FORM 2
THE PATENT ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rulel3)

1. TITLE OF THE INVENTION:
"AN IMPROVED PROCESS FOR PREPARING DARIFENACIN
HYDROBROMIDE"
2. APPLICANT
(a) NAME: WATSON PHARMA PRIVATE LIMITED
(b)NATIONALITY: Indian Company incorporated under the Indian
Companies ACT, 1956
(c) ADDRESS: 201/301, Corporate Enclave, HDO-Corporate BIdg.,
B Wing, B. D. Sawant Marg, Chakala, Off Western Express Highway, Andheri (East), Mumbai - 400 099, Maharashtra, India.

3.PREAMBLE TO THE DESCRIPTION:


The following specification particularly describes the invention and the manner in which it is to be performed

TECHNICAL FIELD OF THE INVENTION:
The present invention relates to an improved process for preparing Darifenacin Hydrobromide
BACKGROUND OF THE INVENTION:
Darifenacin, also known as (S)-2-{l-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrro!idinyl}-2,2-diphenylacetamide (I), is a selective M3 receptor antagonist used for the treatment of overactive bladder.

(I)
Darifenacin, marketed under the tradename Enablex®, is administered as the hydrobromide salt, (S)-2-{l-[2-(2,3-dihydrobenzoruran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-diphenylacetamide hydrobromide (II)

(II)
Darifenacin is disclosed in U.S. Patent No. 5,096,890, which describes various routes for the synthesis of Darifenacin hydrobromide. Each of the synthetic routes disclosed within the '890 patent recite the hazardous Mitsunobu reaction, as described in scheme I below.

2

Within the reaction set forth in Scheme I, l-toyl-3-(R)-pyrrolidinol is reacted with methyl tosylate and diethylazodicarboxylate (DEAD). The product obtained is contaminated with triphenylphosphine oxide, which is difficult to separate from the desired product. Moreover, other toxic and hazardous reagents, such as pyridine and sodium hydride, are used in other steps of the synthesis.
U.S. Patent Publication No. 2003/0191176 discloses a process for the synthesis of Darifenacin that require the use of boron trifluoride and carbonyl diimidazole, both of which are toxic reagents.
U.S. Patent Publication No. 2007/0197631 ("the '631 publication") describes the preparation of Darifenacin via Darifenamine using NaBH4, LiAlH4 and H2/Pd as reducing agents, all of which are hazardous to handle on a commercial scale. The process described within the '631 publication also involves the use of sodium tertiary butoxide, which is also potentially hazardous during commercial manufacturing. The '631 publication further describes the synthesis of Darifenacin from 3-(S)-(+)-hydroxypyrrolidine, comprising:
i. Combining 3-(S)-(+)- hydroxypyrrolidine, a sulfonyl halide, and a base in a suitable solvent to obtain l-X-sulfonyl-3-(S)-(-)-X-suIfonyloxypyrrolidine (III).
ii. reacting l-X-sulfonyI-3-(S)-(-)-X-sulfonyloxypyrrolidine (III),
diphenylacetonitrile and an inorganic base in an organic solvent to obtain (S)-2,2-diphenyl-2-(l -X-sulfonyl-3-pyrrolidinil)acetonitrile (IV)
iii. reacting (S)-2,2-diphenyl-2-(l-X-sulfonyl-3-pyrrolidinil)acetonitrile (IV), a bromine acceptor selected from the group consisting of phenol and naphthol and an acid to obtain (S)-2,2-diphenyI-2-(3-pyrrolidinil)acetonitrile salt (V)
iv. combining (S)-2,2-diphenyl-2-(3-pyrrolidinil)acetonitrile salt (V), 2(2,3-
dihydrobenzofuran-5-yl)ethylchloride (VI) and a base in a suitable solvent to
obtain (S)-2-{l-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-
acetonitrile (VII)
v. converting (S)-2-{l-[2-(2,3-dihydrobenzofuran-5-yI)ethyl]-3-pyrrolidinyl}-2,2-acetonitrile (VII) to Darifenacin hydrobromide .
3

This synthesis is represented below in Scheme II.

Darifenacin hydrobromlde

VII
Scheme II
Though the above-described synthesis is potentially feasible on a commercial scale, the
darifenacin obtained from the synthesis is of a low purity. Also, the deprotection
(detosylation) of the intermediate (S)-2,2-diphenyl-2-(l -X-sulfonyl-3-
pyrrolidinil)acetonitrile (IV) is done in aqueous HBr at a temperature of 120° C, which is also a potential hazard.
Therefore, there is a need in the art for a process for the preparation of darifenacin hydrobromide that does not use toxic and dangerous reagents and is feasible on commercial scale. The present invention provides such a process.
SUMMARY OF THE INVENTION:
The present invention provides a process for preparing Darifenacin hydrobromide using compounds of formula VIII, which are easily available on commercial scale.
4


wherein R is linear or branched Ci_]0 alkyl, phenyl, toiyU ortho, meta or para-xylyl.
The invention encompasses a process for preparing Darifenacin hydrobromide comprising:
a) reacting a compound of formula VIII, a solvent selected from the group
consisting of a C6-9 aromatic hydrocarbon, a pc'lar aprotic organic solvent, water
and mixtures thereof, a sulfonyl halide and a ba$e to obtain compounds of formula
IX

wherein R is linear or branched C1-10alkyl, phenyl, tolyl, ortho, meta or para-xylyl and X is linear or branched C1-10 alkyl, phenyl, tolyl, ortho, meta or para-xylyl;

wherein R is linear or branched C1-10 alkyl, phenyl, tolyl, ortho, meta or para-xylyl;
5
b) reacting compounds of formula IX, diphenylacctonitrile and an inorganic base, in
an inorganic or organic solvent selected from the group consisting of a C6-9
aromatic hydrocarbon, a polar aprotic organic solvent, water and mixtures thereof
to obtain compounds of formula X

c) reacting compounds of formula X with a deprotecting agent (such as trifluoroacetic acid, tetrabutyl ammonium fluoride or mixtures thereof) to obtain (S)2,2-diphenyl-2-(3-pyrrolidiniI)acetonitrile of formula XI

d) reacting (S)-2,2-diphenyI-2-(3-pyrrolidinyl)acetonitrile of formula XI with a hydrolyzing agent (such as sulfuric acid, hydrochloric acid, an aqueous solution of sodium hydroxide, potassium hydroxide or mixtures thereof) to obtain 3-(S)-(+)-(l-carbamoyl-l,l-diphenylmethyl)pyrrolidine of formula XII.

Alternately reacting compounds of formula X with 95% sulfuric acid gives 3-(S)-(+)-(l-carbamoyI-l,l-diphenylmethyl)pyrrolidine of formula XII.
e) combining 3-(S)-(+)-(l-carbamoyl-l,l-diphenylmethyl)pyrrolidine of formula XII with an organic acid (such as L(+)-tartaric acid, d-malic acid, 1-malic acid, d-mandelic, 1-mandelic acid or mixtures thereof) in a solvent comprising of alcohols, a halogenated hydrocarbon, ketones, water or mixtures thereof to get 3-(S)-(+)-(l-carbamoyl-l,l-diphenylmethyl)pyrrolidine salt of formula XIII

6
wherein Z is an acid;

f) combining 3-(S)-(+)-(1-carbamoyl-1,1 -diphenylmethyl)pyrrolidine salt of
formula XIII and a compound of formula XIV, in a solvent selected from the
group consisting of a C6-9 aromatic hydrocarbon, a polar aprotic organic solvent,
water and mixtures thereof and an inorganic base to obtain Darifenacin base of
formula I,
wherein, Y is a leaving group selected from the group consisting of I, CI, Br, brosyl, tosyl, trifluoroacetyl; and
g) reacting darifenacin base of formula I with hydrobromic acid in an organic solvent
selected from the group consisting of alcohols, ketones and water or mixtures
thereof to obtain darifenacin
hydrobromide of formula II.
The process can be described by Scheme-Ill, shown below:
7

TrUluoroacetic acid

90% sulfuric acid

XIII


Darifenacin hydrobromide
Scheme-Ill
The present invention also encompasses a process for the purification of Darifenacin hydrobromide comprising of dissolving crude Darifenacin hydrobromide in 1 to 10 volumes of methanol at reflux temperature, adding a decolorizing agent and filtering to get a clear filtrate, Followed by concentrating the filtrate and adding 5 to 20 volumes of acetone and finally isolating the pure Darifenacin hydrobromide, having purity by HPLC of more than 99.5%.
The present invention also encompasses a process for the purification of crude Darifenacin Hydrobromide comprising of dissolving the crude Darifenacin Hydrobromide in 5 to 25 volumes of water at reflux temperature, adding a decolorizing agent and

filtering to get a clear solution, cooling this clear filtrate to 20° C to 30° C and isolating pure Darifenacin Hydrobromide having purity by HPLC of more than 99.5%.
DETAILED DESCRIPTION OF THE INVENTION:


One aspect of the present invention is to provide a process for the synthesis of Darifenacin hydrobromide of formula II, which can be prepared within the scope of this invention as described in Scheme-Ill, wherein R and X are described above, as illustrated below:
The compound of formula IX is prepared by reacting the compound of formula VIII with a sulfonyl halide in presence of a phase transfer catalyst (such as tetrabutyl ammonium
9

bromide, tetrabutyl ammonium iodide, tetrabutyl ammonium hydroxide or mixtures thereof) in a biphasic reaction medium consisting of water and an organic solvent such as toluene, xylene, tetrahydrofuran or mixtures thereof, in the presence of alkali metal salts such as sodium hydroxide, potassium hydroxide, potassium carbonate or mixtures thereof, at a reaction temperature of about 20° C to about 80° C, and more preferably at a temperature range of about 50° C to about 60° C. The product of formula IX can be isolated and purified by conventional means.
The compound of formula X is prepared by reacting the compound of formula IX with diphenylacetonitrile in the presence of a phase transfer catalyst such as tetrabutyl ammonium bromide, tetrabutyl ammonium iodide, tetrabutyl ammonium hydroxide or mixtures thereof in an aqueous medium and an inorganic base such as sodium hydroxide, potassium hydroxide or mixtures thereof. The aqueous concentration of the inorganic base for the optimal reaction is preferably between about 25% to about 70% and more preferably between about 40% to about 60%. The reaction is carried out at a temperature range of about 60° C to about 110° C and more preferably at a range of about 90° C to about 95° C. The product of formula X can be isolated by extracting in a suitable solvent such as toluene, ethylacetate, methylene chloride or mixtures thereof and further concentrated and crystallized.
(S)-2,2-Diphenyl-2-(3-pyrrolidinil) acetonitrile of formula XI is prepared by reacting the compound of formula X with an acid (such as trifluoroacetic acid, methane sulfonic acid, tetrabutyl ammonium fluoride or mixtures thereof) at a temperature range of about 20° C to about 45° C.
(S)-2,2-Diphenyl-2-(3-pyrrolidinil) acetonitrile of formula XI obtained as above is reacted in presence of an aqueous acid such as sulfuric acid at a strength of between about 75% to about 95% at a reaction temperature of about 70° C to about 120° C and more preferably about 100° C to about 120° C. The volume of aqueous acid used for the reaction range between about 1-10 volumes, more preferably about 6-9 volumes. The product 3-(S)-(+)-(l-carbamoyl -1,1-diphenyl methyl ) pyrrolidine of formula XII is isolated by neutralization by an alkali followed by extraction and isolation of the product as a foam.
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3-(S)-(+)-(l -carbamoyl -1,1-diphenyI methyl)pyrrolidine of formula XII is dissolved in a suitable solvent such as an alcohol selected from the group consisting of methanol, ethanol, isopropanol or mixtures thereof) and L-(+)-Tartaric acid is added at a temperature range of about 20° C to about 60° C and more preferably at a temperature range of about 40° C to about 50° C to give 3-(SH+Hl -carbamoyl -1,1-diphenyl methyl ) Pyrrolidine Tartrate of formula XIII.
Alternatively, 3-(S)-{+Hl"carDamoyl-Ul-diphenyImethyl)pyrrolidine Tartrate of formula XIII can be prepared directly from a compound of formula X by reacting it with aqueous sulfuric acid at a strength of between about 75% to about 95% at a temperature range of about 60° C to about 100° C and more preferably about 75° C to about 90° C. The product 3-(S)-(+)-( I -carbamoyl -1,1-diphenyl methyl) pyrrolidine of formula XII is dissolved in a suitable solvent such as an alcohol selected from the group consisting of methanol, ethanol, isopropanol or mixtures thereof) and L-(+)-Tartaric acid is added at a temperature range of about 20° C to about 60° C and more preferably about 40° C to about 50° C to give 3-(S)-(+)-(l -carbamoyl -1,1-diphenyl methyl ) pyrrolidine Tartrate of formula XIII.
Darifenacin base of formula I is prepared by the reaction of 3-(S)—(+)—(1 -carbamoyl-1,1-diphenylmethyl)pyrrolidine Tartrate of formula XIII with 5-(2-Bromoethyl)dihydrobenzofuran in an aqueous medium in the presence of an inorganic base such as sodium hydroxide, potassium hydroxide, potassium carbonate or mixtures thereof at a reaction temperature range of about 60° C to about 100° C and more preferably about 80° C to about 100° C.
Another aspect of the present invention includes a purification process during the isolation of Darifenacin base of formula I that involves converting crude Darifenacin base to its acetate salt by treating with acetic acid. The acetate salt is dissolved in water and washed with organic solvents such as toluene, hexane, ethyl acetate or mixtures thereof and then converted to the hydrochloride salt in situ by treating with aqueous hydrochloric acid to a pH of about 1 to about 3. The aqueous solution is then extracted with a suitable solvent such as methylene chloride. The methylene chloride extract is washed with water to remove the unreacted 3-(S)-(+)-(l-carbamoyl-l,l-diphenylmethyl)pyrrolidine. The level of the unreacted 3-(S)-(+)-(l-carbamoyl-l,l-diphenylmethyl)pyrrolidine that is
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present in the range of about 2% to about 5% is reduced to a level of about 0.05% to about 0.5%.
Darifenacin hydrobromide of formula II is prepared by dissolving the Darifenacin base obtained above in acetone and treating with aqueous Hydrobromic acid at a temperature range of about 20° C to about 30° C. The Darifenacin base thus obtained has a purity of about 98.5% to about 99%, as measured by HPLC.
An additional aspect of the present invention is to provide a process for the purification of Darifenacin hydrobromide, by dissolving crude Darifenacin hydrobromide in methanol at a temperature range of about 60° C to about 70° C and treating with a decolorizing agent such as activated carbon. The decolorizing agent is filtered off and methanol is distilled out from the reaction mixture. The pure Darifenacin hydrobromide is isolated by adding about 2 to about 15 volumes of acetone and more preferably about 8 to about 10 volumes of acetone.
The crude Darifenacin hydrobromide can be alternatively purified by dissolving in about 10 to about 16 volumes and more preferably about 13 to about 14 volumes of water at about 90° C to about 100° C, followed by treatment with a decolorizing agent. The decolorizing agent is filtered off and the clear filtrate is cooled to a temperature range of from about 10° C to about 50° C and more preferably from about 20° C to about 30° C and the product obtained is filtered to get Darifenacin hydrobromide having HPLC purity of more than about 99.7%.
EXAMPLES Example I
Preparation of 1-Tertiary butyloxy carbonyl -3-(S)-sulfonyloxy pyrrolidine (IX)
100 gms (0.53 moles) of S-(+)-N-BOC-3-hydroxy pyrrolidine was suspended in 500 ml of toluene. 5.0 gm of Terra butyl ammonium bromide and 122 gms (0.64 moles) of p-Toluene sulphonyl chloride were added to the reaction mixture at 25° C -30° C. A solution of 53 gms (1.33 moles) of sodium hydroxide in 123 ml water was slowly added to the reaction mixture in about 90 minutes. The reaction mixture was then heated to 50° C - 60° C and stirred at this temperature for 4 hours. 300 ml of water and 100 ml Toluene
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were added to the reaction mixture at 50° C - 60° C. The reaction mixture was cooled to about 25° C - 30° C and the Toluene layer was separated from the aqueous layer. The Toluene extract was washed with 300 ml water and then dried over anhydrous sodium sulfate. The Toluene layer was then concentrated under vacuum maintaining temperature below 70° C. 100 ml'of hexane was added to the reaction mass and the reaction mixture was concentrated under vacuum to get an oily residue. 500 ml hexane was added to the reaction mass under stirring. The reaction mass was further stirred for 6 hours at 20° C -30° C. The solids obtained were filtered and washed with 200 ml of hexane. The product was dried at 40° C to get 150 gms of 1-tertiary butyloxy carbonyI-3-{S)-sulfonyloxy pyrrolidine as off-white crystals.
Melting range = 56° C-63°C
S.O.R. = +11.6°
HPLC Purity > 99%
Example 2
Preparation of (S)-2,2-DiphenyI-2-[(l-tertiarybutyloxycarbonyl)-3-
pyrrolidiniljacetonitrile (X)
15 gms of Tetrabutylammonium bromide was added to 300 ml of 50% aqueous sodium hydroxide solution under stirring at 25 - 35° C. Diphenylacetonitrile, 56.6 gms (0.29 moles) was added to the reaction mixture and stirred at 25° C - 35° C for 15 minutes. 1-tertiary butyloxy carbonyl-3-(S)-sulfonyloxy pyrrolidine, 100 gms (0.293 moles), was added to the reaction mixture. The reaction mixture was then heated to 90° C - 95° C and stirred at this temperature for 15 to 30 minutes. 200 ml Toluene and 500 ml water was added and the reaction mass was quickly cooled to about 30° C to 40° C and stirred at this temperature for 30 minutes. The reaction mass was allowed to settle and the layers were separated. The aqueous layer was back extracted twice with 300 ml Toluene. The Toluene extracts were combined together and washed twice with 500 ml water. The Toluene extracts was dried over anhydrous sodium sulfate. The reaction mass was then concentrated under vacuum to get an oily mass. 200 ml of hexane was added to the oily mass and heated to reflux. The reaction mixture was stirred at the reflux for 1 hour. The reaction mixture was further cooled to 20° C to 30° C and stirred for 30 minutes. The
13

solids obtained were filtered and washed with 300 ml hexane. The wet product was dried at 40° C - 50° C to get 80 gms of (S)-2,2-Diphenyl-2-((i-tertiary butyloxy carbonyl)-3-pyrrolidinil] acetonitrile as off-white crystals.
Melting Point = 113° C-115° C
S.O.R. - +7.2°
HPLC > 98%
Example 3
Preparation of (S)-2,2-Diphenyl-2-(3-pyrrolidinil) acetonitrile (XI)
100 gms (0.276 moles) of (S)-2,2-Diphenyl-2-[(1-tertiary butyloxy carbonyl)-3-pyrrolidinil] acetonitrile was dissolved in 100 ml triflUOroacetic acid under stirring, maintaining temperature between 25° C and 45° C. The reaction mixture was cooled to 20^ C - 30^ C and' stirred" at this temperature for 1 hour. (1 liter of water was added' slowly to the reaction mixture and stirred for 10 minutes. The reaction mixture was then cooled to 5° C - 15° C. The pH of the reaction mixture was adjusted to 11-12 using 50% aqueous sodium hydroxide solution and maintaining temperature below 30° C. The reaction mass was then extracted with I liter MDC thrice. All the MDC extracts were combined together and washed with 1 liter water twice. The MDC extract was dried over anhydrous sodium sulfate and then concentrated under vacuum below 40° C to remove MDC completely. The reaction mass is degassed for 30 minutes under vacuum at 40° C to obtain (S) -2,2-Diphenyl-2-(3-pyrrolidinil) acetonitrile as oil.
Yield = 70 gms
S.O.R. = +17°
HPLC Purity >98%
Example 4
Preparation of 3-(S)-(+)-(1-carbamoyl -1,1-diphenylmethyl ) pyrrolidine Tartrate
(xm)
14

(S)-2,2-Diphenyl-2-(3-pyrrolidinil) acetonotrile 100 gms ( 0.38 nioles) ,was dissolved in 800 ml of 90% w/w sulfuric acid solution under stirring. The reaction mixture was heated to attain a temperature of 100° C - 110° C. The reaction mixture was stirred at 100° C -110° C about 6 hours. The reaction mixture was cooled to about 25° C-35° C and slowly quenched into 4 L of ice cold water maintaining temperature below 35° C. MDC 1 L was added to the reaction mixture and stirred for 15 minutes at 25° C - 35° C. The layers were separated and the MDC layer was discarded. The aqueous layer was cooled to 10° C - 15° C. The pH of the aqueous layer was slowly adjusted to 11-12 using 50% aqueous sodium hydroxide solution. The reaction mixture was extracted thrice with 1-5 lit MDC. All the MDC extracts were combined and washed twice with 1-5 L water. The MDC extract was dried over anhydrous sodium sulfate and concentrated under vacuum maintaining temperature below 45° C to obtain an 3-(S)—(+)—(1 -carbamoyl -1,1-diphenyl methyl ) pyrrolidine (XII) as oily residue (75 gms).
The oily residue was dissolved in 75 ml methanol. As solution of 40.17 gms (0.267mole) L-(+)-Tartaric acid in 150 ml of methanol was then slowly added to the reaction mixture under stirring maintaining temperature below 50° C. The reaction mixture was stirred at 40° C - 50° C for 15 minutes and then cooled to 20° C - 30° C and stirred at this temperature for 3 hrs. The reaction mixture further cooled at 5° C - 10° C and stirred for 1 hour. The product obtained was filtered and washed with 50 ml chilled methanol. The wet product was dried at 40° C to obtain 80 gms 3-(s)-(+)-(l-carbamoyl-l,I-diphenyl methyl)pyrrolidine Tartrate as white crystals . Melting range = 181° C - 186° C
S.O.R. = +17°
HPLC purity > 98%
Example 5
Alternate preparation of 3-(S)-(+)-(l-carbamoyl-l,l-diphenylniethyl)pyrroIidine (XII) from (S)-2, 2-Diphenyl- 2-[(l- tertiary butyloxy carbonyl)-3-pyrrolidinil] aceto nit rile (X)
15

(S)-2,2-Diphenyl-2-[(l-tertiarybutyloxycarbonyl)-3-pyrrolidinil]acetonitrile, l00gm
(0.276 moles), was suspended in 500 ml of 95% sulfuric acid. The reaction mixture was slowly heated to about 110° C and maintained at this temperature under stirring for 8 hours. The reaction mass was then cooled to about 50° C and slowly quenched into 4 liters of ice-cold water. The reaction mass was extracted twice with 2 liter MDC at 25° C to 30° C. The upper aqueous layer was separated and the pH of the aqueous layer was adjusted to about 10-12 using 50% aqueous sodium hydroxide solution maintaining temperature below 30° C. The reaction mass was extracted thrice with 2 liter MDC. All the MDC extracts were combined together and washed thrice with 2 liter water and then with 2 liter brine solution. The MDC extract was dried over anhydrous sodium sulfate and concentrated under vacuum maintaining temperature below 40° C to get 50 gm of 3-(S)-(+)-(l-carbamoyl -1,1-diphenylmethyl) pyrrolidine (XII) as a foam.
This can be converted to the tartrate salt of formula XIII, as per Example 4.
Example 6
Preparation of Crude Darifenacin hydromide (II)
100 gms (0.23 moles) 3-(S)-(+)-(l-carbamoyl-l,l-diphenyImethyl)pyrrolidine Tartrate was suspended in 300 ml water under stirring at 20° C - 30° C. Powdered Potassium Carbonate 160.46 gms (1.16 moles) was then added to the reaction mixture. 5-(2-Bromoethyl) dihydrobenzofuran, 60.71 gms (0.267 moles) was added to the reaction mixture and heated to about 80° C -100° C. The reaction mixture was stirred maintaining the temperature at 80° C - 100° C for about 1 to 2 hours. The reaction mixture cooled rapidly to attain a temperature of about 40° C - 50° C. Toluene 300 ml was added to the reaction mixture, cooled to 20 -30° C and stirred for 30 minutes. The layers were separated and the aqueous layer was extracted twice with 300 ml Toluene. All the Toluene extracts were combined together and the product was extracted in 400 ml of 20% aqueous acetic solution thrice. The combined acetic acid extracts were washed twice with 200 ml Toluene. The pH of the acetic acid was adjusted to about 1-2 using 20% Hydrochloric acid solution. The reaction mass was extracted with 400 ml MDC thrice. All the MDC extracts were combined together and washed with 300 ml 20% hydrochloric acid solution and then with 300 ml water. The reaction mixture was further washed with 300 ml of saturated aqueous solution sodium bicarbonate twice and then with 300 ml
16

water. The reaction mass was dried over anhydrous sodium sulfate and concentrated under vacuum maintaining temperature below 40° C to obtain oily residue. Acetone 500 ml was added to the oily residue and maintained at 20° C - 30° C for 15 minutes. 38 gms of 48% aqueous HBr solution was added to the reaction mixture at 20° C - 30° C. The reaction mixture was further stirred at 20° C - 30° C for 2 hrs. The precipitated product was filtered and washed with 300 ml chilled acetone. The wet product was dried at 40° C - 45° C under vacuum to obtain 95 gms of Crude Darifenacin hydrobromide as white crystals.
HPLC Purity > 98.5%
Example 7
Purification of Crude Darifenacin hydrobromide
95 gm of crude Darifenacin hydrobromide obtained in Example 5 was suspended in 475 ml methanol. The reaction mass was heated to reflux at about 60 - 70° C to get a clear solution. Activated charcoal 0.2 gm was added to the reaction mixture and stirred maintaining the reflux for 15 minutes. The reaction mixture was then filtered hot over a hyflo bed and the hyflo bed was washed with 95 ml methanol. The clear filtrate was then concentrated under vacuum maintaining temperature below 40° C. Acetone 950 ml was added and the reaction mixture cooled to 20° C -30° C and stirred at this temperature for 1 hour. The product obtained was filtered and washed with 25 ml chilled acetone. The wet product was dried at 50° C under vacuum to obtain 85.5 gms Darifenacin Hydrobromide.
SOR = + 46°
HPLC purity > 99.7%
Example 8
Purification of Crude Darifenacin hydrobromide
100 gm of crude Darifenacin hydrobromide was suspended in 1300 ml water. The suspension was heated to reflux at 90° C - 100° C to get a clear solution. 2 gm activated charcoal was added and the reaction mixture was stirred under reflux for 30 minutes. The
17

reaction mixture was filtered hot over a hyflo bed. The clear filtrate was gradually cooled under stirring to attain 20° C - 30° C temperature. The reaction mass was stirred at this temperature for 2 hours. The product obtained was filtered and washed with 100 ml water. The wet material was dried at 40° C - 50° C under vacuum to obtain 80 gm of pure Darifenacin hydrobromide as white crystals.
HPLC purity > 99.7%
SOR= +46°
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WE CLAIM,
1. An intermediate formed during the synthesis of Darifenacin Hydrobromide comprising a compound of formula X

wherein R is linear or branched C1-10 alkyl, phenyl, tolyl, ortho, meta or para-xylyl.
2. A process for the manufacture of a compound of formula X




wherein R is linear or branched C1-10 alkyl, phenyl, tolyl, ortho,meta or para-xylyl, with p-Toluene sulfonyl chloride in the presence of a phase transfer catalyst and an inorganic base to give a compound of formula IX; and b) reacting a compound of formula IX

wherein R is linear or branched C1-10 alkyl, phenyl, tolyl, ortho, meta or para-
xylyl and X is linear or branched CMO alkyl, phenyl, tolyl, ortho, meta or
para-xylyl,
with diphenylacetonitrile and an inorganic base to give the compound of
formula X.
3. The process of claim 2, wherein the conversion of compound of formula VIII to the compound of formula IX is carried out in a biphasic reaction medium comprising water and one or more organic solvents, in the presence of one or more alkali metal salts.
4. The process of claim 3, wherein the organic solvent is selected from the group consisting of toluene, xylene, tetrahydrofuran and mixtures thereof.
5. The process of claim 3, wherein the one or more alkali metal salts is selected from the group consisting of sodium hydroxide, potassium hydroxide, potassium carbonate and mixtures thereof.
6. The process of claim 2, wherein the conversion of the compound of formula IX to the compound of formula X is carried out in an aqueous solution of one or more inorganic bases in the presence of one or more phase transfer catalysts.
7. The process of claim 6, wherein the one or more inorganic bases is selected from
the group consisting of sodium hydroxide, potassium hydroxide, potassium
carbonate, sodium bicarbonate and mixtures thereof.
8. The process of claim 6, wherein the one or more phase transfer catalysts is selected from the group consisting of tetrabutylammonium bromide, tetrabutylammonium iodide, tetrabutylammonium hydroxide and mixtures thereof.
9. The process of claim 6, wherein the aqueous solution of the one or more inorganic bases has a concentration between about 25% to about 70% w/v.
10. The process of claim 6, wherein the reaction is carried out at the temperature range of between about 60° C to about 110° C.
11. A process for manufacturing Darifenacin from a compound of formula X
20

comprising the steps of
i. reacting the compound of formula X with sulfuric acid to give 3-(S)-(+)—(1 -carbamoyl-1,1 -diphenyl methyl)pyrrolidine of formula XII;

H ~
XII
H \=>
ii. reacting 3-(S)-(+)-(l-carbamoyl-l,l-diphenyl methyl)pyrrolidine of formula XII with L-(+)-Tartaric acid to give 3-(S)—(+)—(l -carbamoyl -1,1-diphenyl methyl) Pyrrolidine Tartrate of formula XIII; and


iii. Reacting the tartrate salt of 3-(S)-(+)-(l-carbamoyl-l,l-diphenylmethyl) pyrrolidine of formula XIII with 5-(2-BromoethyI) dihydrobenzofuran in presence of an inorganic base in an aqueous system to give Darifenacin.
12. The process of claim 11, wherein the strength of sulfuric acid is between about 75% to about 95% w/w.
13. The process of claim 11, wherein the tartrate salt of 3-(S)-(+) -(I-carbamoyl -1,1-diphenyl methyl) pyrrolidine is reacted with 5-(2-Bromoethyl) dihydrobenzofuran in an aqueous solution of one or more inorganic bases.
21

14. The process of claim 13, wherein the one or more inorganic bases is selected from
the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide
and mixtures thereof.
15. The process of claim 13, wherein the reaction is carried out at the temperature range
of about 60° C to about 100° C.
16. A process for purification of Darifenacin hydrobromide comprising:
a. Dissolving crude Darifenacin hydrobromide in methanol at a temperature
range of about 60° C to about 70° C;
b. Filtering the clear methanol solution;
c. Concentrating the clear filtrate; and
d. Adding acetone and isolating pure Darifenacin hydrobromide having HPLC
purity of more than about 99.7%.
17. A process for the purification of Darifenacin hydi-obromide comprising:
i) Dissolving crude Darifenacin hydrobromide in water at a temperature
range of about 90° C to about 100° C; ii) Filtering the clear water solution;
iii) Gradually cooling the clear filtrate to Eibout 20° C to about 30° C; and iv) Isolating pure Darifenacin hydrobroniide having HPLC purity of more
than about 99.7%.
Dated this 24th day of September 2008

Dr. Gopakumar G. Nair Agent for the applicant
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