CLIAMS:We Claim:

1. A process for the preparation of N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5,6,7,8-tetrahydronaphthalene-1-carboxamide (Pal-amide) of formula II:

Formula II
which comprises:
a) conversion of 5,6,7,8-tetrahydro-1-naphthalenecarboxylic acid using thionyl chloride and dimethylformamide in presence of hydrocarbon solvent to provide 5,6,7,8-tetrahydronaphthalene-1-carbonyl chloride; and

b) reaction of the compound of step (a) with (S)-3-amino-1-azabicyclo[2.2.2.]octane or its hydrochloride salt in the presence of hydrocarbon to provide N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5,6,7,8-tetrahydronaphthalene-1-carboxamide of formula II.

2. The process of claim 1, wherein said hydrocarbon is toluene.

3. The process of claim 1, wherein said reaction of (a) and (b) is performed at a temperature of 50 to 55 °C.

4. The process of claim 1, wherein said hydrochloride salt of (S)-3-amino-1-azabicyclo[2.2.2.]octane is dihydrochloride salt.

5. The process of claim 1, wherein said thionyl chloride is selected from the range of 0.9 to 1.1 molar equivalents per molar equivalent of 5,6,7,8-tetrahydro-1-naphthalenecarboxylic acid.

6. The process of claim 1, wherein said N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5,6,7,8-tetrahydronaphthalene-1-carboxamide of formula II is further converted to palonosetron or its hydrochloride salt.
,TagSPECI:DESCRIPTION

The present invention relates to a process for the preparation of intermediate of Palonosetron, N-(1-azabicyclo[2,2,2]oct-3S-yl)-1,2,3,4-tetrahydro-1-naphthalene-1S-ylcarboxamide (pal-amide) and its conversion to palonosetron or its hydrochloride salt.

Palonosetron hydrochloride is chemically known as (3aS)-2-[(S)-1-azabicyclo [2.2.2]oct-3-yl]-2,3,3a,4,5,6-hexahydro-1-oxo-1Hbenz[de]isoquinoline hydrochloride of Formula I

Palonosetron hydrochloride is marketed under the trade name Aloxi® for the treatment nausea and vomiting often accompanying cancer chemotherapy.

U.S. Patent No. 5,202,333 discloses palonosetron and its hydrochloride salt. The US ‘333 patent also discloses a process for the preparation of palonosetron which involves the cyclization of N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5,6,7,8-tetrahydronaphthalene-1-carboxamide (pal-amide) by using n-butyl lithium and dimethylformamide to obtain 2-[(3S)-1-azabicyclo-[2.2.2]oct-3-yl]-2,4,5,6-tetrahydro-1H-benzo[de]isoquinolin-1-one, which is then hydrogenated to obtain palonosetron, which is converted into its hydrochloride salt. However, the process requires number of steps, longer reaction time, and expensive and toxic hydrogenating reagents, which leads to the formation of impurities and lower yield of Palonosetron or its hydrochloride salt.

Chinese application No. 102329314 A1 discloses another process for preparation of palonosetron hydrochloride involves reaction of [1-azabicyclo(2.2.2)octane-3(S)-yl]-(1,2,3,4-tetrahydronaphthalene-1(S)-methyl) amine obtained from Pal-amide with triphosgene via cyclization in the presence of trifluoroboron etherate in toluene at 10-30° for 12-20 hours to give the free Palonosetron base, further salification with hydrochloride to provide the product Palonosetron hydrochloride. However, the process requires longer hours to complete the reaction, which leads to the formation of impurities and lower yield of palonosetron or its hydrochloride salt.

U.S. Patent No. 5,202,333 further discloses a process for the key intermediate of palonosetron, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5,6,7,8-tetrahydronaphthalene-1-carboxamide (pal-amide), which involves conversion of 5,6,7,8-tetrahydro-1-naphthalenecarboxylic acid to 5,6,7,8-tetra-hydronaphthalene-1-carbonyl chloride by using oxalyl chloride and dimethylformamide in the presence of dichloromethane, and then 5,6,7,8-tetra-hydronaphthalene-1-carbonyl chloride is reacted with (S)-3-amino-1-azabicyclo-[2.2.2.]octane in the presence of dichloromethane to obtain N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5,6,7,8-tetrahydronaphthalene-1-carboxamide.

Robin D. Clark et al., in Journal of Medicinal Chemistry (1993) 36: 2645-2657 discloses process for the preparation of key intermediate of palonosetron, pal-amide, which involves the reaction of 5,6,7, 8-tetrahydro-1-naphthalenecarboxylic acid with thionyl chloride in the presence of dimethylformamide and toluene to provide 5,6,7,8-tetrahydronaphthalene-1-carbonyl chloride, which is reacted with (S)-3-amino-1-azabicyclo[2.2.2.]octane in the presence of toluene and ethyl acetate to obtain N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5, 6,7,8-tetrahydronaphthalene-1-carboxamide (Pal-amide).

PCT application No. 2011/013095 A1 also discloses a process for key intermediate of palonosetron, pal-amide, which involves the reaction of 5,6,7, 8-tetrahydro-1-naphthalenecarboxylic acid with thionyl chloride in the presence of dimethylformamide and methylene chloride to provide 5,6,7,8-tetrahydronaphthalene-1-carbonyl chloride, which is reacted with (S)-3-amino-1-azabicyclo[2.2.2.]octane dihydrochloride in the presence of triethylamine and methylene chloride to obtain N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5, 6,7,8-tetrahydronaphthalene-1-carboxamide (pal-amide).

The present inventors found that the preparation of pure pal-amide intermediate from the processes of prior art is very difficult and provides lower yield. Further, the present inventors found that the prior art processes involve use of multiple and expensive solvents and requires longer hours, which are unsuitable and provides impure compound.

Therefore, there is a need to develop an improved process for the preparation of pure intermediate of palonosetron, pal-amide, and its conversion to palonosetron or its hydrochloride salt, which involves simple reaction conditions, shorter reaction time, cost-effective and industrially feasible.

The present inventors developed an improved process to provide intermediate of palonosetron, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5,6,7,8-tetrahydronaphthalene-1-carboxamide (pal-amide), which involves shorter reaction time and single solvent to provide better yield and purity. Further, the present inventors also developed a simple process for the conversion of pure pal-amide to palonosetron or its hydrochloride salt.

In an aspect of the present invention relates to a process for the preparation of N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5,6,7,8-tetrahydronaphthalene-1-carboxamide (pal-amide) of formula II:

Formula II
which includes step of:
a) conversion of 5,6,7,8-tetrahydro-1-naphthalenecarboxylic acid using thionyl chloride and dimethylformamide in presence of hydrocarbon solvent to provide 5,6,7,8-tetrahydronaphthalene-1-carbonyl chloride; and

b) reaction of the compound of step (a) with (S)-3-amino-1-azabicyclo[2.2.2.]octane or its hydrochloride salt in the presence of hydrocarbon to provide N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5,6,7,8-tetrahydronaphthalene-1-carboxamide of formula II.

The step a) involves preparation of acyl chloride, 5,6,7,8-tetrahydronaphthalene-1-carbonyl chloride, from 5,6,7,8-tetrahydro-1-naphthalenecarboxylic acid.

The reaction may be performed at a temperature of about 20 to about 60 °C for a period of 20 minutes to 2 hours. In embodiment, the reaction of step a) is carried out at a temperature of about 50 to about 55 °C.

The reaction utilizes catalytic amount of dimethylformamide to activate the reaction in presence of hydrocarbon. The hydrocarbon solvent includes but not limited to toluene, n-hexane, n-heptane, cyclohexane and the like.

The process of step a) involves lot wise addition of hydrocarbon solvent to the reaction mixture to affect the reaction in a positive side and to regulate the exothermicity.

The amount of thionyl chloride for performing the reaction of step a) may range from 0.9 to 1.5 molar equivalents or 0.9 to 1.1 molar equivalents per molar equivalent of 5,6,7,8-tetrahydro-1-naphthalenecarboxylic acid.

After completion of the reaction, the reaction mixture may be distilled to remove traces of thionyl chloride and dimethylformamide and to provide hydrocarbon solution which contains acyl chloride.

The step b) involves reaction of the compound of step (a) with (S)-3-amino-1-azabicyclo[2.2.2.]octane or its hydrochloride salt in the presence of hydrocarbon solvent such as toluene to provide N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5,6,7,8-tetrahydronaphthalene-1-carboxamide of formula II.

(S)-3-amino-1-azabicyclo[2.2.2.]octane or its hydrochloride salt reacts with acyl chloride obtained from the step (a) of the present invention. The hydrochloride salt of (S)-3-amino-1-azabicyclo[2.2.2.]octane is dihydrochloride salt.

In case of dihydrochloride salt of (S)-3-amino-1-azabicyclo[2.2.2.]octane, the compound is treated with inorganic base or its water solution in presence of hydrocarbon solvent at a temperature of about 25 to about 60 °C or at 50-55 °C for a period of about 15 minutes to about 2 hours or 45 minutes to 1 hour. The inorganic base is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate and the like. The hydrocarbon solvent is toluene.

The reaction mixture so obtained or (S)-3-amino-1-azabicyclo[2.2.2.]octane in hydrocarbon solvent is reacted with acyl chloride, 5,6,7,8-tetrahydronaphthalene-1-carbonyl chloride, at a temperature of about 25 to about 60 °C or 50 to 55 °C for a period of 20 minutes to 1 hour.

After completion of the reaction, the reaction mixture is diluted with water and cooled to below 20 °C or to below 5 °C for a period of 1 to 2 hours to afford crystalline solid of pure pal-amide.

The use of single solvent such as hydrocarbon solvent for the preparation of pal-amide from 5,6,7,8-tetrahydro-1-naphthalenecarboxylic acid of the present invention provides shorter reaction time, better yield and purity for intermediate. The pure intermediate may be utilized for the preparation of palonosetron or its hydrochloride salt without requiring any purification process in any stage.

The purity of pal-amide of formula II obtained from the present invention is greater than 95 % by HPLC (98 – 99%)

In another aspect of the present invention is to provide a process for the preparation of palonosetron or its hydrochloride salt, which comprises:

a) conversion of 5,6,7, 8-tetrahydro-1-naphthalenecarboxylic acid using thionyl chloride and dimethylformamide in presence of toluene to provide 5,6,7,8-tetrahydronaphthalene-1-carbonyl chloride;

b) reaction of 5,6,7,8-tetrahydronaphthalene-1-carbonyl chloride with (S)-3-amino-1-azabicyclo[2.2.2.]octane or its hydrochloride salt in the presence of toluene to provide N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5,6,7,8-tetrahydronaphthalene-1-carboxamide (pal-amide);

c) reaction of pal-amide with sodium borohydride in presence of boron trifluoride etherate and tetrahydrofuran to provide 1-Azabicyclo[2,2,2]oct-3S-yl)-1,2,3,4-tetrahydro-1-naphthalene-1S-yl methyl)amine (Pal-Amine);

d) reaction of pal-amine with triphosgene via cyclization in the presence of trifluoroboron etherate in toluene at above 25°C to provide palonosetron; and

e) treatment of palonosetron with hydrochloric acid in presence of isopropyl alcohol to provide Palonosetron hydrochloride.

The step a) involves preparation of acyl chloride, 5,6,7,8-tetrahydronaphthalene-1-carbonyl chloride, from 5,6,7,8-tetrahydro-1-naphthalenecarboxylic acid in presence of catalytic amount of dimethylformamide in presence of toluene at a temperature of 50 to 55 °C for a period of 1 hour.

The amount of thionyl chloride for performing the reaction of step a) may range from 0.9 to 1.5 molar equivalents or 0.9 to 1.1 molar equivalents per molar equivalent of 5,6,7,8-tetrahydro-1-naphthalenecarboxylic acid.

After completion of the reaction, the reaction mixture may be distilled to remove traces of thionyl chloride and dimethylformamide or may be utilized directly for further reaction.

The step b) involves reaction of the compound of step (a) with (S)-3-amino-1-azabicyclo[2.2.2.]octane or its hydrochloride salt in the presence of toluene at a temperature of 50 to 55 °C for a period of 1 hour to provide N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5,6,7,8-tetrahydronaphthalene-1-carboxamide of formula II.

After completion of the reaction, the reaction mixture is diluted with water and cooled to below 20 °C or to below 5°C for a period of 1 to 2 hours to afford crystalline solid of pure pal-amide.

The step c) involves reaction of pure pal-amide with sodium borohydride in presence of boron trifluoride etherate and tetrahydrofuran at a temperature of 25 to about reflux for a period of 1 to 2 hours to provide 1-Azabicyclo[2,2,2]oct-3S-yl)-1,2,3,4-tetrahydro-1-naphthalene-1S-yl methyl)amine (pal-Amine).

After completion of the reaction, the reaction mixture is quenched with quenching agent such as water or acid, for example, hydrochloric acid. The obtained reaction mixture may be concentrated till to get certain amount, for example, 45-55 %, and then subjected for basic treatment with inorganic base such as potassium hydroxide followed by extraction with organic solvent, for example, ethyl acetate. The resultant organic layer containing Pal-amine may be directly utilized for further reaction or subjected for solid separation by using known techniques, for example, recrystallization.

d) reaction of pal-amine with triphosgene via cyclization in the presence of borontrifluoride etherate in toluene at above 25°C to provide palonosetron.

The reaction conditions such as addition of reagents, temperature, solvent and stirring time of the present invention for formation of palonosetron provides higher yield and purity.

The reaction involves addition of triphosgene to the reaction mixture of Pal-amine in toluene and then heating to reflux to stir for a period of 2 to 4 hours. Then, Boron trifluoride etherate is added to the reaction mixture at room temperature and then subjected for heating to reflux to stir for a period of 4 to 5 hours. After that, hydrochloric acid is added to the reaction mixture at 25 to 35 °C to provide cyclized product, palonosetron or its hydrochloride salt.

After completion of the reaction, the reaction mixture is treated with aqueous solution base, for example, aqueous solution of sodium hydroxide, to provide layer separation and then subjected so obtained organic layer for concentration to provide palonosetron free base as an oil.

e) treatment of Palonosetron with hydrochloric acid or source of hydrochloric acid, such methanolic HCl or isopropanolic HCl in presence of isopropyl alcohol at room temperature to provide Palonosetron hydrochloride.

The solid of palonosetron hydrochloride obtained from the present invention may be purified from the solvent mixture isopropyl alcohol and water by using suitable technique such as recrystallization, concentration to certain amount and make slurry, anti-solvent technique and the like.

In embodiment, the present invention provides purification process for palonosetron hydrochloride comprises dissolution of crude palonosetron hydrochloride in a solvent mixture, isopropyl alcohol and water, at a reflux temperature. The resultant solution is distilled to a certain amount to affect the crystallization of solid and stirred for a period of 1 to 2 hours at below 5 °C to provide pure solid of palonosetron hydrochlroride.

The obtained solid is recovered from the suspension by using known techniques, for example, filtration under vacuum and then dried to afford pure palonosetron.

The purity of palonosetron hydrochloride of the present invention is greater than 99.5% and any single impurity is less than 0.1 by HPLC (0.03-0.05%).

In another aspect, the present invention is to provide a process for the preparation of Palonosetron comprising reacting 1-azabicyclo[2,2,2]oct-3S-yl)-1,2,3,4-tetrahydro-1-naphthalene-1S-ylmethyl)amine (Pal-Amine) of formula III

Formula III

with triphosgene via cyclization in the presence of trifluoroboronetherate in toluene at above 25°C to provide palonosetron.

The reaction involves addition of triphosgene to the reaction mixture of Pal-amine in toluene and then stirred for a period of 2 to 4 hours at reflux. Further, involves addition of boron trifluorideetherate to the reaction mixture at room temperature and then heating to reflux for a period of 4 to 5 hours. After that, hydrochloric acid is added to the reaction mixture at 25 to 35 °C to provide cyclized product, palonosetron or its hydrochloride salt.

The amount of triphosgene may range from 0.5 to 1 molar equivalent per molar equivalent of pal-amine. The triphosgene is cost effective reagent and easier to handle and it does not require any base to provide phosgenated product of Pal-amine. Further, the use of triphosgene provides good yield of phosgenated product when compared to diphosgene.

After completion of the reaction, the reaction mixture is treated with aqueous solution of base, for example, sodium hydroxide, to provide layer separation and then subjected so obtained organic layer for concentration to provide palonosetron free base as oil.

The present invention is further illustrated by the following example, which does not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present application.

EXAMPLES

Example -1: Process for PAL-AMIDE

Step 1: (S)-1,2,3,4-tetrahydro-1-naphthoyl chloride.

To a mixture of 1,2,3,4-tetrahydro-1-naphthoic acid (1.0 Kg) in toluene (4.0 L) and N, N-dimethyl formamide (0.008 L) added thionyl chloride (0.45 L) diluted in toluene (1.0 L) slowly up to 1.0 hour under nitrogen atmosphere. Reaction mixture was stirred for 1 hour at 50 °C followed by distilled up to a volume of approximately 2.50 L and then cooled to room temperature.

Step 2: N- (1-Azabicyclo [2.2.2] oct-3S-yl)-1,2,3,4-tetrahydronaphthalen-1S-yl Carboxamide (PAL-AMIDE).

To a mixture of sodium hydroxide solution [(0.7 Kg) in water (0.7 L)] and toluene (3.0 L) added (S)-1-azabicyclo [2,2,2] oct-3-yl-amine dihydrochloride(1.0 Kg) under stirring. The reaction mixture was heated to 55 °C and stirred for 1.0 hour. Toluene solution of (S)-1,2,3,4-tetrahydro-1-naphthoyl chloride was added slowly (up to 1.0 hr.) under stirring at 55 °C and maintained for 1.0 hour. Water (4.0 L) was added to the mixture and then allowed to cool to 0-5 °C under stirring. The resultant mixture was stirred for 2 hours at 0-5 °C to give a crystalline product. The product was isolated by filtration to give N-(1-azabicyclo[2.2.2]oct-3S-yl)-1,2,3,4-tetrahydronaphthalen-1S-ylcarboxamide (1.10 Kg), m.p. 190°-191 °C.

Example-2: Process for Palonosetron from Pal-amide:

A mixture of N-(1-azabicyclo-[2.2.2.]oct-3S-yl)-1,2,3,4-tetrahydronaphthalen-1S-ylcarboxamide (1.0 Kg) prepared from example 1 and sodium borohydride (1.0 Kg) in 20 L of tetrahydrofuran was cooled to below 15 °C. Borontrifluoride etherate (8.1M, 1.55 Kg) was added over 20 minutes and the mixture was stirred for 30 minutes at room temperature and then at reflux for 2 hours. The mixture was cooled to below 20 °C. and 25.0 L of 2N hydrochloric acid was added slowly. The mixture was distilled to a volume of approximately 25.0 L. The remaining mixture was cooled and 50% potassium hydroxide (7.3 Kg KOH & 7.3 Kg water) was added. The mixture was extracted with ethyl acetate. The combined ethyl acetate layers were dried over Na2SO4, filtered and concentrated to give (1-azabicyclo[2.2.2]oct-3S-yl)-(1,2,3,4-tetrahydronaphthalen-1S-ylmethyl)amine (0.90 Kg).

To a stirred and cooled solution of (1-azabicyclo[2.2.2]oct-3S-yl)(1,2,3,4-tetrahydronaphthalen-1S-yl methyl) amine (1.0 Kg) in toluene (15.0 L ml) added solution of triphosgene (0.375 Kg ~1.26 mole) in toluene (2.0 L). The reaction mixture was stirred at reflux for 3.0 hrs, cooled to 25 °C and then boron trifluorideetherate (1.5 L) was added, stirred for 10 minute at ambient temperature and then maintained at reflux for 5 hours, cooled to 30 °C, and then 2N. HCl (7.5 L) was added. The reaction mixture was stirred at reflux for 2 to3 hours and cooled to 15 °C. The solution of 50% sodium hydroxide was added slowly to attain pH 14, stirred for 15 minutes and then aqueous layer was separated and extracted from toluene. The organic layers so obtained were combined and concentrated under reduced pressure to give palonosetron free base as oil (1.0 Kg).

Example-3: Process for Palonosetron Hydrochloride

The resulting residue (1.0 Kg) of example 2 was dissolved in isopropanol (10 L). Isopropanolic HCl (18-20%) was added drop wise to the solution to attain pH 4. The mixture was stirred at 0 to 5°C for two hours and then filtered to isolate crude palonosetron hydrochloride (1.0 Kg).

The crude solid was dissolved in IPA (15 L) and water (0.80 L) at reflux temperature, to clear solution IPA (4.0 L) was added and distilled to a volume of 5.0 L. The mixture was stirred at 0-5 °C, filtered and dried at 60 °C for 6 hours to form palonosetron hydrochloride (0.9 Kg). m.p. 303 °C. (dec).