FORM 2
THE PATENTS ACT 1970
(Act 39 of 1970)
&
THE PATENTS RULE, 2003
COMPLETE SPECIFICATION
(SECTION 10 and Rule 13)
TITLE OF THE INVENTION "A NOVEL PROCESS FOR PREPARATION OF ROFLUMILAST"
Emcure Pharmaceuticals Limited,
an Indian company, registered under the Indian Company's Act 1957
and having its registered office at
Emcure House, T-184, M.I.D.C, Bhosari, Pune-411026, India.
THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED

FIELD OF THE INVENTION
The present invention relates to an industrially feasible, convenient process for the
preparation of Roflumilast (I) conforming to regulatory specifications. More specifically,
the invention relates to the preparation of imidazol-l-yl-(3-cyclopropylmethoxy-4-
difluoromethoxy)phenylmethanone (IV) from 3-(cyclopropylmethoxy)-4-
difluoromethoxy)benzoic acid and its subsequent reaction with 4-arnino-3,5-dichloropyridine to obtain Roflumilast.
BACKGROUND OF THE INVENTION
Roflumilast of formula (I), chemically known as 3-(cycIopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)benzamide is an anti-inflammatory agent and a selective inhibitor of the phosphodiesterase 4 (PDE4) enzyme. Owing to its antiinflammatory properties, the drug finds use in the treatment of inflammatory conditions such as asthma and chronic obstructive pulmonary disease (COPD).

Literature reports for synthesis of Roflumilast mainly center on the coupling of 3-cycloprbpylmethoxy-4-difluoromethoxy benzoic acid with 4-amino-3, 5-dichloropyridine. US 5,712,298 discloses a process in which 3-cyclopropylmethoxy-4-difluoromethoxy benzoic acid is treated with thionyl chloride to obtain 3-cyclopropylmethoxy-4-difluoromethoxy benzoyl chloride, which is then coupled with 4-amino-3,5-dichloropyridine in presence of a strong base like sodium hydride to yield Roflumilast. The starting material, 4-difluoromethoxy-3-cyclopropylmethoxy benzoic acid is prepared by reaction of 4-difluoromethoxy-3-cyclopropylmethoxy benzaldehyde with sodium chlorite and sulfamic acid in glacial acetic acid.

Use of large excess of environmentally hazardous and a corrosive reagent like thionyl chloride is the main disadvantage. Also, the reactions involving thionyl chloride usually proceed with modest yields of =60%. Further, when the synthesis is to be carried out on industrial scale, the reaction, which proceeds with evolution of sulfur dioxide, necessitates additional facilities for effective scrubbing of the evolved gas. Also, any commercial process, involving a highly moisture sensitive and hazardous reagent like sodium hydride, is generally not preferred on an industrial scale.
US 6,822,114 utilizes carbonylation reaction for coupling of substituted halo benzene with the respective pyridine compound to obtain Roflumilast. The method of synthesis consists of treating l-bromo-3-cyclopropylmethoxy-4-difluoromethoxybenzene and 4-amino-3,5-dichloropyridine with carbon monoxide under pressure at 120 to 150°C in an autoclave and in presence of palladium catalyst and tributyl amine. Although this method avoids lengthy reaction sequence, but utilization of gaseous carbon monoxide and pressure reactors when clubbed with high temperatures, relatively long reaction times and requirement of expensive metal-ligand palladium catalysts such as PdBr2(Ph3P)2 render this synthetic method economically unviable for commercialization of Roflumilast.
US 7,470,791 discloses coupling reaction between 4-amino-3,5-dichloropyridine and activated benzoic acid derivatives such as acid chloride or anhydride in presence of a strong base such as potassium tertiary butoxide. The patent mentions that formation of an associated impurity such as N-(3,5-dichloropyrld-4-yl)-3-cyclopropylmethoxy-4-hydroxybenzamide, can be very substantially averted by the disclosed method. However, the specification does not mention about the purity or impurity level before recrystallization from isopropanol and water, which has obviously been incorporated in the process for removal of an associated impurity and obtaining the desired purity.
Thus, there still exists a need for a convenient, cost-effective method for synthesis of Roflumilast, which requires easily available and economical reagents, is convenient on industrial scale, environment friendly and yields a product, which conforms to regulatory specifications.

The present inventors have developed a method which provides Roflumilast (I) conforming to regulatory specifications by a novel process which avoids the short comings in the prior art.
OBJECT OF THE INVENTION
An object of the present invention is to provide Roflumilast (I) by a novel, cost-effective and convenient process which can be scaled up to commercial scale and does not involve toxic and environmental hazards such as thionyl chloride.
Another object of the invention is to provide Roflumilast (I) with good yield and purity with impurity levels complying with regulatory norms.
SUMMARY OF THE INVENTION
The present invention relates to an improved process for the preparation of Roflumilast (I) which overcomes the limitations faced in the prior art.
An aspect of the present invention relates to a novel, improved and cost-effective process for the preparation of Roflumilast (I), comprising treatment of 3-cyclopropyhnethoxy-4-difluoromethoxy benzoic acid (II) with carbonyldiimidazole (III) in a first organic solvent at room temperature followed by concentration of the reaction mixture and reaction of the resulting compound (IV) with 4-amino-3,5-dichloropyridine (V) dissolved in a second organic solvent and in presence of a base at reflux temperature to give Roflumilast (I) of desired purity.
The following detailed description will make the objectives of the present invention fully apparent.
DETAILED DESCRIPTION OF THE INVENTION
While carrying out extensive experimentation for developing a convenient and cost effective, environment friendly process for Roflumilast, the present inventors, have surprisingly found that the amide linkage in the desired molecule can be easily synthesized by employing a carbonyl coupling agent such as carbonyldiimidazole (CDI). The utilization of CDI not only eliminates use of hazardous reagent such as thionyl chloride but

also provides an economical, easier pathway for synthesis of Roflumilast (I). Further, unlike thionyl chloride reaction which involves evolution of sulfur dioxide, the present method can easily be scaled up to industrial scales due to the safety associated with handling of CDI.

Scheme: Method embodied in the present invention for preparation of Roflumilast (I)
In an embodiment, 3-cyclopropylmethoxy-4-difiuoromethoxy benzoic acid of formula (II) was treated with carbonyldiimidazole (CDI; III) in an organic solvent at room temperature to give imidazol-l-yl-3-(cyclopropylmethoxy-4-(difluoromethoxy)phenylmethanone of formula (IV).
The solvent was selected from the group comprising of halogenated hydrocarbons such as chloroform, dichloromethane, ethylene dichloride etc.
After completion of the reaction as monitored by HPLC, the reaction mixture was concentrated to give a residue containing the compound of formula (IV), which on further

reaction with 4-amino-3,5-dichloropyridine (V) dissolved in a second organic solvent and in presence of a base, provided Roflumilast (I) having the desired purity.
The reaction may be carried out in situ or as a separate synthetic step carried out on isolated imidazole intermediate of formula (IV). In case of insitu reaction, the compound of formula (IV) was dissolved in a second organic solvent.
The second organic solvent was selected from the group comprising of acetonitrile, tetrahydromran, dimethyl formamide, dimethyl acetamide and dimethyl sulfoxide.
The base was selected from the group comprising of hydrides such as sodium hydride, potassium hydride, or alkoxides of alkali metals such as sodium tertiary butoxide, potassium tertiary butoxide etc. The base was preferably an alkoxide.
The base was added to the reaction mixture at a temperature between 0 to 5°C, followed by gradual raising of the temperature to 55 to 65°C. The reaction was continued till completion of the reaction as monitored by HPLC. The reaction mixture was quenched with water followed by neutralization of the reaction mass with a mineral acid. Filtration of the solid followed by washing of the wet cake with an alcohol such as isopropanol yielded Roflumilast (I) which was found to conform to the regulatory specifications with associated impurities normally encountered with prior art methods, well below the permissible limits.
The following examples are meant to be illustrative of the present invention. These examples exemplify the invention and are not to be construed as limiting the scope of the invention.
EXAMPLES
Example 1
Preparation of Roflumilast (I)
3-Cyclopropylmethoxy-4-difluoromethoxy benzoic acid (50.0 g) in dichloromethane (100 ml) was gradually added to a solution of carbonyldiimidazole (47gms dissolved in 200ml of dichloromethane) at 25 to 30 C in an inert atmosphere. The reaction mixture was stirred

at the same temperature till completion of the reaction as monitored by HPLC. After the
reaction was over, as monitored by HPLC, the reaction mixture was concentrated to obtain
a viscous mass containing the compound of formula (IV), which was then dissolved in
tetrahydrofuran (250ml).
A mixture of 4-amino-3,5-dichloropyridine (25gms), sodium tertiary butoxide (74.3 g) and
tetrahydrofuran (500 ml) was cooled to 0 to 5°C and the mixture containing the compound
of formula (IV) was gradually added to it in an inert atmosphere or vice versa. The
resulting reaction mass was heated gradually to reflux temperature and maintained at the
same temperature till completion of the reaction as monitored by HPLC. After completion
of the reaction, the reaction mixture was quenched with water and neutralized with
hydrochloric acid. The solid obtained was filtered, washed with isopropyl alcohol and
dried.
Yield: 56.4gms (71.8%)
Purity: 99.5 % (HPLC)
Example 2
Preparation of Roflumilast (I)
A mixture of carbonyldiimidazole (118gms), 3-cyclopropylmethoxy-4-difluoromethoxy benzoic acid (125gms) in dichloromethane (750ml) was stirred at 25 to 30°C, under inert atmosphere, till completion of the reaction, as monitored by HPLC. When the reaction was complete, the organic solvent was distilled off to obtain a residue as a viscous mass.
Sodium tertiary butoxide (185.8gms) was mixed with tetrahydrofuran (1250 ml) and 4-amino-3,5-dichloropyridine (62.5gms) and the mixture was cooled to- 0 to 5°C. The concentrated mass of carbonyldiimidazole intermediate residue was gradually added to it in inert atmosphere. The resulting mixture was slowly heated to reflux temperature and the reaction was continued till completion as monitored by HPLC. After completion of reaction, the mixture was quenched with water and neutralized with hydrochloric acid. The solid separating out was filtered and washed with isopropyl alcohol to gave Roflumilast (I). Yield: 143.3gms (73.5%) Purity: 98.5% (HPLC)

Claims:
1. A process for the preparation of Roflumilast (I), comprising treatment of 3-cyclopropylmethoxy-4-difluoromethoxy benzoic acid (II) with carbonyldiimidazole (III) in a first organic solvent at room temperature followed by concentration of the reaction mixture and reaction of the resulting compound (IV) with 4-amino-3,5-dichloropyridine (V) in a second organic solvent and in presence of a base at reflux temperature to give Roflumilast (I) of desired purity.
2. A process as claimed in claim 1, wherein the first organic solvent is selected from the group comprising chloroform, dichloromethane and ethylene dichloride
3. A process as claimed in claim 1, wherein the second organic solvent is selected from the group comprising acetonitrile, tetrahydrofuran, dimethyl formamide, dimethyl acetamide and dimethyl sulfoxide.
4. A process as claimed in claim 1, wherein the base is selected from sodium tertiary butoxide, potassium tertiary butoxide, sodium hydride and potassium hydride.