This application claim priority to Indian patent application number 3461/CHE/2010 filed onNovl7,2010.

FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of crystalline Rasagiline base.

BACKGROUND OF THE INVENTION

Rasagiline mesylate is marketed under trade name AZILECT® tablets. Rasagiline is a propargylamine based drug indicated for idiopathic Parkinson's disease. It is a selective irreversible inhibitor of the B-form of monoamine oxidase enzyme (MOA-B). Rasagiline mesylate is designated chemically as lH-Indene-l-amine-2,3-dihydro-N-2-propynyl-, (lR)-,methanesulfonate or R(+)-N-propargyl-l-aminoindan mesylate. Rasagiline is structurally represented in formula I as shown below.

US 5457133 discloses Rasagiline and its pharmaceutically acceptable salts. US 5532415 discloses Rasagiline mesylate. In these patents, Rasagiline free base is obtained as yellow oil.

US 7750051 discloses solid crystalline Rasagiline base. In this patent, liquid Rasagiline is taken in a first organic solvent and completely evaporated to form a residue which is later dissolved in a second organic solvent followed by complete evaporation of the second solvent under vacuum to get residue. The obtained residue is maintained at 0-25 °C to get
solid Rasagiline base. Specifically the process involves dissolution of Rasagiline mesylate in water and toluene followed by basification by sodium hydroxide. Later layers were separated and toluene was concentrated to get residue of Rasagiline base. Residue is dissolved in alcohol solvent ethanol or isopropanol and later concentrated to get oily residue. Later Rasagiline base is isolated using water. Drying was done under vacuum. Melting point reported is around 38°C.

US 2009-0318564 discloses crystalline Rasagiline base having less than 0.5% water content. In this patent application, Rasagiline tartrate is treated with sodium hydroxide solution in water-toluene mixture and later separated. The organic layer is concentrated and isopropyl alcohol is added to the obtained residue. Addition of isopropanol and solvent evaporation under vacuum is repeated. Residue is dissolved in isopropanol followed by addition of water and seeding to obtain solid Rasagiline base.

The present inventors have repeated the process given in US 7750051 and observed that drying of Rasagiline base at temperature below 38°C under vacuum for 48 hours has not reduced water content below 1.3%. Increase in temperature beyond 38°C to facilitate drying, resulted in melting of Rasagiline base. In addition to this, an unknown peak was observed in the organic volatile impurities analysis of Rasagiline base by Gas Chromatography. The peak was observed even at 40°C and intensity of the peak was found to increase with temperature.

The unknown peak was due to the decomposition of Rasagiline base at temperature above its melting point, 38°C.

Hence there exists a need in the art for an improved process of preparing Rasagiline base without any decomposition of the product during drying.

OBJECT AND SUMMARY OF THE INVENTION

The principle object of the present invention is to provide an improved process for preparation of crystalline R(+)-N-propargyl-l-arninoindan.

The main aspect of the present invention is to provide an improved process for preparation of crystalline R(+)-N-propargyl-l-aminoindan comprising the steps of: dissolving Rasagiline salt in water; adjusting pH to basic using a base to precipitate a solid; dissolving the precipitated solid in a halogenated solvent; concentrating the reaction mass; and isolating Rasagiline base in non-polar solvent.

Another aspect of the present invention is to provide an improved process for preparation of crystalline R(+)-N-propargyl-l-aminoindan comprising the steps of: dissolving Rasagiline salt in a mixture of water and water immiscible solvent; adjusting pH to basic using a base; separating the organic layer; concentrating the organic layer and isolating Rasagiline base in non-polar solvent.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides an improved process for preparation of crystalline Rasagiline base, wherein Rasagiline salt is dissolved in water, pH is adjusted by using a base to precipitate a solid and obtained solid is dissolved in a halogenated solvent, concentrated followed by addition of non-polar solvent to give Rasagiline base.

The present invention also provides an improved process for preparing crystalline R(+)-N-propargyl-1-aminoindan, wherein Rasagiline salt is dissolved in water and water immiscible solvent, pH is adjusted by using a base, organic layer is separated and concentrated, and crystalline Rasagiline base isolated in non-polar solvent.

According to the present invention, crystalline R(+)-N-propargyl-l-aminoindan (Rasagiline) is prepared by process comprising the steps of:

a) dissolving Rasagiline salt in water;
b) adjusting pH to basic using a base and precipitating the solid;
c) dissolving the solid in a halogenated solvent;
d) concentrating the reaction mass; and
e) adding a non-polar solvent to isolate crystalline Rasagiline base.

In one embodiment, the Rasagiline salt used as a starting material for the preparation of Rasagiline base can be mesylate, tosylate, hydrochloride, tartrate or any other organic or inorganic acid addition salt preferably mesylate.

In another embodiment, Rasagiline salt is dissolved in water and stirred at 20-25 °C. pH of the reaction mass is adjusted to basic preferably 9-10 using base such as sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate. Solid precipitates out which is filtered and suck dried.

In another embodiment, the solid obtained after pH adjustment is dissolved in a halogenated solvent selected from methylene dichloride, chloroform and tetra chloromethane preferably methylene dichloride. Water if any present is separated from the organic layer. The obtained organic layer is concentrated under vacuum at 20-25 °C to obtain residue.

In another embodiment, the obtained residue is treated with non-polar solvent selected from n-pentane, n-hexane and n-heptane. The reaction mass is cooled to 0-5°C and stirred for 0-90 min preferably 60 min. Solid obtained is filtered and dried under vacuum below 20-25°C for 12-36 hrs preferably 24 hrs.

According to the present invention, crystalline R(+)-N-propargyl-l-aminoindan (Rasagiline) is prepared by process comprising the steps of:

a) dissolving Rasagiline salt in a mixture of water and water immiscible solvent;
b) adjusting pH to basic using a base;
c) separating the organic layer;
d) concentrating the organic layer; and
e) adding a non-polar solvent to isolate crystalline Rasagiline base.

In one embodiment, the Rasagiline salt used as a starting material for the preparation of Rasagiline base can be mesylate, tosylate, hydrochloride, tartrate or any other organic or inorganic acid addition salt preferably mesylate.

In another embodiment, water immiscible solvent used is selected from halogenated solvent such as methylene dichloride, chloroform and tetra chloromethane preferably methylene dichloride.

In another embodiment, the obtained residue is treated with a non-polar solvent selected from n-pentane, n-hexane and n-heptane.

The present inventors have observed that, Rasagiline base is soluble in almost all solvents except water. This limits the option of washing Rasagiline base obtained by filtration, with water miscible solvents to reduce the water content. Washing with water and drying at room temperature renders the possibility of obtaining moisture free Rasagiline base all the more difficult. Hence washing is avoided during isolation of Rasagiline base.

According to the present invention, Rasagiline base is obtained as anhydrous crystalline solid.

According to the present invention, Rasagiline base is obtained as a solid and has water content below 0.5% rendering the product anhydrous. Water content by Karl Fischer was 0.05 to 0.15%.

According to the present invention, Rasagiline base obtained above is characterized by PXRD having diffraction peaks at about 8.35, 12.39, 15.96, 16.75, 20.21, 20.84, 24.99, 25.23, 26.27, 28.19, 30.26, 31.37, 33.12 ± 0.2 9°.

According to the present invention, Rasagiline base is further characterized by having a sharp endofhermic peak at 42°C.

According to the present invention, Rasagiline base is dried below 38°C making sure of no decomposition taking place during drying.

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 9/6 configuration and X'Celerator detector. The Cu-anode X-ray tube was operated at 40kV and 30mA. The experiments were conducted over the 20 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 Mettler Toledo 822 star6 and 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.
The following example illustrates the invention. However it is not intended to limit the scope of the invention in any manner.

EXPERIMENTAL PROCEDURE

Example-1: Process for the preparation of Rasagiline base.
Water 500ml was taken in a reaction vessel and Rasagiline Mesylate (leq, 50g) was added at 20-25 °C. The reaction contents were stirred to obtain clear solution. Later clear solution was further cooled to 0-5 °C. Sodium carbonate [25%] (200ml) was added through addition funnel slowly to attain pH 9-10. Reaction contents were stirred for 1 hour at 0-5 °C. The slurry was filtered and washed with water (2*250ml) and suck dried for 10 min. The product was obtained as white solid.

Methylene dichloride 200ml was added to the solid obtained in another reaction vessel to get a solution. Any water layer that remains in the vessel is separated out. Later solution was dried over sodium sulphate (50g) and distilled out methylene dichloride under vacuum at 20-25 °C to obtain oil. n-Heptane 125ml was added to the oil at 20-25 °C. Later the obtained mass was cooled to 0-5°C and stirred for 1 hour at 0-5 °C. The obtained slurry was filtered and suck dried for 10 min. Solid was dried under vacuum at 20-25 °C for 24 hours. Rasagiline base was obtained as white crystalline solid.

Yield: 25.0 g Purity: 99.95 %

We Claim:

1. A process for the preparation of Rasagiline free base comprising the steps of:

a) dissolving Rasagiline salt in water;
b) adjusting pH to basic using a base and precipitating the solid;
c) dissolving the solid in a halogenated solvent;
d) concentrating the reaction mass; and
e) adding a non-polar solvent to isolate crystalline Rasagiline base.

2. The process according to claim 1, wherein the Rasagiline salt is selected from mesylate, tosylate, hydrochloride and tartrate.

3. The process according to claim 2, wherein the Rasagiline salt is mesylate.

4. The process according to claim 1, wherein the base is selected from sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate

5. The process according to claim 1, wherein the pH of step b) is adjusted to 9-10.

6. The process according to claim1, wherein the halogenated solvent is selected from methylene dichloride, chloroform and tetra chloromethane.

7. The process according to claim 5, wherein the halogenated solvent is methylene dichloride.

8. The process according to claim 1, wherein the non-polar solvent is selected from n-pentane, n-hexane and n-heptane.