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WO2017017696A1 - Procédé de préparation de lumacaftor - Google Patents

Procédé de préparation de lumacaftor Download PDF

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Publication number
WO2017017696A1
WO2017017696A1 PCT/IN2016/050250 IN2016050250W WO2017017696A1 WO 2017017696 A1 WO2017017696 A1 WO 2017017696A1 IN 2016050250 W IN2016050250 W IN 2016050250W WO 2017017696 A1 WO2017017696 A1 WO 2017017696A1
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Prior art keywords
formula
process according
acid
mixtures
compound
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Inventor
Veera Venkata Srinivasa Rao ATTANTI
Umasankara Sastry TUMMALAPALLI
Murali Krishna Potla
Appireddy TALATALA
Veera Venkata Satya Surya Appala Narasimha Tataji GOSULA
Srinivas KOMMARAJU
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Mylan Laboratories Ltd
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Mylan Laboratories 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/61—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring

Definitions

  • the present invention relates to novel process for the preparation of lumacaftor useful for treating a cystic fibrosis transmembrane conductance regulator (CFTR) mediated disease such as cystic fibrosis.
  • CFTR cystic fibrosis transmembrane conductance regulator
  • the present invention provides processes for the preparation of lumacaftor and its pharmaceutically acceptable salts.
  • the present invention provides a process for the preparation of lumacaftor, that may include the steps of:
  • X is any halogen and R is either hydrogen or a carboxylic acid protecting group, as described below.
  • Another aspect of the present invention encompasses processes for the preparation of lumacaftor that may include the steps of:
  • X is any halogen and R is either hydrogen or a carboxylic acid protecting group, as described below.
  • the present invention provides a process for the preparation of a compound of formula II as shown in scheme.
  • the present invention provides a process for the preparation of formula II that may include the step of converting a compound of formula lib to compound of formula II, where X is any halogen.
  • the present invention provides additional processes for the preparation of a com ound of formula II as shown in scheme.
  • the present invention provides a process for the preparation of a compound of formula II that may include the step of converting compound of formula lid to compound of formula II.
  • the present invention provides a process for the preparation of a compound of formula III as shown in scheme.
  • the present invention provides a process for the preparation of a compound of formula III that may include the steps of halogenating the compound of formula Hid with halogenating agent to get a compound of formula III.
  • X is any halogen and R is either hydrogen or a carboxylic acid protecting group, as described below.
  • the present invention relates to process for the preparation of CFTR corrector lumacaftor or its pharmaceutically acceptable salts.
  • LG suitable "leaving groups”
  • halogens e.g., fluorine, chlorine, bromine, iodine
  • methanesulfonyloxy p- toluenesulfonyloxy, trifluoromethanesulfonyloxy, nonafluorobutanesulfonyloxy, (4- bromo-benzene)sulfonyloxy, (4-nitro-benzene)sulfonyloxy, (2-nitro-benzene)- sulfonyloxy, (4-isopropyl-benzene)sulfonyloxy, (2,4,6-tri-isopropyl-benzene)- sulfonyloxy, (2,4,6-trimethyl-benzene)sulfonyloxy, (4-tertbutyl-benzene)sulfonyloxy, benzenesulfonyloxy
  • halogens e.g., flu
  • Suitable alkoxy groups useful within the context of the present invention include, but are not limited to, methoxy, ethoxy, propoxy, 1 -methylethoxy, butoxy, 1 , 1 -dimethyl ethoxy, and 1-methylpropoxy.
  • An alkoxy group may be substituted by one or more halogens, or may be unsubstituted.
  • methoxy, ethoxy, and trifluoromethoxy were found to be particularly effective as leaving groups.
  • X means any halogen. Suitable halogens useful within the context of the present invention include, but are not limited to, fluorine, chlorine, bromine, and iodine.
  • carboxylic acid protecting group means a chemical moiety that protects a carboxylic acid residue from unwanted reaction.
  • Suitable carboxylic acid protecting groups useful with in the context of the present invention include, but are not limited to, alkyl ester such as methyl ester, ethyl ester, t-butyl ester; arakyl ester such as benzyl ester ; silyl ester, and oxazoline.
  • pharmaceutically acceptable salt is well known and understood in the art and refers to salts of pharmaceutically active agents which are suitable for use in contact with the tissues of humans and lower animals without undue adverse effects (e.g., toxicity, irritation, allergic response).
  • pharmaceutically acceptable salts may be found in S. M. Berge, et al., J. Pharmaceutical Sciences, 66: 1-19 (1977), in which all information pertaining to the pharmaceutically acceptable salts and processes for preparation thereof are hereby incorporated by reference.
  • salts can be prepared in situ during the final isolation and purification of the compounds taught herein or separately by reacting a free base or free acid moiety on the active pharmaceutical agent with a suitable reagent.
  • Pharmaceutically acceptable salts include, acid salts, for example, mineral acid salts such as hydrochloride, sulfates salts, nitrate salts, phosphates salts, carbonates salts, hydrogencarbonates or perchlorate; organic acid salts such as acetates, propionates, lactates, maleates, fumarates, tararic acid salts, malates, citrates salts, ascorbates, formic acid; sulfonates such as methanesulfonates, isethionates, benzenesulfonates, or p-toluenesulfonates; and acidic amino acid salts such as aspartates or glutamates.
  • mineral acid salts such as hydrochloride, sulfates salts, nitrate salts, phosphates salts, carbonates salts, hydrogencarbonates or perchlorate
  • organic acid salts such as acetates, propionates, lactates, maleates, fuma
  • the present invention provides a process for the preparation of lumacaftor that may include the steps of:
  • X is any halogen and R is either hydrogen or a carboxylic acid protecting group, as described above.
  • reaction of compound of formula II with formula III may be carried out in the presence of a catalyst, a ligand, base, and a suitable solvent.
  • the base useful in this embodiment may be an organic base, an inorganic base, or mixtures thereof.
  • Suitable organic bases useful for this reaction include, but are not limited to pyridine, trimethylamine, N, N-diisopropylethylamine, and mixturest thereof.
  • Suitable inorganic bases for use in this reaction include, but are not limited to, alkaline metal hydroxides, alkaline metal bicarbonates, alkaline metal carbonates, alkaline alkoxides, and mixtures thereof.
  • Suitable alkaline metal hydroxides for use in this reaction include, but are not limited to, sodium hydroxide, potassium hydroxide, and mixtures thereof.
  • Suitable alkaline metal bicarbonates useful in this reaction include, but are not limited to, sodium bicarbonate, potassium bicarbonate, and mixtures thereof.
  • Suitabel alkaline metal carbonates useful in this reaction include, but are not limited to, sodium carbonate, potassium carbonate, cesium carbonate, and mixtures thereof.
  • Suitable alkaline alkoxides useful in this reaction include, but are not limited to, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium propoxide, sodium tert-butoxide, potassium tert-butoxide, and mixtures thereof.
  • cesium carbonate or sodium tert-butoxide as a base was found to be effective.
  • the catalyst may be a palladium-containing catalyst.
  • Suitable palladium-containing catalysts include, but are not limited to, bis(dibenzylideneacetone)palladium [Pd(dba)2] , tris(dibenzylideneacetone)dipalladium [Pd2(dba)3], palladium(II) acetate [Pd(OAc)2], [ 1 , 1 '-bis(diphenylphosphino) ferrocene]dichloropalladium(II)[Pd(dppf)C12], tetrakis (triphenylphosphine)palladium [Pd(PPh3)4], allylpalladium(II) chloride dimer [Pd(C3H5)Cl], and mixtures thereof.
  • Pd(OAc)2 was found to be useful as a catalyst.
  • Suitable ligands useful for this reaction include, but are not limited to, 4,5-bis(diphenylphosphino)-9,9- dimethylxanthene [xantphos], 2,2'-bis(diphenylphosphino)-l,l'-binaphthalene [BINAP], l,l '-bis(diphenyl phosphine) ferrocene [DPPF], 2-(diphenyl phosphine phenyl) ether [DPEphos], tri-t-butyl phosphine [Fu's salt], 2-dicyclohexylphosphino-2'-(N,N- dimethylamino)biphenyl [DavePhos], 2-di-tert-butylphosphino-2'-(N,N-dimethylamino) biphenyl [t-BuDavePhos], triphenylphosphine, trial
  • the use of xantphos and BINAP as a ligand was found to be particularly effective.
  • the solvent used may be a non-polar solvent, a polar aprotic solvent, a polar protic solvent, or mixtures thereof.
  • Suitable non-polar solvents useful within this reaction include, but are not limited to, 1,4-dioxane, toluene, benzene, xylene, methyl t-butyl ether (MTBE), dichloromethane, and mixtures thereof.
  • Suitable polar aprotic solvents useful within this reaction include, but are not limited to, acetone, acetonitrile, methyl ethyl ketone (MEK), methyl isobutyl ketone, N,N- dimethylformamide(DMF), N,N-dimethylacetamide (DMA), N-methylpyrrolidinone (NMP), dimethylsulfoxide (DMSO), 1 ,2-dimethoxyethane and mixtures thereof.
  • Suitable polar protic solvents useful within this reaction include, but are not limited to, water, methanol, ethanol, isopropyl alcohol, n-butanol, and mixtures thereof. In some particularly useful embodiments, the use of 1,4-dioxane or toluene as a solvent was found to be particularly effective.
  • this deprotection of formula la may be carried out as disclosed in PCT App. Pub. No. WO2009076142, which is hereby incorporated by reference for those process.
  • deprotection of formula la may be carried out in presence of acid and a suitable solvent.
  • the acid used in the deprotection step may be an organic acid or an inorganic acid.
  • Suitable organic acids useful in this step include, but are not limited to, formic acid, acetic acid, propanoic acid, tartaric acid, oxalic acid, maleic acid, mandellic acid, malonic acid, methane sulphonic acid, p-toluene sulphonic acid, trifluoroacetic acid, benzene sulfonic acid, and combinations thereof.
  • Suitable inorganic acids useful in this step include, but are not limited to, hydrochloric acid, hydrobromic acid, hydro iodic acid, sulphuric acid, nitric acid, boric acid, phosphoric acid, chromic acid, and combinations thereof. In some particularly useful embodiments, formic acid or hydrochloric acid is used as the acid.
  • the solvent may be a polar aprotic solvent or a polar protic solvent.
  • Suitable polar aprotic solvents include, but are not limited to, acetone, acetonitrile, methyl ethyl ketone (MEK), methyl isobutyl ketone, N,N- dimethylformamide(DMF), N,N-dimethylacetamide (DMA), N-methylpyrrolidinone (NMP), dimethylsulfoxide (DMSO), 1 ,2-dimethoxyethane and mixtures thereof.
  • Suitable polar protic solvents include, but are not limited to, water, methanol, ethanol, isopropyl alcohol, n-butanol, and mixtures thereof. In some particularly useful embodiments, acetonitrile is used as the solvent.
  • the present invention further provides a process for the preparation of lumacaftor that may include the steps of:
  • X refers to any halogen and R is either hydrogen or a carboxylic acid protecting group, as described above.
  • halogenation of the compound formula IV may be carried out in presence of halogenating agent, base, and suitable solvent.
  • Suitable halogenating agents include, but are not limited to, phosgene, oxalyl chloride, thionyl chloride, phosphorus pentachloride, phosphorous trichloride, phosphorus oxychloride, carbonyl dibromide, oxalyl bromide, thionyl bromide, phosphorous bromide, phosphorus oxybromide, chloroacetyl chloride, methane sulfonyl chloride, benzene sulfonyl chloride, p-toluene sulfonyl chloride, and mixtures thereof.
  • the specific identity of the halogenating agent will be impacted by the specific halogen that is being attached to the compound of Formula IV.
  • phosphorus oxychloride is used as the halogenating agent.
  • the base may be an organic base or an inorganic base.
  • Suitable inorganic base useful in this step include, but are not limited to, alkaline metal hydroxides, alkaline metal bicarbonates, alkaline metal carbonates, alkaline alkoxides, and mixtures thereof.
  • Suitable alkaline metal hydroxides useful in this step include, but are not limited to, sodium hydroxide, potassium hydroxide, and mixtures thereof.
  • Suitable alkaline metal bicarbonates useful in this step include, but are not limited to, sodium bicarbonate, potassium bicarbonate, and mixtures thereof.
  • Suitable alkaline metal carbonates useful in this step include, but are not limited to, sodium carbonate, potassium carbonate, cesium carbonate, and mixtures thereof.
  • Suitable alkaline alkoxides useful in this step include, but are not limited to, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium propoxide, sodium tert-butoxide, potassium tert-butoxide, and mixtures thereof.
  • Suitable organic bases useful in this step include, but are not limited to, pyridine, triethylamine. N,N- diisopropylethylamine, tributyl amine, diisopropyl amine, and mixtures thereof. In some particularly useful embodiments, trimethylamine is used as the base.
  • the solvent may be a non-polar solvent, a polar aprotic solvent, a polar protic solvent, or mixtures thereof.
  • Suitable non-polar solvents for this step include, but are not limited to, 1,4-dioxane, toluene, benzene, xylene, methyl t-butyl ether (MTBE), dichloromethane, and mixtures thereof.
  • Suitable polar aprotic solvents useful in this step include, but are not limited to, acetone, acetonitrile, methyl ethyl ketone (MEK), methyl isobutyl ketone, N,N-dimethylformamide(DMF), N,N- dimethylacetamide (DMA), N-methylpyrrolidinone (NMP), dimethylsulfoxide (DMSO), 1 ,2-dimethoxyethane, and mixtures thereof.
  • Suitable polar protic solvents include, but are not limited to, water, methanol, ethanol, isopropyl alcohol, n-butanol, and mixtures thereof. In some particularly useful embodiments, dichloromethane is used as the solvent.
  • coupling the compound of formula V with a compound of formula VI may be carried out in presence of a base, catalyst, and a suitable solvent to get compound formula la.
  • the base may be an organic base or an inorganic base.
  • Suitable inorganic base useful in this step include, but are not limited to, alkaline metal hydroxides, alkaline metal bicarbonates, alkaline metal carbonates, alkaline alkoxides, and mixtures thereof.
  • Suitable alkaline metal hydroxides useful in this step include, but are not limited to, sodium hydroxide, potassium hydroxide, and mixtures thereof.
  • Suitable alkaline metal bicarbonates useful in this step include, but are not limited to, sodium bicarbonate, potassium bicarbonate, and mixtures thereof.
  • Suitable alkaline metal carbonates useful in this step include, but are not limited to, sodium carbonate, potassium carbonate, cesium carbonate, and mixtures thereof.
  • Suitable alkaline alkoxides useful in this step include, but are not limited to, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium propoxide, sodium tert-butoxide, potassium tert-butoxide, and mixtures thereof.
  • Suitable organic bases useful in this step include, but are not limited to, pyridine, triethylamine. N,N- diisopropylethylamine, tributyl amine, diisopropyl amine, and mixtures thereof. In some particularly useful embodiments, the base is potassium bicarbonate or sodium bicarbonate.
  • Suitable catalysts useful for this step include, but are not limited to, Pd(dba) 2 , Pd 2 (dba) 3j Pd(OAc) 2, Pd(dppf)Cl 2 , Pd(PPh 3 ) 4 , copper, cuprous bromide, cuprous iodide, 2,2'-bis- diphenylphosphanyl[l, l'] binaphtalenyl (rac-Binap), [Pd(C 3 H5)Cl] 2 , and mixtures thereof.
  • Pd(dppf)Cl 2 is used as a catalyst.
  • the solvent may be a polar aprotic solvent or a polar protic solvent.
  • Suitable polar aprotic solvents useful in this step include, but are not limited to, acetone, acetonitrile, methyl ethyl ketone (MEK), methyl isobutyl ketone, N,N-dimethylformamide (DMF), ⁇ , ⁇ -dimethylacetamide (DMA), N- methylpyrrolidinone (NMP), dimethylsulfoxide (DMSO), 1 ,2-dimethoxyethane, and mixtures thereof.
  • Suitable polar protic solvents include, but are not limited to, water, methanol, ethanol, isopropyl alcohol, n-butanol, and mixtures thereof. In some particularly useful embodiments, N,N-dimethylformamide is used as a solvent.
  • the present invention further provides a process for the preparation of a compound of formula II as shown in the following scheme.
  • X refers to any halogen.
  • This embodiment thus provides a process for the preparation intermediate of a compound of formula II that may include the step of converting the compound of formula lib to compound of formula II.
  • conversion of the compound of formula lib to the compound of formula II may be carried out in the presence of an ammonia source and a suitable solvent.
  • suitable ammonia sources useful in the step include, but are not limited to, ammonium hydroxide, ammonia gas, ammonium acetate, ammonium formate, and mixtures thereof.
  • the ammonia source is ammonium hydroxide.
  • the solvent may be a non-polar solvent.
  • suitable non-polar solvents useful in this step include, but are not limited to 1,4- dioxane, toluene, benzene, xylene, methyl t-butyl ether, dichloromethane, and mixtures thereof.
  • the solvent is toluene.
  • the present invention also provides processes for the preparation of a compound of formula II as shown in the following scheme.
  • Formula Ila Formula lib Formula II within the context of this embodiment, X may be any halogen.
  • This embodiment thus provides an in situ process for the preparation of an intermediate of the compound of formula II that may include the steps of: a) halogenating a compound of formula Ila with halogenating agent to get a compound of formula lib; and b) converting the compound of formula lib to a compound of formula II.
  • halogenation of formula Ila may be carried out as disclosed in U.S. Patent App. Pub. No. 20080306062 and PCT App. Pub. No. WO2009076142, both of which are incorporated by reference with respect to those processes.
  • halogenation may occur in the presence of a halogenating agent and a suitable solvent.
  • Suitable halogenating agents useful for this step include, but are not limited to, phosgene, oxalyl chloride, thionyl chloride, phosphorus pentachloride, phosphorous trichloride, phosphorus oxychloride, carbonyl dibromide, oxalyl bromide, thionyl bromide, phosphorous bromide and phosphorus oxybromide chloroacetyl chloride, methane sulfonyl chloride, benzene sulfonyl chloride, p-toluene sulfonyl chloride, and mixtures thereof.
  • thionyl chloride was found to be effective as a halogenating agent.
  • the solvent used in this embodiment may be a polar aprotic solvents or a polar protic solvent.
  • Suitable polar aprotic solvents useful within this reaction include, but are not limited to, acetone, acetonitrile, methyl ethyl ketone (MEK), methyl isobutyl ketone, acetone, N,N-dimethylformamide(DMF), N,N-dimethylacetamide (DMA), N- methylpyrrolidinone (NMP), dimethylsulfoxide (DMSO), 1 ,2-dimethoxyethane, and mixtures thereof.
  • MEK methyl ethyl ketone
  • NMP N-methylpyrrolidinone
  • DMSO dimethylsulfoxide
  • Suitable polar protic solvents useful within this reaction include, but are not limited to, water, methanol, ethanol, isopropyl alcohol, n-butanol, and mixtures thereof.
  • N,N-dimethylformamide was found to be effective as a solvent.
  • conversion compound of formula lib to compound of formula II may be carried out in presence of an ammonia source and a suitable solvent.
  • Suitable ammonia sources useful in this step include, but are not limited to, ammonium hydroxide, ammonia gas, ammonium acetate, ammonium formate, and mixtures thereof. In some particularly useful embodiments, ammonium hydroxide was found to be effective as an ammonia source.
  • the solvent useful in this step may be a non-polar solvent.
  • Suitable non-polar solvents useful in this step include, but are not limited to 1,4-dioxane, toluene, benzene, xylene, methyl t-butyl ether, dichloromethane, and mixtures thereof. In some particularly useful embodiments, toluene was found to be effective as the solvent.
  • This embodiment provides a process of hydrolysis of cyano compound of formula lid which may be carried out in presence an acid and a base. Additionally, peroxides (e.g., hydrogen peroxide) may optionally be utilized to get to compound of formula II.
  • the acid used in this reaction may be an organic acid or an inorganic acid. Suitable organic acids useful in this step include, but are not limited to, formic acid, acetic acid, propanoic acid, methane sulphonic acid, p-toluene sulphonic acid, trifluoroacetic acid, and mixtures thereof.
  • Suitable inorganic acids useful in this step include, but are not limited to, hydrochloric acid, hydrobromic acid, hydro iodic acid, sulphuric acid, nitric acid, and combinations thereof. In some particularly useful embodiments, trifluoroacetic acid, sulphuric acid, and mixtures thereof were used as the acid.
  • the base used in this reaction may be an organic base or an inorganic base.
  • Suitable inorganic bases useful in this reaction include, but are not limited to, alkaline metal hydroxides, alkaline metal bicarbonates, alkaline metal carbonates, alkaline alkoxides, and mixtures thereof.
  • Suitable alkaline metal hydroxides useful in this reaction include, but are not limited to, sodium hydroxide, potassium hydroxide, and mixtures thereof.
  • Suitable alkaline metal bicarbonates useful in this reaction include, but are not limited to, sodium bicarbonate, potassium bicarbonate, and mixtures thereof.
  • Suitable alkaline metal carbonates useful in this reaction include, but are not limited to, sodium carbonate, potassium carbonate, cesium carbonate, and mixtures thereof.
  • Suitable alkaline alkoxides useful in this reaction include, but are not limited to, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium propoxide, sodium tert- butoxide, potassium tert-butoxide, and mixtures thereof.
  • Suitable organic bases useful in this reaction include, but are not limited to, pyridine, triethylamine and N, N- diisopropylethylamine, tributyl amine, diisopropyl amine, and mixtures thereof. In some particularly useful embodiments, potassium carbonate was used as the base..
  • the solvent may be a polar aprotic solvent or a polar protic solvent.
  • Suitable polar aprotic solvents for this reaction include, but are not limited to, acetone, acetonitrile, methyl ethyl ketone (MEK), methyl isobutyl ketone, N,N-dimethylformamide(DMF), ⁇ , ⁇ -dimethylacetamide (DMA), N-methylpyrrolidinone (NMP), dimethylsulfoxide (DMSO), 1 ,2-dimethoxyethane and mixtures thereof.
  • Suitable polar protic solvents useful in this reaction include, but are not limited to, water, methanol, ethanol, isopropyl alcohol, n-butanol, and mixtures thereof. In some particularly useful embodiments, DMSO was utilized as the solvent.
  • an additional in situ process for the preparation of a compound of formula II as depicted in scheme may include the steps of: a) reacting a compound of formula lie with a compound of formula He to get a compound of formula lid; and b) converting the compound of formula lid to compound of formula II.
  • LG represents leaving group, as described above.
  • a compound of formula lie is reacted with a compound of formula He to get a compound of formula lid.
  • This process may be carried out as disclosed in U.S. Patent App. Pub. No. 20080306062 and PCT App. Pub. No. WO2009076142, both of which are hereby incorporated by reference with respect to those processes.
  • present invention provides a process for the preparation of a compound of formula III as shown in scheme.
  • this embodiment provides processes for the preparation of a compound of formula III, comprising, halogenating the compound of formula Hid with halogenating agent to get the compound of formula III.
  • halogenation a compound of formula Hid may be carried out in presence of a halogenating agent, a base, and a solvent.
  • Suitable halogenating agents for this reaction include, but are not limited to, phosgene, oxalyl chloride, thionyl chloride, phosphorus pentachloride, phosphorous trichloride, phosphorus oxychloride, carbonyl dibromide, oxalyl bromide, thionyl bromide, phosphorous bromide, phosphorus oxybromide, chloroacetyl chloride, methane sulfonyl chloride, benzene sulfonyl chloride, p-toluene sulfonyl chloride, and mixtures thereof.
  • phosphorus oxychloride is used as a halogenating agent.
  • the base may be an organic base or an inorganic base.
  • Suitable inorganic bases for this reaction include, but are not limited to, alkaline metal hydroxides, alkaline metal bicarbonates, alkaline metal carbonates, alkaline alkoxides, and mixtures thereof.
  • Suitable alkaline metal hydroxides useful in this reaction include, but are not limited to sodium hydroxide, potassium hydroxide, and mixtures thereof.
  • Suitable alkaline metal bicarbonates useful for this reaction include, but are not limited to, sodium bicarbonate, potassium bicarbonate, and mixtures thereof.
  • Suitable alkaline metal carbonates useful for this reaction include, but are not limited to, sodium carbonate, potassium carbonate, cesium carbonate, and mixtures thereof.
  • Suitable alkaline alkoxides useful in this step include, but are not limited to, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium propoxide, sodium tert-butoxide, potassium tert-butoxide, and mixtures thereof.
  • Suitable organic bases useful for this reaction include, but are not limted to pyridine, trimethylamine, N,N- diisopropylethylamine, and mixtures thereof
  • the solvent may be a non-polar solvent.
  • Suitable non-polar solvents for this reaction include, but are not limited to 1,4-dioxane, toluene, benzene, xylene, methyl t-butyl ether (MTBE), dichloromethane, and mixtures thereof. In some particularly useful embodiments, dichloromethane was used as the solvent.
  • the present invention provides process for the preparation of a compound of formula III as shown in scheme.
  • Formula Ilia Formula Illb Formula IIIc Formula Hid Formula III
  • X is any halogen and R is either hydrogen or a carboxylic acid protecting group, as described above.
  • This embodiment provides a process for the preparation of a compound of formula III, comprising the steps of: a) coupling the compounds of formula Ilia and Illb to get a compound of formula IIIc;
  • coupling the compounds of formula Ilia and Illb may be carried out in the presence base and catalyst to get a compound of formula IIIc, followed by oxidizing the compound of formula IIIc with a suitable oxidizing agent to get a compound of formula Hid as disclosed in the PCT App. Pub. No. WO2009076142, which is hereby incorporated by reference for those processes.
  • aqueous ammonia solution (40 mL) was slowly added at 10-15 °C and maintained for 2 hours at 25-30 °C. After completion of reaction, 20 ml of water was added to the reaction mixture, and the reaction mixture was then stirred for 15 min. The layers were separated, the aqueous layer was extracted with 40 ml toluene. The combined toluene layer was washed with water. The remaining solvent was completely removed under vacuum at 50-55 °C. The resulting residue was triturated with acetone and hexane mixture (10 mL) for 1 hour. The obtained solid was filtered and washed with hexane (5 ml).
  • the combined ethyl acetate layer was washed with water.
  • the solvent was completely removed under vacuum at 50-55 °C.
  • 50 ml dimethyl sulfoxide, 1.12 g potassium carbonate and 8.7 g 30% hydrogen peroxide were added at 15-20 °C.
  • the reaction mixture was heated to 25- 30 °C and maintained for 3 hours.
  • 100 ml water, 100 ml toluene were added to the reaction mixture.
  • the layers were seapareted, and the aqueous layer was extracted with 50 ml toluene.
  • the toluene layer was washed with 50ml 10% sodium sulfite, followed by washing with 50 ml water.
  • reaction mass was filtered through Hyflo and washed with 10 ml 1,4-dioxane. Filtrate was isolated completely under vacuum. 100 ml toluene was then added and the reaction mass was stirred for 10 min. The reaction mass was washed with 20 ml of water. Toluene was distilled out completely under vacuum to afford 16 g of crude 3-(6-(l-(2,2- difluorobenzo[d] [ 1 ,3]dioxol-5-yl)cyclopropane carboxamido) -3-methylpyridin-2-yl)-t- butylbenzoate ( 95.8% yield).

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  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne des procédés de préparation de lumacaftor utile dans le traitement d'une maladie liée à un dysfonctionnement du canal CFTR - Régulateur de la conductance transmembranaire de la fibrose kystique - , telle que la mucoviscidose. La présente invention concerne également des intermédiaires utiles dans la préparation de lumacaftor.
PCT/IN2016/050250 2015-07-27 2016-07-25 Procédé de préparation de lumacaftor Ceased WO2017017696A1 (fr)

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EP3565814A4 (fr) * 2017-01-09 2020-08-19 Laurus Labs Limited Procédé et formes cristallines de lumacaftor

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3565814A4 (fr) * 2017-01-09 2020-08-19 Laurus Labs Limited Procédé et formes cristallines de lumacaftor
EP4434581A2 (fr) 2017-01-09 2024-09-25 Laurus Labs Limited Procédé et formes cristallines de lumacaftor

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