FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
(See section JO, rule 13)
1. Title of the invention
"Process for preparation of Cevimeline hydrochloride"
2. Applicant(s)
Name Nationality Address
USV LIMITED Indian company incorporated B.S.D Station Road Govandi, Mumbai- - 400 088
under Companies Act, 1956 Maharashtra
3. Preamble to the description
The following specification particularly describes the invention and the manner in which it is to be performed.

Field of the invention:
The present invention relates to an improved process for preparation and purification
of (±) cis-2-methylspiro{l-azabicyclo[2.2.2]octene-3,5'-[l,3]oxathiolane}
hydrochloride (Cevimeline hydrochloride).
Background of the invention:
Cevimeline, a quinuclidine derivative of acetylcholine, is an agonist at muscarinic M, and M3 receptors. It has been used for the treatment of dry mouth symptoms (xerostomia) in patients with Sjogren syndrome, an autoimmune disease. Cevimeline hydrochloride marketed by Daiichi Pharmaceutical under the brand name EVOXAC®, is available as white, hard gelatin capsules containing 30 mg of Cevimeline hydrochloride.

US4855290 (hereinafter referred as US'290) discloses process for preparation of Cevimeline which comprises a) preparation of 3-hydroxy-3-mercaptomethylquinuclidine (IV), wherein the epoxide of 3-methylenequinuclidine (III) is reacted with hydrogen sulfide in presence of aqueous sodium hydroxide; b) 3-hydroxy-3-mercaptomethylquinuclidine (IV) which is obtained in a yield of 33% is treated with acetaldehyde and boron trifluoride etherate at 25°C; c) the obtained reaction mixture is treated with 10% aqueous sodium hydroxide solution to get oily residue d) the obtained oily residue is dissolved in ether and precipitated by addition of gaseous HC1 to get the product as a mixture of two geometric isomers of Cevimeline in a ratio of 0.8-1.2:1. It is disclosed that the desired isomer is separated from this isomeric mixture of HC1 salt by multiple fractional recrystallization. The overall yield of cis-trans mixture (V) is 4.6% from quinuclidine-3-one (II). 3-hydroxy-3-mercaptomethylquinuclidine (IV) is characterized by X-ray powder diffraction pattern having peaks at about : 8.88, 11.55, 12.07, 13.05, 15.04, 16.65, 17.34, 18.29, 19.20, 19.84,

20.23, 23.23,24.16,28.17, 33.02, 33.74, 34.90, 35.62,37.06, 38.84 ± 0.2 degrees 2 theta (as
shown in Fig. 2).
This process is depicted in Scheme-I below.

Scheme-1
US2008249312 (hereinafter referred as US'312) describes process for preparation of 2-methylspiro(l,3-oxathiolane-5,3')quinuclidine comprising (a) epoxidation of 3-quinuclidinone (II) or salt thereof in a solvent to form the epoxide of 3-methylenequinuclidine; (b) reaction of the epoxide of 3-methylenequinuclidine with thiocarboxylic acid of formula RCOSH, in a solvent; (c) treatment of the product formed with an acid or a base; and (d) reaction of the product formed with acetaldehyde dialkyl acetal in a solvent to get a mixture of diastereomers (VII) in a 2.5-3.5:1 cis/trans ratio. This process does not disclose separation of cis-isomer of Cevimeline from cis-trans mixture (VII). The overall yield is very low (32.4%). The above process is depicted in Scheme-II,


Scheme-II
US 20090182146 describes process for the preparation and purification of cis-isomer of 2-methylspiro(l ,3-oxathiolane-5,3')quinuclidine from its cis/trans mixture. The process comprises preparation of cis/trans mixture [95:5] of Cevimeline organic sulfonic acid salt by reacting cis/trans-Cevimeline containing about 70% of the cis-isomer with organic sulfonic acid and the obtained salt is purified by recrystallization to get pharmaceutically acceptable cis-isomer of 2-methylspiro(l,3-oxathiolane-5,3')quinuclidine.
US5571918 discloses a method for producing 2-methylspiro(l,3-oxathiolane-5,3')quinuclidine, which comprises reacting 3-hydroxy-3-mercaptomethyIquinuclidine or a salt thereof and a carbonyl compound in the presence of a catalyst made of at least one member selected from the group consisting of tin halides, oxyacids of phosphorus, phosphorus oxyhalides and organic sulfonic acids, to produce cis-form 2-methylspiro(l,3-oxathiolane-5,3')quinuclidine or a salt thereof.
The drawbacks of above discussed processes for the preparation of (±)-cis-2-methylspirofl-azabicyclo[2.2.2]octane-3,5'-[1,3]oxathiolane} are as follows:

a) US'290 teaches cleavage of epoxide ring of compound (III) using hydrogen sulfide gas in presence of aqueous sodium hydroxide solution yielding 3-hydroxy-3-mercaptomethylquinuclidine (IV) which makes work up of the reaction very tedious. The product is obtained by multiple chloroform extractions due to higher solubility of 3-hydroxy-3-mercaptomethylquinuclidine (IV) in water.
b) Following the process of US'290, it was observed that during epoxide ring opening, 30 to 40% of dimer impurity (A) is formed which goes on increasing as reaction time is prolonged which results in lower yield [about 32% w/w] and purity [60-65%] of the desired compound, 3-hydroxy-3-mercaptomethyIquinuclidine (IV). The cis /trans spirocompound is obtained in about 1:1.
c) Large quantities of solvent viz., acetone (220ml/gm) or ethylacetate (600ml/gm) is used for crystallization which increases the cost and thus is not suitable for industrial scale up. Separation of cis-spiro compound at final stage is carried out by multiple fractional crystallization.
d) The process disclosed in US'312 provides cis/trans mixture of diastereomers of 2-methylspiro(l,3-oxathiolane-553')quinuclidine in a ratio of about 3:1. Further it does not disclose the separation of desired product.
There exists a need for an improved process for industrial production of highly pure
(±)-cis-2-memylspiro{l-azabicyclo[2.2.2]octane-3,5'41;3]oxathiolane} or its
hydrochloride salt. The present invention provides a simple and high yielding process for preparation of highly pure (±)-cis-2-methylspiro{l-azabicyclo[2.2.2]octane-3,5'-[l,3]oxathiolane} or its hydrochloride salt which overcomes the disadvantages of the prior art processes as discussed above. Drug substance existing in various polymorphic forms, differ from each other in terms of stability, solubility, compressibility, flowability and spectroscopic properties, thus affecting dissolution, bioavailability and handling characteristics of the substance. We have carried out polymorphic screening
of (±)-cis-2-methylspiro{l-azabicyclo[2.2.2]octane-3,5'-[l,3]oxathiolane}
hydrochloride and its intermediate.

Object of the present invention:
An object of the present invention is to provide a simple and cost effective process for
the preparation of (±)-cis-2-methylspiro{l-azabicyclo[2.2.2]octane-3,5r-
[l,3]oxathiolane} or pharmaceutically acceptable salt thereof in high yield and purity.
Another object of the present invention is to provide process for the preparation of 3-
hydroxy-3-mercaptomethylquinuclidine (IV) in high yield and purity.
Yet another object of the present invention is to provide separation/purification of (±)-
cis-2-methylspiro{l-azabicyclo[2.2.2]octane-3,5'-[l,3]oxathiolane} hydrochloride from
its cis-trans mixture by solvent crystallization or by chromatography.
Another object of the present invention is to provide highly pure (±)-cis-2-
methylspiro{l-azabicyclo[2.2.2]octane-3,5'-[l,3]oxathiolane} hydrochloride having all
impurities less than about 0.15% preferably less than about 0.1%.
Summary of the invention:
The present invention provides a process for preparation of (±)-cis-2-methylspiro{l-azabicyclo[2.2.2]octane-3,5'-[l,3]oxathiolane} or pharmaceutically acceptable salt thereof comprising treating 3-methyIene quinuclidineoxide with hydrogen sulphide in absence of base to get 3-hydroxy-3-mercaptomethylquinuclidine and converting the obtained 3-hydroxy-3-mercaptomethylquinuclidine to (±)-cis-2-methylspiro{l-azabicyc]o[2.2.2]octane-3,5'-[l,3]oxathiolane} or pharmaceutically acceptable salt thereof.
Preferably the treatment of 3-methylene quinuclidineoxide with hydrogen sulphide is performed at temperature of-30 to -10°C in alcohol selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol or mixture thereof.
Another aspect of the present invention provides conversion of 3-hydroxy-3-mercaptomethylquinuclidine to (±)-cis-2-methylspiro{ 1 -azabicyclo[2.2.2]octane-3,5'-[l,3]oxathiolane} or pharmaceutically acceptable salt thereof comprising reacting 3-hydroxy-3-mercaptomethylquinuclidine with aldehyde or derivative thereof in presence of acid/anhydride or boron trifluoride etherate preferably in presence of acid and/or anhydride.

Preferably aldehyde is acetaldehyde and is used in an amount of about 3 moles with respect to 3-hydroxy-3-rnercaptomethylquinuclidine and said aldehyde derivative is selected from the group consisting of 1,1-diethoxy ethane, 1,1 -dimethoxy ethane, 1,1-dipropoxy ethane, 1,1-dibutoxy ethane or mixture thereof.
Another aspect of the present invention provides 3-hydroxy-3-mercaptomethylquinuclidine having at least one characteristic X-ray diffraction peak selected from the group consisting of 11.51, 14.31, 17.07, 17.75, 19.24, 19.72, 21.48, 23.02, 26.69, 30.38, 30.66, 31.24, 31.83, 33.17, 35.86 ± 0.2 degrees 2 theta. Another aspect of the present invention provides isolated compound selected from

Yet another aspect of the present invention provides a process for separating/purifying
(±)-cis-2-methylspiro{ 1 -azabicyclo[2.2.2]octane-3,5'-[l ,3]oxathioIane} or
pharmaceutical!y acceptable salt thereof wherein the separation/purification is performed using normal phase or reverse phase chromatography.
Brief description of the drawing:
Fig.l: X-ray powder diffraction pattern of (±)-cis-2-methylspiro{l-
azabicyclo[2.2.2]octane-3,5'-[l,3]oxathiolane} hydrochloride (Cevimeline
hydrochloride) obtained according to the present invention.
Fig,2: X-ray powder diffraction pattern of 3-hydroxy-3-mercaptomethylquinuclidine
(IV) obtained by following the process of US4855290.
Fig.3: X-ray powder diffraction pattern of 3-hydroxy-3-mercaptomethylquinucIidine
(IV) obtained according to the present invention.
Description of the invention:
The present invention describes an improved process for the preparation of (±)-cis-2-methylspiro{1 -azabicyclo[2.2.2]octane-3,5'-[l,3]oxathiolane} or pharmaceutically acceptable salt thereof in high yield and purity comprising the steps of;

a) epoxidation of 3-quinuclidinone (II) or salt thereof to get epoxide of 3-methylenequinuclidine (III);

b) treating the compound (III) obtained in step a) with hydrogen sulfide in
presence of alcoholic solvent to get 3-hydroxy-3-mercaptomethyl quinuclidine
(IV);
c) optionally purifying compound (IV);

d) cyclizing 3-hydroxy-3-mercaptomethylquinuclidine (IV) of step b) or c) with aldehyde or derivative thereof to get cis-trans 2-methylspiro azabicyclo[2.2.2]octane-3,5'-[l,3]oxathiolane}(VH);

e) optionally converting cis-trans 2-methylspiro{l-azabicyclo[2.2.2]octane-3,5'-[l,3]oxathiolane}(VII) obtained in step d) into its pharmaceutically acceptable salts, preferably hydrochloride salt;
f) separating/purifying (±)-cis-2-methylspiro {1 -azabicyclo[2.2.2]octane-3,5'-[l,3]oxathio!ane} or its pharmaceutically acceptable salt from the cis-trans mixture obtained in step d) or e) by crystallization or by chromatographic techniques to get highly pure (±)-cis-2-methylspiro{l-azabicyclo[2.2.2]octane-3,5'-[l,3]oxathiolane} or its pharmaceutically acceptable salt having HPLC purity at least 98%, preferably more than 99% .

The process of the present invention is represented in the following scheme;

In a preferred embodiment, quinucIidine-3-one (II) is stirred in suitable solvent at 25-30°C followed by addition of trimethylsulfoxonium iodide. The obtained reaction mixture is cooled below 15°C and suitable base preferably sodium hydride is added lotwise to the mixture with stirring maintaining the temperature between 15-20°C followed by dropwise addition of dimethyl sulfoxide (DMSO) at the same temperature. The reaction mixture is stirred and maintained at 25-30°C for 10-12 hrs. After the completion of reaction, the reaction mass is quenched in chilled water and the obtained product is stirred with suitable solvent, preferably chloroform. The separated organic layer is distilled under reduced pressure to get oily mass of 3-methyIenequinuclidine oxide (III) having purity > 98% (by GC method). The product thus obtained is used for the next step without further purification.
Epoxide of 3-methylenequinuclidine (III) thus obtained is dissolved in alcoholic solvent, preferably methanol followed by chilling the solution to low temperature in the range of about -30°C to -10°C, preferably between -30°C to -25°C. H2S gas is purged into the chilled solution at the same temperature. After the completion of reaction, the reaction mixture is allowed to attain the temperature between 25 to 30°C. The solvent is distilled out completely from the reaction mixture under vacuum to get 3-hydroxy-3-

mercaptomethylquinuclidine (IV) in high yield and purity with reduced content of dimer impurity (A).
According to the process of the present invention, compound (IV) is obtained in high yield (about 95-98%), purity (more than 93%) and with reduced content of dimer impurity (A) (about 2-3%) as compared to the prior art process (disclosed in US'290)by which the dimer impurity (A) is formed in about 8% and disulphide impurity (B) in about 40%.

3-hydroxy-3-mercaptornethylquinuclidine (IV) obtained according to the present invention is used for the next step without any further purification.The molar ratio of 3-methylenequinuclidine oxide (III) and H2S gas is about 1:1-10 moles preferably 1:3 moles, more preferably 1:2 moles. The alcoholic solvent is used in 10 to 20 volumes per gram of 3-methylenequinuclidine oxide, preferably 10 volumes.
The alcoholic solvent is selected from the group consisting of methanol, ethanol, isopropanol, n-propanol, ri-butanol or mixture thereof.
The powder X-ray diffraction pattern of compound (IV) according to the present invention exhibits the following peaks (as shown in Fig. 3),

Pos. [°2Th.] Rel. Int. [%]
11.5101 63.13
13.7010 8.16
14.3144 90.83
15.9825 5.17
17.0778 27.19
17.7532 93.31
19.2490 100.00
19.7200 10.05
20.1807 5.37
21.4826 22.59
22.1263 9.12
23.0232 26.47
24.5093 6.96

25.1249 6.78
26.6931 38.28
28.1728 8.00
28.7657 2.46
30.3885 13.4]
30.6610 12.01
31.2406 15.94
31.8381 11.89
33.1791 26.04
35.0398 3.65
35.8680 21.96
36.6364 1.36
40.3317 3.61
41.8570 9.85
42.3389 6.31
42.9991 4.33
45.0035 2.50
46.7879 4.86
47.3982 3.04
3-hydroxy-3-mercaptomethylquinuclidine (IV), if desired, can be purified by heating a solution of 3-hydroxy-3-mercaptornethylquinuclidine (IV) in suitable solvent at 45-50°C to get clear solution; adding neutral alumina at low temperature, preferably at a temperature in the range of 10 to 20°C followed by stirring for 30 minutes and filtering out the alumina. The obtained filtrate is distilled out to get pure 3-hydroxy-3-mercaptomethylquinuclidine having purity of more than 95% (by HPLC).
3- hydroxy-3-mercaptomethylquinuclidine (IV) is dissolved in suitable solvent preferably methylene dichloride (MDC) at 25-30°C. The solution is cooled to 5-10°C followed by dropwise addition of acetaldehyde. BF3 etherate is slowly added to the reaction mixture with stirring at the same temperature. The reaction mass is stirred for 4 to 5 hrs at a temperature of 25-30°C. After the completion of reaction, the pH of the reaction mass is adjusted to 13 using 10% alkali metal hydroxide solution, preferably sodium hydroxide solution. The reaction mixture is extracted with suitable solvent, preferably methylene dichloride and the separated organic layer is evaporated under reduced pressure to get oily mass.
The obtained oily mass is subjected to short path distillation and distillate having a boiling point of about I20-140°C is collected under vacuum (1 mm to 5 mm Hg). The distillate thus collected is stirred with ethereal solvent, preferably methyl tertiary butyl

ether at 25-30°C. The reaction mass is cooled at 5 to 10 °C and dry HC1 gas is purged to the cooled reaction mixture to get cis-trans mixture of 2-methylspiro{l-azabicyclo[2.2.2]octane-3,5'-[l,3]oxathiolane}hydrochloride (V) [ratio of cis:trans isomer is 65:35].
The amount of acetaldehyde used in this step is 3 moles with respect to 3-hydroxy-3-mercaptomethylquinuclidme (IV) which is very less as compared to prior art (US'290) which discloses use of 10 moles of acetaldehyde in cyclisation step b), thus the present process is economically and industrially viable.
Said separation of ' (±)-cis-2-methylspiro{l-azabicyclo[2.2.2]octane-3,5'-
[l,3]oxathiolane} hydrochloride from hydrochloride salt of cis-trans 2-methylspiro{l-azabicyclo[2.2.2]octane-3,5,-[l,3]oxathiolane}(V) is performed by crystallization or using preparative column chromatography to get highly pure (±)-cis-2-methylspiro{l-azabicyclo[2.2.2]octane-3,5'-[l,3]oxathiolane} hydrochloride having HPLC purity at least 98%.
Said separation by crystallisation is performed by dissolving hydrochloride salt of cis-trans 2-methylspiro{l-azabicyclo[2.2.2]octane-3,5'-[lJ3]oxathiolane}(V) (ratio of cis/trans is about 65 : 35) in suitable solvent and isolating the desired product (I).

The isolation of the desired product comprises adding antisolvent to the solution containing hydrochloride salt of cis-trans 2-methylspiro{l-azabicyclo[2.2.2]octane-3,5'-[l,3]oxathiolane}(V). The obtained solution is stirred for 3-5 hours followed by filtration of the precipitated solid (trans-isomer). Suitable antisolvent is again added to the obtained filtrate and the precipitated solid is filtered. The obtained filtrate is concentrated to get the pure (±)-cis-2-methylspiro{l-azabicyclo[2.2.2]octane-3,5'-[l,3]oxathiolane} hydrochloride (I).

This precipitation process may be repeated twice or more to get highly pure (±)-cis-2~methylspiro{l-azabicyclo[2.2.2]octane-3,5'-[l,3]oxathioIane} hydrochloride having a purity of at least 98%, preferably more than 99%.
Suitable solvent used for separation of (±)-cis-2-methylspiro{l-
azabicyclo[2.2.2]octane-3,5'-[l,3]oxathiolane} hydrochloride is selected from the group consisting of alcohol, ester, halogenated hydrocarbon or mixture thereof. Preferably the solvent is selected from ethanol, methanol, ethyl acetate, methyl acetate, dichloromethane or chloroform, preferably ethanol. Suitable antisolvent used for separation of (±)-cis-2-methylspiro{l-azabicyclo[2.2.2]octane-3,5'-[l,3]oxathio!ane} hydrochloride is selected from hydrocarbons such as hexane, n-heptane, cyclohexane, toluene; ethers such as diethyl ether, diisopropyl ether, methyl tertbutyl ether; ketones such as acetone, methyl ethyl ketone or methyl isobutyl ketone ; and esters such as methyl acetate, ethyl acetate or n-butyl acetate or mixture thereof. Preferably the antisolvent used is ethyl acetate and methyl tertiarybutyl ether.
Preferably the volume of the solvent used is 10 to 30 w/v of alcohol or 10 to 15 w/v of ester per gm of compound (V) and antisolvent is used in an amount of 30 to 40 w/v per gm of compound (V).
Another embodiment of the present invention comprises treating a solution of 3-hydroxy-3-mercaptomethylquinuclidine (IV) with suitable aldehyde or derivative thereof in presence of an acid and/or an anhydride to get cis-trans mixture of 2-methylspiro{l-azabicyclo[2.2.2]octane-3,5'-[l,3]oxathiolane} (VII) having at least 95% of cis-isomer and optionally converting it into its hydrochloride salt. This process of the present invention is represented in the following scheme,


Said aldehyde is acetadehyde and said aldehyde derivative is selected from the group consisting of 1,1-diethoxy ethane, 1,1-dimethoxy ethane, 1,1-dipropoxy ethane, 1,1-dibutoxy ethane and the like. Said acid used is halogeriated aliphatic carboxylic acid preferably trihalogenated aliphatic carboxylic acid selected from the group consisting of trifluoro acetic acid, trichloro acetic acid, tribtvmo acetic acid, triiodo acetic acid and the like. Said anhydride used is halogenated aliphatic carboxylic acid anhydride preferably trihalogenated aliphatic carboxylic acid anhydride selected from the group consisting of trifluoro acetic acid anhydride, trichloro acetic acid anhydride, tribromo acetic acid anhydride, triiodo acetic acid anhydride and the like. Said acid or anhydride is used in an amount of 1.5-5 molar equivalents with respect to compound (IV). The preferred ratio of compound (lV):acid or compound (IV):anhydride is 1: 2.5.
In a preferred embodiment of the present invention, 3-hydroxy-3-mercaptomethylquinuclidine (IV) is dissolved in suitable solvent such as chlorinated solvent, preferably chloroform at 25 to 35°C and the obtained solution is cooled to 10 to 15°C. 1,1-diethoxy ethane (acetaldehyde diethyl acetal) is added to the cooled solution, maintaining the same temperature. The obtained reaction mixture is then treated with an acid preferably trichloro acetic acid followed by addition of an anhydride, preferably trichloro acetic anhydride maintaining the same temperature. The mixture is stirred for 10 to 15 minutes. The temperature of the reaction mass is raised slowly to 25 to 35°C and maintained for 24 hrs. After the completion of reaction the mixture is cooled to 10 to 15°C and the pH of reaction mass is adjusted to 13 using alkali metal hydroxide

solution preferably sodium hydroxide solution to get 2-mefhylspiro{l-azabicyclo[2.2.2]octane-3,5'-[l,3]oxathiolane}(VH),
The obtained product (VII) is extracted using suitable water immiscible solvent, preferably chloroform. The combined organic layer is cooled to 10 to 15°C and acidified using suitable acid preferably 5% aqueous sulphuric acid at 10 to 15°C. The separated organic layer is discarded and the pH of the aqueous layer is adjusted to 13 using sodium hydroxide solution followed by extraction using suitable water immiscible solvent preferably hexane. The separated organic layer is distilled out under reduced pressure to get oily mass. The oily mass is dissolved in ethereal solvent, preferably methyl t-butyl ether at 30°C and dry HC1 gas is passed into the reaction mixture at 25-30°C to get pure cis-2-methylspiro{l-azabicyclo[2.2.2]octane-3,5'-[l,3]oxathiolane}hydrochloride [the ratio of cis:trans is 95:05].
None of the processes known in the prior art provide 2-methylspiro{l-azabicyclo[2.2,2]octane-3,5'-[l,3]oxathidlane} with high content of its cis-isomer. The inventors of the present invention invented a simple process to get cis-2-methylspiro{l-azabicyclo[2.2.2]octane-3,5'-[l,3]oxathiolane} hydrochloride with high content of cis-isomer. The key inventive step of the present invention is the use of suitable acid and/or anhydride in cyclization of compound (IV) as described herein which solves the problem of getting 2-methylspiro{l-azabicyclo[2.2.2]octane-3,5'-[l,3]oxathiolane} hydrochloride with high cis-isomer content and in high yield. The present process thus avoids multiple crystallization, saves time and cost and provides 2-methylspiro{l-azabicyclo[2.2.2]octane-3;5'-[l,3]oxathiolane} hydrochloride containing at least 95% of cis-isomer, without any separation techniques or recrystallization.
The separation of highly pure (±)-cis-2-methylspiro{l-azabicyclo[2.2.2]octane-3,5'-[l,3]oxathiolane} hydrochloride having more than 99% purity and containing less than about 0.15% of trans isomer is achieved using easily available and commercially viable techniques such as crystallization, preparative chromatography, HPLC, MPLC, Flash Chromatography preferably preparative column chromatography to get the desired

i somer, (±)-ci s-2 -methy lspiro {1 -azabicy clo [2.2.2] octane- 3,5'- [ 1,3 ] oxathiolane}
hydrochloride.
The process for separating/purifying (±)-cis-2-methylspiro{l-azabicyclo[2.2.2]octane-
3,5'-[l,3]oxathiolane} or pharmaceutically acceptable salt thereof according to the
present invention comprises the following steps,
a) passing through a packed chromatographic column a solution containing cis-trans mixture of 2-methylspiro{l-azabicyclo[2.2.2]octane-3,5'-[l,3]oxathio!ane} or pharmaceutically acceptable salt thereof and
b) eluting the packed chromatographic column loaded with cis-trans mixture with a suitable solvent to get pure (±)-cis-2-methylspiro{l-azabicyclo[2.2.2]octane-3,5'-[l,3]oxathiolane} or pharmaceutically acceptable salt thereof.
According to one preferred embodiment of the present invention purification of Cevimeline or its pharmaceutically acceptable salt is performed by reverse phase column chromatography. The stationary phase used is reverse phase silica Cg, Cis and like. The eluent comprises one or more solvent selected from alcohol, acetonitrile, tetrahydrofuran, water; optionally containing buffer.
Preferably the eluent comprises of water and acetonitrile. The buffer is selected from sodium, potassium and ammonium salt of phosphate, formate and acetate or mixture thereof preferably potassium dihydrogen phosphate.
According to another preferred embodiment of the present invention, the separation/purification of (±)-cis-2-methylspiro{ l-azabicyclo[2.2.2]octane-3,5'-[l,3]oxathiolane} hydrochloride is achieved by reverse phase preparative column chromatography under the conditions mentioned below, Sample preparation: Sample dissolved in water and injected. Column: 50mm DAC column packed with CI 8 Silica lOp, bed length = 25 cm Buffer Preparation: 0.05M KH2P04 + 0.5% TEA,^H adjusted to 3.5 with dil. H3P04 Mobile phase: Buffer : Acetonitrile (95:05)v/v Flow Rate: lOOml/min

Detector wavelength: 210nm
(±)-cis-2-methylspiro{l-azabicyclo[2.2.2]octane-3;5'-[l,3]oxathiolane} hydrochloride (Cevimeline hydrochloride) obtained according to the present invention is characterized by X-ray powder diffraction (XRPD) having the following peaks as shown in Fig.l,

Pos. [°2Th.] Rel. Int. [%]
6.2008 6.74
.12.3624 18.35
14.8132 27.04
15.2131 42.82
15.7144 5.18
15.9702 16.45
16.1696 19.25
18.4029 3.95
19.0974 5.97
19.5283 9.08
20.2243 100.00
21.6937 30.30
22.8694 15.64
23.5654 10.62
24.0595 8.31
24.3636 10.29
24.8371 17.37
25.0365 11.99
25.3478 15.92
25.5681 10.77
26.0440 7.22
26.9022 8.60
27.2376 4.51
29.3048 10.87
29.8403 3.62
30.6569 5.61
31.1601 6.70
31.4910 12.33
31.7458 9.50
33.6984 10.65
34.9506 36.95
The highly pure (±)-cis-2-methylspiro{l-azabicyclo[2.2.2]octane-3,5'-
[l,3]oxathiolane} hydrochloride obtained according to the present invention has all impurities less than 0.15%, preferably less than 0.1%, preferably Cevimeline or

pharmaceutically acceptable salt thereof obtained by the process of the present invention having impurity A or Impurity B each less than 0.15 %. A major advantage of the process of the present invention is that all the reaction steps of the process provide high yield and can be easily transferred at an industrial scale. Quinuclidine-3-one (II) is prepared by treating quinuclidine-3-one hydrochloride with chilled/cooled aqueous solution of base preferably sodium hydroxide followed by stirring the mixture at 25 to 30°C. The reaction mass is then extracted using suitable solvent which is distilled under reduced pressure to get quinuclidine-3-one (II).
The term "highly pure" used herein means purity of greater than about 99%, specifically greater than about 99.5%, more specifically greater than about 99.9% as measured by HPLC.
The suitable solvent used is selected from dipolar aprotic solvent, polar protic solvent, non-polar solvent or mixture thereof. The dipolar aprotic solvent is selected from the group consisting of acetonitrile, acetone, dimethylforaminde (DMF), dimethylacetamide (DMA), N-methylacetamide, N-methylformamide, N,N-dimethylpyrrolidinone, N,N-dimethylpropionamide, dimethyl sulfoxide, sulfolane or esters selected from methyl acetate, ethyl acetate, butyl acetate and the like or mixture thereof. The polar protic solvent is selected from the group consisting of water, methanol, ethanol, n-propanol, isopropanol, n-butanol, acetic acid and the like or mixture thereof. Non polar solvent is selected from aliphatic hydrocarbon, aromatic hydrocarbon, halogenated hydrocarbon, ether or mixture thereof.
The aromatic hydrocarbon is selected from toluene or chlorobenzene. The aliphatic hydrocarbon is selected from straight chain or branched chain ( C5 to C]2) hydrocarbon such as hexane, propane, pentane or n-heptane. The halogenated hydrocarbon is selected from the group consisting of chloroform, carbon tetrachloride methylene chloride (MDC), ethylene chloride, 1,1,1-trichIoroethane, 1,1,2-ethylene trichloride or mixture thereof. Ether is selected from the group consisting of diethyl ether, diisopropyl ether, methyl ter/-butyl ether, tetrahydrofuran, 1,4-dioxane or mixture thereof.

Said acid is selected from cone, hydrochloric acid, cone, sulphuric acid, phosphoric acid, acetic acid, methane sulphonic acid and the like. The base used is selected from sodium hydride, sodium hydroxide, potassium hydroxide, potassium tertiary butoxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, calcium or cesium hydroxide.
According to the present invention, (±)-cis-2-methylspiro{l-azabicyclo[2.2.2]octane-3,5'-[l,3]oxathiolane} hydrochloride has mean particle size less than about 500 micron, preferably less than about 250 micron and more preferably less than about 100 microns. Particularly, about 90% of particles of (±)-cis-2-methyIspiro{l-azabicyclo[2.2.2]octane-3,5'-[l,3]oxathiolane} hydrochloride are in the range of 20 to 250 microns and more preferably 20 to 100 microns which may be further micronized using known techniques to enhance the desired properties of the active in the pharmaceutical composition. The micronized particles of (±)-cis-2-methylspiro{l-azabicyclo[2.2.2]octane-3,5'-[l,3]oxathiolane} hydrochloride are in the range of about 1 to 30 microns preferably less than about 10 microns. Any milling, grinding or other particle size reduction method known in the art can be used to bring the active into any desired particle size range as set forth above.
The following examples are given only to illustrate the present invention. It should be understood that the invention is not to be limited to the specific conditions or details described in those examples.
Example 1 : Preparation of Quinuclidine-3-one (TI):
227 gm of sodium hydroxide in 500 ml of water was cooled to 25 to 30°C with stirring and 500 gm of quinuclidine-3-one hydrochloride was added dropwise to it with continued stirring for about 30 minutes. The obtained reaction mass was subjected to extraction using chloroform [2 X 800 ml, 1 X 500 ml and 1 X 250 ml]. The combined organic layer was washed with 2 X 1000 ml of water, dried over sodium sulfate and distilled under reduced pressure to get quinuclidine-3-one (360 gm). Yield: 92.8%

Example 2 : Preparation of 3-Methylene quinuclidinc oxide (III):
300 g of quinuclidine-3-one was dissolved in 1.2 L of toluene at 25 to 30°C and 690 gm of trimethyloxosulfonium iodide was added slowly to the obtained solution at 25 to 30°C for 30 minutes. 136 gm of sodium hydride was added lot wise to the obtained reaction mixture at temperature below 20°C and then stirred for 15-20 minutes. 783 ml of DMSO was added to reaction mixture dropwise maintaining temperature below 20°C and the reaction mass was maintained at 25-30°C for 10-12 hrs. After the completion of reaction, the reaction mass was quenched in 3L cold water and the product was extracted using chloroform (4 X 800 ml). The combined chloroform layer was washed with water (4 X 900 ml) and distilled under reduced pressure to get 220 gm of oily mass of 3-methylenequinuclidine oxide. Yield: 67.44%
Example 3 : Preparation of 3-hydroxy-3-mercaptomethyIquinuclidine(IV):
100 g of 3-methylenequinuclidine oxide was dissolved in 1L of methanol at 25 to 30°C and the reaction mass was cooled to -25 to -30°C. H2S gas was purged into the cooled solution maintaining the temperature below -30°C. The solution was cooled after purging of H2S gas followed by stirring the reaction mixture at 25 to 30°C for 15 minutes. Excess of H2S was removed by purging nitrogen gas into the reaction mass at 25 to 30 °C for 15 minutes. The solvent was distilled out completely from the reaction mixture under vacuum to get crude 3-hydroxy-3-mercaptomethylquinuclidine (100 gm). Yield : 80.38% Purity: more than 93%
Purification: 3-hydroxy-3-mercaptomethylquinuclidine (100 g ) was dissolved in 900 ml of chloroform and the reaction mass was heated to 45 to 50°C to get clear solution. 100 gm of neutral alumina was added to the clear solution and the mixture was stirred for 15 minutes at 45 to 50°C. The reaction mass was filtered. The obtained filtrate was evaporated under reduced pressure at 50°C to get pure 3-hydroxy-3-mercaptomethylquinuclidine (90 gm). Yield : 58.76%
Example 4 Preparation of 2-methylspiro{l-azabicyclol2.2.2]octane-3,5'-[l,3]oxathiolane} hydrochloride.

150 gm of 3-hydroxy-3-mercaptomethylquinuclidine was charged in 2.5 L of chloroform and stirred at 25 to 30°C. The reaction mass was cooled to 5-10°C and 146 ml of acetaldehyde was added to it dropwise in 1.5 hrs. 283 ml of BF3-etherate was added to the obtained reaction mixture at the same temperature and stirred for 4-5 hrs at 25-30°C. After the completion of reaction, pH of the reaction mass was adjusted to 13 using 10 % aqueous sodium hydroxide solution. The reaction mixture was extracted with 300 ml MDC. The MDC layer was washed with 300 ml of water. The organic layer was evaporated under vacuum to get oily mass. The oily mass is subjected to short path distillation. The distillate was collected at boiling point in range of 80-140°C under vacuum to get 125 gm of the titled compound which was taken in 1.25 L of MTBE and dry HC1 gas was passed to it till its pH is acidic. The slurry was filtered and washed with MTBE to get 120 gm of the titled product (cis isomer 65 % and trans isomer 35 %). Yield: 58.76%
Separation/purification of cis-2-methylspiro{l-azabicyclo[2.2.2]octane-3,5'-
|l,3]oxathiolane} hydrochloride: Example 5 :
40 gm of cis-2-methylspiro{l-azabicyclo[2.2.2]octane-3,5'-[l,3]oxathiolane} hydrochloride (cis: trans content is 65:35) was charged in 400ml ethanol and stirred at 25 to 30°C to get the clear solution. 400 ml ethyl acetate and 800 ml methyl tertiarybutylether (MTBE) was added to the obtained clear solution and the mixture was stirred for 5 hrs at 25 to 30°C. The precipitated solid was filtered. 400 ml of MTBE was added to the obtained filtrate and stirred at 25 to 30°C for 4-5 hrs. The solid obtained was filtered. 400 ml of MTBE was added to the obtained clear filtrate, stirred at 25 to 30°C for 5 hrs and the solid was filtered. The obtained filtrate was concentrated to get 15 gm of product (cis isomer:94%; trans isomer:6%). Yield: 37.8%
Example 6:
2-methylspiro{ l-azabicyclo[2.2.2]octane-3,5'-[l)3]oxathiolane} hydrochloride is subjected to preparative column chromatography (Novasep process). The separated fraction after chromatography was taken and pH was adjusted to 13-14 by using

aqueous NaOH solution followed by extraction with methylene dichloride (MDC). The organic layer was dried on sodium sulphate and concentrated under vacuum to get residue. The residue obtained was dissolved in 20 volumes of ethyl acetate ( per gm of 2-methylspiro{l-azabicyclo[2.2.2]octane-3,5'-[l,3]oxathiolane}) and dry HC1 gas was passed to reaction mass to get a solid. The solid was filtered, washed with chilled ethyl acetate and dried under vacuum to get pure cis-2-methylspiro{l-azabicyclo[2.2.2]octane-3,5'-[l,3]oxathiolane} hydrochloride enriched with cis-isomer content 99.85 % and trans- isomer content 0.15 %. Yield: 70%
Example 7: Preparation of cis-2-methylspiro{l-azabicyclo[2.2.2]octane-3,5'-[l,3]oxathiolane} hydrochloride
50 gm of 3-hydroxy-3-mercaptomethylquinuclidine was charged in 3.75L of chloroform and stirred at 25 to 30°C. The reaction mass was cooled to 10-15°C and 57 ml of 1,1 diethoxyethane was added to it drop wise in 0.5 hrs. A solution of 114 gm of trichloroacetic acid in 250 ml of chloroform was added to the reaction mixture at the same temperature and the temperature was raised to 25-30°C. 128 ml of trichloroacetic anhydride was added in 30 minutes to the reaction mixture and stirred for 24 hrs at 25-30 °C. After the completion of reaction, pH of the reaction mass was adjusted up to 13 using 10 % aqueous sodium hydroxide solution. The reaction mixture was extracted with 500 ml chloroform. The combined chloroform layer was acidified with 340 gm of 5% sulfuric acid solution. The separated aqueous layer was basified with 10% sodium hydroxide solution followed by. extraction using n-hexane. The n-hexane layer was dried over sodium sulphate and concentrated under reduced pressure at 45 to 50°C to get oily mass of 2-methylspiro{l-azabicyclo[2.2.2]octane-3,5'-[l,3]oxathioIane}. The oily mass was further dissolved in methyl t-butyl ether at 25 to 35°C and dry HC1 gas was purged to the reaction mass. The obtained slurry was filtered and washed with methyl t-butyl ether to get 42 gm of the cis-2-methylspiro{l-azabicyclo[2.2.2]octane-3,5'-[l:3]oxathiolane} hydrochloride(containing cis-isomer 96% and trans-isomer 4%). Yield: 61.7%.

Example 8: Preparation of cis-2-methylspiro{l-azabicyclo[2.2.2]octane-3,5t-[1,3]oxathiolane} hydrochloride
50 gm of 3-hydroxy-3-mercaptomethylquinuclidine was charged in 3.75L of chloroform and stirred the solution at 25 to 30°C. The reaction mass was cooled to 10-15°C and 57 ml of 1,1 diethoxyethane was added drop wise in 0.5 hrs. A solution of 114 gm of trifluoroacetic acid in 250 ml of chloroform was added to the reaction mixture at the same temperature and the temperature was raised to 25-30°C followed by addition of 128 ml of trifluoroacetic anhydride in 30 minutes. The reaction mixture was stirred for 24 hrs at 25-30°C. After the completion of reaction, pH of the reaction mass was adjusted to 13 using 10 % aqueous sodium hydroxide solution and reaction mixture was extracted with 500 ml chloroform. The combined chloroform layer was acidified with 340 gm of 5% sulfuric acid solution; The separated aqueous acidic layer was basified with 190 gm of 10% sodium hydroxide solution. The mixture was then extracted using n-hexane from aqueous layer. The separated organic layer was dried over sodium sulphate, concentrated under reduced pressure at 45 to 50°C to get oily mass of Cevimeline base. The obtained oily mass was dissolved in methyl t-butyl ether at 25 to 35°C and dry HC1 gas was purged to the reaction mass. The slurry was filtered and washed with methyl t-butyl ether to get 41 gm of cis-2-methylspiro{l-azabicyclo[2.2.2]octane-3,5'-[l,3]oxathiolane} hydrochloride (containing cis-isomer 94% and trans isomer 6%). Yield: 60.24%.
Example 9: Preparation of cis-2-methylspiro{l-azabicycIo[2.2.2]octane-3,5'-[l,3]oxathiolane} hydrochloride
50 gm of 3-hydroxy-3-mercaptomethylquinuclidine was charged in 3.75L of chloroform and stirred the solution at 25 to 30°C. The solution was cooled to 10-15°C and 57 ml of 1,1 diethoxyethane was added drop wise to it in 0.5 hrs. A solution of 207 gm of tribromoacetic acid in 250 ml of chloroform was added to the reaction mixture at the same temperature. The temperature of the reaction mixture was raised to 25-30°C and 128 ml of trichloroacetic anhydride was added in 30 minutes to it followed by stirring the mixture for 24 hrs at 25-30 °C. After the completion of reaction, pH of the reaction mass was adjusted to 13 using 10 % aqueous sodium hydroxide solution. The

reaction mixture was extracted with 500 ml chloroform and the combined chloroform layer was acidified with 340 gm of 5% sulfuric acid solution. The separated aqueous acidic layer was basified with 190 gm of 10% sodium hydroxide solution. The mixture was extracted with n-hexane and the separated organic layer was dried over sodium sulphate and concentrated under reduced pressure at 45 to 50°C. The oily mass thus obtained was dissolved in methyl t-butyl ether at 25 to 35°C and dry HCI gas was purged to the solution to get the slurry. The obtained slurry was filtered and washed with methyl t-butyl ether to get 36 gm of cis-2-methylspiro{l-azabicyclo[2.2.2]octane-3,5'-[l,3]oxathiolane} hydrochloride (containing cis isomer 94% and trans isomer 6%). Yield: 52.89%
Example 10: Preparation of cis-2-methyIspiro{l-azabicycIo[2.2.2]octane-3,5'-[l,3]oxathiolane} hydrochloride
50 gm of 3-hydroxy-3-mercaptomethylquinuclidine was charged in 3.75L of chloroform and stirred at 25 to 30°C. The reaction mass was cooled to 10-15°C and 57 ml of 1,1 diethoxyethane was added to it drop wise in 0.5 hrs. A solution of 114 gm of trichloroacetic acid in 250 ml of chloroform was added to the reaction mixture at the same temperature and the temperature was raised to 25-30°C and stirred for 24 hrs at 25-30 °C. After the completion of reaction, pH of the reaction mass was adjusted up to 13 using 10 % aqueous sodium hydroxide solution. The reaction mixture was extracted with 500 ml chloroform. The combined chloroform layer was acidified with 340 gm of 5% sulfuric acid solution. The separated aqueous layer was basified with 10% sodium hydroxide solution followed by extraction using n-hexane. The n-hexane layer was dried over sodium sulphate and concentrated under reduced pressure at 45 to 50°C to get oily mass of 2-methylspiro{l-azabicyclo[2.2.2]octane-3,5'-[l,3]oxathiolane}. The oily mass was further dissolved in methyl t-butyl ether at 25 to 35°C and dry HCI gas was purged to the reaction mass. The obtained slurry was filtered and washed with methyl t-butyl ether to get 11.2 gm of the cis-2-methylspiro{l-azabicyclo[2.2.2]octane-3,5'-[l,3]oxathiolane} hydrochloride(containing cis-isomer-80.8% and trans-isomer-19.2%). Yield: 17.6%.

We claim,
l.A process for preparation of (±)-cis-2-methylspiro{l-azabicyclo[2.2.2]octane-3;5'-[l,3]oxathiolane} or pharmaceutically acceptable salt thereof comprising treating 3-methylene quinuclidineoxide with hydrogen sulphide in absence of base to get 3-hydroxy-3-mercaptomethyIquinuclidine and converting the obtained 3-hydroxy-3-rnercaptomethylquinuclidine to (±)-cis-2-methylspiro{l-azabicyclo[2.2.2]octane-3,5'-[l,3]oxathiolane} or pharmaceutically acceptable salt thereof.
2.The process as claimed in claim 1 wherein said treatment of 3-methylene quinuclidineoxide with hydrogen sulphide is performed at temperature of-30 to -10°C in alcohol selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol or mixture thereof.
3.The process as claimed in claim 1 wherein said conversion of 3-hydroxy-3-
mercaptomethylquinuclidine to (±)-cis-2-methylspiro{l-
azabicyclo[2.2.2]octane-3,5'-[l,3]oxathiolane} or pharmaceutically acceptable salt thereof comprises reacting 3-hydroxy-3-mercaptomethylquinuclidine with aldehyde or derivative thereof in presence of acid/anhydride or boron trifluoride etherate.
4.The process as claimed in claim 3 wherein said aldehyde is acetaldehyde and is used in an amount of about 3 moles with respect to 3-hydroxy-3-mercaptomethylquinuclidine and said aldehyde derivative is selected from the group consisting of 1,1-diethoxy ethane, 1,1-dimethoxy ethane, 1,1-dipropoxy ethane, 1,1-dibutoxy ethane or mixture thereof.
5.The process as claimed in claim 3 wherein said acid is trihalogenated aliphatic carboxylic acid selected from trichloro acetic acid, trifluoro acetic acid, tribromo acetic acid and triiodo acetic acid and said anhydride is trihalogenated aliphatic carboxylic anhydride selected from trichloro acetic anhydride, trifluoro acetic anhydride, tribromo acetic anhydride and triiodo acetic anhydride.
6.( ±)-cis-2-methylspiro{l-azabicyclo[2.2.2]octane-3,5'-[l,3]oxathiolane} or
pharmaceutically acceptable salt thereof having impurity A or impurity B in an amount less than about 0.15%


7.A process for preparation of (±)-cis-2-methylspiro{l-azabicyclo[2.2.2]octane-3,5'-[l,3]oxathiolane} or pharmaceutically acceptable salt thereof comprising treating 3-hydroxy-3-mercaptomethylquinuclidine with aldehyde or derivative thereof in presence of an acid and/or anhydride.
8.3- hydroxy-3-mercaptomethylquinuclidine having at least one characteristic X-ray diffraction peak selected from the group consisting of 13.70, 17.07, 21.48, 26.69 ± 0.2 degrees 2 theta.
9.1s olated compound selected from

10. A process for separating/purifying (±)-cis-2-methylspiro{l-
azabicyclo[2.2.2]octane-3,5'-[l,3]oxathiolane} or pharmaceutically acceptable salt thereof wherein the separation/purification is performed using normal phase or reverse phase chromatography.