FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of pure Palonosetron of Formula I,

and its pharmaceutically acceptable salts thereof.

BACKGROUND OF THE INVENTION

Palonosetron is chemically known as (3aS)-2-[(3S)-l-azabicyclo[2.2.2]oct-3yl]-2,3,3a,4,5,6-hexahydro-lH-benz[de]isoquinolin-l-one. Palonosetron is an antiemetic drug, marketed as its hydrochloride salt under the trade name ALOXI® in the form of injectable and capsule.
US 5,510,486 discloses a process to prepare Palonosetron hydrochloride, which is as shown below:

The process is not stereo-selective and the resolution of 1,2,3,4-tetrahydro-l-naphthalenecarboxylic acid (V) requires a costly material like quinine, which is disadvantageous for large scale production.

US 5,202,333 discloses a process for preparing Palonosetron hydrochloride, which is as shown below:

Similar routes to prepare Palonosetron hydrochloride have been disclosed in Journal of Medicinal Chemistry, 1993, 36(18), 2645 and US 7,737,280 B2.

One of the major drawbacks of the above process is the fact that dichloromethane is highly unsuitable as a solvent as it leads to the formation of an impurity of Formula X duringthe preparation of the amide compound of Formula III.

Further, the present inventors also observed that during the conversion of compound II into compound III in the absence of a base in toluene/ethyl acetate reaction medium, the reaction remains incomplete, high temperature is required and overall yield is low.

The catalytic hydrogenation in the final stage has been carried out in acetic acid as the reaction medium, which is not feasible at industrial level.

The same reaction is also disclosed in a biphasic medium, where the temperature required is about 70°C for preparing compound HI and thereafter converting compound III to compound IV a very low temperature is required. This process is also unattractive as the obtained cyclic amide compound IV is of poor quality.

Therefore, there is a need to develop a process for the preparation of Palonosetron hydrochloride, which is industrially feasible and commercially applicable.

OBJECTIVE OF THE INVENTION

The main objective of the present invention is to provide an improved, cost effective and useful process for the preparation of pure Palonosetron, which is industrially applicable.
Yet another objective of the present invention is to provide an improved process for the preparation of key intermediate 7V,-(3S)-l-azabicyclo[2.2.2]oct-3-yl-5,6,7,8-tetrahydro-1-napthalenecarboxamide, which is simple and easy to implement on a large scale.

SUMMARY OF THE INVENTION

The present invention relates to an improved process for the preparation of Palonosetron of Formula I,

and its pharmaceutically acceptable salts thereof, which comprises:

a) activating 5,6,7,8-tetrahydro-l-naphthalenecarboxylic acid of Formula II,

with a halogenating agent in the presence or absence of a solvent to give 5,6,7,8-tetrahydro-l-naphthalenecarbonyl chloride derivative of Formula IX;

b) reacting 5,6,7,8-tetrahydro-l-naphthalenecarbonyl chloride of Formula IX with
(S)-3-aminoquinuclidine dihydrochloride in the presence of a base, in aqueous
medium diluted with a polar aprotic organic solvent at a temperature 25-50°C to
give N-(3S)-l-azabicyclo[2.2.2]oct-3-yl-5,6,7,8-tetrahydro-l-
napthalenecarboxamide of Formula III;

c) cyclizing the N-(3S)-l-azabicyclo[2.2.2]oct-3-yl-5,6,7,8-tetrahydro-l-
napthalenecarboxamide of Formula III using a strong base in the presence of an inert solvent to give 2-(35)-(l-azabicyclo[2,2,2]oct-3-yl)-2,4,5,6-tetrahydro-lH-benz[de]isoquinolin-l-one of Formula IV;

d) reducing the 2-(3S)-(l-azabicyclo[2,2,2]oct-3-yl)-2,4,5,6-tetrahydro-1H-benz[de]isoquinolin-l-one of Formula IV using a reducing agent consisting of 20-22% hydrogenation catalyst to give palonosetron of Formula I; and

e) isolating the compound of Formula I.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to an improved process for the preparation of Palonosetron, which comprises activating 5,6,7,8-tetrahydro-l-naphthalenecarboxylic acid with a halogenating agent selected from thionyl chloride, oxalyl chloride, cyanuric chloride, in the presence or absence of a solvent selected from toluene, dichloromethane or mixtures thereof to give 5,6,7,8-tetrahydro-l-naphthalenecarbonyl chloride which is condensed with (S)-3-Aminoquinuclidine dihydrochloride.

The free base of (S)-3-aminoquinuclidine dihydrochloride is required during amidation to form compound III. One way of generating the free base is by using potassium hydroxide in methanol followed by the separation of salt after dilution with toluene and subsequent filtration and isolation of the base from the filtrate as described in patent US 5,567,818. In this process the amine is generated using methanol solvent, where all the inorganic salts formed will not be removed completely. Therefore, this process is not suitable.
Thus, the present invention also relates to generation of (S)-3-Aminoquinuclidinefree base from its dihydrochloride, which is useful for large scale manufacture, where an inorganic base may be used to liberate the free amine in situ in an aqueous medium preferably diluted with an aprotic, water soluble and polar organic solvent.

(S)-3-Aminoquinuclidine dihydrochloride is first treated with a base selected from sodium carbonate, potassium carbonate, sodium bicarbonate sodium hydroxide, potassium hydroxide, in aqueous medium such as water, diluted with a polar aprotic organic solvent selected from tetrahydrofuran, dimethyl formamide, 1,3-dimethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinone (DMPU) or mixtures thereof to give (S)-3-Aminoquinuclidine free base, which is thereafter reacted with 5,6,7,8-tetrahydro-l-naphthalenecarbonyl chloride. The reaction of the acid chloride (IX) with amine (III) proceeds smoothly at 25-50°C, preferably at ambient temperature.

The N-(3S)-1 -azabicyclo[2.2.2]oct-3-yl-5,6,7,8-tetrahydro-1 -napthalenecarboxamide thus formed is treated with a strong base selected from n-butyllithium, s-butyllithium, lithium diisopropylamide, lithium bis(trimethylsilyl)arnide, preferably n-butyllithium in the presence of a solvent selected from tetrahydrofuran, DMPU, toluene, hexanes or mixtures thereof, followed by the addition of dimethylformamide and dilute hydrochloric acid successively. The amount of base required is about 2-2.5 mole equivalents. The product may be isolated by extraction with a suitable solvent such as toluene, ether, dichloromethane, ethyl acetate, preferably toluene.

2-[(3S)-(l-azabicyclo[2.2.2]oct-3-yl)]-2,4,5,6-tetrahydro-lH-benz[de]isoquinoline-l-one is reduced by catalytic hydrogenation, wherein the catalyst is preferably 20-22% and is selected from Palladium on carbon, Raney-Ni, Platinum oxide, Ruthenium on carbon, Rhodium on carbon in the presence of hydrogen and a solvent, which is selected from methanol, ethanol, ethyl acetate in the presence or absence of water.

The following examples illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the invention.

EXAMPLE 1

PREPARATION OF N-(3S)-1-AZABICYCLO[2.2.2]OCT-3-YL-5,6,7,8-
TETRAHYDRO-1-NAPTHALENECARBOXAMIDE

5,6,7,8-Tetrahydro-l-naphthoic acid (53 g, 0.30 moles) was suspended in toluene (400 ml) at 25-30°C, and a catalytic amount of dimethylformamide (1.9 g) and thionyl chloride (43 g, 0.36 moles) were added. A clear solution was obtained, which was warmed to 40°C for about 1 hour. The toluene was distilled off and 5,6,7,8-tetrahydro-1-naphthalenecarbonyl chloride was obtained as a viscous oil.

Sodium hydroxide (45.12 g, 1.13 moles) was dissolved in water (50 ml) and (S)-3-aminoquinuclidine dihydrochloride (50g) was added followed by tetrahydrofuran (250 ml).

To this suspension a solution of 5,6,7,8-tetrahydro-l-naphthalenecarbonyl chloride in tetrahydrofuran (250 ml) was added at 25-45°C. The reaction mixture was stirred at 25-30°C and monitored by TLC till completion of the reaction. The resultant mixture was distilled to remove tetrahydrofuran, followed by the addition of water (250 ml) and toluene (400 ml). It was then warmed and the aqueous layer was separated and extracted with toluene (4 x 50 ml). The combined organic layer was distilled off and thereafter hexane (200 ml) was added to the reaction mixture and cooled to 10-15°C. The precipitated solid was filtered, washed with hexane (100 ml) and dried to obtain the title compound.

Yield: 67 g

Chromatographic Purity: 100%

EXAMPLE 2

PREPARATION OF N-(3S)-l-AZABICYCLO[2.2.2]OCT-3-YL-5,6,7,8-
TETRAHYDRO-1-NAPTHALENECARBOXAMIDE

Sodium hydroxide (45.12 g, 1.13 moles) was dissolved in water (50 ml) and (S)-3-aminoquinuclidine dihydrochloride (50g) was added followed by THF (250 ml). To this suspension a solution of 5,6,7,8-tetrahydro-l-naphthalenecarbonyl chloride (Prepared as per examplel) in tetrahydrofuran (250 ml) was added at 35-45°C. The reaction mixture was stirred at 25-30°C and after completion of the reaction, tetrahydrofuran was distilled. Water (250 ml) was added to dilute the reaction mixture. The precipitated product was stirred at ambient temperature for 1 hour, filtered, washed with water (50 ml) and dried under reduced pressure to obtain the title compound. Yield: 67 g Chromatographic Purity: 99.57 %

EXAMPLE 3

PREPARATION OF N-(3S)-l-AZABICYCLO[2.2.2]OCT-3-YL-5,6,7,8-

TETRAHYDRO-1-NAPTHALENECARBOXAMIDE

5,6,7,8-tetrahydro-l-naphthalene carboxylic acid (10.6 g, 0.86 mole) was added to thionyl chloride (8.36 g, 0.07 mole) and dimethylformamide (0.32 g). The mixture was stirred at 40°C and after the completion of the reaction the resultant mixture was distilled to remove excess thionyl chloride. The resultant acid chloride was dissolved in tetrahydrofuran (50 ml).

Sodium hydroxide (9.03 g, 0.22 mole) was dissolved in water (10 ml) and (S)-3-aminoquinuclidine dihydrochloride (50g, 0.25 mole) was added. To this suspension a solution of 5,6,7,8-tetrahydro-l-naphthalenecarbonyl chloride in tetrahydrofuran was added at 30°C. The reaction was monitored by TLC and after completion of the reaction the reaction mixture was distilled to remove tetrahydrofuran. To the residue toluene (140 ml) and water (50 ml) was added and stirred. The aqueous layer was separated and the organic layer was distilled off and thereafter hexane (40 ml) was added to the residue. The precipitated solid was filtered, washed with hexane (20 ml) and dried to obtain the title compound. Yield: 13.4 g Chromatographic Purity: (95.86%)

EXAMPLE 4

PREPARATION OF (S)-2-(1-AZABICYCLO[2,2,2]OCT-3-YL)-2,4,5,6-
TETRAHYDRO-1H-BENZ[DE]ISOQUINOLIN-1-ONE

N-(35)-l-azabicyclo[2.2.2]oct-3-yl-5,6,7,8-tetrahydro-l-naphthalenecarboxamide (lOOg, 0.35 mole) was dissolved in tetrahydrofuran (1000 ml) and cooled to -40°C under a nitrogen atmosphere. Then n-butyllithium, 1.6M in hexane (375g, 0.88 mole) was slowly added in about lh and the reaction mixture was stirred at -35°C for 30 min. The scarlet solution was kept stirring and dimethylformamide (77g, 1.06 mole) was added during a period of lh. The resultant pale yellow reaction mixture was stirred for 30 min and the temperature was allowed to rise to 0°C. Dilute hydrochloric acid (6JV) was added to it at 0-10°C and stirring was continued till product formation was completed. The aqueous layer was separated from the organic layer and the latter was washed with water. Toluene was added to the aqueous layer and the mixture was basified to pH 10. The toluene layer was separated and the aqueous layer was reextracted with toluene (300 ml).The combined organic layer was distilled under reduced pressure and 2-propanol (400ml) was added to the residue followed by cone, hydrochloric acid (42.2 g). The reaction mixture was stirred for 30 min, concentrated and another 400 ml of 2-propanol was added. The contents were cooled to 5°C and stirred for lh. The precipitated solid was filtered, washed with 2-propanol and dried under reduced pressure to give the title product.

Yield: 134 g

Chromatographic purity (by HPLC): 99.79%

EXAMPLE 5

PREPARATION OF PALONOSETRON

2-[(3S)-(l-azabicyclo[2.2.2]oct-3-yl)]-2,4,5,6-tetrahydro-lH-benz[de]isoquinoline-l-one (50g, 0.15mole), Palladium on carbon (llg, 22% w/w) was suspended in ethanol (600 ml) and water (50 ml) in a pressure reactor. Then hydrogen was applied at a pressure of 9 Kg/cm2 and the reaction mixture was heated to 75°C. The contents were stirred till the completion of the reaction and thereafter it was cooled to 8°C. A solution of sulphur dioxide in ethanol is (2 ml) was added and stirred for 1 hr. The catalyst was filtered off and the filtrate was concentrated under reduced pressure at 45°C. Ethanol (100 ml) was added and distilled completely. The residue is stirred in ethanol (150 ml), cooled to 5°C and filtered to produce crude Palonosetron hydrochloride.

The crude material is dissolved in 2-propanol (542 ml) and water (19 ml) at 80°C, concentrated to a volume of 384 ml and cooled slowly to 5°C. The crude solid was filtered and recrystallized from 2-propanol/water to furnish Palonosetron hydrochloride

Yield: 16.2g

Chromatographic purity (by HPLC): 99.91%

PREPARATION OF [N-(3S)-l-AZABICYCLO[2.2.2]OCT-3-YL-5,6,7,8-
TETRAIIYDRO-l-NAPHTHALENECARBOXAMIDO]CHLOROMETHYL AMMONIUM CHLORIDE IMPURITY (FORMULA X)

(S)-3-aminoquinuclidine dihydrochloride (11.34g 0.57 moles) was added to a solution of potassium hydroxide (9.38g, 0.14 moles) in methanol (50ml) and stirred at 25-30°C for lh. The reaction mass was cooled to room temperature and toluene (110ml) was added. The precipitate formed was filtered off and the filtrate distilled completely. Then dichloromethane (100ml) and triethylamine (14ml) were added. The solution of the acid chloride was added at 5°C and the reaction mixture was refluxed for 12 h. after completion of the reaction the reaction mass was cooled to room temperature and the precipitated solid was filtered off, washed with dichloromethane and dried to give title compound.

Yield: 13g

1H NMR (dmso-d6)5: 1.71 (m, 4H), 1.88 (m,1H), 2.04 (m, 2H), 2.25 (m, 2H), 2.75 (m, 4H), 3.53 (m, 5H), 4.02 (m, 1H), 4.37 (m, 1H), 5.45 (s, 2H), 7.15 (m, 3H), 8.84 (d, 1H) l3C NMR (dmso-d6)5: 18.1 (CH2), 22.0 (CH2), 22.3 (CH2), 22.6 (CH2), 24.5 (CH), 26.2 (CH2), 29.2 (CH2), 44.8 (CH), 52.7 (CH), 52.8 (CH), 58.0 (CH2), 67.7 (CH2), 124.6 (CH), 125.1 (CH), 130.3 (CH), 133.9 (C), 136.7 (C), 137.3 (C), 169.8 (C) Mass (ESI):333[M]+

WE CLAIM

1. An improved process for the preparation of Palonosetron of Formula I,
and its pharmaceutically acceptable salts thereof, which comprises:

a) activating 5,6,7,8-tetrahydro-l -naphthalenecarboxylic acid of Formula II,

with a halogenating agent in the presence or absence of a solvent to give 5,6,7,8-tetrahydro-l-naphthalenecarbonyl chloride derivative of Formula IX;

b) reacting 5,6,7,8-tetrahydro-l-naphthalenecarbonyl chloride of Formula IX with
(S)-3-aminoquinuclidine dihydrochloride in the presence of a base, in aqueous
medium diluted with a polar aprotic organic solvent at a temperature 25-50°C to
give N-(35)-l-azabicyclo[2.2.2]oct-3-yl-5,6,7,8-tetrahydro-l-
napthalenecarboxamide of Formula III;

c) cyclizing the N-(35)-l-azabicyclo[2.2.2]oct-3-yl-5,6,7,8-tetrahydro-l-
napthalenecarboxamide of Formula III using a strong base in the presence of an
inert solvent to give 2-(35)-(l-azabicyclo[2,2,2]oct-3-yl)-2,4,5,6-tetrahydro-lH-
benz[de]isoquinolin-l-one of Formula IV;

d) reducing the 2-(3S)-(l-azabicyclo[2,2,2]oct-3-yl)-2,4,5,64etrahydro-lH-benz[de]isoquinolin-l-one of Formula IV using a reducing agent consisting of 20-22% hydrogenation catalyst to give palonosetron of Formula I; and

e) isolating the compound of Formula I.

2. The process as claimed in claim 1, wherein halogenating agent in step (a) is selected from thionyl chloride, oxalyl chloride, cyanuric chloride in the presence or absence of a solvent selected from toluene, dichloromethane or mixtures thereof.

3. The process as claimed in claim 1, wherein base in step (b) is selected from sodium carbonate, potassium carbonate, sodium bicarbonate sodium hydroxide, potassium hydroxide, in aqueous medium such as water, diluted with a polar aprotic organic solvent selected from tetrahydrofuran, dimethyl formamide, l,3-dimethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinone (DMPU) or mixtures thereof.

4. The process as claimed in claim 1, wherein strong base in step (c) is selected from n-butyllithium, s-butyllithium, lithium diisopropylamide, lithiumbis(trimethylsilyl) amide, preferably n-butyllithium in the presence of a inert solvent selected from tetrahydrofuran, DMPU, toluene, hexanes or mixtures thereof, followed by the addition of dimethylformarnide and dilute hydrochloric acid successively.

5. The process as claimed in claim 1, wherein the amount of base required is about 2-2.5 mole equivalents.

6. The process as claimed in claim 1, wherein reduction in step (d) is carried out using the catalyst preferably 20-22% and is selected from Palladium on carbon, Raney-Ni, Platinum oxide, Ruthenium on carbon, Rhodium on carbon in the presence of hydrogen and a solvent, which is selected from methanol, ethanol, ethyl acetate in the presence or absence of water.