PREPARATION OF GRANISETRON AND INTERMEDIATES THEREOF

INTRODUCTION

Aspects of this disclosure relate to processes for the preparation of endo-9-methyl-9-azabicyclo [3.3.1] nonan-3-amine, 1-methyl-indazole-3-carboxylic acid, an intermediate for the preparation of granisetron and its pharmaceutical acceptable salts, and pharmaceutical compositions.

Granisetron hydrochloride has a chemical name endo-N-(9-methyl-9-azabicyclo[3.3.1] non-3-yl)-1-methyl-1H-indazole-3-carboxamine hydrochloride, and is represented by structural Formula I.

Formula I

The salt compound, granisetron hydrochloride, is the active ingredient in products sold by Roche as KYTRIL™, in the forms of an injection, oral solution, and tablets, indicated for the prevention of nausea and vomiting associated with radiation, including total body irradiation and fractionated abdominal radiation.

U.S. Patent No. 4,886,808 discloses granisetron, its physiologically acceptable salts, pharmaceutical compositions comprising granisetron or its physiologically acceptable salts, and their methods of use.

U.S. Patent No. 4,248,960, International Application Publication Nos. WO 2007/08857A1 and WO 2007/054784A1 disclose processes for the preparation of granisetron hydrochloride and its pharmaceutical compositions. The processes have serious problems, such as low yield and purity.

A need remains for improved processes to prepare granisetron and its salts.

SUMMARY

In an aspect, the present invention relates to 1N-methyl-3-indazole carboxylic acid a key intermediate for the preparation of granisetron and its pharmaceutically acceptable salts, an embodiment of a process comprising at least one of the steps of:

a) reacting 1H-indole-2,3-dione of Formula VII with a methylating agent, in the presence of suitable base and suitable solvent, to give 1-methyl-1H- indole-2,3-dione of Formula VI;

Formula VII Formula VI

b) reacting 1-methyl-1H-indole-2,3-dione of Formula VI with trimethyl orthoformate, in the presence of a solvent under suitable reaction conditions, to give ketal protected 3,3-dimethoxy-1-methyl-1,3-dihydro- indol-2-one of Formula V; and

Formula V

c) hydrolyzing ketal protected 3,3-dimethoxy-1-methyl-1,3-dihydro-indol-2- one of formula V under basic conditions, followed by N-amination using suitable chloramines, which further undergo acid mediated cyclization, to give 1 N-methyl-3-indazole carboxylic acid of Formula III.

Formula III

In an embodiment the present disclosure include substantially pure endo-9-methyl-9-azabicyclo [3.3.1] nonan-3-amine (granatamine) of Formula IV or its acid addition salts, an intermediate for the preparation of granisetron and its pharmaceutically acceptable salts.

Formula IV In another embodiment the present disclosure also includes processes for the purification of endo-9-methyl-9-azabicyclo [3.3.1] nonan-3-amine (granatamine), embodiments comprising at least one of the steps of:

a) reacting a solution of crude granatamine in an organic solvent with an organic acid to form a compound of Formula IV(a),

Formula IV(a) where Org is an anion of the organic acid;

b) isolating the organic acid addition salt of Formula IV(a); and

c) suspending the acid addition salt in a non-polar solvent and adding an aqueous inorganic base, then isolating a purified amine intermediate of Formula IV.
In an embodiment, there is provided a process for the preparation of granatamine, an intermediate for the preparation of endo-9-methyl-9-azabicyclo [3.3.1]nonan-3-amine (granatamine) and its pharmaceutically acceptable salts, comprising at least one of the steps of:

a) reacting glutaraldehyde of Formula VIII with mixture of methyl amine hydrochloride and 1,3-acetone dicarboxylic acid, in the presence of aqueous disodium hydrogen orthophosphate and water as a solvent, to give 9-methyl-9-azabicyclo[3.3.1]nonan-3-one of Formula IX;

Formula VIM Formula IX

b) reacting 9-methyl-9-azabicyclo[3.3.1]nonan-3-one of Formula IX with a mixture of sodium acetate and hydroxylamine hydrochloride, in the presence of methanol as a solvent, to give 9-methyl-9-azabicyclo [3.3.1]non-3-one oxime of Formula X; and

Formula X

c) reducing 9-methyl-9-azabicyclo [3.3.1]non-3-one oxime of Formula X with
Raney nickel and hydrogen, in a basic medium and isopropanol as a solvent, to give encfo-9-methyl-9-azabicyclo [3.3.1]nonan-3-amine of Formula IV.

Formula IV In another aspect of the present invention there is provided an organic acid addition salt of Formula IV(a),

Formula IV(a) wherein Org" is an anion from an organic acid.

In a further embodiment, there is provided a compound of Formula IV(b).

Formula IV(b)

In an aspect the present disclosure includes processes for the preparation of granisetron and its pharmaceutically acceptable salts, embodiments comprising at least one of the steps of:

a) reacting N-methyl-indazole-3-carboxylic acid of Formula III with thionyl chloride, in the presence of a suitable base and solvent, to give N-methyl- indazole-3-carboxylic acid chloride of Formula II; and

Formula III Formula II

b) condensing N-methyl-indazole-3-carboxylic acid chloride of Formula II with endo-N-(9-methyl-9-azabicyclo[3.3.1]nonane hydrochloride of Formula IV(c), in the presence of a suitable base and solvent, to give granisetron hydrochloride of Formula I.

Formula IV(c)

In an aspect, there are provided processes for the preparation of pure granisetron and its pharmaceutically acceptable salts, substantially free of process related impurities.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 is a schematic representation of a process for the preparation of Formula I.

Fig. 2 is a schematic representation of a process for the preparation of N-methyl indazole carboxylic acid.

Fig. 3 is a schematic representation of process for the preparation of 9-methyl-9-azobicyclo [3.3.1] nonane-3-amine.

DETAILED DESCRIPTION

According to an aspect of the invention, there is provided an improved process for the preparation of granisetron and its pharmaceutically acceptable salts, substantially free of process related impurities.

An embodiment of the present invention relates to the preparation of N-methyl-3-indazole carboxylic acid, an intermediate for the preparation of granisetron and its pharmaceutically acceptable salts, comprising at least one of the steps of;

a) reacting 1H-indole-2,3-dione of Formula VII with a methylating agent, in the presence of a suitable base and suitable solvent, to give 1-methyl-1H-indole-2,3-dione of Formula VI;
Formula VII Formula VI

b) reacting 1-methyl-1H-indole-2,3-dione of Formula VI with trimethyl orthoformate, in the presence of a solvent, to give ketal protected 3,3- dimethoxy-1-methyl-1,3-dihydro-indol-2-one of Formula V;

Formula V

c) hydrolyzing ketal protected 3,3-dimethoxy-1-methyl-1,3-dihydro-indol-2- one of Formula V under basic conditions, followed by N-amination using a suitable chloramine and acid mediated cyclization, to give 1N-methyl-3- indazole carboxylic acid of Formula III.

Formula III

Step a) involves reacting 1H-lndole-2,3-dione of Formula VII with a methylating agent, in the presence of a suitable base and suitable solvent, to give 1-methyl-1H-indole-2,3-dione of Formula VI.

Suitable methylating agents include, but are not limited to, methyl iodide and dimethyl sulfate.

Suitable bases used in the reaction in step 1) include, without limitation thereto: hydroxides of alkali metals such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; carbonates of alkali metals such as sodium carbonate, potassium carbonate and the like; bicarbonates of alkali metals such as sodium bicarbonate, potassium bicarbonate, and the like; as solids or in the form of solutions in water. Hydrides like sodium hydride, lithium hydride, potassium hydride, and the like are also useful.

Suitable organic solvents include, but are not limited to: CrC4 straight chain alcohols such as methanol, ethanol, isopropyl alcohol, n-butanol, and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone, and the like; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate, and the like; nitriles such as acetonitrile, propionitrile, and the like; halogenated hydrocarbons such as dichloromethane, ethylene dichloride, chloroform, and the like; aprotic solvents such as N,N-dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP), dimethylsulfoxide (DMSO), N,N-dimethylacetamide (DMA), and the like; and mixtures thereof or their combinations with water in various proportions.

Temperatures for conducting the reaction can range from about 0-70°C, or about 0-5°C, or the reflux temperature of the solvent used.

Step 2) involves reaction of 1-methyl-1H-indole-2,3-dione of Formula VI with trimethyl orthoformate, in the presence of a solvent, to give ketal protected 3,3-dimethoxy-1-methyl-1,3-dihydro-indol-2-one of Formula XII.

Suitable organic solvents used in step 2) include, but are not limited to: CrC4 straight chain alcohols such as methanol, ethanol, isopropyl alcohol, n-butanol, and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone, and the like; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate, and the like; nitriles such as acetonitrile, priopionitrile, and the like; aprotic solvents such as N,N-dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP), dimethylsulfoxide (DMSO), N,N-dimethylacetamide (DMA), and the like; and mixtures thereof or their combinations with water in various proportions.

Suitable acids used in step 2) include organic and inorganic acids. Examples of organic acids include formic acid, acetic acid, p-toluenesulfonic acid and pyridinium p-toluenesulphonate, and the like. Examples of inorganic acids include sulphuric acid, hydrochloric acid, and the like, mixtures thereof, and their combinations in various propositions with water.

Suitable temperatures for conducting the reaction range from about 0 to 60°C, or at the reflux temperature of the solvent used.

Step 3) involves basic hydrolysis of ketal protected 3,3-dimethoxy-1-methyl-1,3-dihydro-indol-2-one of Formula XII, followed by N-amination using a suitable chloramine (either in situ generated or an isolated chloramine) followed by acid mediated cyclization, to give 1 N-methyl-3-indazole carboxylic acid of Formula III.

Suitable bases used in the basic hydrolysis include, but are not limited to: hydroxides of alkali metals such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; carbonates of alkali metals such as sodium carbonate, potassium carbonate and the like; bicarbonates of alkali metals such as sodium bicarbonate, potassium bicarbonate, and the like; as solids or in the form of solutions in water.

N-amination can be done in this reaction step using in situ generated chloramines. The chloramines that can be generated in situ include, but are not limited to, sodium hypochlorite and aqueous ammonia, ammonium chloride and sodium hydroxide, and the like. Suitable temperatures for conducting N-amination can range from about 0-50°C.
Cyclization can be done in this reaction step in an acid medium. Suitable organic acids include formic acid, acetic acid, p-toluenesulfonic acid and the like; examples of inorganic acids include sulphuric acid, hydrochloric acid, and the like, or mixtures thereof or their combinations in various proportions with water. Suitable temperatures for conducting the reaction range from about 0 to 60°C, or the reflux temperature of the solvent used.

In an embodiment, the present disclosure includes substantially pure endo-9-methyl-9-azabicyclo [3.3.1] nonan-3-amine (granatamine) of Formula IV or its acid addition salts, an intermediate for the preparation of granisetron and its pharmaceutically acceptable salts.

Formula IV In another embodiment, the present disclosure includes a process for the purification of eA7do-9-methyl-9-azabicyclo [3.3.1]nonan-3-amine (granatamine) or its organic acid addition salts, substantially free from impurities, comprising at least one of the steps:

a) reacting a solution of a crude granatamine in a organic solvent with an
OrQaniC acid tO form a nf Formula l

Formula IV(a) wherein Org is an anion of the organic acid;

b) isolating the organic acid addition salt of Formula IV(a); and

c) suspending the acid addition salt in a non-polar solvent and adding an aqueous inorganic base, then isolating a purified amine intermediate of Formula IV(a).
Suitable organic solvents used in this step (a) include, but are not limited to, methanol, acetone, acetonitrile, and the like.

Org" is the anion of an organic acid. Typical organic acids include, but are not limited to, benzoic acid, formic acid, succinic acid, oxalic acid, and the like. Organic acid addition salts generally give less reactivity associated with the moiety of the amine intermediate of Formula II than do mineral acids, which may result in lessened formation of impurities that affect the overall purity of granatamine and its salts such as the hydrochloride.

Suitable non-polar halogenated solvents used in step (c) for forming a purified amine intermediate of Formula IV(a) include, without limitation thereto, dichloromethane, dichloroethane, chloroform, and mixtures thereof.

An aspect of the present disclosure provides an organic acid addition salt of
Formula IV(a), such as is prepared according to the aforesaid process, where Org" is an anion of an organic acid.

Formula IV(a) In a further aspect of the present disclosure, there is provided a benzoate addition salt of Formula IV(b).

Formula IV(b)

Suitable organic solvents that may be used in the step include, but are not limited to: alcohols such as methanol, ethanol, isopropyl alcohol, and n-butanol; ketones such as acetone, methyl isobutyl ketone, methyl ethyl ketone, and n-butanone; and mixtures thereof in various proportions.

Suitably, benzoic acid can be added by dissolving the benzoic acid salt in the same solvent used to dissolve granatamine. Suitable times for combining with a granatamine solution may range from about 15 minutes to about 5 hours, or longer.

Suitable temperatures for conducting the reaction range from about 0°C to about 45°C, and increasing the temperature and time of the reaction may lead to undesirable formation of side products and process-related impurities.

The reaction may be carried about for any desired time periods to achieve the desired product yield and purity. The reaction times vary from about 30 minutes to about 10 hours, or longer.

Recovery of solid can be carried out by conventional techniques such as filtration, decantation, centrifugation, and the like, in the presence or absence of an inert atmosphere, such as for example nitrogen and the like.

The product may optionally be further dried. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer and the like. The drying can be carried out at temperatures about 35°C to about 90°C, with or without vacuum. The drying can be carried out for any desired times until the required product purity is achieved, time periods from about 1 to 20 hours frequently being sufficient.

The compound of Formula IV(b) obtained according to the present process is substantially free from process related impurities. A pure granatamine of Formula IV(b) obtained by the described process has purity at least 98%, as determined using high performance liquid chromatography (HPLC).

In another embodiment, there is provided a process for the preparation of granatamine, an intermediate for the preparation of e/7Cfo-9-methyl-9-azabicyclo [3.3.1]nonan-3-amine (granatamine) of Formula IV and its pharmaceutically acceptable salts, comprising at least one of the steps of:

a) reaction of glutaraldehyde of Formula VIII with a mixture of methyl amine hydrochloride and 1,3-acetone dicarboxylic acid, in the presence of aqueous disodium hydrogen orthophosphate and water as a solvent, to give 9-methyl-9-azabicyclo[3.3.1]nonan-3-one of Formula IX;

b) reaction of 9-methyl-9-azabicyclo[3.3.1]nonan-3-one of Formula IX with a mixture of sodium acetate and hydroxyl amine hydrochloride, in the presence of methanol as a solvent, to give 9-methyl-9-azabicyclo [3.3.1]non- 3-one oxime of Formula X;

Formula X

c) reduction of 9-methyl-9-azabicyclo [3.3.1]non-3-one oxime of Formula X with Raney nickel in a basic medium and isopropanol as a solvent, to give encfo-9-methyl-9-azabicyclo [3.3.1]nonan-3-amine of Formula IV.

Formula IV Step (a) involves reaction of glutaraldehyde of Formula VIII with a mixture of disodium hydrogen orthophosphate and 1,3-acetone dicarbaxylic acid, in the presence of aqueous methyl amine base and acetone as a solvent, to give 9-methyl-9-azabicyclo[3.3.1]nonan-3-one of Formula IX.

After completion of the reaction, the reaction mass is decomposed with basic water and the product extracted using a water immiscible organic solvent.

Optionally, the obtained organic solvent can be distilled off or the solution can be progressed to the next stage in situ without isolation of a compound of Formula IX.
Step (b) involves areaction of 9-methyl-9-azabicyclo[3.3.1]nonan-3-one of Formula IX with a mixture of sodium acetate and hydroxylamine hydrochloride, in the presence of methanol as a solvent, to give 9-methyl-9-azabicyclo [3.3.1]non-3-one oxime of Formula X.

After completion of the reaction, the reaction mass is distilled completely and quenched with basic water, and the product is extracted with a water immiscible organic solvent.
Optionally, the organic solvent can be distilled off or the solution can be progressed to the next stage in situ without isolation of a compound of Formula X.

Step (c) involves reduction of 9-methyl-9-azabicyclo [3.3.1]non-3-one oxime of Formula X with Raney nickel and hydrogen, in the presence of a basic medium and isopropanol as a solvent, to give encfo-9-methyl-9-azabicyclo [3.3.1]nonan-3-amine of Formula IV.
For the complete conversion of the compound of Formula X to the compound of Formula IV, the hydrogen gas pressure can range from about 2 kg/cm2 to about 5 kg/cm2 and the temperatures can range from about 0°C to about 45°C. Other suitable temperatures for conducting the reaction range from about 20°C to about 50°C, or about 25°C to about 30°C. Representative times for the completion of the reaction can range from about 30 minutes to about 25 hours, depending on the conditions.

The present invention includes granatamine, substantially free from exo-9-methyl-9-azabicyclo [3.3.1]nonan-3-amine of Formula (XI) with a relative retention time (RRT, granatamine=1) of about 0.82 as determined by HPLC.

Formula XI The above-mentioned impurity can analyzed by HPLC using an Inertsil C8-3 (250*4.6)mn 5 column.

Mobile phase A: 0.3 % trifluoroacetic acid in water.
Flow: 0.5 mL/minute.
Diluent: Mobile Phase A
Unit cell temp: 35°C.
Run time: 40 minutes.

"Substantially free of related impurities" means that granatamine free base is at least about 98%, or at least about 99.5%, or at least about 99.9% pure, and, correspondingly, the level of impurities may be less than about 2%, or less than about 0.5%, or less than about 0.1%, by weight as determined using high performance liquid chromatography (HPLC).

In an aspect, the present disclosure includes processes for the preparation of granisetron and its pharmaceutically acceptable salts, embodiments comprising at least one of the steps:

a) reacting N-methyl-indazole-3-carboxylic acid of Formula (III) with thionyl chloride, in the presence of a suitable base and solvent, to give N-methyl- indazole-3-carboxylic acid chloride of Formula (II);

b) condensing N-methyl-indazole-3-carboxylic acid chloride of Formula (II) with e/7do-N-(9-methyl-9-azabicyclo[3.3.1]nonane hydrochloride of Formula IV (c), in the presence of a suitable base and solvent, to give the granisetron hydrochloride salt of Formula I.

Step a) involves a reaction of N-methyl-indazole-3-carboxylic acid with thionyl chloride in the presence of a suitable solvent to give N-methyl-indazole-3-carboxylic acid chloride.

Suitable organic solvents include, but are not limited to: ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; esters such as ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, t-butyl acetate and the like; nitriles such as acetonitrile, propionitrile, and the like; halogenated hydrocarbons such as dichloromethane, ethylene dichloride, chloroform, and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, methyl t-butyl ether, tetrahydrofuran, 1,4-dioxane, and the like; hydrocarbons such as toluene, xylene, n-hexane, n-heptane, cyclohexane, and the like; and mixtures thereof in various proportions without limitation.

Temperatures for conducting the reaction can range from about 0-80°C, or about 50-60°C, or the reflux temperature of the solvent.

Step b) involves condensation of N-methyl-indazole-3-carboxylic acid chloride with encfo-N-(9-methyl-9-azabicyclo[3.3.1]nonane or its acid addition salts, in the presence of a suitable base and solvent, to give granisetron free base

Suitably, the endo-N-(9-methyl-9-azabicyclo[3.3.1]nonane used in the reaction step may be either the free base or its acid addition salt.

Suitable bases used in the reaction in step b) include, but are not limited to: hydroxides of alkali metals such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; carbonates of alkali metals such as sodium carbonate, potassium carbonate and the like; bicarbonates of alkali metals such as sodium bicarbonate, potassium bicarbonate, and the like; as solids or in the form of solutions in water.

Temperatures for conducting the reaction can range from about 0-80°C, or about 50-60°C, or the reflux temperature of the solvent.

The processes of the present invention are simple, improved, ecologically-friendly, cost-effective, commercially viable, robust, and reproducible on an industrial scale.

Certain specific aspects and embodiments are further described with reference to particular embodiments in the following illustrative examples, and those skilled in the art will appreciate modifications that can be made that do not depart from the spirit and scope of the disclosure. The examples are provided to aid in understanding specific aspects and embodiments, but are not intended to, and should not be construed to; limit the scope of the disclosure in any way. The examples do not include detailed descriptions of conventional methods. Such methods are well known to those of ordinary skill in the art and are described in numerous publications.

EXAMPLES EXAMPLE 1: PREPARATION OF 9-METHYL-9-AZABICYCLO
[3.3.1JNON-3-ONE OXIME (FORMULA III).
Gluteraldehyde (100 g) is charged into a round bottom flask containing water (200 mL) and stirred for about 10 minutes. Methylamine hydrochloride (101 g) dissolved in water (500 mL) was added and stirred for about 10 minutes. 1,3-Acetone dicarboxylic acid (67.6 g ) dissolved in water (500 mL) was added and stirred for about 10 minutes Sodium hydrogen phosphate (71 g) dissolved in basic water (14.4 g of NaOH dissolved in 400 mL water) was charged and stirred at 25-30°C until completion of the reaction. After completion of the reaction, pH was adjusted to 10-12 by adding 20% NaOH solution (about 500 mL) and stirred for about 1 hour at 25-30°C. The mass was extracted by dichloromethane (1 L x 3). The combined organic layer was washed with water and distilled completely under vacuum to produce a residue.

The residue was charged into a clean, dry round bottom flask containing methanol (500 mL). Hydroxylamine hydrochloride (138.8 g) and sodium acetate (245.7 g) were added and stirred for about 2-3 hours at 25-30°C. After completion of the reaction, the mass was distilled completely under vacuum and water (500 mL) was charged to the residue and stirred for about 10 minutes. pH was adjusted to a basic value by adding 2 N NaOH solution. The solution was extracted with dichloromethane (1 L * 3) and the combined organic layer was washed with water (100 mL). The organic layer was distilled completely under vacuum to afford 108 g of the title compound. Purity by gas chromatography (GC) = 99.7%.

EXAMPLE 2: PREPARATION OF ENDO-9-METHYL-9-AZABICYCLO [3.3.1]NONAN-3-AMINE.

9-methyl-9-azabicyclo [3.3.1]non-3-one oxime (40 g) was charged into an autoclave containing isopropyl alcohol (400 mL), 25 % aqueous ammonia (162 mL), and Raney nickel (10 g), and stirred for about 10-15 minutes. Hydrogen gas pressure (50-60 psi) was applied and maintained at about 25-30°C until completion of the reaction. After completion of the reaction, the mass was filtered though a Hyflow (flux-calcined diatomaceous earth) bed and the bed was washed with isopropyl alcohol (80 mL). The filtrate was distilled completely under vacuum to afford a residue. To the residue, water (400 mL) was added and stirred for about 10 minutes. The solution was extracted with dichloromethane (400 mL * 2) and the combined organic layer was washed with water (400 ML). The organic solution was distilled completely under vacuum to afford 40 g of the title compound as a brown oil. Purity by GC = 83.27%.

EXAMPLE: 3 PURIFICATION OF GRANATAMINE FROM AMINE AND KETONE IMPURITITES.

Crude granatamine (20 g) was charged into a clean dry round bottom flask containing water (200 mL). Pivalic acid (26.5 g) dissolved in dichloromethane (200 mL) was added and stirred for about 1-2 hours at 25-30°C. Dichloromethane was added in portions (200 mL * 5) and stirred for 30 minutes until the ketone impurity was absent, and then the organic and aqueous layers were separated. The aqueous layer was charged into a round bottom flask and pH of was adjusted to 12 by adding 20% NaOH solution (50 mL) and the mixture was stirred for about 10-15 minutes. The solution was extracted with dichloromethane (200 mL x 3). The separated organic layer was distilled completely under vacuum to obtain a light brown colored title compound. Purity by GC = 97.3%.

EXAMPLE 4: PREPARATION OF ENDO-9-METHYL-9-AZABICYCLO [3.3.1]NONAN-3-AMINE.

9-methyl-9-azabicyclo [3.3.1]non-3-one oxime (2 g) was charged into an autoclave containing isopropyl alcohol (20 mL), 4N potassium hydroxide solution (60 mL), and Raney nickel (0.5 g), and stirred for about 10-15 minutes. Hydrogen gas pressure (50-60 psi) was applied and maintained at about 25-30°C until completion of the reaction. After completion of the reaction, the mass was filtered though a hyflow bed and the bed was washed with isopropyl alcohol (20 mL). The obtained filtrate was distilled completely under vacuum to afford 2.4 g of the title compound as brown oil. Purity by GC = 94.81%.

EXAMPLE 5: PURIFICATION OF GRANATAMINE HYDROCHLORIDE.

Granatamine hydrochloride (25 g) was charged into a round bottom flask containing water (125 mL) and stirred for about 10 minutes. The mass was cooled to 10-20°C and (25 g of NaOH dissolved in 125 ml water) sodium hydroxide solution in water was added and stirred for about 30 minutes. Dichloromethane (250 mL) was added and stirred for about 10 minutes, and the mixture was filtered. The layers were separated and the aqueous layer was extracted with dichloromethane (125 mL * 2). The combined organic layer was distilled completely under vacuum to obtain a residue.

The residue was charged into a round bottom flask containing ethyl acetate (375 mL). Benzoic acid (20.15 g) was added and stirred for about 2 hours. The formed solid was filtered, washed with ethyl acetate, and suction dried for about 30 minutes. The solid was charged into a round bottom flask containing isopropyl alcohol (300 mL) and stirred for about 10 minutes. The mass was heated to 80-85°C and stirred for about 2 hours, then was cooled to room temperature and stirred for solid formation. The solid was filtered, washed with isopropyl alcohol, and suction dried for about 30 minutes to afford a granatamine benzoate salt.

The granatamine benzoate salt was charged into a round bottom flask containing water (270 mL) and cooled to 10-20°C. pH was adjusted to 13-14 by adding sodium hydroxide solution, and the solution was stirred for about 15-20 minutes. The mass was extracted with dichloromethane (125 mL * 3). The combined organic layer was washed with water (400 mL) and then was distilled completely under vacuum to afford a residue.

The residue was mixed with hydrogen chloride (16-20%) in isopropyl alcohol and stirred for about two hours at 25-30°C for solid formation. The solid was filtered, washed with isopropyl alcohol, and suction dried for about 30 minutes to afford the title compound.

EXAMPLE 6: PREPARATION OF ENDO-N-(9-METHYL-9-AZABICYCLO[3.3.1] NONAN-3-YL)-1-METHYL 1H-INDAZOLE-3-CARBOXAMIDE HYDROCHLORIDE.

9-methyl-9-azobicyclo [3.3.1]nonane-3-amine hydrochloride (25 g) was charged into a clean dry round bottom flask containing water (125 mL), cooled to 10-20°C, and stirred for about 15 minutes. Sodium hydroxide solution (25 g dissolved in 125 mL of water) was added slowly over about 15-30 minutes at 10-20°C and stirred for about 30 minutes at 25-35°C. The obtained solution was extracted with dichloromethane (125 * 3 mL). The combined organic layer was washed with sodium chloride solution (125 mL) and distilled completely under vacuum to afford a residue. To the residue, toluene (125 mL) and molecular sieve (2.5 g) were added, stirred for about 15 minutes, and filtered to produce moisture free 9-methyl-9-azobicyclo [3.3.1]nonane-3-amine solution.

N-methyl indazole-3-carboxylic acid (25 g) was charged into a clean round bottom flask containing N,N-dimethylformamide (1.1 mL) and stirred for about 15 minutes. Thionyl chloride (50.71 g) was added slowly, heated to 55-60°C, and stirred for about 2-3 hours.
After completion of the reaction, the mass was distilled under vacuum below 60°C to give N-methyl indazole-3-carbonyl chloride. To this compound, toluene (125 mL x 4) was added and distilled completely to remove the traces of unreacted thionyl chloride and afford a residue.

To the residue, toluene (250 mL) and 9-methyl-9-azobicyclo [3.3.1]nonane-3-amine were added and stirred for about 2-3 hours at 25-35°C. The solid was filtered, washed with toluene (50 mL) and suction dried. The obtained wet cake was charged into a clean, dry round bottom flask containing hydrogen chloride (16-20%) in isopropanol (250 mL) and stirred at about 25-35°C for one hour. The solid was filtered, washed with toluene (50 mL), and suction dried to give crude granisetron hydrochloride (purity 97-98%).

The crude granisetron hydrochloride was charged into a clean round bottom flask containing isopropanol (250 mL) and water (50 mL) and stirred for about 10 minutes. Norit™ charcoal (5 g) was added and the mixture was heated to 70-80°C to produce a clear solution. The solution was filtered through a Hyflow bed, the bed was washed with isopropanol (50 mL), and the filtrate was distilled completely under vacuum. To the residue, isopropanol (250 mL * 4) was added and more than 70% of the volume was distilled under vacuum. The mass was cooled to 25-30°C and stirred for solid formation.
The solid was filtered and washed with isopropanol (50 mL) to afford granisetron hydrochloride. Purity by HPLC = 99.7%.

EXAMPLE 7: PREPARATION OF GRANISETRON FREE BASE.

Granisetron hydrochloride (2 g) was charged into a clean dry round bottom flask containing water (10 mL) and stirred for about 15 minutes. Sodium hydroxide solution (2g dissolved in 20 mL water) was added and stirred for about one hour at 25-35°C. The formed solid was filtered, washed with water (4 mL), and suction dried for 30 minutes.

The solid was charged into a round bottom flask, water (20 mL) was added, and the mixture was heated to about 70°C for 4 hours. The solid was filtered, washed with water (4 mL) and suction dried for 30 minutes. The obtained solid was dried under vacuum at 60-60°C to give pure granisetron free base.

PREPARATION OF GRANISETRON AND INTERMEDIATES THEREOF

INTRODUCTION

Aspects of this disclosure relate to processes for the preparation of endo-9-methyl-9-azabicyclo [3.3.1] nonan-3-amine, 1-methyl-indazole-3-carboxylic acid, an intermediate for the preparation of granisetron and its pharmaceutical acceptable salts, and pharmaceutical compositions.

Granisetron hydrochloride has a chemical name endo-N-(9-methyl-9-azabicyclo[3.3.1] non-3-yl)-1-methyl-1H-indazole-3-carboxamine hydrochloride, and is represented by structural Formula I.

Formula I

The salt compound, granisetron hydrochloride, is the active ingredient in products sold by Roche as KYTRILTM, in the forms of an injection, oral solution, and tablets, indicated for the prevention of nausea and vomiting associated with radiation, including total body irradiation and fractionated abdominal radiation.

U.S. Patent No. 4,886,808 discloses granisetron, its physiologically acceptable salts, pharmaceutical compositions comprising granisetron or its physiologically acceptable salts, and their methods of use.

U.S. Patent No. 4,248,960, International Application Publication Nos. WO 2007/08857A1 and WO 2007/054784A1 disclose processes for the preparation of granisetron hydrochloride and its pharmaceutical compositions. The processes have serious problems, such as low yield and purity.

A need remains for improved processes to prepare granisetron and its salts.

SUMMARY

In an aspect, there are provided processes for the preparation of pure granisetron and its pharmaceutically acceptable salts, substantially free of process related impurities.

In an aspect, the present invention relates to 1N-methyl-3-indazole carboxylic acid a key intermediate for the preparation of granisetron and its pharmaceutically acceptable salts, an embodiment of a process comprising at least one of the steps of:

a) reacting 1H-indole-2,3-dione of Formula VII with a methylating agent, in the presence of suitable base and suitable solvent, to give 1-methyl-1H-indole-2,3-dione of Formula VI;

Formula VII Formula VI
b) reacting 1-methyl-1H-indole-2,3-dione of Formula VI with trimethyl orthoformate, in the presence of a solvent under suitable reaction conditions, to give ketal protected 3,3-dimethoxy-1-methyl-1,3-dihydro-indol-2-one of Formula V; and

Formula V
c) hydrolyzing ketal protected 3,3-dimethoxy-1-methyl-1,3-dihydro-indol-2-one of formula V under basic conditions, followed by N-amination using suitable chloramines, which further undergo acid mediated cyclization, to give 1N-methyl-3-indazole carboxylic acid of Formula III.

Formula III
In an embodiment the present disclosure include substantially pure endo-9-methyl-9-methyl-azabicyclo [3.3.1] nonan-3-amine (granatamine) of Formula IV or its acid addition salts, an intermediate for the preparation of granisetron and its pharmaceutically acceptable salts.

Formula IV
In another embodiment the present disclosure also includes processes for the purification of endo-9-methyl-9-methyl-azabicyclo [3.3.1] nonan-3-amine (granatamine), embodiments comprising at least one of the steps of:

a) reacting a solution of crude granatamine in an organic solvent with an organic acid to form a compound of Formula IV(a),

Formula IV(a)

where Org- is an anion of the organic acid;

b) isolating the organic acid addition salt of Formula IV(a); and

c) suspending the acid addition salt in a non-polar solvent and adding an aqueous inorganic base, then isolating a purified amine intermediate of Formula IV.

In an embodiment, there is provided a process for the preparation of granatamine, an intermediate for the preparation of endo-9-methyl-9-methyl-azabicyclo [3.3.1]nonan-3-amine (granatamine) and its pharmaceutically acceptable salts, comprising at least one of the steps of:

a) reacting glutaraldehyde of Formula VIII with mixture of methyl amine hydrochloride and 1,3-acetone dicarboxylic acid, in the presence of aqueous disodium hydrogen orthophosphate and water as a solvent, to give 9-methyl-9-azabicyclo[3.3.1]nonan-3-one of Formula IX;

Formula VIII Formula IX
b) reacting 9-methyl-9-azabicyclo[3.3.1]nonan-3-one of Formula IX with a mixture of sodium acetate and hydroxylamine hydrochloride, in the presence of methanol as a solvent, to give 9-methyl-9-azabicyclo [3.3.1]non-3-one oxime of Formula X; and

Formula X
c) reducing 9-methyl-9-azabicyclo [3.3.1]non-3-one oxime of Formula X with Raney nickel and hydrogen, in a basic medium and isopropanol as a solvent, to give endo-9-methyl-9-methyl-azabicyclo [3.3.1]nonan-3-amine of Formula IV.

Formula IV
In another aspect of the present invention there is provided an organic acid addition salt of Formula IV(a),

Formula IV(a)
wherein Org is an anion from an organic acid.
In a further embodiment, there is provided a compound of Formula IV(b).

Formula IV(b)
In an aspect the present disclosure includes processes for the preparation of granisetron and its pharmaceutically acceptable salts, embodiments comprising at least one of the steps of:

a) reacting N-methyl-indazole-3-carboxylic acid of Formula III with thionyl chloride, in the presence of a suitable base and solvent, to give N-methyl-indazole-3-carboxylic acid chloride of Formula II; and

Formula III Formula II
b) condensing N-methyl-indazole-3-carboxylic acid chloride of Formula II with endo-N-(9-methyl-9-azabicyclo[3.3.1]nonane hydrochloride of Formula IV(c), in the presence of a suitable base and solvent, to give granisetron hydrochloride of Formula I.

Formula IV(c)
BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 is a schematic representation of a process for the preparation of Formula I.

Fig. 2 is a schematic representation of a process for the preparation of N-methyl indazole carboxylic acid.

Fig. 3 is a schematic representation of process for the preparation of 9-methyl-9-azobicyclo [3.3.1] nonane-3-amine.

DETAILED DESCRIPTION

According to an aspect of the invention, there is provided an improved process for the preparation of granisetron and its pharmaceutically acceptable salts, substantially free of process related impurities.
An embodiment of the present invention relates to the preparation of N-methyl-3-indazole carboxylic acid, an intermediate for the preparation of granisetron and its pharmaceutically acceptable salts, comprising at least one of the steps of;

a) reacting 1H-indole-2,3-dione of Formula VII with a methylating agent, in the presence of a suitable base and suitable solvent, to give 1-methyl-1H-indole-2,3-dione of Formula VI;

Formula VII Formula VI
b) reacting 1-methyl-1H-indole-2,3-dione of Formula VI with trimethyl orthoformate, in the presence of a solvent, to give ketal protected 3,3-dimethoxy-1-methyl-1,3-dihydro-indol-2-one of Formula V;

Formula V
c) hydrolyzing ketal protected 3,3-dimethoxy-1-methyl-1,3-dihydro-indol-2-one of Formula V under basic conditions, followed by N-amination using a suitable chloramine and acid mediated cyclization, to give 1N-methyl-3-indazole carboxylic acid of Formula III.

Formula III
Step a) involves reacting 1H-Indole-2,3-dione of Formula VII with a methylating agent, in the presence of a suitable base and suitable solvent, to give 1-methyl-1H-indole-2,3-dione of Formula VI.

Suitable methylating agents include, but are not limited to, methyl iodide and dimethyl sulfate.

Suitable bases used in the reaction in step 1) include, without limitation thereto: hydroxides of alkali metals such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; carbonates of alkali metals such as sodium carbonate, potassium carbonate and the like; bicarbonates of alkali metals such as sodium bicarbonate, potassium bicarbonate, and the like; as solids or in the form of solutions in water. Hydrides like sodium hydride, lithium hydride, potassium hydride, and the like are also useful.

Suitable organic solvents include, but are not limited to: C1-C4 straight chain alcohols such as methanol, ethanol, isopropyl alcohol, n-butanol, and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone, and the like; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate, and the like; nitriles such as acetonitrile, propionitrile, and the like; halogenated hydrocarbons such as dichloromethane, ethylene dichloride, chloroform, and the like; aprotic solvents such as N,N-dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP), dimethylsulfoxide (DMSO), N,N-dimethylacetamide (DMA), and the like; and mixtures thereof or their combinations with water in various proportions.

Temperatures for conducting the reaction can range from about 0-70°C, or about 0-5°C, or the reflux temperature of the solvent used.

Step 2) involves reaction of 1-methyl-1H-indole-2,3-dione of Formula VI with trimethyl orthoformate, in the presence of a solvent, to give ketal protected 3,3-dimethoxy-1-methyl-1,3-dihydro-indol-2-one of Formula XII.

Suitable organic solvents used in step 2) include, but are not limited to: C1-C4 straight chain alcohols such as methanol, ethanol, isopropyl alcohol, n-butanol, and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone, and the like; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate, and the like; nitriles such as acetonitrile, priopionitrile, and the like; aprotic solvents such as N,N-dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP), dimethylsulfoxide (DMSO), N,N-dimethylacetamide (DMA), and the like; and mixtures thereof or their combinations with water in various proportions.

Suitable acids used in step 2) include organic and inorganic acids. Examples of organic acids include formic acid, acetic acid, p-toluenesulfonic acid and pyridinium p-toluenesulphonate, and the like.

Examples of inorganic acids include sulphuric acid, hydrochloric acid, and the like, mixtures thereof, and their combinations in various propositions with water.
Suitable temperatures for conducting the reaction range from about 0 to 60°C, or at the reflux temperature of the solvent used.

Step 3) involves basic hydrolysis of ketal protected 3,3-dimethoxy-1-methyl-1,3-dihydro-indol-2-one of Formula XII, followed by N-amination using a suitable chloramine (either in situ generated or an isolated chloramine) followed by acid mediated cyclization, to give 1N-methyl-3-indazole carboxylic acid of Formula III.

Suitable bases used in the basic hydrolysis include, but are not limited to: hydroxides of alkali metals such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; carbonates of alkali metals such as sodium carbonate, potassium carbonate and the like; bicarbonates of alkali metals such as sodium bicarbonate, potassium bicarbonate, and the like; as solids or in the form of solutions in water.

N-amination can be done in this reaction step using in situ generated chloramines. The chloramines that can be generated in situ include, but are not limited to, sodium hypochlorite and aqueous ammonia, ammonium chloride and sodium hydroxide, and the like. Suitable temperatures for conducting N-amination can range from about 0-50°C.

Cyclization can be done in this reaction step in an acid medium. Suitable organic acids include formic acid, acetic acid, p-toluenesulfonic acid and the like; examples of inorganic acids include sulphuric acid, hydrochloric acid, and the like, or mixtures thereof or their combinations in various proportions with water. Suitable temperatures for conducting the reaction range from about 0 to 60°C, or the reflux temperature of the solvent used.

In an embodiment, the present disclosure includes substantially pure endo-9-methyl-9-methyl-azabicyclo [3.3.1] nonan-3-amine (granatamine) of Formula IV or its acid addition salts, an intermediate for the preparation of granisetron and its pharmaceutically acceptable salts.

Formula IV
In another embodiment, the present disclosure includes a process for the purification of endo-9-methyl-9-methyl-azabicyclo [3.3.1]nonan-3-amine (granatamine) or its organic acid addition salts, substantially free from impurities, comprising at least one of the steps:

a) reacting a solution of a crude granatamine in a organic solvent with an organic acid to form a compound of Formula IV(a);

Formula IV(a)
where Org- is an anion of the organic acid;

b) isolating the organic acid addition salt of Formula IV(a); and

c) suspending the acid addition salt in a non-polar solvent and adding an aqueous inorganic base, then isolating a purified amine intermediate of Formula IV(a).

Suitable organic solvents used in this step (a) include, but are not limited to, methanol, acetone, acetonitrile, and the like.

Org– is the anion of an organic acid. Typical organic acids include, but are not limited to, benzoic acid, formic acid, succinic acid, oxalic acid, and the like. Organic acid addition salts generally give less reactivity associated with the moiety of the amine intermediate of Formula II than do mineral acids, which may result in lessened formation of impurities that affect the overall purity of granatamine and its salts such as the hydrochloride.

Suitable non-polar halogenated solvents used in step (b) for forming a purified amine intermediate of Formula IV(a) include, without limitation thereto, dichloromethane, dichloroethane, chloroform, and mixtures thereof.

An aspect of the present disclosure provides an organic acid addition salt of Formula IV(a), such as is prepared according to the aforesaid process, where Org- is an anion of an organic acid.

Formula IV(a)
In a further aspect of the present disclosure, there is provided a benzoate addition salt of Formula IV(b).

Formula IV(b)
Suitable organic solvents that may be used in the step include, but are not limited to: alcohols such as methanol, ethanol, isopropyl alcohol, and n-butanol; ketones such as acetone, methyl isobutyl ketone, methyl ethyl ketone, and n-butanone; and mixtures thereof in various proportions.

Suitably, benzoic acid can be added by dissolving the benzoic acid salt in the same solvent used to dissolve granatamine. Suitable times for combining with a granatamine solution may range from about 15 minutes to about 5 hours, or longer.

Suitable temperatures for conducting the reaction range from about 0°C to about 45°C, and increasing the temperature and time of the reaction may lead to undesirable formation of side products and process-related impurities.

The reaction may be carried about for any desired time periods to achieve the desired product yield and purity. The reaction times vary from about 30 minutes to about 10 hours, or longer.

Recovery of solid can be carried out by conventional techniques such as filtration, decantation, centrifugation, and the like, in the presence or absence of an inert atmosphere, such as for example nitrogen and the like.

The product may optionally be further dried. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer and the like. The drying can be carried out at temperatures about 35°C to about 90°C, with or without vacuum. The drying can be carried out for any desired times until the required product purity is achieved, time periods from about 1 to 20 hours frequently being sufficient.

The compound of Formula IV(b) obtained according to the present process is substantially free from process related impurities. A pure granatamine of Formula IV(b) obtained by the described process has purity at least 98%, as determined using high performance liquid chromatography (HPLC).

In another embodiment, there is provided a process for the preparation of granatamine, an intermediate for the preparation of endo-9-methyl-9-methyl-azabicyclo [3.3.1]nonan-3-amine (granatamine) of Formula IV and its pharmaceutically acceptable salts, comprising at least one of the steps of:

a) reaction of glutaraldehyde of Formula VIII with a mixture of methyl amine hydrochloride and 1,3-acetone dicarboxylic acid, in the presence of aqueous disodium hydrogen orthophosphate and water as a solvent, to give 9-methyl-9-azabicyclo[3.3.1]nonan-3-one of Formula IX;

Formula VIII Formula IX
b) reaction of 9-methyl-9-azabicyclo[3.3.1]nonan-3-one of Formula IX with a mixture of sodium acetate and hydroxyl amine hydrochloride, in the presence of methanol as a solvent, to give 9-methyl-9-azabicyclo [3.3.1]non-3-one oxime of Formula X;

Formula X

c) reduction of 9-methyl-9-azabicyclo [3.3.1]non-3-one oxime of Formula X with Raney nickel in a basic medium and isopropanol as a solvent, to give endo-9-methyl-9-methyl-azabicyclo [3.3.1]nonan-3-amine of Formula IV.

Formula IV
Step (a) involves reaction of glutaraldehyde of Formula VIII with a mixture of disodium hydrogen orthophosphate and 1,3-acetone dicarbaxylic acid, in the presence of aqueous methyl amine base and acetone as a solvent, to give 9-methyl-9-azabicyclo[3.3.1]nonan-3-one of Formula IX.

After completion of the reaction, the reaction mass is decomposed with basic water and the product extracted using a water immiscible organic solvent.

Optionally, the obtained organic solvent can be distilled off or the solution can be progressed to the next stage in situ without isolation of a compound of Formula IX.

Step (b) involves areaction of 9-methyl-9-azabicyclo[3.3.1]nonan-3-one of Formula IX with a mixture of sodium acetate and hydroxylamine hydrochloride, in the presence of methanol as a solvent, to give 9-methyl-9-azabicyclo [3.3.1]non-3-one oxime of Formula X.

After completion of the reaction, the reaction mass is distilled completely and quenched with basic water, and the product is extracted with a water immiscible organic solvent.

Optionally, the organic solvent can be distilled off or the solution can be progressed to the next stage in situ without isolation of a compound of Formula X.

Step (c) involves reduction of 9-methyl-9-azabicyclo [3.3.1]non-3-one oxime of Formula X with Raney nickel and hydrogen, in the presence of a basic medium and isopropanol as a solvent, to give endo-9-methyl-9-methyl-azabicyclo [3.3.1]nonan-3-amine of Formula IV.

For the complete conversion of the compound of Formula X to the compound of Formula IV, the hydrogen gas pressure can range from about 2 kg/cm2 to about 5 kg/cm2 and the temperatures can range from about 0°C to about 45°C. Other suitable temperatures for conducting the reaction range from about 20°C to about 50°C, or about 25°C to about 30°C. Representative times for the completion of the reaction can range from about 30 minutes to about 25 hours, depending on the conditions.

The present invention includes granatamine, substantially free from exo-9-methyl-9-azabicyclo [3.3.1]nonan-3-amine of Formula (XI) with a relative retention time (RRT, granatamine=1) of about 0.82 as determined by HPLC.

Formula XI
The above-mentioned impurity can analyzed by HPLC using an Inertsil C8-3 (250*4.6)mn 5 column.
Mobile phase A: 0.3 % trifluoroacetic acid in water.
Flow: 0.5 mL/minute.
Diluent: Mobile Phase A
Unit cell temp: 35°C.
Run time: 40 minutes.

“Substantially free of related impurities” means that granatamine free base is at least about 98%, or at least about 99.5%, or at least about 99.9% pure, and, correspondingly, the level of impurities may be less than about 2%, or less than about 0.5%, or less than about 0.1%, by weight as determined using high performance liquid chromatography (HPLC).

In an aspect, the present disclosure includes processes for the preparation of granisetron and its pharmaceutically acceptable salts, embodiments comprising at least one of the steps:

a) reacting N-methyl-indazole-3-carboxylic acid of Formula (III) with thionyl chloride, in the presence of a suitable base and solvent, to give N-methyl-indazole-3-carboxylic acid chloride of Formula (II);

Formula III Formula II

b) condensing N-methyl-indazole-3-carboxylic acid chloride of Formula (II) with endo-N-(9-methyl-9-azabicyclo[3.3.1]nonane hydrochloride of Formula IV (c), in the presence of a suitable base and solvent, to give the granisetron hydrochloride salt of Formula I.

Formula IV (c)
Step a) involves a reaction of N-methyl-indazole-3-carboxylic acid with thionyl chloride in the presence of a suitable solvent to give N-methyl-indazole-3-carboxylic acid chloride.

Suitable organic solvents include, but are not limited to: ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; esters such as ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, t-butyl acetate and the like; nitriles such as acetonitrile, propionitrile, and the like; halogenated hydrocarbons such as dichloromethane, ethylene dichloride, chloroform, and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, methyl t-butyl ether, tetrahydrofuran, 1,4-dioxane, and the like; hydrocarbons such as toluene, xylene, n-hexane, n-heptane, cyclohexane, and the like; and mixtures thereof in various proportions without limitation.

Temperatures for conducting the reaction can range from about 0-80°C, or about 50-60°C., or the reflux temperature of the solvent.

Step b) involves condensation of N-methyl-indazole-3-carboxylic acid chloride with endo-N-(9-methyl-9-azabicyclo[3.3.1]nonane or its acid addition salts, in the presence of a suitable base and solvent, to give granisetron free base suitably, the endo-N-(9-methyl-9-azabicyclo[3.3.1]nonane used in the reaction step may be either the free base or its acid addition salt.

Suitable bases used in the reaction in step b) include, but are not limited to: hydroxides of alkali metals such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; carbonates of alkali metals such as sodium carbonate, potassium carbonate and the like; bicarbonates of alkali metals such as sodium bicarbonate, potassium bicarbonate, and the like; as solids or in the form of solutions in water.

Temperatures for conducting the reaction can range from about 0-80°C, or about 50-60°C., or the reflux temperature of the solvent.

The processes of the present invention are simple, improved, ecologically-friendly, cost-effective, commercially viable, robust, and reproducible on an industrial scale.

Certain specific aspects and embodiments are further described with reference to particular embodiments in the following illustrative examples, and those skilled in the art will appreciate modifications that can be made that do not depart from the spirit and scope of the disclosure. The examples are provided to aid in understanding specific aspects and embodiments, but are not intended to, and should not be construed to; limit the scope of the disclosure in any way. The examples do not include detailed descriptions of conventional methods. Such methods are well known to those of ordinary skill in the art and are described in numerous publications.

EXAMPLES
EXAMPLE 1: PREPARATION OF 9-METHYL-9-AZABICYCLO [3.3.1]NON-3-ONE OXIME (FORMULA III).
Gluteraldehyde (100 g) is charged into a round bottom flask containing water (200 mL) and stirred for about 10 minutes. Methylamine hydrochloride (101 g) dissolved in water (500 mL) was added and stirred for about 10 minutes. 1,3-Acetone dicarboxylic acid (67.6 g ) dissolved in water (500 mL) was added and stirred for about 10 minutes Sodium hydrogen phosphate (71 g) dissolved in basic water (14.4 g of NaOH dissolved in 400 mL water) was charged and stirred at 25-30°C until completion of the reaction. After completion of the reaction, pH was adjusted to 10-12 by adding 20% NaOH solution (about 500 mL) and stirred for about 1 hour at 25-30°C. The mass was extracted by dichloromethane (1 L × 3). The combined organic layer was washed with water and distilled completely under vacuum to produce a residue.

The residue was charged into a clean, dry round bottom flask containing methanol (500 mL). Hydroxylamine hydrochloride (138.8 g) and sodium acetate (245.7 g) were added and stirred for about 2-3 hours at 25-30°C. After completion of the reaction, the mass was distilled completely under vacuum and water (500 mL) was charged to the residue and stirred for about 10 minutes. pH was adjusted to a basic value by adding 2 N NaOH solution. The solution was extracted with dichloromethane (1 L × 3) and the combined organic layer was washed with water (100 mL). The organic layer was distilled completely under vacuum to afford 108 g of the title compound. Purity by gas chromatography (GC) = 99.7%.

EXAMPLE 2: PREPARATION OF ENDO-9-METHYL-9-AZABICYCLO [3.3.1]NONAN-3-AMINE.
9-methyl-9-azabicyclo [3.3.1]non-3-one oxime (40 g) was charged into an autoclave containing isopropyl alcohol (400 mL), 25 % aqueous ammonia (162 mL), and Raney nickel (10 g), and stirred for about 10-15 minutes. Hydrogen gas pressure (50-60 psi) was applied and maintained at about 25-30°C until completion of the reaction. After completion of the reaction, the mass was filtered though a Hyflow (flux-calcined diatomaceous earth) bed and the bed was washed with isopropyl alcohol (80 mL). The filtrate was distilled completely under vacuum to afford a residue. To the residue, water (400 mL) was added and stirred for about 10 minutes. The solution was extracted with dichloromethane (400 mL × 2) and the combined organic layer was washed with water (400 ML). The organic solution was distilled completely under vacuum to afford 40 g of the title compound as a brown oil. Purity by GC = 83.27%.

EXAMPLE: 3 PURIFICATION OF GRANATAMINE FROM AMINE AND KETONE IMPURITITES.
Crude granatamine (20 g) was charged into a clean dry round bottom flask containing water (200 mL). Pivalic acid (26.5 g) dissolved in dichloromethane (200 mL) was added and stirred for about 1-2 hours at 25-30°C. Dichloromethane was added in portions (200 mL × 5) and stirred for 30 minutes until the ketone impurity was absent, then the organic and aqueous layers were separated. The aqueous layer was charged into a round bottom flask and pH of was adjusted to 12 by adding 20% NaOH solution (50 mL) and the mixture was stirred for about 10-15 minutes. The solution was extracted with dichloromethane (200 mL × 3). The separated organic layer was distilled completely under vacuum to obtain a light brown colored title compound. Purity by GC = 97.3%.

EXAMPLE 4: PREPARATION OF ENDO-9-METHYL-9-AZABICYCLO [3.3.1]NONAN-3-AMINE.
9-methyl-9-azabicyclo [3.3.1]non-3-one oxime (2 g) was charged into an autoclave containing isopropyl alcohol (20 mL), 4N potassium hydroxide solution (60 mL), and Raney nickel (0.5 g), and stirred for about 10-15 minutes. Hydrogen gas pressure (50-60 psi) was applied and maintained at about 25-30°C until completion of the reaction. After completion of the reaction, the mass was filtered though a hyflow bed and the bed was washed with isopropyl alcohol (20 mL). The obtained filtrate was distilled completely under vacuum to afford 2.4 g of the title compound as a brown oil. Purity by GC = 94.81%.

EXAMPLE 5: PURIFICATION OF GRANATAMINE HYDROCHLORIDE.
Granatamine hydrochloride (25 g) was charged into a round bottom flask containing water (125 mL) and stirred for about 10 minutes. The mass was cooled to 10-20°C and (25 g of NaOH dissolved in 125 ml water) sodium hydroxide solution in water was added and stirred for about 30 minutes. Dichloromethane (250 mL) was added and stirred for about 10 minutes, and the mixture was filtered. The layers were separated and the aqueous layer was extracted with dichloromethane (125 mL × 2). The combined organic layer was distilled completely under vacuum to obtain a residue.

The residue was charged into a round bottom flask containing ethyl acetate (375 mL). Benzoic acid (20.15 g) was added and stirred for about 2 hours. The formed solid was filtered, washed with ethyl acetate, and suction dried for about 30 minutes. The solid was charged into a round bottom flask containing isopropyl alcohol (300 mL) and stirred for about 10 minutes. The mass was heated to 80-85°C and stirred for about 2 hours, then was cooled to room temperature and stirred for solid formation. The solid was filtered, washed with isopropyl alcohol, and suction dried for about 30 minutes to afford a granatamine benzoate salt.

The granatamine benzoate salt was charged into a round bottom flask containing water (270 mL) and cooled to 10-20°C. pH was adjusted to 13-14 by adding sodium hydroxide solution, and the solution was stirred for about 15-20 minutes. The mass was extracted with dichloromethane (125 mL × 3). The combined organic layer was washed with water (400 mL) and then was distilled completely under vacuum to afford a residue.

The residue was mixed with hydrogen chloride (16-20%) in isopropyl alcohol and stirred for about two hours at 25-30°C for solid formation. The solid was filtered, washed with isopropyl alcohol, and suction dried for about 30 minutes to afford the title compound.

EXAMPLE 6: PREPARATION OF ENDO-N-(9-METHYL-9-AZABICYCLO[3.3.1] NONAN-3-YL)-1-METHYL 1H-INDAZOLE-3-CARBOXAMIDE HYDROCHLORIDE.
9-methyl-9-azobicyclo [3.3.1]nonane-3-amine hydrochloride (25 g) was charged into a clean dry round bottom flask containing water (125 mL), cooled to 10-20°C, and stirred for about 15 minutes. Sodium hydroxide solution (25 g dissolved in 125 mL of water) was added slowly over about 15-30 minutes at 10-20°C and stirred for about 30 minutes at 25-35°C. The obtained solution was extracted with dichloromethane (125 × 3 mL). The combined organic layer was washed with sodium chloride solution (125 mL) and distilled completely under vacuum to afford a residue. To the residue, toluene (125 mL) and molecular sieve (2.5 g) were added, stirred for about 15 minutes, and filtered to produce moisture free 9-methyl-9-azobicyclo [3.3.1]nonane-3-amine solution.

N-methyl indazole-3-carboxylic acid (25 g) was charged into a clean round bottom flask containing N,N-dimethylformamide (1.1 mL) and stirred for about 15 minutes. Thionyl chloride (50.71 g) was added slowly, heated to 55-60°C, and stirred for about 2-3 hours. After completion of the reaction, the mass was distilled under vacuum below 60°C to give N-methyl indazole-3-carbonyl chloride. To this compound, toluene (125 mL × 4) was added and distilled completely to remove the traces of unreacted thionyl chloride and afford a residue.

To the residue, toluene (250 mL) and 9-methyl-9-azobicyclo [3.3.1]nonane-3-amine were added and stirred for about 2-3 hours at 25-35°C. The solid was filtered, washed with toluene (50 mL) and suction dried. The obtained wet cake was charged into a clean, dry round bottom flask containing hydrogen chloride (16-20%) in isopropanol (250 mL) and stirred at about 25-35°C for one hour. The solid was filtered, washed with toluene (50 mL), and suction dried to give crude granisetron hydrochloride (purity 97-98%).

The crude granisetron hydrochloride was charged into a clean round bottom flask containing isopropanol (250 mL) and water (50 mL) and stirred for about 10 minutes. Norit™ charcoal (5 g) was added and the mixture was heated to 70-80°C to produce a clear solution. The solution was filtered through a Hyflow bed, the bed was washed with isopropanol (50 mL), and the filtrate was distilled completely under vacuum. To the residue, isopropanol (250 mL × 4) was added and more than 70% of the volume was distilled under vacuum. The mass was cooled to 25-30°C and stirred for solid formation. The solid was filtered and washed with isopropanol (50 mL) to afford granisetron hydrochloride. Purity by HPLC = 99.7%.

EXAMPLE 7: PREPARATION OF GRANISETRON FREE BASE.
Granisetron hydrochloride (2 g) was charged into a clean dry round bottom flask containing water (10 mL) and stirred for about 15 minutes. Sodium hydroxide solution (2g dissolved in 20 mL water) was added and stirred for about one hour at 25-35°C. The formed solid was filtered, washed with water (4 mL), and suction dried for 30 minutes.

The solid was charged into a round bottom flask, water (20 mL) was added, and the mixture was heated to about 70°C for 4 hours. The solid was filtered, washed with water (4 mL) and suction dried for 30 minutes. The obtained solid was dried under vacuum at 60-60°C to give pure granisetron free base.

EXAMPLE 8: PREPARATION OF 1-METHYL-INDAZOLE-3-CARBOXYLIC ACID
(FORMULA III)

Step a - Preparation of N-methyl isatin
N-methyl -2-pyrrolidone (125 ml) and sodium hydride (20-33 g) was charged into a clean dry round bottom flask and cooled to 0-5°C and stirred for 5 minutes. A mixture of isatin (50 g) and methyl iodide (73.3 g) was dissolved in N-methyl-2-pyrrolidone (125 ml) and added slowly over about 15-30 minutes at 0°C and stirred the reaction mass for about 1-2 hours at 0-5°C up tot completion of the reaction. After completion of the reaction the reaction mass was quenched with acetic acid and extracted with dichloromethane (3x150ml). The combined organic layer was washed with water (3x150 ml) and distilled completed under vacuum to afford a residue. To the obtained residue di-isopropyl ether was added and stirred for solid separation. The separated solid was filtered and washed with di-isopropyl ether to give N-methyl isatin. Step b - Preparation of ketal protected N-methyl isatin:

N-methyl isatin (25 g) and methanol was charged into a clean dry round bottom flask and stirred for about 10 min. Trimethyl orthoformate (25.5 ml) was added slowly over about 5-10 min and catalytic amount of p-toluene sulphonic acid was added and heated of reflux and maintained for about 6-8 hours. After completion of the reaction mass was cooled to 0-5°C and pH of the reaction solution was adjusted 8-9 using triethyl amine. The resultant reaction solution was distilled off completely under vaccum to afford crude. To the obtained crude was dissolved in water (100 ml) and extracted with ethyl acetate (3x100 ml) and the combined organic layer was distilled off under vaccum to obtained crude. To the obtained crude n-hexane was added and stirred for solid separation. The separated solid was filtered and washed with n-heptane to afford 93 % of the title compound ketol protected N-methyl isatin. Step C: Preparation of 1 N-methyl-3-indazole carboxylic acid:

Ketal protected N-methyl isatin (10 g) and sodium hydroxide (6.7 g) was charged into the clean dry round bottom flask containing THF and water and heated to about 65-70°C for about 24 hours up to completion of the reaction. Distill of the THF completely under vaccum and charge sodium hydroxide (1.93 g) and ammonium chloride (15.2 g) and ammonium hydroxide (50 ml) in to the reaction mass and 7.7 % of sodium hypochloride solution (342.4 ml) was added slowly through and stirred for about 2-3 hours at room temperature up to completion of the reaction. The obtained reaction mass was cooled to 0-10°C and pH of the reaction solution was adjusted to 2-3 by adding Cone. Hydrochloric acid and stirred at room temperature for about 10 hours. The resultant reaction mass was extracted with ethyl acetate (2x250 ml) and combined organic layer was washed with water and brine solution and distilled off the organic solution completely under vacuum. The obtained crude was purified by column purification by using 30:60 ethyl acetate and hexane to get pure 1-methyl-3-indazole carboxylic acid with 40% yield.

We claim;

1) A process for the preparation of endo-9-methyl-9-azabicyclo[3.3.1]non-3-amine
(granatamine) and its pharmaceutical^ acceptable salts comprising the sets of;

a) reacting glutaraldehyde of Formula VIII with mixture of methyl amine hydrochloride and 1,3-acetone dicarboxylic acid, in the presence of aqueous disodium hydrogen orthophosphate and water, to give 9-methyl-9-azabicyclo[3.3.1]nonan-3-one of Formula IX;

b) reacting 9-methyl-9-azabicyclo[3.3.1]nonan-3-one of Formula IX with a mixture of sodium acetate and hydroxylamine hydrochloride, in the presence of methanol, to give 9-methyl-9-azabicyclo [3.3.1]non-3-one oxime of Formula X; and

c) reducing 9-methyl-9-azabicyclo [3.3.1]non-3-one oxime of Formula X with Raney nickel and hydrogen, in a basic medium and isopropanol as a solvent, to give enc/o-9-methyl-9-azabicyclo [3.3.1]nonan-3-amine of Formula IV.

2) A process for the purification of endo-9-methyl-9-azabicyclo [3.3.1]nonan-3-amine
comprises the steps of

a) reacting a solution of a crude granatamine in a organic solvent with an organic acid to form a compound of Formula IV(a);

Formula IV(a)
where Org is an anion of the organic acid such as benzoic acid, formic acid, succinic acid, oxalic acid and the like;

b) isolating the organic acid addition salt of Formula IV(a); and

c) suspending the acid addition salt in a non-polar solvent and adding an aqueous inorganic base, then isolating a purified endo-9-methyl-9-azabicyclo [3.3.1]nonan-3-amine

3) A process according to claim 2, wherein said halogenated solvent used in step (c) are dichloromethane, dichloroethane, chloroform.

4) A pure endo-3-methyl-azabicyclo [3.3.1]nonan-3-amine benzoic acid of formula (IV)b;
Formula (IV)b

5) A process for the preparation of granisetron and its pharmaceutically acceptable
salts, comprising at least one of the steps of:

a) reacting N-methyl-indazole-3-carboxylic acid of Formula III with thionyl chloride, in the presence of a N.N-dimethylformamide, to give N-methyl-indazole-3-carboxylic acid chloride of Formula II;

b) condensing N-methyl-indazole-3-carboxylic acid chloride of Formula II with pure endo-N-(9-methyl-9-azabicyclo[3.3.1]nonane salt purified as per claim 2, which further reacted with hydrogen chloride to give granisetron hydrochloride.

6) A process for the preparation of 1 N-methyl-3-indazole carboxylic acid a key intermediate for the preparation of granisetron and its pharmaceutically acceptable salts comprises the steps of;

a) reacting 1H-indole-2,3-dione of Formula VII with a methylating agent, in the presence of a sodium hydride and suitable solvent, to give 1-methyl-1H-indole-2,3-dione of Formula VI;

b) reacting 1-methyl-1H-indole-2,3-dione of Formula VI with trimethyl orthoformate, in the presence of a solvent, to give ketal protected 3,3-dimethoxy-1-methyl-1,3-dihydro-indol-2-one of Formula V;

c) hydrolyzing ketal protected 3,3-dimethoxy-1-methyl-1,3-dihydro-indol-2-one of Formula V under basic conditions, followed by N-amination using a suitable chloramine and acid mediated cyclization, to give 1N-methyl-3-indazole carboxylic acid of Formula III.

7) A process as claimed in claim 6, where in the solvent used in step (a) aprotic solvent such as aprotic solvents such as N,N-dimethylformamide (DMF), Dimethylsulfoxide (DMSO), N,N-dimethylacetamide (DMA), and the like; and mixtures thereof.

8) A process as claimed in claim 6, where in the solvent used in the step (b) alcoholic solvents such as methanol, ethanol, isopropyl alcohol, n-butanol.

9) A process as claimed in claim 6, where in the chloramines used in step (c) for N-amination are sodium hypochlorite and aqueous ammonia, ammonium chloride and sodium hydroxide.

10) A process as claimed in claim 6, wherein acid catalyst used in the step (d) for cyclization are organic acids such as organic acids include formic acid, acetic acid, p-toluenesulfonic acid and the like; examples of inorganic acids include sulphuric acid, hydrochloric acid.