Field of the Invention:

The present invention relates to the novel amine salts of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid and its use in the preparation of 3-(cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy) benzamide compound of formula-l represented by the following structure

Formula-l 3-(cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy) benzamide is commonly known as roflumilast, Roflumilast is a drug which acts as a selective, long-acting inhibitor of the enzyme PDE-4. It has anti-inflammatory effects and is under development as an orally administered drug for the treatment of inflammatory conditions of the lungs such as asthma, and chronic obstructive pulmonary disease(COPD). It was recently approved in EU and marketed under the brand name DAXAS.

Background of the Invention:

3-cyclopropylmethoxy-4-difluoromethoxy benzoic acid is an important intermediate in the preparation of roflumilast. Preparation of 3-cyclopropylmethoxy-4-difluoromethoxy benzoic acid and its use in the preparation of roflumilast were disclosed in analogous marker in US 5712298. The disclosed process involves the reaction of 4-hydroxy-3-cyclopropylmethoxy benzaldehyde with difluorochloromethane followed by oxidation with aqueous sodium chlorite in presence of sulphamic acid in acetic acid provides 3-cyclopropyl methoxy-4-difluoromethoxy benzoic acid and the same has been converted into roflumilast by condensation with amino dichloride pyridine. The obtained 3-cyclopropyl methoxy-4-difluoromethoxy benzoic acid having very low purity of around 89-92% and the same has been utilized in the next step without any purification, which leads to the formation of high levels of impurities in the final compound roflumilast. In order to get the ICH grade purity of roflumilast repeated purification was required, which
further decreases the yield and increases over all cost of product.

International publication WO 2005/026095 discloses the preparation of 3-cyclopropyl methoxy-4-difluoromethoxy benzoic acid and its conversion to roflumilast. The disclosed process involves the column purification of 4-hydroxy-3- cyclopropyl methoxy benzoate to get high purity before converting into 3-cyclopropyl methoxy-4-difluoromethoxy benzoic acid by subjected it into difluoromethylation followed by hydrolysis to get the 3-cyclopropyl methoxy-4-difluoromethoxy benzoic acid with the purity of 94%, However the said process involves the column purification of intermediate to get the desired purity of 3-cyclopropyl methoxy-4-difluoromethoxy benzoic acid.

The present inventors prepared the 3-cyclopropyl methoxy-4-difluoromethoxy benzoic acid as per the prior art process which is showing low purity along with high levels of impurities at RRT 0.60,109 and 1.40. When we were working in the laboratory to prepare a highly pure roflumilast with out any column purification, repeated crystallization and specifically through high pure intermediates, we surprisingly found that the formation of organic amine salts with 3-cyclopropyl methoxy-4-difluoromethoxy benzoic acid and converting back into free acid leading to highly pure 3-cyclopropyl methoxy-4-difluoromethoxy benzoic acid with the purity of around 98-99.8% with low levels of impurities and utilizing the same in the preparation of roflumilast provides highly pure roflumilast without repeated crystallizations.

The main embodiment of the present invention provides novel salts of 3-cyclopropyl methoxy-4-difluoromethoxy benzoic acid and its use in the preparation of highly pure 3-cyclopropyl methoxy-4-difluoromethoxy benzoic acid and roflumilast by avoiding the problems reported in prior art.

Summary of the Invention:

The first aspect of the present invention is to provide novel amine salts of 3-cyclopropylmethoxy-4-difluoromethoxy benzoic acid compound of general formula-6, process for its preparation and its use.

The second aspect of the present invention is to provide a 3-cyclopropylmethoxy-4-difluoromethoxy benzoic acid dicyclohexylamine compound of formula-6a as a crystalline solid, process for its preparation and its use.

The third aspect of the present invention is to provide an improved process for the preparation of highly pure 3-(cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-(difluoro methoxy) benzamide compound of formula-l, which comprises of

a) Reacting the dihydroxy benzaldehyde compound of formula-2 with chlorodifluoro acetic acid in the presence of base in a suitable solvent to provide 4-(difluoro methoxy)-3-hydroxybenzaldehyde compound of formula-3,

b) reacting the compound of formula-3 in-situ with bromomethyl cyclopropane in the presence of a base in a suitable solvent to provide 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzaldehyde compound of formula-4,

c) oxidizing the compound of formula-4 with a suitable oxidizing agent in a suitable solvent provides 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzoic acid compound of formula-5,

d) reacting the compound of formula-5 with organic amine in a suitable solvent to provide the corresponding amine salt of 3-(cyclopropylmethoxy)-4-(difluoro methoxy)benzoic acid compound of general formula-6,

e) treating the compound of general formula-6 with a suitable acid in a suitable solvent to provide highly pure 3-(cyclopropylmethoxy)-4-(difluoro methoxy)benzoic acid compound of formula-5,

f) reacting the compound of formula-5 with a suitable chlorinating agent to provide 3-(cyclopropyl methoxy)-4-(difluoromethoxy)benzoyl chloride compound of formula-7,

g) reacting the compound of formula-7 in-situ with 4-amino 3,5-dichloro pyridine in the presence of suitable base in a suitable solvent to provide 3-(cyclopropyl methoxy)-N-(3,5-dichloropyridin-4-yl)-4-(difluoro methoxy)benzamide compound of formula-l,

h) optionally recrystallizing the compound of formula-l from a suitable solvent provides highly pure roflumilast compound of formula-l.

The fourth aspect of the present invention is to provide a process for the preparation of highly pure 3-(cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-(difluoro methoxy) benzamide compound of formula-l.

Brief Description of the Drawings:

Figure-l: Powder X-ray diffraction pattern of roflumilast compound of formula-1
obtained as per the present invention

Detailed description of the invention:

As used herein the term "alkyl" refers to straight or branched or cyclic C1-C12 alkyl.
As used herein the term "aryl" refers to C6-C12 aromatic group include phenyl, tolyl, xylyl, biphenyl, naphthyl and the like. The aryl may have 1 to 3 substituent independently selected from the group consisting of lower alkyl, halogen, amino, cyano, hydroxy.

As used herein the term "aralkyl" refers to C1-C6 lower alkyl substituted C6-C12 aromatic aryl group defined above. For example are benzyl, phenyl ethyl, phenyl propyl and the like each of which may have 1 to 3 substituent independently selected from the group consisting of lower alkyl, halogen, amino, cyano, hydroxy and the like.

As used herein the present invention the term "suitable solvents" refers to solvents selected from "ester solvents" like ethyl acetate, methyl acetate, isopropyl acetate; "ether solvents" like tetrahydrofuran, diethyl ether, methyl tert-butyl ether; "hydrocarbon solvents" like toluene, hexane, heptane and cyclohexane; "polar aprotic solvents" like dimethyl acetamide, dimethyl formamide, dimethyl sulfoxide; "ketone solvents" like acetone, methyl ethyl ketone, methyl isobutyl ketone; "alcoholic solvents" like methanol, ethanol, n-propanol, isopropanol, n-butanol and isobutanol; "chloro solvents" like methylene chloride, chloroform and ethylene dichloride; "nitrile solvents" like acetonitrile and propionitrile; polar solvents like water; and mixtures thereof.

As used herein the present invention the term "suitable bases" refers to the bases selected from inorganic bases like alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide; alkali metal hydrides such as lithium hydride, sodium hydride; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide; alkali metal carbonates like lithium carbonate, sodium carbonate, potassium carbonate; alkali metal bicarbonates like sodium bicarbonate and potassium bicarbonate; and organic bases like triethylamine, isopropyl ethylamine, diisopropyl amine, diisopropyl ethylamine, N-methyl morpholine, piperidine, pyridine and their mixtures there of.

The first aspect of the present invention provides novel amine salts of 3-cyclopropylmethoxy-4-difluoromethoxy benzoic acid compound of general formula-6,
Wherein "RNHR' is an organic amine" refers to methyl amine, ethyl amine, n-propyl amine, isopropyl amine, n-butyl amine, tertiary butyl amine, (+/-)-sec-butyl amine, Octyl amine, 2-ethyl hexylamine, benzyl amine, a-methyl-benzylamine, phenyl ethylamine, dibenzylamine, N-methylbenzylamine, N,N-dimethylbenzylamine, N,N-diethyl benzyl amine, N-ethyl-N-methylbenzylamine, tribenzyl amine, cyclopentylamine, cyclohexyl -amine, cycloheptylamine, N-methylcyclopentylamine, N-ethylcyclohexyl amine, N-ethyl cycloheptylamine, dicyclohexylamine, N,N-dimethylcyclo pentylamine, N,N-dimethyl cyclohexylamine, N,N-diethylcycloheptylamine and the like.

Novel amine salt compound of general formula-6 of the present invention is used to prepare highly pure 3-cyclopropylmethoxy-4-difluoromethoxy benzoic acid and roflumilast compound of formula-1.

Further the present invention provides a process for the preparation of novel amine salts of 3-cyclopropylmethoxy-4-difluoromethoxy benzoic acid compound of general formula-6, which comprise of reacting the 3-cyclopropylmethoxy-4-difluoromethoxy benzoic acid compound of formula-5 with suitable organic amine as discussed above in a suitable solvent to provide the corresponding salt compound of formula-6.

The suitable solvent used for salt preparation is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic
solvents, chloro solvents, nitrile solvents, polar solvents like water, and mixtures thereof.
The second aspect of the present invention provides a S-cyclopropylmethoxy- 4-difluoromethoxy benzoic acid dicyclohexylamine salt compound of formula-6a as a crystalline solid.

Formula-6a

The crystalline compound of formula-6a of the present invention characterized by its melting point i.e., 118-124°C. The crystalline 3-cyclopropyl methoxy-4-difluoromethoxy benzoic acid dicyclohexylamine salt of the present invention is used to prepare highly pure compound of formula-5 and formula-1.

Further the present invention provides a process for the preparation of 3-cyclo propylmethoxy-4-difluoromethoxy benzoic acid dicyclohexyl amine compound of formula-6a, which comprising of the following steps:

a) dissolving the 3-cyclopropylmethoxy- 4-difluoromethoxy benzoic acid compound of formula-5 in a suitable solvent,

b) adding a solution of dicyclohexyl amine dissolved in a suitable solvent at a suitable temperature,

c) stirring the reaction mixture at a suitable temperature up to salt formation,

d) filtering the precipitated solid and washing the solid,

e) drying the solid to get the 3-cyclopropylmethoxy-4-difluoromethoxy benzoic acid dicyclohexyl amine salt compound of formula-6a.

Wherein in step-a & step-b) the solvent is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents, nitrile solvents, polar solvents like water, and mixtures thereof; preferably ethyl acetate
In step-b & step-c) the suitable temperature is 0°C to reflux temperature of the solvent
used in the reaction

The third aspect of the present invention provides an improved process for the preparation of 3-(cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-(difluoro methoxy)benzamide compound of formula-l, which comprises of

a) Reacting dihydroxy benzaldehyde compound of formula-2
with chlorodifluoro acetic acid in the presence of base in a suitable solvent to provide 4-(difluoromethoxy)-3-hydroxybenzaldehyde compound of formula-3

b) reacting the compound of formula-3 in-situ with bromomethyl cyclopropane in the presence of a base in a suitable solvent provides 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzaldehyde compound of formula-4.

c) oxidizing the compound of fonnula-4 with a suitable oxidizing agent in the presence of sulphamic acid in a suitable solvent at a suitable temperature provides 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzoic acid compound of formula-5.

d) reacting the compound of formula-5 with a suitable organic amine in a suitable solvent to provide corresponding amine salt of 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzoic acid compound of general formula-6,

e) treating the salt compound of general formula-6 with a suitable acid in a suitable solvent provides highly pure 3-(cyclopropylmethoxy)-4-(difluoro methoxy)benzoic acid compound of formula-5,

f) reacting the compound of formula-5 with a suitable chlorinating agent in a suitable solvent provides 3-(cyclo propylmethoxy)-4-(difluoromethoxy)benzoyl chloride compound of formula-7,

g) reacting the compound of formula-7 in-situ with 4-amino 3,5-dichloro pyridine in the presence of a base in a suitable solvent provides 3-(cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-(difluoro methoxy) benzamide compound of formula-1,
h) optionally recrystallizing the compound of formula-1 in a suitable solvent provides highly pure 3-(cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-(difluoro methoxy) benzamide compound of formula-1.

Wherein in step a) The suitable base is selected from inorganic bases like alkali metal hydroxides, alkali metal hydrides, alkali metal alkoxide, alkali metal carbonates, alkali metal bicarbonates or organic bases or mixtures thereof; preferably sodium methoxide and lithium carbonate; the suitable solvent selected from ester solvents, ether solvents, glycol ether solvents like 2-methoxy ethanol, ethylene glycol monoethyl ether, ethylene glycol mono t-butyl ether; hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents, nitrile solvents, polar solvents like water, and mixtures thereof. Preferably 2-methoxyethanol in step b) the suitable base is selected from inorganic bases like alkali metal hydroxides, alkali metal hydrides, alkali metal alkoxides, alkali metal carbonates, alkali metal bicarbonates; preferably potassium carbonate and the suitable solvent is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents, nitrile solvents, polar solvents like water, and mixtures thereof; preferably dimethyl formamide.

in step c) the suitable oxidizing agent is selected from nitric acid, hydrogen peroxide, per acids such as peracetic acid, trifluoro peracetic acid, perbenzoic acid, m-chloro perbenzoic acid and the like; ozone, manganese dioxide, potassium permanganate, chromic acid, chromium trioxide, selenium dioxide, sodium chlorite, sodium hypochlorite, sodium metaperiodate, preferably aqueous sodium chlorite; the suitable solvent is glacial acetic acid and the suitable temperature is 10-20°C.

in step d) the suitable organic amine is selected from methyl amine, ethyl amine, n-propyl amine, isopropyl amine, n-butyl amine, tertiary butyl amine, (+/-)-sec-butyl amine, Octyl amine, 2-ethyl hexylamine, benzyl amine, a-methyl-benzylamine, phenyl ethylamine, dibenzylamine, N-methylbenzylamine, N,N-dimethylbenzylamine, N,N-diethyl benzyl amine, N-ethyl-N-methylbenzylamine, tribenzyl amine, cycloheptylamine, cyclohexyl -amine, cycloheptylamine, N-methylcyclopentylamine, N-ethylcyclohexyl amine, N-ethyl cycloheptylamine, dicyclohexylamine(DCHA), N,N-dimethylcyclo ethylamine, N,N-dimethyl cyclohexylamine, N,N-diethylcycloheptylamine and the like; preferably dicyclohexyl amine(DCHA); the suitable solvent is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents, nitrile solvents, polar solvents like water, and mixtures thereof; preferably ethyl acetate and the suitable temperature is 20-3 5 °C.

in step e) the suitable acid is selected from inorganic acids like hydrochloric acid, hydro bromic acid, sulfuric acid or organic acids like acetic acid, para toluene sulfonic acid, methane sulfonic acid, trifluoro acetic acid preferably hydrochloric acid and the suitable solvent is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents, nitrile solvents, polar solvents like water, and mixtures thereof; preferably toluene.

in step f) the suitable solvent is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents, nitrile solvents, polar solvents like water, and mixtures thereof; preferably toluene.

in step g) the suitable base is selected from inorganic bases like alkali metal hydroxides, alkali metal hydrides, alkali metal alkoxides, alkali metal carbonates, alkali metal bicarbonates; preferably sodium hydride and the suitable solvent is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents, nitrile solvents, polar solvents like water, and mixtures thereof; preferably tetrahydrofuran.

in step h) the suitable solvent is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents, nitrile solvents, polar solvents like water, preferably isopropyl alcohol.
In a preferred embodiment, the process for the preparation of 3-(cyclopropyl methoxy)-N-(3,5 -dichloropyridin-4-yl)-4-(difluoromethoxy)benzamide compound of formula-1 comprises of the following steps,

a) Reacting the dihydroxy benzaldehyde compound of formula-2 with chlorodifluoro acetic acid in the presence of lithium carbonate and sodium methoxide in methoxy ethanol provides 4-(difluoromethoxy)-3-hydroxybenzaldehyde compound of formula-3,

b) reacting the compound of formula-3 in-situ with bromomethyl cyclopropane in presence of potassium carbonate in dimethyl formamide provides 3-(cyclopropyl methoxy)-4-(difluoro methoxy)benzaldehyde compound of formula-4,

c) oxidizing the compound of formula-4 with sodium chlorite in the presence of sulphamic acid in aqueous acetic acid provides 3-(cyclopropyl methoxy)-4-(difluoromethoxy)benzoic acid compound of formula-5,

d) reacting the compound of formula-5 with dicyclohexyl amine in ethyl acetate provides 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzoic acid dicyclohexyl amine salt compound of formula-6a,

e) treating the compound of formula-6a with aqueous hydrochloric acid in toluene provides the highly pure 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzoic acid compound of formula-5,

f) reacting the compound of formula-5 with thienyl chloride in toluene provides 3 (cyclopropyl methoxy)-4-(difluoromethoxy)benzoyl chloride compound of formula-7,

g) condensing the compound of formula-7 in-situ with 4-amino 3,5-dichloro pyridine in the presence of sodium hydride in tetrahydrofuran provides 3-(cyclopropyl methoxy) N-(3,5-dichloro pyridin-4-yl)-4-(difluoro methoxy) benzamide compound of formula-1,

h) recrystallizing the compound of formula-l from isopropyl alcohol to provide pure roflumilast compound of formula-1.

The fourth aspect of the present invention provides highly pure 3-cyclopropyl methoxy-4-difluoromethoxy benzoic acid compound of formula-5 and process for its preparation.
The process for the preparation of highly pure 3-cyclopropylmethoxy-4-difluoromethoxy benzoic acid compound of formula-5 comprises of,

a) reacting the compound of formula-5 with organic amine as defined above in a suitable solvent to provide corresponding amine salt of 3-(cyclopropylmethoxy)-4-(difluoromethoxy) benzoic acid compound of general formula-6,

b) treating the compound of general formula-6 with suitable acid in a suitable solvent to provide highly pure 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzoic acid compound of formula-5.

The roflumilast prepared as per the present invention is having purity greater than 99.50% by HPLC; preferably 99.75%; more preferably 99.95% by HPLC.
3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzoic acid prepared as per the present invention containing less than 0.1% of impurities at RRT 0.60, 1.09 and 1.40; preferably less than 0.05% by HPLC.

Further the present invention provides crystalline form of 3-(cyclopropyl methoxy)-N-(3,5-dichloro pyridin-4-yl)-4-(difluoro methoxy) benzamide compound of formula-1, herein designated as crystalline form-I. The crystalline form-I of the present invention is characterized by it's powder x-ray diffractogram having characteristic peaks at 5.53,11.06,12.27, 16.59, 21.54,22.31,24.10,24.64, 25.35,26.79, 28.02, 28.68, 34.36, 37.89, 40.16, 40.76, 45.61 and 48.77 ± 0.2 degrees of 29 substantially as illustrated in figure-1.

3-(cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy) benzamide compound of formula-1 of the present invention can be further micronized or milled to get the desired particle size. Milling or micronization may be performed before drying, or after the completion of drying of the product. Techniques that may be used for particle size reduction include, with out limitation, ball, roller and hammer mills, and jet mills.
The related substances of 3-(cyclopropylmethoxy)-4-(difluoromethoxy) benzoic acid and roflumilast measured using HPLC with the following chromatographic conditions: Column: Waters Spheres orb ODS-1, (250x4.6 mm, 5 μ) or equivalent column. Other parameters of the method are as shown in the following table.

(Table)

The present invention schematically represented as follows

The process described in the present invention was demonstrated m examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.

Examples:

ExampIe-1: Preparation of 3-cyclopropylmethoxy 4-difluoromethoxy benzaldehyde:
175.8 g of sodium methoxide was lot wise added to 750 ml of 0-5°C precooked methoxy ethanol at below 50°C. Cooled the reaction mixture to 25-30°C, 1-chlorodifluoro acetic acid was added to it at below 50°C. Stirred the reaction mixture for 15 minutes at same temperature. It was added to a mixture of 250 g of dihydroxy benzaldehyde and 147.2 g of lithium carbonate dissolved in 500 ml methoxy ethanol. Heated the reaction mixture to reflux temperature and stirred for 25 hours at the same temperature. Cooled the reaction mixture to 25-30°C and 2500 ml of water was added to it. Stirred the reaction mixture for 1 hour at same temperature and filtered. 2000 ml of toluene was added to the filtrate. Separated the both aqueous and organic layers. Acidified the aqueous layer with acetic acid at 25-30°C and stirred for 30 minutes at the same temperature. 2500 ml of dichloromethane was added to it and stirred for 30 minutes. Separated the both aqueous and organic layers. The aqueous layer was extracted with dichloride methane. Combined the both organic layers and washed with 3000 ml of water. Distilled off the solvent completely under reduced pressure. 1300 ml of toluene was added to the obtained residue at 25-30°C. Cooled the reaction mixture to 10-15°C and stirred for 30 minutes. Filtered the reaction mixture and completely distilled off the solvent from the filtrate. The obtained residue was dissolved in 550 ml of dimethyl formamide at 25-30°C and stirred for 15 minutes. 100 g of potassium carbonate and 117.1 g of bromomethyl cyclopropane were added to the above reaction mixture at same temperature and stirred for 15 minutes. Heated the reaction mixture to 70°C and stirred for 8 hours at same temperature. Cooled the reaction mixture to 25-30°C. Filtered the reaction mixture and washed with toluene. Water was added to the filtrate and stirred for 15 minutes. Separated the both aqueous and organic layers and the aqueous layer was extracted with toluene. Combined the organic layers and washed with water. Distilled off the solvent completely from the organic layer under reduced pressure to get the title compound. Yield: 240 grams

Example-2: Preparation of 3-cyclopropyImethoxy 4-difluoromethoxy benzoic acid:
A solution of 5.6 g of sodium chlorite dissolved in 16 ml of water was added to the mixture of l0g of 3-cyclopropylmethoxy 4-difluoromethoxy benzaldehyde, 50 ml of acetic acid and 4.8 g of sulphamic acid at 10°C. Stirred the reaction mixture for 2 hrs at same temperature. Water was added to the reaction mixture and stirred for 2 hours at 25°C. Filtered the precipitated solid. Water was added to the obtained wet compound and stirred for 2 hrs at 25-30°C. Filtered the solid and washed with water. Dried the material to get the title compound. Yield: 7.5 grams Purity by HPLC: 93.1%; Impurity at 0.60 RRT: 1.60%; Impurity at 1.09 RRT: 2.18%: Impurity at 1.40 RRT: 1.35%

Example-3: Preparation of 3-cyclopropylmethoxy 4-difIuoromethoxy benzoic acid dicyclohexylamine (DCHA) salt:
A solution of 77.9 ml of dicyclohexylamine dissolved in 85 ml of ethyl acetate was added to solution of 85 g of 3-cyclopropylmethoxy 4-difluoromethoxy benzoic acid dissolved in 340 ml of ethyl acetate at 25-30°C. Stirred the reaction mixture for 10 hours at the same temperature. Filtered the precipitated solid and washed with chilled ethyl acetate. Dried the material to get the title compound as a solid. Yield: 120 grams MR: 118-124°C.

Example-4: Preparation of 3-cyclopropylmethoxy 4-difluoromethoxy benzoic acid:
Aqueous hydrochloric acid (23 ml of HC1 dissolved in 200 ml of water) was added a solution of 80 g of 3-cyclopropylmethoxy 4-difluoromethoxy benzoic acid DCHA salt obtained in example-3 dissolved in 960 ml of toluene at 25-30°C. Stirred the reaction mixture for 30 minutes. Separated the both aqueous and organic layers and the organic layer was washed with water. Distilled off the solvent completely under reduced pressure to get the pure title compound.
Yield: 41 grams
Purity by HPLC: 99.46%; Impurity at 0.60 RRT: 0.1%; Impurity at 1.09 RRT: 2.18%:
0.07%; Impurity at 1.40 RRT: 0.06%

Example-5: Preparation of 3-(cyclopropylmethoxy)-N-(3,5-dichloropyridiii-4-yl)-4-(difluoromethoxy) benzamide.

a) 47 g of 3-cyclopropylmethoxy 4-difluoromethoxy benzoic acid was dissolved in 800 ml of toluene. 26.4 ml of thionyl chloride was added to the reaction mixture at 25-30°C. Heated the reaction mixture to 70°C and stirred for 1 hour at same temperature. Heated the reaction mixture to reflux temperature and stirred for 2 hrs at same temperature. Distilled off the solvent completely and the obtained residue was dissolved in toluene. Distilled off the solvent completely under reduced pressure.

b) 16 g of NaH was added to 400 ml of pre cooled tetrahydrofuran at 5°C under nitrogen atmosphere. Cooled the reaction mixture to -10°C, 29.6 g of 4-amino 3,5-dichloro pyridine was added lot wise at same temperature and stirred for 30 minutes. To this reaction mixture added a compound obtained in step a) was dissolved in 240 ml of tetrahydrofuran at -10°C. Stirred the reaction mixture for 1 hr at same temperature. Quenched the reaction mixture with aqueous acetic acid at 5°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for 5 hrs at same temperature. Filtered the precipitated compound and washed with water. Isopropyl alcohol was added to the obtained compound and heated the reaction mixture to reflux temperature. Stirred the reaction mixture for 1 hr at same temperature. Cooled the reaction mixture to 25°C and stirred for 2 hrs at same temperature. Filtered the precipitated compound and dried the material to get the title compound.
Yield: 74 grams
Purity by HPLC: 99.25%

Example-6: Purification of 3-(cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy) benzamide.
To 15 g of 3-(cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy) benzamide added 105 ml of isopropyl alcohol. Heated the reaction mixture to reflux
temperature. 1.5 g of carbon was added to the reaction mixture and stirred for 30 minutes at same temperature. Filtered the reaction mixture at same temperature and the filtrate was cooled to 25°C. Stirred the reaction mixture for 90 minutes at same temperature. Filtered the precipitated compound and dried the material to get the pure title compound. Yield: 13 grams Purity by HPLC: 99.85%

We Claim:

1. Organic amine salts of 3-cyclopropylmethoxy-4-difluoromethoxy benzoic acid represented by the following structural formula,
Wherein "RNHR' is an organic amines" refers to methyl amine, ethyl amine, n-propyl amine, isopropyl amine, n-butyl amine, tertiary butyl amine, (+/-)-sec-butyl amine, octyl amine, 2-ethyl hexyl amine, benzyl amine, a-methyl-benzyl amine, phenyl ethylamine, dibenzylamine, N-methylbenzylamine, N,N-dimethylbenzylamine, N,N-diethyl benzyl amine, N-ethyl-N-methylbenzylamine, tribenzyl amine, cycloheptylamine, cyclohexyl -amine, cycloheptylamine, N-methylcyclopentylamine, N-ethylcyclohexyl amine, N-ethyl cycloheptylamine, dicyclohexylamine, N,N-dimethylcyclo pentylamine, N,N-dimethyl cyclohexylamine, N,N-diethylcycloheptylamine and the like.

2. A process for the preparation of novel amine salts of 3-cyclopropylmethoxy-4-difluoromethoxy benzoic acid compound of general formula-6 of claim-1, which comprise of reacting the 3-cyclopropylmethoxy-4-difluoromethoxy benzoic acid compound of formula-5 with a suitable organic amine in a suitable solvent to provide the corresponding salt compound of formula-6.

3. A process according to claim-3, where in the organic amine is selected from methyl amine, ethyl amine, n-propyl amine, isopropyl amine, n-butyl amine, tertiary butyl amine, (+/-)-sec-butyl amine, octyl amine, 2-ethyl hexylamine, benzyl amine, a-methyl-benzylamine, phenyl ethylamine, dibenzylamine, N-methylbenzylamine, N,N-dimethylbenzylamine, N,N-diethyl benzyl amine, N-ethyl-N-methylbenzylamine, tribenzyl amine, cyclopentylamine, cyclohexyl -amine, cycloheptylamine, N-methylcyclopentylamine, N-ethylcyclohexyl amine, N-ethyl cycloheptylamine, dicyclohexylamine(DCHA), N,N-dimethylcyclo pentylamine, N,N-dimethyl
cyclohexylamine, N,N-diethylcycloheptylamine; and the suitable solvent is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents, nitrile solvents, polar solvents like water, and mixtures thereof.

4. Crystalline dicyclohexylamine salt of 3-cyclopropylmethoxy 4-difluoromethoxy benzoic acid characterized by its melting point of 118-124°C.

5. Use of amine salt compounds claimed in claim 1 and 4 in the preparation of highly pure 3-cyclopropylmethoxy-4-difluoromethoxy benzoic acid and roflumilast.

6. A process for the preparation of highly pure roflumilast compound of formula-1, comprises of

a) Forming the organic amine salts of 3-cyclopropylmethoxy-4-difluoromethoxy benzoic acid of claim-1,

b) Converting the amine salts of 3-cyclopropylmethoxy-4-difluoromethoxy benzoic acid compound into roflumilast by the conventional method.

7. A process for the purification of 3-cyclopropylmethoxy-4-difluoromethoxy benzoic acid compound of formula-5 comprises of converting the compound of formula-5 into its organic amine salts of claim-1 and converting into free acid by treating with a suitable acid in a suitable solvent to provide highly pure 3-cyclopropylmethoxy-4-difluoromethoxy benzoic acid compound of formula-5.

8. An improved process for highly pure roflumilast compound of formula-1, which comprises of the following steps,

a) Reacting dihydroxy benzaldehyde compound of formula-2
Formula-2 with chlorodifluoro acetic acid in the presence of base in a suitable solvent to
provide 4-(difluoromethoxy)-3-hydroxybenzaldehyde compound of fonnula-3
Formula-3

b) reacting the compound of formula-3 in-situ with bromomethyl cyclopropane in the presence of a base in a suitable solvent provides 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzaldehyde compound of formula-4,
Formula-4

c) oxidizing the compound of formula-4 with a suitable oxidizing agent in the presence of sulphamic acid in a suitable solvent at a suitable temperature provides 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzoic acid compound of formula-
Formula-5

d) reacting the compound of formula-5 with a suitable organic amine in a suitable solvent to provide corresponding amine salt of 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzoic acid compound of general formula-6,

e) treating the salt compound of general formula-6 with suitable acid in a suitable solvent to provide highly pure 3-(cyclopropylmethoxy)-4-(difluoromethoxy) benzoic acid compound of formula-5 ,

f) reacting the compound of formula-S with a suitable chlorinating agent in a suitable solvent to provide 3-(cyclo propylmethoxy)-4-(difluoromethoxy)benzoyl chloride compound of formula-7,

g) condensing the compound of formula-7 in-situ with 4-amino 3,5-dichloro pyridine in the presence of a base in a suitable solvent pro vides 3-(cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-(difluoro methoxy) benzamide compound of formula-1,

h) optionally recrystallizing the compound of formula-1 in a suitable solvent provides highly pure 3-(cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-(difluoro methoxy) benzamide compound of formula-1.

9. 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzoic acid having purity 99.50% by HPLC; preferably 99.75% by HPLC

10. 3-(cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy) benzamide having purity 99.50% by HPLC; preferably 99.75% by HPLC; more preferably 99.95% by HPLC