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

Formula II
the process comprises the step of
a) condensing S-aminoquinuclidine hydrochloride with S-tetrahydronaphthoic acid in a solvent in presence of coupling agent and base,
b) optionally adding the activating agent in the reaction mixture of step (a),
c) isolating the amide intermediate of Formula II from the reaction mixture thereof.

2. The process of claim 1, wherein coupling agent is selected from comprises one or more of N,N'-dicyclohexylcarbodiimide (DCC), N,N'-diisopropyl carbodiimide (DIC) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC).

3. The process of claim 2, wherein coupling agent is 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide.

4. The process of claim 1, wherein activating agent is selected from comprises one or more of hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (NHS), 2-hydroxypyridine, N-hydroxyphthalimide esters and 1,1'-carbonyldiimidazole (CDI).

5. The process of claim 4, wherein activating agent is hydroxybenzotriazole (HOBt)

6. The process of claim 1, wherein solvent is selected from the group comprising one or more dimethyl formamide and dimethyl acetamide.

7. The process of claim 6, wherein solvent is dimethyl formamide.

8. The process of claim 1, wherein base is selected from the one or more ammonia, dimethylamine, diethylamine triethylamine, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide or potassium hydroxide and potassium t-butoxide.

9. The process of claim 8, wherein base is triethyl amine.

10. The process of claim 1, wherein N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5,6,7,8-tetrahydronaphthalene-1-carboxamide, is further converted to Palonosetron or its hydrochloride salt in subsequent steps.
,TagSPECI:Field of Invention

The present invention relates to an improved process for the preparation of N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5,6,7,8-tetrahydronaphthalene-1-carboxamide (referred hereinafter as “amide intermediate”). In a particular aspect of the present invention relates to one pot process for the preparation of amide intermediate, which is used as a key intermediate for the preparation of Palonosetron.

Background of the invention

Palonosetron Hydrochloride under the trade name Aloxi is approved in the USA as 5-HT3 antagonist used in the prevention and treatment of chemotherapy-induced nausea and vomiting (CINV).

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

Formula-I

U.S. Patent No. 5,202,333 describes the 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 (amide intermediate) 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.
There is several other reported processes known for the preparation of Palonosetron or its intermediate in Chinese application No. 102329314 A1, PCT application No. 2011/013095 A1, Robin D. Clark et al., in Journal of Medicinal Chemistry (1993) 36: 2645-2657.

The present inventors found that the preparation of pure amide intermediate from the processes of prior art is very tedious cumbersome and leads lower yield. Further, the present inventors found that the prior art processes involve use of multiple solvents, reaction runs longer hours, which decreases the efficiency of the process and quality of product.

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

Hence, there is a need for a simple cost effective and industrially viable process for of the preparation of amide intermediate, which is further converted to Palonosetron or its hydrochloride salt. The present inventors developed a one-pot process for the preparation of amide intermediate of palonosetron, which involves shorter reaction time and single solvent to provide better yield and purity.

Summary of the Invention

The present invention relates to a process for the preparation of amide intermediate of Palonosetron and its conversion 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 of formula II:

Formula II
which includes step of:
a) condensing S-aminoquinuclidine hydrochloride with S-tetrahydronaphthoic acid in a solvent in the presence of a coupling agent and base,
b) optionally adding the activating agent in the reaction mixture of step (a),
c) isolating amide intermediate of Formula II from the reaction mixture thereof.

The purity of amide intermediate of formula II obtained from the present invention is more than 97 % when measured by HPLC.

Description of the Invention

For purposes of the present invention, the following terms are defined below.

The N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5,6,7,8-tetrahydronaphthalene-1-carboxamide, intermediates and starting materials of the present invention may be prepared/used as free bases or its salts.

The salt used is pharmaceutically acceptable salt and it refers to inorganic or organic salt. Inorganic salt may include hydrochloride, hydrobromide, and the like; organic salt may include acetate, mesylate, tosylate, trifluoroacetate, fumarate, mandalate, lactate, glutamate, ascorbate, citrate and the like.

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

Formula II
which includes step of:
a) condensing S-aminoquinuclidine hydrochloride with S-tetrahydronaphthoic acid in a solvent in presence of a coupling agent and base,
b) optionally adding the activating agent in the reaction mixture of step (a)
c) isolating the amide intermediate of Formula II from the reaction mixture thereof.

The step a) involves the condensing S-aminoquinuclidine hydrochloride with S-tetrahydronaphthoic acid in the presence of a coupling agent, base and solvent, at the temperature in between range of 40°C to 50°C, wherein coupling agent is carbodiimide derivative. The carbodiimide derivative coupling agent is selected from the group comprising one or more N,N'-dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC).

The solvent is selected from the group comprising one or more dimethyl formamide and dimethyl acetamide.

The base may be selected from the group comprising one or more of organic base such as ammonia, dimethylamine, diethylamine or triethylamine and inorganic base such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide or potassium t-butoxide.

The step b) involves the adding the activating agent in the reaction mixture of step (a), wherein the activating agent is hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (NHS), 2-hydroxypyridine, N-hydroxyphthalimide esters and 1,1'-carbonyldiimidazole (CDI).

The step c) involves the isolation of amide intermediate by adjusting the pH of reaction mixture to about 10 to 12 by adding 20% aqueous sodium hydroxide in presence of water. The amide intermediate is extracted with ethyl acetate. The partial removal of ethyl acetate yields the crystalline solid of N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5,6,7,8-tetrahydronaphthalene-1-carboxamide, which is amide intermediate.

The step (a) to (c) of the present invention may be carried out using a one-pot procedure.

The obtained compound of N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5,6,7,8-tetrahydro naphthalene-1-carboxamide according to present invention process can be converted to Palonosetron by known method in art, e.g. U.S. Patent No. 5,202,333

The present invention may further be illustrated by the following examples which may be provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents may be apparent to those skilled in the art and may be intended within the scope of the present invention.

EXAMPLE

Preparation of N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5,6,7,8-tetrahydro naphthalene-1-carboxamide

Charged S-aminoquinuclidine hydrochloride (11.3 gm) in dimethylformamide (50 ml) in a flask and stirred at room temperature. Followed by triethyl amine (15.8 ml) and S-Tetrahydronaphthoic acid (10gm) were added. After stirring for 20 minutes, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (13.58 gm) and hydroxybenzotriazole (7.66 gm) were added and reaction mixture temperature were maintained at 40°C for the completion. After completion of reaction, water (100 ml) was added, pH was adjusted to 10 by using 20% aqueous solution of sodium hydroxide. The title compound was extracted from the reaction mass in ethyl acetate. The ethyl acetate was removed under reduced temperature to its 1/3rd volume to obtain the title compound as crystalline off white solid.
Yield: 14.0gm
HPLC Purity: 98%
1H NMR (400 MHz, CDCl3, TMS): d: 1.36-1.24(m, 2 H), 2.02-1.93(m, 6H), 2.24 (m, 2H), 2.88-2.71 (m, 6H), 3.26-3.21 (m, 1H), 3.68-3.66 (m, 1H), 3.94-3.92 (t, 1H), 5.96 (s, 1H), 7.20-7.08 (m, 4H).
Mass: 284.2