WO2011013095A1 - Processes for the preparation of palonosetron - Google Patents

Processes for the preparation of palonosetron Download PDF

Info

Publication number
WO2011013095A1
WO2011013095A1 PCT/IB2010/053462 IB2010053462W WO2011013095A1 WO 2011013095 A1 WO2011013095 A1 WO 2011013095A1 IB 2010053462 W IB2010053462 W IB 2010053462W WO 2011013095 A1 WO2011013095 A1 WO 2011013095A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
azabicyclo
oct
tetrahydronaphthalene
carboxamide
Prior art date
Application number
PCT/IB2010/053462
Other languages
French (fr)
Inventor
Gyanendra Pandey
Surender Kumar Dhingra
Kaptan Singh
Mohan Prasad
Original Assignee
Ranbaxy Laboratories Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ranbaxy Laboratories Limited filed Critical Ranbaxy Laboratories Limited
Publication of WO2011013095A1 publication Critical patent/WO2011013095A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems

Definitions

  • the present invention relates to processes for the preparation of N- [(3S)-I - azabicyclo[2.2.2]oct-3-yl]-5,6,7,8-tetrahydronaphthalene-l-carboxamide of Formula I.
  • the present invention further relates to processes for the preparation of palonosetron or its salts thereof using N-[(35 r )-l-azabicyclo[2.2.2]oct-3-yl]-5,6,7,8- tetrahydronaphthalene-1-carboxamide of Formula I as an intermediate.
  • Palonosetron is chemically (3aS)-2-[(S)-l-azabicyclo[2.2.2]oct-3-yl]-2,3,3a,4,5,6- hexahydro-l-oxo-lHbenz[ ⁇ ie]isoquinoline of Formula II having the structure as depicted below:
  • Palonosetron is marketed in the form of its hydrochloride salt. It is a 5- ⁇ T3 receptor antagonist and is used for the treatment of nausea and vomiting often
  • N-[(35 r )-l-Azabicyclo[2.2.2]oct-3-yl]-5,6,7,8-tetrahydronaphthalene-l- carboxamide of Formula I is an important intermediate involved in above process.
  • U.S. Patent No. 5,202,333 and /. Med. Chem. (1993) 36:2645-2657 provide processes to prepare this intermediate from 5,6,7, 8-tetrahydro-l-naphthalenecarboxylic acid of Formula IV and (S)-3-amino-l-azabicyclo[2.2.2.]octane of Formula V.
  • the process provided in /. Med. Chem. (1993) 36:2645-2657 also involves the conversion of 5,6,7, 8-tetrahydro-l-naphthalenecarboxylic acid of Formula IV into 5,6,7,8- tetrahydronaphthalene-1-carbonyl chloride of Formula VI by using thionyl chloride and dimethylformamide in the presence of toluene, and the compound of Formula VI is reacted with (S)-3-amino-l-azabicyclo[2.2.2.]octane of Formula V in the presence of toluene and ethyl acetate to obtain N-[(35 r )-l-azabicyclo[2.2.2]oct-3-yl]-5, 6,7,8- tetrahydronaphthalene- 1 -carboxamide of Formula I.
  • the present inventors have observed that the preparation of iV-fQ ⁇ -l-azabicyclo- [2.2.2]oct-3-yl]-5,6,7,8-tetrahydronaphthalene-l-carboxamide of Formula I from 5,6,7,8- tetrahydro-1-naphthalenecarboxylic acid of Formula IV and (S)-3-amino-l- azabicyclo[2.2.2.]octane of Formula V by following the methods provided in the prior arts mentioned above has a disadvantage in terms of the reaction taking up to 40 hours to go to completion. This makes these processes economically unsuitable for commercial production. The processes also require the formation of the acyl chloride of Formula VI and its subsequent isolation.
  • the present inventors have developed advantageous processes for the preparation of N-[(35 r )-l-azabicyclo[2.2.2]oct-3-yl]-5,6,7,8-tetrahydronaphthalene-l-carboxamide of Formula I.
  • the present invention eliminates the need of the preparation of acyl chloride of Formula VI, and provides a way to directly react (S)-3-amino-l-azabicyclo[2.2.2.]octane with 5,6,7, 8-tetrahydro-l-naphthalene-carboxylic acid in the presence of a condensing agent.
  • a first aspect of the present invention provides a process for the preparation of N- [(35 r )-l-azabicyclo[2.2.2]oct-3-yl]-5,6,7,8-tetrahydronaphthalene-l-carboxamide of Formula I,
  • a second aspect of the present invention provides a process for the preparation of palonosetron of Formula II or its salts thereof,
  • 5,6,7,8-Tetrahydro-l-naphthalenecarboxylic acid of Formula IV may be prepared according to the method provided in /. Org. Chem. (1986) 51:5452. 5,6,7, 8-Tetrahydro-l- naphthalenecarboxylic acid is reacted with (S)-3-amino-l-azabicyclo[2.2.2.]octane of Formula V. (S)-3-amino-l-azabicyclo[2.2.2.]octane can be used in the form of free base or in the form of its salt. The reaction is carried out in the presence of a condensing agent and an organic solvent.
  • the condensing agent may be selected from a group consisting of dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIPC), l-ethyl-3-(3- dimethylaminopropyl)carbodiimide, 2-( 1 -hydrobenzotriazol- 1 -yl)- 1 ,1,3,3- tetramethyluronium hexafluorophosphate ( ⁇ BTU), 2-(l -hydrobenzotriazol- l-yl)-l, 1,3,3- tetramethyluronium tetrafluoroborate (TBTU), diphenylphosphorylazide (DPPA), and diphenyiphosphorocyanidate (DEPC).
  • the condensing agent is, for example,
  • the organic solvent may be selected from a group consisting of aliphatic hydrocarbons, halogenated hydrocarbons, aromatic hydrocarbons, alkanols, ethers, esters and ketones.
  • the organic solvent may be, for example, methylene chloride, toluene or ethyl acetate or a mixture thereof.
  • a catalytic quantity of a base may optionally be used in the reaction.
  • the base may be, for example, 4-dimethylaminopyridine, l,8-diazabicyclo[5.4.O]undec-7-en, triethylamine, diisopropylethylamine, N-methylpyrrolidine, N-methylmorpholine, pyridine or methyl pyridine.
  • the reaction may be carried out at a temperature of about 0 0 C to about 60 0 C, for example, at about 15°C to about 35°C.
  • the reaction is optionally facilitated by stirring the reaction mixture for about 1 hour to about 30 hours.
  • JV-[QS)-I- azabicyclo[2.2.2]oct-3-yl]-5,6,7,8-tetrahydronaphthalene-l-carboxamide of Formula I is isolated from the reaction mixture by conventional methods, for example, by
  • the above treatment may be carried out by dissolving iV-[(3S)-l- Azabicyclo[2.2.2]oct-3-yl]-5,6,7,8-tetrahydro-naphthalene-l-carboxamide in an organic solvent selected from a group consisting of cyclic ethers, aromatic ethers and
  • the organic solvent may be, for example, tetrahydrofuran, hexanes or a mixture thereof.
  • the dissolution may be affected by stirring and/or heating the reaction mixture.
  • the solution obtained may be further treated with a formylating agent in the presence of a strong base.
  • the formylating agent may be, for example, dimethylformamide.
  • the strong base may be an alkyllithium, for example, n-butyllithium, methyllithium, tert-butyllithium, sec- butyllithium, chloromethyllithium or bromomethyllithium.
  • the reaction may be carried out at a temperature of about 0 0 C or below, for example, at a temperature from about -5°C to about -75°C.
  • the 2-[(3S)-l-azabicyclo[2.2.2]oct-3-yl]-2,4,5,6-tetrahydro-lH- benzo[ ⁇ ie]isoquinolin-l-one of Formula VII is isolated from the reaction mixture.
  • the compound of Formula VII may be isolated, for example, in the form of its acid addition salt by treating with an organic or inorganic acid.
  • the compound of Formula VII or its acid addition salt is treated with a reducing agent.
  • the reducing agent may be palladium on carbon, platinum (IV) oxide, nickel, rhodium on alumina, palladium hydroxide, palladium on barium sulfate, palladium on alumina or palladium on strontium carbonate.
  • the reducing agent is, for example, palladium on carbon.
  • the reduction may be carried out under standard hydrogenation conditions in a polar organic solvent.
  • the polar organic solvent may be, for example, ethanol, water, methanol, dimethylformamide, acetic acid or a mixture thereof.
  • Palonosetron so obtained is isolated from the reaction mixture as a free base or in the form of its acid addition salt by treatment with an organic or inorganic acid, for example, hydrochloric acid.
  • the isolation may be carried out by conventional methods, for example, concentration, precipitation, decantation, filtration, distillation or a combination thereof.
  • a third aspect of the present invention provides a process for the preparation of N- [(35 r )-l-azabicyclo[2.2.2]oct-3-yl]-5,6,7,8-tetrahydronaphthalene-l-carboxamide of Formula I,
  • step a) combining the reaction mixture obtained in step a) with 5,6,7, 8-tetrahydro- naphthalene-1-carbonyl chloride of Formula VI,
  • a fourth aspect of the present invention provides a process for the preparation of palonosetron of Formula II or its salts thereof,
  • the acid addition salt of (S)-3-amino-l-azabicyclo[2.2.2.]-octane of Formula V may be, for example, (S)-3-amino-l-azabicyclo[2.2.2.]octane dihydrochloride.
  • the acid addition salt of (S)-3-amino-l-azabicyclo[2.2.2.]octane of Formula V is treated with an amine at a temperature of about 40 0 C or below, for example, at about -10° to about 25°C.
  • the amine may be a primary, secondary or tertiary amine or ammonia.
  • the amine may be, for example, triethylamine, or diisopropylamine.
  • An organic solvent may be optionally used while treating the acid addition salt of (S)-3-amino-l-azabicyclo[2.2.2.]octane of Formula V with the amine.
  • the reaction mixture so obtained is combined with 5,6,7,8- tetrahydro-naphthalene-1-carbonyl chloride of Formula VI.
  • the combined mixture is subjected to suitable reaction conditions in the presence of an organic solvent to obtain N- [(3S)-l-azabicyclo[2.2.2]oct-3-yl]-5,6,7,8-tetrahydronaphthalene-l-carboxamide of Formula I.
  • the organic solvent may be selected from a group consisting of aliphatic hydrocarbons, halogenated hydrocarbons, aromatic hydrocarbons, alkanols, ethers, esters and ketones.
  • the organic solvent may be, for example, methylene chloride, toluene or ethyl acetate, or a mixture thereof.
  • the reaction may require a temperature condition of about 0 0 C to about 60 0 C, for example, about 15°C to about 35°C.
  • the reaction may be facilitated by stirring the reaction mixture for about 1 hour to about 10 hours.
  • JV-[QS)-I- azabicyclo[2.2.2]oct-3-yl]-5,6,7,8-tetrahydro-naphthalene-l-carboxamide of Formula I may be isolated from the reaction mixture by conventional methods, for example, by concentration, precipitation, decantation, filtration, distillation or a combination thereof, and optionally purified.
  • the above treatment may be carried out by dissolving iV-[(3S)-l- Azabicyclo[2.2.2]oct-3-yl]-5,6,7,8-tetrahydronaphthalene-l-carboxamide in an organic solvent selected from a group consisting of cyclic ethers, aromatic ethers and hydrocarbons.
  • the organic solvent may be, for example, tetrahydrofuran, hexanes or a mixture thereof.
  • the dissolution may be affected by stirring and/or heating the reaction mixture.
  • the solution obtained may be further treated with a formylating agent in the presence of a strong base.
  • the formylating agent may be, for example, dimethylformamide.
  • the strong base may be an alkyllithium, for example, n-butyllithium, methyllithium, tert-butyllithium, sec- butyllithium, chloromethyllithium or bromomethyllithium.
  • the reaction may be carried out at a temperature of about 0 0 C or below, for example, at a temperature from about -5°C to about -75°C.
  • the 2-[(35)-l-azabicyclo[2.2.2]oct-3-yl]-2,4,5,6-tetrahydro-lH " - benzo[ ⁇ ie]isoquinorin-l-one of Formula VII is isolated from the reaction mixture.
  • the compound of Formula VII may be isolated, for example, in the form of its acid addition salt by treating with an organic or inorganic acid.
  • the compound of Formula VII or its acid addition salt is treated with a reducing agent.
  • the reducing agent may be palladium on carbon, platinum (IV) oxide, nickel, rhodium on alumina, palladium hydroxide, palladium on barium sulfate, palladium on alumina or palladium on strontium carbonate.
  • the reducing agent is, for example, palladium on carbon.
  • the reduction may be carried out under standard hydrogenation conditions in a polar organic solvent.
  • the polar organic solvent may be, for example, ethanol, water, methanol, dimethylformamide, acetic acid or a mixture thereof.
  • Palonosetron so obtained is isolated from the reaction mixture as a free base or in the form of its acid addition salt by treatment with an organic or inorganic acid, for example, hydrochloric acid.
  • the isolation may be carried out by conventional methods, for example, concentration, precipitation, decantation, filtration, distillation or a combination thereof.
  • Step 1 5,6,7, ⁇ -tetrahydro-l-naphthalenecarboxylic acid (5 g) was dissolved in methylene chloride (25 ml) at about 25°C. Dimethylformamide (0.1 ml) was added to the solution at about 25°C followed by a slow addition of thionyl chloride (3.9 g) at 0 0 C. The reaction mixture was refluxed for 2 hours at 40° to 45°C. The solvent was removed from the reaction mixture by concentration under vacuum at 40° to 45°C to get a residue. The residue was re-dissolved in methylene chloride (25 ml)
  • Step 2 Triethylamine (8.6 g) was added to a mixture of (S)-3-amino-l- azabicyclo[2.2.2.]octane dihydrochloride (5.65 g) and methylene chloride (50 ml) at 0° to - 5°C in 30 minutes time.
  • the solution obtained from step 1 was added slowly into the above solution in 30 minutes time at 25° to 30 0 C.
  • the reaction mixture was stirred at about 25°C for 4 hours and washed with water (25 ml).
  • the organic layer was dried over anhydrous sodium sulfate (1 g) and concentrated under vacuum at 40° to 45°C to get a residue.
  • the residue obtained was crystallized from ethyl acetate (10 ml) in the same manner as set forth in Method A to obtain the title compound.
  • N-[(35 r )-l-Azabicyclo[2.2.2]oct-3-yl]-5,6,7,8-tetrahydronaphthalene-l-carboxamide (0.8 Kg) was added to tetrahydrofuran (8 L) at about 25°C under nitrogen atmosphere and stirred to obtain a clear solution. The solution was cooled to -3O 0 C under nitrogen atmosphere.
  • n-Butyl Lithium 1.6 Molar solution in Hexanes; 2.63 Kg was added to the above solution slowly at -30° to -25 0 C in about 1 to 1.5 hours.
  • the solution was stirred at - 30° to -25 0 C for 1 hour followed by the addition of dimethylformamide (308.8 g) slowly at -30° to -25 0 C for 1 hour.
  • the reaction mixture was stirred at -30° to -25 0 C for 2 hours followed by the addition of 6N HCl (3 L) at 0° to 5 0 C.
  • the reaction mixture was stirred at about 25°C for 2 hours.
  • the tetrahydrofuran layer was separated and the aqueous layer was made basic (pH 9.5) with aqueous sodium hydroxide solution (200 g in 2 L of deionised water). The aqueous layer was extracted with ethyl acetate (3 x 2 L).
  • Denaturated spirit (6.0 L), 2-[(3S)-l-azabicyclo[2.2.2]oct-3-yl]-2,4,5,6-tetrahydro-lH- benzo[ ⁇ ie]isoquinorin-l-one hydrochloride (600 g) and deionised water (390 ml) were added together at about 25°C and stirred at the same temperature for 30 minutes.
  • the reaction mixture was transferred to a hydrogenator and 10% palladium-carbon (50% wet, 300 g) was added to the reaction mixture at about 25°C.
  • the reaction mixture was stirred under 7 to 8 Kg pressure of hydrogen gas at about 25°C.
  • the catalyst was filtered off the reaction mixture and washed with denaturated spirit (0.6 L) at about 25 0 C.
  • the reaction mixture was concentrated to dryness under vacuum (680 to 710 mm ⁇ g) at 40° to 45 0 C to obtain the title compound as a residue.
  • Palonosetron free base 60 g was added to absolute ethanol (300 ml) at about 25°C. The reaction mixture was stirred at the same temperature for 15 minutes. A solution of isopropyl alcohol - hydrochloric acid (6.0 ml) was added to the reaction mixture at about 25°C and stirred for 12 to 15 hours. The reaction mixture was cooled to 5 0 C and stirred at 5-8 0 C for 2 hours. The reaction mixture was filtered under nitrogen atmosphere and washed with cold absolute ethanol (30 ml) to obtain a wet solid.
  • Absolute ethanol (300 ml) was added to the wet solid at about 25°C and heated to 75° to 78 0 C followed by the addition of deionised water (18-24 ml) until dissolution at 75° to 78 0 C. The solution was stirred at the same temperature for 10 to 15 minutes, cooled to about 25°C and stirred for 2 hours. The solid obtained was filtered, washed with cold absolute ethanol (30 ml), dried under vacuum (680 to 710 mmHg) at 40° to 45 0 C for 12 hours to obtain the title compound.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to novel processes for the preparation of N-[(3S)-1- azabicyclo[2.2.2]oct-3-yl]-5,6,7,8-tetrahydronaphthalene-1-carboxamide of Formula I. The present invention further relates to processes for the preparation of palonosetron or its salts thereof using N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5,6,7,8- tetrahydronaphthalene-1-carboxamide of Formula I as an intermediate.

Description

PROCESSES FOR THE PREPARATION OF PALONOSETRON
Field of the Invention
The present invention relates to processes for the preparation of N- [(3S)-I - azabicyclo[2.2.2]oct-3-yl]-5,6,7,8-tetrahydronaphthalene-l-carboxamide of Formula I.
Figure imgf000002_0001
The present invention further relates to processes for the preparation of palonosetron or its salts thereof using N-[(35r)-l-azabicyclo[2.2.2]oct-3-yl]-5,6,7,8- tetrahydronaphthalene-1-carboxamide of Formula I as an intermediate.
Background of the Invention
Palonosetron is chemically (3aS)-2-[(S)-l-azabicyclo[2.2.2]oct-3-yl]-2,3,3a,4,5,6- hexahydro-l-oxo-lHbenz[<ie]isoquinoline of Formula II having the structure as depicted below:
Figure imgf000002_0002
Palonosetron is marketed in the form of its hydrochloride salt. It is a 5-ΗT3 receptor antagonist and is used for the treatment of nausea and vomiting often
accompanying cancer chemotherapy. Processes for the preparation of palonosetron hydrochloride are described in U.S. Patent Nos. 5,202,333, 5,567,818, and 5,510,486; /. Med. Chem. (1993), 36:2645-2657, and Organic Process Research & Development (1997) j_:117-120.
The process provided in U.S. Patent No. 5,202,333 involves the cyclization of N- [(3S)-l-azabicyclo[2.2.2]oct-3-yl]-5,6,7,8-tetrahydronaphthalene-l-carboxamide of Formula I,
Figure imgf000003_0001
by using n-butyl lithium and dimethylformamide to obtain 2-[(35r)-l-azabicyclo- [2.2.2]oct-3-yl]-2,4,5,6-tetrahydro-lH-benzo[<ie]isoquinolin-l-one of Formula III,
Figure imgf000003_0002
and catalytically hydrogenating the compound of Formula III to obtain palonosetron, which is converted into its hydrochloride salt.
N-[(35r)-l-Azabicyclo[2.2.2]oct-3-yl]-5,6,7,8-tetrahydronaphthalene-l- carboxamide of Formula I is an important intermediate involved in above process. U.S. Patent No. 5,202,333 and /. Med. Chem. (1993) 36:2645-2657 provide processes to prepare this intermediate from 5,6,7, 8-tetrahydro-l-naphthalenecarboxylic acid of Formula IV and (S)-3-amino-l-azabicyclo[2.2.2.]octane of Formula V.
Figure imgf000004_0001
According to the process provided in U.S. Patent No. 5,202,333, 5,6,7,8- tetrahydro-1-naphthalenecarboxylic acid of Formula IV is first converted into 5,6,7,8- tetra-hydronaphthalene-1-carbonyl chloride of Formula VI,
Figure imgf000004_0002
by using oxalyl chloride and dimethylformamide in the presence of dichlorome-thane, and the compound of Formula VI is reacted with (S)-3-amino-l-azabicyclo-[2.2.2.]octane of Formula V in the presence of dichloromethane to obtain N-[(35r)-l-azabicyclo[2.2.2]oct-3- yl]-5,6,7,8-tetrahydronaphthalene-l-carboxamide of Formula I.
The process provided in /. Med. Chem. (1993) 36:2645-2657 also involves the conversion of 5,6,7, 8-tetrahydro-l-naphthalenecarboxylic acid of Formula IV into 5,6,7,8- tetrahydronaphthalene-1-carbonyl chloride of Formula VI by using thionyl chloride and dimethylformamide in the presence of toluene, and the compound of Formula VI is reacted with (S)-3-amino-l-azabicyclo[2.2.2.]octane of Formula V in the presence of toluene and ethyl acetate to obtain N-[(35r)-l-azabicyclo[2.2.2]oct-3-yl]-5, 6,7,8- tetrahydronaphthalene- 1 -carboxamide of Formula I. The processes mentioned above use (S)-3-amino-l-azabicyclo[2.2.2.]octane in the form of free base, which is not commercially available due to its relatively low stability. (S)-3-Amino-l-azabicyclo[2.2.2.]octane needs to be isolated from its hydrochloride salt by base treatment and then be employed in the prior art processes. Synthesis (1996) 816-818, provides a method for preparing the (S)-3-amino-l-azabicyclo[2.2.2.]octane from its hydrochloride salt. The method involves treating (S)-3-amino-l-azabicyclo[2.2.2.]octane dihydrochloride with a solution of potassium hydroxide in methanol and stirring at 500C for 1 hour.
The present inventors have observed that the preparation of iV-fQ^-l-azabicyclo- [2.2.2]oct-3-yl]-5,6,7,8-tetrahydronaphthalene-l-carboxamide of Formula I from 5,6,7,8- tetrahydro-1-naphthalenecarboxylic acid of Formula IV and (S)-3-amino-l- azabicyclo[2.2.2.]octane of Formula V by following the methods provided in the prior arts mentioned above has a disadvantage in terms of the reaction taking up to 40 hours to go to completion. This makes these processes economically unsuitable for commercial production. The processes also require the formation of the acyl chloride of Formula VI and its subsequent isolation.
Summary of the Invention
The present inventors have developed advantageous processes for the preparation of N-[(35r)-l-azabicyclo[2.2.2]oct-3-yl]-5,6,7,8-tetrahydronaphthalene-l-carboxamide of Formula I. The present invention eliminates the need of the preparation of acyl chloride of Formula VI, and provides a way to directly react (S)-3-amino-l-azabicyclo[2.2.2.]octane with 5,6,7, 8-tetrahydro-l-naphthalene-carboxylic acid in the presence of a condensing agent. The present inventors have also found that the free base of (S)-3-amino-l- azabicyclo[2.2.2.]octane can be generated from its hydrochloride salt without any requirement for heating. The present processes proceed comparatively faster and gets completed in a shorter reaction time with better yield. Thus, the preparation of palonosetron using N-[(35r)-l-azabicyclo[2.2.2]oct-3-yl]-5, 6,7, 8-tetrahydronaphthalene-l- carboxamide of Formula I is made simple, efficient and industrially preferable. Detailed Description of the Invention
A first aspect of the present invention provides a process for the preparation of N- [(35r)-l-azabicyclo[2.2.2]oct-3-yl]-5,6,7,8-tetrahydronaphthalene-l-carboxamide of Formula I,
Figure imgf000006_0001
wherein said process comprises,
a) reacting 5,6,7, 8-tetrahydro-l-naphthalenecarboxylic acid of Formula IV
Figure imgf000006_0002
with (S)-3-amino-l-azabicyclo[2.2.2.]octane of Formula V
Figure imgf000006_0003
in the presence of a condensing agent to obtain N-[(35r)-l-azabicyclo[2.2.2]oct- 3-yl]-5,6,7,8-tetrahydronaphthalene-l-carboxamide of Formula I, and b) isolating N-[(35r)-l-azabicyclo[2.2.2]oct-3-yl]-5,6,7,8-tetrahydronaphthalene-l- carboxamide of Formula I from the reaction mixture thereof. A second aspect of the present invention provides a process for the preparation of palonosetron of Formula II or its salts thereof,
Figure imgf000007_0001
wherein said process comprises,
a) reacting 5,6,7,8-tetrahydro-l-naphthalenecarboxylic acid of Formula IV
Figure imgf000007_0002
with (S)-3-amino-l-azabicyclo[2.2.2.]octane of Formula V
Figure imgf000007_0003
in the presence of a condensing agent to obtain N-[(35r)-l-azabicyclo[2.2.2]oct- 3-yl]-5,6,7,8-tetrahydronaphthalene-l-carboxamide of Formula I,
Figure imgf000008_0001
b) treating Λf-røSH-azabicycloP^^oct-S-y^-SAV^-tetrahydronaphthalene-l- carboxamide of Formula I with a formylating agent in the presence of a strong base to obtain 2-[(3S)-l-azabicyclo[2.2.2]oct-3-yl]-2,4,5,6-tetrahydro-lH- benzo[<ie]-isoquinorin-l-one of Formula VII,
Figure imgf000008_0002
c) reducing 2-[(3S)-l-azabicyclo[2.2.2]oct-3-yl]-2,4,5,6-tetrahydro-lH- benzo[<ie]-isoquinorin-l-one of Formula VII to obtain palonosetron, and d) isolating palonosetron or its salts thereof from the reaction mixture thereof.
5,6,7,8-Tetrahydro-l-naphthalenecarboxylic acid of Formula IV may be prepared according to the method provided in /. Org. Chem. (1986) 51:5452. 5,6,7, 8-Tetrahydro-l- naphthalenecarboxylic acid is reacted with (S)-3-amino-l-azabicyclo[2.2.2.]octane of Formula V. (S)-3-amino-l-azabicyclo[2.2.2.]octane can be used in the form of free base or in the form of its salt. The reaction is carried out in the presence of a condensing agent and an organic solvent. The condensing agent may be selected from a group consisting of dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIPC), l-ethyl-3-(3- dimethylaminopropyl)carbodiimide, 2-( 1 -hydrobenzotriazol- 1 -yl)- 1 ,1,3,3- tetramethyluronium hexafluorophosphate (ΗBTU), 2-(l -hydrobenzotriazol- l-yl)-l, 1,3,3- tetramethyluronium tetrafluoroborate (TBTU), diphenylphosphorylazide (DPPA), and diphenyiphosphorocyanidate (DEPC). The condensing agent is, for example,
dicyclohexylcarbodiimide (DCC) or diisopropylcarbodiimide (DIPC). The organic solvent may be selected from a group consisting of aliphatic hydrocarbons, halogenated hydrocarbons, aromatic hydrocarbons, alkanols, ethers, esters and ketones. The organic solvent may be, for example, methylene chloride, toluene or ethyl acetate or a mixture thereof. A catalytic quantity of a base may optionally be used in the reaction. The base may be, for example, 4-dimethylaminopyridine, l,8-diazabicyclo[5.4.O]undec-7-en, triethylamine, diisopropylethylamine, N-methylpyrrolidine, N-methylmorpholine, pyridine or methyl pyridine. The reaction may be carried out at a temperature of about 00C to about 600C, for example, at about 15°C to about 35°C. The reaction is optionally facilitated by stirring the reaction mixture for about 1 hour to about 30 hours. JV-[QS)-I- azabicyclo[2.2.2]oct-3-yl]-5,6,7,8-tetrahydronaphthalene-l-carboxamide of Formula I is isolated from the reaction mixture by conventional methods, for example, by
concentration, precipitation, decantation, filtration, distillation or a combination thereof, and optionally purified.
Λ^(3S)-l-azabicyclo[2.2.2]oct-3-yl]-5,6,7,8-tetrahydronaphthalene-l-carboxamide of Formula I is treated with a formylating agent in the presence of a strong base to obtain 2-[(35r)-l-azabicyclo[2.2.2]oct-3-yl]-2,4,5,6-tetrahydro-lH-benzo[Je]isoquinolin-l-one of Formula VII. The above treatment may be carried out by dissolving iV-[(3S)-l- Azabicyclo[2.2.2]oct-3-yl]-5,6,7,8-tetrahydro-naphthalene-l-carboxamide in an organic solvent selected from a group consisting of cyclic ethers, aromatic ethers and
hydrocarbons. The organic solvent may be, for example, tetrahydrofuran, hexanes or a mixture thereof. The dissolution may be affected by stirring and/or heating the reaction mixture. The solution obtained may be further treated with a formylating agent in the presence of a strong base.
The formylating agent may be, for example, dimethylformamide. The strong base may be an alkyllithium, for example, n-butyllithium, methyllithium, tert-butyllithium, sec- butyllithium, chloromethyllithium or bromomethyllithium. The reaction may be carried out at a temperature of about 00C or below, for example, at a temperature from about -5°C to about -75°C. The 2-[(3S)-l-azabicyclo[2.2.2]oct-3-yl]-2,4,5,6-tetrahydro-lH- benzo[<ie]isoquinolin-l-one of Formula VII is isolated from the reaction mixture. The compound of Formula VII may be isolated, for example, in the form of its acid addition salt by treating with an organic or inorganic acid.
The compound of Formula VII or its acid addition salt is treated with a reducing agent. The reducing agent may be palladium on carbon, platinum (IV) oxide, nickel, rhodium on alumina, palladium hydroxide, palladium on barium sulfate, palladium on alumina or palladium on strontium carbonate. The reducing agent is, for example, palladium on carbon. The reduction may be carried out under standard hydrogenation conditions in a polar organic solvent. The polar organic solvent may be, for example, ethanol, water, methanol, dimethylformamide, acetic acid or a mixture thereof.
Palonosetron so obtained is isolated from the reaction mixture as a free base or in the form of its acid addition salt by treatment with an organic or inorganic acid, for example, hydrochloric acid. The isolation may be carried out by conventional methods, for example, concentration, precipitation, decantation, filtration, distillation or a combination thereof.
A third aspect of the present invention provides a process for the preparation of N- [(35r)-l-azabicyclo[2.2.2]oct-3-yl]-5,6,7,8-tetrahydronaphthalene-l-carboxamide of Formula I,
Figure imgf000010_0001
wherein said process comprises,
a) treating an acid addition salt of (S)-3-amino-l-azabicyclo[2.2.2.]octane of
Formula V,
Figure imgf000010_0002
with an amine at a temperature of about 400C or below, and b) combining the reaction mixture obtained in step a) with 5,6,7, 8-tetrahydro- naphthalene-1-carbonyl chloride of Formula VI,
Figure imgf000011_0001
in the presence of an organic solvent to obtain N-[(35r)-l-azabicyclo[2.2.2]oct- 3-yl]-5,6,7,8-tetrahydronaphthalene-l-carboxamide of Formula I.
A fourth aspect of the present invention provides a process for the preparation of palonosetron of Formula II or its salts thereof,
Figure imgf000011_0002
wherein said process comprises,
a) treating an acid addition salt of (S)-3-amino-l-azabicyclo[2.2.2.]octane of Formula V,
Figure imgf000011_0003
with an amine at a temperature of about 400C or below, and b) combining the reaction mixture obtained in step a) with 5,6,7,8-tetrahydro- naphthalene-1-carbonyl chloride of Formula VI,
Figure imgf000012_0001
in the presence of an organic solvent to obtain iV-[(35)-l-azabicyclo[2.2.2]oct- 3-yl]-5,6,7,8-tetrahydronaphthalene-l-carboxamide of Formula I,
Figure imgf000012_0002
c) treating N-[(35)-l-azabicyclo[2.2.2]oct-3-yl]-5,6,7,8-tetrahydronaphthalene-l- carboxamide of Formula I with a formylating agent in the presence of a strong base to obtain 2-[rø-l-azabicyclo[2.2.2]oct-3-yl]-2,4,5,6-tetrahydro-lf7- benzo[<fe]isoquinolin-l-one of Formula VII,
Figure imgf000012_0003
d) reducing 2-[(35)-l-azabicyclo[2.2.2]oct-3-yl]-2,4,5,6-tetrahydro-lH- benzo[<fe]isoquinolin-l-one of Formula VII to obtain palonosetron, and e) isolating palonosetron or its salts thereof from the reaction mixture thereof. 5,6,7, 8-Tetrahydronaphthalene-l-carbonyl chloride of Formula VI may be prepared from 5,6,7,8-Tetrahydro-l-naphthalenecarboxylic acid of Formula IV according to the methods provided in U.S. Patent No. 5,202,333 or /. Med. Chem. (1993) 36:2645- 2657. The acid addition salt of (S)-3-amino-l-azabicyclo[2.2.2.]-octane of Formula V may be, for example, (S)-3-amino-l-azabicyclo[2.2.2.]octane dihydrochloride. The acid addition salt of (S)-3-amino-l-azabicyclo[2.2.2.]octane of Formula V is treated with an amine at a temperature of about 400C or below, for example, at about -10° to about 25°C. The amine may be a primary, secondary or tertiary amine or ammonia. The amine may be, for example, triethylamine, or diisopropylamine. An organic solvent may be optionally used while treating the acid addition salt of (S)-3-amino-l-azabicyclo[2.2.2.]octane of Formula V with the amine. The reaction mixture so obtained is combined with 5,6,7,8- tetrahydro-naphthalene-1-carbonyl chloride of Formula VI. The combined mixture is subjected to suitable reaction conditions in the presence of an organic solvent to obtain N- [(3S)-l-azabicyclo[2.2.2]oct-3-yl]-5,6,7,8-tetrahydronaphthalene-l-carboxamide of Formula I.
The organic solvent may be selected from a group consisting of aliphatic hydrocarbons, halogenated hydrocarbons, aromatic hydrocarbons, alkanols, ethers, esters and ketones. The organic solvent may be, for example, methylene chloride, toluene or ethyl acetate, or a mixture thereof. The reaction may require a temperature condition of about 00C to about 600C, for example, about 15°C to about 35°C. The reaction may be facilitated by stirring the reaction mixture for about 1 hour to about 10 hours. JV-[QS)-I- azabicyclo[2.2.2]oct-3-yl]-5,6,7,8-tetrahydro-naphthalene-l-carboxamide of Formula I may be isolated from the reaction mixture by conventional methods, for example, by concentration, precipitation, decantation, filtration, distillation or a combination thereof, and optionally purified.
Λ^(3S)-l-azabicyclo[2.2.2]oct-3-yl]-5,6,7,8-tetrahydronaphthalene-l-carboxamide of Formula I is treated with a formylating agent in the presence of a strong base to obtain 2-[(3S)-l-azabicyclo[2.2.2]oct-3-yl]-2,4,5,6-tetrahydro-lH-benzo[de]-isoquinolin-l-one of Formula VII. The above treatment may be carried out by dissolving iV-[(3S)-l- Azabicyclo[2.2.2]oct-3-yl]-5,6,7,8-tetrahydronaphthalene-l-carboxamide in an organic solvent selected from a group consisting of cyclic ethers, aromatic ethers and hydrocarbons. The organic solvent may be, for example, tetrahydrofuran, hexanes or a mixture thereof. The dissolution may be affected by stirring and/or heating the reaction mixture. The solution obtained may be further treated with a formylating agent in the presence of a strong base.
The formylating agent may be, for example, dimethylformamide. The strong base may be an alkyllithium, for example, n-butyllithium, methyllithium, tert-butyllithium, sec- butyllithium, chloromethyllithium or bromomethyllithium. The reaction may be carried out at a temperature of about 00C or below, for example, at a temperature from about -5°C to about -75°C. The 2-[(35)-l-azabicyclo[2.2.2]oct-3-yl]-2,4,5,6-tetrahydro-lH"- benzo[<ie]isoquinorin-l-one of Formula VII is isolated from the reaction mixture. The compound of Formula VII may be isolated, for example, in the form of its acid addition salt by treating with an organic or inorganic acid.
The compound of Formula VII or its acid addition salt is treated with a reducing agent. The reducing agent may be palladium on carbon, platinum (IV) oxide, nickel, rhodium on alumina, palladium hydroxide, palladium on barium sulfate, palladium on alumina or palladium on strontium carbonate. The reducing agent is, for example, palladium on carbon. The reduction may be carried out under standard hydrogenation conditions in a polar organic solvent. The polar organic solvent may be, for example, ethanol, water, methanol, dimethylformamide, acetic acid or a mixture thereof.
Palonosetron so obtained is isolated from the reaction mixture as a free base or in the form of its acid addition salt by treatment with an organic or inorganic acid, for example, hydrochloric acid. The isolation may be carried out by conventional methods, for example, concentration, precipitation, decantation, filtration, distillation or a combination thereof.
While the present invention has been described in terms of its specific
embodiments, 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 invention. EXAMPLES
Example 1: Preparation of N-r(3^)-l-azabicyclor2.2.21oct-3-yll-5,6,7,8- tetrahvdronaphthalene- 1 -carboxamide:
Method A:
(S)-3-Amino-l-azabicyclo[2.2.2.]octane dihydrochloride (22.74 g) was converted into its free base as per the method provided in Synthesis, (1996) 816-818, and stirred with methylene chloride (200 ml). 5,6,7,8-Tetrahydro-l-naphthalenecarboxylic acid (20 g) was added to the reaction mixture followed by the addition of dicyclohexylcarbodiimide (23.44 g) and 4-dimethylaminopyridine (1 g). The reaction mixture was stirred at about 25°C for 24 hours. The reaction mixture was filtered and washed with methylene chloride (40 ml). The methylene chloride solution was washed with deionised water (20 ml), dried over sodium sulfate (2 g) and the solvent was recovered under vacuum. Ethyl acetate (100 ml) was added to the residue obtained and heated to reflux temperature. The hot solution was filtered through Celite bed and washed with hot ethyl acetate (40 ml). The filtrate was concentrated to about 40 ml and stirred at about 25°C for 2 hours. The reaction mixture was cooled to 10° to 15°C and stirred for 2 hours. The solid was filtered, washed with cold ethyl acetate (10 ml) and dried under vacuum at 40° to 45°C for 8 hours to obtain the title compound.
Yield: 24 g
Method B:
Step 1: 5,6,7, δ-tetrahydro-l-naphthalenecarboxylic acid (5 g) was dissolved in methylene chloride (25 ml) at about 25°C. Dimethylformamide (0.1 ml) was added to the solution at about 25°C followed by a slow addition of thionyl chloride (3.9 g) at 00C. The reaction mixture was refluxed for 2 hours at 40° to 45°C. The solvent was removed from the reaction mixture by concentration under vacuum at 40° to 45°C to get a residue. The residue was re-dissolved in methylene chloride (25 ml)
Step 2: Triethylamine (8.6 g) was added to a mixture of (S)-3-amino-l- azabicyclo[2.2.2.]octane dihydrochloride (5.65 g) and methylene chloride (50 ml) at 0° to - 5°C in 30 minutes time. The solution obtained from step 1 was added slowly into the above solution in 30 minutes time at 25° to 300C. The reaction mixture was stirred at about 25°C for 4 hours and washed with water (25 ml). The organic layer was dried over anhydrous sodium sulfate (1 g) and concentrated under vacuum at 40° to 45°C to get a residue. The residue obtained was crystallized from ethyl acetate (10 ml) in the same manner as set forth in Method A to obtain the title compound.
Yield: 5.7 g
Example 2: Preparation of Palonosetron Hydrochloride:
a) Preparation of 2-[(35)-l-azabicyclo[2.2.2]oct-3-yl]-2,4,5,6-tetrahydro-lH- benzo[<fe]isoquinolin-l-one Hydrochloride:
N-[(35r)-l-Azabicyclo[2.2.2]oct-3-yl]-5,6,7,8-tetrahydronaphthalene-l-carboxamide (0.8 Kg) was added to tetrahydrofuran (8 L) at about 25°C under nitrogen atmosphere and stirred to obtain a clear solution. The solution was cooled to -3O0C under nitrogen atmosphere. n-Butyl Lithium (1.6 Molar solution in Hexanes; 2.63 Kg) was added to the above solution slowly at -30° to -250C in about 1 to 1.5 hours. The solution was stirred at - 30° to -250C for 1 hour followed by the addition of dimethylformamide (308.8 g) slowly at -30° to -250C for 1 hour. The reaction mixture was stirred at -30° to -250C for 2 hours followed by the addition of 6N HCl (3 L) at 0° to 50C. The reaction mixture was stirred at about 25°C for 2 hours. The tetrahydrofuran layer was separated and the aqueous layer was made basic (pH 9.5) with aqueous sodium hydroxide solution (200 g in 2 L of deionised water). The aqueous layer was extracted with ethyl acetate (3 x 2 L). The ethyl acetate layers were combined together and dried over anhydrous sodium sulfate (200 g) followed by concentration under vacuum (680-710 mmHg) at 40° to 450C to obtain a residue. Isopropyl alcohol (2 L) was added to the residue and stirred at about 25°C for 10 to 15 minutes followed by the addition of isopropyl alcohol - hydrochloric acid (0.7 L, 18.5%) at about 25°C. The reaction mixture was stirred at the same temperature for 6 hours, filtered and washed with chilled (-5 0C) isopropyl alcohol (500 ml). The solid was dried under vacuum (680 to 710 mmHg) at 40° to 450C for 12 hours to obtain the title compound.
Yield: 0.8 Kg
Purity by HPLC: 98% b) Preparation of Palonosetron Free Base:
Denaturated spirit (6.0 L), 2-[(3S)-l-azabicyclo[2.2.2]oct-3-yl]-2,4,5,6-tetrahydro-lH- benzo[<ie]isoquinorin-l-one hydrochloride (600 g) and deionised water (390 ml) were added together at about 25°C and stirred at the same temperature for 30 minutes. The reaction mixture was transferred to a hydrogenator and 10% palladium-carbon (50% wet, 300 g) was added to the reaction mixture at about 25°C. The reaction mixture was stirred under 7 to 8 Kg pressure of hydrogen gas at about 25°C. The catalyst was filtered off the reaction mixture and washed with denaturated spirit (0.6 L) at about 250C. The reaction mixture was concentrated to dryness under vacuum (680 to 710 mmΗg) at 40° to 450C to obtain the title compound as a residue.
Yield: 600 g
c) Preparation of Palonosetron Hydrochloride:
Palonosetron free base (60 g) was added to absolute ethanol (300 ml) at about 25°C. The reaction mixture was stirred at the same temperature for 15 minutes. A solution of isopropyl alcohol - hydrochloric acid (6.0 ml) was added to the reaction mixture at about 25°C and stirred for 12 to 15 hours. The reaction mixture was cooled to 50C and stirred at 5-80C for 2 hours. The reaction mixture was filtered under nitrogen atmosphere and washed with cold absolute ethanol (30 ml) to obtain a wet solid. Absolute ethanol (300 ml) was added to the wet solid at about 25°C and heated to 75° to 780C followed by the addition of deionised water (18-24 ml) until dissolution at 75° to 780C. The solution was stirred at the same temperature for 10 to 15 minutes, cooled to about 25°C and stirred for 2 hours. The solid obtained was filtered, washed with cold absolute ethanol (30 ml), dried under vacuum (680 to 710 mmHg) at 40° to 450C for 12 hours to obtain the title compound.
Yield: 19.2 g
Purity by HPLC: 98%

Claims

We claim:
1. A process for the preparation of N-[(35r)-l-azabicyclo[2.2.2]oct-3-yl]-5, 6,7,8- tetrahydronaphthalene-1-carboxamide of Formula I,
Figure imgf000018_0001
wherein said process comprises,
a) reacting 5,6,7, 8-tetrahydro-l-naphthalenecarboxylic acid of Formula IV,
Figure imgf000018_0002
with (S)-3-amino-l-azabicyclo[2.2.2.]octane of Formula V,
Figure imgf000018_0003
in the presence of a condensing agent to obtain N-[(35r)-l-azabicyclo[2.2.2]oct- 3-yl]-5,6,7,8-tetrahydronaphthalene-l-carboxamide of Formula I, and b) isolating N-[(35r)-l-azabicyclo[2.2.2]oct-3-yl]-5,6,7,8-tetrahydronaphthalene-l- carboxamide of Formula I from the reaction mixture thereof. A process for the preparation of palonosetron of Formula II or its salts thereof,
Figure imgf000019_0001
wherein said process comprises,
a) reacting 5,6,7,8-tetrahydro-l-naphthalenecarboxylic acid of Formula IV,
Figure imgf000019_0002
with (S)-3-amino-l-azabicyclo[2.2.2.]octane of Formula V,
Figure imgf000019_0003
in the presence of a condensing agent to obtain N-[(35r)-l-azabicyclo[2.2.2]oct- 3-yl]-5,6,7,8-tetrahydronaphthalene-l-carboxamide of Formula I,
Figure imgf000019_0004
b) treating N-[(35r)-l-azabicyclo[2.2.2]oct-3-yl]-5,6,7,8-tetrahydronaphthalene-l- carboxamide of Formula I with a formylating agent in the presence of a strong base to obtain 2-[(3S)-l-azabicyclo[2.2.2]oct-3-yl]-2,4,5,6-tetrahydro-lH- benzo [de] isoquinolin- 1 -one of Formula VII,
Figure imgf000020_0001
c) reducing 2-[(3S)-l-azabicyclo[2.2.2]oct-3-yl]-2,4,5,6-tetrahydro-lH- benzo [de] isoquinolin- 1 -one of Formula VII to obtain palonosetron, and d) isolating palonosetron or its salts thereof from the reaction mixture thereof. 3. A process according to claim 1 or 2, wherein the condensing agent is selected from a group consisting of dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIPC), l-ethyl-3-(3-dimethylaminopropyl)carbodiimide, 2-(l-hydrobenzotriazol- l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate (ΗBTU),
2-(l- hydrobenzotriazol-l-yl)-l,l,3,
3-tetramethyluronium tetrafluoroborate (TBTU), diphenylphosphorylazide (DPPA), and diphenyiphosphorocyanidate (DEPC).
4. A process according to claim 3, wherein the condensing agent is
dicyclohexylcarbodiimide (DCC) or diisopropylcarbodiimide (DIPC).
5. A process according to claim 1 or 2, wherein step a) is carried out in the presence of an organic solvent.
6. A process according to claim 5, wherein the organic solvent is selected from a group consisting of aliphatic hydrocarbons, halogenated hydrocarbons, aromatic hydrocarbons, alkanols, ethers, esters and ketones.
7. A process according to claim 6, wherein the organic solvent is methylene chloride, toluene or ethyl acetate or a mixture thereof.
A process for the preparation of N-[(35r)-l-azabicyclo[2.2.2]oct-3-yl]-5, 6,7,8- tetrahydronaphthalene-1-carboxamide of Formula I,
Figure imgf000021_0001
wherein said process comprises,
a) treating an acid addition salt of (S)-3-amino-l-azabicyclo[2.2.2.]octane of Formula V,
Figure imgf000021_0002
with an amine at a temperature of about 400C or below, and
b) combining the reaction mixture obtained in step a) with 5,6,7,8- tetrahydronaphthalene-1-carbonyl chloride of Formula VI,
Figure imgf000021_0003
in the presence of an organic solvent to obtain N-[(35r)-l-azabicyclo[2.2.2]oct- 3-yl]-5,6,7,8-tetrahydronaphthalene-l-carboxamide of Formula I.
A process for the preparation of palonosetron of Formula II or its salts thereof,
Figure imgf000022_0001
wherein said process comprises,
a) treating an acid addition salt of (S)-3-amino-l-azabicyclo[2.2.2.]octane of Formula V,
Figure imgf000022_0002
with an amine at a temperature of about 400C or below, and
b) combining the reaction mixture obtained in step a) with 5,6,7,8- tetrahydronaphthalene-1-carbonyl chloride of Formula VI,
Figure imgf000022_0003
in the presence of an organic solvent to obtain N-[(35r)-l-azabicyclo[2.2.2]oct- 3-yl]-5,6,7,8-tetrahydronaphthalene-l-carboxamide of Formula I,
Figure imgf000023_0001
c) treating N-[(35r)-l-azabicyclo[2.2.2]oct-3-yl]-5,6,7,8-tetrahydronaphthalene-l- carboxamide of Formula I with a formylating agent in the presence of a strong base to obtain 2-[(3S)-l-azabicyclo[2.2.2]oct-3-yl]-2,4,5,6-tetrahydro-lH- benzo[<ie]isoquinorin-l-one of Formula VII,
Figure imgf000023_0002
d) reducing 2-[(35r)-l-azabicyclo[2.2.2]oct-3-yl]-2,4,5,6-tetrahydro-lH- benzo[<ie]isoquinorin-l-one of Formula VII to obtain palonosetron, and e) isolating palonosetron or its salts thereof from the reaction mixture thereof.
10. A process according to claim 8 or 9, wherein step a) is carried out at a temperature of about -10° to about 25°C.
PCT/IB2010/053462 2009-07-31 2010-07-29 Processes for the preparation of palonosetron WO2011013095A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1588DE2009 2009-07-31
IN1588/DEL/2009 2009-07-31

Publications (1)

Publication Number Publication Date
WO2011013095A1 true WO2011013095A1 (en) 2011-02-03

Family

ID=42830062

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2010/053462 WO2011013095A1 (en) 2009-07-31 2010-07-29 Processes for the preparation of palonosetron

Country Status (1)

Country Link
WO (1) WO2011013095A1 (en)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5202333A (en) 1989-11-28 1993-04-13 Syntex (U.S.A.) Inc. Tricyclic 5-HT3 receptor antagonists
US5510486A (en) 1994-07-26 1996-04-23 Syntex (U.S.A.) Inc. Process for preparing 2-(1-azabicyclo 2.2.2!oct-3-yl)-2,3,3A,4,5,6-hexahydro-1H-benz de!isoquinolin-1-one
US5567818A (en) 1994-07-08 1996-10-22 Syntex (U.S.A.) Inc. Processes for preparing 2-(1-azabicyclo[2.2.2]oct-3-yl)-1H-benz[de] isoquinolin-1-one derivatives and intermediates useful therein

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5202333A (en) 1989-11-28 1993-04-13 Syntex (U.S.A.) Inc. Tricyclic 5-HT3 receptor antagonists
US5567818A (en) 1994-07-08 1996-10-22 Syntex (U.S.A.) Inc. Processes for preparing 2-(1-azabicyclo[2.2.2]oct-3-yl)-1H-benz[de] isoquinolin-1-one derivatives and intermediates useful therein
US5510486A (en) 1994-07-26 1996-04-23 Syntex (U.S.A.) Inc. Process for preparing 2-(1-azabicyclo 2.2.2!oct-3-yl)-2,3,3A,4,5,6-hexahydro-1H-benz de!isoquinolin-1-one

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
CLARK ET AL: "2-(Quinuclidin-3-yl)pyrido[4,3-b]indol-1-ones", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, WASHINGTON, US LNKD- DOI:10.1021/JM00070A008, vol. 36, no. 18, 1 January 1993 (1993-01-01), pages 2645 - 2657, XP002124268, ISSN: 0022-2623 *
J. MED. CHEM., vol. 36, 1993, pages 2645 - 2657
J. ORG. CHEM., vol. 51, 1986, pages 5452
ORGANIC PROCESS RESEARCH & DEVELOPMENT, vol. 1, 1997, pages 117 - 120
SYNTHESIS, 1996, pages 816 - 818

Similar Documents

Publication Publication Date Title
AU2005304950B2 (en) 4-Hydroxybenzomorphans
KR101539561B1 (en) Process for the synthesis of moxifloxacin hydrochloride
EP1706113B1 (en) A process for the preparation of 4-(2-dipropylaminoethyl)-1,3-dihydro-2h-indol-2-one hydrochloride
BRPI0610147A2 (en) method for preparing and synthesizing substituted 3-cyanoquinolines and 4-amino-3-cyanoquinolines
CA2598347A1 (en) Isoxazoline derivative and novel process for its preparation
CA2709971A1 (en) Solid and crystalline dutasteride and processes for preparation thereof
EP2590947A1 (en) Intermediates and process for preparing a thrombin specific inhibitor
JP4485192B2 (en) Industrial production method of tropenol
JP3911297B2 (en) N-[(1-nbutyl-4-piperidyl) methyl] -3,4-dihydro-2H- [1,3] oxazino [3,2-a] indole-10-carboxamide and salts and intermediates in the production
WO2011013095A1 (en) Processes for the preparation of palonosetron
EP1165543B1 (en) PROCESS FOR PREPARING S-(R*,S*)] -$g(b) - 1- 1-OXO-3- (4-PIPERIDINYL) PROPYL] -3-PIPERIDINYL] CARBONYL] AMINO] -3- PYRIDINEPROPANOIC ACID AND DERIVATIVES
JP5315337B2 (en) Crystalline form of topotecan hydrochloride and method for producing the same
KR20140028433A (en) Proces for purifying fluvoxamine free base and process for preparing high purity fluvoxamine maleate using the same
TWI777079B (en) Preparation method of condensed tricyclic γ-amino acid derivatives and intermediates thereof
WO2011116491A1 (en) Preparation method for nortropine benzilate and its salts and intermediates used in said method
EP1968970A2 (en) Processes for the preparation of alfuzosin
CN111320622A (en) Method for synthesizing moxifloxacin hydrochloride
JP4597141B2 (en) New synthesis method of enamide derivatives
CN112358447B (en) Synthesis method of 7-fluoroisoquinoline-1-carboxylic acid
CN107778307B (en) Preparation method of central alpha 2 adrenoreceptor agonist
US20040010146A1 (en) Process for the preparation imidazo[1,2-A]pyridine-3-acetamides
CN116396290A (en) Method for preparing moxifloxacin intermediate (S, S) -2, 8-diazabicyclo [4,3,0] nonane
JP4441260B2 (en) Process for producing 4-amino-4-phenylpiperidines
CN117946066A (en) Synthesis method of bripiprazole intermediate
WO2008146283A2 (en) Novel palonosetron salts and processes for preparation and purification thereof

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 10742906

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 10742906

Country of ref document: EP

Kind code of ref document: A1