Field of the Invention
The present invention relates to an improved process for the preparation of Granisetron hydrochloride of formula (I). More particularly this invention relates to the preparation of Granisetron hydrochloride using methyl isobutyl ketone (MIBK) as a single solvent in presence of organic base triethyl amine.

Granisetron hydrochloride which is chemically known as endo-1-Methyl-N- (9-methyl-9-azabicyclo [3.3.1] non-3-yl)-lH indazole-3 carboxamide hydrochloride is a 5-HT (5-hydroxytriptamine) antagonists, and has the following structural formula:

Granisetron hydrochloride is useful as an anti-emetic and it is marketed as Kytril ® by Roche.

EP-A-0200 444 (Beecham Group pic) describes certain 5-HT (5-hydroxytryptamine) antagonists which are described as possessing a number of therapeutic utilities, inter alia the prevention of vomiting following the administration of cytotoxic agents. The compound described in Example 6 is endo-N-(9-methyl-9-azabicyclo[3.3. l]non-3-yl)-l-methylindazole-3-carboxamide, and this compound has been assigned the INN granisetron. EP-A-0200444 also discloses that granisetron can be prepared by reacting l-methylindazole-3-carboxylic acid chloride with endo-3-amino-9-methyl-9-azabicyclo [3.3.1] nonane.
EP 748321 claims the process for preparing granisetron or a pharmaceutical acceptable salt thereof. The process comprises the condensation of compound (3) and (4) followed by de-protecting the intermediate compound of structure (2) to get the granisetron or optionally forming a pharmaceutically accepted salt of Granisetron. The scheme is presented below in which Q= leaving group displaceable by a secondary amine, R= benzyl, benzyl substituted with one or more chloro, alkyl or alkoxy group, t-butyl, allyl or a - butyldimethylsilylgroup.

US Pat. No. 6,268,498 discloses an alternative process for preparing granisetron, by cyclisation of a previously methylated compound of formula (2). It should be noted that the methylation prior to cyclisation is carried out with sodium hydride and methyl iodide as disclosed in example 1 (b) of said patent. However, the cyclisation conditions applied to that compound of formula (2) may facilitate demethylation of the indazole N of the granisetron so obtained. Thus, for example, examples 2 and 3 of said patent describe the cyclisation reaction, but although in Example 2 the reaction leads to granisetron, in Example 3, when the reaction time is increased under the same conditions, quantitatively demethylated granisetron is provided.


ES 2,124,162 patent disclosed a procedure for the preparation of granisetron or its pharmaceutical^ acceptable salts consists of reaction of l-methylindazole-3-carboxamide with 9-methyl-9-azabicyclononane of formula II (L = halogen, OMs, OTs; halogen = esp. CI, Br; Ms SO2Me = ; Ts = SO2C6H4Me4 Thus, l-methylindazole-3-carboxamide in THF containing tetramethylethylenediamine is treated with BuLi in hexane followed by addition of endo-3- (mesyloxy)-9-methyl-9-azabicyclo [3.3.1] nonane hydrochloride (II; L = OMs) to give the title compound i.e. Granisetron The scheme is represented below.

With reference to the above-discussed procedures none of the prior art references disclosed or claimed the use of methyl isobutyl ketone (MIBK) as a single solvent in presence of organic base triethyl amine for the preparation of compound of formula (I).
We focused our research to develop an improved and efficient process for the preparation of the compound of formula (I) in substantial good yield and high purity. The disclosed process has advantages over the processes described in the above-mentioned prior art documents.

Objectives of the Invention
The main objective of the present invention is to provide an improved process for the preparation of compound of formula (I) using methyl isobutyl ketone (MIBK) as a solvent in presence of base triethyl amine.
Another objective of the present invention is to provide a process for the preparation of compound of formula (I), which would be easy to implement on commercial scale, which can avoid the use of toxic solvents like methylene chloride, dimethylformamide, toluene, benzene etc.
Another objective of the present invention is to recover methyl isobutyl ketone (MIBK) and the recovered MIBK is used in subsequent batches to make process more economical and commercially viable.
Still another objective of the present invention is to provide a process for the preparation of compound of formula (I) in good yield and high purity.
Summary of the Invention
Accordingly, the present invention provides an improved process for the preparation of Granisetron hydrochloride (I), which consists the steps of,


(i) reacting 1-methyl indazole-3-carboxylic acid of formula (II) with ethyl chloro formate of formula (III) in the presence of base triethyl amine (TEA) using methyl isobutyl ketone (MIBK) as solvent at a temperature in the range of (-) 5° C to 0° C to get the mixed anhydride of formula (IV);
(ii) condensing the mixed anhydride of formula (IV) with compound of formula (V) to get the compound of formula (VI);
(iii) optionally purifying the compound of formula (VI) by using methanol;
(iv) converting the compound of formula (VI) is converted in to compound of formula (I) by using either isopropyl alcohol / hydrochloric acid or aqueous hydrochloric acid.


Description of the Invention
In an embodiment of the present invention, the reaction step is performed in a single solvent. The solvent is selected from the group consisting of ketonic solvents such as methyl ethyl ketone, methyl isopropyl ketone, methyl propyl ketone, N-methyl pyrrolidone and esters solvents such as ethyl acetate; the most preferred solvent for this reaction is methyl isobutyl ketone (MIBK).
In still another embodiment of the present invention the organic base used for the reaction is such as an alkylamine base which includes triethylamine, N,N-diethyl methylamine, N,N-diethyl aniline, N,N-diethylethylenediamine, or N,N-diisopropylethylamine, dimethylaminopyridine (DMAP) with diisopropylethylamine (DIEA), N-methylmorpholine, N-methylpyrrolidine, 2,6-di-tertbutyl-4-methylpyridine or pyridine, the most preferred base for this reaction is triethyl amine.
In another embodiment of the present invention, the reacting step is preferably performed at a temperature in the range of (-) 15° C to room temperature. Most preferably; the reaction step is performed at a temperature in the range of (-) 5° C to 0° C.
In another embodiment of the present invention, the purification step is preferably performed in an alcoholic solvent which is selected from the group consisting of methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butanol, isobutanol, tertiary butanol, and mixtures thereof, the most preferred alcoholic solvent for the said reaction is methanol.
Starting materials of this invention are prepared according to the literature available in the prior art.
The present invention is illustrated with the following examples, which should not be construed for limiting the scope of the invention.

Example 1
Charged methyl isobutyl ketone (MIBK), tri ethylamine (1.3 Mole) and 1-Methyl Indazole -3-Carboxylic acid (Imole) at room temperature in 250ml RBF. Stirred the reaction mass to get a clear solution. Cool 0°C to -5°C and added drop wise ethyl chloro formate at 0°C to -5°C and maintained for 1 hour to which endo-9 -methyl -9-aza bicycolo[3.3.1] nonan -3 amine (lmole)in MIBK (2 volume) was added, maintained for another 2 hrs the reaction was quenched with water and stirred the reaction mass for 10 mins, the organic layer (upper layer) separated and distilled at 55-60°C U/N vacuum up to 8 volumes, cooled the reaction mass to room temperature and charged 5 volumes of MEBK and further added drop wise IPA / HC1 (0.75mole) at room temperature with in 25 to 30 mins. and maintained at room temperature for 2 hrs. Filtered the reaction mass & washed with MIBK. Dried the Granisetron hydrochloride at 60-70°C U/N vacuum.
Example 2
Charged ethyl acetate, tri ethylamine (1.3 Mole) and 1-Methyl Indazole -3-Carboxylic acid (lmole) at room temperature in 250ml RBF. Stirred the reaction mass to get a clear solution. Cool 0°C to -5°C and added drop wise ethyl chloro formate at 0°C to -5°C and maintained for 1 hour to which endo-9 -methyl -9-aza bicycolo[3.3.1] nonan -3 amine (lmole) was added, maintained for another 2 hrs the reaction was quenched with water and stirred the reaction mass for 10 mins, separated the organic layer (upper layer) and distilled the organic layer at 55-60°C U/N vacuum up to 8 volumes, cooled the reaction mass to room temperature and charged 5 volumes of ethylacetate and further added drop wise IPA / HC1 (0.75mole) at room temperature with in 25 to 30 mins. and maintained at room temperature for 2 hrs. Filtered the reaction mass & washed with ethylacetate. Dried the Granisetron hydrochloride at 60-70°C U/N vacuum.

Example 3
Charged methyl isobutyl ketone (MIBK), tri ethylamine (1.4Mole) and 1-Methyl Indazole -3-Carboxylic acid (lmole) at room temperature in 250ml RBF. Stirred the reaction mass to get a clear solution. Ethyl chloro formate was added drop wise at 20°C to 25°C and maintained for 1 hour to which endo-9-methyl-9-aza bicycolo[3.3.1] nonan-3 amine (lmole) in MIBK (2 volume) was added, maintained for another 2 hrs. The reaction was quenched with water and stirred for 10 mins, the organic layer (upper layer) separated, washed with 5% sodium carbonate solution and distilled at 55°C to 60°C U/N vacuum up to 4 to 5 volumes, cooled the reaction mass to room temperature filter the solid and dry the solid at 50°C to 55°C to obtain granisetron free base. Charged Granisetron freebase (10 Gms) and methanol (100ml) in a 3N RBF. Heated the reaction mass to 40°C to 55°C and filtered the reaction mass. Con. hydrochloric acid (1.1 moles), is added to the filtrate and diluted the reaction with MIBK (200 ml.). Heated the reaction mass to 60°C to 65°C Distilled the reaction mass U/N vacuum to 10-tol2 vol. Cooled the reaction mass to room temperature, filtered and washed with MIBK and dried the solid to get Granisetron Hydrochloride (Dry Wt 10 Gms.).HPLC Purity 99.97%

We Claim:
(1) An improved process for the preparation of Granisetron hydrochloride (I), which comprising the steps of;
(a) reacting the 1-methyl indazole-3-carboxylic acid of formula (II) with ethyl chloro
formate of formula (HI) in the presence of organic base using ketonic solvent at a
low temperature to get the mixed anhydride of formula (IV);
(b) condensing the mixed anhydride of formula (IV) with compound of formula (V)
to get the compound of formula (VI);
(c) optionally purifying the compound of formula (VI) by using alcoholic solvent or
mixture thereof;
(d) converting the compound of formula (VI) in to compound of formula (I) by either
using isopropyl alcohol / hydrochloric acid or aqueous hydrochloric acid.


(2) Process as claimed in claim no. 1, wherein the said reaction is carried out in ketonic
solvent which is selected from the group consisting of methyl ethyl ketone, methyl
isopropyl ketone, methyl propyl ketone, N-methyl pyrrolidone or mixture thereof;
the most preferred solvent for the said reaction is methyl isobutyl ketone (MIBK).
(3) Process as claimed in claim no. 1, wherein the said reaction is carried out in
presence of an organic base such as an alkylamine base which is selected from
the group consisting of triethylamine, N,N-diethyl methylamine, N,N-diethyl
aniline, N,N-diethylethylenediamine, or N,N-diisopropylethylamine,
dimethylaminopyridine (DMAP) with diisopropylethylamine (DIEA), N-
methylmorpholine, N-methylpyrrolidine, 2,6-di-tertbutyl-4-methylpyridine or
pyridine, the most preferred organic base for the said reaction is triethyl amine
(4) Process as claimed in claim no. 1, wherein the said low temperature is preferably
in the range of (-) 15° C to room temperature; the most preferred temperature
range for the reaction is (-) 5° C to 0° C.
(5) Process as claimed in claim no. 1, wherein the purification is carryout in presence
of an alcoholic solvent which is selected from the group consisting of methanol,
ethanol, n-propyl alcohol, isopropyl alcohol, n-butanol, isobutanol, tertiary
butanol, and mixtures thereof, the most preferred alcoholic solvent for the said
reaction is methanol.