FORM 2
THE PATENTS ACT 1970
(Act 39 of 1970)
PROVISIONAL SPECIFICATION (SECTION 10, rule 13)
"AN IMPROVED PROCESS FOR THE PREPARATION OF TROSPIUM CHLORIDE"

Enaltec Labs Private Limited
An Indian Company,
Registered under the Indian company's Act 1957
And having its registered office at
501-502 Great Eastern Summit B Sector-15,
CBD Belapur, Navi Mumbai-400 614, INDIA


Enaltec Labs
Chemistry Applied
THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THE
INVENTION
FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of Trospium chloride.
BACKGROUND OF THE INVENTION
Trospium chloride, (lR,3r,5S)-3-[(Hydroxydiphenylacetyl)oxy]spiro[8-azoniabicyclo[3,2,l]octane-8,r-pyrrolidinum]chloride, has the following structure,


Formula (I) Trospiumchlorid is a very potent spasmolytic. Trospium chloride is an antispasmodic, antimuscarinic agent. Because of their excellent spasmolytic properties, azoniaspironortropane derivatives are frequently used pharmaceutically. These compounds are prepared from the naturally occurring tropine but the known processes are laborious and time-consuming and, because of the low yields obtained, are also expensive.Trospium chloride was first disclosed in US 3,480,626.
The oxidative demethylation of tropine to give nortropine (step a) is described by S. P. Findley in J.A.C.S., 75, 3204/1953. However, this process, which takes place with a supersaturated tropine solution at 15 DEG C. and with a reaction time of from 4 to 7
2

,V Enaltec Labs
'\ Chemistry Applied
days, cannot be carried out on a technical scale since, under these reaction conditions, the tropine concentration needed for the reaction cannot be kept stable because the tropine precipitates out spontaneously and is thus removed from the further reaction. A homogenisation of the precipitated tropine, for example by an in-line homogeniser, also did not produce any noticeable improvement.
The preparation of azoniaspironortropane derivatives by quaternisation and esterification or by the reverse reaction sequence is known from Federal Republic of Germany Patent Specification No. 1,194,422 and from Arzneimittelforschung, 17, 714-719/1967 (steps b and c or steps b' and c'). The hydroxyl group of the nortropine or of the corresponding azoniaspiro compound is thereby esterified by reaction with the appropriate acid chlorides, the hydroxyl group of hydroxycarboxylic acids and possibly the NH group of the nortropine thereby having to be protected. A disadvantage of the processes described in these publications is the poor yield, the esterification of the nortropine (step b') and the subsequent reaction with a dihalide (step c') thereby also requiring two further reaction steps. It has long been known to use acid imidazolides as reagents for the esterification of alcohols (see Chem. Ber., 95, 1284-1297/1962). In particular, Federal Republic of Germany Patent Specification No. 2,003,680 describes the reaction of benzilic acid imidazolide with alcohols of thioalcohols which contain a tertiary amino group.
US4, 855,422 disclosed the process for the preaparation of Trospium chloride.The process comprising, reaction nortropine with dichloroalkane followed by reaction with benzilate ester to Trospium chloride. The process involves huge volumes of solvents and tedious workup process for isolation.
So it is necessary to develop the process, which can be carried out on a technical scale and which permits these compound to be prepared in a simple manner in good yield.

,V Enaltec Labs
\ Chemistry Applied SUMMARY OF THE INVENTION:
In accordance with one aspect, the present invention relates to a modified process for the preparation of (lR,3r,5S)-3-[(Hydroxydiphenylacetyl)oxy]spiro[8-azoniabicyclo[3,2,l] octane-8,r-pyrrolidinum]chloride of formula I.
In accordance with another aspect the present invention relates to provide purification method for Tropspium chloride.
DETAILED DESCRIPTION OF THE INVENTION:
It is an object of of the present invention to provide modified process for the preparation of (1 R,3r,5S)-3-[(Hydroxydiphenylacetyl)oxy]spiro[8-azoniabicyclo[3,2,1 ] octane-8,1 '-pyrrolidinumjchloride of formula I..
The process comprising,
a) Reacting 3-hydroxyspiro[8-azoniabicyclo[3.2.1]octane-8,r-pyrrolidine]chloride with 2-Hydroxy-l-imidazole-l-yl-2, 2-diphenyl-ethanone in presence of suitable base in suitable polar aprotic solvent,
b) Isolate the crude solid using filtration techniques,
c) Purifying the solid in suitable solvents.
Definitions
Polar aprotic solvents includes, but not limited to, dimethyl formamide, dimethyl acetamide, dioxane and hexamethylphosphorotriamide, tetrahydrofuran.
The term base includes organic or inorganic base, "organic base" includes, but is not limited to, trialkyl amines, such as triethylamine and diisopropylamines, and heterocylic amines, such as imidazole, pyridine, pyridazine, pyrimidine, and pyrazine; anionic nitrogen bases, such as lithium diisopropylamide, and potassium bis(trimethylsilyamide), and bicyclic amines, such as DBN, and DBU.
4

,V Enaltec Labs
f\ Chemistry Applied
The term "inorganic base" includes, but is not limited to, carbonates such as lithium carbonate sodium carbonate, sodium bicarbonate and cesium carbonate. The substances according to the invention are isolated and purified in a manner known per se, e.g. by distilling off the solvent in vacuum and recrystallizing the residue obtained from a suitable solvent or subjecting it to one of the customary purification methods, such as column chromatography on a suitable support material.
In general, organic solvents include, but are not limited to, the ethereal solvents described herein as well as chlorinated solvents, aromatic solvents, alcoholic solvents, diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran, diisopropyl ether, and 1,4 dioxane. Suitable chlorinated solvents include, but are not limited to, dichloromethane, 1,2-dichloroethane, chloroform, and carbon tetrachloride. Suitable aromatic solvents include, but are not limited to, benzene and toluene. Suitable alchoholic solvents include, but are not limited to, methanol, ethanol, n-propanol, isopropanol, and tert-butanol. Sutiable polar aprotic solvents include, but are not limited to, N,N-dimethylformamide and dimethyl sulfoxide. In general, the compounds prepared in the above described processes are obtained in pure form by using well known techniques such as crystallization using solvents such as pentane, diethyl ether, isopropyl ether, chloroform, dichloromethane, ethyl acetate, acetone, methanol, ethanol, isopropanol, water or their combinations, or column chromatography using alumina or silica gel and eluting the column with solvents such as hexane, petroleum ether (pet. ether), chloroform, ethyl acetate, acetone, methanol or their combinations.
It will be understood that the present invention has been described above by way of example only. The example is not intended to limit the scope of the invention.

Examples
Example-1
Preparation of 2-Hydroxy-l-imidazole-l-yl-2, 2-diphenyl-ethanone:-
N,N-carbonyldiimidazole (150 gm) was dissolved in dichloromethane(1480 ml) under nitrogen at 15-20°C and add Benzilic acid (211 gm), stir for lhrs .Filter the reaction mass and wash with dichloromethane (100 ml) to get 2-Hydroxy-l-imidazole-l-yl-2,2-diphenyl-ethanone (147 gm ).
Example-2
Preparation of Trospium chloride crude:-
Dimethyl formamide (750 ml),3-hydroxyspiro[8-azoniabicyclo[3.2.1]octane-8,l'-pyrrolidine]chloride( 75 gm) and 4-(dimethylamino)-pyridine (42.6 gm) was heated to 80°C ,add 2-Hydroxy-l-imidazole-l-yl-2, 2-diphenyl-ethanone in lots at 80°C,stir the mass for additional 3 hrs then cool to 25°C ,stir and filter the reaction mass and wash with acetonitrile (75 ml) to get crude Trospium chloride (135 gm, 91%).
ExampIe-3
Purification of Trospium chloride:-
Trospium chloride (50 gm) was dissolved in Methanol (500ml) at 20-25°C add activated charcoal (2.5 gm) stir for 1 hrs. Filter reaction mass through hyflo and wash with Methanol (100 ml).Distill methanol under vacuum. Strip with Isopropanol (50 ml).Degas the reaction mass for lhrs. Reaction mass was dissolve in Isopropanol (250 ml) & heat reaction mass 40-50°C. Maintain for 10 min then cool to 0°C.again maintain forlhrs.Filter the reaction mass & wash with chill Isopropanol (50 ml) to get pure Trospium chloride (45 gm, 90 %) HPLC purity-99.87 %.

Although the invention herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and applications of the present invention. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the present invention as defined by the above specification.

All patent and non-patent publications cited in this specification are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated herein by reference.