b) isolating crystalline form-M of Tezacaftor compound of formula- 1.
  • dissolving Tezacaftor in step-a) can be carried out at a temperature ranging from about 25°C to reflux temperature of the solvent used.
  • the solvent in step-a) is selected from ether solvent; isolating crystalline form-M of Tezacaftor in step-b) is by solvent removal by known techniques which are selected from combining with an anti-solvent, distillation, decanting, filtration, cooling the mixture to lower temperatures to precipitate the solid followed by filtration of the mixture, crystallization.
  • the anti-solvent is a mixture of ether solvents and hydrocarbon solvents.
  • step a) or step-b) optionally involve seeding with crystalline form-M of compound of formula- 1.
  • crystalline form-M of Tezacaftor may be isolated by any of the methods known in the art or may be isolated by employing any of the techniques, but not limited to distillation, decantation, filtration by gravity or suction, centrifugation, adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used and the like.
  • Crystalline form-M of Tezacaftor obtained according to the present invention has particle size of about less than about 300 ⁇ m or less than about 200 ⁇ m or less than about 150 ⁇ m or less than about 100 ⁇ m or less than about 50 ⁇ m or any other suitable particle sizes.
  • Third embodiment of the present invention provides a process for preparation of Tezacaftor of formula- 1 comprising: a) reacting 2-bromo-5-fluoro-4-nitroaniline of formula-2 with (((2,2-dimethylbut-3- yn- 1 -yl)oxy)methyl)benzene of formula-3 to provide 2-(4-(benzyloxy)-3,3- dimethylbut- 1 -yn- 1 -yl)-5-fluoro-4-nitroaniline formula-4, b) cyclizing 2-(4-(benzyloxy)-3,3-dimethylbut-1-yn-1-yl)-5-fluoro-4-nitroaniline formula-4 to provide 2-(1-(benzyloxy)-2-methylpropan-2-yl)-6-fluoro-5-nitro- lH-indole of formula-5, c) converting 2-(1-(benzyloxy)-2-methylpropan-2-yl)-6-fluoro-5-nitro-1H-indole formula
  • the reaction of step-a) can be carried out in presence of a catalyst, wherein the suitable catalyst is effective in catalyzing Sonogashira-type reaction comprising cross-coupling of a terminal alkyne with an aryl electrophile.
  • the catalyst may be selected from [1,1'- bis(diphenylphosphino) ferrocene]dichloropalladium(II) ([Pd(dppf)Cl 2 ]), [1,1'-bis(di- tert-butylphoshino) ferrocene]dichloropalladium(I) ([Pd(dtbpf)Cl 2 ]) tetrakis (triphenylphosphine) palladium (0)(Pd(PPh3) 4 ), bromo(tri-tert-butylphosphine) palladium(I) dimer ([Pd(p-Br)(t-Bu 3 P)] 2 ), bis(tri-tert-butylphosphine)palladium(0) ([Pd(tBu 3 P)] 2 ), palladium(II) acetate (Pd(OAc) 2 ), palladium(II) chloride (PdC
  • catalyst (C2) is bis(benzonitrile)palladium(II) dichloride ([Pd(PhCN) 2 Cl 2 ]) ⁇
  • Catalyst may be used in combination with a co-catalyst and/or a ligand.
  • Co-catalyst is preferably a copper (I) catalyst, and most preferably is copper (I) iodide (Cul).
  • the reaction of step-a) can be carried out in presence of a base; wherein the base can be selected from tertiary amines, metal carbonates and metal phosphates.
  • the reaction of step-a) can be carried out in a solvent, wherein the solvent can be selected from but not limited to polar solvents such as water, polar-aprotic solvents, alcohol solvents, ether solvents, nitrile solvents, chloro solvents, ester solvents, hydrocarbon solvents, ketone solvents or mixtures thereof.
  • polar solvents such as water, polar-aprotic solvents, alcohol solvents, ether solvents, nitrile solvents, chloro solvents, ester solvents, hydrocarbon solvents, ketone solvents or mixtures thereof.
  • the cyclization of compound of formula-4 can be carried out in presence of a catalyst; wherein the catalyst is selected from tetrakis(triphenylphosphine) palladium(0) (Pd(PPh 3 ) 4 ), palladium(II) chloride (PdCl 2 ), palladium(II) iodide (Pdl 2 ), bis (benzonitrile)palladium(II) dichloride ([Pd(PhCN) 2 Cl 2 ]), bis(triphenylphosphine) palladium(II) dichloride ([Pd(PPh3) 2 Cl 2 ]), bis(acetonitrile) palladium(II) dichloride ([Pd(NCMe) 2 Cl 2 ]), palladium(II) trifluoroacetate (Pd(TFA) 2 ), copper(II) acetate (Cu(OAc) 2 ), and indium(III) bromide (InBr
  • the cyclization of compound of formula-4 can be carried out in a solvent; wherein the solvent can be selected from but not limited to polar solvents such as water, polar-aprotic solvents, alcohol solvents, ether solvents, chloro solvents, ester solvents, hydrocarbon solvents, ketone solvents or mixtures thereof.
  • polar solvents such as water, polar-aprotic solvents, alcohol solvents, ether solvents, chloro solvents, ester solvents, hydrocarbon solvents, ketone solvents or mixtures thereof.
  • converting the compound of formula-5 to Tezacaftor can be done by any of the process described in the present application.
  • Fourth embodiment of the present invention provides a process for the preparation of (R)-2-( 1 -(benzyloxy)-2-methylpropan-2-yl)- 1 -((2,2-dimethyl- 1,3- dioxolan-4-yl) methyl)-6-fluoro-5-nitro-1H-indole of formula-7 comprising: reacting 2-(1-(benzyloxy)-2-methylpropan-2-yl)-6-fluoro-5-nitro-1H-indole of formula-5 with compound of formula-6 to provide compound of formula-7.
  • the reaction can be carried out in a solvent, wherein the solvent can be selected from but not limited to polar solvents such as water, polar-aprotic solvents, nitrile solvents, alcohol solvents, ether solvents, chloro solvents, ester solvents, ketone solvents or mixtures thereof.
  • polar solvents such as water, polar-aprotic solvents, nitrile solvents, alcohol solvents, ether solvents, chloro solvents, ester solvents, ketone solvents or mixtures thereof.
  • reduction and debenzylation can be carried out in presence of a catalyst; wherein the suitable catalyst can selected from one or more of the group consisting of a hydrogen source, palladium catalyst such as selected from: palladium on carbon, palladium on alumina, palladium on barium sulfate, palladium on calcium carbonate, palladium on barium carbonate, palladium on strontium carbonate, palladium on silica, and palladium hydroxide on carbon (Pearlman's catalyst), Pt/C, PtO 2 , Fe, Fe in acidic media like acetic acid, HQ, NH 4 Cl; Sn-HCl, Stannous chloride (SnCl 2 ), Zn in acidic media like acetic acid, NH 4 Cl, Zinc dust, Ni, Raney Ni.
  • a hydrogen source palladium catalyst such as selected from: palladium on carbon, palladium on alumina, palladium on barium sulfate, palladium on calcium carbonate, pal
  • reduction and debenzylation can be carried out in a solvent; wherein the solvent can be selected polar solvents such as water, polar-aprotic solvents, nitrile solvents, alcohol solvents, ether solvents, chloro solvents, ester solvents, hydrocarbon solvents, ketone solvents or mixtures thereof.
  • polar solvents such as water, polar-aprotic solvents, nitrile solvents, alcohol solvents, ether solvents, chloro solvents, ester solvents, hydrocarbon solvents, ketone solvents or mixtures thereof.
  • the (R)-2-(5-amino-1-((2,2-dimethyl-1,3- dioxolan-4-yl)methyl)-6-fluoro-1H-indol-2-yl)-2-methylpropan- 1-ol formula-8 is further converted into Tezacaftor.
  • Converting compound of formula-8 to Tezacaftor can be done by any of the processes described in literature such as US7645789 B2 or other references or present application.
  • the reduction in step-a) can be carried out in presence of a reducing agent optionally in presence of a hydrogen pressure; wherein the reducing agent can be selected from Raney nickel or palladium-on- carbon, platinum (IV) oxide, or Urushibara nickel, iron in acidic media, sodium hydrosulfite, Sodium sulfide (or hydrogen sulfide and base), tin(II) chloride, titanium(III) chloride, Fe-acetic acid, Fe-hydrochloric acid or Fe in combination with ammonium chloride.
  • a reducing agent optionally in presence of a hydrogen pressure
  • the reducing agent can be selected from Raney nickel or palladium-on- carbon, platinum (IV) oxide, or Urushibara nickel, iron in acidic media, sodium hydrosulfite, Sodium sulfide (or hydrogen sulfide and base), tin(II) chloride, titanium(III) chloride, Fe-acetic acid, Fe-hydrochloric acid or Fe in combination
  • the reaction in step-b) can carried out in presence of a coupling agent; wherein the coupling agent can be selected form halogenating agents, carbodiimides, uranium reagents and carbonyldiimidazoles in solvent.
  • a coupling agent can be selected form halogenating agents, carbodiimides, uranium reagents and carbonyldiimidazoles in solvent.
  • the debenzylation in step-c) can carried out in presence of a hydrogen source optionally in presence of a catalyst; wherein hydrogen source is selected from one or more selected from hydrogen, hydrazine hydrate, ammonium formate, formic acid and formic acid-triethylamine azeotrope; catalyst can be selected from Pd-C and/or Pt-C.
  • the deprotection in step-d) can be carried out in presence of an acid or a base; wherein the acid is selected from organic acid or inorganic acid; the base is selected from organic base or inorganic base.
  • the steps-a) to step-d) can be carried out in a solvent; wherein the solvent can be selected polar solvents such as water, polar- aprotic solvents, nitrile solvents, alcohol solvents, ether solvents, chloro solvents, ester solvents, hydrocarbon solvents, ketone solvents or mixtures thereof.
  • polar solvents such as water, polar- aprotic solvents, nitrile solvents, alcohol solvents, ether solvents, chloro solvents, ester solvents, hydrocarbon solvents, ketone solvents or mixtures thereof.
  • Seventh embodiment of the present invention provides a process for the preparation of Tezacaftor comprises: a) deprotecdng compound of formula- 11 to provide compound of formula-13. b) debenzylation of compound of formula- 13 to provide Tezacaftor,
  • the step-a) and step-b) can be carried out in a solvent; wherein the solvent can be selected polar solvents such as water, polar-aprotic solvents, nitrile solvents, alcohol solvents, ether solvents, chloro solvents, ester solvents, hydrocarbon solvents, ketone solvents or mixtures thereof.
  • polar solvents such as water, polar-aprotic solvents, nitrile solvents, alcohol solvents, ether solvents, chloro solvents, ester solvents, hydrocarbon solvents, ketone solvents or mixtures thereof.
  • novel intermediates selected from compound of formula-4, compound of formula-5, compound of formula-7, compound of formula-9, compound of formula- 11 and compound of formula- 13 obtained as per the present invention are useful in the preparation of Tezacaftor.
  • Ninth embodiment of present invention provides one or more novel intermediates of Tezacaftor selected from compound of formula-4, compound of formula-5, compound of formula-7, compound of formula-9, compound of formula- 11 and compound of formula-13.
  • Tezacaftor prepared according to the present invention having a purity of about 95%; preferably greater than about 97%; more preferably greater than about 99% as measured by HPLC.
  • Tezacaftor prepared according to the present invention can be further micronized or milled in conventional techniques to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements.
  • Techniques that may be used for particle size reduction include, but not limited to ball milling, roll milling and hammer milling, and jet milling. Milling or micronization may be performed before drying, or after the completion of drying of the product.
  • compositions comprising Tezacaftor and one or more pharmaceutically acceptable excipient.
  • pharmaceutical compositions include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.
  • the “excipient” is selected from but not limited to polyvinylpyrrolidone (povidone or PVP), polyvinylpolypyrrolidone, polysorbate, copovidone, cross linked polyvinyl pyrrolidone (crospovidone), polyethylene glycol (macrogol or PEG), polyvinyl alcohol, polyvinyl chloride, polyvinyl acetate, propylene glycol, cellulose, cellulose acetate phthalate (CAP), methyl cellulose, carboxymethyl cellulose (CMC, its sodium and calcium salts), carboxymethylethyl cellulose (CMEC), ethyl cellulose, hydroxymethyl cellulose, ethyl hydroxyethyl cellulose, hydroxyethylcellulose, hydroxypropyl cellulose (HPC), hydroxypropyl cellulose acetate succinate, hydroxypropyl methyl cellulose (hypromellose or HPMC), hydroxypropyl methylcellulose acetate succinate (HPMC-
  • a pharmaceutical composition comprising Tezacaftor prepared according to the present invention and one or more pharmaceutically acceptable carriers for the treatment of cystic fibrosis in aged 12 years and older who are homozygous for the F508del mutation or who are heterozygous for the F508del mutation and have one of the following mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.
  • CFTR cystic fibrosis transmembrane conductance regulator
  • the PXRD analysis of compounds of the present invention is carried out by using BRUKER/D8 ADVANCE X-Ray diffractometer using CuK ⁇ radiation of wavelength 1.5406Ao and at a continuous scan speed of 0.03°/min.
  • the best mode of carrying out the present invention was illustrated by the below mentioned example. These examples were provided as illustration only and hence should not be construed as limitation to the scope of the invention.
  • Example-1 Preparation of crystalline form-M Tezacaftor
  • Example-2 Preparation of crystalline form-M Tezacaftor A solution of Tezacaftor (90 gm) in tetrahydrofuran (900 ml) at 25-30°C was added to pie-cooled mixture of methyl tertiary butyl ether (1800 ml) and n-heptane (1800 ml) at -25 °C to -30°C. Raised the temperature of mixture to 0-5 °C and stirred for 3 hours at the same temperature. Filtered the precipitated solid and dried to get the title compound.
  • Triethyl amine (0.76 g) was added to the solution of (R)-2-(1-(benzyloxy)-2- methylpropan-2-yl)- 1 -((2,2-dimethyl- 1 ,3-dioxolan-4-yl)methyl)-6-fluoro- 1 H-indol-5- amine (formula-9) (0.8 g) in dichloromethane at 25-30°C.
  • acid chloride was added at 25-30°C and stirred.
  • Aqueous sodium carbonate solution was added to the resultant reaction mixture.
  • Aqueous phase was extracted with dichloromethane. Distilled off the solvent from the organic phase to get the title compound.
  • Para-toluene sulfonic acid (0.087 g) was added to the mixture (R)-N-(2-(1- (benzyloxy)-2-methylpropan-2-yl)- 1 -((2,2-dimethyl- 1 ,3-dioxolan-4-yl)methyl)-6- fluoro-1H-indol-5-yl)- 1 -(2,2-difluorobenzo[d] [ 1 ,3]dioxol-5-yl)cyclopropane carboxamide of Formula- 11 (0.8 g), methanol (13.6 ml) and water (1.36 ml) at 25- 30°C. Heated the mixture to 75-80°C and stirred. Distilled off the solvent completely from the mixture. Water and ethyl acetate were added to the obtained compound and stirred. The resultant organic phase was washed with aqueous sodium chloride solution. Distilled off the solvent to get title compound.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une nouvelle forme cristalline du composé 1-(2,2-difluoro-2H-1,3-benzodioxol-5-yl)-N-{1-[(2R)-2,3-dihydroxypropyl]-6-fluoro-2-(1-hydroxy-2-méthylpropan-2-yl)-1H-indol-5-yl}cyclopropane-1-carboxamide de formule 1 et son procédé de préparation. Formule 1 La présente invention concerne également le nouveau procédé de préparation du composé 1-(2,2-difluoro-2H-1,3-benzodioxol-5-yl)-N-{1-[(2R)-2,3-dihydroxypropyl]-6-fluoro-2-(1-hydroxy-2-méthylpropan-2-yl)-1H-indol-5-yl}cyclopropane-1-carboxamide de formule 1.
PCT/IN2021/050021 2020-01-07 2021-01-07 Nouvelle forme cristalline de 1-(2,2-difluoro-2h-1,3-benzodioxol-5-yl)-n-{1-[(2r)-2,3-dihydroxypropyl]-6-fluoro-2-(1-hydroxy-2-méthylpropan-2-yl)-1h-indol-5-yl}cyclopropane-1-carboxamide et son procédé de préparation WO2021140525A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
IN202041000696 2020-01-07
IN202041000696 2020-01-07
IN202041033111 2020-08-01
IN202041033111 2020-08-01

Publications (1)

Publication Number Publication Date
WO2021140525A1 true WO2021140525A1 (fr) 2021-07-15

Family

ID=76787886

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2021/050021 WO2021140525A1 (fr) 2020-01-07 2021-01-07 Nouvelle forme cristalline de 1-(2,2-difluoro-2h-1,3-benzodioxol-5-yl)-n-{1-[(2r)-2,3-dihydroxypropyl]-6-fluoro-2-(1-hydroxy-2-méthylpropan-2-yl)-1h-indol-5-yl}cyclopropane-1-carboxamide et son procédé de préparation

Country Status (1)

Country Link
WO (1) WO2021140525A1 (fr)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106083832A (zh) * 2010-03-25 2016-11-09 弗特克斯药品有限公司 (r)‑1(2,2‑二氟苯并[d][1,3]间二氧杂环戊烯‑5‑基)‑n‑(1‑(2,3‑二羟基丙基)‑6‑氟‑2‑(1‑羟基‑2‑甲基丙‑2‑基)‑1h‑吲哚‑5‑基)环丙烷甲酰胺的固体形式

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106083832A (zh) * 2010-03-25 2016-11-09 弗特克斯药品有限公司 (r)‑1(2,2‑二氟苯并[d][1,3]间二氧杂环戊烯‑5‑基)‑n‑(1‑(2,3‑二羟基丙基)‑6‑氟‑2‑(1‑羟基‑2‑甲基丙‑2‑基)‑1h‑吲哚‑5‑基)环丙烷甲酰胺的固体形式

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
HUGHES D.L ET AL.: "Patent Review of Synthetic Routes and Crystalline Forms of the CFTR-Modulator Drugs Ivacaftor, Lumacaftor, Tezacaftor, and Elexacaftor", 19 September 2019 (2019-09-19), pages 12 - 14 *

Similar Documents

Publication Publication Date Title
US10703731B2 (en) Process for the preparation of Trisodium (4- {[1S,3R)-1-([1,1′-biphenyl]-4-ylmethyl)-4-ethoxy-3-methyl-4-oxobutyl]amino}-4-oxobutanoate)-(N-petanoyl-N-{[2′-(1H-tetrazol-1-1D-5-yl)[1,1′-biphenyl]-4-yl]methyl}- L-valinate) and its polymorphs thereof
US20080090835A1 (en) Polymorphic forms of ziprasidone HCl and processes for their preparation
US20070173536A1 (en) Crystalline forms of zolmitriptan
US20220105033A1 (en) Stable solid dispersion of a b-raf kinase dimer inhibitor, methods of preparation, and uses therefor
US20120122915A1 (en) Crystalline forms of palonosetron hydrochloride
KR20060111675A (ko) 테가세로드 염기 및 그것의 염의 다형태
KR20130038258A (ko) 삭사글립틴 중간체, 삭사글립틴 다형 및 이들의 제조 방법
WO2006090268A2 (fr) Procedes de preparation d'alfuzosine et de ses sels, nouvelles formes cristallines d'alfuzosine
WO2010092591A2 (fr) Nouveaux polymorphes cristallins de la 5-[[(2r,3s)-2-[(1r)-1-[3,5-bis(trifluorométhyl)phényl]éthoxy]-3-(4-fluorophényl)-4-morpholinyl]méthyl]-1,2-dihydro-3h-1,2,4-triazol-3-one et leur procédé de préparation
US20170267633A1 (en) Novel crystalline arylalkylamine compound and process for producing the same
WO2019016828A1 (fr) Nouveaux procédés pour la préparation de chlorhydrate de trans-n-{4-[2-[4-(2,3-dichlorophényl)pipérazine-1-yl]éthyl] cyclohexyl}-n',n'-diméthyl urée et polymorphes de celui-ci
US11149026B2 (en) Solid state forms of 5-chloro-6-[(2-iminopyrrolidin-1-yl)methyl]pyrimidine-2,4-(1H,3H)-dione hydrochloride and their processes for the preparation thereof
WO2020141562A1 (fr) Nouvelles formes cristallines et procédé de préparation de 4-{8-amino-3-[(2s)-1-(but-2-ynoyl)pyrrolidin-2-yl]imidazo[1,5-a]pyrazin-1-yl)}-n-(pyridine-2-yl)benzamide
WO2021140525A1 (fr) Nouvelle forme cristalline de 1-(2,2-difluoro-2h-1,3-benzodioxol-5-yl)-n-{1-[(2r)-2,3-dihydroxypropyl]-6-fluoro-2-(1-hydroxy-2-méthylpropan-2-yl)-1h-indol-5-yl}cyclopropane-1-carboxamide et son procédé de préparation
WO2019058387A1 (fr) Procédé amélioré de préparation de (5α,6α)-17-allyl-6-(2,5,8,11,14,17,20-heptaoxadocosan-22-yloxy) -4,5-époxymorphinane-3,14-diol et de ses sels pharmaceutiquement acceptables
WO2018029699A1 (fr) Formes à l'état solide de (2e)-n-hydroxy-3-[3- (phénylsulfamoyl) phényl] prop-2-énamide et leur procédé de préparation
WO2019142206A1 (fr) Procédé amélioré pour la préparation de succinate de ribociclib et de ses nouvelles formes cristallines associées
WO2022009235A1 (fr) Procédé de préparation de fumarate de giltéritinib
WO2020225831A1 (fr) Procédé amélioré pour la préparation de 4-{8-amino-3-[(2s)-1-(but-2-ynoyl)pyrrolidin-2-yl] imidazo[1,5-a]pyrazin-1-yl)}-n-(pyridine-2-yl)benzamide
WO2023157030A1 (fr) Procédé de préparation de 1-(4-(((6-amino-5-(4-phénoxyphényl)pyrimidin-4-yl) amino)méthyl)pipéridin-1-yl)prop-2-én-1-one
EP2162434B1 (fr) Sels de périndopril
Rajan et al. Novel process for the preparation of methyl N-{(2S)-1-[(4-{3-[5-chloro-2-fluoro-3 (methanesulfonamido) phenyl]-1-(propan-2-yl)-1H-pyrazol-4-yl} pyrimidin-2-yl) amino] propan-2yl} carbamate
WO2018092151A1 (fr) Procédé de préparation de l'acide 2- (e)-n-hydroxy-3-[4- [[ [2- (2-méthyl -1 h-indol-3-yl) éthyl] amino] méthyl] phényl]-2-propénamide 2-hydroxypropanoïque (1 : 1) et ses polymorphes
WO2018096550A1 (fr) Procédé de préparation de méthyle 4,6-diamino-2-[1-(2-fluorobenzyl)-1h-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(méthyl)carbamate et ses polymorphes
WO2021117062A1 (fr) Procédé de préparation de 4-[7-(6-cyano-5-trifluorométhylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-n-méthylbenzamide et de ses polymorphes

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: 21738666

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: 21738666

Country of ref document: EP

Kind code of ref document: A1