This application claims priority to Indian patent application number 3840/CHE/2011 filed on Nov 09, 2011.

FIELD OF THE INVENTION:

The present invention relates to an improved process for the preparation of Roflumilast and novel crystalline Form-I of the Roflumilast.

BACKGROUND OF THE INVENTION:

Roflumilast, chemically known as 3-cyclopropylmethoxy-4-difluoromethoxy-N-[3,5-di-chloropyrid-4-yl]-benzamide of Formula-I is an PDE4-inhibitor.

Roflumilast is an effective phosphodiesterase-4-inhibitor (PDE4-inhibitor), which can be used in the treatment of asthma, inflammation, bronchitis, allergy, and osteoporosis, dermatoses and disorders related to immune system, heart and kidney.

Roflumilast is sold under the trademark Daliresp® and is available in two dosage forms i.e. tablets and orally. It is recommended at 500mcg once daily.

US Patent No.5712298 claims Roflumilast and its analogs. This patent also discloses process for the preparation Roflumilast.

US 6448274, WO 2005026095 and WO 2004033430 also disclose process for the preparation Roflumilast.

Polymorphism of Roflumilast is not reported in Literature.

The present invention provides stable and industrially scalable novel crystalline form of Roflumilast and an improved process for the preparation of Roflumilast.

OBJECT AND SUMMARY OF THE INVENTION:

Principle object of the present invention is to provide an improved process for the preparation of Roflumilast.

One aspect of the present invention provides, an improved process for the preparation of Roflumilast comprising the steps of:

a) reacting 4-Difluoromethoxy-3-hydroxy benzaldehyde with cyclopropylmethylhalide in presence of an organic base to obtain 3-cyclopropylmethoxy-4-Difluoromethoxy benzaldehyde wherein L is a leaving group selected from halogen, arylsulfonyloxy, alkylsulfonyloxy,

b) oxidising the obtained aldehyde compound into 3-cyclopropylmethoxy-4-
Difluoromethoxy benzoic acid,

c) converting 3-cyclopropylmethoxy-4-Difluoromethoxy benzoic acid to its acid
halide then condensing with 4-amino-3,5 Dichloropyridine in presence of base to
obtain Roflumilast, and


d) optionally purifying Roflumilast in an organic solvent to get pure Roflumilast.
Another object of the present invention is to provide novel crystalline Form-I of Roflumilast and process for preparation of the same.

BRIEF DESCRIPTION OF THE DRAWINGS:

Further objects of the present invention together with additional features contributing thereto and advantages accruing there from will be apparent from the following description of preferred embodiments of the invention which are shown in the accompanying drawing figures wherein :
Figure 1: illustrates the powder X-ray diffraction pattern of Roflumilast Crystalline Form-I.

Figure 2: illustrates DSC thermo gram of Roflumilast Crystalline Form-I.
Figure 3: illustrates TGA of Roflumilast Crystalline Form-I.

DETAILED DESCRIPTION OF THE INVENTION:

The present invention relates to an improved process for the preparation of Roflumilast and novel polymorphic form of Roflumilast.

The main aspect of the present invention is to provide an improved process for the preparation of Roflumilast comprising the steps of:

a) reacting 4-Difluoromethoxy-3-hydroxy benzaldehyde with cyclopropylmethylhalide in presence of an organic base to obtain 3- cyclopropylmethoxy-4-Difluoromethoxy benzaldehyde wherein L is a leaving group selected from halogen, arylsulfonyloxy, alkylsulfonyloxy,

b) oxidising the obtained aldehyde compound into 3-cyclopropylmethoxy-4-
Difluoromethoxy benzoic acid;

c) converting 3-cyclopropylmethoxy-4-Difluoromethoxy benzoic acid to its acid halide then condensing with 4-amino-3,5 Dichloropyridine in presence of base to obtain Roflumilast; and

d) optionally purifying Roflumilast in an organic solvent to get pure Roflumilast.
In one more embodiment, organic base used in the step-a is selected from alkylamines such as triethylamine, disioproylethylamine; amidine compounds such as 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), preferably l,8-Diazabicyclo[5.4.0]undec-7-ene.

In one more embodiment, reaction of 4-Difluoromethoxy-3-hydroxy benzaldehyde with cyclopropylmethylhalide can be carried out using phase transfer catalyst.

In one more embodiment, leaving group used in step-a is selected from halogens such as F, CI, Br and I; para-toluene sulfonate and methane sulfonate.

The compound of step-a (3-cyclopropylmethoxy-4-Difluoromethoxy benzaldehyde) obtained by reacting 4-Difluoromethoxy-3 -hydroxy benzaldehyde with cyclopropylmethylhalide is isolated in mixture of EtOAc/water solvent system.

In another embodiment, oxidation of aldehyde compound in step-b is carried out in presence of sulfamic acid and sodium chlorite.

In another embodiment, 3-cyclopropylmethoxy-4-Difluoromethoxy benzoic acid in step-c is converting into its acid halide by reacting with halogenating agents such as thionyl chloride, phosphorus oxychloride preferably thionyl chloride.

In another embodiment, the base used in the step-c is selected from alkali metal hydrides or alkali metal carbonates. The alkali metal hydride used in this reaction is selected from sodium hydride and potassium hydride, preferably sodium hydride. The alkali metal carbonate used in this reaction is selected from sodium carbonate and potassium carbonate.

In one more embodiment, the organic solvent used in step-d for the purification of Roflumilast is selected from alcoholic solvents such as methanol, ethanol and isopropanol.

In one more embodiment, 4-Difiuoromethoxy-3-hydroxy benzaldehyde is prepared by reacting 3,4 Dihydroxybenzaldehyde with Difluorochloromethane in an organic solvent in presence of a base to obtain 4-Difluoromethoxy-3-hydroxy benzaldehyde,


In this reaction the base is selected from potassium carbonate or sodium carbonate, preferably potassium carbonate and organic solvent is selected from N,N-Dimethylformamide, Dimethylacetamide or Dimethylsulfoxide, specifically N,N-Dimethylformamide.

Prior art procedures involve column purification of the 4-Difluoromethoxy-3-hydroxy benzaldehyde. Column purification avoided in the present invention, which results commercially feasible process in the high yields. The compound 4-Difluoromethoxy-3-hydroxy benzaldehyde obtained by the condensation of 3,4 Dihydroxybenzaldehyde with Difluorochloromethane is isolated in mixture of EtOAc (Ethyl acetate)/ Heptane solvent system by avoiding the column purification.

Another aspect of the present invention is to provide novel crystalline Form-I of Roflumilast and process for the preparation of the same.

Instrumentation

Powder X-ray Diffraction (PXRD)

The said polymorphs of the present invention are characterized by their X-ray powder diffraction pattern. Thus, the X-ray diffraction patterns of said polymorphs of the invention were measured on PANalytical, X'Pert PRO powder diffractometer equipped with goniometer of 0/9 configuration and X'Celerator detector. The Cu-anode X-ray tube was operated at 40kV and 30mA. The experiments were conducted over the 29 range of 2.0°-50.0°, 0.030° step size and 50 seconds step time.

Differential Scanning Calorimetry (DSC)

The DSC measurements were carried out on TA Q1000 of TA instruments. The experiments were performed at a heating rate of 10.0 °C/min over a temperature range of 30°C-300°C purging with nitrogen at a flow rate of 50ml/min. Standard aluminum crucibles covered by lids with three pin holes were used.

Thermogravimetric analysis (TGA)

TGA was recorded on out using the instrument Mettler Toledo TGA/SDTA 85 le and TGA Q5000 of TA instruments. The experiments were performed at a heating rate of 10.0 °C/min over a temperature range of 30°C-300°C purging with nitrogen at a flow rate of25ml/min.
The present invention provides novel crystalline Form-I of Roflumilast.

In one embodiment, crystalline Form-I of Roflumilast is characterized by X-ray powder diffraction having characteristic peak at 5.59 ±0.2° 29.

In another embodiment, crystalline Form-I of Roflumilast is characterized by X-ray powder diffraction having characteristic peaks at 5.59 and 22.4±0.2° 29.

In another embodiment, crystalline Form-I of Roflumilast is characterized by the Powder X-ray diffraction as depicted in Figure 1.

In one more embodiment, crystalline Form-I of Roflumilast is characterized by DSC thermogram as depicted in Figure 2.

In another embodiment, crystalline Form-I of Roflumilast is characterized by TGA as depicted in Figure 3.

Another aspect of the present invention provides process for the preparation of crystalline Form-I of Roflumilast comprising crystallization of Roflumilast in an organic solvent.

In one embodiment the organic solvents used for the crystallization of Roflumilast are selected from methanol, ethylacetate, isopropanol, n-heptane or mixtures there of.
The invention is illustrated with the following examples, which are provided by way of illustration only and should not be construed to limit the scope of the invention.
Experimental procedure:

Example - 1: Process for the Preparation of 4-Difluoromethoxy-3-hydroxy
Benzaldehyde

Mixture of N, N-Dimethylformamide (5 vol. with respect to 3, 4 Dihydroxybenzaldehyde) and Potassium carbonate (1.2eq respect to 3,4 Dihydroxybenzaldehyde) was taken in a vessel at 20-25°C. To this 3,4 Dihydroxybenzaldehyde was added and stirred for 10 min. The reaction mixture was heated to 80-85°C. Difluorochloromethane gas was purged for 8-10 hours. After completion of reaction, reaction mixture was cooled to 25-30 °C. Potassium carbonate was filtered off and washed with N, N Dimethylformamide. Water was added to filtrate slowly and extracted with EtOAc. EtOAc extracts are washed with aq. HC1 and water. EtOAc was distilled under vacuum, 100-lOmbar at 45-50°C to get thick oil. The oil was taken in toluene & water and stirred for 10-15 min. To this Potassium carbonate in water was added and stirred for 1 hour. Layers were separated and toluene layer was again washed with water for 10-15 min. To this 10% (W/V) Potassium carbonate in water was added and stirred for 1 hour. Layers were separated and combined aq. layer was washed with toluene. Aq layer was cooled to 5-10 ° C, acidified with Acetic acid and stirred for 1 hour at 20-25 ° C. The solid was filtered and dried under vacuum at 45-50°C. The above solid was taken in 10% EtOAc/Heptane mixture and heated to reflux for 30min. Slurry was filtered and the filtrate was concentrated under vacuum to get 4-Difiuoromethoxy 3-hydroxy benzaldehyde.

Example - 2: Alternative process for the Preparation of 4-Difluoromethoxy-3-hydroxy benzaldehyde

Mixture of N, N-Dimethylformamide (5 vol. with respect to 3, 4 Dihydroxybenzaldehyde) and Potassium carbonate (1.2eq respect to 3,4 Dihydroxybenzaldehyde) was taken in a vessel at 20-25°C. To this 3,4 Dihydroxybenzaldehyde was added and stirred for 10 min. The reaction mixture was heated to 80-85°C. Difluorochloromethane gas was purged for 8-10 hours. After completion of reaction, reaction mixture was cooled to 25-30°C. Potassium carbonate was filtered off and washed with N, N Dimethylformamide. Water was added to filtrate slowly and extracted with EtOAc. EtOAc extracts are washed with aq. HC1 and water. EtOAc was distilled under vacuum, 100-10mbar at 45-50°C to get thick oil. The oil was taken in toluene & water and stirred for 10-15 min. To this Potassium carbonate in water was added and stirred for 1 hour. Layers were separated and combined aq. layer was washed with toluene. Aq layer was cooled to 5-10 ° C, acidified with Acetic acid and stirred for 1 hour at 20-25 ° C. The solid was taken in 10% EtOAc/Heptane mixture and heated to 79-82 ° C for 15 min. Slurry was filtered and silica gel was added to filtrate and heated to 79-82 ° C for 15 min. Slurry was filtered and concentrated under vacuum at 55-60 °C to get solid. The solid was taken in n-Heptane and stirred for 30 minutes at 5-10 °C. The solid was concentrated under vacuum to get 4-Difluoromethoxy 3-hydroxy benzaldehyde.

Example - 3: Process for the Preparation of 3-cycIopropylmethoxy-4-Difluoromethoxy benzaldehyde

4-Difluoromethoxy 3-hydroxy benzaldehyde in Tetrahydrofuran (5 vol with respect to 4-Difluoromethoxy 3-hydroxy benzaldehyde) was taken in a vessel and DBU (1.5eq respect to 4-Difluoromethoxy 3-hydroxy benzaldehyde) was added. To this first lot of cyclopropylmethylbromide (1.5eq respect to 4-Difluoromethoxy 3-hydroxy benzaldehyde) was added and heated to 75-80°C. After 2 hours second lot of cyclopropylmethyl bromide (0.5 eq with respect to 4-Difluoromethoxy 3-hydroxy benzaldehyde) was added and maintained at 75-80°C for 2 hours. To this third lot of cyclopropylmethyl bromide (0.5 eq with respect to 4-Difluoromethoxy 3-hydroxy benzaldehyde) was added and maintained for 2 hours. The reaction mass was cooled to 20-25 C and water was added. The reaction mixture was extracted with EtOAc and EtOAc extracts was washed with water. EtOAc was distilled out under reduced pressure at 40°C to get 3-cyclopropylmethoxy 4-Difluoromethoxy benzaldehyde as brown oil.

Example - 4: Process for the Preparation of 3-cyclopropylmethoxy-4-Difluoromethoxy benzoic acid

Glacial acetic acid (5 vol. with respect to 3-cyclopropylmethoxy 4-Difluoromethoxy benzaldehyde) was taken in a vessel and to this mixture of 3-cyclopropylmethoxy 4-Difluoromethoxy benzaldehyde and sulfamic acid (1.35 eq with respect to 3-cyclopropylmethoxy 4-Difluoromethoxy benzaldehyde) was added. The reaction mass was cooled to 5-10 °C under stirring. In another clean reaction vessel sodium chlorite (1.63eq) was taken in water (1.5 vol. with respect to 3-cyclopropylmethoxy 4-Difluoromethoxy benzaldehyde) and added dropwise to the above prepared reaction solution at temperature below 10 °C. The reaction mixture was stirred for 1 hr at 5-10°C. After completion of reaction, water was added to get white slurry. The solid was filtered and washed with water and dried under vacuum at 45-50°C to get 3-cyclopropylmethoxy 4-Difluoromethoxy benzoic acid.

Example - 5: Process for the Preparation of crude Roflumilast

In a clean reaction vessel, Tetrahydrofuran (5 vol. with respect to 3-cyclopropylmethoxy 4-Difluoromethoxy benzoic acid) was taken and to this 3-cyclopropylmethoxy 4-Difluoromethoxy benzoic acid (1 eq) was added under stirring to get clear solution. To this thionyl chloride (1.5 eq with respect to 3-cyclopropylmethoxy 4-Difluoromethoxy benzoic acid) was added drop wise at 20-25°C and stirred for 30min at 40-45°C. Thionyl chloride was distilled out at 40- 45°C to get oil. This was swapped with Tetrahydrofuran. In another flask Sodium hydride (2.4 eq with respect to to 3-cyclopropylmethoxy 4-Difluoromethoxy benzoic acid) was taken in THF (5 vol. with respect to to 3-cyclopropylmethoxy 4-Difluoromethoxy benzoic acid). To this 4-amino 3,5 Dichloropyridine (1.2eq with respect to 3-cyclopropylmethoxy 4-Difluoromethoxy benzoic acid) was added and stirred for 30 minutes. The above obtained acid chloride was dissolved in Tetrahydrofuran (5 vol. with respect to to 3-cyclopropylmethoxy 4-Difluoromethoxy benzoic acid) and added dropwise to the above prepared mixture of 4-amino 3, 5 Dichloropyridine and Sodium hydride at temperature below 30°C .The above reaction mixture was stirred for 1 hr at 20-25 °C . To this EtOAc was added followed by the addition of water. EtOAc layer was separated and the aqueous layer was extracted with EtOAc. Combined EtOAc layer was washed with 10% HC1 and then with 10% aq. NaOH solution. This was washed with water and ethyl acetate and distilled out at 45" 50 C to get light yellow colored solid. To this Isopropanol was added and heated to reflux till clear solution was obtained. Cooled to 20-25°C slowly and maintained at 20-25 °C for 1 hour. The solid was filtered and washed Isopropanol to get crude Roflumilast.

Example - 6: Purification of Roflumilast

Roflumilast obtained in example 4 (leq) and Isopropanol (5vol with respect to Roflumilast) was refluxed to get clear solution. The reaction mass was cooled to 20-25°C and maintained at 20-25°C for 1 hour. The solid was washed with Isopropanol and dried under vacuum at 50°C to get Roflumilast.

Example - 7: Process for the preparation of Form-I

Roflumilast (1 Eq) in indicated solvents at the indicated volumes was refluxed to get clear solution. The reaction mass was cooled to 20-25 °C and maintained at 20-25 °C for 1 hour and obtained solid was filtered and identified as Form-I.

We claim:

1. An improved process for the preparation of Rofiumilast comprising the steps of:

a) reacting 4-Difluoromethoxy-3-hydroxy benzaldehyde with cyclopropylmethylhalide in presence of an organic base to obtain 3-cyclopropylmethoxy-4-Difluoromethoxy benzaldehyde
wherein L is a leaving group,
b) oxidising the obtained aldehyde compound into 3-cyclopropylmethoxy-4-Difiuoromethoxy benzoic acid,

c) converting 3-cyclopropylmethoxy-4-Difluoromethoxy benzoic acid to its acid halide then condensing with 4-amino 3,5-Dichloropyridine in presence of base to obtain Rofiumilast, and


d) optionally purifying Roflumilast in an organic solvent to get pure Roflumilast.

2. The process according to claim 1, wherein organic base used in the step-a is 1,8-Diazabicyclo[5.4.0]undec-7-ene(DBU).

3. The process according to claim 1, wherein Leaving group in step-a is selected from halogen, alkylsulfonyloxy, arylsulfonyloxy.

4. The process according to claim 1, wherein oxidation in step-b is carried out in presence of sulfamic acid and sodium chlorite

5. The process according to claim 1, wherein the base used in the step-c is selected from alkali metal hydrides or alkali metal carbonates.

6. The process according to claim 5, wherein base is selected from sodium hydride or potassium hydride.

7. The process according to claim 1, wherein halogenating agent used in the step-c is thionyl chloride.

8. The process according to claim 1, wherein organic solvent used in step-d for the purification of Roflumilast is selected from alcoholic solvents such as methanol, ethanol or isopropanol.

9. Crystalline Form-I of Roflumilast.

10. The compound according to claim 9, wherein crystalline Form-I of Roflumilast is characterized by X-ray powder diffraction having characteristic peak at 5.59 ±0.2° 29.

11. The compound according to claim 9, wherein crystalline Form-I of Roflumilast is characterized by X-ray powder diffraction having characteristic peaks at 5.59 and 22.4±0.2° 29.

12. The compound according to claim 9, wherein crystalline Form-I of Roflumilast is characterized by the Powder X-ray diffraction as depicted in Figure 1.

13. The compound according to claim 9, wherein crystalline Form-I of Roflumilast is characterized by DSC thermogram as depicted in Figure 2.

14. The compound according to claim 9, wherein crystalline Form-I of Roflumilast is characterized by TGA as depicted in Figure 3.

15. A process for the preparation of crystalline Form-I of Roflumilast comprising crystallization of Roflumilast in an organic solvent wherein, the organic solvent is selected form methanol, ethylacetate, isopropanol, n-heptane and mixtures thereof.