WO2005026095A1 - Process for the preparation of roflumilast - Google Patents

Process for the preparation of roflumilast Download PDF

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WO2005026095A1
WO2005026095A1 PCT/IB2004/002959 IB2004002959W WO2005026095A1 WO 2005026095 A1 WO2005026095 A1 WO 2005026095A1 IB 2004002959 W IB2004002959 W IB 2004002959W WO 2005026095 A1 WO2005026095 A1 WO 2005026095A1
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formula
compound
alkali metal
iodide
bromide
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PCT/IB2004/002959
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French (fr)
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Prosenjit Bose
Yoginder Pal Sachdeva
Ramendra Singh Rathore
Yatendra Kumar
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Ranbaxy Laboratories Limited
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
    • C07C51/353—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by isomerisation; by change of size of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
    • C07C51/363—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/31—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of functional groups containing oxygen only in singly bound form
    • 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

  • PROCESS FOR THE PREPARATION OF ROFLUMILAST Field of the invention relates to a process for the preparation of 3- cyclopropylmethoxy-4-difluoromethoxy benzoic acid of Formula I, and to the use of this compound as an intermediate for the preparation of roflumilast.
  • roflumilast is 3-(cyclopropylmethoxy)-N-(3,5-dichloro-4- pyridinyl)-4-(difluoromethoxy)benzamide of Formula VI, and is known from U.S. Patent No. 5,712,298.
  • FORMULA VI Roflumilast is an effective phosphodiesterase-4-inhibitor (PDE4-inhibitor), which can be used in the treatment of asthma, inflammation, bronchitis, allergy, osteoporosis, dermatoses and disorders related to immune system, heart and kidney.
  • PDE4-inhibitor phosphodiesterase-4-inhibitor
  • U.S. Patent No. 5,712,298 discloses the preparation of 3-cyclopropylmethoxy- 4-difluoromethoxy benzoic acid comprising reacting 4-hydroxy-3- cyclopropylmethoxybenzaldehyde with dichlorofluoromethane followed by oxidation.
  • 6,712,274 discloses the preparation of 3-cyclopropylmethoxy- 4-difluoromethoxy benzoic acid comprising reacting dihydroxybenzaldehyde with tertiarybutyl difluorochloroacetate in the presence of lithium carbonate and reacting the obtained 4-difluoromethoxy-3-hydroxy benzaldehyde with cyclopropylmethyl bromide in the presence of potassium carbonate followed by oxidation to yield 3- cyclopropylmethoxy-4-difluoromethoxy benzoic acid.
  • Summary of the Invention hi one general aspect there is provided a process for the preparation of 3- cyclopropylmethoxy-4-difluoromethoxy benzoic acid. The process includes reacting the compound of Formula II,
  • FORMULA V wherein X is a leaving group, in the presence of a base.
  • a novel compound 3- cyclopropylmethoxy-4-hydroxy benzoate of Formula II.
  • a novel compound of Formula III in another general aspect there is provided a process for the preparation of roflumilast. The process includes reacting compound of Formula I with 4-amino-3,5- dichloro pyridine.
  • a pharmaceutical composition that includes a therapeutically effective amount of roflumilast; and one or more pharmaceutically acceptable carriers, excipients or diluents. The details of one or more embodiments of the inventions are set forth in the description below.
  • alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, secondary butyl and tert- butyl groups.
  • alkenyl groups include vinyl, allyl, isopropenyl, pentenyl and hexenyl groups.
  • the substituted phenyl includes phenyl substituted by 1-3 substituents, which are independently bromine, chlorine, fluorine, - C 4 alkyl, C ⁇ -C alkoxy, and nitro groups.
  • alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy and butoxy groups.
  • the substituted benzyl includes p-nitro benzyl, p-methoxy benzyl, o-nitro benzyl, p-bromo benzyl, and 2,4,6-trimethyl benzyl groups.
  • the difluoro methylating agent which can be used for preparing 3- cyclopropylmethoxy-4-difluoromethoxy benzoic acid of Formula I include difluorochloromethane (Freon-22 ® ), alkyl difluorochloroacetate such as methyl difluorochloroacetate, ethyl difluorochloro acetate and tertiarybutyl difluorochloroacetate.
  • the bases which can be used include organic and inorganic bases.
  • organic bases examples include trimethylamine, triethylamine, tributylamme, triisopropylami Le, diisopropylethylamine, DBU (1,8-diazabicyclo- [5.4.0]-undec-7-ene), DBN (1,5- diazabicyclo-[4.3.0]-non-5-ene), 4-dimethylamino pyridine and mixtures thereof.
  • inorganic bases include alkali metal carbonate, bicarbonate, hydroxide and mixtures thereof. Examples of alkali metal carbonates include lithium carbonate, sodium carbonate and potassium carbonate. Examples of alkali metal bicarbonates include sodium bicarbonate and potassium bicarbonate.
  • phase transfer catalysts include quaternary ammonium salts such as tetramethyl ammonium iodide, tetrabutyl ammonium iodide, benzyltributyl ammonium bromide, 1-methyl ⁇ yridinium iodide, tetramethyl-2-butylammonium chloride, trimethylcyclopropylammonium chloride, tetrabutylammonium bromide and t-butylethyldimethylammonium bromide; quaternary phosphonium salts such as tributylmethylphosphonium iodide, triethylmethylphosphonium iodide, methyltriphenoxyphosphonium iodide, tetrabutyl phosphonium bromide;
  • the reaction of compound of Formula II with difluoromethylating agent may be carried out in the presence of a suitable solvent.
  • suitable solvents are inert organic solvents that do not change under the reaction conditions. Examples of such solvents include alkyl ethers such as diethylether, diisopropylether and dimethoxyethane; nitriles such as acetonitrile and benzonitrile; alcohols such as methanol, ethanol, isopropanol and butanol; ketones such as acetone and methyl isobutyl ketone; chlorinated hydrocarbons such as methylene chloride, ethylene dichloride and carbon tetrachloride; esters such as ethylacetate and isopropylacetate; hydrocarbons such as benzene, xylene, toluene , hexane, cyclohexane, heptane and octane; dipolar aprotic solvents such as di
  • the reaction may be carried out at a temperature of from about 20°C to about 120°C, for example at a temperature of from about 25°C to about 50°C.
  • the compound of Formula HI is converted to the compound of Formula I by conventional methods including hydrolysis or hydrogenation, in case R is a benzylic group.
  • Examples of leaving group X, in the compound of Formula V, include chlorine, bromine, iodine, sulphate and tosylate.
  • the base, phase transfer catalyst and solvent, which may be used for preparing 3-cyclopropylmethoxy-4-hydroxy benzoate of Formula II from compound of Formula rv, can be the same as those which can be used in reaction of compound of Formula II with difluoromethylating agent.
  • roflumilast of Formula VI is prepared by reacting an activated derivative of the acid of Formula I, such as acid halide or a reactive ester, with 4-amino- 3,5-dichloro pyridine.
  • roflumilast can be prepared by reacting the corresponding acid chloride of the compound of Formula I with 4-amirro-3,5-dichloro pyridine in the presence of sodium hydride in tetrahydrofuran.
  • the resulting roflumilast may be formulated into ordinary dosage forms such as, for example, tablets, capsules, pills, solutions, etc. i these cases, the medicaments can be prepared by conventional methods with conventional pharmaceutical excipients.
  • the compositions include dosage forms suitable for oral, buccal, rectal, and parenteral (including subcutaneous, intramuscular, and ophthalmic) administration.
  • the oral dosage forms may include solid dosage forms, like powder, tablets, capsules, suppositories, sachets, troches and lozenges as well as liquid suspensions, emulsions, pastes and elixirs.
  • Parenteral dosage fonns may include intravenous infusions, sterile solutions for intramuscular, subcutaneous or intravenous administration, dry powders to be reconstituted with sterile water for parenteral administration, and the like.
  • the roflumilast can be administered for the treatment the treatment of asthma, inflammation, bronchitis, allergy, osteoporosis, dermatoses and disorders related to immune system, heart and kidney in a warm-blooded animal.
  • a warm-blooded animal is a member of the animal kingdom possessed of a homeostatic mechanism and includes mammals and birds.
  • Example 1 Preparation of 3 -Cvclopropylmethoxy-4-hvdroxy methyl benzoate 3,4-Dihydroxy methyl benzoate (50 g) was stirred with cyclopropylmethyl bromide (50.2 g) and potassium carbonate (82.1 g) in acetone (350 ml) for 18 hours at 40°C. The reaction mixture was filtered over a hyflo bed followed by concentration of the organic layer.
  • Example 2 Preparation of 3 -Cvclopropyhnethoxy-4-difluoromethoxy benzoic acid
  • the product obtained from Example 1 (10 g) was subjected, to difluoromethylation using difluorochloromethane, 35 % w/w sodium hydroxide aqueous solution (50 ml), tetrabutyl ammonium bromide (5.9 g) in toluene (100 ml) as solvent at 20 to 35° C.
  • the resulting product, 3-cyclopropylmethoxy-4-difluoromethoxy methyl benzoate was hydrolyzed in situ by adding 50 ml water and heating the reaction mixture to 50 to 55°C.
  • Example 3 Preparation of roflumilast The product obtained from Example 2 (lOg) was heated with thionyl chloride (5.8g) and catalytic amount of dimethylformamide (0.5ml) at 80 to 85°C for 1 hour. The solution was evaporated in vacuo and the oily residue was dissolved in dry tetrahydrofuran (50 ml). This was added dropwise at 0°C to a suspension prepared from sodium hydride (3.75 g, 60% suspension) and 4-amino-3,5-dichlorO pyridine (9.5g) in dry tetrahydrofuran (50 ml) with stirring. The reaction mixture was stirred for 30 minutes and then acidified to pH 2 with hydrochloric acid (1 N).
  • reaction mixture was extracted with ethyl acetate.
  • the extracted solvent was washed with sodium bicarbonate solution (5%) and water followed by evaporation in vacuum.
  • the residue was dissolved in methanol (45 ml) at 60°C and 5 ml of water was added to get precipitate.
  • the mixture was then cooled to 10°C and filtered to o " btain roflumilast.

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Abstract

The present invention relates to a process for the preparation of 3-cyclopropylmethoxy-4-difluromethoxy benzoic acid of structural Formula I, and to the use of this compound as an intermediate for the preparation of roflumilast.

Description

PROCESS FOR THE PREPARATION OF ROFLUMILAST Field of the invention The field of the invention relates to a process for the preparation of 3- cyclopropylmethoxy-4-difluoromethoxy benzoic acid of Formula I, and to the use of this compound as an intermediate for the preparation of roflumilast.
Figure imgf000002_0001
FORMULA I
Background of the Invention Chemically, roflumilast is 3-(cyclopropylmethoxy)-N-(3,5-dichloro-4- pyridinyl)-4-(difluoromethoxy)benzamide of Formula VI, and is known from U.S. Patent No. 5,712,298.
Figure imgf000002_0002
FORMULA VI Roflumilast is an effective phosphodiesterase-4-inhibitor (PDE4-inhibitor), which can be used in the treatment of asthma, inflammation, bronchitis, allergy, osteoporosis, dermatoses and disorders related to immune system, heart and kidney. U.S. Patent No. 5,712,298 discloses the preparation of 3-cyclopropylmethoxy- 4-difluoromethoxy benzoic acid comprising reacting 4-hydroxy-3- cyclopropylmethoxybenzaldehyde with dichlorofluoromethane followed by oxidation. U.S. Patent No. 6,712,274 discloses the preparation of 3-cyclopropylmethoxy- 4-difluoromethoxy benzoic acid comprising reacting dihydroxybenzaldehyde with tertiarybutyl difluorochloroacetate in the presence of lithium carbonate and reacting the obtained 4-difluoromethoxy-3-hydroxy benzaldehyde with cyclopropylmethyl bromide in the presence of potassium carbonate followed by oxidation to yield 3- cyclopropylmethoxy-4-difluoromethoxy benzoic acid. Summary of the Invention hi one general aspect there is provided a process for the preparation of 3- cyclopropylmethoxy-4-difluoromethoxy benzoic acid. The process includes reacting the compound of Formula II,
Figure imgf000003_0001
FORMULA II wherein R represents alkyl of C^ , alkenyl of Cι-C6, substituted or unsubstituted phenyl, benzhydryl, triphenylmethyl, or substituted or unsubstituted benzyl, with difluoro methylating agent in the presence of a base to obtain compound of Formula III,
Figure imgf000003_0002
FORMULA III wherein R is as defined above; and desterification of the compound of Formula III to obtain the compound of Formula I. In another general aspect there is provided a process for the preparation of 3- cyclopropylmethoxy-4-hydroxy benzoate of Formula II. The process includes reacting 3,4-dihydroxy benzoate of Formula IV,
Figure imgf000004_0001
FORMULA IV wherein R is as defined above, with cyclopropylmethyl derivative of Formula V,
Figure imgf000004_0002
FORMULA V wherein X is a leaving group, in the presence of a base. In another general aspect there is provided a novel compound, 3- cyclopropylmethoxy-4-hydroxy benzoate of Formula II. In another general aspect there is provided a novel compound of Formula III. In another general aspect there is provided a process for the preparation of roflumilast. The process includes reacting compound of Formula I with 4-amino-3,5- dichloro pyridine. In another aspect there is provided a pharmaceutical composition that includes a therapeutically effective amount of roflumilast; and one or more pharmaceutically acceptable carriers, excipients or diluents. The details of one or more embodiments of the inventions are set forth in the description below. Other features, objects and advantages of the inventions will be apparent from the description and claims. Detailed Description of the Invention The inventors have developed an efficient process for the preparation of 3- cyclopropylmethoxy-4-difluoromethoxy benzoic acid. The process involves reacting the compound of Formula II, wherein R represents alkyl of Cι-C6, alkenyl of Cι-C6. substituted or unsubstituted phenyl, benzhydryl, triphenylmethyl, or substituted or unsubstituted benzyl, with difluoro methylating agent in the presence of a base to obtain compound of Formula III, wherein R is as defined above; and desterification of the compound of Formula III to obtain the compound of Formula I. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, secondary butyl and tert- butyl groups. Examples of alkenyl groups include vinyl, allyl, isopropenyl, pentenyl and hexenyl groups. The substituted phenyl includes phenyl substituted by 1-3 substituents, which are independently bromine, chlorine, fluorine, - C4 alkyl, Cι-C alkoxy, and nitro groups. Examples of alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy and butoxy groups. The substituted benzyl includes p-nitro benzyl, p-methoxy benzyl, o-nitro benzyl, p-bromo benzyl, and 2,4,6-trimethyl benzyl groups. The difluoro methylating agent which can be used for preparing 3- cyclopropylmethoxy-4-difluoromethoxy benzoic acid of Formula I include difluorochloromethane (Freon-22®), alkyl difluorochloroacetate such as methyl difluorochloroacetate, ethyl difluorochloro acetate and tertiarybutyl difluorochloroacetate. The bases which can be used include organic and inorganic bases. Examples of organic bases include trimethylamine, triethylamine, tributylamme, triisopropylami Le, diisopropylethylamine, DBU (1,8-diazabicyclo- [5.4.0]-undec-7-ene), DBN (1,5- diazabicyclo-[4.3.0]-non-5-ene), 4-dimethylamino pyridine and mixtures thereof. Examples of inorganic bases include alkali metal carbonate, bicarbonate, hydroxide and mixtures thereof. Examples of alkali metal carbonates include lithium carbonate, sodium carbonate and potassium carbonate. Examples of alkali metal bicarbonates include sodium bicarbonate and potassium bicarbonate. Examples of alkali metal hydroxides include sodium hydroxide and potassium hydroxide. The reaction of compound of Formula II with difluoromethylating agent may "be carried out in the presence of phase transfer catalyst. Examples of such phase transfer catalysts include quaternary ammonium salts such as tetramethyl ammonium iodide, tetrabutyl ammonium iodide, benzyltributyl ammonium bromide, 1-methylρyridinium iodide, tetramethyl-2-butylammonium chloride, trimethylcyclopropylammonium chloride, tetrabutylammonium bromide and t-butylethyldimethylammonium bromide; quaternary phosphonium salts such as tributylmethylphosphonium iodide, triethylmethylphosphonium iodide, methyltriphenoxyphosphonium iodide, tetrabutyl phosphonium bromide, benzyltriphenyl phosphonium bromide, and tetraphenyl phosphonium chloride. The reaction of compound of Formula II with difluoromethylating agent may be carried out in the presence of a suitable solvent. Suitable solvents are inert organic solvents that do not change under the reaction conditions. Examples of such solvents include alkyl ethers such as diethylether, diisopropylether and dimethoxyethane; nitriles such as acetonitrile and benzonitrile; alcohols such as methanol, ethanol, isopropanol and butanol; ketones such as acetone and methyl isobutyl ketone; chlorinated hydrocarbons such as methylene chloride, ethylene dichloride and carbon tetrachloride; esters such as ethylacetate and isopropylacetate; hydrocarbons such as benzene, xylene, toluene , hexane, cyclohexane, heptane and octane; dipolar aprotic solvents such as dimethylsulfoxide and dimethylformamide; cyclic ethers such as dioxane and tetrahydrofuran, and mixtures thereof. The reaction may be carried out at a temperature of from about 20°C to about 120°C, for example at a temperature of from about 25°C to about 50°C. The compound of Formula HI is converted to the compound of Formula I by conventional methods including hydrolysis or hydrogenation, in case R is a benzylic group. Examples of leaving group X, in the compound of Formula V, include chlorine, bromine, iodine, sulphate and tosylate. The base, phase transfer catalyst and solvent, which may be used for preparing 3-cyclopropylmethoxy-4-hydroxy benzoate of Formula II from compound of Formula rv, can be the same as those which can be used in reaction of compound of Formula II with difluoromethylating agent. The reaction may be performed at a temperature from about 20°C to about 120°C. hi particular, it may be performed at a temperature from about 25°C to 50°C. In general, roflumilast of Formula VI is prepared by reacting an activated derivative of the acid of Formula I, such as acid halide or a reactive ester, with 4-amino- 3,5-dichloro pyridine. For example, roflumilast can be prepared by reacting the corresponding acid chloride of the compound of Formula I with 4-amirro-3,5-dichloro pyridine in the presence of sodium hydride in tetrahydrofuran. The resulting roflumilast may be formulated into ordinary dosage forms such as, for example, tablets, capsules, pills, solutions, etc. i these cases, the medicaments can be prepared by conventional methods with conventional pharmaceutical excipients. The compositions include dosage forms suitable for oral, buccal, rectal, and parenteral (including subcutaneous, intramuscular, and ophthalmic) administration. The oral dosage forms may include solid dosage forms, like powder, tablets, capsules, suppositories, sachets, troches and lozenges as well as liquid suspensions, emulsions, pastes and elixirs. Parenteral dosage fonns may include intravenous infusions, sterile solutions for intramuscular, subcutaneous or intravenous administration, dry powders to be reconstituted with sterile water for parenteral administration, and the like. The roflumilast can be administered for the treatment the treatment of asthma, inflammation, bronchitis, allergy, osteoporosis, dermatoses and disorders related to immune system, heart and kidney in a warm-blooded animal. For the purpose of this disclosure, a warm-blooded animal is a member of the animal kingdom possessed of a homeostatic mechanism and includes mammals and birds. hi the following section embodiments are described by way of excamples to illustrate the process of invention. However, these do not limit the scope of the present invention. Variants of these examples would be evident to persons ordinarily skilled in the art.
Example 1: Preparation of 3 -Cvclopropylmethoxy-4-hvdroxy methyl benzoate 3,4-Dihydroxy methyl benzoate (50 g) was stirred with cyclopropylmethyl bromide (50.2 g) and potassium carbonate (82.1 g) in acetone (350 ml) for 18 hours at 40°C. The reaction mixture was filtered over a hyflo bed followed by concentration of the organic layer.
The crude product was purified over a silica gel column (eluting with 5 °/o ethyl acetate in hexane) to obtain the title product. Yield: 16 g.
HPLC Purity: 99.5% Example 2: Preparation of 3 -Cvclopropyhnethoxy-4-difluoromethoxy benzoic acid The product obtained from Example 1 (10 g) was subjected, to difluoromethylation using difluorochloromethane, 35 % w/w sodium hydroxide aqueous solution (50 ml), tetrabutyl ammonium bromide (5.9 g) in toluene (100 ml) as solvent at 20 to 35° C. The resulting product, 3-cyclopropylmethoxy-4-difluoromethoxy methyl benzoate was hydrolyzed in situ by adding 50 ml water and heating the reaction mixture to 50 to 55°C. pH of the reaction mixture was adjusted to 3-4 by adding concentrated hydrochloric acid at 20 to 30°C followed by extraction with ethyl acetate (48 ml) .The solvent was evaporated under vacuum and the product was collected. Yield: 10 g.
HPLC Purity: 94.0%
Example 3: Preparation of roflumilast The product obtained from Example 2 (lOg) was heated with thionyl chloride (5.8g) and catalytic amount of dimethylformamide (0.5ml) at 80 to 85°C for 1 hour. The solution was evaporated in vacuo and the oily residue was dissolved in dry tetrahydrofuran (50 ml). This was added dropwise at 0°C to a suspension prepared from sodium hydride (3.75 g, 60% suspension) and 4-amino-3,5-dichlorO pyridine (9.5g) in dry tetrahydrofuran (50 ml) with stirring. The reaction mixture was stirred for 30 minutes and then acidified to pH 2 with hydrochloric acid (1 N). The reaction mixture was extracted with ethyl acetate. The extracted solvent was washed with sodium bicarbonate solution (5%) and water followed by evaporation in vacuum. The residue was dissolved in methanol (45 ml) at 60°C and 5 ml of water was added to get precipitate. The mixture was then cooled to 10°C and filtered to o"btain roflumilast.
Yield: 9.2 g Purity: 99% m.p.: 157-158°C
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are included within the scope of the present invention.

Claims

We claim:
1. A process for the preparation of 3-cyclopropylmethoxy-4-difluoromethoxy benzoic acid of Formula I,
Figure imgf000009_0001
FORMULA I the process comprising reacting compound of Formula II,
Figure imgf000009_0002
FORMULA II wherein R represents alkyl of CpC6, alkenyl of Cι-C6, substituted or unsubstituted phenyl, benzhydryl, triphenylmethyl, or substituted or unsubstituted benzyl, with difluoro methylating agent in the presence of a base to obtain compound of Formula III,
Figure imgf000009_0003
FORMULA III wherein R is as defined above; and desterification of the compound of Formula III to obtain the compound of Formula I. The process of claim 1, wherein R represents methyl or ethyl.
3. The process of claim 1, wherein the difluoromethylating agent comprises one or more of difluorochloromethane (Freon-22®) and all yl difluorochloroacetate. 4. The process of claim 3, wherein the alkyl difluorochloroacetate comprises one or more of methyl difluorochloroacetate, ethyl difluorochloroacetate and tertiary butyl difluorochloroacetate. 5. The process of claim 1, wherein the base comprises one or more of inorganic and organic bases. 6. The process of claim 5, wherein the organic base comprises one or more of trimethylamine, triethylamine, tributylamme, triisopropylamine, diisopropylethylamine, DBU (1,8-diazabicyclo- [5.4.0]-undec-7-ene), DBN (1,5- diazabicyclo-[4.3.0]-non-5- ene), and 4-dimethylamino pyridine. 7. The process of claim 5, wherein the inorganic base comprises one or more of alkali metal carbonates, alkali metal bicarbonates and alkali metal hydroxides. 8. The process of claim 7, wherein the alkali metal carbonate comprises one or more of lithium carbonate, sodium carbonate and potassium carbonate. 9. The process of claim 7, wherein the alkali metal bicarbonate comprises one or both of sodium bicarbonate and potassium bicarbonate. 10. The process of claim 7, wherein the alkali metal hydroxide comprises one or both of sodium hydroxide and potassium hydroxide. 11. The process of claim 1 , wherein the reaction is carried out in the presence of a phase transfer catalyst. 12. The process of claim 11, wherein the phase transfer catalyst comprises one or more of quaternary ammonium salts and quaternary phosphonium salts. 13. The process of claim 12, wherein the quaternary ammonium salt comprises one or more of tetramethyl ammonium iodide, tetrabutyl ammonium iodide, benzyltributyl ammonium bromide, 1-methylpyridinium iodide, tetramethyl-2-butylammonium chloride, trimethylcyclopropylammonium chloride, tetrabutylammonium bromide, and t-butylethyldimethylammonium bromide.
14. The process of claim 12, wherein the quaternary phosphonium salt comprises one or more of tributyhnethylphosphonium iodide, triethylmethylphosphonium iodide, methyltriphenoxyphosphonium iodide, tetrabutyl phosphonium bromide, benzyltriphenyl phosphonium bromide, and tetraphenyl phosphonium chloride. 15. The process of claim 1 , wherein the reaction is carried out in a solvent. 16. The process of claim 15, wherein the solvent comprises one or more of alkyl ethers, alcohols, ketones, chlorinated hydrocarbons, esters, hydrocarbons, dipolar aprotic solvents, cyclic ethers, and nitriles. 17. The process of claim 16, wherein the ether comprises one or more of diethylether, diisopropylether and dimethoxyethane. 18. The process of claim 16, wherein the alcohol comprises one or more of methanol, ethanol, isopropanol and butanol. 19. The process of claim 16, wherein the ketone comprises one or both of acetone and methyl isobutyl ketone. 20. The process of claim 16, wherein the chlorinated hydrocarbon comprises one or more of methylene chloride, ethylene dichloride and carbon tetrachloride. 21. The process of claim 16, wherein the ester comprises one or both of ethylacetate and isopropylacetate. 22. The process of claim 16, wherein the hydrocarbon comprises one or more of benzene, xylene, toluene, hexane, cyclohexane, heptane and octane. 23. The process of claim 16, wherein the dipolar aprotic solvent comprises one or both of dimethylsulfoxide, and dimethylformamide. 24. The process of claim 16, wherein the cyclic ether comprises one or both of dioxane, and tefrahydrofuran. 25. The process of claim 16, wherein the nitrile comprises one or both of acetonitrile and benzonitrile. 26. The process of claim 1 , wherein the reaction of compound of Formula II with difluoro methylating agent is carried out at temperature of from about 25°C to about 50°C.
27. A process for the preparation of 3-cyclopropylmethoxy-4-hydroxy benzoate of Formula II,
Figure imgf000012_0001
FORMULA II wherein R represents alkyl of Ci-Cό, alkenyl of Cι-C6, substituted or unsubstituted phenyl, benzhydryl, triphenylmethyl, or substituted or unsubstituted benzyl, the process comprising reacting 3,4-dihydroxy benzoate of Formula IV,
Figure imgf000012_0002
FORMULA IV wherein R is as defined above with cyclopropylmefhyl derivative of Formula V,
Figure imgf000012_0003
FORMULA V wherein X is a leaving group, in the presence of a base.
28. The process of claim 27, wherein R represents methyl or ethyl.
29. The process of claim 27, wherein the base comprises one or more of inorganic and organic bases.
30. The process of claim 29, wherein the organic base comprises one or more of trimethylamine, triethylamine, tributylamine, triisopropylamine, diisopropylethylamine, DBU (1,8-diazabicyclo- [5.4.0]-undec-7-ene), DBN (1,5- diazabicyclo-[4.3.0]-non-5- ene), and 4-dimethylamino pyridine.
31. The process of claim 29, wherein the inorganic base comprises one or more of alkali metal carbonates, alkali metal bicarbonates and alkali metal hydroxides. 32. The process of claim 31, wherein the alkali metal carbonate comprises one or more of lithium carbonate, sodium carbonate and potassium carbonate. 33. The process of claim 31 , wherein the alkali metal bicarbonate comprises one or both of sodium bicarbonate and potassium bicarbonate. 34. The process of claim 31 , wherein the alkali metal hydroxide comprises one or both of sodium hydroxide and potassium hydroxide. 35. The process of claim 27, wherein the reaction is carried out in the presence of a phase transfer catalyst. 36. The process of claim 35, wherein the phase transfer catalyst comprises one or more of quaternary ammonium salts and quaternary phosphonium salts. 37. The process of claim 36, wherein the quaternary ammonium salt comprises one or more of tetramethyl ammonium iodide, tetrabutyl ammonium iodide, benzyltributyl ammonium bromide, 1-methylpyridinium iodide, tetramethyl-2- butylammonium chloride, trimethylcyclopropylarnmonium chloride, tetrabutylammonium bromide, and t-butylethyldimethylammonium bromide. 38. The process of claim 36, wherein the quaternary phosphonium salt comprises one or more of tributylmethylphosphonium iodide, triethylmethylphosphonium iodide, methyltriphenoxyphosphonium iodide, tetrabutyl phosphonium bromide, benzyltriphenyl phosphonium bromide, and tetraphenyl phosphonium chloride. 39. The process of claim 27, wherein the reaction is carried out in a solvent. 40. The process of claim 39, wherein the solvent comprises one or more of alkyl ethers, alcohols, ketones, chlorinated hydrocarbons, esters, hydrocarbons, dipolar aprotic solvents, cyclic ethers, and nitriles. 41. The process of claim 27, wherein the leaving group X in the compound of Formula V represents chlorine, bromine, iodine, sulphate and tosylate. 42. The process of claim 27, wherein the reaction of compound of Formula IV with cyclopropylmethyl derivative of Formula V is carried out at temperature of from about 25°C to about 50°C.
43. The process of claim 1, further comprising reacting an activated derivative of the compound of Formula I with 4-amino-3,5-dichloro pyridine,
Figure imgf000014_0001
FORMULA VI to give a compound of Formula VI.
44. The process of claim 43, wherein the activated derivative is acid halide or a reactive ester of the compound of Formula I.
45. The process of claim 44, wherein the reaction of activated derivative of the Formula I with 4-amino-3,5-dichloro pyridine in carried out in the presence of sodium hydride in tetrahydrofuran.
46. A pharmaceutical composition comprising a therapeutically effective amount of roflumilast obtained by the process of claim 43; and one or more pharmaceutically acceptable carriers, excipients or diluents.
47. A method of treating asthma, inflammation, bronchitis, allergy, osteoporosis, dermatoses and disorders related to immune system, heart and kidney in a warmblooded animal comprising administering a pharmaceutical composition that includes roflumilast prepared by the process of claim 43.
48. A compound of Formula II,
Figure imgf000015_0001
FORMULA II wherein R represents alkyl of Cι-C6, alkenyl of Cι-C6, substituted or unsubstituted phenyl, benzhydryl, triphenylmethyl, or substituted or unsubstituted benzyl.
49. The compound of claim 48, wherein R represents methyl or ethyl.
50. A compound of Formula ILT,
Figure imgf000015_0002
FORMULA III wherein R represents alkyl of Cι-C6, alkenyl of Cι-C6, substituted or unsubstituted phenyl, benzhydryl, triphenylmethyl, or substituted or unsαbstituted benzyl.
51. The compound of claim 50, wherein R represents methyl or ethyl.
PCT/IB2004/002959 2003-09-12 2004-09-13 Process for the preparation of roflumilast WO2005026095A1 (en)

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