Field of the Invention

The present invention provides an improved and eco-friendly process for the preparation of Palonosetron HC1 of formula (I).

Background of the Invention

Palonosetron is chemically known as 2-(l-azabicyclo[2.2.2]oct-3S-yl)-2,3,3aS,4,5,6-hexahydro-lH-benz[de]isoquinolin-l-one used as an antiemetic and antinauseant agent. The hydrochloride salt of Palonosetron is marketed under trade name of ALOXI® by Helsinn Healthcare. United States Patent No. 5,202,333 discloses and claims Palonosetron or its salts and derivatives and process for its preparation. The process disclosed in this patent involves the use of n-butyl lithium as a reagent in formulation reaction which is highly hazardous, inflames in air and commercialization by using this reagent is industrially not viable. Further the hydrogenation of (S)-2[l-azabicyclo[2.2.2]oct-3-yl]-2,4,5,6-tetrahydro-lH-benz[de] isoquinolin-1-one is carried out in the presence of acetic acid, containing few drops of s70% perchloric acid and 20% palladium hydroxide-on-carbon at 85 C for 24 hours.

WO 96/01824 discloses a process wherein the hydrogenation of (S)-2[l-azabicyclo [2.2.2] oct-3-yl]-2, 4,5,6-tetrahydro-lH-benz[de]isoquinolin-l-one takes more than 5 days in the presence of tetrahydrofuran (THF) as a solvent.

WO 2009/010987 discloses a process for the preparation of Palonosetron hydrochloride by hydrogenating (S)-2[l-azabicyclo [2.2.2] oct-3-yl]-2,4,5,6-tetrahydro-lH-benz[de]isoquinolin-l-one mono hydrochloride in an aliphatic alcohol using palladium catalyst followed by isolating the palonosetron HC1 directly from the reaction mixture.

US 2011/0213150 discloses the use of n-propanol for hydrogenation of (S)-2[l-azabicyclo[2.2.2]oct-3-yl]-2,4,5,6-tetrahydro-lH-benz[de]isoquinolin-l-one mono hydro chloride and US 8,093,391 B2 discloses the use of ethyl acetate for the hydrogenation of (S)-2[l-azabicyclo[2.2.2]oct-3-yl]-2,4,5,6-tetrahydro-lH- benz[de]isoquinolin-1 -one.

US 7,737,280 B2 discloses a process in which (S)-2-(l-azabicyclo[2,2,2]oct-3-yl)-2,4,5,6-tetrahydro-lH-benz[de]isoquinolin-l-one salt is converted to free base, followed by hydrogenation in an alcohol solvent using a catalyst chosen from 20% palladium hydroxide on carbon, 10% palladium on carbon, Pearlmans catalyst (50% water 20% palladium content), palladium/barium sulphate, rhodium on alumina and rhodium on carbon.

As discussed above, the prior art processes suffers one or more following disadvantages:

1 use of corrosive inorganic acids like acetic acid, perchloric acid which is not suitable in terms of manufacturing point of view

2 use of organic solvent for the hydrogenation reaction

3 unreacted starting material is difficult to remove.

This may result in the increase in the overall cost of the production.

US 8,304,544 B2, discloses a hydrogenation process in which (S)-2[l- azabicyclo [2.2.2] oct-3-yl]-2, 4, 5, 6-tetrahydro-lH-benz [de]iso quinolin-l-one is hydrogenated using water. However the use of free base as starting material results in getting the product as a mixture with other isomer which requires several purifications to get pure product.

Considering the commercial importance of Palonosetron hydrochloride and environment friendly process, there is a need for a simple, economical and industrially viable process for the synthesis of Palonosetron hydrochloride. The applicant focused developing a simple, improved and environment friendly process for the synthesis of Palonosetron hydrochloride in enatiomerically pure form.

Objectives of the Invention

The main objective of the present invention is to provide an improved process for the preparation of Palonosetron HC1 of formula (I) that avoids the use of corrosive agents like perchloric acid.
Still another objective of the present invention is to provide the environment friendly process for preparation of Palonosetron HC1 with good stability, purity and yield.

Summary of the Invention

Accordingly, the first aspect of the present invention is to provide an improved process for palonosetron hydrochloride of formula (I)
comprising the steps of:

a) hydrogenating the salt of 2-(l-azsabicyclo[2.2.2]oct-3-yl)-2,4,5,6-tetrahydro-lH-benz[de]isoquinolin-l-one of formula (II)
wherein x represents salt, using hydrogenation catalyst, in water to obtain palonosetron free base of formula (III);

b) optionally isolating the Palonosetron free base; and

c) converting the Palonosetron free base into Palonosetron HClof formula (I) using a source of HC1 in the presence of acetone or isopropanol or a mixture of acetone and organic solvent.

Detailed Description of the Invention

In an embodiment of the present invention, salt of 2-(l-azabicyclo[2.2.2]oct-3-yl)-2,4,5,6-tetrahydro-lH-benz[de]isoquinolin-l-one is selected from the group consisting of hydrochloric acid, hydrobromic acid, hydrofluoric acid, HI, methane sulfuric acid, sulfuric acid, acetic acid, p-toluenesulfonic acid and phosphoric acid, preferable as HC1 salt.

In another embodiment of the present invention, the hydrogenation catalyst used in step (a) is selected from palladium on carbon, palladium hydroxide, palladium hydroxide on carbon platinum, nickel, and rhodium or alumina. Preferably the hydrogenation catalyst is palladium on carbon. The said reaction is carried out under hydrogen gas pressure of 2 to about 10 kg/cm2 pressure and a temperature in the range ofabout20toabout85 °C.

After hydrogenation reaction, the palonosetron is optionally isolated as solid from the reaction mass or converted to palonosetron HC1 directly in situ manner.

In yet another embodiment of the present invention, the palonosetron free base is converted to palonosetron hydrochloride, the said process comprising dissolving the palonosetron free base or its residue in acetone or a mixture of acetone and an organic solvent selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutyl alcohol, tertiary butyl alcohol tetrahydrofuran (THF), diethyl ether, methylethylether, diisopropylether, methyltertiarybutyl ether, ethyl acetate and the like or mixtures thereof followed by treating the resultant solution with hydrochloric acid source. The HC1 source used may be selected from Cone. HC1, HC1 gas or HC1 gas dissolved in an organic solvent such as methanol, ethanol or isopropranol. The use of acetone for the HC1 preparation helps to yield palonosetron with enhanced isomeric purity and the isolated product is contain pharmaceutically acceptable level of starting material as an impurity. The obtained product according to the present invention has an isomeric purity of at least 97%, more preferably of about 99 to 99.5%.

The use of water for the hydrogenation reaction has many advantages as it avoids the use of corrosive acid and costly solvents. Hence the present invention is economically viable and also eco-friendly. Further the use of salt 2-(l- azabicyclo[2.2.2]oct-3-yl)-2,4,5,6-tetrahydro-lH-benz[de]isoquinolin-l-one has several advantages like 1) the reaction proceeds smoothly 2) all the starting material consumed 3) starting material obtained with good purity 4) yield palonosetron with high enantiomeric purity.

Palonosetron hydrochloride prepared by the present invention is a free flowing solid and suitable for pharmaceutical composition. Further Palonosetron hydrochloride obtained as per the present invention can be further micronized, milled or sieved to get the desired particle size (d90 less than 50 micron, preferably less than 10 micron) required for pharmaceutical composition to achieve the desired dissolution profile.

Many other beneficial results can be obtained by applying disclosed invention in a different manner or by modifying the invention with the scope of disclosure. The present invention is provided by the examples below, which are provided by way of illustration only and should not be considered to limit the scope of the invention.

Example 1

Preparation of 3aS-[2-[(S)-l-Azabicylco [2.2.2]oct-3-yl]-2,3?3a,4,5,6-hexahydro- 1H-benz[de]iso-quinolin-l-one hydrochloride (Palonosetron hydrochloride)

To a hydrogenation flask, 2-[(S)-l-azabicylco [2.2.2] oct-3-yl]-2,4,5,6-tetrahydro-lH-benz[de]iso-quinolin-l-one hydrochloride (10 g), 10% pd-C (50% wet; 10g), and water (80 ml) were charged at 25-35°C. The mass was stirred for 15 minutes and hydrogen pressure of 6-8 kg/cm2was applied at room temperature. The temperature was raised to 65-70 °C under 6-8 kg/cm hydrogen pressure and maintained until completion of the reaction. The reaction mass was cooled and filtered. The filtrate was basified to pH 11-12 with caustic lye solution and extracted with methylene dichloride. The MDC layer was concentrated. The residue was dissolved in acetone and adjusted pH below 1.0 using IPA-HC1. The separated product was filtered and dried to get crude product (4.0 g). If required the crude product is
recrystallized from methanol (40 ml) and IPA (20 ml) to get pure palonosetron hydrochloride (HPLC purity : 99.5%)

Example 2

Preparation of 3aS-[2-[(S)-l-Azabicylco [2.2.2]oct-3-yl]-2,3,3a,4,5,6-hexahydro- 1H-benz[de]iso-quinolin-l-one hydrochloride (Palonosetron hydrochloride)

To a hydrogenation flask, 2-[(S)-l-azabicylco [2.2.2] oct-3—y1]-2, 4, 5, 6-tetrahydro-1H-benz [de]iso-quinolin-l-one hydrochloride (10 g), 10% pd-C (50% wet; 10g), and water (80 ml) were charged at 25-35°C. The mass was stirred for 15 minutes and hydrogen pressure of 6-8 kg/cm was applied at room temperature. The temperature was raised to 65-70°C under 6-8 kg/cm hydrogen pressure and maintained until completion of the reaction. The reaction mass was cooled and filtered. The filtrate was basified to pH 11-12 with caustic lye solution and extracted with methylene dichloride. The MDC layer was concentrated. The residue was dissolved in a mixture of acetone and IPA and adjusted pH below 1.0 using IPA-HC1. The separated product was filtered and dried to get crude product (4.0 g). If required the crude product is recrystallized from methanol and isopropanol to get pure palonosetron hydrochloride (HPLC purity: 99.6%)

Example 3

Preparation of 3aS-[2-[(S)-l-Azabicylco [2.2.2]oct-3-yl]-2,3,3a,4,5,6-hexahydro-lH-benz|de|iso-quinolin-l-one hydrochloride (Palonosetron hydrochloride)
To a hydrogenation flask, 2-[(S)-l-azabicylco [2.2.2] oct-3~yl]-2, 4, 5, 6-tetrahydro-lH-benz[de]iso-quinolin-l-one hydrochloride (10 g), 10% pd-C (50% wet; 10g), and water (80 ml) were charged at 25-35°C. The mass was stirred for 15 minutes and hydrogen pressure of 6-8 kg/cm2was applied at room temperature. The temperature was raised to 65-70°C under 6-8 kg/cm2 hydrogen pressure and maintained until completion of the reaction. The reaction mass was cooled and filtered. The filtrate was basified to pH 11-12 with caustic lye solution and separated palonosetron free base was filtered and dried. Palonosetron free base was dissolved in 40 ml of acetone and 40 ml of IPA adjusted pH below 1.0 with IPA-HC1. The separated product was filtered and dried to get crude product (4.0 g). The crude product was recrystallized from methanol (40 ml) and IPA (20 ml) to get pure palonosetron hydrochloride (1.0 g).

Example 4

Preparation of 3aS-[2-[(S)-l-Azabicylco [2.2.2] oct-3-yl]-2,353a, 4, 5, 6-hexahydro-1H-benz [de]iso-quinolin-l-one hydrochloride (Palonosetron hydrochloride) 2-[(S)-l-azabicylco [2.2.2]oct-3~yl]-2,4,5,6-tetrahydro-lH-benz[de]iso-quinolin-l-one hydrochloride (10 g), 10% pd - C (50% wet; 10g), and water (80 ml) were charged into a hydrogenation flask at 25-35 °C. The vessel was flushed twice with hydrogen gas. The mass was stirred for 15 minutes and hydrogen pressure of 6-8 kg/cm2 was applied at room temperature. The temperature was raised to 65-70 °C under 6-8 kg/cm2 hydrogen pressure and maintained until completion of the reaction. The reaction mass was cooled and filtered. The filtrate was basified to pH 11-12 with 50% CS lye solution and separated base was filtered on Buchner funnel and dried to get palonosetron free base. Palonosetron free base was dissolved in 80 ml of IPA adjusted pH below 1.0 with IPA-HC1. The separated product was filtered and dried to get crude product (4.0 g). The crude product was recrystallized from Methanol (40 ml) and IPA (20 ml) to get pure palonosetron hydrochloride (1.0 g).

Example -5

Preparation of 3aS-[2-[(S)-l-Azabicylco [2.2.2]oct-3-yl]-2,3, 3a, 4, 5, 6-hexahydro- 1H-benz[de]iso-quinolin-l-one hydrochloride (Palonosetron hydrochloride) 2-[(S)-l-azabicylco [2.2.2]oct-3~yl]-2,4,5,6-tetrahydro-lH-benz[de]iso-quinolin-l-one hydrochloride (10 g), 10% pd-C (50% wet; 12g), and water (80 ml) were charged into a hydrogenation flask at 25-35 °C. The vessel was flushed twice with hydrogen gas. The mass was stirred for 15 minutes and hydrogen pressure of 6-8 kg/cm2was applied at room temperature. The temperature was raised to 65-70 °C under 6-8 kg/cm hydrogen pressure and maintained until completion of the reaction. The reaction mass was cooled and filtered. The filtrate was basified to pH 11-12 with 50% CS lye solution and separated base was filtered on Buchner funnel and dried to get palonosetron free base. Palonosetron free base was dissolved in 80 ml of IP A adjusted pH below 1.0 with IPA-HC1. The separated product was filtered and dried to get crude product (4.0 g). The crude product was recrystallized from mixture of methanol (40 ml) and IPA (20 ml) to get pure palonosetron hydrochloride (1.0 g).

We claim;

1. An improved process for the preparation of palonosetron hydrochloride, comprising the steps of:
a) Hydrogenating the salt of 2-(l-azabicyclo [2.2.2] oct-3-yl)-2,4,5,6-tetrahydro-lH-benz[de]isoquinolin-l-one of formula (II)
wherein x represents salt, using hydrogenation catalyst, in water to obtain palonosetron free base of formula (III),

b) optionally isolating the Palonosetron free base and

c) converting the Palonosetron free base into Palonosetron HC1 of formula (I) using a source of HC1 in the presence of acetone or isopropanol or a mixture of acetone and organic solvent.

2. The process as claimed in claim 1, wherein salt of formula (II) is selected from group consisting of hydrochloric acid, hydrobromic acid, hydrofluoric acid, HI, methanesulfonic acid, sulfuric acid, acetic acid, toluenesulfonic acid and phosphoric acid.

3. The process as claimed in claim 1, wherein the hydrogenation catalyst is selected from palladium on carbon, palladium hydroxide, palladium hydroxide on carbon platinum, nickel, and rhodium or alumina.

4. The process as claimed in claim 1, wherein HC1 source is selected from Conc.HCl, HC1 gas, HC1 gas dissolved in an organic solvent selected from methanol, ethanol or isopropranol.

5. The process as claimed in claim 1, wherein the organic solvent used in step (c) is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutyl alcohol, tertiary butyl alcohol tetrahydrofuran (THF), diethyl ether, methylethylether, diisopropylether, methyltertiarybutyl ether, ethyl acetate or mixtures thereof.

6. The process as claimed in claim 1, wherein Palonosetron free base is isolated as solid.

7. An improved process for the preparation of palonosetron hydrochloride, prepared according to the examples as described herein.