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WO2021140525A1 - Novel crystalline form of 1-(2,2-difluoro-2h-1,3benzo dioxol-5-yl)-n-{1-[(2r)-2,3-dihydroxypropyl]-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1h-indol-5-yl}cyclopropane-1-carboxamide and its process for the preparation thereof - Google Patents

Novel crystalline form of 1-(2,2-difluoro-2h-1,3benzo dioxol-5-yl)-n-{1-[(2r)-2,3-dihydroxypropyl]-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1h-indol-5-yl}cyclopropane-1-carboxamide and its process for the preparation thereof Download PDF

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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
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formula
solvents
palladium
process according
tezacaftor
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French (fr)
Inventor
Thirumalai Rajan Srinivasan
Eswaraiah Sajja
Vijayavitthal T MATHAD
Venkata Narasayya SALADI
Satyanarayana Revu
Suresh Challa
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MSN Laboratories Pvt Ltd
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MSN Laboratories Pvt Ltd
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    • 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.

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Abstract

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. Formula-1 The present application also relates to the novel process for the preparation 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.

Description

Novel crystalline form of 1-(2,2 -difluoro-2H-1,3benzo dioxol-5-yl)-N-{ 1-
[(2R)-2.3-dihydroxypropyl]-6-fluoro-2-(1-hvdroxy-2-methylpropan-2-yl)-
1H-indol-5-yl}cyclonronane-1-carboxamide and its process for the preparation thereof
Cross-Reference to related applications
This application claims the benefit of priority of our Indian patent application numbers 202041000696 filed on January 7, 2020 and 202041033111 filed on August 1, 2020 which are incorporated herein by reference.
Field of the invention:
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.
Figure imgf000003_0001
Formula- 1.
The present application also relates to the novel process for the preparation 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)- 1 H-indol-5-yl } cyclopropane- 1 -carboxamide compound of formula- 1.
Background of the invention:
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.
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.
US9035072B2 discloses the process for the preparation of Tezacaftor compound of formula- 1.
Polymorphism is the occurrence of different crystalline forms of a single compound and it is a property of some compounds and complexes. Thus, polymorphs are distinct solids sharing the same molecular formula, yet each polymorph may have distinct physical properties. Therefore, a single compound may give rise to a variety of polymorphic forms where each form has different and distinct physical properties, such as different solubility profiles, different melting point temperatures and/or different X-ray diffraction peaks. Since the solubility of each polymorph may vary, identifying the existence of pharmaceutical polymorphs is essential for providing pharmaceuticals with predicable solubility profiles. It is desirable to investigate all solid-state forms of a drug, including all polymorphic forms, and to determine the stability, dissolution and flow properties of each polymorphic form.
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.
Brief description of the invention:
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.
Fifth embodiment of the present invention provides a process for the preparation of (R)-2-(5-amino- 1 -((2,2-dimethyl- 1 ,3-dioxolan-4-yl)methyl)-6-fluoro- 1 H-indol-2-yl)-2-methylpropan- 1 -ol formula-8.
Sixth embodiment of the present invention provides a process for the preparation of Tezacaftor
Seventh embodiment of the present invention provides another process for the preparation of Tezacaftor.
Eighth embodiment of present invention, the novel intermediates obtained as per the present invention are useful in the preparation of Tezacaftor of formula- 1.
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.
Brief Description of the Drawings:
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.
Detailed description of the Invention:
The “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, dimethylsulfoxide, N- methylpyrrolidone (NMP) and mixtures thereof; “chloro solvents” such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and mixtures thereof; “ketone solvents” such as acetone, methyl ethyl ketone, methyl isobutyl ketone and mixtures thereof; “nitrile solvents” such as acetonitrile, propionitrile, isobutyronitrile and mixtures thereof; “alcohol solvents” such as methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, 2-butanol, tert-butanol, ethane- 1,2- diol, propane- 1,2-diol and mixtures thereof; “polar solvents” such as water; formic acid, acetic acid and the like or mixture of any of the afore mentioned solvents.
The term “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, diisopropylethyl amine (DIPEA), diisobutylamine, triethylamine, tert.butyl amine, pyridine, 4-dimethylaminopyridine (DMAP), N-methyl morpholine (NMM), n- methyl pyridine (NMP), 1 ,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5- diazabicyclo[4.3.0]non-5-ene (DBN), 1 ,4-diazabicyclo[2.2.2]octane (DABCO), imidazole; “alkali metal alkoxides” such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert.butoxide, potassium tert.butoxide and the like; “alkali metal amides” such as sodium amide, potassium amide, lithium amide, lithium diisopropyl amide (LDA), sodium bis(trimethylsilyl)amide (NaHMDS), potassium bis(trimethylsilyl)amide, lithium bis(trimethysilyl)amide (LiHMDS) and the like; or mixtures thereof.
As used herein 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.
As used herein the term “acid” in the present invention refers to inorganic acid and organic acid; inorganic acid is selected from such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, sulfuric acid; organic acids such as acetic acid, maleic acid, malic acid, oxalic acid, succinic acid, fumaric acid, trifluoroacetic acid, methane sulfonic acid, p-toluene sulfonic acid; chiral acids such as S-(+) mandelic acid, R-(-) mandelic acid, L-(+)tartaric acid, D-(-)tartaric acid, L-malic acid, D-malic acid, D-maleic acid, ( lR)-(-)-camphor sulfonic acid, (1S)- (+)- camphor sulfonic acid ( 1 R)-(+)-bromocamphor- 10-sulfonic acid etc., and like. The first embodiment of the present invention provides novel crystalline form of Tezacaftor of formula- 1, herein after designated as crystalline form-M.
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. As used herein, the term "pharmaceutical compositions" or "pharmaceutical formulations" include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.
The fourth aspect of the first embodiment provides a pharmaceutical composition comprising crystalline form-M 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).
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.
Wherein, 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.
The first aspect of the second embodiment, step a) or step-b) optionally involve seeding with crystalline form-M of compound of formula- 1.
In the process of the present invention, 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 μm or less than about 200 μm or less than about 150 μm or less than about 100 μm or less than about 50 μm 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-5 to Tezacaftor of formula- 1.
In the first aspect of third embodiment, 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. For example, the catalyst may be selected from [1,1'- bis(diphenylphosphino) ferrocene]dichloropalladium(II) ([Pd(dppf)Cl2]), [1,1'-bis(di- tert-butylphoshino) ferrocene]dichloropalladium(I) ([Pd(dtbpf)Cl2]) tetrakis (triphenylphosphine) palladium (0)(Pd(PPh3)4), bromo(tri-tert-butylphosphine) palladium(I) dimer ([Pd(p-Br)(t-Bu3P)]2), bis(tri-tert-butylphosphine)palladium(0) ([Pd(tBu3P)]2), palladium(II) acetate (Pd(OAc)2), palladium(II) chloride (PdCl2), bis (benzonitrile)palladium(n) dichloride ([Pd(PhCN)2Cl2]), bis(triphenylphosphine) palladium(II) dichloride ([Pd(PPh3)2Cl2]), bis (acetonitrile)palladium(II) dichloride ([Pd(NCMe)2Cl2]), bis[di-tert-butyl(4-dimethyl aminophenyl)phosphine] dichloro palladium(II) ([Pd(amphos)Cl2]), bis[di-tert-butyl(4-dimethylaminophenyl) phosphine] palladium(0) (Pd(amphos)2), and allylpalladium(II) chloride dimer ([PdCl(C3H5)]2). Preferably, catalyst (C2) is bis(benzonitrile)palladium(II) dichloride ([Pd(PhCN)2Cl2])· 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). Ligand is preferably selected from the group consisting of 1,4- Butanediylbis[diphenylphosphine] (dppb), 2-dicyclohexylphosphino-2',4',6'- triisopropyl biphenyl (‘XPhos’), 2-(dicyclohexylphosphino)-2',6'-isopropoxybiphenyl (‘RuPhos’), 4,5-bis(diphenyl phosphino)-9,9-dimethylxanthene (‘Xantphos’), tricyclo hexylphosphine (‘PCy3’), tri-tert-butylphosphine (P(t-Bu)3), 2,2'-bis
(diphenylphosphino)- 1,1 '-binaphthyl (‘BINAP’) and 1 , 1 '-bis(diphenylphosphino) ferrocene (‘dppf’).
In the second aspect of third embodiment, 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.
In the third aspect of third embodiment, 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. In fourth aspect of third embodiment, 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(PPh3)4), palladium(II) chloride (PdCl2), palladium(II) iodide (Pdl2), bis (benzonitrile)palladium(II) dichloride ([Pd(PhCN)2Cl2]), bis(triphenylphosphine) palladium(II) dichloride ([Pd(PPh3)2Cl2]), bis(acetonitrile) palladium(II) dichloride ([Pd(NCMe)2Cl2]), palladium(II) trifluoroacetate (Pd(TFA)2), copper(II) acetate (Cu(OAc)2), and indium(III) bromide (InBr3), Cul, CuBr, or copper (II) triflate in bases TEA, DIPEA, pyridine or addition of dehydrating agent such as acetic anhydride, acetyl chloride or phophorus oxy chloride.
In fifth aspect of third embodiment, 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.
In sixth aspect of third embodiment, 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.
In first aspect of fourth embodiment, the reaction can be carried out in presence of a base; wherein the base can be selected from the inorganic bases or organic bases.
In second aspect of fourth embodiment, 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.
In third aspect of the fourth embodiment, the (R)-2-(1-(benzyloxy)-2- methylpropan-2-yl)- 1 -((2,2-dimethyl- 1 ,3-dioxolan-4-yl)methyl)-6-fluoro-5-nitro- 1H- indole formula-7 is further converted into Tezacaftor.
Fifth embodiment of the present invention provides a process for the preparation of (R)-2-(5-amino-1 -((2, 2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro- lH-indol-2-yl)-2-methylpropan-1-ol formula-8 comprising: reduction followed by debenzylation 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 to provide compound of formula-8.
In first aspect of fifth embodiment, 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, PtO2, Fe, Fe in acidic media like acetic acid, HQ, NH4Cl; Sn-HCl, Stannous chloride (SnCl2), Zn in acidic media like acetic acid, NH4Cl, Zinc dust, Ni, Raney Ni.
In second aspect of fifth embodiment, 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.
In third aspect of fifth embodiment, 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.
Sixth embodiment of the present invention provides a process for the preparation of Tezacaftor comprising: a) reducing (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 to provide compound of formula-9, b) reacting compound of formula-9 with 1-(2,2-difluorobenzo[d] [ 1 ,3]dioxol-5-yl) cyclopropanecarboxylic acid of formula- 10 to provide compound of formula-11, c) debenzylating compound of formula- 11 to provide compound of formula- 12, d) deprotecdng compound of formula- 12 to provide Tezacaftor.
In first aspect of sixth embodiment, 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.
In second aspect of sixth embodiment, 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. Suitable halogenating agent is selected from thionyl chloride, phosphorous trichloride and phosphorous pentachloride; suitable carbodiimide is selected from of Ν,Ν-dicyclohexylcarbodiimide (DCC), Ν,Ν-diisopropylcarbodiimide (DIC), N-(3- dimethylaminopropyl)-N-ethylcarbodiimide (EDC) and N-(3-dimethylaminopropyl)- N-ethylcarbodiimide hydrochloride (EDC.HCI); carbodiimide is used in combination with an additive such as 1 -hydroxy-7-azabenzotriazole (HO At) or 1 -hydroxy- 1H- benzotri azole (HOBt); suitable Uranium reagent is selected from O-(7- azabenzotriazol- 1-yl)- 1 , 1 ,3,3-tetramethyluronium hexafluorophosphate (HATU) and O-(benzotriazol- 1 -yl)- 1 , 1 ,3,3-tetramethyluroniumhexafluorophosphate (HBTU).
In third aspect of sixth embodiment, 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.
In fourth aspect of sixth embodiment, 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.
In fifth aspect of sixth embodiment, 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.
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,
In first aspect of seventh embodiment, the deprotection in step-a) 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.
In second aspect of seventh embodiment, the debenzylation in step-b) 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.
In third aspect of seventh embodiment, 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.
Eighth embodiment of present invention, the 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.
In an embodiment of the present invention provides a pharmaceutical composition comprising Tezacaftor and one or more pharmaceutically acceptable excipient. As used herein, the term "pharmaceutical compositions" or "pharmaceutical formulations" include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.
Wherein 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-AS), hydroxyethyl methyl cellulose succinate (HEMCS), hydroxypropyl cellulose acetate succinate (HPCAS), hydroxypropyl methylcellulose phthalate (HPMC-P), hydroxypropyl methylcellulose acetate phthalate, microcrystalline cellulose (MCC), cross linked sodium caiboxymethyl cellulose (erase armellose sodium), cross linked calcium caiboxymethyl cellulose, magnesium stearate, aluminium stearate, calcium stearate, magnesium carbonate, talc, iron oxide (red, yellow, black), stearic acid, dextrates, dextrin, dextrose, sucrose, glucose, xylitol, lactitol, sorbitol, mannitol, maltitol, maltose, raffinose, fructose, maltodextrin, anhydrous lactose, lactose monohydrate, starches such as maize starch or com starch, sodium starch glycolate, sodium caiboxymethyl starch, pregelatinized starch, gelatin, sodium dodecyl sulfate, edetate disodium, sodium phosphate, sodium lauryl sulfate, triacetin, sucralose, calcium phosphate, polydextrose, α-, β-, γ-cyclodextrins, sulfobutylether beta-cyclodextrin, sodium stearyl fumarate, fumaric acid, alginic acid, sodium alginate, propylene glycol alginate, citric acid, succinic acid, carbomer, docusate sodium, glyceryl behenate, glyceryl stearate, meglumine, arginine, polyethylene oxide, polyvinyl acetate phthalates and the like.
In another embodiment of the present invention provides 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.
The process for the preparation of Tezacaftor of present application is schematically represented as below:
Figure imgf000017_0001
PXRD Method of Analysis:
The PXRD analysis of compounds of the present invention is carried out by using BRUKER/D8 ADVANCE X-Ray diffractometer using CuKα 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.
Examples:
Example-1: Preparation of crystalline form-M Tezacaftor
A solution of Tezacaftor (1 gm) in tetrahydrofuran (10 ml) at 25-30°C was added to pie-cooled mixture of methyl tertiary butyl ether (15 ml) and n-hexane (15 ml) at - 25°C to -30°C. Raised the temperature of mixture to 0-5 °C and stirred for 2 hours at the same temperature. Filtered the precipitated solid and dried to get the title compound.
Yield: 0.77 g; PXRD pattern of the obtained compound is depicted in figure- 1. 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.
Yield: 60 g; PXRD pattern of the obtained compound is depicted in figure-2.
Purity by HPLC data: 99.99%.
Example-3: Preparation of 2-(4-(benzyloxy)-3,3-dimethylbut-1-yn-1-yl)-5-fluoro- 4-nitroaniline [Formula-4]
2-Bromo-5-fluoro-4-nitroaniline (5 g) dissolved in acetonitrile (50 ml) under nitrogen atmosphere. Palladium acetate (0.52 g), 1 ,4-Butanediylbis [diphenylphosphine] (0.498 g), potassium carbonate (6.7 g), copper iodide (1.21 g) and (((2,2-dimethylbut-
3-yn-1-yl) oxy)methyl)benzene (12 g) were added to the reaction mixture and stirred under nitrogen atmosphere at 25-30°C. Heated the reaction mixture to 80-85°C and stirred. Cooled the reaction mixture to 25-30°C. Filtered the mixture and distilled off the solvent to get title compound. Yield: 5.5 g. Example-4: Preparation of 2-(4-(benzyloxy)-3,3-dimethylbut-1-yn-1-yl)-5-fluoro- 4-nitroaniline [Formula-4]
2-Bromo-5-fluoro-4-nitroaniline (20 g) dissolved in acetonitrile (200 ml) under nitrogen atmosphere. Palladium acetate (2 g), 1,4-Butanediylbis [diphenylphosphine] (1.99 g), potassium carbonate (27 g), copper iodide (4.86 g) and (((2,2-dimethylbut-3- yn-1-yl) oxy)methyl)benzene (40 g) were added to the reaction mixture under nitrogen atmosphere at 25-30°C. Heated the reaction mixture to 80-85°C and stirred. Cooled the reaction mixture to 25-30°C. Filtered the mixture and distilled off the solvent from the filtrate. The obtained compound is slurried in the mixture of cyclohexane and silica gel followed by the mixture of dichloromethane and silica gel to get the title compound.
Yield: 21 g.
Example-5: Preparation of 2-(1-(Benzyloxy)-2-methylpropan-2-yl)-6-fluoro-5- nitro-1H-indole [Formula-5]
Mixture of 2-(4-(benzyloxy)-3,3-dimethylbut-1-yn-1-yl)-5-fluoro-4-nitroaniline (5 g), acetonitrile (50 ml) and palladium dichloride (1.29 g) was heated to 80-85°C and stirred. Cooled the reaction mixture to 25-30°C. Filtered the mixture and distilled off the solvent from the filtrate to get the title compound.
Example-6: Preparation of 2-(1-(Benzyloxy)-2-methylpropan-2-yl)-6-fluoro-5- nitro-1H-indole [Formula-5]
Mixture of 2-(4-(benzyloxy)-3,3-dimethylbut-1-yn-1-yl)-5-fluoro-4-nitroaniline (20 g), acetonitrile (200 ml) and palladium dichloride (5.1 g) was heated to 80-85°C and stirred. Cooled the reaction mixture to 0-5°C. Filtered the mixture and distilled off the solvent from the filtrate. Isopropyl alcohol and n-heptane were added to obtained compound at 25-30°C and stirred. Cooled the mixture to 0-5°C and stirred. Filtered the solid, washed with n-Heptane and dried to get the title compound.
Yield: 13 g.
Example-7: 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 [Formula-7] Water collected from the mixture of 2-(1-(Benzyloxy)-2-methylpropan-2-yl)-6- fluoro-5-nitro-1H-indole (5 g), N,N-dimethylformamide (25 ml) and cesium carbonate (14 g) was at 45-50°C under azeotropic conditions. Cooled the reaction mixture to 25-30°C and (S)-(2, 2-dimethyl-1,3-dioxolan-4-yl)methyl 4-methyl benzenesulfonate (10.4 g) was added. Heated the resultant mixture to 110-115°C and stirred. Cooled the reaction mixture to 25-30°C and extracted with ethyl acetate. Organic phase was washed with aqueous sodium chloride solution and dried with sodium sulphate. Distilled off the solvent completely from the organic layer to get the title compound.
Yield: 4.5 g
Example-8: Preparation of (R)-2-(1-(benzyloxy)-2-methylpropan-2-yl)-1-((2,2- dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-1H-indol-5-amine [Formula-9]
(R)-2-( 1 -(benzyloxy)-2-methylpropan-2-yl)- 1 -((2,2-dimethyl- 1 ,3-dioxolan-4- yl)methyl)-6-fluoro-5-nitro-1H-indole (formula-7) (1 g) in methanol (35 ml) taken in autoclave, 5% Pd/C was added to it. Hydrogen pressure was applied and stirred the reaction mixture at 25-30°C. Filtered the reaction mixture, washed with methanol and distilled off the solvent completely to get the title compound.
Yield: 0.9 g
Example-9: Preparation (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)cyclopropanecarboxamide [Formula-11]
Thionyl chloride (0.66 g) was added to the mixture 1 -(2,2- difluorobenznzo[d][1,3]dioxol-5-yl)cyclopropane carboxylic acid (0.45 g), cyclohexane (8 ml) and dimethyl formamide (0.1 ml) at 25-30°C. Heated the mixture to 60-65°C and stirred. Distilled off the solvent completely form the reaction mixture. 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. To this mixture, above obtained 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.
Yield: 0.9 g.
Example-10: Preparation (R)-N-(2-(1-(benzyloxy)-2-methylpropan-2-yl)-1-(2,3- dihydroxypropyl)-6-fluoro-1H-indol-5-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5- yl) cyclopropanecarboxamide [Formula-13]
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.
Example-11: Preparation of Tezacaftor [Formula-1]
Ammonium formate (1.6 g) was added to the solution of R)-N-(2-(1-(benzyloxy)-2- methylpropan-2-yl)- 1 -(2,3-dihydroxypropyl)-6-fluoro- 1 H-indol-5-yl)- 1-(2,2-difluoro benzo[d] [ 1 ,3]dioxol-5-yl) cyclopropanecarboxamide of formula- 13 (0.8 g) in methanol (20 ml) at 25-30°C. Pd/C was added to the mixture, heated the resultant mixture to 80-85°C and stirred. Cooled the reaction mixture to 25-30°C and filtered. Distilled off the solvent from the filtrate. Water and ethyl acetate were added to the resultant residue. Distilled off the solvent from the resultant organic phase to get title compound.
Yield: 0.2 g.
***********

Claims

We claim:
1. Crystalline fonn-M of Tezacaftor of formula- 1
Figure imgf000022_0001
Formula- 1 characterized by PXRD (powder X-Ray diffractogram) pattern having peaks at about 5.6°, 9.8° and 11.3° ± 0.2° 2θ.
2. A process for the preparation of crystalline form-M of Tezacaftor, comprising: a) dissolving Tezacaftor in a solvent, b) isolating crystalline form-M of Tezacaftor compound of formula- 1.
3. The process according to claim 2, wherein dissolving Tezacaftor in step-a) is 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.
4. The process according to claim 3, wherein the anti-solvent is a mixture of ether solvents and hydrocarbon solvents.
5. A process for the preparation of Tezacaftor of formula-1 comprising one or more of the following steps: a)
Figure imgf000023_0001
Formula-2 Formula-3 Formula-4 b)
Figure imgf000023_0002
Formula-4 Formula-5
C)
Figure imgf000023_0003
Formula-5 Formula-6 Formula-7
Wherein X= halo, mesyl, tosyl d)
Figure imgf000023_0004
Formula-7 Formula-9 e)
Figure imgf000024_0001
Formula-8
Formula-7 f)
Figure imgf000024_0002
Formula-9 Formula -10 Formula-11 g)
Figure imgf000024_0003
Formula-11 Formula-13 h)
Figure imgf000024_0004
Formula-13 Tezacaftor i)
Figure imgf000025_0001
Formula-11 Formula-12 or j)
Figure imgf000025_0002
Formula-12 Tezacaftor
6. The process according to claim 5, wherein the process 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) converting 2-(4-(benzyloxy)-3,3-dimethylbut-1-yn-1-yl)-5-fluoro-4- nitroaniline formula-4 to Tezacaftor of formula- 1.
7. The process according to claim 6, wherein the reaction of step-a) is carried out in presence of a base, a catalyst and in a solvent.
8. The process according to claim 7, wherein the catalyst is selected from [1,1 - bis(diphenylphosphino) ferrocene]dichloropalladium(II) ([Pd(dppf)Cl2]), [1,1 - bis(di-tert-butylphoshino) ferrocene]dichloropalladium(I) ([Pd(dtbpf)Cl2]) tetrakis (triphenylphosphine) palladium (0)(Pd(PPh3)4), bromo(tri-tert- butylphosphine) palladium(I) dimer ([Pd(p-Br)(t-Bu3P)]2), bis(tri-tert- butylphosphine)palladium(0) ([Pd(tBu3P)]2), palladium(II) acetate (Pd(OAc)2), palladium(II) chloride (PdCl2), bis (benzonitrile)palladium(II) dichloride ([Pd(PhCN)2Cl2]), bis(triphenylphosphine) palladium(II) dichloride ([Pd(PPh3)2Cl2]), bis (acetonitrile)palladium(II) dichloride ([Pd(NCMe)2Cl2]), bis[di-tert-butyl(4-dimethyl aminophenyl)phosphine] dichloro palladium(II) ([Pd(amphos)Cl2]), bis[di-tert-butyl(4-dimethylaminophenyl)phosphine] palladium(0) (Pd(amphos)2), and allylpalladium(II) chloride dimer ([PdCl(C3H5)]2); catalyst (C2) is bis(benzonitrile)palladium(II) dichloride ([Pd(PhCN)2Cl2]); catalyst is used in combination with a co-catalyst and/or a ligand; co-catalyst is selected from a copper (I) catalyst such as copper (I) iodide (Cul); ligand is selected from the group consisting of 1,4- Butanediylbis[diphenylphosphine] (dppb), 2-dicyclohexylphosphino-2',4',6'- triisopropyl biphenyl (‘XPhos’), 2-(dicyclo-hexylphosphino)-2',6'- isopropoxybiphenyl (‘RuPhos’), 4,5-bis(diphenyl phosphino)-9,9- dimethylxanthene (‘Xantphos’), tricyclo hexylphosphine (‘PCy3’), tri-tert- butylphosphine (P(t-Bu)3), 2,2'-bis (diphenyl phosphino)-1,1 '-binaphthyl (‘BINAP’) and 1,1'-bis(diphenylphos-phino) ferrocene (‘dppf’).
9. The process according to claim 7, wherein the base is selected from tertiary amines, metal carbonates and metal phosphates; solvent is selected from 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.
10. The process according to claim 5, wherein the process comprising: a) cyclizing 2-(4-(benzyloxy)-3,3-dimethylbut-1-yn-1-yl)-5-fluoro-4- nitroaniline of formula-4 to provide 2-(1-(benzyloxy)-2-methylpropan-2-yl)- 6-fluoro-5-nitro-1H-indole of formula-5, b) converting 2-(1-(benzyloxy)-2-methylpropan-2-yl)-6-fluoro-5-nitro-1H- indole of formula-5 to Tezacaftor.
11. The process according to claim 10, wherein the cyclization of step-a) is carried out in presence a catalyst and in a solvent.
12. The process according to claim 11, wherein the catalyst is selected from tetrakis(triphenylphosphine) palladium(0) (Pd(PPh3)4), palladium(II) chloride (PdCl2), palladium(II) iodide (PdI2), bis (benzonitrile)palladium(II) dichloride ([Pd(PhCN)2Cl2]), bis(triphenylphosphine) palladium(II) dichloride ([PdCPPh3)2Cl2]), bis(acetonitrile) palladium(II) dichloride ([Pd(NCMe)2Cl2]), palladium(II) trifluoroacetate (Pd(TFA)2), copper(II) acetate (Cu(OAc)2), and indium(III) bromide (InBr3), Cul, CuBr, or copper (II) triflate optionally in bases TEA, DIPEA, pyridine or addition of dehydrating agent such as acetic anhydride, acetyl chloride or phophorus oxy chloride; the solvent is selected from polar solvents such as water, nitrile solvents, polar-aprotic solvents, alcohol solvents, ether solvents, chloro solvents, ester solvents, hydrocarbon solvents, ketone solvents or mixtures thereof.
13. The process according to claim 5, wherein the process comprising: a) reacting 2-(1-(benzyloxy)-2-methylpropan-2-yl)-6-fluoro-5-nitro-1H- indole of formula-5 with compound of formula-6 to provide the compound of formula-7, b) converting the compound of formula-7 to Tezacaftor of formula- 1.
14. The process according to claim 13, wherein the reaction of step-a) is carried out in presence of a base and in a solvent.
15. The process according to claim 14, wherein the base is selected from the inorganic bases or organic bases, the solvent is selected from 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.
16. The process according to claim 5, wherein the process comprising: a) reducing the compound of formula-7 with a reducing agent optionally in presence of a hydrogen pressure in a solvent to provide the compound of formula-9, b) converting the compound of formula-9 to Tezacaftor of formula- 1.
17. The process according to claim 16, wherein the reducing agent of step-a) is selected from Raney nickel or palladium-on-carbon, platinum (IV) oxide, Urushibara nickel, 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; solvent is 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.
18. The process according to claim 5, wherein the process comprising: a) reacting the compound of formula-9 with a compound of formula- 10 in presence of a coupling agent in a solvent to provide the compound of formula- 11, b) converting the compound of formula- 11 to Tezacaftor of formula- 1.
19. The process according to claim 18, wherein the coupling agent of step-a) is selected form halogenating agents, carbodiimides, uranium reagents and carbonyldiimidazoles; suitable halogenating agent is selected from thionyl chloride, phosphorous trichloride and phosphorous pentachloride; suitable carbodiimide is selected from of Ν,Ν-dicyclohexylcarbodiimide (DCC), N,N- diisopropylcarbodiimide (DIC), N-(3-dimethylaminopropyl)-N- ethylcarbodiimide (EDC) and N-(3-dimethylaminopropyl)-N- ethylcarbodiimide hydrochloride (EDC.HCI); carbodiimide is used in combination with an additive such as 1-hydroxy-7-azabenzotriazole (HOAt) or 1 -hydroxy-1H-benzotriazole (HOBt); suitable Uranium reagent is selected from O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluoro phosphate (HATU) and O-(benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU); solvent is 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.
20. The process according to claim 5, wherein the process comprising: a) deprotecting the compound of formula- 11 to provide the compound of formula- 13, b) debenzylating the compound of formula- 13 to provide Tezacaftor.
21. The process according to claim 20, wherein the deprotection in step-a) is carried out in presence of an acid is selected from organic acid or inorganic acid.
22. The process according to claim 20, wherein debenzylation in step-b) is carried out in presence of a hydrogen source optionally in presence of a catalyst.
23. The process according to claim 22, wherein hydrogen source is 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.
24. The process according to claim 20, wherein step-a) and step-b) are carried out in a solvent is 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.
25. The process according to claim 5, wherein the process comprising: a) debenzylating the compound of formula- 11 to provide the compound of formula- 12, b) deprotecting the compound of formula- 12 to provide Tezacaftor.
26. The process according to claim 25, wherein debenzylation in step-a) is carried out in presence of a hydrogen source optionally in presence of a catalyst.
27. The process according to claim 26, wherein hydrogen source is 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.
28. The process according to claim 25, wherein the deprotection in step-b) is carried out in presence of an acid is selected from organic acid or inorganic acid.
29. The process according to claim 25, wherein step-a) and step-b) are carried out in a solvent is 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.
30. The process according to claim 5, wherein the process comprising: a) reduction followed by debenzylation of the compound of formula-7 to provide the compound of formula-8, b) converting the compound of formula-8 to Tezacaftor of formula- 1.
31. The process according to claim 30, wherein reduction and debenzylation are carried out in presence of a catalyst and is selected from the group consisting of a hydrogen source, palladium catalyst such as 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, PtO2, Fe, Fe in acidic media like acetic acid, HCI, NH4CI; Sn-HCl, Stannous chloride (SnCl2), Zn in acidic media like acetic acid, NH4CI, Zinc dust, Ni, Raney Ni.
32. The process according to claim 30, wherein reduction and debenzylation is carried out in a solvent and is 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.
33. A compound selected from the group consisting of:
Figure imgf000031_0001
Formula-4 Formula-5 Formula-7
Figure imgf000031_0002
Formula-4 Formula-5 and
Figure imgf000031_0003
Formula-13
34. A method of preparing Tezacaftor using the compounds of claim 33.
35. A pharmaceutical composition comprising Crystalline form-M of Tezacaftor of claim 1 and at least one pharmaceutically acceptable excipient.
36. A method of treating a mammal by administering a therapeutically effective amount of Crystalline form-M of Tezacaftor of claim 1 for treating 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.
PCT/IN2021/050021 2020-01-07 2021-01-07 Novel crystalline form of 1-(2,2-difluoro-2h-1,3benzo dioxol-5-yl)-n-{1-[(2r)-2,3-dihydroxypropyl]-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1h-indol-5-yl}cyclopropane-1-carboxamide and its process for the preparation thereof Ceased WO2021140525A1 (en)

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