PRIORITY

[0001 ] This application claims the benefit of Indian Provisional Application

1345/MUM/201 1 , filed on April 28, 201 1 , the contents of which are incorporated by reference herein.

FIELD OF THE INVENTION

[0002] The present invention relates to a novel process of preparing roflumilast.

BACKGROUND OF THE INVENTION

[0003] 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),

[0004] It is under development as an orally administered drug for the treatment of inflammatory conditions of the lungs such as asthma, chronic obstructive pulmonary disease and emphysema.

[0005] There are several art on the process of making fluoroalkoxy-substituted benzamides. Illustratively, International Patent Publication WO 1995/001 338 (WO'338) discloses fluoroalkoxy-substituted benzamides, including roflumilast. 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.

[0006] International Patent Publication WO2004/033430 discloses a method for the preparation of fluoroalkoxy-substituted benzamides, including roflumilast, in a six-step carbonylation process.

[0007] International Patent Publication WO2004/080967 discloses a process for the preparation of high-purity roflumilast. The process involves reacting the anion of 4- amino-3, 5-dichloropyridine, with an activated derivative of 4-difluoromethoxy-3- cyclopropyl methoxybenzoic acid with molar ratio of at least 1.5 and at most 3, preferably 2.2. Roflumilast resulting from the process is recrystallized in a mixture of isopropanol and water.

[0008] International Patent Publication WO2005/026095 discloses a process for the preparation of 4-difluoromethoxy-3-cyclopropylmethoxy benzoic acid and use of this compound as an intermediate in the preparation of roflumilast.

[0009] In prior art references a large number of chemical transformations are required for the synthesis of roflumilast and their intermediates, disadvantageous^ affecting the overall chemical yield of the product. One of the known processes involves six steps for the preparation of roflumilast with an overall yield of only 4 percent. Further, the processes of the prior art present a number of practical difficulties that limit their use to relatively small scale applications. Prompted by the realization that roflumilast is a significantly important PDE IV inhibitor, there is a need for the development of a simple and industrially advantageous cost-effective process.

[0010] To overcome the above difficulties, the present invention provides an alternate process which is efficient and industrially advantageous process for the synthesis of roflumilast.

SUMMARY OF THE INVENTION

[0011] The present invention relates to a process for the preparation of rofl compound of formula (I),

(I)

comprising:

reacting.4-nitrophenyl-3-(cyclopropylmethoxy)-4-(difluoro methoxy) benzoate, compound of formula (V)

(V)

with 4-amino-3,5-dichloropyridine in the presence of a base to obtain rofiumilast of (I).

[0012] In one embodiment the present invention provides a process for the preparation of rofiumilast, compound of formula (I), comprising:

(I) a) reacting 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzoic acid, compound of formula (IV)

(IV)

with 4-nitro phenol to obtain 4-nitrophenyl-3-(cyclopropylmethoxy)-4-(difluoromethoxy) benzoate, compound of form coupling agent; and

b) reacting 4-nitrophenyl-3-(cyclopropylmethoxy)-4-(difluoromethoxy) benzoate, compound of formula (V), with 4-amino-3,5-dichloropyridine in the presence of a base to obtain roflumilast of formula (I).

[0013] In one embodiment, the present invention provides a process for purification of roflumilast comprising:

a) adding of roflumilast to a suitable solvent,

b) adding of base to a),

c) adding of a mineral or organic acid to b),

c) isolation of pure roflumilast.

[0014] In one embodiment, the present invention provides a compound of formula V.

[0015] In one embodiment, 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 θ± 0.2°θ at about 9.7, 10.4, 1 5.4, 20.0, 20.4± 0.2°, which is substantially in accordance with fig.1 . [0016] In one embodiment the present invention provides use of compound of formula V in the preparation of roflumilast.

[0017] In one embodiment, 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 θ± 0.2°θ at about 5.6, 16.7, 22.4, 25.4, 28.1 ± 0.2°± 0.2°, which is substantially in accordance with fig.2.

BRIEF DESCRIPTION OF DRAWINGS

[0018] Fig. 1 represents an XRD diffractogram of 4-nitrophenyl-3-

(cyclopropylmethoxy)-4-(difluoromethoxy) benzoate, a compound of formula (V).

[0019] Fig. 2 represents an XRD diffractogram of 3-(cyclopropylmethoxy)-N-(3, 5- dichloropyridin-4-yl)-4-(difluoromethoxy) benzamide, roflumilast, compound of formula (1).

Detailed Description of the Invention

[0020] The present invention provides a process for the preparation of roflumilast,

3-(cyclopropylmethoxy)-N-(3, 5-dichloropyridin-4-yl)-4-(difluoromethoxy)benzamide, compound of formula (I)

comprising:

reacting 4-nitrophenyl-3-(cyclopropylmethoxy)-4-(difluoromethoxy) benzoate, compound of formula (V) v with 4-amino-3,5-dichloropyridine in the presence of a base to obtain roflumilast, compound of formula (I).

[0021] 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]-undec-7-ene (DBU ), l ,5-diazabicyclo-[4,3 0]-non-5-ene and 4-diemthyl amino pyridine (DBN). Preferably the base is sodium hydride.

[0022] The 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. Preferably the solvent is dimethyl formamide.

[0023] 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. Preferably the reaction transpires between about 20 to 30°C. [0024] In one embodiment, 4-nitrophenyl-3-(cyclopropylmethoxy)-4-

(difluoromethoxy) benzoate, compound of formula (V) is reacted with 4-amino-3, 5- dichloropyridine in the presence of sodium hydride in dimethyl formamide at a temperature of about 0 to 5°C to obtain roflumilast, compound of formula (I).

[0025] In one embodiment, 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. Preferably 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 (IV).

[0026] In one embodiment, 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. Preferably 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.

[0027] . In one embodiment, the present invention provides a process for the preparation of roflumilast, compound of formula (I), comprising:

a) 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 a suitable coupling age

b) reacting 4-nitrophenyl 3-(cyclopropylmethoxy)-4-(difluoromethoxy) benzoate, compound of formula (V) with 4-amino-3,5-dichloropyridine in the presence of base to obtain roflumilast of formula (I).

[0028] In a) of the process described directly above, 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. Preferably the coupling agent is l -(3-dimethylaminopropyl)-3- ethylcarbodiimide.

[0029] The 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. Preferably the solvent is tetrahydrofuran.

[0030] The 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.

[0031] In one embodiment, 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. 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.

[0032] In one embodiment, 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.

IVA

wherein X is halogen such as chloride, bromide, iodide, alkoxy, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl,

[0033] Examples of substituted phenyl include, but are not limited to, phenyl substituted with chlorine, bromine, C 1 -C4 alkyl, C 1 -C4 alkoxy. Examples of alkyl groups include methyl, ethyl, propyl and the like. Examples of alkoxy include but are not limited to methoxy, ethoxy and the like. Examples of substituted benzyl include, but are not limited to, p-chloro benzyl, p-methoxy benzyl.

[0034] 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.

[0035] In one embodiment, 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

(II) (III)

b) oxidizing 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzaldehyde, compound of formula (III) with one or more oxidizing agent to obtain 3-(cyclopropylmethoxy)-4- (difluoromethoxy) benzoic acid, compound of formula (IV).

[0036] In a) of the process directly above, a suitable cyclopropylmethyl halide that can be used, include but are not limited to, cyclopropylmethyl bromide, cyclopropylmethyl chloride or cyclopropylmethyl iodide. Preferably the cyclopropylmethyl halide is cyclopropylmethyl bromide.

[0037] 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. Preferably, the base used is potassium carbonate.

[0038] 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. Preferably the solvent used is dimethyl formamide.

[0039] 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. Preferably the reaction transpires between about 100 to 1 10°C.

[0040] The reaction time may vary from about 2 to 10 hours. Preferably the reaction transpires from about 1 .5 to 3.5 hours.

[0041] In one embodiment, 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. Preferably the reaction transpires over a temperature range of about 1 10 to 120°C.

[0042] 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).

[0043] In b) of the process directly described, 3-(cyclopropylmethoxy)-4- (difluoromethoxy) benzaldehyde, compound of formula (III), is oxidized to obtain 3- (cyclopropylmethoxy)-4-(difluoromethoxy) benzoic acid, a compound of formula (IV) with one or more oxidizing agent in a suitable solvent.

[0044] 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. Preferably the oxidizing agent is a combination of sulphamic acid and sodium chlorite. [0045] 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. Preferably the solvent used is acetone.

[0046] The addition of 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.

[0047] In one embodiment, a solution of 3-(cyclopropylmethoxy)-4-

(difluoromethoxy) benzaldehyde, compound of formula (III), in acetone is cooled to a temperature of about 0 to 5°C. Solution of sulphamic acid in water is added to the reaction mass over a period of about 20 to 60 minutes. This is followed by the addition of a solution of a second oxidizing agent such as sodium chlorite in water.

[0048] The reaction transpires over a period of about 1 to 3 hours. Preferably over a period of about 1 hour. Thus 3-(cyclopropylmethoxy)-4-(difluoromethoxy) benzoic acid, compound of formula (IV) is isolated from the reaction mass by known methods.

[0049] In one embodiment, the present invention provides a process for the preparation of roflumilast represented schematically in scheme 1

[0050] Roflumilast thus obtained can be further purified to give highly pure compound of formula (I).

[0051] In one embodiment, the present invention provides a process for the purification of roflumilast comprising:

[0052] addition of roflumilast to a suitable solvent;

[0053] addition of base to a)

[0054] addition of a mineral acid or organic acid to b); and

[0055] isolation of pure roflumilast.

[0056] In a) of the process described directly above, 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. Preferably the solvents are isopropanol and methanol.

[0057] In b) of the process directly described above, 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. Preferably the base is aqueous ammonia.

[0058] In c) of the process directly described above, 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. Preferably the acid used is hydrochloric acid.

[0059] In d) of the process directly described above, 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.

[0060] ^' In one embodiment, 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.

[0061] in one embodiment, the present invention provides ammonium salt of roflumilast.

[0062] In one embodiment, the present invention further provides a compound of formula V.

[0063] In one embodiment, the present invention further provides compound of formula (V), in crystalline form exhibiting X-ray diffraction pattern having characteristic peaks expressed in degrees 2 θ± 0.2°θ 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.

[0064] In one embodiment, the present invention provides roflumilast in crystalline form exhibiting X-ray diffraction pattern having characteristic peaks expressed in degrees 2 θ± 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.

[0065] In one embodiment, the present invention provides roflumilast having purity greater than 99%, as determined by high performance liquid chromatography.

[0066] In one embodiment the present invention provides roflumilast having purity greater than 99.9%, as determined by high performance liquid chromatography.

[0067] In one embodiment, 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. Thus, a D50 of about 250μιη means that 50% of the particles composition comprising of roflumilast has a diameter less than about 250μηι.

[0068] 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.

[0069] Unless otherwise stated, work-up implies the following operations: distribution of the reaction mixture between the organic and aqueous phase, separation of layers, drying the organic layer over sodium sulfate, filtration and evaporation of the organic solvent. Purification, unless otherwise mentioned, refers to purification techniques, in suitable solvents.

[0070] In the scheme above, where specific bases, reagents, solvents, oxidizing agents, are mentioned, it is understood that other bases, acids, reagents, solvents, oxidizing agents, known to one of ordinary skill in the art may also be used and are therefore envisioned within the scope of this invention.

[0071] The details of the process of the invention are provided in the examples given below, which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention.

EXAMPLES

[0072] Example 1

3-(Cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-(diflu oromethoxy) benzamide Step 1 : Preparation of 4-difluoromethoxy-3-hydroxy benzaldehyde

To a well stirred suspension of 3,4-dihydroxy benzaldehyde (100 gm) and anhydrous potassium carbonate (120 gm) in dry Ν,Ν-dimethyl formamide (1.0 lit) was passed chlorodifluoromethane gas for about 30 minutes at about 80-85 C. After an hour, another lot of anhydrous potassium carbonate (25.0 gm) was added and stirred for about 1.5hours. The third lot of anhydrous potassium carbonate (25.0 gm) was added and stirred for about 1.5hours. The reaction mixture was then stirred for about 5-6 hours at ambient temperature. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue obtained was diluted with water (500 mL) and extracted with ethyl acetate (3 x 200 mL). The combined organic layers were dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude product obtained was purified through silica gel column to give 4-difluoromethoxy-3 -hydroxybenzaldehyde. Yield: 25-30 %.

Step 2: Preparation of 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzaldehyde

In a clean dry round bottomed flask, a solution of 3-hydroxy-4-(difluoromethoxy) benzaldehyde (25 g, 0.1329 mol) in N,N-dimethylformamide ( 150 mL) was charged. Potassium carbonate (27.5 g, 0.1993 mol) was added to the solution and the mixture was stirred at about 100 to 1 10°C for about an hour. The reaction mixture was cooled to about room temperature (25 -30°C). To this mixture cyclopropyl methyl bromide (21.5 g, 0.1594 mol) was added and stirred at about 105 to 1 10°C for about 2-3 hours. N,N- dimethylformamide was distilled off under reduced pressure; the resultant residue was diluted with water (600 mL) followed by extraction with ethyl acetate. The organic layer was dried and concentrated under reduced pressure to afford the desired oily product.

Yield: 30 g

% Yield: 98

HPLC Purity: 95.0 %

Step 3: Preparation of 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzoic acid

In a clean dry round bottomed flask, a solution of 3-(cyclopropylmethoxy)-4- (difluoromethoxy)benzaldehyde, obtained in Step 1 (30 g, 0.1238 mol) in acetone (300 mL) was charged at about 5tol0°C and to this solution, sulphamic acid (14.41 g, 0.1485 mol) was added. Subsequently the reaction mixture was stirred at about 0to l 0°C for about 15 min. To this mixture was added sodium chlorite (16.72 g, 0.1857 mol) and stirred at about 25 to30°C for another 2-3 hours. The reaction mixture was quenched by the addition of water (3000 mL) and stirred for about 30 min. The resultant mixture was filtered off, washed with water (200 mL) and dried at about 50 -55°C to afford the desired product.

Yield: 28 g

% Yield: 90

HPLC Purity: 95.0 %.

Step 4: Preparation of 4-nitrophenyl 3-(cyclopropylmethoxy)-4-(difluoromethoxy) benzoate

In a clean dry round bottomed flask, a solution of 3-(cyclopropylmethoxy)-4- (difluoromethoxy)benzoic acid, obtained in Step 3 (25.0 g, 0.0968 mol) in tetrahydrofuran (250 mL) was charged followed by addition of l -ethyl-3-(3-dimethylaminopropyl) carbodiimide) hydrochloride (27.73 g, 0.1452 mol) and p-nitrophenol ( 16.14 g, 0.1 161 mol) and reaction mixture was heated at about 75-80°C for about 1 -2 hours. 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.

Yield: 27 g

% Yield: 75

HPLC Purity: 98.0 %

Step 5: 3-(Cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-(diflu oromethoxy) benzamide (roflumilast)

In a clean dry round bottomed flask, a solution of 4-amino-3,5-dichloro pyridine (9.5 g, 0.0579 mol) in Ν,Ν-dimethylformamide was charged at about 0-5°C; then to this subsequently added 60% sodium hydride (4.22 g, 0.1054 mol) lotwisely and the reaction mixture was maintained for about an hour at about 0 to5°C. To this mixture was added a solution of 4-nitrophenyl 3-(cyclopropylmethoxy)-4-(difluoromethoxy) benzoate, obtained in Step 4 (20 g, 0.0527 mol) in N,N-dimethylformamide (80 mL) at about 0 -5°C. 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%).

Purification: Ammonia gas was purged to a solution of above step 4 crude product (20 g) in isopropanol (200 mL) and methanol (60 mL) to get a clear solution at about 20-25°C. The resultant clear solution was treated with activated charcoal (2 g) and stirred for about 30 min and filtered off on Celite bed. The filtrate was cooled down to about 10-15°C; pH was adjusted at about 2 with cone. HCl and maintained for about an hour. The resultant precipitate was filtered off, washed with isopropanol (50 mL), water (200 mL) and dried to yield white roflumilast.

Yield: 18.50 g, % Yield: 87.20, HPLC Purity: 99.0 %

[0073] Example 2

Step 1 : Preparation of 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzaldehyde

In a clean dry round bottomed flask, a solution of 3-hydroxy-4-(difluoromethoxy) benzaldehyde (25 g, 0.1329 mol) in N,N-dimethylformamide (150 mL) was charged. Potassium carbonate (27.5 g, 0.1993 mol) was added to the solution and the mixture was stirred at about 75 to 100°C for about an hour. To this mixture, cyclopropyl methyl bromide (21.5 g, 0.1594 mol) was added and stirred at about 1 15to 120°C for about 2-3 hours. N,N- dimethylformamide was distilled off under reduced pressure; the resultant residue was diluted with water (600 mL) followed by extraction with ethyl acetate. The organic layer was dried and concentrated under reduced pressure to afford the desired oily product.

Yield: 30 g, % Yield: 98, HPLC Purity: 95.0 %

Step 2: Preparation of 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzoic acid

In a clean dry round bottomed flask, 3-(cyclopropylmethoxy)-4-(difluoromethoxy) benzaldehyde, obtained in Step I (30 g, 0.1238 mol) in acetone (300 mL) was charged and the reaction mass was cooled to about Oto 5°C. To this solution, sulphamic acid (14.41 g, 0.1485 mol) was added and subsequently the reaction mixture was stirred at about 0 to 10°C for about 15 min. To this mixture was added sodium chlorite (16.72 g, 0.1857 mol) and stirred at about 25-30°C for about another 2-3 hours. The reaction mixture was quenched by the addition of water (3000 mL) and stirred for about 30 min. The resultant mixture was filtered off, washed with water (200 mL) and dried at about 50-55°C to afford the desired product.

Yield: 28 g, % Yield: 90, HPLC Purity: 95.0 %.

Step 3: Preparation of 4-nitrophenyl 3-(cyclopropylmethoxy)-4-(difluoromethoxy) benzoate

In a clean dry round bottomed flask, a solution of 3-(cyclopropylmethoxy)-4- (difluoromethoxy) benzoic acid, obtained in Step 2 (25.0 g, 0.0968 mol) in tetrahydrofuran (250 mL) was charged followed by addition of l -ethyl-3-(3-dimethylaminopropyl) carbodiimide) hydrochloride (27.73 g, 0.1452 mol) and p-nitrophenol (16.14 g, 0.1 161 mol) and reaction mixture was heated at about 65 to 75°C for about an 1 to 2hours. 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-(diflu oromethoxy) benzamide (roflumilast)

In a clean dry round bottomed flask, a solution of 4-amino-3,5-dichloro pyridine ( 19.6 g,) gm dimethylformamide was charged. The reaction mass was cooled to about 0to5°C. To the above solution, 60% sodium hydride (8g) was added lot wise and the reaction mixture was maintained for about an hour at about 0to5°C. To this mixture was added a solution of 4- riitrophenyl 3-(cyclopropylmethoxy)-4-(difluoromethoxy) benzoate, obtained in Step 3 (38g!) in dimethylformamide (182.4 mL) at about 0-5°C. The resultant mixture was stirred at about 25-30°C for about 1 -2 hours. The 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.

Yield: 17.6g, purity (HPLC): 99.52%.

Purification:

Ammonia gas was purged to a solution of above step 4 crude product (29 g) in isopropanol (232 mL) and methanol (87 mL) to get a clear solution at about 20to25°C. The resultant clear solution was treated with activated charcoal (1.45 g) and stirred for about 30 min and filtered off on a Celite bed. The filtrate was cooled down to about 10tol 5°C; pH was adjusted to about 2 with cone. HCl and maintained for about an hour. The resultant precipitate was filtered off, washed with isopropanol (15 mL), water (145 mL) and dried to yield 26.1 g of white roflumilast.

HPLC Purity: 99.83%.

Recovery of 3-(cyclopropylmethoxy)-4-(difluoromethoxy) benzoic acid, compound of formula IV.

In a clean dry round bottomed flask, the filtrate of above step 4 crude product was charged and was subjected to acidification using con hydrochloric acid to adjust pH to about 1 to about 3. The reaction mixture was stirred for a period of about 30 minutes and filtered to yield 3-(cyclopropylmethoxy)-4-(difluoromethoxy) benzoic acid.

[0074] Although the invention herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and applications of the present invention. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the present invention as described above.

[0075] All publications and patent applications cited in this application are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated herein by reference.