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WO2012147098A2 - Nouveau procédé de préparation de 3-(cyclopropylméthoxy)-n-(3,5-dichloropyridin-4-yl)-4-(difluorométhoxy) benzamide - Google Patents

Nouveau procédé de préparation de 3-(cyclopropylméthoxy)-n-(3,5-dichloropyridin-4-yl)-4-(difluorométhoxy) benzamide Download PDF

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Publication number
WO2012147098A2
WO2012147098A2 PCT/IN2012/000266 IN2012000266W WO2012147098A2 WO 2012147098 A2 WO2012147098 A2 WO 2012147098A2 IN 2012000266 W IN2012000266 W IN 2012000266W WO 2012147098 A2 WO2012147098 A2 WO 2012147098A2
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Prior art keywords
formula
compound
difluoromethoxy
roflumilast
cyclopropylmethoxy
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WO2012147098A3 (fr
Inventor
Sachin Baban Gavhane
Sanjay Maruti WAKADE
Suresh Mahadev Kadam
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Glenmark Generics Ltd
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Glenmark Generics Ltd
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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
    • C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/39—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by esterified hydroxy groups
    • C07C205/42—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by esterified hydroxy groups having nitro groups or esterified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C205/43—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by esterified hydroxy groups having nitro groups or esterified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton to carbon atoms of the same non-condensed six-membered aromatic ring or to carbon atoms of six-membered aromatic rings being part of the same condensed ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C07C45/70—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form
    • C07C45/71—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form being hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/16—Preparation of carboxylic acids or their salts, halides or anhydrides by oxidation
    • C07C51/29—Preparation of carboxylic acids or their salts, halides or anhydrides by oxidation with halogen-containing compounds which may be formed in situ
    • 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
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring

Definitions

  • the present invention relates to a novel process of preparing roflumilast.
  • Roflumilast is a drug with anti-inflammatory effects, which acts as a selective, long-acting inhibitor of the phosphodiesterase enzyme PDE IV and is chemically designatectas 3-(cyclopropylmethoxy)-N-(3, 5-dichloropyridin-4-yl)-4- (difluoromethoxy)benzamide.
  • Roflumilast is represented by the following formula (I),
  • WO '338 discloses a process for the preparation of roflumilast, which comprises haloalkylation of 4-hydroxy-3- cyclopropylmethoxybenzaldehyde with chlorodifluoromethane to obtain 4-difluoromethoxy- 3-cyclopropylmethoxy benzaldehyde, which is oxidised using sulphamic acid and sodium chlorite in the presence of glacial acetic acid to obtain 4-difluoromethoxy-3- cyclopropylmethoxybenzoic acid.
  • the acid group of 4-difluoromethoxy-3-cyclopropyl methoxybenzoic acid was converted into acid chloride on treatment with thionyl chloride to produce 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzoyl chloride.
  • This acid chloride was added to a suspension of 4-amino-3, 5-dichloropyridine and sodium hydride in dry tetrahydrofuran to obtain roflumilast.
  • the present invention provides an alternate process which is efficient and industrially advantageous process for the synthesis of roflumilast.
  • the present invention relates to a process for the preparation of rofl compound of formula (I),
  • the present invention provides a process for the preparation of rofiumilast, compound of formula (I), comprising:
  • the present invention provides a process for purification of roflumilast comprising:
  • the present invention provides a compound of formula V.
  • the present invention further provides compound of formula (V), which is in crystalline form and exhibits an X-ray diffraction pattern having characteristic peaks in degrees 2 ⁇ 0.2° ⁇ at about 9.7, 10.4, 1 5.4, 20.0, 20.4 ⁇ 0.2°, which is substantially in accordance with fig.1 .
  • the present invention provides use of compound of formula V in the preparation of roflumilast.
  • the present invention further provides roflumilast, which is in crystalline form and exhibits an X-ray diffraction pattern having characteristic peaks expressed in degrees 2 ⁇ 0.2° ⁇ at about 5.6, 16.7, 22.4, 25.4, 28.1 ⁇ 0.2° ⁇ 0.2°, which is substantially in accordance with fig.2.
  • Fig. 1 represents an XRD diffractogram of 4-nitrophenyl-3-
  • Fig. 2 represents an XRD diffractogram of 3-(cyclopropylmethoxy)-N-(3, 5- dichloropyridin-4-yl)-4-(difluoromethoxy) benzamide, roflumilast, compound of formula (1).
  • the present invention provides a process for the preparation of roflumilast
  • Bases include, but are not limited to, inorganic bases for example metal hydroxide such as sodium hydroxide, potassium hydroxide, cesium hydroxide, metal alkoxides such as sodium methoxide, potassium methoxide, potassium tert-butoxide, sodium ethoxide, alkali metal hydrides such as sodium hydride, potassium hydride or mixtures thereof, alkali metal carbonates such as sodium carbonate, potassium carbonate, alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate, organolithium reagents such as n-butyl lithium; organic bases such as N, N dimethyl aniline, N, N diisopropyl ethyl amine, pyridine, 4-dimethyl amino pyridine, triethyl amine, trimethyl amine, tributyl amine, triisopropylamine, diisopropyl ethyl amine, 1 , 8, diazabicyclo-[5,4 0]
  • reaction may be carried out in the presence of a suitable solvent.
  • Suitable solvents include aprotic polar solvents; for example, dimethylformamide or dimethylsulfoxide, hydrocarbons such as toluene, hexane, xylene and the like, nitriles such as acetonitrile, ethers such as tetrahydrofuran, diethyl ether, straight or branched alcohols such as methanol, ethanol, isopropanol, chlorinated solvents such as methylene dichloride, ethylene dichloride, ketones such as acetone, methyl isobutyl ketone, esters such as ethyl acetate, butyl acetate and the like.
  • the solvent is dimethyl formamide.
  • the reaction can take place over a wide range of temperatures.
  • the temperature can range from about 0°C to about reflux temperature of solvent.
  • the present invention relates to a process for the purification of roflumilast.
  • the product, roflumilast, obtained from the reaction mixture is treated with a basic solution selected from the group consisting of carbonate such as sodium carbonate, potassium carbonate; bicarbonate such as sodium bicarbonate, potassium bicarbonate; hydroxides such as sodium hydroxide, potassium hydroxide, tert-butoxide; ammonia.
  • a basic solution selected from the group consisting of carbonate such as sodium carbonate, potassium carbonate; bicarbonate such as sodium bicarbonate, potassium bicarbonate; hydroxides such as sodium hydroxide, potassium hydroxide, tert-butoxide; ammonia.
  • roflumilast is treated with a solution of sodium bicarbonate and isolated by standard methods such as filtration, centrifugation and the like.
  • the roflumilast thus obtained is free of 3-(cyclopropylmethoxy)-4-(difluoromethoxy) benzoic acid, compound of formula
  • the present invention provides a process for the recovery of 3-(cycIopropylmethoxy)-4-(difluoromethoxy) benzoic acid, a compound of formula (IV), comprising obtaining the filtrate after isolation of roflumilast from the basic solution and is treated with an acid.
  • the term "acid” refers to a substance that tends to release a proton.
  • the acid may be selected from hydrohilic acid such as hydrochloric acid, hydrobromic acid; acetic acid.
  • the acid used is hydrochloric acid and the pH adjusted to about 1 to about 3.
  • the process just described further comprising isolating the 3- (cyclopropyImethoxy)-4-(difluoromethoxy) benzoic acid, compound of formula IV from the slurry thus formed.
  • the present invention provides a process for the preparation of roflumilast, compound of formula (I), comprising:
  • suitable coupling agents include, but are not limited to hydroxybenzotriazole, N, N'-dicyclohexylcarbodiimide, N, N'- diisopropylcarbodiimide, l -(3-dimethylaminopropyl)-3-ethylcarbodiimide or salt and mixtures thereof.
  • the coupling agent is l -(3-dimethylaminopropyl)-3- ethylcarbodiimide.
  • reaction may be carried out in the presence of one or more solvents.
  • the solvents include, but are not limited to, for example ethers such as tetrahydrofuran, diethyl ether, diisopropyl ether, aprotic solvents such as dimethylformamide, dimethylsulfoxide, nitriles such as acetonitrile, or mixtures thereof.
  • ethers such as tetrahydrofuran, diethyl ether, diisopropyl ether
  • aprotic solvents such as dimethylformamide, dimethylsulfoxide, nitriles such as acetonitrile, or mixtures thereof.
  • the solvent is tetrahydrofuran.
  • reaction of 3-(cyclopropylmethoxy)-4-(difluoromethoxy) benzoic acid, compound of formula IV and 4-nitrophenol may be carried out at ambient temperatures or at elevated temperatures. Preferably the reaction transpires at about 50 to 80°C.
  • the present invention provides the process the preparation of roflumilast comprising reacting 3-(cyclopropylmethoxy)-4- (difluoromethoxy)benzoic acid, compound of formula (IV) with 4-nitro phenol to obtain 4- nitrophenyl 3-(cyclopropylmethoxy)-4-(difluoromethoxy) benzoate, compound of formula (V), in the presence of l -Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC.HCl) and tetrahydrofuran.
  • EDC.HCl l -Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride
  • the reaction transpires at a temperature of about 65 to 70°C over a period of about 1 to 2 hours to obtain compound of formula V.
  • the present invention provides the preparation of 4- nitrophenyl-3-(cyclopropylmethoxy)-4-(difluoromethoxy) benzoate, compound of formula (V) comprising reacting 4-nitro phenol with an activated derivative of 3- (cyclopropylmethoxy)-4-(difluoromethoxy) benzoic acid, compound of formula (IVA), such as acid halide or a reactive ester.
  • X is halogen such as chloride, bromide, iodide, alkoxy, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl,
  • substituted phenyl examples include, but are not limited to, phenyl substituted with chlorine, bromine, C 1 -C4 alkyl, C 1 -C4 alkoxy.
  • alkyl groups include methyl, ethyl, propyl and the like.
  • alkoxy examples include but are not limited to methoxy, ethoxy and the like.
  • substituted benzyl examples include, but are not limited to, p-chloro benzyl, p-methoxy benzyl.
  • the activated derivative of 3-(cyclopropylmethoxy)-4-(difluoromethoxy) benzoic acid, compound of formula (IVA) may be for example 3-(cyclopropylmethoxy)-4- (difluoromethoxy) benzoyl halide, or ester of 3-(cyclopropylmethoxy)-4-(difluoromethoxy) benzoic acid.
  • the present invention relates to a process for the preparation of 3-(cyclopropylmethoxy)-4-(difluoromethoxy) benzoic acid, compound of formula IV comprising: a) reacting 3-hydroxy-4-(difluoromethoxy) benzaldehyde, compound of formula (II) with cyclopropylmethyl halide in the presence of a base to obtain 3-(cyclopr pylmethoxy)-4- (difluoromethoxy) benzaldehyde, compound of formula (III); and
  • a suitable cyclopropylmethyl halide that can be used, include but are not limited to, cyclopropylmethyl bromide, cyclopropylmethyl chloride or cyclopropylmethyl iodide.
  • the cyclopropylmethyl halide is cyclopropylmethyl bromide.
  • the reaction may be carried out in the presence of one or more bases.
  • the base may be selected from, but is not limited to, organic bases such as N, N-dimethyl aniline, N, N-diisopropylethyl amine, pyridine, 4-dimethylamino pyridine, triethylamine or mixtures thereof; inorganic bases include alkali metal carbonates such as potassium carbonate, sodium carbonate or lithium carbonate; alkali metal bicarbonate such as include potassium bicarbonate or sodium bicarbonate; alkali metal hydroxide such as sodium hydroxide or potassium hydroxide; alkali metal alkoxides such as sodium methoxide, potassium methoxide or mixtures thereof.
  • the base used is potassium carbonate.
  • the reaction may be carried out in the presence of a suitable solvent.
  • suitable solvents include, but are not limited to, ethers for example diethyl ether, tetrahydrofuran or dioxane, aliphatic hydrocarbons, for example hexane or heptane; aromatic hydrocarbons, for example toluene or xylene; halogenated solvents, for example dichloromethane, dibromomethane, chloroform, or carbon tetrachloride; aprotic polar solvents, for example dimethylformamide or dimethylsulfoxide; protic polar solvents, for example methanol, ethanol, isopropanol, butanol or isobutanol or mixtures thereof.
  • the solvent used is dimethyl formamide.
  • the reaction can take place over a wide range of temperatures.
  • the temperature can range from about 10°C to about reflux temperature of solvent.
  • the reaction time may vary from about 2 to 10 hours. Preferably the reaction transpires from about 1 .5 to 3.5 hours.
  • 3-hydroxy-4-(difluoromethoxy) benzaldehyde, compound of formula (II) is reacted with cyclopropyl methyl bromide in dimethyl formamide and potassium carbonate is added to the solution.
  • the reaction mass is heated to a temperature of about 60 to 90°C.
  • the reaction transpires over a temperature range of about 1 10 to 120°C.
  • the reaction transpires over a period of about 45 to 90 minutes. Preferably the reaction transpires over a period of about 60 minutes to obtain 3-(cyclopropylmethoxy)-4- (difluoromethoxy) benzaldehyde, compound of formula (III).
  • Suitable oxidizing agents include, but are not limited to, selenium dioxide, dichlorodicyanoquinone, sodium hypochlorite/tetrabutylammoniumsulphate, sulphamic acid/sodium chlorite, ozone/silicon dioxide, pyridiniumchlorochromate/acetonitrile, eerie ammonium nitrate, pyridiniumchlorochromate/acetic acid or mixtures thereof.
  • the oxidizing agent is a combination of sulphamic acid and sodium chlorite.
  • the reaction may be carried out in the presence of a suitable solvent.
  • Suitable solvents include, but are not limited to, ethers, for example, diethyl ether, tetrahydrofuran or dioxane; aprotic polar solvents, for example, dimethylformamide or dimethylsulfoxide; protic polar solvents, for example, methanol, ethanol, isopropanol, butanol or isobutanol; ketones, for example, acetone or methyl isobutyl ketone or mixtures thereof.
  • the solvent used is acetone.
  • oxidizing agent can take place over a wide range of temperatures.
  • the temperatures can range from about 0 to 30°C, preferably from about 5 to 10°C.
  • Addition of a second oxidizing agent can take place at a temperature of about 0 to 40°C, preferably from about 25°C to about 30°C.
  • reaction transpires over a period of about 1 to 3 hours. Preferably over a period of about 1 hour.
  • 3-(cyclopropylmethoxy)-4-(difluoromethoxy) benzoic acid, compound of formula (IV) is isolated from the reaction mass by known methods.
  • the present invention provides a process for the preparation of roflumilast represented schematically in scheme 1
  • the present invention provides a process for the purification of roflumilast comprising:
  • a suitable solvent include, but are not limited to, alcoholic solvents such as ethanol, methanol, isopropanol;chlorinated solvents, such as, ethylene dichloride, methylene dichloride; esters, such as ethyl acetate, isopropyl acetate; nitriles, such as acetonitrile, ethers such as diethyl ether, diisopropyl ether; hydrocarbons, such as heptane, hexane, toluene, xylene; nitriles, such as acetonitrile; water or mixtures thereof.
  • the solvents are isopropanol and methanol.
  • bases include inorganic base which may be selected from, but not limited to, ammonia; alkali metal hydroxides, such as sodium hydroxide, potassium hydroxide; alkaline metal hydroxide, such as magnesium hydroxide or calcium hydroxide, lithium hydroxide and the like; carbonates, such as sodium carbonate, potassium carbonate, lithium carbonate; meta.1 alkoxide, such as sodium methoxide, sodium ethoxide or magnesium methoxide and the like; bicarbonates, such as sodium carbonate, potassium carbonate, lithium carbonate; organic bases, such as triethylamine, diisopropylethylamine, pyridine.
  • the base is aqueous ammonia.
  • mineral acid or an organic acid is selected from, but are not limited, to hydrohilic acid such as hydrochloric acid, hydrobromic acid, acetic acid, sulfuric acid, nitric acid or trifluoroacetic acid.
  • hydrohilic acid such as hydrochloric acid, hydrobromic acid, acetic acid, sulfuric acid, nitric acid or trifluoroacetic acid.
  • the acid used is hydrochloric acid.
  • roflumilast is isolated from the reaction mixture by standard methods known in the art such as filtration, centrifugation and the like. Preferably pure roflumilast is isolated by filtration.
  • the process for the purification of roflumilast comprises adding a base such as ammonia to roflumilast in a suitable solvent; subjecting the basic solution thus obtained to charcoal treatment; adding mineral or organic acid such as hydrochloric acid to the filtrate obtained after charcoal removal, ; and adjusting the pH of the solution below 3; isolating pure roflumilast by techniques known in the art.
  • the present invention provides ammonium salt of roflumilast.
  • the present invention further provides a compound of formula V.
  • the present invention further provides compound of formula (V), in crystalline form exhibiting X-ray diffraction pattern having characteristic peaks expressed in degrees 2 ⁇ 0.2° ⁇ at about 9.7, 10.4, 15.4, 20.0, 20.4 ⁇ 0.2°, which is substantially in accordance with Fig. 1.
  • X-ray powder determination was performed on ARL X-ray diffractometer model XPERT-PRO (PANalytical) scanning parameters start position [°2Th.] 2.01 and end position [°2Th.] 49.98.
  • the present invention provides roflumilast in crystalline form exhibiting X-ray diffraction pattern having characteristic peaks expressed in degrees 2 ⁇ 0.2°0 at about 5.6, 16.7, 22.4, 25.4, 28.1 ⁇ 0.2°, which is substantially in accordance with Fig. 2, X-ray powder was performed on ARL X-ray diffractometer model XPERT-PRO (PANalytical) scanning parameters start position [°2Th.] 2.01 and end position [°2Th.] 49.98.
  • the present invention provides roflumilast having purity greater than 99%, as determined by high performance liquid chromatography.
  • the present invention provides roflumilast having purity greater than 99.9%, as determined by high performance liquid chromatography.
  • the present invention provides roflumilast obtained by the processes described herein, can have a D 50 and D90 particle size of less than about 400 microns, preferably less than about 200 microns, more preferably less than about 150 microns, still more preferably less than about 50 microns and most preferably less than about 25 microns.
  • the particle size can be determined by techniques known in the art, Illustratively, particle size distribution (PSD) can be obtained by Malvern light scattering, a laser light scattering technique, using a Malvern® Mastersizer 2000. It is noted the notation D x means that X% of the particles have a diameter less than a specified diameter D.
  • a D50 of about 250 ⁇ means that 50% of the particles composition comprising of roflumilast has a diameter less than about 250 ⁇ .
  • the particle size reduction methods known in the art can be employed to achieve particle sizes of the roflumilast; and these may include milling, grinding, micronizing to bring the solid state roflumilast or its pharmaceutically acceptable salts to the desired particle size range.
  • Tetrahydrofuran was distilled off under reduced pressure; and 500ml water was charged to the resultant residue and subsequently stirred at about room temperature (25°C -30°C) for about an hour.
  • the resultant precipitated solid was filtered off and dried under vacuum (u/v) to afford 35 g of crude yellow solid which was further purified in acetonitrile and diisopropyl ether (DIPE) mixture to afford desired off white solid.
  • DIPE diisopropyl ether
  • Step 5 3-(Cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy) benzamide (roflumilast)
  • the resultant mixture was stirred at about 25-30°C for about 1 -2 hours.
  • the reaction mixture was quenched in water (2000 mL) and acidified with Cone. HC1 (adjust pH to 2).
  • the resultant mixture was filtered off, washed with water (250 mL) and dried to afford crude 22.0 g of white solid ( HPLC Purity 98%).
  • Step 1 Preparation of 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzaldehyde
  • Tetrahydrofuran was distilled off under reduced pressure; and a mixture of 2 liter acetonitrile and 500ml water was charged to the resultant residue and subsequently stirred at a temperature of about 25-30°C for an hour.
  • the resultant precipitated solid was filtered off and dried under vacuum (u/v) to afford 35 g of 4-nitrophenyl 3-(cyclopropylmethoxy)-4- (difluoromethoxy) benzoate. Yield; 22gm
  • Step 4 3-(Cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy) benzamide (roflumilast)
  • reaction mixture was quenched in water (2280 mL) and acidified with Cone. HC1 (adjust pH to 2).
  • the resultant mixture was filtered off, washed with water (190 mL) and dried to afford crude roflumilast.
  • the wet cake was stirred in a sodium bicarbonate solution and the slurry was filtered to obtain roflumilast.

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Abstract

La présente invention concerne un procédé de préparation de roflumilast.
PCT/IN2012/000266 2011-04-28 2012-04-13 Nouveau procédé de préparation de 3-(cyclopropylméthoxy)-n-(3,5-dichloropyridin-4-yl)-4-(difluorométhoxy) benzamide Ceased WO2012147098A2 (fr)

Applications Claiming Priority (2)

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IN1345/MUM/2011 2011-04-28
IN1345MU2011 2011-04-28

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WO2012147098A2 true WO2012147098A2 (fr) 2012-11-01
WO2012147098A3 WO2012147098A3 (fr) 2013-03-21

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102942521A (zh) * 2012-11-27 2013-02-27 四川科伦药物研究有限公司 罗氟司特的制备方法
CN103012256A (zh) * 2012-12-11 2013-04-03 四川科伦药物研究有限公司 罗氟司特的合成方法
WO2013072938A3 (fr) * 2011-11-09 2013-11-07 Mylan Laboratories Ltd Procédé amélioré pour la préparation de roflumilast
CN103497150A (zh) * 2013-10-12 2014-01-08 国药集团致君（苏州）制药有限公司 一种高纯度罗氟司特的精制方法
WO2014060464A1 (fr) * 2012-10-17 2014-04-24 Interquim, S.A. Procédé de préparation de roflumilast
CN104447244A (zh) * 2014-10-29 2015-03-25 成都森科制药有限公司 罗氟司特中间体及罗氟司特的制备方法
CN104447245A (zh) * 2014-10-29 2015-03-25 成都森科制药有限公司 罗氟司特中间体、中间体制备方法及罗氟司特的制备方法

Family Cites Families (4)

* Cited by examiner, † Cited by third party
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ES2335498T3 (es) * 2003-03-10 2010-03-29 Nycomed Gmbh Nuevo proceso para la preparacion de reflumilast.
EP1670742A1 (fr) * 2003-09-12 2006-06-21 Ranbaxy Laboratories Limited Procede de preparation de roflumilast
CN102351787B (zh) * 2011-08-18 2014-08-13 天津市汉康医药生物技术有限公司 高生物利用度的罗氟司特化合物
CN102336705B (zh) * 2011-10-28 2013-03-27 成都苑东药业有限公司 一种制备n-(3,5-二氯吡啶-4-基)-3-环丙基甲氧基-4-二氟甲氧基苯甲酰胺的方法

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WO2013072938A3 (fr) * 2011-11-09 2013-11-07 Mylan Laboratories Ltd Procédé amélioré pour la préparation de roflumilast
US9145365B2 (en) 2011-11-09 2015-09-29 Mylan Laboratories Ltd. Process for the preparation of Roflumilast
WO2014060464A1 (fr) * 2012-10-17 2014-04-24 Interquim, S.A. Procédé de préparation de roflumilast
CN102942521A (zh) * 2012-11-27 2013-02-27 四川科伦药物研究有限公司 罗氟司特的制备方法
CN103012256A (zh) * 2012-12-11 2013-04-03 四川科伦药物研究有限公司 罗氟司特的合成方法
CN103497150A (zh) * 2013-10-12 2014-01-08 国药集团致君（苏州）制药有限公司 一种高纯度罗氟司特的精制方法
CN104447244A (zh) * 2014-10-29 2015-03-25 成都森科制药有限公司 罗氟司特中间体及罗氟司特的制备方法
CN104447245A (zh) * 2014-10-29 2015-03-25 成都森科制药有限公司 罗氟司特中间体、中间体制备方法及罗氟司特的制备方法

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