FORM 2
THE PATENTS ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
TITLE: PROCESS FOR THE PREPARATION OF CEVIMELINE
Solara Active Pharma Sciences Limited
An Indian company having its registered office at
201, Devavrata, Sector 17, Vashi, Navi Mumbai- 400 703,
Maharashtra, India
The following specification particularly describes the invention and the manner in which it is to be performed.

FIELD OF THE INVENTION
The present application relates to an improved process for the preparation of Cevimeline or a pharmaceutically acceptable salt thereof. More particularly, the present application relates to an improved process for the preparation of Cevimeline hydrochloride hemihydrate.
BACKGROUND OF THE INVENTION
Cevimeline hydrochloride (EVOXAC®), a cholinergic agonist which binds to muscarinic receptors, is useful in the treatment of symptoms of dry mouth in patients with Sjogren's Syndrome. Cevimeline hydrochloride is chemically known as cis-2'-methylspiro {1-azabicyclo [2.2.2] octane-3, 5' -[1,3] oxathiolane} hydrochloride,hydrate (2:1). The chemical structure of Cevimeline hydrochloride is represented as formula I

Preparation of Cevimeline or salt thereof is described in various patents including the U.S. Patent Nos. 4,855,290, 5,571,918 and 4,861,886, 8,080,663 and 8,143,400. However, there remains a need for an efficient process for the preparation of Cevimeline hydrochloride, which offers significant commercial advantages when preparing on an industrial scale.
SUMMARY OF THE INVENTION
The present invention aims to provide an improved process and efficient process for preparing Cevimeline hydrochloride, in high yield and purity.
In an aspect, the present invention provides a process for preparing Cevimeline hydrochloride hemihydrate of formula I,


the process comprising:
a) reacting a mixture comprising 3-quinuclidinone hydrochloride of formula II,

trimethylsulfoxonium iodide and potassium hydroxide in tetrahydrofuran to provide 3-methylenequinuclidine epoxide of formula III in situ;

b) reacting 3-methylenequinuclidine epoxide of formula III in situ with thioacetic acid
in tetrahydrofuran to provide 3-hydroxy-3-acetoxymercaptomethylquinuclidine
thioacetic acid salt of formula IV;


c) treating 3-hydroxy-3-acetoxymercaptomethylquinuclidine thioacetic acid salt of
formula IV with p-toluenesulfonic acid monohydrate in isopropyl alcohol to obtain
3-hydroxy-3-mercaptomethylquiniclidine of formula V in situ;

d) contacting 3-hydroxy-3-mercaptomethylquiniclidine of formula V in situ with a
reaction mixture comprising trifluoroacetic anhydride and acetaldehyde diethyl
acetal in chloroform to provide 2-methylspiro(1,3-oxathiolane-5,3') quinuclidine of
formula VI in situ;

e) treating 2-methylspiro(1,3-oxathiolane-5,3') quinuclidine of formula VI in situ with a
reaction mixture comprising racemic camphorsulfonic acid, toluene and methanol
to provide cis-2-methylspiro(1,3-oxathiolane-5.3') quinuclidine camphorsulfonic
acid salt of formula VII

f) optionally purifying cis-2-methylspiro(1,3-oxathi-olane-5,3') quinuclidine camphorsulfonic acid salt of formula VII; and
g) converting cis-2-methylspiro(l,3-oxathi-olane-5,3') quinuclidine camphorsulfonic acid salt to Cevimeline hydrochloride hemihydrate of formula I.

DETAILED DESCRIPTION OF THE INVENTION
DEFINITIONS
Listed below are definitions of various terms used to describe this invention. These definitions apply to the terms as they are used throughout this specification, unless otherwise limited in specific instances.
As used herein, the term "salt" or "pharmaceutically acceptable salt" refers to those salts of the compounds formed by the process of the present invention which are safe and effective in human beings and that possess the desired biological activity. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977). The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free acid or base with a suitable base or acid. Examples of pharmaceutically acceptable salts include, but are not limited to: hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, perchloric acid, acetic acid, maleic acid, tartaric acid, citric acid, succinic acid, malonic acid, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorsulfonate, citrate, formate, fumarate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, representative alkali or alkaline earth metal salts such as sodium, lithium, potassium, calcium, magnesium, nontoxic ammonium/quaternary ammonium, and the like.
All percentages and ratios used herein are by weight of the total composition and all measurements made are at about 25°C and about atmospheric pressure, unless otherwise designated. All temperatures are in degrees Celsius unless specified otherwise. As used herein, the terms "comprising" and "comprises" mean the elements recited, or their equivalents in structure or function, plus any other element or elements which are not recited. The terms "having" and "including" are also to be construed as open ended. The terms "about," "substantially" and the like are to be construed as

modifying a term or value such that it is not an absolute, but does not read on the prior art. Such terms will be defined by the circumstances and the terms that they modify as those terms are understood by one skilled in the art. All ranges recited herein include the endpoints, including those that recite a range between two values. Whether so indicated or not, all values recited herein are approximate as defined by the circumstances, including the degree of expected experimental error, technique error, and instrument error for a given technique used to measure a value.
The term "optionally" is taken to mean that the event or circumstance described in the specification may or may not occur, and that the description includes instances where the event occurs and instances where it does not.
Unless otherwise specified, the terms "pure" "purity", refer to a compound with 99% chemical purity or greater, as determined by methods conventional in art such as high-performance liquid chromatography (HPLC) or other known methods. In general, this refers to purity with regard to undesired residual solvents, reaction by-products, impurities, and unreacted starting materials. In some instances, the terms "pure" and "purity" may also include chiral purity or enantiomeric excess.
The term "compound" as used herein, refers to the compounds of this application, which includes the key starting materials, intermediates and/or the final product. Specifically, it refers to the compounds of formulae I, II, III, IV, V, VI and/or VII, isomers thereof, and pharmaceutically acceptable salts thereof.
The current process is advantageous, economical and significantly efficient in the commercial manufacture of Cevimeline hydrochloride. The present process, avoids, multiple isolation, tedious work up procedures and hazardous reagents, enables the reaction to be stable at higher temperatures and produces Cevimeline hydrochloride in high yields.
In an aspect, the present invention provides a process for preparing Cevimeline hydrochloride hemihydrate of formula I,


the process comprising:
a) reacting a mixture comprising 3-quinuclidinone hydrochloride of formula II,

trimethylsulfoxonium iodide and potassium hydroxide in tetrahydrofuran to provide 3-methylenequinuclidine epoxide of formula III in situ;

b) reacting 3-methylenequinuclidine epoxide of formula III in situ with thioacetic acid
in tetrahydrofuran to provide 3-hydroxy-3-acetoxymercaptomethylquinuclidine
thioacetic acid salt of formula IV;

c) treating 3-hydroxy-3-acetoxymercaptomethylquinuclidine thioacetic acid salt of
formula IV with p-toluenesulfonic acid monohydrate in isopropyl alcohol to obtain
3-hydroxy-3-mercaptomethylquiniclidine of formula V in situ;


V
d) contacting 3-hydroxy-3-mercaptomethylquiniclidine of formula V in situ with a
reaction mixture comprising trifluoroacetic anhydride and acetaldehyde diethyl
acetal in chloroform to provide 2-methylspiro(1,3-oxathiolane-5,3') quinuclidine of
formula VI in situ;

e) treating 2-methylspiro(1,3-oxathiolane-5,3') quinuclidine of formula VI in situ with a
reaction mixture comprising racemic camphorsulfonic acid, toluene and methanol
to provide cis-2-methylspiro(1,3-oxathiolane-5.3') quinuclidine camphorsulfonic
acid salt of formula VII

f) optionally purifying cis-2-methylspiro(1,3-oxathi-olane-5,3') quinuclidine camphorsulfonic acid salt of formula VII; and
g) converting cis-2-methylspiro(l,3-oxathi-olane-5,3') quinuclidine camphorsulfonic acid salt to Cevimeline hydrochloride hemihydrate of formula I.
The compound of formula II used in the reaction, some of which are known from the literature, may be obtained by methods known from the literature, or using methods known to one skilled in the art.
In certain embodiments, the compound of formula II used in the reaction may include:

i. direct use of a reaction mixture containing formula II compound that is obtained in the course of its synthesis and that comprises a suitable solvent, or by combining a solvent with the reaction mixture; or
ii. dissolving formula II compound in a solvent.
In embodiments of step a), c) and d), the reaction is carried out in situ without isolating the compounds of formula III, V and VI, respectively.
In embodiments of step f), compound of formula VII can be optionally purified by providing a solution comprising compound of formula VII in one or more suitable solvent, heating the reaction mixture to a suitable temperature, cooling the reaction mixture to a suitable temperature and the resulting solid is filtered, washed with a suitable solvent and dried in an oven under reduced pressure.
In certain embodiments, suitable solvents for the reaction include, but are not limited to: alcohols, such as methanol, ethanol, 1 -propanol, isopropyl alcohol; ethers, such as diethyl ether, diisopropyl ether, methyl tertiary-butyl ether, tetrahydrofuran, and dioxane; esters, such as methyl acetate, ethyl formate, ethyl acetate, isopropyl acetate; ketones, such as acetone, methyl ethyl ketone, methyl isobutyl ketone, and diethyl ketone; nitriles, such as acetonitrile and propionitrile; amides, such as formamide, N,N-dimethylformamide, and N,N-dimethylacetamide; sulfoxides, such as dimethyl sulfoxide; aliphatic and aromatic hydrocarbons, such as n-pentane, isopentane, hexane, isohexane, 3-methylpentane, 2,3-dimethylbutane, neohexane, n-heptane, cyclohexane, cycloheptane, petroleum ethers, benzene, toluene, m-xylene, o-xylene, chlorobenzene and anisole; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride; water; or mixtures of two or more thereof.
Unless otherwise specified, in embodiments of step a) to g), the reaction may optionally be carried out in presence of a suitable solvent. The suitable solvent useful for this purpose are as described hereinbefore.
The process of the invention can be schematically represented as follows:


The chemical transformations described throughout the application may be carried out using substantially stoichiometric amounts of reactants, though certain reactions may benefit from using an excess of one or more of the reactants.
In various embodiments, the reaction is carried out at suitable temperatures less than about 150°C, less than about 100°C, less than about 80°C, less than about 60°C, less than about 40°C, less than about 30°C, less than about 20°C, less than about 10°C, or any other suitable temperatures.
Compounds employed at various stages of the process described herein can be prepared as a pharmaceutically acceptable salt by reacting the free acid or base form of the compound with a pharmaceutically acceptable inorganic or organic acid or base. The free acid or free base forms of the compounds of the invention can be prepared from the corresponding base addition salt or acid addition salt from, respectively. For example, a compound of the invention in an acid addition salt form can be converted to the corresponding free base by treating with a suitable base. The completion of the reaction can be monitored by any suitable analytical technique.
In certain embodiments, suitable base used in the reaction include organic or an inorganic base such as for example, diisopropylamine, dimethylamine, ethylenediamine, N,N-diisopropylmethylamine, 4-dimethylaminopyridine, N,N-diisopropylethylamine, triethylamine, aniline, pyridine, piperidine, potassium carbonate, potassium hydrogen carbonate, potassium hydroxide, potassium acetate, potassium methoxide, sodium hydride, sodium carbonate, sodium hydrogen

carbonate, sodium hydroxide, sodium acetate, sodium methoxide, sodium ethoxide, sodium tert-butoxide, lithium carbonate, lithium hydrogen carbonate, lithium hydroxide, lithium acetate, lithium methoxide, barium hydroxide, calcium oxide; ammonia, ammonium chloride, and the like.
The compounds at various stages of the processes including the final compound, of the present application may be isolated using conventional techniques known in the art. For example, useful techniques include, but are not limited to, decantation, centrifugation, gravity filtration, suction filtration, concentrating, cooling, stirring, shaking, combining a solution with an anti-solvent, adding seed crystals, evaporation, flash evaporation, simple evaporation, rotational drying, spray drying, thin-film drying, freeze-drying, and the like. The isolation may be optionally carried out at atmospheric pressure or under a reduced pressure. The solid that is obtained may carry a small proportion of occluded mother liquor containing a higher than desired percentage of impurities and, if desired, the solid may be washed with a solvent to wash out the mother liquor. Evaporation as used herein refers to distilling a solvent completely, or almost completely, at atmospheric pressure or under a reduced pressure. Flash evaporation as used herein refers to distilling of solvent using techniques including, but not limited to, tray drying, spray drying, fluidized bed drying, or thin-film drying, under atmospheric or a reduced pressure.
Unless otherwise specified, the compounds obtained by the chemical transformations at various steps described herein can be used for their following steps without further purification, or can be effectively separated and purified by employing a conventional method known to one skilled in the art, such as recrystallization, column chromatography, by transforming them into a salt form, or by washing with an organic solvent or with an aqueous solution, eventually adjusting the pH. The compounds obtained at various stages of the processes may be purified by precipitation or slurrying in suitable solvents, or by commonly known recrystallisation techniques. The suitable recrystallisation techniques include, but are not limited to, steps of concentrating, cooling, stirring, or shaking a solution containing the compound, combination of a solution containing a compound with an anti-solvent, seeding, removal/partial removal of the solvent, or combinations thereof, evaporation, flash evaporation, or the like. An anti-solvent as used herein refers to a liquid in which a compound is poorly soluble. Compounds can be subjected to any of the purification

techniques more than one time, or can be subjected to more than one of the purification techniques, until the desired purity is attained.
Compounds of the processes described herein may also be purified by slurrying in suitable solvents, for example, by providing a compound in a suitable solvent, if required heating the mixture to higher temperatures, subsequently cooling, and recovering a compound having a higher purity. Optionally, precipitation or crystallization at any of the steps described herein can be initiated by seeding of the reaction mixture with a small quantity of the desired product. Suitable solvents that can be employed for recrystallization or slurrying include, but are not limited to: alcohols, such as methanol, ethanol, 1 -propanol, sopropyl alcohol; ethers, such as diethyl ether, diisopropyl ether, methyl tertiary-butyl ether, tetrahydrofuran, and dioxane; esters, such as methyl acetate, ethyl formate, ethyl acetate, isopropyl acetate; ketones, such as acetone, methyl ethyl ketone, methyl isobutyl ketone, and diethyl ketone; nitriles, such as acetonitrile and propionitrile; amides, such as formamide, N,N-dimethylformamide, and N,N-dimethylacetamide; sulfoxides, such as dimethyl sulfoxide; aliphatic and aromatic hydrocarbons, such as n-pentane, isopentane, hexane, isohexane, 3-methylpentane, 2,3-dimethylbutane, neohexane, n-heptane, cyclohexane, cycloheptane, petroleum ethers, benzene, toluene, m-xylene, o-xylene, chlorobenzene and anisole; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride; water; or mixtures of two or more thereof.
In certain aspects of the present application, the purified Cevimeline may be optionally washed with suitable solvent and dried under suitable drying conditions. Drying may be suitably carried out using equipment such as air tray dryer, vacuum tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, and the like, at atmospheric pressure or under reduced pressure. The drying may be carried out at atmospheric pressure or under a reduced pressure at temperatures of less than about 150°C, or less than about 120°C, or less than about 100°C, or less than about 80°C, or less than about 65°C, or any other suitable temperature as long as Cevimeline or a salt thereof is not degraded in quality. The drying may be carried out for any desired time until the required purity is achieved. For example, it may vary from about 1 to about 10 hours, or about 1 to 24 hours, or longer.

The dried product may optionally be subjected to a particle size reduction technique to obtain desired particle sizes and distributions. Milling or micronization may be performed before drying, or after the completion of drying of the product. Techniques that may be used for particle size reduction include, without limitation sifting; milling using mills, such as, for example, ball, roller, or hammer mills, or jet mills, including, for example, air jet mills; or any other conventional technique. The desired particle sizes may also be achieved directly from the reaction mixture by selecting equipment that is able to provide the compound with the desired particle sizes. Accordingly, Cevimeline hydrochloride hemihydrate may have a desired particle size of less than about 200 μm, less than about 150 μm, less than about 100 μm, less than about 90 μm, less than about 80 μm, less than about 60 μm, less than about 50 μm, less than about 40 μm, less than about 30 μm, less than about 20 μm, less than about 10 μm or less than about 5 μm.
In another aspect, the present application provides Cevimeline hydrochloride hemihydrate which is substantially free of process related impurities. In yet another aspect, Cevimeline hydrochloride hemihydrate prepared according to the present invention has purity at least about 90%, at least about 95%, at least about 98% or at least about 99% by High-performance liquid chromatography (HPLC).
In certain aspects, Cevimeline or a salt thereof can be conveniently prepared, or formed during the process of the invention, as solvates (e.g., hydrates). Hydrates can be conveniently prepared by recrystallization from an aqueous/organic solvent mixture. In certain aspects, Cevimeline or a pharmaceutically acceptable salt thereof can conveniently be prepared in a desired solid-state form using techniques known in the art. The starting material, which can be used for the preparation of desired solid-state form, can be crude or pure Cevimeline obtained by any method known in the art. The starting material for preparing a desired polymorphic form include crystalline forms, amorphous, or mixtures of amorphous and crystalline forms of Cevimeline in any proportions, obtained by any method. For example, amorphous form of Cevimeline or a salt thereof can be obtained by, preparing a solution comprising Cevimeline or a salt thereof, and isolating an amorphous form of Cevimeline or a salt thereof. Isolation may be effected by removing the solvent, or by a precipitation technique. Suitable techniques which may be used for the removal of the solvent include using a rotational distillation device such as a Buchi RotavaporⓇ, spray drying,

thin film drying, freeze drying (lyophilization), and the like, or any other suitable techniques. The solvent may be removed, optionally under reduced pressures, at temperatures less than about 100° C, less than about 75° C, less than about 60° C, less than about 50° C, or any other suitable temperatures.
The choice of solvents, anti-solvents, methods of purification and isolation, is customary to one skilled in the art.
The invention illustratively described herein suitably may be practiced in the absence of any element or elements, limitation or limitations which is not specifically disclosed herein. Thus, for example, in each instance herein any of the terms "comprising" and "consisting of may be replaced with either of the terms. In addition, the solvents, temperatures, reaction durations, etc. delineated herein are for purposes of illustration only and one of ordinary skill in the art will recognize that variation of the reaction conditions can produce the desired products accordingly.
Certain specific aspects and embodiments of the present invention will be better understood in connection with the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner.
EXAMPLES
Example 1: Preparation of 3-hydroxy-3-acetoxymercaptomethylquinuclidine thiolacetic acid salt (Formula IV)
Tetrahydrofuran (600 mL) was charged in to a round bottom flask followed by trimethylsulfoxonium iodide (150 g), and potassium hydroxide (174 g) at 20-30°C. The reaction mixture was stirred for 30-60 minutes at 20-30°C. 3-Quinuclidinone hydrochloride (100 g) was added into the reaction mixture at 20-30°C and rinsed with tetrahydrofuran (50 mL). Further the reaction mixture was stirred at 20-30°C for 10 minutes and then heated to 40-45° C for 15 hours. After the reaction is complete, the reaction mixture was cooled to 0-5 °C, the inorganics were filtered, and slurry was washed with tetrahydrofuran (250 mL). Sodium sulfate was added to the filtrate and stirred for 15 minutes and washed with tetrahydrofuran (50 mL). The tetrahydrofuran containing filtrate was cooled to 0-10°C and thioacetic acid (88.5 g) was added slowly

into the reaction mixture at 0-10°C. The reaction mixture was stirred for 4-5 hours at 0-5°C. The resulting solid was filtered, washed with tetrahydrofuran (100 mL) and dried under suction. The resultant solid was dried in oven under vacuum at 20-30 °C for 4-6 hours to obtain title compound.
Yield: 145 g; 80.56%; purity 96.96%.
Example 2: Preparation of 2-methylspiro(1,3-oxathiolane-5,3') quinuclidine (Formula VI)
Isopropanol (490 mL) was charged in to a round bottom flask followed by solution of 3-hydroxy-3-acetoxymercaptomethylquinuclidine thiolacetic acid salt (140 g) and p-toluene sulfonic acid monohydrate (280 g) at 20-30°C. The reaction mixture was then heated to reflux under stirring for 5 hours at 75-85°C. The reaction mixture was cooled to room temperature, distilled the isopropyl alcohol under vacuum at below 45°C. The oily mass was dissolved in chloroform (6300 ml) and cooled to 0-10°C. A solution of trifluoroacetic anhydride (329 g) in chloroform (140 mL) was added slowly into the reaction mixture for 45-90 minutes at 0-10°C. The resulting mixture was then stirred for 1 hour at 0-10°C. A solution of acetaldehyde diethyl acetal (126 g) in chloroform (140 mL) was added slowly into the reaction mixture at 0-10°C. and stirred for 15 hours at 5-10°C. 10% Aqueous sodium hydroxide solution (2100 mL) was added to the reaction mixture at 0-10°C and temperature raised to 15-25°C. The layers were separated. To the organic layer 5% aqueous sulfuric acid solution (2100 mL) was added slowly at 10-20°C, stirred for 15 minutes and the layers were separated. Obtained aqueous layer was basified with 10% aqueous sodium hydroxide solution at 10-20°C and extracted with methyl tert-butyl ether (2 X 1400 mL, 1 X 700 mL). Combined all the organic layers and distilled methyl tert-butyl ether completely under vacuum below 40°C to obtain the title compound as thick oily mass.
Yield: 77.5 g -4:1 cis/trans ratio mixture of diastereomers.
Example 3: Preparation of cis-2-methylspiro(1,3-oxathiolane-5,3') quinuclidine camphorsulfonic acid salt (Formula VII)
Toluene (387.5 mL) was charged in to a round bottom flask followed by a mixture of 2-methylspiro(l,3-oxathi-olane-5,3') quinuclidine (77.5 g) containing -80% of the cis-

isomer, racemic 1 -camphorsulfonic acid (99.2 g) and methanol (7.75 mL). The reaction mixture was heated to 45-55°C under stirring for 1 hour. The resulting suspension was cooled to 15-25°C and stirred for 15 hours at 15-25°C. The resulting solid was filtered, washed with toluene (193.75 mL) to obtain the title compound as white solid.
Yield: 123 g HPLC cis: trans ratio 95.79:4.21.
Example 4: Purification of the cis-2-methylspiro(1,3-oxathiolane-5,3') quinuclidine camphorsulfonic acid salt, (Formula VII)
Toluene (615 mL) was charged in to a round bottom flask followed by a mixture of Cis/trans-2-methylspiro(1,3-oxathi-olane-5,3') quinuclidine camphorsulfonic acid salt (123 g) containing 95.79% of the cis-isomer and methanol (12.3 mL) was heated to 70-80°C under stirring for 15 minutes to obtain a clear solution. The reaction mixture was cooled to 15-25°C and stirred for 15 hours at 15-25°C. The resulting solid was filtered, washed with toluene (307.5 mL) and dried under suction. The resultant solid was dried in oven under vacuum at 55-65 °C for 12-15 hours to obtain the title compound.
Yield: 73.9 g HPLC: trans isomer 0.08%.
Example 5: Preparation of the Cevimeline hydrochloride hemihydrate (Formula I)
A solution of cis-2-methylspiro(l,3-oxathi-olane-5,3') quinuclidine camphorsulfonic acid salt (62 g) and water (496 mL) was charged in to a round bottom flask and cooled to 0-5 °C. 10% aqueous sodium hydroxide solution was added slowly to adjust pH>12 at 0-5 °C. The aqueous layer was then extracted with methyl tert-butyl ether (1 x 310 mL, 2 x 186 mL). The combined organic layers were evaporated, treated with fresh methyl tert-butyl ether and cooled to 0-5 °C. 20% hydrochloric acid in isopropanol solution was added slowly for 1-3 hours until a pH = -1 was obtained. The reaction mixture was stirred for 2-3 hours at 0-5 °C. The resulting solid was filtered, washed with methyl tert-butyl ether (62 mL) and dried under suction. The resultant solid was dried in oven under vacuum at 45-50 °C for 22-26 hours to obtain the title compound.
Yield: 31.5 g; 90.7%, HPLC: trans isomer 0.09%)

We Claim:
1. A process for preparing Cevimeline hydrochloride hemihydrate of formula I,

the process comprising:
a) reacting a mixture comprising 3-quinuclidinone hydrochloride of formula II,

trimethylsulfoxonium iodide and potassium hydroxide in tetrahydrofuran to provide 3-methylenequinuclidine epoxide of formula III in situ;

b) reacting 3-methylenequinuclidine epoxide of formula III in situ with thioacetic
acid in tetrahydrofuran to provide 3-hydroxy-3-
acetoxymercaptomethylquinuclidine thioacetic acid salt of formula IV;


c) treating 3-hydroxy-3-acetoxymercaptomethylquinuclidine thioacetic acid
salt of formula IV with p-toluenesulfonic acid monohydrate in isopropyl
alcohol to obtain 3-hydroxy-3-mercaptomethylquiniclidine of formula V in
situ;

d) contacting 3-hydroxy-3-mercaptomethylquiniclidine of formula V in situ with
a reaction mixture comprising trifluoroacetic anhydride and acetaldehyde
diethyl acetal in chloroform to provide 2-methylspiro(1,3-oxathiolane-5,3')
quinuclidine of formula VI in situ;

e) treating 2-methylspiro(1,3-oxathiolane-5,3') quinuclidine of formula VI in situ
with a reaction mixture comprising racemic camphorsulfonic acid, toluene
and methanol to provide cis-2-methylspiro(1,3-oxathiolane-5.3')
quinuclidine camphorsulfonic acid salt of formula VII

f) optionally purifying cis-2-methylspiro(1,3-oxathi-olane-5,3') quinuclidine
camphorsulfonic acid salt of formula VII; and

g) converting cis-2-methylspiro(l,3-oxathi-olane-5,3') quinuclidine
camphorsulfonic acid salt to Cevimeline hydrochloride hemihydrate of formula I.
2. The process as claimed in claim 1, wherein the reaction of step a) is carried out in situ without isolating compound of formula III.
3. The process as claimed in claim 1, wherein the reaction of step c) is carried out in situ without isolating compound of formula V.
4. The process as claimed in claim 1, wherein the reaction of step d) is carried out in situ without isolating compound of formula VI.
5. The process as claimed in claim t, wherein the purification of compound of formula VII is carried out in a suitable solvent selected from the group consisting of methanol, ethanol, isopropyl alcohol and toluene.
6. The process as claimed in claim 5, wherein the purification of compound of formula VII is carried out in the group selected from toluene and methanol.
7. The process as claimed in claim 1, wherein the conversion of compound of formula VII to Cevimeline hydrochloride hemihydrate of formula I is carried out by reacting the compound of formula VII with a suitable base in presence of a solvent and further treating with hydrochloric acid in a solvent.
8. The process as claimed in claim 7, wherein the suitable base is selected from potassium hydroxide and sodium hydroxide.
9. The process as claimed in claim 7, wherein the solvent is selected from water, alcohol, ester, ether, hydrocarbons, ketone and mixtures thereof.
10.The process as claimed in claim 7, wherein the Cevimeline hydrochloride hemihydrate is prepared by using 20% hydrochloric acid in isopropyl alcohol.