FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
COMPLETE SPECIFICATION
(See Section 10)
"AN IMPROVED PROCESS FOR THE MANUFACTURING OF ROFLUMILAST"
We, M/s. Ajanta Pharma Ltd, a company registered under The Companies Act, 1956, having its registered office located at Ajanta Pharma Limited 98, Ajanta House, Charkop, Kandivli (West) Mumbai, 400 067. Maharashtra, India, India
The following specification particularly describes the nature of this invention and the manner in which it is to be performed:-

TECHNICAL FIELD OF THE INVENTION
The field of the invention relates to an improved process for manufacture of 4-amino-3,5-dichloropyridine anion (III) and to the use of this for the preparation of Roflumilast (I).

BACKGROUND
Chemically, Roflumilast is 3- (cyclopropylmethoxy)-N- (3, 5-dichloro-4- pyridinyl)-4-(difiuoromethoxy) benzamide of Formula I. and is known from U. S. Patent No. 5,712. 298.
Roflumilast is an effective phosphodiesterase-4-inhibitor (PDE4-inhibitor): which can be used in the treatment of asthma, inflammation, bronchitis, allergy, osteoporosis, dermatoses and disorders related to immune system, heart and kidney.

US5712298 discloses the preparation Roflumilast which involves Sodium hydride as a base to generate anion of 4-amino-3,5-dichloropyridine.
WO2001090076, WO2004033430, WO2005026095, IN2004MU00478, and US6712274 discloses the preparation of roflumilast which involves Sodium hydride as a base to generate anion of 4-amino-3,5-dichloropyridine.
Perhaps the nearest prior art to the present invention is the form of WO2004080967, which discloses the preparation of roflumilast which involved strong base selected from group of KOtBu, NaOtBu and LiOtBu is used to prepare anion of 4-amino-3,5-dichloropyridine.
As has been seen, a lot of knowledge in the present field of invention is available; however, there remain some problems, which problems defined the scope for our further investigations. It can be seen that almost all prior art have the same reactants. Reactions are carried out in presence of sodium hydride as strong base which is very moisture sensitive and pyrophoric in nature, which have safety issues to handle at commercial scale and difficult work up as hydrogen gas evolved during quenching.
In the processes where the use of sodium hydride as strong base is avoided, the resultant products are formed with higher impurities. The processes involving use of metal alkoxide. which is moisture sensitive and required super dry condition. At large scale the products formed with higher impurity levels necessitate extra purifications, which increase the cost of manufacturing the product.
Therefore, it is of importance to develop a process for manufacture of roflumilast, which process is safe at large scale production, yielding high quality with higher yields and easy to work up, which also avoids the expense maintaining extra dry condition.
OBJECTIVES
An objective of the present invention is therefore to develop an improved process for manufacture Roflumilast, in high yields, with higher purity, and with better operator-friendly operations, at cheaper prices.

SUMMARY
This invention relates to an improved industrial process for manufacturing RoflumilasL represented by Formula (I)

comprising the steps of:
i. preparation 3-cydopropylmethoxy-4-difiuoromethoxybenzoic acid halide (V) as per prior art teaching.;
ii. generation of anion of the 4-amino-3,5-dichIoropyridine (II). reaction of the 4-amino-3,5-dichloropyridine anion (III) with an activated derivative 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid halide (V) in inert solvent to produce crude compound having Formula (I);
iii. Purifying the crude compound to obtain pure compound having Formula (I).
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to an improved process for manufacture of 4-amino-3.5-dichloropyridine anion (III) and to the use of this for the preparation of Roflumilast (1) in higher purity, avoiding use of pyrophoric base and easy work up, thus enabling cheaper and safe manufacturing process.


The present invention involves optimization with respect to use of strong base, solvent and the molar ratio of reactants in order to achieve higher-purity and higher yields, by avoiding the very moisture sensitive and pyrophoric base seen in the prior art teachings, and thus enable the commercial scale suitable process and avoiding the need for extra purification of Roflumilast.
According to present invention process for the preparation of Roflumilast of formula-1

comprising:
i. Preparation of compound having formula (V) using halogenating agent in inert solvent.


ii. Preparation of anion of the compound having formica (II) using strong base in inert solvent and in-situ reaction of anion having formula (III) with compound having formula (V) in inert solvent to obtained crude compound having Formula (I).

iii. Purifying the crude compound to obtain pure compound having Formula (I).
According to present invention wherein halogenating agents used in step (i) are thionyl chloride, hydrochloride (HC1), hydrobromide (HBr); more preferably thionyl chloride.
According to present invention wherein strong base used in step (ii) for the preparation of the anion are Sodium hydroxide (NaOH), Potassium hydroxide (KOH) or Lithium hydroxide (LiOH), more preferred Sodium hydroxide (NaOH) or Potassium hydroxide (KOH) and most preferably Sodium hydroxide (NaOH).
According to present invention, wherein inert solvent used in step (it) are dimethylformamide, dimethyl suphoxide, N-methylpyrrolidone, and/or tetrahydrofuran, more preferably dimethyl formamide and/or tetrahydrofurane.
According to present invention; purification process involves steps of;
i. Stirring crude compound having formula (I) in solvent selected from isopropyl alcohol, acetonitrile, acetone, methanol or ethanol at temperature in the range of 0-100°C, preferably 60-80°C & more preferably reflux temperature of the solvent.
ii. Pure product precipitate by cooling at temperature in the range of -5 °C-10 °C, preferably -5 °C-0 °C or by addition of water as anti solvent at temperature in the

range of 0-10 C, preferably 0-5 °C and filtering the pure product to obtain pure roflumilast (I) According to present invention process involves two steps for preparation of the compound having formula (I) as following;
i. preparation compound having formula (V) by reaction of compound formula (IV)
with thionyl chloride in inert solvent. The represented as shown in step I.

Stepl
ii. preparation of anion of the compound having formula (II) to produce anion having formula (III) using strong base in inert solvent, the anion having formula (111) react in-situ with compound having formula (V) in inert solvent to product crude compound having formula (I). The reaction is represented as shown in step 2.


Step 2
Strong bases selected from the group of NaOH, KOH and LiOH are particularly suitable for preparing the anion of 4-amino-3, 5-dichloropyridine. The use of NaOH or KOH is preferred. The molar ratio of employed base to 4-amino-. 3, 5-dichloropyridine is in this case advantageously in the range from 1.8 to 3.0 and preferably in the range from 1.9 to 2.2. The inert solvent dimethylformamide. dimethyl suphoxide or N-methylpyrrolidone, the use of dimethyl formamide is preferred.
The quantity of anion of 4-amino-3, 5-dichloropyridine to the 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid chloride is in the range of 1.2 to 2.0, most preferable 1.4 to 1.6. The inert solvent dimethylformamide, dimethyl suphoxide. N-methylpyrrolidone, tetrahydrofuran, and/or mixture thereof; more preferably dimethyl formamide and/or tetrahydrofuran.

iii. Purifying the crude compound having formula (I) to obtain pure compound having Formula (I).
The process according to present invention wherein about 1.8 to 3 mole preferably about 1.9 to 2.2 mole of strong base to 1 mole of the compound of formula (II) is used to prepare anion of the formula (111).
The process according to present invention, wherein about 1.2 to 2.0. most preferable 1.4 to 1.6 mole of anion having formula (III) reacted with about 1 moles of compound having Formula (V).
Example-1
Preparation of 3-cycIopropyImethoxy-4-difluoromethoxybenzoyl chloride
A mixture of 3-cyclopropylmethoxy-4-difluromethoxybenzoic acid (1.0 Kg, 3.87 mol). toluene (05 w/v) and DMF (0.01 w/v) stirred in 4-neck round bottom flask under nitrogen atmosphere at 25°C to 30°C. Thionyl chloride (0.991 Kg, 8.32 mol) added under nitrogen and heated to 65°C to 67°C for 2.0 hrs. After completion of reaction excess thionyl chloride and toluene were evaporated under reduced pressure to get an oily mass of 3-cyclopropylmethoxy-4-difluoromethoxybenzoyl chloride. Oily mass keep under nitrogen and used for further step.
Example-2
Preparation of Roflumilast crude
a) A mixture of NaOH (powdered, 0.465 kg, 11.62 mol), anhydrous DMF (5 w/v) and 4-amino-3,5-dichloropyridine (0.947 kg , 5.80 mol) stirred in 4-neck round bottom flask under nitrogen to form a slurry mass. Then 3-cyclopropylmethoxy-4-difluoromethoxybenzoyl chloride solution in anhydrous THF (4 w/v) was added to above slurry mass at 0°C to 5°C within 1.0 hrs. After completion of reaction water (7 w/v) was added to the reaction mass and extracted in ethyl acetate (2x5 w/v). The organic layer washed with IN HC1 solution (2x5 w/v), water (7.5 w/v) and saturated sodium

bicarbonate solution (10 w/v). The organic layer was washed with brine solution (7.5 w/v) and evaporated under reduced pressure to obtain Roflumilast crude 1.2 kg.
b) A mixture of KOH (Powdered, 0.326 kg , 5.5 mol), anhydrous DMF (5 w/v) and 4-amino-3,5-dichloropyridine(0.473 kg , 2.9 mol) stirred in 4-neck round bottom flask under nitrogen to form a slurry mass. The of 3-cyclopropylmethoxy-4-difluoromethoxybenzoyl chloride solution in anhydrous THF (4 w/v) was added to above slurry mass at 0°C to 5°C within 1.0 hrs. After completion of reaction water (7 w/v) was added to the reaction mass and extracted in ethyl acetate (2x5 w/v). The organic layer washed with IN HC1 solution (2x5 w/v), water (7.5 w/v) and saturated sodium bicarbonate solution (10 w/v). The organic layer was washed with brine solution (7.5 w/v) and evaporated under reduced pressure to obtain Roflumilast crude 1.25 kg .
c) A mixture of anhydrous LiOH (Powdered, 0.140 kg, 6.1 mol), anhydrous DMF (5 w/v) and 4-amino-3, 5-dichloropyridine (0.473 kg, 2.9 mol) stirred in 4-neck round bottom flask under nitrogen to form a slurry mass. The of 3-cyclopropylmethoxy-4-difluoromethoxybenzoyl chloride solution in anhydrous THF (4 w/v) was added to above slurry mass at 0°C to 5°C within 1.0 hrs. After completion of reaction water (7 w/v) was added to the reaction mass and extracted in ethyl acetate (2x5 w/v). The organic layer washed with IN HC1 solution (2x5 w/v), water (7.5 w/v) and saturated sodium bicarbonate solution (10 w/v). The organic layer was washed with brine solution (7.5 w/v) and evaporated under reduced pressure to obtain Roflumilast crude 0.575 kg.
Example-3: Purification of Roflumilast crude-
a) Purification of Roflumilast crude in Isopropyl alcohol
Roflumilast crude ( 1.2 kg ) stir with isopropyl alcohol ( 08 w/v) in 4-neck round bottom flask to get suspension. The suspension heat to reflux temperature for 30 min to get clear solution, activated charcoal (5% w/w) added to the clear solution and stir for 15 min. Solution filtered through Celite to remove charcoal. The filtrate was cooled at 25°C to 30°C and stir for 30 min. The solid product filtered and washed with IPA to get Roflumilast pure (0.960 kg).

b) Purification of Roflumilast crude in Isopropyl alcohol ancJ water
Roflumilast crude (1.2 kg ) stir with isopropyl alcohol (06 w/v) in 4-neck round bottom flask to get suspension and heat up to reflux temperature for 30 min. Water ( 02 w/v ) added drop wise to get white precipitated, and cool at 25°C to 30°C and stir for 30 min. The solid product filtered and washed with 50% aqueous IPA to get Roflumilast pure (0.985 kg).
c) Purification of Roflumilast crude in Acetonitrile-
Roflumilast crude (1.2 kg) stir with Acetonitrile (10 w/v) in 4-neck round bottom flask to get suspension The suspension heat to reflux temperature for 30 min o get clear solution, activated charcoal (5%) added to the clear solution and stir for 15 min. Solution filtered through Celite to remove charcoal. The filtrate was cooled at 25°C to 30°C and stir for 30 min. The solid product filtered and washed with Acetonitrile to get Roflumilast pure (0.940 kg).

We claim
1. A process for the preparation of Roflumilast of formula-I

comprising:
i. Preparation of compound having formula (V) using halogenating agent in inert
solvent.


iii. Purifying the crude compound to obtain pure compound having Formula (I).
ii. Preparation of anion of the compound having formula (II) using strong base in inert solvent and in-situ reaction of anion having formula (III) with compound having formula (V) in inert solvent to obtained crude compound having Formula (I).

2. The process as claimed in claim 1, wherein halogenating agents used in step (i) are thionyl chloride, hydrochloride (HC1), hydrobromide (HBr); more preferably thionyl chloride.
3. The process as claimed in claim 1, wherein strong base used in step (ii) for the preparation of the anion are Sodium hydroxide (NaOH), Potassium hydroxide (KOH) or Lithium hydroxide (LiOH), more preferred Sodium hydroxide (NaOH) or Potassium hydroxide (KOH) and most preferably Sodium hydroxide (NaOH).
4. The process as claimed in claim 1, wherein inert solvent used in step (ii) are dimethylformamide, dimethyl suphoxide, N-methylpyrrolidone. tetrahydrofuran, and/or mixture thereof; more preferably dimethyl formamide and/or tetrahydrofurane.
5. The process as claimed in claim 1, wherein about 1.8 to 3 mole preferably about 1.9 to 2.2 mole of strong base to 1 mole of the compound of formula (II) is used to prepare anion of the formula (III).
6. The process as claimed in claim 1, wherein about 1.2 to 2.0, most preferable 1.4 to 1.6 mole of anion having formula (III) reacted with about 1 moles of compound having Formula (V).
7. The process as claimed in claim 1, wherein purification step involves steps of
i. Stirring crude compound having formula (I) in solvent selected from isopropyl alcohol, acetonitrile, acetone, methanol or ethanol at temperature in the range of 0-100°C. preferably 60-80°C & more preferably reflux temperature of the solvent.
ii. Pure product precipitate by cooling at temperature in the range of -5 °C-10 C, preferably -5 °C-0 °C or by addition of water as anti solvent at temperature in the range of 0-10 °C, preferably 0-5 °C and filtering the pure product to obtain pure roflumilast (I)
8. A process for preparation of compound of Formula (I) substantially as herein described and
illustrated with reference to the accompanying examples.