DESC:FIELD OF THE INVENTION
The present invention relates to a process for the preparation of Indacaterol acetate of Formula-I,

The present invention also relates to a novel crystalline form of Indacaterol acetate.

BACKGROUND OF THE INVENTION
Indacaterol is marketed as maleate salt. It is chemically know as (R)-5-[2-(5,6-diethylindan-2-ylamino)-1-hydroxyethyl]-8­hydroxy-1H-quinolin-2-one maleate and is represented by the structural Formula-II:

Indacaterol is a selective long acting inhaled ß2-adrenergic agonist indicated for long-term, once-daily maintenance bronchodilator treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema. The drug is marketed by Sunovion Pharmaceuticals Inc under the brand name ARCAPTA NEOHALER® in US.

Indacaterol and its salts thereof were first disclosed in the U.S. Pat. No. 6,878,721. Indacaterol acetate, is used as an intermediate in the synthesis of Indacaterol maleate. Further, Indacaterol acetate is currently being evaluated in clinical trials.

U.S. Pat. No. 8,198,450 discloses crystalline Indacaterol acetate characterized by powder X-ray diffraction values at 4.3°, 8.4°, 11.4°, 15.1°, 17.0°, 18.6°, 19.19, 19.70, 20.50, 22.9°, 23.3°, 23.5°, 24.6°, 25.6°, 28.9° and 30.5° ± 0.2 degrees of two-theta. The patent also discloses the process for the preparation of Indacaterol acetate which comprises reacting Indacaterol free base with acetic acid.

One of the most important physical properties of pharmaceutical compounds is their solubility in aqueous solution, particularly their solubility in the gastric juices of a patient. For example, where absorption through the gastrointestinal tract is slow, it is often desirable for a drug that is unstable to conditions in the patient's stomach or intestine to dissolve slowly so that it does not accumulate in a deleterious environment. Different solid state forms or polymorphs of the same pharmaceutical compounds can and reportedly do have different aqueous solubilities.

The discovery of new polymorphic forms of Indacaterol acetate provides a new opportunity to improve the performance of the synthesis of the active pharmaceutical ingredient (“API”). Therefore, there is a need for additional solid state forms of Indacaterol acetate and additional methods for preparing Indacaterol acetate crystal forms that provide Indacaterol efficiently and can be applied in an industrial scale.

SUMMARY OF THE INVENTION
Accordingly the invention provides an improved process for the preparation of Indacaterol acetate of Formula-I

comprising,
i) basifying the acid addition salt of compound of Formula-III,

wherein R is a hydroxy protecting group; in a solvent in the presence of a base to give freebase of compound of Formula-III.
ii) deprotecting the compound of Formula-III in a solvent in the presence of a reducing agent and acetic acid to give compound of Formula-I.

In another aspect, the present invention provides novel crystalline form of Indacaterol acetate.

In yet another aspect, the present invention provides novel crystalline form of Indacaterol acetate characterized by PXRD pattern with strong peaks at about 2.9, 12.9 and 23.5 ± 0.2 ° 2?.

In yet another aspect, the present invention provides novel crystalline form of Indacaterol acetate further characterized by PXRD pattern with peaks at about 17.4, 17.6, 19.9, 20.3, 22.3 and 27.1 ± 0.2 ° 2? and PXRD pattern substantially as depicted in FIG. 1.

In yet another aspect, the present invention provides process for the preparation of novel crystalline form of Indacaterol acetate comprising the steps of:
i) dissolving compound of Formula-I in methanol;
ii) heating the reaction mixture in step (i) to reflux temperature;
iii) adding ethylacetate to the reaction mixture obtained in step (ii);
iv) heating the reaction mixture obtained in step (iii) to reflux temperature;
v) isolating crystalline compound of Formula-I and
vi) optionally repeating steps (i) to (v) to obtain pure crystalline compound of Formula-I.

In yet another aspect, the present invention provides process for the preparation of novel crystalline form of Indacaterol acetate comprising the steps of:
i) basifying the acid addition salt of compound of Formula-III,

wherein R is a hydroxy protecting group; in a solvent in the presence of a base to give freebase of compound of Formula-III;
ii) deprotecting the compound of Formula-III in a solvent in the presence of a reducing agent and acetic acid to give compound of Formula-I;
iii) dissolving compound of Formula-I in methanol;
iv) heating the reaction mixture in step (iii) to reflux temperature;
v) adding ethylacetate to the reaction mixture obtained in step (iv);
vi) heating the reaction mixture obtained in step (v) to reflux temperature;
vii) isolating crystalline compound of Formula-I and
viii) optionally repeating steps (iii) to (vii) to obtain pure crystalline compound of Formula-I.

In yet another embodiment, the invention encompasses a process for preparing Indacaterol salt by preparing Indacaterol acetate of Formula-I according to the processes described above and converting it to a pharmaceutically acceptable salt of Indacaterol.

BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 represents powder X-ray diffraction pattern of Indacaterol acetate.

DETAILED DESCRIPTION OF THE INVENTION
The present invention provides an improved process for the preparation of Indacaterol acetate of Formula-I and its polymorph thereof.

In one embodiment, the invention provides an improved process for the preparation of Indacaterol acetate of Formula-I

comprising,
i) basifying the acid addition salt of compound of Formula-III,

wherein R is a hydroxy protecting group; in a solvent in the presence of a base to give freebase of compound of Formula-III;
ii) deprotecting the compound of Formula-III in a solvent in the presence of a reducing agent and acetic acid to give compound of Formula-I.

The base used for the basification in step (i) is selected from a group comprising sodium hydroxide, potassium hydroxide, sodium bi-carbonate, sodium carbonate, potassium carbonate, ammonium hydroxide or triethylamine. Preferably sodium carbonate is used. The solvent used is selected from a group comprising diethyl ether, diisopropyl ether, chloroform, methylene chloride, hexanes, ethylene dichloride, toluene, benzene, xylene, ethyl acetate or isopropyl acetate. Preferably methylene chloride is used. Hydroxy protecting group denoted as ‘R’ in compound of Formula-III is selected from silyl, alkyl, aryl, alkoxy, alkenyl, aralkyl and haloalkyl. Benzyl protected compound of Formula-III is preferred. Acid addition salt of compound of Formula III are selected from maleic acid, tartaric acid, mandelic acid, oxalic acid and succinic acid. Preferable acid addition salt of compound of Formula-III is maleate.

The solvents used in the deprotection in step (ii) is selected from alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or t-butanol. Preferably the solvent used is methanol. Reducing agent used in the reaction is selected from ceric ammonium nitrate, sodium bromate with sodium diathionate, platinum, platinum oxide, palladium, Raney nickel or Rhodium, on a support such as charcoal, aluminium oxide or mixtures thereof. Preferably deprotection is carried out by using palladium on carbon with hydrogen.

In a preferred embodiment, the present invention provides an improved process for the preparation of Indacaterol acetate of Formula-I

comprising,
i) basifying maleate salt of compound of Formula-IIIa

in methylene dichloride in the presence of sodium carbonate to give freebase of compound of Formula-IIIb and

ii) debenzylating the compound of Formula-IIIb in methanol in the presence of hydrogen, palladium on carbon and acetic acid to give compound of Formula-I.

In another embodiment, the present invention provides novel crystalline form of Indacaterol acetate characterized by PXRD pattern with strong peaks at about 2.9, 12.9 and 23.5 ± 0.2 ° 2?.

In yet another embodiment, the present invention provides novel crystalline form of Indacaterol acetate further characterized by PXRD pattern with peaks at about 17.4, 17.6, 19.9, 20.3, 22.3 and 27.1 ± 0.2 ° 2? and PXRD pattern substantially as depicted in FIG. 1.

In another preferred embodiment, the present invention provides process for the preparation of novel crystalline form of Indacaterol acetate comprising the steps of:
i) dissolving compound of Formula-I in methanol;
ii) heating the reaction mixture in step (i) to 50-55 ºC;
iii) adding ethylacetate to the reaction mixture obtained in step (ii) at 50-55 ºC;
iv) heating the reaction mixture obtained in step (iii) to 65-75 ºC;
v) isolating crystalline compound of Formula-I and
vi) optionally repeating steps (i) to (v) to obtain pure crystalline compound of Formula-I.

As used herein, the term “isolating” means isolating the crystalline form of compound of Formula-I by way of solvent crystallization method, partial removal of the solvent from the solution, sonication, solvent/antisolvent method, slurry, cooling, seeding, filtration, filtration under vacuum, centrifugation, decantation, distillation, evaporation, evaporation under reduced pressure. The product obtained may be further or additionally dried to achieve the desired moisture values. For example, the product may be dried in a tray drier, dried under vacuum and/or in a Fluid Bed Drier.

In yet another preferred embodiment, the present invention provides an improved process for the preparation of Indacaterol acetate of Formula-I

comprising,
i) basifying maleate salt of compound of Formula-IIIa

in methylene dichloride in the presence of sodium carbonate to give freebase of compound of Formula-IIIb and

ii) debenzylating the compound of Formula-IIIb in methanol in the presence of hydrogen, palladium on carbon and acetic acid to give compound of Formula-I;
iii) dissolving compound of Formula-I in methanol;
iv) heating the reaction mixture in step (iii) to 50-55 ºC;
v) adding ethylacetate to the reaction mixture obtained in step (iv) at 50-55 ºC;
vi) heating the reaction mixture obtained in step (v) to 65-75 ºC;
vii) isolating crystalline compound of Formula-I and
viii) optionally repeating steps (iii) to (vii) to obtain pure crystalline compound of Formula-I.

Compound of Formula-III and its acid addition salt used as starting material for the preparation of crystalline form of Indacaterol acetate of compound of Formula-I of the present invention may be obtained by any of processes reported in literature, for example, according to the methods disclosed in U.S. patent application Ser. No. 15/110,410, which is incorporated herein by reference.

Crystalline form of Indacaterol acetate of compound of Formula-I may be converted to Indacaterol maleate by reacting with maleic acid for example, according to the Example-5 disclosed in U.S. patent application Ser. No. 15/110,410, which is incorporated herein by reference.

Having thus described the invention with reference to particular preferred embodiments and illustrative examples, those in the art can appreciate modifications to the invention as described and illustrated that do not depart from the spirit and scope of the invention as disclosed in the specification. The Examples are set forth to aid in understanding the invention but are not intended to, and should not be construed to, limit its scope in any way.

EXAMPLES
X-Ray Powder Diffractions were performed on ARL (Scintag) X-Ray powder diffractometer model X'TRA, Cu-tube, solid state detector. A round standard aluminum sample holder with round zero background quartz plate was used. Scanning parameters: range 2-40° 2?, continuous scan, rate 5 deg/min.

Example 1: Preparation of crystalline form of Indacaterol acetate of Formula-I.
To a mixture of Benzyl Indacaterol maleate (IIIa) (120 grams) and methylene dichloride (850 mL) was added sodium carbonate solution (84 grams of sodium carbonate dissolved in 360 mL water) at 25-30 ºC and stirred for about 10 minutes. Separated the organic layer, extracted the aqueous layer with methylene dichloride (360 mL) and washed all the combined organic layers with water (360 mL). Distilled off the solvent in the organic layer completely under vacuum below. Mixture of methanol (1080 mL) and acetic acid (120 mL) was added to the residue thus obtained and stirred for about 15 minutes at 25-30 ºC. Flushed the reaction mass with nitrogen for three times. 5% Palladium on carbon (6.0 grams) was charged under the nitrogen atmosphere, hydrogen gas was bubbled and maintained the reaction at the same temperature for about 3 hours at 25-30 ºC. Filtered the catalyst under nitrogen atmosphere and washed with methanol (120 mL). Reaction mass was treated with activated carbon (2 X 10 grams) to reduce the Palladium content to 1.0 ppm. Distilled off the solvent in the filtrate completely under vacuum, co-distilled off with ethylacetate (120 mL). Cooled the reaction mass to 25-30 ºC, methanol (240 mL) was added and heated the reaction mass to 50-55 ºC. Ethylacetate (720 mL) was charged, heated the reaction mass to reflux temperature of 65-75 ºC and maintained the reaction at the same temperature for about 1 hour. Cooled the reaction mass to 25-30 ºC and maintained at the same temperature for about 2 hours. Filtered the reaction mass, washed with ethyl acetate (120 mL) and suck dried for 1 hour. Methanol (240 mL) was charged to the wet compound thus obtained and heated the reaction mass to 50-55 ºC. Ethylacetate (720 mL) was charged slowly, heated the reaction mass to reflux temperature of 65-75 ºC and maintained the reaction at the same temperature for about 30 minutes. Cooled the reaction mass to 25-30 ºC and maintained at the same temperature for about 1 hour. Filtered the reaction mass, washed with ethyl acetate (120 mL) and suck dried for 1 hour. The wet compound was dried at 60-65 ºC under vacuum for about 12 hours to yield 68 grams of the title compound.
,CLAIMS:1. A process for preparing Indacaterol acetate of compound of Formula-I,

wherein the process comprises:
i) basifying the acid addition salt of compound of Formula-III,

wherein R is a hydroxy protecting group; in a solvent in the presence of a base to give freebase of compound of Formula-III;
ii) deprotecting the compound of Formula-III in a solvent in the presence of a reducing agent and acetic acid to give compound of Formula-I.

2. Crystalline form of Indacaterol acetate.

3. Crystalline form according to claim 2, wherein the X-ray diffraction pattern has the characteristic strong peaks at 2? values of 2.9, 12.9 and 23.5 ± 0.2 ° 2?.

4. Crystalline form according to claim 3, wherein the X-ray diffraction pattern has the following characteristic peaks at 2? values of at 2.9, 12.9, 17.4, 17.6, 19.9, 20.3, 22.3, 23.5 and 27.1 ± 0.2 ° 2? and is substantially as shown in FIG. 1.

5. A process for preparing crystalline form of Indacaterol acetate of compound of Formula-I, wherein the process comprises:
i) dissolving Indacaterol acetate of compound of Formula-I in methanol;
ii) heating the reaction mixture in step (i) to reflux temperature;
iii) adding ethylacetate to the reaction mixture obtained in step (ii);
iv) heating the reaction mixture obtained in step (iii) to reflux temperature;
v) isolating crystalline compound of Formula-I and
vi) optionally repeating steps (i) to (v) to obtain pure crystalline compound of Formula-I.

6. A process for the preparation of crystalline form of Indacaterol acetate comprising the steps of:
i) basifying the acid addition salt of compound of Formula-III,

wherein R is a hydroxy protecting group; in a solvent in the presence of a base to give freebase of compound of Formula-III;
ii) deprotecting the compound of Formula-III; in a solvent in the presence of a reducing agent and acetic acid to give compound of Formula-I;
iii) dissolving compound of Formula-I in methanol;
iv) heating the reaction mixture in step (iii) to reflux temperature;
v) adding ethylacetate to the reaction mixture obtained in step (iv);
vi) heating the reaction mixture obtained in step (v) to reflux temperature;
vii) isolating crystalline compound of Formula-I and
viii) optionally repeating steps (iii) to (vii) to obtain pure crystalline compound of Formula-I.

7. The process according to claims 1&6, wherein the base used in in step (i) is selected from a group comprising sodium hydroxide, potassium hydroxide, sodium bi-carbonate, sodium carbonate, potassium carbonate, ammonium hydroxide or trimethylamine.

8. The process according to claims 1&6, wherein the solvent used in step (i) is selected from a group comprising diethyl ether, diisopropyl ether, chloroform, methylene chloride, hexanes, ethylene dichloride, toluene, benzene, xylene, ethyl acetate or isopropyl acetate.

9. The process according to claim 1&6, wherein the reducing agent used in step (ii) is selected from ceric ammonium nitrate, sodium bromate with sodium diathionate, platinum, platinum oxide, palladium, Raney nickel or Rhodium, on a support such as charcoal, aluminium oxide or mixtures thereof.

10. The process according to claim 1&6, wherein the solvent used in step (ii) is selected from alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or t-butanol.