WO2016075703A2 - Procédé amélioré de préparation de 5-amino-2,4-di-tert-butylphénol ou d'un sel d'addition acide de celui-ci - Google Patents

Procédé amélioré de préparation de 5-amino-2,4-di-tert-butylphénol ou d'un sel d'addition acide de celui-ci Download PDF

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Publication number
WO2016075703A2
WO2016075703A2 PCT/IN2015/000421 IN2015000421W WO2016075703A2 WO 2016075703 A2 WO2016075703 A2 WO 2016075703A2 IN 2015000421 W IN2015000421 W IN 2015000421W WO 2016075703 A2 WO2016075703 A2 WO 2016075703A2
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Prior art keywords
acid
formula
compound
amino
butylphenol
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PCT/IN2015/000421
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English (en)
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WO2016075703A3 (fr
Inventor
Suresh Thatipally
Venkata Krishna REDDY
Venkata Lakshmi Narasimha Rao Dammalapati
Seeta Rama Anjaneyulu GORANTLA
Satyanarayana Chava
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Laurus Labs Private Limited
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Publication of WO2016075703A3 publication Critical patent/WO2016075703A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
    • C07C201/06—Preparation of nitro compounds
    • C07C201/08—Preparation of nitro compounds by substitution of hydrogen atoms by nitro groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
    • C07C201/06—Preparation of nitro compounds
    • C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/74—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
    • C07C215/76—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton of the same non-condensed six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms 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
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
    • C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4

Definitions

  • the present invention generally relates to an improved process for preparation of 5- Amino-2,4-di-/ert-butylphenol or an acid ⁇ addition salt thereof, which is an intermediate of Ivacaftor.
  • the drug compound having the adopted name Ivacaftor has a chemical name N-(2,4- di-fert-butyl-5-hydroxyphenyl)-l ,4-dihydro-4-oxoquinoline-3-carboxamide, and is represented by structure of:
  • Ivacaftor was approved by FDA and marketed by Vertex pharma for the treatment of cystic fibrosis under the brand name KALYDECO ® in the form of 150 mg oral tablets.
  • U.S. Patent No. 7,495,103 discloses modulators of ATP-binding cassette transporters such as Ivacaftor.
  • the ⁇ 03 patent further discloses a process for the preparation of 5-Amino-2,4-di-fert-butylphenol of Formula I, by hydroxy protection of 2,4-di-tert-butylphenol with methyl chloroformate to obtain hydroxy protected compound of Formula II, followed by nitration in a mixture of sulfuric acid and nitric acid to obtain a mixture of 2,4-di-tert-butyl-5-nitro-phenol of Formula III and 2,4-di-tert-butyl-6-nitro-phenol of Formula Ilia, then deprotection of the hydroxy protected group and chromatography separation of 2,4-di-tert-butyl-5-nitro-phenol of Formula TV and then reduction of nitro group in presence of PdVC and ammonium formate to obtain compound of Formula I as a free base, which is useful intermediate
  • U.S. Patent No. 8,476,442 discloses a process for the preparation of hydroxy protected intermediate of 5-amino-2,4-di-tert-butylphenyI ⁇ methyl carbonate of Formula la from 2,4-di-te7-r-butylphenol.
  • the process disclosed in the ⁇ 29 patent is schematically represented as follo
  • present inventors focused research to simplify the process for the preparation of 5-Amino-2,4-di-tert-butylphenol or an acid addition salt thereof of Formula I, which involves mainly isolation of Formula I as an acid addition salt to avoid degradation vis-a-vis to increase stability and making the process more suitable for commercial applications with higher purity and obviate the problems associated with the reported process.
  • the present invention provides a process for the preparation of 5-Amino-2,4-di-tert- butylphenol or a hydroxyl protective derivative thereof or an acid addition salt thereof of Formula I, useful intermediate for the preparation of Ivacaftor.
  • the present invention provides an improved process for the preparation of 5-Amino-2,4-di-fert-butylphenol or a hydroxyl protective derivative thereof or an acid addition salt thereof of Formula I,
  • the present invention provides an improved process for the preparation of 5-Amino-2,4-di-tert-butylphenol or an acid addition salt thereof of Formula la,
  • the present invention provides an improved process for the preparation of 5-Amino-2,4-di-fert-butylphenol or an acid addition salt thereof of Formula I, comprising:
  • the nitrate source is selected from the group comprising nitric acid, sodium nitrate, potassium nitrate, calcium nitrate and the like; an acid is selected from the group comprising hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid, phosphoric acid, acetic acid, trifluoro acetic acid, trichloro acetic acid, methane sulfonic acid and the like and mixtures thereof; suitable reducing agent is selected from the group comprising Iron in HC1, Iron/NH Cl, SnCl 2 , Sodium hydrosulfite, Tin (II) chloride, Titanium (III) chloride, Zinc/ NH 4 CI, Zn/hydrazine hydrate, Iron/hydrazine hydrate, raney nickel and the like and mixtures thereof.
  • an acid is selected from the group comprising hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid, phosphoric acid, acetic acid, trifluoro
  • the present invention provides an improved process for the preparation of 5-Amino-2,4-di-tert-butylphenol or an acid addition salt thereof of Formula I, comprising: a) nitrating a compound of Formula II, wherein "P" represent a suitable protecting group in presence of a nitrate source and an acid to obtain a compound of Formula III, wherein "P" represent a suitable protecting group; and
  • the present invention provides an improved process for the preparation of 5-Amino-2,4-di-tert-butylphenol or an acid addition salt thereof of Formula I, comprising: reducing a compound of Formula IV with a suitable reducing agent in a suitable solvent to obtain a compound of Formula I; wherein the suitable reducing agent is selected from the group comprising Iron in HC1, Iron/N3 ⁇ 4Cl, SnCl 2 , Sodium hydrosulfite, Tin (II) chloride, Titanium ( ⁇ ) chloride, Zinc/ NH 4 CI, Zn/hydrazine hydrate, Iron hydrazine hydrate, raney nickel and the like and mixtures thereof.
  • the present invention provides an acid addition salt of Formula I or a hydroxyl protective derivative thereof,
  • the acid is selected from the group comprising: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, sulfamic acid, acetic acid, oxalic acid, fumaric acid, citric acid, succinic acid, tartaric acid, salicylic acid, benzoic acid, glycolic acid, methane sulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, lactic acid, aleic acid, malonic acid, malic acid, isethionic acid, lactobionic acid, mandelic acid.
  • the present invention provides 5-Amino-2,4- di-tert-butylphenol hydrochloride salt.
  • the present invention provides 5-Amino-2,4- di-tert-butylphenol hydrochloride salt characterized by a protan Nuclear magnetic resonance ⁇ H-NMR) spectrum substantially in accordance with Figure 1.
  • the present invention provides an improved process for the preparation of ivacaftor, comprising:
  • the present invention provides an improved process for the preparation of Ivacaftor, comprising preparing the 5-Amino-2,4-di- fefi-butylphenol hydrochloride salt as process described above, and converting the 5- Anxino-2,4-di-tert-butylphenol hydrochloride salt in to Ivacaftor.
  • the present invention provides a pharmaceutical composition, comprising Ivacaftor prepared by the processes of the present invention and at least one pharmaceutically acceptable excipient.
  • Figure 1 represents the protan Nuclear magnetic resonance ('H-NMR) spectrum of hydrochloric acid salt of 5-Amino-2,4-di-tert-butylphenol.
  • the present invention encompasses an improved process for the preparation of 5- Amino-2,4-di-t-?rf-butylphenol or a hydroxyl protective derivative thereof or an acid addition salt thereof of Formula I with high product yield and quality and substantially free of compound of Formula A, which process involves isolation of Formula I as an acid addition salt to avoid formation of degraded impurity of Formula A and also involves the use of novel mixture of nitrate source and an acid for nitration of compound of Formula II to avoid the temperature shoot-up thereby makes the process viable for large scale manufacturing and minimizing the formation of impurities.
  • the present invention provides an improved process for the preparation of 5-Amino-2,4-di-fert-butylphenol. or a hydroxyl protective derivative thereof or an acid addition salt thereof of Formula I,
  • the suitable protecting group "P” includes but is not limited to methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, acetyl, allyl ether and the like.
  • the starting materials, a compound of Formula II is known in the art and can be produced by methods known and recognized by the organic chemist of ordinary skill in the art. For example, such a process is described in US Patent No. 7,495,103 which is included by reference herein in its entirety.
  • acid addition salt means a salt of an acid selected from the group containing hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, sulfamic acid, acetic acid, oxalic acid, fumaric acid, citric acid, succinic acid, tartaric acid, salicylic acid, benzoic acid, glycolic acid, methane sulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, lactic acid, maleic acid, malonic acid, malic acid, isethionic acid, lactobionic acid, mandelic acid.
  • the '103 patent discloses a process for preparation of compound of Formula I, which involves nitration of Formula Ila in a mixture of sulfuric acid and nitric acid without using any solvent, reduction of nitro group in Formula III in presence of a highly pyrophoric reagent like palladium on carbon in ethanol followed by isolation of compound of 5-Amino-2,4-di-1 ⁇ 2rt-butylphenol of Formula I as a highly unstable free base.
  • nitration reactions are very exothermic while addition of sulfuric acid and nitric acid to the reaction mass, generally temperature may rapidly increases and is difficult to control, particularly on commercial scale and thus requires more labor and utmost care to conduct reaction.
  • the disclosed process involves tedious chromatographic purifications, which contributes significant impact on the final yield and purity, makes the process not viable for large scale manufacturing.
  • the inventors of the present invention have replaced nitration mixture with a novel mixture of nitrate source and an acid in presence of solvent to avoid the temperature shoot-up and formation of process impurities and to make the nitration reaction convenient at commercial scale operations.
  • isolation process of 5-Amino-2,4-di-tert-butylphenol of Formula I as a free base results an impure compound as it readily degrades under normal atmosphere in to a compound of Formula A as an impurity, which is as such participated in the coupling reaction for the preparation of Ivacaftor along with Formula I, thereby resulting the product having less pure and low yields.
  • the inventors of the present invention have surprisingly found that isolation of compound of Formula I as its salt form, which results highly stable compound and retain its physical characteristic even after long time.
  • the step a) of nitrating a compound of Formula II; wherein "P" represent a suitable protecting group; preferably methoxycarbonyl is carried out in presence of a nitrate source and an acid to obtain a compound of Formula III; wherein "P" represent a suitable protecting group; preferably methoxycarbonyl.
  • the compound of Formula II and Formula III specifically represents as following compound of Formula Ila or Formula Ilia:
  • the nitrate source may be selected from the group comprising nitric acid, sodium nitrate, potassium nitrate, calcium nitrate and the like and mixture thereof; preferably nitric acid.
  • the acid may be selected from the group comprising hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid, phosphoric acid, acetic acid, trifluoro acetic acid, trichloro acetic acid, methane sulfonic acid and the like and mixtures thereof; preferably trifluoro acetic acid.
  • the nitration of Formula Ila in presence of a nitrate source and an acid may be carried out in a suitable solvent.
  • the suitable solvent includes but is not limited to halogenated hydrocarbons, aromatic hydrocarbons, amides, sulfoxides, nitriles and mixtures thereof.
  • the halogenated hydrocarbons include, but are not limited to methylene chloride, ethylene chloride, chloroform and the like; aromatic hydrocarbons include, but are not limited to toluene, xylene and the like; amides include, but are not limited to dimethyl formamide, dimethyl acetamide, N-methyl pyrrolidinone and the like; sulfoxides include, but are not limited to dimethyl sulfoxide and the like; nitriles include, but are not limited to acetonitrile, propionitrile and the like and mixtures thereof; preferably methylene chloride, dimethyl formamide, acetonitrile; more preferably methylene chloride.
  • the nitration of compound of Formula Ila in presence of a nitrate source and an acid is carried out at a temperature of about 25°C to about reflux temperature; preferably at about 30°C to 50°C.
  • the reaction mass may be treated with water and the product containing organic layer may be separated and treated with a suitable base such as sodium chloride, potassium chloride, sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate and the like; preferably sodium chloride.
  • the product containing organic solvent may be evaporated under vacuum to obtain a compound of Formula III, preferably compound of Formula Ilia.
  • step b) of the aforementioned process involves deprotecting the compound of Formula III; wherein "P" defmed as above; in presence of a suitable base, to obtain a , compound of Formula IV.
  • the compound of Formula ill specifically represents as Formula Ilia.
  • the suitable base of step b) includes, but is not limited to inorganic bases selected from alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide and the like; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate and the like; alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate and the like; and organic bases selected from the group consisting of triethylamine, isopropyl ethylamine, diisopropyl amine, diisopropyl ethylamine, N-methyl morpholine, piperidine, pyridine and the like and mixtures thereof; preferably potassium hydroxide, sodium methoxide, sodium carbonate; more preferably potassium hydroxide,
  • the step b) reaction is carried out at a temperature of about 25 °C to about reflux temperature; preferably at about 30°C to 60°C.
  • the deprotection of Formula Ilia may be carried out in a suitable solvent.
  • the suitable solvent includes but is not limited to methanol, ethanol, isopropanol, n- butanol, formic acid, nitromethane, acetic acid, water and the like and mixtures thereof; preferably methanol.
  • the step b) reaction mass may be subjected to evaporation under vacuum and charged water and water immiscible organic solvent, then the reaction mass may be treated with a suitable acid such as hydrochloric acid, acetic acid and the like.
  • the product containing water immiscible organic solvent may be separated and subjected to evaporation under vacuum and then optional purification by known techniques to obtain compound of Formula IV.
  • the water immiscible organic solvent include, but are not limited to esters such as ethyl acetate, isopropyl acetate and the like; ethers such as methyl tertiary butyl ether, diethyl ether and the like; aromatic hydrocarbons such as toluene, xylene and the like; halogenated solvents such as methylene chloride, chloroform and the like and mixtures thereof; preferably methylene chloride or ethyl acetate.
  • the step c) of nitro reduction process of the aforementioned process involves reduction of the compound of Formula IV with a suitable reducing agent in a suitable solvent to obtain a compound of Formula I.
  • the step c) of nitro reduction process is carried out from compound of Formula Ilia without carrying out the step b) of deprotection.
  • the suitable reducing agent is selected from the group comprising Iron in HC1, Iron/NH-iCl, SnCl 2 , Sodium hydrosulfite, Tin (II) chloride, Titanium (III) chloride, Zinc/ NFL4CI, Zn/hydrazine hydrate, Iron/hydrazine hydrate, raney nickel and the like and mixtures thereof; preferably Iron/NTLtCl.
  • the suitable solvent for nitro reduction of compound of Formula TV is used herein is selected from the group comprising of alcohols, ethers, aromatic hydrocarbons, water and mixtures thereof.
  • the alcohols include, but are not limited to methanol, ethanol, propanol, isopropanol and the like;
  • ethers include, but are not limited to tetrahydrofuran, dimethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1 ,4- dioxane and the like;
  • aromatic hydrocarbons include, but are not limited to toluene, xylene and the like and mixtures thereof; preferably methanol, ethanol, tetrahydrofuran; more preferably ethanol.
  • the step c) of nitro reduction is carried out at a temperature of about 25°C to about reflux temperature; preferably at about 50°C to 90°C.
  • the step c) reaction mass may be subjected to filtration and then the resultant filtrate is converted in to stage d) for saltification of the invention.
  • the step d) of isolating the compound of Formula I as an acid addition salt thereof is carried out by treating the filtrate obtained from step c) with a suitable acid to obtain compound of Formula I as its acid addition salt thereof.
  • the product can be. isolated by conventional techniques known in the art such as isolated by solvent precipitation, crystallization, concentrated by subjecting the solution to heating, spray drying, freeze drying, evaporation on rotary evaporator under vacuum, agitated thin film evaporator (ATFE) and the like; preferably solvent evaporation followed by solvent precipitation method by adding water at temperature less than 35° C.
  • Compound of Formula I acid addition salt can be recovered by any conventional techniques known in the art, for example filtration.
  • the suitable acid of step c) includes, but is not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, sulfamic acid, acetic acid, oxalic acid, fumaric acid, citric acid, succinic acid, tartaric acid, salicylic acid, benzoic acid, glycolic acid, methane sulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toiuenesulfonic acid, lactic acid, maleic acid, malomc acid, malic acid, isethionic acid, lactobionic acid, mandelic acid; preferably hydrochloric acid.
  • the present invention provides acid addition salt of Formula I recovered using the process of the present invention is hydrochloride salt.
  • the present invention provides a compound of Formula I or hydroxyl protective derivative thereof or an acid addition salt thereof prepared by the process as described above having a purity of at least about 97%, as measured by HPLC, preferably at least about 98% as measured by HPLC, and more preferably at least about 99.8%, as measured by HPLC; and content of Formula A is less than about 0.05%, as measured by HPLC, more preferably less than about 0.01% as measured by HPLC.
  • the present invention provides an acid addition salt of Formula I or a hydroxyl protective derivative thereof, 2
  • the acid is selected from the group comprising: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, sulfamic acid, acetic acid, oxalic acid, fumaric acid, citric acid, succinic acid, tartaric acid, salicylic acid, benzoic acid, glycolic acid, methane sulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, lactic acid, maleic acid, malonic acid, malic acid, isethionic acid, lactobionic acid, mandelic acid.
  • the present invention provides 5-Amino-2,4-di-terf- butylphenol hydrochloride salt. In another embodiment, the present invention provides 5-Amino-2,4-di-tert- butylphenol hydrochloride salt characterized by a protan Nuclear magnetic resonance (1H-NMR) spectrum substantially in accordance with Figure 1.
  • the present invention provides an improved process for the preparation of ivacaftor, comprising:
  • the present invention provides convertion of the above obtained compound of Formula I or hydroxyl protective derivative thereof or acid addition salt thereof, preferably 5-Amino-2,4-di-tert-butylphenol hydrochloride salt in to Ivacaftor by any process known in the art or by the process described in the present specification.
  • the present invention provides a process for the preparation of Ivacaftor, comprising providing a compound of Formula I or hydroxyl protective derivative thereof or an acid addition salt thereof as obtained by the process described above, as a starting material or as an intermediate, where the purity of the Ivacaftor having at least about 98% as measured by HPLC, preferably at least about 99.8% as measured by FJPLC and substantially free of impurity of Formula A; wherein the word "substantially free” refers to Ivacaftor having less than about 0.05% of Formula A as measured by HPLC, preferably less than about 0.02% of Formula A as measured by HPLC; more preferably less than about 0.01% of Formula A as measured by HPLC.
  • the present invention provides stability comparison data of free base of Formula I and hydrochloride salt of Formula I, when dissolved in ethanol:
  • the present invention provides compound of Formula I or acid addition salt thereof, obtained by the above process, as analyzed using high performance liquid chromatography (“HPLC”) with the conditions are tabulated below:
  • the word "substantially free” refers to compound of Formula I or acid addition salt thereof having less than 0.05 % of compound of Formula A by HPLC, preferably less than 0.01% by HPLC.
  • reaction mass was washed with water (2> 125 ml) and separated the organic layer.
  • the organic layer was washed with con. HC1 (12.5 ml) and separated the organic layer followed by washed with water (125 ml).
  • the organic layer was concentrated up to 250 ml remains in the flask under atmospheric conditions at below 40°C.
  • nitration mixture prepared by addition of 70% nitric acid (39.72 gms) to trifluoroacetic acid (128 ml)
  • the reaction mass was heated to 38°C to 40°C and stirred for 2 hrs.
  • reaction mass was heated to 38°C to 40°C and stirred for 2 hrs.
  • reaction mass was allowed to cool to 20°C to 25°C and washed with water (160 ml).
  • the aqueous layer was extracted with methylene chloride (160 ml) and the combined organic layer was washed with water (160 ml) followed by 10% sodium chloride (160 ml).
  • the organic layer separated and distilled off completely under vacuum at below 40°C to obtain a residue.
  • reaction mass was concentrated to about 130 ml remains in the flask at below 50°C under vacuum.
  • the reaction mass was allowed to cool to 30°C to 35°C and water (188 ml) and methylene chloride (188 ml), concentrated hydrochloric acid (52.5 ml) was charged and separated the organic layer.
  • the aqueous layer was extracted with methylene chloride (188 ml) and the combined organic layer was washed with water (188 ml).
  • the obtained organic layer was distilled up to rrrniimum volume present under vacuum at below 40°C and was purified by column chromatography by eluting with solvent system (2% ethyl acetate: hexane) and distilled solvent fractions under vacuum at below 45°C.
  • solvent system 2% ethyl acetate: hexane
  • distilled solvent fractions under vacuum at below 45°C.
  • To the obtained solid was charged hexane (75 ml) and heated to reflux for 1 to 1.5 hrs. The solid was filtered and washed with hexane (10 ml). The wet product was dried at about 40°C to about 45°C under vacuum to provide the title compound.
  • reaction mass was heated to 70°C to 75°C and was added ammonium chloride solution (31.9 gms ammonium chloride was dissolved in 75 ml of water) at 70°C to 75°C and stirred for 2 to 3 hrs. After completion of the reaction, reaction mass was allowed to cool to 50°C to 55°C and filtered through celite bed and washed with ethanol (30 ml).
  • thermometer To a 500 ml round bottom flask fitted with a mechanical stirrer, thermometer was charged DMF (50 ml), 4-oxo-l,4-dihydroquinoline-3-carboxy lie acid (5 gms), N,N- diisopropyl emylamine (10.93 gms) and l-[Bis(dimethylamino)methylene]-lH-l,2,3- triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU) (10.05 gms) at 30°C and stirred for 60 min.
  • DMF 50 ml
  • 4-oxo-l,4-dihydroquinoline-3-carboxy lie acid 5 gms
  • N,N- diisopropyl emylamine (10.93 gms)
  • reaction mass was charged 5-Amino-2,4-di-fert- butylphenol HC1 (8.2 gms), then heated the reaction mass to 80°C and stirred for 12 hrs at 80°C to 85°C. After completion of the reaction, reaction mass was allowed to cool to 30°C to 35°C and sodium carbonate solution (sodium carbonate 11.25 gms was dissolved in 225 ml of water) was added at 20°C. The precipitated solid was filtered and washed with water (25 ml).
  • the obtained product was dissolved in ethyl acetate (150 ml) at 45°C and was washed with sodium carbonate solution (2.5 gms of sodium carbonate in 50 ml of water) and the organic layer was washed with 1% aqueous HC1 (50 ml) followed water (2> ⁇ 50ml). The organic layer was separated off and distilled out solvent completely under vacuum at below 50°C.
  • ethanol 450 ml was charged and heated to reflux for 1 hr.
  • the reaction mass was allowed to cool to 30°C to 35°C and precipitated solid was filtered and washed with ethanol (2x7.5 ml).
  • the wet product was dried at about 60°C to about 70°C under vacuum to provide the title compound as off white solid.

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Abstract

La présente invention concerne, de façon générale, un procédé amélioré de préparation de 5-amino-2,4-di-tert-butylphénol ou d'un dérivé hydroxylé de celui-ci ou d'un sel d'addition acide de celui-ci, constituant un intermédiaire pour l'ivacaftor. La présente invention concerne, plus précisément, un procédé de préparation du sel d'acide chlorhydrique du 5-amino-2,4-di-tert-butylphénol.
PCT/IN2015/000421 2014-11-13 2015-11-13 Procédé amélioré de préparation de 5-amino-2,4-di-tert-butylphénol ou d'un sel d'addition acide de celui-ci WO2016075703A2 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017037672A1 (fr) 2015-09-02 2017-03-09 Laurus Labs Private Limited Procédés de préparation d'ivacaftor
US9670163B2 (en) 2005-12-28 2017-06-06 Vertex Pharmaceuticals Incorporated Solid forms of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide

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CN110092717B (zh) * 2019-05-31 2020-11-03 江苏极易新材料有限公司 一种抗氧剂3,5-甲酯的制备方法

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US9573902B2 (en) * 2013-02-15 2017-02-21 Laurus Labs Private Ltd. Process for the preparation of Ivacaftor and its intermediates

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9670163B2 (en) 2005-12-28 2017-06-06 Vertex Pharmaceuticals Incorporated Solid forms of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide
WO2017037672A1 (fr) 2015-09-02 2017-03-09 Laurus Labs Private Limited Procédés de préparation d'ivacaftor

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