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"Processes For Preparing Darifenacin Hydrobromide"

Abstract: Abstract: The invention encompasses processes for the preparation of darifenacin hydrobromide.

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Patent Information

Application #
Filing Date
28 April 2008
Publication Number
32/2008
Publication Type
INA
Invention Field
CHEMICAL
Status
Email
Parent Application

Applicants

TEVA PHARMACEUTICAL INDUSTRIES LTD
5 BASEL STREET,P.O.BOX 3190, PETAH TIQVA 49131, ISRAEL

Inventors

1. MERLI VALERIANO
VIA CESARE BATTISTI, NO. 21, CREMELLA LECCO, 23894, ITALY
2. AUGUSTO CANAVESI
VIA M.ROSA 16, LOCATE VARESINO, 22070, ITALY
3. PAOLA DAVERIO
VIA PITAGORA 14, VILASANTA, MILANO, 20058, ITLAY

Specification

PROCESSES FOR PREPARING DARIFENACIN HYDROBROMIPE CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of priority to U.S. provisional application Serial Nos. 60/754,395, filed December 27,2005; 60/772,250, filed February 9, 2006; 60/776,311, filed February 23, 2006; 60/809,147, filed May 25, 2006; 60/813,579, filed June 8, 2006; 60/836,557, filed August 8, 2006; 60/837,407, filed August 10, 2006; 60/850,184, filed October 5, 2006; 60/859,332, filed November 15, 2006; and 60/873,680, filed December 7, 2006, hereby incorporated by reference. This application is also related to U.S. application Serial Nos. --/---/---, filed December 27, 2006 and entitled "Processes for Preparing Darifenacin Hydrobromide" [Attorney docket no. 12670/82309B]; and --/---,—, filed December 27, 2006 and entitled "Pure Darifenacin Hydrobromide Substantially Free of Oxidized Darifenacin and Salts Thereof and Process for the Preparation Thereof [Attorney docket no. 12670/A400US1], hereby incorporated by reference. FIELD OF THE INVENTION [0002] The invention encompasses processes for the preparation of darifenacin hydrobromide. BACKGROUND OF THE INVENTION [0003] Darifenacin, (S)-2-{l-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}- 2,2-diphenylacetamide, a compound having the chemical structure, (Structure Removed) Darifenacin is a selective M3 receptor antagonist. Blockade of destructor muscle activity manifests in an increase in urine volume that the bladder can retain, reduction of urination frequency, and decrease in pressure and urgency associated with the urge to urinate, and thereby episodes of incontinence are reduced. [0004] Darifenacin is administered as the hydrobromide salt, (S)-2-{l-[2-(2,3- dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-22-diphenylacetamide hydrobromide, of the structure (Structure Removed) Darifenacin hydrobromide, and is marketed under the trade name ENABLEX® by Novartis. [0005] U.S. patent No. 5,096,890, hereby incorporated by reference, discloses three routes for the synthesis of darifenacin hydrobromide; all of which comprise the cumbersome and hazardous Mitsunobu reaction, described in the following Scheme. Tos OH DEAD.THF Tos"^ ^oTos Accordingly, l-tosyl-3-(R)-pyrrolidinol is reacted with methyl tosylate, and with diethylazodicarboxylate (DEAD), a very dangerous reagent. Typically, the product is contaminated with triphenylphosphine oxide, which is very difficult to separate from the desired product. Moreover, other toxic and hazardous reagents, such as pyridine and NaH, are used in other steps of the synthesis. [0006] The process disclosed in U.S. publication No. 20003/0191176 for the preparation of darifenacin hydrobromide requires the use of BF3, which is a toxic reagent. [0007] Therefore, there is a need in the art for a process for the preparation of darifenacin hydrobromide that does not use toxic and dangereous reagents and that can be perfomed on an industrial scale. The present invention provides such processes. SUMMARY OF THE INVENTION [0008] The invention encompasses a process for preparing darifenacin hydrobromide. The process comprises: a) combining 3-(S)-(+)-hydroxypyrrolidine, a solvent selected from the group consisting of a C6-9 aromatic hydrocarbon, a polar aprotic organic solvent, and mixtures thereof, a sulfonyl halide, and a base to obtain l-X-sulfonyl-3-(S)-(-)-X-sulfbnyloxypyrrolidine of formula I, (Formula Removed) b) reacting the l-X-sulfonyl-3-(S)-(-)-X-sulfonyloxypyrrolidine of formula I, diphenylacetonitrile, and an inorganic base, in an organic solvent selected from the group consisting of a C6-9 aromatic hydrocarbon, a polar aprotic organic solvent, and mixtures thereof, to obtain (S)-2,2-diphenyl-2-(l-X-sulfonyl-3-pyrrolidinil)acetonitrile of formula II; (Formula Removed) c) reacting the (S)-2,2-diphenyl-2-(l-X-sulfonyl-3-pyrrolidinil)acetonitrile intermediate of formula II, a bromine acceptor selected from the group consisting of phenol and naphthol, and an acid to obtain (S)-2,2-diphenyl-2-(3-pyrrolidinil) acetonitrile salt of formula III, (Formula Removed) wherein the bromine acceptor is phenol only when the acid is HBr; d) combining the (S)-2,2-diphenyl-2-(3-pyrrolidinil)acetonitrile salt of formula HI, a compound of the formula V, (Formula Removed) a solvent selected from the group consisting of a C6-9 aromatic hydrocarbon, a polar organic solvent, water, and mixtures thereof, and a base to obtain a mixture; e) heating the mixture of step d; f) admixing the mixture of step d with an acid to obtain a (S)-2-{l-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-acetonitrile salt of formula IV; and (Formula Removed) g) admixing the (S)-2-{l-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2- acetonitrile salt of formula IV, an inorganic base and a protic solvent; and h) reacting with hydrobromic acid to obtain darifenacin hydrobromide, wherein X is either Ci-io alkyl or C6-9 aryl, wherein Y is a leaving group selected from the group consisting of I, CI, Br, mesyl, tosyl, brosyl, trifluoroacetyl, and trifluoromethansulfonyl, wherein Z1and Z2 are independently an acid. [0009] The invention also encompasses a process for preparing a (S)-2-{l-[2-(2,3- dihydrobenzofuran-5-yl)ethyyl]-3-pyrrolidinyl}-2,2-acetonitrile salt of formula IV, (Formula Removed) V comprising: a) combining (S)-2,2-diphenyl-2-(3-pyrrolidinil)acetonitrile salt of formula III, (Formula Removed) a compound of the formula V, (Formula Removed) a solvent selected from the group consisting of a C6-9 aromatic hydrocarbon, a polar organic solvent, water, and mixtures thereof, and a base to form a mixture; b) heating the mixture of step b, and c) reacting the mixture of step b with an acid to obtain to obtain a (S)-2-{l-[2-(2,3-dihydroberizofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-acetonitrile salt of formula IV; wherein Z1 and Z2 are independently an acid; wherein Y is a leaving group selected from the group consisting of I, CI, Br, brosyl, mesyl, tosyl, trifluoroacetyl, and trifluoromethansulfonyl. [0010] The invention encompasses a process for preparing Darifenacin hydrobromide of the following formula (Formula Removed) by a process comprising preparing a (S)-2-{l-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3- pyrrolidinyl}-2,2-acetonitrile salt of formula IV by the process of the present invention, and converting it to Darifenacin hydrobromide. [0011] The invention also encompasses another process for preparing darifenacin hydrobromide. [0012] The process comprises: a) combining 3-(S)-(+)-hydroxypyrrolidine, a solvent selected from the group consisting of a C6-9 aromatic hydrocarbon, a polar aprotic organic solvent, and mixtures thereof, a sulfonyl halide, and a base to obtain l-X-sulfonyl-3-(S)-(-)- X-sulfonyloxypyrrolidine of formula I, b) reacting the l-X-sulfonyl-3-(S)-(-)-X-sulfonyloxypyrrolidine of formula I, diphenylacetonitrile, and an inorganic base, in an organic solvent selected from the group consisting of a C6-9 aromatic hydrocarbon, a polar aprotic organic solvent, and mixtures thereof, to obtain (S)-2,2-diphenyl-2-(l-X-sulfonyl-3-pyrrolidinil)acetonitrile of formula II; (Formula Removed) c) reacting the (S)-2,2-diphenyl-2-(l-X-sulfonyl-3-pyrrolidinil)acetonitrile intermediate of formula n, a bromine acceptor selected from the group consisting of phenol and naphthol, and an acid to obtain (S)-2,2-diphenyl-2-(3-pyrrolidinil) acetonitrile salt of formula HI, (Formula Removed) wherein the bromine acceptor is phenol only when the acid is HBr; d) reacting the (S)-2,2-diphenyl-2-(3-pyrrolidiml)acetonitrile salt of formula III with an inorganic base in a solvent selected from the group consisting of a water immiscible organic solvent, a polar aprotic organic solvent, water and mixtures thereof to obtain a mixture; e) acidifying the mixture of step d; f) heating the mixture of step e; g) basifying the mixture of step f to obtain 3-(S)-(+)-(l-carbamoyldiphenylmethyl)pyrrolidine of formula XI; (Formula Removed) h) combining the 3-(S)-(+)-(l-carbamoyldiphenylmethyl)pyrrolidine of formula XI, 2-(2,3-dihydrobenzofuran-5-yl)acetaldehyde of formula XII, (Formula Removed) XII and a C6-9 aromatic hydrocarbon to obtain a (S)-darifenamine of formula VII; (Formula Removed) i) admixing the (S)-darifenamine of formula VII with a C1-8 alcohol and a reducing agent to obtain the (S)-darifenacin of formula VIII; and (Formula Removed) j) admixing the (S)-darifenacin of formula VIII with HBr to obtain darifenacin hydrobromide, wherein X is either C1-10 alkyl or C6--9 aryl, preferably, C6--9 aryl, more preferably, tolyl, and Z1 is an acid, preferably, either HBr or HC1. [0013] The present further provides a process for the preparation of 2-(2,3- dihydrobenzofuran-5-yl)acetaldehyde of formula XII (Formula Removed) XII comprising: a) combining 2,3-dihydrobenzofura-5-yl-carboxyaldehyde of formula IX, (Formula Removed) a C2-4 alkylhaloacetate, an alkoxide, and an alkaline hydroxide to obtain the epoxide of the following formula; (Formula Removed) b) admixing the epoxide with a solvent selected from a group consisitng of C6-9 aromatic hydrocarbons, C1-2 halogenated hydrocarbons, water, and mixtures thereof, and an acid selected from a group consisitng of H3PO4, acetic acid, HCl sulfonic acid, and HBr to obtain 2-(2,3-dihydrobenzofuran-5-yl)acetaldehyde of formula XII. [0014] The invention also encompasses 2-(2,3-dihydrobenzofuran-5-yl)acetaldehyde- bisulfite complex of formula X. (Formula Removed) [0015] The invention also encompasses a process for purifying 2-(2,3- dihydrobenzofuran-5-yl)acetaldehyde of formula XII comprising: a) combining 2-(2,3- dihydrobenzofuran-5-yl)acetaldehyde, a water immiscible hydrocarbon, and Na2S2O5 to form a mixture; and b) admixing with a base to the mixture to obtain purified 2-(2,3- dihydrobenzofuran-5-yl)acetaldehyde of formula XII. [0016] The invention also encompasses (S)-darifenamine of formula VII (Formula Removed) [0017] The invention also encompasses a process for preparing (S)-darifenamine of formula VII (Formula Removed) comprising: combining 3-(S)-(+)-(l-carbamoyldiphenylmethyl)pyrrolidine of formula XI, (Formula Removed) 2-(2,3-dihydrobenzofuran-5-yl)acetaldehydeof formula XII, and a C6--9 aromatic hydrocarbon to form obtain (S)-darifenarnine of formula VII. [0018] The present invention further provides the use of the new compound, (S)-Darifenamine of formula VII for the preparation of (S)-Darifenacin hydrobromide. The present invention also provides a process for the preparation of (S)-Darifenacin hydrobromide comprising preparing (S)-Darifenamine of formula VII by the process of the present invention, and converting it to (S)-Darifenacin hydrobromide. [0019] The invention also encompasses a process for preparing the (S)-darifenacin of comprising: combining (S)-darifenamine of formula VII, formula VIII (Formula Removed) a Ci-g alcohol, and a reducing agent to obtain to obtain (S)-darifenamine of formula VII. [0020] The present invention provides a process for the preparation of (S)- Darifenacin hydrobromide comprising preparing (S)-Darifenacin by the process of the present invention, and converting it to (S)-Darifenacin hydrobromide. [0021] The invention also encompasses a process for preparing oxidized darifenacin 3-(S)-(+)-(l-carbamoyldiphenyhnethyl)pyrrolidine of the formula DC (Formula Removed) hydrobromide comprising combining an oxidized derivative of ethyl-dihydrobenzofuran of the following formula (Formula Removed) an inorganic base and water; and admixing with HBr to obtain oxidized darifenacin hydrobromide; wherein Y is a leaving group selected from the group consisting of I, CI, brosyl, mesyl, tosyl, trifluoroacetyl, and trifluoromethansulfonyl. Preferably, Y is CI. [0022] The invention also encompasses another process for the preparation of 3-(S)-(+)-(l-carbamoyldiphenylmethyl)pyrrolidine of the formula DC (Formula Removed) darifenacin hydrobromide comprising: a) combining an oxidized derivative of ethyl-dihydrobenzofuran of the following formula (Formula Removed) an inorganic base and water; b) admixing with HBr to obtain oxidized darifenacin hydrobromide; and c) admixing with a reducing agent to obtain darifenacin hydrobromide, wherein Y is a leaving group selected from the group consisting of I, CI, brosyl, mesyl, tosyl, trifluoroacetyl, and trifluoromethansulfonyl. Preferably, Y is CI. [0023] The present invention encompasses a process for preparing Darifenacin hydrobromide by a process comprising preparing oxidized Darifenacin hydrobromide by the process of the present invention, and converting it to Darifenacin hydrobromide. DETAILED DESCRIPTION OF THE INVENTION [0024] The present invention relates to an improved process for preparing Darifenacin hydrobromide; wherein the cumbersome Mitsunobu reaction is avoided. Also, the synthesis can be scaled up, minimiZ1ng production hazards. [0025] The invention encompasses a process for the preparation of darifenacin hydrobromide, comprising: a) combining 3-(S)-(+)-hydroxvpyrrolidine, a solvent selected from the group consisting of a C6--9 aromatic hydrocarbon, a polar aprotic organic solvent, and mixtures thereof, a sulfonyl halide, and a base to obtain l-X-sulfonyl-3-(S)-(-)-X-sulfonyloxypyrrolidine of formula I, (Formula Removed) b) reacting the l-X-suIfonyl-3-(S)-(-)-X-sulfonyloxypyrrolidine of formula I, diphenylacetonitrile, and an inorganic base, in an organic solvent selected from the group consisting of a Cg-9 aromatic hydrocarbon, a polar aprotic organic solvent, and mixtures thereof, to obtain (S)-2,2-diphenyl-2-(l-X-sulfonyl-3-pyrrolidinil)acetonitrile of formula II; (Formula Removed) c) reacting the (S)-2,2-diphenyl-2-(l-X-sulfonyl-3-pyrrolidinil)acetonitrile intermediate of formula II, a bromine acceptor selected from the group consisting of phenol and naphthol, and an acid to obtain (S)-2,2-diphenyl-2-(3-pyrrolidinil) acetonitrile salt of formula in, (Formula Removed) wherein the bromine acceptor is phenol only when the acid is HBr; d) combining the (S)-2,2-diphenyl-2-(3-pyrrolidinil)acetonitrile salt of formula HI, a compound of the formula V, (Formula Removed) a solvent selected firom the group consisting of a C6-9 aromatic hydrocarbon, a polar organic solvent, water, and mixtures thereof, and a base to obtain a mixture; e) heating the mixture of step d; f) admixing the mixture of step d with an acid to obtain a (S)-2-{l-[2-(2,3-dihydroberjzofuran-5-yl)ethyyl]-3-pyrrolidinyl}-2,2-acetonitrile salt of formula IV; and (Formula Removed) g) admixing the (S)-2- {1 -[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl} -2,2- acetonitrile salt of formula IV, an inorganic base and a protic solvent; and h) reacting with hydrobromic acid to obtain darifenacin hydrobromide, wherein X is either C1-10alkyl or C6-9 aryl. wherein Y is a leaving group selected from the group consisting of I, CI, Br, mesyl, tosyl, brosyl, trifluoroacetyl, and trifluoromethansulfonyl, wherein Z1 and Z2 are independently an acid. [0026] The process can be described by the following scheme: (Scheme Removed) Darifenacin hydrobromide wherein X, Y, Z1 and Z2 are described before. [0027] Preferably, X is C6-9 aryl, more preferably, tolyl. Preferably, Y is CI. Preferably, the acid, is either HBr or HC1. [0028] The N-O-sulfonation reaction of the present invention is performed using solvents, which are not hazardous and toxic, as compared to pyridine that is used in US Patent No. 5,096,890. Also, the reaction is much shorter, and leads to a much higher yield, 96% vs. 75%. Moreover, the product is isolated very easily from a mixture of toluene and water, as compared to the difficult isolation performed in US patent No. 5096890, which includes recovering the product by time consuming steps, such as distillation of pyridine, extractions with dichloromethane, and crystallization from n-propanol. Hence, the sulfonation reaction limits the process from being scaled up. [0029] The intermediate of formula I, 1 -X-sulfonyl-3-(S)-(-)-X- sulfonyloxyp yrrolidine (Formula Removed) is prepared by a process comprising combining 3-(S)-(+)-hydroxypyrrolidine of the following formula, (Formula Removed) H 3-(S)-(+)-hydroxypyrrolidine a solvent selected from the group consisting of a C6-9 aromatic hydrocarbon, a polar aprotic organic solvent, and mixtures thereof, a sulfonyl halide, and a base; wherein X is either C1-10 alkyl or C6--9 aryl. Preferably, X is C6-9 aryl, and more preferably tolyl. [0030] Typically, the 1 -X-sulfonyl-3-(S)-(-)-X-sulfonyloxypyrrolidine of formula I is obtained by the above process in a purity of about 95% to about 99% area by HPLC. [0031 ] The starting material, 3-(S)-(+)-hydroxypyrrolidine is commercially available. [0032] Typically, combining the 3-(S)-(+)-hydroxypyrrolidine and the solvent provides a solution. The sulfonyl halide is then added to the solution to form a mixture. The addition of the sulfonyl hahde to the solution leads to a rise in the temperature of the solution, typically to about 35°C to about 40°C. Preferably, the base is then added to the mixture to form a reaction mixture, which leads to a second rise in temperature, typically to about 50°C to about 60°C. Preferably, after the base is added, the reaction mixture is maintained at a temperature of about 25°C to about reflux, more preferably, at about 50°C to about 55°C. After the addition of the base, the reaction mixture is maintained for about 2 to about 10 hours, more preferably, for about 4 to about 6 hours. [0033] Preferably, the C6-9 aromatic hydrocarbon is toluene or o-, m-, or p-xylene. Preferably, the polar aprotic organic solvent is a C1-10halogenated aliphatic hydrocarbon, amide, or sulfoxide. A preferred C1-10 halogenated aliphatic hydrocarbon is a C1-5 halogenated hydrocarbon, and more preferably dichloromethane (referred to as DCM), l,2,dichloroethane or dichloropentane. Preferably, the amide is either dimethylformamide (referred to as DMF) or dimethylacetamide (referred to as DMA). Preferably, the sulfoxide is a C1-4 sulfoxide, and more preferably dimethylsulfoxide (referred to as DMSO). The more preferred solvent is toluene. [0034] Optionally, a phase transfer catalyst (referred to as PTC) may be used to increase the reaction rate. When the solvent is a C6--9 aromatic hydrocarbon, preferably, a phase transfer catalyst is used. Preferably, the PTC is added to the solution of 3-(S)-(+)-hydroxypyrrolidine prior to the addition of the sulfonyl halide. Preferably, the PTC is selected from the group consisting of tetrabutylammonium bromide, ALIQUAT® tributylmethylammonium chloride, tetrabutylammonium sulfate, and DMSO, and more preferably tetrabutylammonium bromide. [0035] Preferably, the halide moiety of the sulfonyl halide is selected from chloride, bromide, and iodide, and more preferably chloride. Preferably, the sulfonyl halide is tosylchloride, mesylchloride, or brosylchloride, and more preferably tosylchloride. Preferably, the sulfonyl halide is added portion-wise. [0036] Preferably, the base is either an inorganic base or an organic base. A preferred organic base is selected from the group consisting of aliphatic and aromatic amines. Preferably, the ahphatic amine is triethylamine, methylmorpholine, or N,N-diisopropylethyl amine. A preferred aromatic amine is pyridine. The inorganic base is added, preferably, in a form of an aqueous solution. The aqueous solution contains, preferably, an alkali base, and more preferably either sodium hydroxide or potassium hydroxide. Preferably, the base is added slowly, more preferably over about a half an hour to about two hours, and even more preferably over about one hour. [0037] The process for preparing l-X-sulfonyl-3-(S)-(-)-X-sulfonyloxypyrrolidine of formula I may further comprise a recovery step. The l-X-sulfonyl-3-(S)-(-)-X- sulfonyloxypyrrolidine may be recovered by any method known to one of ordinary skill in the art. Such methods include, but are not limited to, adding water to the reaction mixture; cooling the reaction mixture to obtain a precipitate of the l-X-suIfonyI-3-(S)-(-)-X- sulfonyloxypyrrolidine, and filtering the precipitate from the reaction mixture. [0038] Preferably, the addition of water provides a suspension. Preferably, the suspension is cooled to a temperature of about 20°C to about -5°C, and more preferably to about 5°C to about 0°C, to induce precipitation of the l-X-sulfonyl-3-(S)-(-)-X- sulfonyloxypyrrolidine. Preferably, the cooled suspension is maintained for at least about one hour, preferably, for about 1 to about 2 hours, to give a precipitate of l-X-sulfonyl-3-(S)- (-)-X-sulfonyloxypyrrolidine. The precipitate is then filtered and dried. [0039] The 1 -X-sulfonyl-3 -(S)-(-)-X-sulfonyloxypyrrolidine of formula I thus obtained may then be converted to (S)-2,2-diphenyl-2-(l-X-sulfonyl-3- pyrrolidinil)acetonitrile EL. [0040] The intermediate of formula II, (S)-2,2-diphenyl-2-(l-X-sulfonyl-3- pyrrolidinil)acetonitrile (Formula Removed) is prepared by a process comprising combining l-X-sulfonyl-3-(S)-(-)-X-sulfonyloxypyrrolidine of formula I, diphenylacetonitrile, an organic solvent selected from the group consisting of a C6-9 aromatic hydrocarbon, a polar aprotic organic solvent, and mixtures thereof, and an inorganic base; wherein X is either C1-10 alkyl or C6-9 aryl. Preferably, X is C5-9 aryl, and more preferably tolyl. [0041] (S)-2,2-diphenyl-2-(l-X-sulfonyl-3-pyrrolidinil)acetonitrile of the formula II is obtained by the above process in a purity of about 95% to about 99% area by HPLC, and more preferably about 99% to about 100% area by HPLC. [0042] Typically, combining the diphenylacetonitrile and the organic solvent provides a first mixture. The addition of the inorganic base to the first mixture typically causes the temperature of the first mixture to rise to about 20°C to about 40°C, and preferably to about 25°C to about 35°C. Preferably, the first mixture is cooled to a temperature of about 30°C to about 15°C, and more preferably to a temperature of about 25°C to about 15°C, prior to the addition of the l-X-sulfonyl-3-(S)-(-)-X-sulfonyloxypyrrolidine of formula I. Typically, the addition of the l-X-sulfonyl-3-(S)-(-)-X-sulfonyloxypyrrolidine of formula I provides a second mixture. Preferably, the second mixture is heated to a temperature of about 50°C to about 100°C, and more preferably to a temperature of about 70°C to about 75°C. The heated second mixture is maintained, preferably, for about 3 to about 6 hours, and more preferably, for about 4 to about 5 hours. [0043] Preferably, the C6--9 aromatic hydrocarbon is toluene. Preferably, the polar aprotic organic solvent is either an amide or a sulfoxide. A preferred amide is a C1-2 amide, and more preferably either DMF or DMA. A preferred sulfoxide is a C1-4 sulfoxide, and more preferably DMSO. The more preferred organic solvent is DMF. [0044] Preferably, the inorganic base is either a metal alkoxide or an alkali hydroxide. A preferred metal alkoxide is either sodium tert-butoxide or sodium methoxide. A preferred alkali hydroxide is either sodium or potassium hydroxide. The more preferred inorganic base is a metal alkoxide, most preferably either sodium or potassium tert-butoxide. [0045] The process for preparing (S)-2,2-diphenyl-2-(l -X-sulfonyI-3- pyrrolidinil)acetonitrile of formula II may further comprise a recovery step. The recovery may be may be done by a process comprising adding to the second mixture to a mixture of water and a solvent selected from the group consisting of toluene, DCM, ethyl acetate (referred to as EtOAc), butyl acetate (referred to as BuOAc), and n-butanol to form a mixture having an aqueous and an organic phase; separating the aqueous and organic phases; washing the organic phase with water; and concentrating the organic phase under reduced pressure to obtain a concentrated residue. The residue is then cooled to a temperature of about 10°C to about -10°C, and preferably to about 3°C to about -3°C, to give a precipitate of (S)-2,2-diphenyl-2-(l-X-sulfonyl-3-pyrrolidinil)acetonitrile. [0046] The (S)-2,2-diphenyl-2-(l -X-sulfonyl-3-pyrrolidinil)acetonitrile of formula II thus obtained may then be converted to S)-2,2-diphenyl-2-(3-pyrrolidinil)acetomtrile salt of formula DDL [0047] The intermediate of formula m, (S)-2,2-diphenyl-2-(3-pyrrolidinil)acetonitrile salt, is prepared by a process comprising heating a mixture comprising the compound of formula II, a bromine acceptor selected from phenol and naphthol and an acid, wherein the bromine acceptor is phenol only when the acid is HBr. Preferably, the mixture is heated to a temperature of about 80°C to about 120°C, more preferably, to about 117°C to about 120°C. Preferably, the heated mixture is maintained for about 1 hour to about 2 hours, more preferably, for about 1 hour to about 1.5 hours. Preferably, the acid is HBr, H2SO4, H3PO4, HCIO4, or CF3SO3H, and more preferably HBr. When using HBr as the acid, it is added in a form of an aqueous solution, having a concentration of about 30% to about 60%, more preferably, of about 48% to about 60%. [0048] The (S)-2,2-diphenyl-2-(3-pyrrolidinil)acetonitrile salt of formula III may be recovered by a process comprising cooling the mixture to a temperature of about 30°C to about 15°C, more preferably, to a temperature of about 30°C to about 25°C, followed by extracting with a C1-10 halogenated aliphatic hydrocarbon, and washing with brine. The organic phase is then concentrated under reduced pressure to give a residue containing the compound of formula HI and the solvent. Preferably, the C1-10 halogenated aliphatic hydrocarbon is a C1-5 halogenated hydrocarbon, more preferably, a C1-3 halogenated hydrocarbon. Most preferably, the C1-3 halogenated hydrocarbon is selected from the group consisting of DCM, chloroform, dichloroethane, 1,1-dichloroethane, and 1,5-dichloropentane. The residue is then combined with a second solvent selected from the group consisting of BuOAc, toluene, acetone, 2-butanone, and diisopropylether, followed by a complete removal of the C1-10 halogenated aliphatic hydrocarbon, preferably, by distillation, to give a second residue. [0049] The second residue, containing the compound of formula in and a solvent selected form the group consisting of BuOAc, toluene, acetone, 2-butanone, and diisopropylether can be purified by a crystallization process from a solvent selected from the group consisting of C1-10 ester, C1-10 ketone, CI-IO ether, C1-10 aliphatic hydrocarbon, C6-9 aromatic hydrocarbon, and mixtures thereof. Preferably, the C1-10 ester is ethylacetate, n-butylacetate, i-butylacetate, or n-propylacetate, more preferably, ethylacetate. Preferably, the C1-10 ketone is acetone, 2-butanone, methyl-isobutylketone, or cyclohexanone. A preferred C1-10 ether is diethylether, diisopropylether, dibutylether, or methyl isobutylether. Preferably, the C1-10 aliphatic hydrocarbon is pentane, hexanes, heptanes, or petroleum ether. Preferably, the C6-9 aromatic hydrocarbon is toluene or xylenes. Preferably, a mixture of EtOAc and hexane is used. [0050] The compound of formula III thus obtained may then be converted to (S)-2- {l-[2-(2,3-dihydroberi2ofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-acetoriitrile salt of formula IV. [0051] The intermediate of formula IV, (S)-2- {1 -[2-(2,3-dihydrobenzofuran-5- yl)ethyl]-3-pyrrolidinyl}-2,2-acetonitrile salt, (Formula Removed) is prepared by a process comprising: a) combining (S)-2,2-diphenyl-2-(3-pyrrolidinil)acetonitrile salt of formula m, (Formula Removed) derivative of ethyl-dihydrobenzofuran of the formula V, (Formula Removed) a solvent selected from the group consisting of a C6-9 aromatic hydrocarbon, a polar organic solvent, water, and mixtures thereof, and a base to obtain a mixture; b) heating the mixture of step b; and c) reacting the mixture of step c with an acid; wherein Z\ and Z2 are independently an acid. Preferably, the acid is either HBr or HC1. [0052] When Z1 and Z2 are HBr, the compound of formula III corresponds to (S)-2,2- diphenyl-2-(3-pyrrolidinil)acetonitrile-hydrobromide of the following formula, (Formula Removed) and the compound of formula IV corresponds to (S)-2-{l-[2-(2,3-dihydrobenzofuran-5-yl)emyl]-3-pvn:olidinyl}-2,2-acetonitrile-hydrobromide of the following formula. (Formula Removed) When Z1 and Z2 are HC1, the.compound of formula HI corresponds to (S)-2,2-diphenyl-2-(3-pyrrolidinil)acetonitrile-hydrochloride of the following formula, (Formula Removed) and the compound of formula IV corresponds to (S)-2-{l-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-acetonitrile-hydrochloride of the following formula. (Formula Removed) [0053] Typically, the base and the solvent are combined, initially, to obtain a first mixture. This mixture is then combined with (S)-2,2-diphenyl-2-(3-pyrrolidinil)acetonitrile salt of formula III, and with a derivative of ethyl-dihydrobenzofuran of the formula V, to obtain a a second mixture, the mixture of step a. Preferably, the mixture of step a is heated to a temperature of about 50°C to about reflux, more preferably, to a temperature of about 75°C to about 80°C. Preferably, the heated mixture is maintained for about 3 hours to about 7 hours, where the following compound, (Formula Removed) is expected to be formed. More preferably, the heated mixture is maintained for about 4 hours to about 5 hours. The above compound may be recovered before the addition of the acid. [0054] Preferably, the base is either an inorganic base or an organic base. A preferred organic base is selected from the group consisting of aliphatic and aromatic amines. Preferably, the aliphatic amine is triethylarnine, tribytulamine, methylmorpholine, pyridine, or N,N-diisopropylethyl amine. When an inorganic base is used, it is in the form of an aqueous solution. A preferred inorganic base is an alkali hydroxide, alkali carbonate, alkali bicarbonate, or alkoxide. A preferred alkali hydroxide is either sodium hydroxide or potassium hydroxide. Preferably, an alkali carbonate is sodium carbonate or potassium carbonate. Preferably, alkali bicarbonate is either sodium bicarbonate or potassium bicarbonate. A preferred alkoxide is either sodium methoxide or potassium methoxide. The more preferred base is an alkali hydroxide, even more preferably, sodium hydroxide. [0055] Preferably, the C3, a water immiscible hydrocarbon, and a reducing agent to form a mixture comprising of the alcohol of the following formula; (Formula Removed) and combining the mixture with a solvent selected from the group consisting of C 1.2 halogenated hydrocarbons, C3.6 esters, and Cfr.9 aromatic hydrocarbons, and a substance containing a leaving group selected from the group consisting of CI, Br, mesyl, brosyl, tosyl, trifluoroacetyl, and trifluoromethansulfonyl to obtain the compound of formula V, wherein Y is a leaving group selected from the group consisting of I, CI, brosyl, Br, mesyl, tosyl, trifluoroacetyl, and trifluoromethansulfonyl, preferably, CI. [00108] Preferably, NaOH is added to a suspension of the compound of formula X in water to obtain a basic mixture comprising 2-(2,3-dihydrobenzofuran-5-yl)acetaldehyde of formula XII. Preferably, the pH of the basic mixture is about 9 to about 11, more preferably about 9.5 to about 10.5, and even more preferably about 10 to about 10.2. [00109] Preferably, after adjusting the pH,Na2C03 and a water immiscible hydrocarbon are added to obtain a mixture. Preferably, the water immiscible hydrocarbon is either a C6-9 aromatic hydrocarbon or a saturated hydrocarbon. Preferably, the C6-9 aromatic hydrocarbon is toluene. A preferred saturated hydrocarbon is either heptane or cyclohexane. The more preferred solvent is toluene. [00110] Preferably, the mixture is cooled to a temperature of about 20°C to about 0°C, more preferably to about 10°C to about 5°C, prior to the addition of the reducing agent. Adding a reducing agent provides a reaction mixture. Preferably, the reducing agent is selected from the group consisting of NaBH4, LiAlH^ and H2Pd. A solution or solid NaBH4 may be used. Preferably, a solution of NaBH4 is used. Preferably, the NaBELt is in solution in water or an alcohol. Preferably, the alcohol is a C3-6 alcohol. The more preferred solvent is water. [00111] Preferably, the solution of the reducing agent is added drop-wise. Preferably, the drop-wise addition is done over a period of about 0.5 hour to about 1.5 hours, and more preferably over about 45 to about 60 minutes. [00112] Preferably, a pH of about 9 to about 11, more preferably, about 9.8 to about 10.2 is maintained during the addition. [00113] Preferably, after the addition of the reducing agent, the temperature was raised to about 10°C to about 25°C, more preferably, to about 15°C to about 25DC.Preferably, after raising the temperature, the reaction mixture is maintained for about 0.5 hour to about 1.5 hours, more preferably, for about 1 hour, leading to the corresponding alcohol of the following formula. [00114] Preferably, the transformation of the alcohol to the compound of formula V is as described before. [00115] The process for preparing (S)-darifenamine of formula VII may further comprise a process for converting it to (S)-darifenacin hydrobromide. [00116] The conversion of (S)-darifenamine of formula VII to (S)-darifenacin hydrobromide may be done through the intermediate, (S)-darifenacin of formula VIII. [00117] The intermediate (S)-darifenacin of formula VDI (Formula Removed) VIII is prepared by a process comprising combining (S)-Darifenamine of formula VII, (Formula Removed) a C1-8 alcohol, and a reducing agent to obtain (S)-darifenacine of formula VIII. [00118] (S)-Darifenacin of formula VIII may be prepared step-wise or in one step, i.e., without isolation of (S)-Darifenarnine of formula VII. Preferably, (S)-Darifenacin of formula VTH is prepared in one step. [00119] Preferably, the reducing agent is added to a reaction mixture comprising (S)-Darifenamine of formula VH. [00120] Preferably, the reducing agent is selected from the group consisting of NaBH4, LiAULi, andH/Pd and more preferably NaBH4- Preferably, a solution of NaBH4 in the C1-8 alcohol is used. [00121] Preferably, the C1-8 alcohol is selected from the group consisting of methanol, ethanol, propanol, isopropanol, butanol, isobutanol, pentanol, and hexanol. The more preferred C1-8 alcohol is ethanol. [00122] Preferably, the reducing agent is added portion-wise to a mixture of (S)-Darifenamine and the alcohol, to obtain a reaction mixture. Preferably, the portion-wise addition is done over a period of about 15 minutes to about 1 hour, and more preferably for about 20 to about 30 minutes. [00123] After the portion-wise addition is complete, the reaction mixture is maintained for about 2 hours to about 10 hours, more preferably, for about 2 hours to about 4 hours. Preferably, the mixture is maintained at a temperature of about 0°C to about 50°C, more preferably, about 10°C to about 30°C. The reaction may be monitored by HPLC. Preferably, the formation of (S)-Darifenacin is monitored by HPLC. [00124] The process for preparing (S)-Darifenacin of formula VIII may further comprise a recovery step. The recovery may be done according to a process known to a skilled artisan. The recovery may be done by washing the reaction mixture with water, followed by removing the solvent. [00125] The (S)-darifenacin of formula VIII may then be converted to (S)-darifenacin hydrobromide, for example, according to the process disclosed in U.S. patent No. 5,096,890. [00126] Preferably, (S)-darifenacin is converted to (S)-darifenacin hydrobromide by a process comprising: adding an aqueous solution of HBr to a solution of (S)-darifenacin in n-butanol, followed by removing the water to obtain a suspension. The suspension is cooled to induce precipitation of the (S)-darifenacin hydrobromide, and the precipitate of (S)-darifenacin hydrobromide is then collected by filtration. [00127] The invention also encompasses a process for preparing oxidized darifenacin 3-(S)-(+)-(l-carbamoyldiphenylmethyl)pyrrolidine of the formula IX (Formula Removed) hydrobromide comprising combining an oxidized derivative of ethyl-dihydrobenzofuran of the following formula (Formula Removed) an inorganic base and water; admixing with HBr to obtain oxidized darifenacin hydrobromide; wherein Y is a leaving group selected from the group consisting of I, CI, brosyl, mesyl, tosyl, trifluoroacetyl, and trifluoromethansulfonyL Preferably, Y is CI. [00128] The invention also encompasses another process for the preparation of 3-(S)-(+)-(l-carbamoyldiphenylmethyl)pyrrolidine of the formula DC darifenacin hydrobromide by a process comprising: a) combining an oxidized derivative of ethyl-dihydrobenzofuran of the following formula (Formula Removed) IX an inorganic base and water; b) admixing with HBr to obtain oxidized darifenacin hydrobromide; and c) admixing with a reducing agent to obtain darifenacin hydrobromide; wherein Y is a leaving group selected from the group consisting of I, CI, brosyl, mesyl, tosyl, trifluoroacetyl, and trifluoromethansulfonyl. Preferably, Y is CI. [00129] Preferably, the inorganic base is K2CO3, Na2CO3, or Cs2CO3. [00130] Preferably, after combining all the above substances, the combination is heated to reflux temperature, more preferably to about 100-120°C. Typically, the combination is heated to induce the formation of oxidized darifenacin. Preferably, the combination is heated to for about 5 hours to about 10 hours. [00131] After obtaining darifenacin oxide, a work-up of the heated reaction mixture is done. The work-up is done, prior to admixing with HBr. Preferably, the work-up comprises: cooling the heated combination; admixing with C4-8 alcohol, providing a solvent system comprising of at least a two-phases; separating the phases, and concentrating the organic phase. [00132] Preferably, the heated combination is cooled to a temperature of about 90°C to about 60°C, more preferably, to 90°C to about 85°C. Preferably, the C4-8 alcohol is n-butanol, i-butanol, amylalcohol, cyclohexanol, or t-butanol. The solvent system having at least two- phases comprises an aqueous phase and an organic phase. After separating the phases, preferably, the organic phase is concentrated by distillation. Preferably, the concentrated organic phase is admixed with acetic anhydride, prior to the admixing with HBr. The addition of HBr provides a precipitate of oxidized darifenacin hydrobromide. [00133] The process for preparing oxidized Darifenacin hydrobromide may further comprise recovering the oxidized Darifenacin hydrobromide. The recovery can be done by any process known to a skilled artisan. Preferably, the recovery comprises filtering the precipitate, washing and drying. [00134] The process for preparing the oxidized Darifenacin hydrobromide may further comprise converting oxidized Darifenacin hydrobromide to Darifenacin hydrobromide. The conversion can be done, for example, according to the process disclosed in Example 8 of U.S. patent No. 5,096,890 (reproduced below as Comparative Example 24). [00135] Typically, oxidized Darifenacin hydrobromide is reduced by reacting with a reducing agent providing Darifenacin hydrobromide. Preferably, the reaction of oxidized Darifenacin hydrobromide and the reducing agent is done in the presence of an acid. Preferably, the acid is acetic acid. Preferably, the reducing agent is selected from the group consisting of NaBH4, LiA1H4, and H2/catalyst and more preferably, the reducing agent is a combination of a catalyst and hydrogen gas. Preferably, the catalyst is palladium, platinum, ruthenium, rhodium, or nickel. More preferably, the palladium is absorbed on charcoal. [00136] Typically, the reaction is done under heating. Preferably, the heating is to a temperature of about 45°C to about 50°C. Preferably, the hydrogen gas is present at atmospheric pressure. [00137] Preferably, the reaction is maintained for about 6 to about 7 wherein the formation of Darifenacin hydrobromide is expected. [00138] The process for preparing Darifenacin hydrobromide may further comprise a recovery step. The recovery can be done by any process known to a skilled artisan. Preferably, the recovery is done by filtering the catalyst; concentrating the filtrate; admixing the concentrated filtrate with n-butanol and HBr to obtain a mixture, and concentrating the mixture to obtain a precipitate of Darifenacin hydrobromide. [00139] Preferably, the mixture is concentrated to obtain a filtrate having less than 1 % of water. [00140] The obtained precipitate can be isolated by filtration, washing and drying. [00141] Having described the invention with reference to certain preferred embodiments, other embodiments will become apparent to one of ordinary skill in the art from consideration of the specification. The invention is further defined by reference to the following examples. It will be apparent to those of ordinary skill in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention. EXAMPLES Example 1: Preparation of l-tosvI-3-(SV(-)tosvloxvpvrrolidine (Formula I) [00142] (S)-3-pyrrolidinol (30 g, 0.344 moles) was dissolved in toluene (150 ml) and tetrabutylammonium bromide (3.39 g, 0.0105 moles) was added to the solution, p- Toluensulfonylchloride (140.94 g, 0.7393 moles) was then added portion-wise to the solution, causing the temperature of the solution to rise to 35 to 40°C. Then, 30% NaOH (112.1 g, 0.8407 moles) was slowly added to the soulution over about lhour, causing the temperature of the solution to rise to 55 to 60°C. After maintaining the solution for 5 hours at 55-60°C, the reaction was complete. Water (30 ml) was then added, and the resulting suspension was cooled to 0°C over 1 hour to give a solid. The solid was filtered and washed with cold toluene and water to give the title compound. (Dry weight 127.95 g, yield 94%, HPLC purity 99.2% area). The main impurity is l-tosyl-3-(S)-pyrrolidinol (reaction intermediate) in an amount of 0.05% area by HPLC. Example 2: Preparation of fSV2,2-diphenvl-2-(l-tosvl-3-pvrrolidini1")acetonitrile (Formula m [00143] Diphenylacetonitrile (63.7 g, 0.3296 moles) was dissolved in DMF (395 ml), followed by adding sodium tert-butylate (31.75 g, 0.33 moles), which caused the temperature of the solution to rise to 35°C. After cooling the solution to 20°C, l-tosyl-3-(S)-(-)tosyloxypyrrolidine (126.5 g, 0.3198 moles) was added. The solution was warmed to 70 to 75°C, and, after maintaining the solution at 70 to 75°C for 4 hours, the reaction was complete. Water (250 ml) and toluene (500 ml) were then added to the solution to form a two phase mixture having an aqueous and an organic phase. The phases were stirred at 70°C and separated. The aqueous phase was extracted with toluene (50 ml), followed by washing the combined organic phases three times with water (100 ml each), and concentrating under vacuum to give a 250 ml residual volume. The residual volume was cooled to 0°C to obtain a precipitate. The precipitate was filtered and washed with toluene and water to give the title compound. (Dry weight 116 g, yield 86.5%, and HPLC purity 99.3% area). The main impurities present are residual starting materials: diphenylacetonitrile and N-0-ditosyl-3-(S)-pyrrolidinol in amounts of 0.1% area by HPLC each. Example 3: Preparation of (S)V2.2-diphenvl-2-(3-pvrrolidinil)acetonitrile hvdrobromide(S-DIPACP.HBr) (Formula III [00144] In a 2 1 reactor equipped with mechanical stirrer, thermometer and condenser load under nitrogen HBr 48% (1 100ml), Phenol (44,08g), S-DIPACP-N-Tosyl [(S)-2,2-diphenyl-2-(l-tosyl-3-pyrrolidinil)acetonitrile] (220g) were loaded under nitrogen. The suspension was warmed to reflux (118-120°C) to obtain a biphasic system. After lhr, the reaction was complete (residual starting material 0.33%). The reaction mixture was then cooled to 25-30°C and dichloromethane (478ml) was added. After stirring (5min) the phases were separated (organic phase is upper layer) and the aqueous phase was extracted with dichloromethane (100ml) and the phases again separated (organic phase is upper layer). The collected organic phases were concentrated to 280-290ml by solvent distillation at atmospheric pressure obtaining an oily residue (Tint 64°C). Maintaining internal temperature at 65-70°C ethylacetate (287ml) was slowly added to the residue. (It is necessary to maintain temperature and to add ethyl acetate slowly to avoid sudden product crystallization). Distillation was contined at atmospheric pressure to reach a volume of 380-390ml (Tjnt 80°C, Thead 70°C). Ethyl acetate (191ml) was added to the obtained suspension and distillation was continued at atmospheric pressure to reach a volume of 380-390ml (Tjnt 84°C, Thead 72°C). Repeated distillations are necessary to eliminate as much dichloromethane as possible in such a way as to increase yield. The suspension was cooled at 50-55°C and ethyl acetate (300ml) was added. The suspension was cooled to 20-25 °C and after lhr, was cooled to -7-8°C. After 2hrs, the suspension was filtered and washed three times with cold ethyl acetate (95 ml) each. After washings, the product became white (initially it was pink). The wet product was dried under vacuum at 50-55°C for 6-7 hrs to obtain the title compound. (Dry weight 166.3g, yield 87.4%, HPLC purity 99.93% area). Example 4: (SV2.2-diphenvl-2-(3-pvrrolidmil)acetonitrile hvdrobromide using (3-Naphtol as bromine acceptor (Formula EOT) [00145] (S)-2,2-diphenyl-2-( 1 -tosyl-3-pyrrolidinil)acetonitrile (5 g, 0.0120 moles) was added to 48% HBr (25 ml) together with p-naphtol (1.73 g, 0.0120 moles), to give a suspension. The suspension was warmed to reflux (117-120°C), and, after lhour the reaction was complete. After cooling to 30°C, dichloromethane (10 ml) was added, and the mixture was stirred for 5 minutes. The phases were separated, and the aqueous phase was extracted with dichloromethane (5 ml). The combined organic phases were washed with saturated solution of NaCl, and then concentrated under vacuum to give a residual volume of 10 ml. [00146] Ethyl acetate (10 ml) was added to the residual volume, and the distillation was continued at atmospheric pressure until a residual volume of 8 ml was obtained. Ethyl acetate was added, and the distillation continued until the dichloromethane was eliminated (residual volume 8 ml). Ethyl acetate (15 ml) and hexane (10 ml) were added to give a suspension. The suspension was cooled to 0°C for 2 hours to give a precipitate that was filtered and washed with ethyl acetate to give the title compound. (Dry weight 3.0 g; yield 72.4%). Example 5: Preparation of (S)-2-{1-2-(2,3-dihvdrobenzofuran-5-yl)ethvn-3-pvrrolidinvl)-2.2-acetonitrile hydrobromide (Formula III) [00147] Potassium carbonate (14.94 g, 0.1081 moles) was dissolved in water (45 ml), followed by adding (S)-2,2-diphenyl-2-(3-pyrrolidinil)acetonitrile hydrobromide (18.55 g, 0.0540 moles) and 5-(2-bromoethyl)-2(3-dihydrobenzo[2,3-b]furan (13.5 g, 0.05945 moles) to give a suspension. The suspension was warmed to 75 °C, and, after 4 hours, the reaction was considered to be complete (unreacted starting material 1.5% area by HPLC). The heterogeneous mixture was cooled to 25°C and ethyl acetate (100 ml) was added. After stirring, the phases were separated, the organic layer was washed with water, and the phases separated. 48% hydrobromic acid (9.6 g, 0.05668 moles) was added, and (S)-2-{l-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-acetonitrile hydrobromide was crystallized from the suspension. The suspension was cooled to 15-18°C for one hour, and the precipitate was filtered and washed with ethyl acetate to give the title compound. (Dry weight 23.8 g; yield 89.93%). Example 6: Preparation of 3-(SV(-')-(l-carbamovl-l.l-diphenvlmethvn-l-[2-2-(2.3-dihvdrobenzofuran-5-vDethvllpyrrolidine hydrobromide (Formula III [00148] KOH (1.95 g, 0.03134 moles) was added to 2-methyl-2-butanol (7 ml), to obtain a suspension. The suspension was warmed to 60°C for 1 hour, followed by adding (S)-2-{l-[2-(2,3-d^hydrobenzofluran-5-yl)emyl]-3-pyrrolidinyl}-2,2-acetonitrile hydrobromide (1 g, 0.00204 moles), and warming the reaction mixture (suspension) to reflux for 21-22 hours. After cooling, water (5 ml) was added to the reaction mixture to form a two-phase mixture, and the phases were separated. The solvent was distilled from the organic phase under vacuum, and a residue (0.900 g) was obtained and dissolved in methylethylketone (3 ml). The solution was filtered to eliminate undissolved solid, and 48% HBr (0.344 g, 0.00204 moles) was added. The solvent was distilled under vacuum, and a solid foam was obtained. The foam was slurried in diisopropylether, filtered, and washed to give the title compound. (Dry weight 0.750 g; yield 72%). Example 7: Preparation of 3-(S)-(+)-(l -carbamoyl-1,1 -diphenylmethvi)pvrrolidine Tartrate (Formula VI) [00149] 3-(S)-(+)-(l-Cyano-l,l-diphenylmethyl)pyrrolidine hydrobromide (80 g 0.2330 moles) was converted into its corresponding free base by treating with dichloromethane (400 ml), water (150 ml) and 30% NaOH (35 g). After phase separation and evaporation of the solvent from the organic phase, an oil residue was obtained. The oil residue was added to 90% H2SO4 (130 ml), and the mixture was heated to 100°C for 17 hours. After cooling, the mixture was neutralized with sulfuric acid until a pH of 12 was obtained. The product was extracted with dichloromethane (250 ml). After washings with water, the solvent was evaporated by distillation, and the product was obtained as a foam (45.7 g). The foam was dissolved in 96% ethanol (460 ml), and L-Tartaric acid (26.9 g) was added, followed by cooling to 0°C, to induce crystallization of the tartrate salt. The salt was filtered after 1 hour, and washed with 96% ethanol to give the title compound. (Dry weight 64.5 g; yield 64.5%). Example 8: Preparation of 3-(S)-(+)-(l -carbamoyl-1 ,diphenvlmethvl)pvrrolidine Tartrate (Formula VD a) Free base preparation [00150] A four necked round bottomed flask equipped with a thermometer, mechanical stirrer and condenser was charged, under N2, with 3-(S)-(+)-(l-carbamoyl-l,l-diphenylmethyl)pyrrolidine hydrobromide (96 g), Dichloromethane (280 ml), and water (20 ml). The temperature was maintained at 25-30°C during the loading of NaOH 30% (41.2 g). The obtained heterogeneous system was stirred for 5 min. and the phases were separated. The organic phase was washed with water (41.2 ml), and the phases were separated. The organic phase was concentred under vacuum until a final volume of 120 ml was obtained. b) Hydrolysis reaction [00151] A four necked round bottomed flask equipped with thermometer, mechanical stirrer and condenser to eliminate dichloromethane by distillation, was charged under N2 with H2SO4 90%(180ml). [00152] The sulfuric acid solution was warmed to 50-55°C, and the organic solution obtained above (120ml) was added slowly allowing dichloromethane elimination by distillation. During the addition the mixture was wanned continuously to maintain an internal temperature of 60-65°C. When dichloromethane distillation stopped, the internal temperature was raised to 98-102°C allowing residual dichloromethane elimination by distillation. Then, the temperature was maintained.at 98-102°C for 14-14.5 hrs. [00153] The reaction mixture was cooled to 25-30°C and added slowly to a mixture of NaOH 30% (958.3 g), water (720 g), and toluene (480ml), allowing the internal temperature to reach 55-60°C. After stirring at 55-60°C the phases were separated at 55-60°C. The aqueous phase was been extracted at 55-60°C with toluene (160 ml). [00154] The collected organic phases, maintained at 60-65°C, were washed at 60-65°C with water 240 ml, and then n-butanol (200 ml), water (20 ml) and L-tartaric acid (42.05 g) were added to the separated organic phase at 45-65°C. The mixture was stirred at 45-65°C until the L-tartaric acid was almost completely dissolved. At the same time a formation of a salt was detected, at the beginning as a white oil, and then as white solid. The suspension was cooled to!5-25°C and filtered after two hours. When the suspension was too sticky it was found useful to warm to 60-65°C and after 10-15 min to cool to 15-25°C and filter. The cake was washed three times with n-butanol (50 ml each), and after 15 hrs of drying at 50-55°C under vacuum 107 g of the title compound was obtained. (Yield: 88.9%. HPLC purity: 99.88% area). Example 9: Preparation of 2(2,3-Dihvdrobenzofura-5-v)acetic acid, methyl ester [00155] 98% H2S04 (2g) was added to a solution of 2(2,3-Dihydrobenzofura-5- y)acetic acid (200g) in MeOH (500ml), and the mixture was refluxed for 3hrs (TLC: Sio2, toluene/AcOEt 8:2; starting material not detected). After cooling to room temperature, NaHC03 (6.7g) was added to the reaction mixture, and the solvent was distilled off at atmospheric pressure (about 440 ml), to give a light pink oily residue. [00156] The oily residue was dissolved in toluene (250 ml), and washed with NaHCC«3 6% (50 ml). After the phases were separated, the solvent was eliminated under vacuum distillation to obtain a light pink oily residue (227 g). Example 10: Preparation of 2(2,3-Dihvdrobenzofura-5-y) ethanol [00157] 2(2,3-Dihydrobenzofura-5-y)acetic acid, methyl ester (227 g residue) was dissolved in t-BuOH (600 ml), and then NaBH4 (46.8 g) was added. The suspension was warmed to reflux and methanol (100 ml) was added very slowly in about 6 hrs maintaining reaction mixture at reflux. After the methanol addition, the reaction was maintained at reflux for half an hour (in process control revealed complete ester transformation). 400 ml of the t-BuOH-MeOH mixture was distilled off at atmospheric pressure. Water (400 ml) was added to residue and the distillation continued until Tim = 93°C and T head =83°C. Water (400 ml) was added, and the distillation continued until T,-nt.96°C and T head =96°C. The reaction mixture was cooled to 70-75°C and toluene (300 ml) was added. The separated organic phase was washed with water (100 ml) and NaCl 15% (100 ml). After the solvent was eliminated under vacuum distillation, an oily residue (176.8 g ) of the title compound was obtained. The residue solidified upon cooling. Example 11: 2<-2.3-Dihvdrobenzofuran-5-v') ethvlchloride [00158] SOCI2 (74.7g) was added to a solution of 2(2,3-Dihydrobenzofura-5-y) ethanol 80g in toluene (400 ml) while maintaining the temperature below 25°C. The reaction mixture was stirred at 60°C for 14h and then cooled to room temperature. A reaction sample was quenched into 10%Na2CO3 (Residual 2(2,3-Dihydrobenzofura-5-y) ethanol 0.6% area by HPLC), and the pH was adjusted to 10-11 (measured on aqueous phase) by addition of 10% NaOH (about 480 ml) while maintaining the temperature below 30°C. The organic phase was separated. The aqueous phase was extracted with toluene (50 ml). The collected organic phases were washed twice with H2O (100 ml each) and anhydrified under vacuum distillation (residual pressure 40-50 mm Hg, Tint 50-55°C). To the organic phase, 20 g of TONSIL® silicate decoloriZ1ng agent and 4.2 g of ANTICHROMOS charcoal were added, stirred for 30 min at room temperature, filtered off and washed with toluene (2x30 ml), the decolorized solution was concentrated under vacuum (residual pressure 40-50 mm Hg, Tjnt 50-55°C) to eliminate toluene. Water (25 ml) was added to obtain a residue, and the residual toluene was eliminated by azeotropic distillation under vacuum (residual pressure 40-50 mm Hg, Tint 50-55°C). This residue was dissolved in methanol (373 ml) and charcoal (2g) were added. After 20 minutes at 50-55°C charcoal was filtered off and washed with hot methanol (2x10ml). The obtained decolorized solution was cooled at 20°-30°C, and 2(2,3-Dihydrobenzofuran-5-y) ethvlchloride crystallized in the suspension. Water (280 ml) was added to the suspension at 25°-30°C over about 60 min to obtain a sticky, but stirrable, suspension. After 1 hr at 20-25 °C the solid was filtered, and washed three times with MeOH-Water 1:1 (20 ml each). The wet solid was dried at 35-40°C max for 15 hrs to give the title compound. (Dry weight 81.8 g. Yield 92%. HPLC purity 99.2% area). Example 12: Preparation of (S)darifenacin hydrobromide [00159] A 50 ml reactor was loaded with -(S)-(+)-(l-carbamoyl-l,l- diphenyImethyl)pyrrolidine Tartrate (4 g, 9.29mmoles), 2(2,3-Dihydrobenzofuran-5-y) ethylchlonde (1.95 g, 10.68mmoles), potassium carbonate (6.14 g, 44.42mmoles), and water (12.5 ml), to obtain a heterogeneous mixture. The heterogeneous mixture was heated to reflux (103°C) for 2.5 hours. After cooling, dichloromethane, EtOAc or BuOAc (15 ml) were added, and, after stirring, the phases were separated. Acetic anhydride (0.5 ml) was added to the organic phase, and, after 1 hour at room temperature, the residual 3-(S)-(+)-(l-carbamoyl-1 ,l-diphenylmethyl)pyrrolidine was transformed into N-Acetyl derivative. The solvent was removed by distillation, and n-butanol (25 ml) was added to the residue. 48% hydrobromic acid (1.72 g) was also added, and the residual DCM was removed under vacuum distillation. In the case of EtOAc or BuOAc, distillation under vacuum is useful to eliminate water. Darifenacin hydrobromide crystallized, and, after cooling to room temperature, the darifenacin hydrobromide was filtered and washed. (Wet solid 4.17 g). Example 13: Preparation of (S)Vdarifenacin hydrobromide [00160] A 50 ml reactor was loaded with (S)-(+)-(l-carbamoyl-l,l- diphenylmethyl)pyrrolidine free base (2.6 g, 9.29mmoles), 2(2,3-Dihydrobenzofuran-5-y) ethylchloride (1.95 g, 10.68mmoles), potassium carbonate (6.14 g, 44.42mmoles), and water (12.5 ml) to obtain a heterogeneous mixture. The heterogeneous mixture was heated to reflux (103°C) for 2 to 5 hours. After cooling, dichloromethane, Ethyl acetate, or Butylacetate (15 ml) was added, and, after stirring, the phases were separated. Acetic anhydride (0.5 ml) was added to the organic phase, and, after 1 hour at room temperature, the residual 3-(S)-(+)-(l-carbamoyl-l,l-diphenylmethyl)pyrrolidine was transformed into N-Acetyl derivative (as described in example 11). Half of the solvent was removed by distillation, and n-butanol (25 ml) was added to the residue. 48% hydrobromic acid (1.72 g) was also added, and the residual DCM was removed under vacuum distillation. In the case of EtOAC or BuOAc, distillation under vacuum is useful to eliminate water. Darifenacin hydrobromide crystallized, and, after cooling to room temperature, the darifenacin hydrobromide was filtered and washed. (Dry solid 2.5 g). Example 14: Preparation of (SVdarifenacin hvdrobromide [00161] A 150 ml reactor was loaded with water (37.5. ml), potassium carbonate (12 g), and 2(2,3-Dihydrobenzofuran-5-yl-ethylchloride (DBF-EtCl) (5.48 g). The mixture was warmed to 60-65°C and DBF-EtCl melted. Then, (S)-(+)-(l-carbamoyl-1,1-diphenylmethyl)pyrrolidine tartrate (12 g) was loaded and the heterogeneous mixture was warmed to reflux (101-102°C) for 5 hrs. [00162] The reaction mixture was cooled to 80-85°C and n-butanol (60 ml) was added. The internal temperature was maintained at 75-80°C, and the mixture was stirred until complete dissolution was obtained. Then, the mixture was cooled to 25-30°C and the phases were separated. The organic phase was washed twice with water (30 ml) and the phases were separated. [00163] Water was removed by vacuum distillation until a residual volume of 60 ml was obtained, and then n-butanol (30 ml) was added. Then, acetic anhydride (0.6 ml) was loaded and the mixture was stirred at 20-3 0°C for 1 hr, followed by loading HBr 48% (4.7g) at 25-27°C. The water and 20 ml of butanol were removed by vacuum distillation to obtain a suspension of darifenacin hydrobromide. The suspension was stirred at 25-30°C for 2 hrs, and then cooled to 0-5°C, and filtered after 1 hr. The cake was washed with cold n-Butanol (3x 3ml), and dried under vacuum at 50-55°C for 6-7 hrs. (Dry weight 11.2- 11.5. Yield 79-81%). Example 15: Crystallization of (SVdarifenacin hvdrobromide [00164] A 100 ml reactor was loaded with crude darifenacin hydrobromide (10 g), n-butanol (70 ml), and charcoal (0.3g). The mixture was warmed to reflux to obtain a solution. The charcoal was filtered at reflux and washed with n-butanol (5ml). [00165] The solution was maintained at 100°C and seeded to induce crystallization. After 30 min at 100°C, the mixture was cooled to 0°C over 3 hrs, and after 1 hr at 0°C the mixture was filtered. The product was washed with cold butanol (3x3ml). (Dry weight 8.8-8.9g. Yield 88-89%. HPLC purity 99.65-99.75% area). Example 16: Preparation of (S)-darifenacin hvdrobromide via (S)-darifenamine [00166] 3-(S)-(+)-(l-Carbamoyl-l,l-diphenylmethyl)pyrrolidine (2.1 g, 7.5 mmoles) and 2,3-dihydrobenzofuran-5-yl,acetaldehyde (1.4 g, 8.6 mmoles) were combined with toluene (20 ml) at room temperature, and reacted for 15 hours to give (S)-darifenamine. [00167] At this point, a solution of NaBH4 (0.57 g, 15 mmoles) in ethanol (10 ml) was added slowly, and after 3 hours at room temperature, HPLC analysis revealed formation of (S)-Darifenacin. After washing with water, the solvent was eliminated by distillation, and the obtained residue was dissolved in n-BuOH followed by the addition of HBr 48% (1.5 g, 9 mmoles). Water was eliminated under vacuum, and a slow crystallization was observed. After cooling, the product was filtered and washed with n-BuOH to give the title compound. (Dry weight 0.7 g). [00168] The same reaction has been performed in presence of molecular sieves and titanium isopropylate with similar results. Example 17: Purification of Darifenacin HBr [00169] The product of Example 16 (3.6 g) was suspended in n-Butanol (25 ml), and heated to reflux to obtain a solution. Charcoal (0.1 g) was added, and, after 5 minutes at reflux, was filtered off. After cooling to room temperature, Darifenacin HBr was filtered, washed, and dried at 45-50°C under vacuum for 10 hours. (Dry solid 3.20 g; overall yield 68%; HPLC purity 99.86% area). Example 18: 2,3-Dihvdrobenzofura-5-yl, acetaldehyde [00170] In a four necked round bottomed flask equipped with thermometer, mechanical stirrer and condenser, was charged under N2, 2,3-Dihydrobenzofura-5-yl, carboxaldehyde (50 g, 0.33moles) and 2-butylchloroacetate (66.5 g, 0.4415 moles). The solution was warmed to 40-45°C, followed by a dropwise addition (in about 1 hour) of 288 ml of 17%(w/v) potassium 2-butylate solution in 2-butyl alcohol (0.43 moles). The reaction was maintained at a temperature of 40-45°C, and after 1 hour at 40-45°C, HPLC analysis revealed almost complete transformation of carboxaldehyde. The suspension was slowly added to a solution of KOH 90% (24.5 g, 0.3937 moles) in water (47 ml), followed by maintaining at 45-50°C. After lhour at 45°C, TLC analysis revealed complete hydrolysis, and a thick suspension was obtained. At this point toluene (120 ml) and water (180 ml) were added, and the suspension was cooled to 1-5°C. Then, 75% H3PO4 (about 50 g) was added drop-wise to obtain a pH in range of 5.4-5.8. During acidification CO2 evolves and almost complete solid dissolution is observed. After the phases are separated, the organic phase was washed with water (200 ml) and then with sat NaCI, (100 ml). After solvent elimination under vacuum, a residual oil (47 g) of the title compound was obtained. (GC purity 91%.) Example 19: 2f2.3-Dihvdrobenzofura-5-v>) acetaldehvde. bisulfitic complex [00171 ] In a four necked round bottomed flask equipped with thermometer, and mechanical stirrer, was loaded 2,3-Dihydrobenzofura-5-yl, acetaldehyde, of example 18 (47 g, 0.29 moles) and toluene (500 ml) to obtain a solution. Then, water (100 ml) and Na2S2o4 (58.6 g) were added. The bisulfitic adduct precipitated and after 3 hours at room temperature it was filtered and washed twice with toluene (50 ml each). (Wet product: 95 g). Example 20: 2(2.3-Dihvdrobenzofura-5-y) ethanol [00172] The obtained wet bisulfitic adduct of example 19 was suspended in water (150 ml), and the pH was adjusted to 10-10.2 with NaOH 30%. Na2C03 10% (50 ml) and toluene (100 ml) were added and, after cooling to 5-10°C, a solution of NaBEU (5.8 g, 0.1526 moles)) in water (40 ml) was added drop-wise over about 45-60 minutes, while maintaining the pH at 9.8-10.2. The temperature was raised to 15-20°C and after 1 hour the phases were separated. The aqueous phase was extracted with toluene (25 ml), and the combined organic phases were washed with water (50 ml). The solvent was eliminated under vacuum distillation, and the obtained oil solidified to give the title compound (26 g). Example 21: Synthesis of (S)V2-[l-[2-fbenzofuran-5-vnethvll-3-pvrrolidinvl}-2.2-diphenylacetamide [00173] S-DIPAMP tartrate (12g); BF-EtCl ( 5.6 g) K2CO3 (12 g) and Water 37,5 ml were heated at reflux for 5 hrs. After cooling to 85-90°C n-butanol (60ml) was added. After phases separation and washings (2 x 30ml water) the organic phase was anhydrified by distillation and treated with AC2O (0.65 ml) for three hrs. 48% HBr was added slowly and DRF-Ox-HBr crystallized. After 2 hrs at 15°C the solid was filtered and washed with Butanol (3 x 5ml). Wet solid was dried under vacuum at 50-55°C for 15 hrs. (Dry weight 8.8g). Example 22: Synthesis of (SV2-{l-f2-f2.3-dihvdrobenzofuran-5-vl')ethvn-3-pvrrolidinv1}-2,2-diphenvlacetaniide (DRF.HBr) [00174] Pd/C 10% (0.8g) was added to a solution of S)-2-{l-[2-(benzofuran-5- yl)ethyl]-3-pyrrolidinyl}-2,2-diphenylacetamide (8g) in acetic acid (160 ml). The mixture was hydrogenated at 45-50°C and at atmospheric pressure for about 6-7 hrs. Catalyst was filtered off and solution was concentrated under vacuum obtaining an oily residue, n- Butanol (40 ml) was added and stirred to obtain a solution. 48% HBr (3,5 g) was added and a mixture n-Butanol/water was eliminated by distillation to reduce water content to less then 1%. Darifenacin .HBr crystallizes and after 2 hrs at 15-20°C was filtered and washed with n-Butanol ( 3x5ml). After drying at 55-60° C under vacuum 8.1 g of Darifenacin hydrobromide were obtained. (Yield 85%). Example 23: Preparation of Darifenacin hvdrobromide [00175] Water (ml 203) Potassium carbonate (g 65) and DBF-EtCl (g 29.7) were heated to 60-65 °C To the mixture (S)-DIPAMP Tartrate (g 65) was added and the heterogeneous mixture was heated to reflux (101-102°C) for 5 hrs. After cooling to 85-90°C n-Butanol(ml 325) was added and after stirring phases were separated. [00176] The organic phase was washed twice with water ml 160 (each) and then water was removed from organic phase by vacuum distillation, n- Butanol(ml 160) and Acetic anhydride (ml 3.25) were added and the solution was stirred at 20-30°C for 1 hr. 48% HBr (g 25.5) was dropped, water was removed by vacuum distillation and DRF-HBr crystallized. Initial volume was restored by addition of n-BuOH. Suspension was stirred at 15-20°C for 2 hrs, than product was recovered by filtration. The cake was washed with n-Butanol (3x 30ml) and wet solid (85-90g) was crystallized without drying. [00177] Crude wet DRF-HBr (85g), n-Butanol( 455 ml) and charcoal (4.63 g) were warmed to reflux to obtain a solution. After half an hour charcoal was filtered off keeping mixture at near reflux. Clear solution at 100°C was seeded with DBR.HBr and after 30 min at 100°C the solution was cooled to 15-20°C in 2 hrs. Suspension was stirred at 15-20°C for 2 hrs and then product was recovered by filtration. Cake was washed with n-butanol (3 x 25ml). Wet pure DRF-HBr was dried under vacuum at 50-55°C for 10-12 hrs. Dry weight 59.2 g. Overall Yield 77.2 % Comparative Example 24: Example 8 from U.S. Patent No. 5.096.890 (col. 12,11. 1-52) Preparation of 3-(S)-(-)-(l-carbamoyl-l,l-diphenylmethyl)-l-[2-(2,3-dihydrobenzofuran-5-y l)ethyl]pyrrolidme (alternative to Example 1(B)) (Formula Removed) [00178] 10% Palladium-on-carbon (10 mg) was added to a solution of 3-(S)-(-)-(l- carbamoyl-l,l-diphenylmethyl)-l-[2-(benzofuran-5-yl)ethyl]pyrrolidme (0.1 g—see Example 7) in acetic acid (2 ml) and the mixture was hydrogenated at 40°C and atmospheric pressure for 6 hours. The catalyst was filtered off and washed with water (20 ml). The combined filtrate and washings were transferred to a separating funnel, dichloromethane (20 ml) was added, and the mixture was basified by the addition of 10% aqueous sodium hydroxide. The layers were separated and the aqueous layer was further extracted with dichloromethane (3x30 ml). The combined dichloromethane extracts were dried (MgSC>4) and concentrated in vacuo to give a colourless solid which was purified by column chromatography on silica eluting with dichloromethane containing methanol (4%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a colourless glass, yield 0.048 g, which was characterised spectroscopically to be identical to the product of Example 1(B). [00179] l H-N.M.R. (CDC13), 8-7.50-7.20 (m, 11H); 7.00 (s, 1H); 6.90 (d, 1H); 6.70 (d, 1H); 5.45-5.30 (brs, 1H); 4.60-4.50 (t, 2H); 3.60-3.45 (m, 1H); 3.25-3.15 (t, 2H); 3.05-2.50 (m, 8H); 2.10-1.95 (m, 2H) ppm. [00180] While it is apparent that the invention disclosed herein is well calculated to fulfill the objects stated above, it will be appreciated that numerous modifications and embodiments may be devised by those skilled in the art. Therefore, it is intended that the appended claims cover all such modifications and embodiments as falling within the true spirit and scope of the present invention. We claim: 1. A process for preparing darifenacin hydrobromide comprising: a) combining 3-(S)-(+)-hydroxypyrrolidine, a solvent selected from the group consisting of a C6-9 aromatic hydrocarbon, a polar aprotic organic solvent, and mixtures thereof, a sulfonyl halide, and a base to obtain l-X-sulfonyl-3-(S)-(-)-X-sulfonyloxypyrrolidine of formula I, (Formula Removed) b) reacting the l-X-sulfonyl-3-(S)-(-)-X-sulfonyloxypyrrolidine of formula I, diphenylacetonitrile, and an inorganic base, in an organic solvent selected from the group consisting of a C6-9 aromatic hydrocarbon, a polar aprotic organic solvent, and mixtures thereof, to obtain (S)-2,2-diphenyl-2-(l-X-sulfonyl-3-pyjrrolidinil)acetonitrile of formula II; (Formula Removed) c) reacting the (S)-2,2-diphenyl-2-(l-X-sulfonyl-3-pyrrolidinil)acetonitrile intermediate of formula II, a bromine acceptor selected from the group consisting of phenol and naphthol, and an acid to obtain (S)-2,2-diphenyl-2-(3-pyrrolidinil) acetonitrile salt of formula III, (Formula Removed) wherein the bromine acceptor is phenol only when the acid is HBr; d) combining the (S)-2,2-diphenyl-2-(3-pyrrolidinil)acetonitrile salt of formula HI, a compound of the formula V, (Formula Removed) a solvent selected from the group consisting of a C6-9 aromatic hydrocarbon, a polar organic solvent, water, and mixtures thereof, and a base to obtain a mixture; e) heating the mixture of step d; f) admixing the mixture of step d with an acid to obtain a (S)-2-{l-[2-(2,3-dihydrobenzomran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-acetonitrile salt of formula IV; and (Formula Removed) g) admixing the (S)-2- {1 -[2-(2,3-dihydrobenzofuran-5.-yl)ethyl]-3-pyrrolidinyl} -2,2-acetonitrile salt of formula IV, an inorganic base and a protic solvent; and h) reacting with hydrobromic acid to obtain darifenacin hydrobromide, wherein X is either C1-10 alkyl or C6-9 aryl, wherein Y is a leaving group selected from the group consisting of I, CI, Br, mesyl, tosyl, brosyl, trifluoroacetyl, and trifluoromethansulfonyl, wherein Z1 and Z2 are independently an acid. 2. The process of claim 1, wherein X is C6-9 aryl. 3. The process of claim 1 or 2, wherein X is tolyl. 4. The process of any one of claims 1 to 3, wherein Y is CI. 5. The process of any one of claims 1 to 4, wherein Z1 and Z2 are independently HBr or HC1. 6. The process of any one of claims 1 to 5, further comprising recovering the darifenacin hydrobromide. 7. A process for preparing a (S)-2-{1 -[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-acetonitrile salt of formula IV, (Formula Removed) comprising: a) combining (S)-2,2-diphenyl-2-(3-pyrrolidinil)acetonitrile salt of formula m, (Formula Removed) a compound of the formula V, a solvent selected from the group consisting of a C6-9 aromatic hydrocarbon, a polar organic solvent, water, and mixtures thereof, and a base to form a mixture; b) heating the mixture to obtain a mixture having a compound of the following formula (Formula Removed) and c) reacting the mixture of step b with an acid to obtain to obtain a (S)-2-{l-[2-(2,3- dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-acetonitrile salt of formula IV; wherein Zi and Z2 are independently an acid; wherein Y is a leaving group selected from the group consisting of I, CI, Br, brosyl, mesyl, tosyl, trifluoroacetyl, and trifluoromethansulfonyl. 8. The process of claim 7, wherein the mixture is heated to a temperature of about 50°C to about reflux. 9. The process of claim 7 or 8, wherein the compound of the following formula, is recovered prior to reacting with the acid. 10. The process of claim 7 or 8, wherein the compound of the following formula (Formula Removed) is reacted with the acid without being recovered. 11. The process of any one of claims 7 to 10, wherein the base is an aliphatic or aromatic amine, an alkali hydroxide, an alkali carbonate, an alkali bicarbonate, or alkoxide. 12. The process of claim 11, wherein the base is triethylamine, tribytulamine, methylmorpholme, pyridine, N,N-diisopropylethyI amine, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium methoxide, or potassium methoxide. 13. The process of any one of claims 7 to 12, wherein the C6-9 aromatic hydrocarbon is toluene. 14. The process of any one of claims 7 to 13, wherein the polar organic solvent is an amide, a sulfoxide, or a nitrile. 15. The process of claim 14, wherein the polar organic solvent is dimethylformamide, dimethylacetamide, dimethylsulfoxide, or acetonitrile. 16. The process of any one of claims 7 to 15, further comprising recovering the (S)-2- {1 -[2-(2,3-dihydrobenzofuran-5-yl)emyl]-3-pyrrolidinyl}-2,2-acetonitrile salt of formula IV. 17. A process for preparing darifenacin hydrobromide comprising: a) preparing a (S)-2-{l-[2-(2,3-dihydrobenzomran-5-yl)ethyl]-3-pyrrolidmyl}-2,2-acetonitrile salt of the following formula IV (Formula Removed) IV by the process of any one of claims 7 to 16; and b) converting the (S)-2-{l-[2-(2,3- dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-acetonitrile salt into darifenacin hydrobromide, whererin Z2 is an acid. 18. A process for preparing darifenacin hydrobromide comprising: a) combining 3-(S)-(+)-hydroxypyrrolidine, a solvent selected from the group consisting of a C6-9 aromatic hydrocarbon, a polar aprotic organic solvent, and mixtures thereof, a sulfonyl halide, and a base to obtain l-X-sulfonyl-3-(S)-(-)-X-sulfonyloxypyrrolidine of formula I, b) reacting the l-X-sulfonyl-3-(S)-(-)-X-sulfonyloxypyrrolidme of formula I, diphenylacetonitrile, and an inorganic base, in an organic solvent selected from the group consisting of a C6-9 aromatic hydrocarbon, a polar aprotic organic solvent, and mixtures thereof, to obtain (S)-2,2-diphenyl-2-(l-X-sulfonyl-3-pyrrolidinil)acetonitrile of formula II; (Formula Removed) c) reacting the (S)-2,2-diphenyl-2-(l-X-sulfonyl-3-pyrrolidinil)acetonitrile intermediate of formula n, a bromine acceptor selected from the group consisting of phenol and naphthol, and an acid to obtain (S)-2,2-diphenyl-2-(3-pyrrolidinil) acetonitrile salt of formula HE, (Formula Removed) wherein the bromine acceptor is phenol only when the acid is HBr; d) reacting the (S)-2,2-diphenyl-2-(3-pyrrolidinil)acetonitrile salt of formula HI with an inorganic base in a solvent selected from the group consisting of a water immiscible organic solvent, a polar aprotic organic solvent, water and mixtures thereof to obtain a mixture; e) acidifying the mixture of step d; f) heating the mixture of step e; g) basifying the mixture of step f to obtain 3-(S)-(+)-(l-carbamoyldiphenylmethyl)pyrrolidine of formula XI; (Formula Removed) h) combining the 3-(S)-(+)-(l-carbarnoyldiphenylmethyl)pyrrolidine of formula XI, 2-(2,3-dihydrobenzofuran-5-yl)acetaldehyde of formula XII, (Formula Removed) and a Cg.9 aromatic hydrocarbon to obtain a (S)-darifenamine of formula VII; (Formula Removed) i) admixing the (S)-darifenamine of formula VTI with a C1-8 alcohol and a reducing agent to obtain the (S)-darifenacin of formula VIII; and (Formula Removed) j) admixing the (S)-darifenacin of formula VIII with HBr to obtain darifenacin hydrobromide, wherein X is either C1-10alkyl or C6-9 aryl, preferably, C6-9 aryl, more preferably, tolyl, and Z1 is an acid, preferably, either HBr or HC1. 19. The process of claim 18, wherein X is C6-9aryl. 20. The process of claim 18 or 19, wherein X is tolyl. 21. The process of any one of claims 18 to 20, wherein Y is CI. 22. The process of any one of claims 18 to 21, wherein Zi is HBr or HC1. 23. (S)-darifenamine of formula VII. (Formula Removed) 24. A process for preparing the (S)-darifenamine of formula of claim 23 comprising: combining 3-(S)-(+)-(l-carbamoyldiphenylmethyl)pyrrolidine of formula XI, (Formula Removed) 2-(2,3-dihydrobenzofuran-5-yl)acetaldehyde of formula XQ, (Formula Removed) and a C6-9 aromatic hydrocarbon. 25. The process of claim 24, wherein the combination is maintained at a temperature of about 0°C to about 70°C. 26. The process of claim 24 or 25, wherein the C6-9 aromatic hydrocarbon is selected from the group consisting of toluene, xylene, or trimethylbenzene. 27. The process of any one of claims 24 to 26, further comprising recovering the (S)-Darifenamine of formula VH. VIII comprising: combining (S)-darifenamine of formula VII, (Formula Removed) 28. A process for preparing (S)-darifenacin hydrobromide comprising: a) preparing (S)-darifenamine by the process of any one of claims 24 to 27; and b) converting the (S)-darifenarnine to (S)-darifenacin hydrobromide. 29. Use of the (S)-Darifenamine of formula VII of claim 23 for the preparation of (S)-Darifenacin hydrobromide. 30. A process for preparing (S)-darifenacin of formula VIII (Formula Removed) VII a C1-8 alcohol, and a reducing agent to obtain to obtain (S)-darifenacin of formula VIII. 31. The process of claim 30, wherein (S)-Darifenacin of formula VIII is prepared without isolation of (S)-Darifenamine of formula VII. 32. The process of claim 30 or 31, wherein the reducing agent is selected from the group consisting of NaBH4, LiA1H4, and H2/Pd. 33. The process of any one of claims 30 to 32, wherein the C1-8alcohol is selected from the group consisting of methanol, ethanol, propanol, isopropanol, butanol, isobutanol, pentanol, and hexanol. 34. The process of any one of claims 30 to 33, wherein the combination is maintained at a temperature of about 0°C to about 50°C. 35. The process of any one of claims 30 to 34, further comprising recovering the (S)-darifenacin of formula VIII 36. A process for preparing (S)-darifenacin hydrobromide comprising: a) preparing (S)-darifenacin by the process of any one of claims 30 to 35; and b) converting the (S)-darifenacin to (S)-darifenacin hydrobromide. 37. The process of claim 36, wherein the conversion is done by a process comprising: adding an aqueous solution of HBr to a solution of (S)-darifenacin in n-butanol, followed by removing the water to obtain a suspension, and cooling the suspension to induce precipitation of the (S)-darifenacin hydrobromide. 38. A process for the preparation of 2-(2,3-dihydrobenzofuran-5-yl)acetaldehyde of formula XII (Formula Removed) XII comprising: a) combining 2,3-dihydrobenzofura-5-yl-carboxyaldehyde of formula IX, (Formula Removed) a C2-4 alkylhaloacetate, an alkoxide, and an alkaline hydroxide to obtain the epoxide of the following formula; (Formula Removed) and b) admixing the epoxide with a solvent selected from a group consisitng of C6-9 aromatic hydrocarbons, C1-2 halogenated hydrocarbons, water, and mixtures thereof, and an acid selected from a group consisitng of H3PO4, acetic acid, HC1 sulfonic acid, and HBr to obtain 2-(2,3-dihydrobenzofuran-5-yl)acetaldehyde of formula XII, wherein M is an alkali metal. 39. The process of claim 38, wherein the 2,3-dihydrobenzofura-5-yl-carboxyaldehyde of formula IX and C2-4 alkylhaloacetate are combined to form a solution, prior to the addition of the alkoxide. 40. The process of claim 39, wherein the solution is heated to a temperature of about 30°C to about 60°C. 41. The process of any one of claims 38 to 40, wherein the C2-4 alkylhaloacetate is 2-butylchloroacetate. 42. The process of any one of claims 38 to 41, wherein the alkoxide is t-butoxide. 43. The process of claim 39, wherein the alkoxide is added to the solution at a temperature of about 30°C to about 60°C to form a suspension. 44. The process of claim 43, wherein the obtained suspension is added slowly to the alkaline hydroxide to obtain a mixture. 45. The process of claim 44, wherein the the alklaine hydroxide is selected from a group consisitng of NaOH, KOH, LiOH. 46. The process of claim 44 or 45, wherein the addition is done at a temperature of about 30°C to about 60°C. 47. The process of any one of claims 44 to 46, wherein the mixture comprises, the epoxide of the following formula; (Formula Removed) wherein M is an alkali metal. 48. The process of any one of claims 38 to 47, wherein the C6-9 aromatic hydrocarbon is toluene. 49. The process of any one of claims. 38 to 48, wherein the C1-2 halogenated hydrocarbon is dichloromethane. 50. The process of any one of claims 38 to 49, wherein the acid is selected from a group consisting of H3PO4, acetic acid, HC1, sulfonic acid and HBr. 51. The process of any one of claims 38 to 50, wherein adding the acid results in a pH of about 5 to about 7. 52. The process of any one of claims 38 to 51, further comprising recovering the 2-(2,3-dihydrobenzofuran-5-yl)acetaldehyde of formula XII. 53. 2-(2,3-dihydrobenzofuran-5-yl)acetaldehyde-bisulfite complex of formula X. (Formula Removed) 54. Use of the bisulfite complex of claim 53 to purify 2-(2,3-dihydrobenzofuran-5-yl)acetaldehyde. 55. A process for purifying 2-(2,3-dihydrobenzofuran-5-yl)acetaldehyde comprising a) combining 2-(2,3-dihydrobenzofuran-5-yl)acetaldehyde, a water immiscible hydrocarbon, and NazS2O5 to form a mixture; and b) admixing the mixture with a base to obtain purified 2-(2,3-dihydrobenzofuran-5-yl)acetaldehyde. 56. The process of claim 55, wherein the water immiscible hydrocarbon is either a Ce-9 aromatic hydrocarbon or a saturated hydrocarbon. 57. The process of claim 56, wherein the C6-9 aromatic hydrocarbon is toluene. 58. The process of any one of claims 55 to 57, wherein the mixture of step a) is maintained at a temperature of about 15°C to about 35°C. 59. The process of any one of claims 55 to 58, further comprising recovering the purified 2-(2,3-dihydrobenzofuran-5-yl)acetaldehyde. 60. A process for preparing oxidized darifenacin hydrobromide comprising combining an oxidized derivative of ethyl-dihydrobenzofuran of the following formula (Formula Removed) 3-(S)-(+)-(l-carbamoyldiphenylmethyi)pyrrolidine of the formula IX (Formula Removed) IX an inorganic base and water; and admixing with HBr to obtain oxidized darifenacin hydrobromide; wherein Y is a leaving group selected from the group consisting of I, CI, brosyl, mesyl, tosyl, trifluoroacetyl, and trifiuoromethansulfonyl. 61. The process of claim 60, wherein Y is CI. 62. The process of claim 60 or 61, wherein the inorganic base is K2CO3. 63. The process of any one of claims 60 to 62, wherein the c reflux. 64. The process of any one of claims 60 to 63, wherein a work-up is done, prior to admixing with HBr. 65. The process of any one of claims 60 to 64, further comprising recovering the oxidized darifenacin hydrobromide. 66. A process for preparing darifenacin hydrobromide comprising: a) combining an oxidized derivative of ethyl-dihydrobenzofuran of the following formula (Formula Removed) 3-(S)-(+)-(l-carbamoyldiphenylmethyl)pyrrolidine of the formula DC (Formula Removed) an inorganic base and water, b) admixing with HBr to obtain oxidized darifenacin hydrobromide, and c) admixing with a reducing agent to obtain darifenacin hydrobromide; wherein Y is a leaving group selected from the group consisting of I, CI, brosyl, mesyl, tosyl, trifluoroacetyl, and trifluoromethansulfonyl. 67. The process of claim 66, wherein Y is CI. 68. The process of claim 66 or 67, wherein the inorganic base is K2CO3. 69. The process of any one of claims 66 to 68, wherein the combination of is heated to reflux. 70. The process of any one of claims 66 to 69, wherein a work-up is done, prior to admixing with HBr. 71. The process of claim 70, wherein the work-up comprises: cooling the heated combination; admixing with C4-8alcohol, providing a solvent system comprising of at least two-phases; separating the phases, and concentrating the organic phase. 72. The process of any one of claims 66 to 71, wherein the reaction of oxidized darifenacin hydrobromide and the reducing agent is done in the presence of an acid. 73. The process of claim 72, wherein the acid is acetic acid. 74. The process of any one of claims 66 to 73, wherein the reducing agent is a combination of a catalyst and hydrogen gas, NaBH4, or LiAlH4- 75. The process of claim 74, wherein the catalyst is palladium, platinum, ruthenium, rhodium, or nickel. 76. l The process of claim 74 or 75, wherein the catalyst palladium is absorbed on charcoal. 77. The process of any one of claims 74 to 76, wherein the hydrogen gas is present at atmospheric pressure. 78. The process of any one of claims 66 to 77, wherein step c further comprises heating to a temperature of about 45°C to about 50°C. 79. The process of any one of claims 66 to 78, further comprising recovering the darifenacin hydrobromide.

Documents

Application Documents

# Name Date
1 3567-delnp-2008-pct-308.pdf 2011-08-21
1 3567-DELNP-2008_EXAMREPORT.pdf 2016-06-30
2 3567-delnp-2008-abstract.pdf 2011-08-21
2 3567-delnp-2008-pct-306.pdf 2011-08-21
3 3567-delnp-2008-pct-304.pdf 2011-08-21
3 3567-delnp-2008-claims.pdf 2011-08-21
4 3567-delnp-2008-pct-237.pdf 2011-08-21
4 3567-delnp-2008-correspondence-others.pdf 2011-08-21
5 3567-delnp-2008-pct-220.pdf 2011-08-21
5 3567-delnp-2008-description (complete).pdf 2011-08-21
6 3567-delnp-2008-pct-210.pdf 2011-08-21
6 3567-delnp-2008-form-1.pdf 2011-08-21
7 3567-delnp-2008-gpa.pdf 2011-08-21
7 3567-delnp-2008-form-18.pdf 2011-08-21
8 3567-delnp-2008-form-2.pdf 2011-08-21
8 3567-delnp-2008-form-5.pdf 2011-08-21
9 3567-delnp-2008-form-3.pdf 2011-08-21
10 3567-delnp-2008-form-5.pdf 2011-08-21
10 3567-delnp-2008-form-2.pdf 2011-08-21
11 3567-delnp-2008-gpa.pdf 2011-08-21
11 3567-delnp-2008-form-18.pdf 2011-08-21
12 3567-delnp-2008-pct-210.pdf 2011-08-21
12 3567-delnp-2008-form-1.pdf 2011-08-21
13 3567-delnp-2008-pct-220.pdf 2011-08-21
13 3567-delnp-2008-description (complete).pdf 2011-08-21
14 3567-delnp-2008-pct-237.pdf 2011-08-21
14 3567-delnp-2008-correspondence-others.pdf 2011-08-21
15 3567-delnp-2008-pct-304.pdf 2011-08-21
15 3567-delnp-2008-claims.pdf 2011-08-21
16 3567-delnp-2008-pct-306.pdf 2011-08-21
16 3567-delnp-2008-abstract.pdf 2011-08-21
17 3567-DELNP-2008_EXAMREPORT.pdf 2016-06-30
17 3567-delnp-2008-pct-308.pdf 2011-08-21