WO2009153649A1 - Process for preparing 3-substituted pyrrolidine compounds - Google Patents

Abstract

Disclosed is a process for preparing 3 -substituted pyrrolidine compounds of formula (VII) or salts thereof, wherein R1 is described herein, which are intermediate compounds useful for the synthesis of darifenacin which is indicated for the treatment of overactive bladder with symptoms of urge, urinary incontinence, and the like, and pharmaceutically acceptable salts thereof. Also disclosed is a process for preparing darifenacin and pharmaceutically acceptable salts thereof.

Description

PROCESS FOR PREPARING 3-SUBSTITUTED PYRROLIDINE COMPOUNDS

CROSS-REFERENCE TO A RELATED APPLICATION

[0001] This patent application claims the benefit of U.S. Provisional Patent Application No. 61/074,000, filed June 19, 2008, which is incorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

[0002] Darifenacin is an active pharmaceutical substance indicated for the treatment of overactive bladder with symptoms of urge, urinary incontinence, urgency and frequency. Darifenacin is the international common accepted name for (S)-2-{\-[2-(2,3- dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl} -2,2-diphenylacetamide hydrobromide, having an empirical formula Of C₂₈H₃₀N₂O₂-HBr and the structure of formula (I) below:

[0003] Darifenacin and its pharmaceutically acceptable salts are reported in U.S. Patent No. 5,096,890 ("the '890 patent"), which is incorporated herein by reference. The '890 patent discloses processes for preparing darifenacin and pharmaceutically acceptable salts thereof, all of which make use of 3 -substituted pyrrolidine compounds of formula (VII), or salts thereof:

wherein R¹ is -CN or -CONH₂, as intermediate compounds. The process disclosed in the '890 patent for the preparation of compounds of formula (VII) or salts thereof is depicted as shown in Scheme 1. Illustrative compounds of formula (VII) include compound of formula (Vila) and compound of formula (VIIb), or salts thereof, as depicted in Scheme 1. N, NaH reflux

Scheme 1

[0004] However, this process has significant drawbacks in that it comprises the cumbersome and hazardous Mitsunobu reaction of enantiopure l-tosyl-3-(/?)-pyrrolidinol (compound of formula IV) in order to obtain the (5)-enantiomer of the 3 -substituted pyrrolidine compounds of formula (VII) or salts thereof. More particularly, compound (IV) is reacted with methyl tosylate, triphenylphosphine, and diethylazodicarboxylate (DEAD), a very toxic and dangerous reagent. Typically, the product is contaminated with triphenylphosphine oxide, which is very difficult to separate from the desired product. [0005] In order to avoid the Mitsunobu reaction step in the preparation of darifenacin, International Patent Publication No. WO 2007/076158 ("the '158 publication") discloses a method which makes use of the starting compound, 3-(S)-(+)-hydroxypyrrolidine (compound of formula (S)-(III)), as shown in Scheme 2 below. However, given that compound (iS)-(III) is particularly expensive, the preparation of the L-(+)-tartrate salt of compound (VIIb), and hence the preparation of darifenacin described in the '158 publication is not cost-effective and is not desirable for industrial implementation.

darifenacin, (I)

(S)-(III) (S)-(VIIb)

Scheme 2

[0006] In view of the foregoing, there is an unmet need for an improved process for preparing a compound of formula (VII) and salts thereof, which can be used as an intermediate compounds in the preparation of darifenacin and pharmaceutically acceptable salts thereof.

BRIEF SUMMARY OF THE INVENTION

[0007] The present invention provides an improved process for preparing 3 -substituted pyrrolidine compounds or salts thereof, as intermediate compounds useful for the synthesis of 1,3-disubstituted pyrrolidine compounds (e.g., (S)-2-{l-[2-(2,3-dihydrobenzofuran-5- yl)ethyl]-3-pyrrolidinyl}-2,2-diphenylacetamide hydrobromide, that is, darifenacin hydrobromide). The present invention further provides a process for preparing darifenacin, and pharmaceutically acceptable salts thereof, using 3-substituted pyrrolidine compounds prepared according to a process of the invention.

[0008] Processes in accordance with the invention have one or more of the following advantages: avoid the hazardous Mitsunobu reaction, reduces the use of toxic and dangerous reagents, makes use of low-priced and easily available starting compounds, and hence are cost-effective and suitable for the preparation of darifenacin on a large scale.

DETAILED DESCRIPTION OF THE INVENTION

[0009] In accordance with an embodiment, the invention provides a process for preparing a compound of formula (S)-(VH):

wherein R is selected from the group consisting of -CN and -CONH₂. [0010] In keeping with an embodiment of the invention, a process for preparing a compound of formula (S)-(VU) comprises i) reacting (5)-malic acid of formula (S)-(VIII):

with a compound of formula (XIV):

H₂N-Q (X₁V)₅

wherein Q is a nitrogen protecting group, in a first organic solvent, to obtain a compound of formula (IX),

[0011] In some embodiments, a process of the invention comprises ii) optionally, isolating a compound of formula (IX).

[0012] In keeping with an embodiment of the invention, a process for preparing a compound of formula (S)-(VII) comprises iii) reacting compound of a formula (IX) with a carbonyl reducing agent, in a second organic solvent, to obtain a compound of formula (X):

HQ.

O° (X).

[0013] In some embodiments, a process of the invention comprises iv) optionally, isolating a compound of formula (X).

[0014] In keeping with an embodiment of the invention, a process for preparing a compound of formula (S)-(VII) comprises v) converting the hydroxyl group of compound of formula (X) into a leaving group by reacting a compound of formula (X) with an oxygen activating agent, in a third organic solvent, and a base, to obtain a compound of formula (XI):

YO

O° (X,), wherein -OY is a leaving group.

[0015] In some embodiments, a process of the invention comprises vi) optionally, isolating a compound of formula (XI).

[0016] In keeping with an embodiment of the invention, a process for preparing a compound of formula (S)-(VH) comprises vii) reacting a compound of formula (XI) with a compound of formula (XV):

Ph

CH H--RR¹¹

Ph (XV), wherein R¹ is selected from the group consisting of -CN and -CONH₂, with a base, and in a fourth organic solvent, to obtain a compound of formula (XII): Ph R¹

^Ph\-.

O^Q (_XII).

[0017] In some embodiments, a process of the invention comprises viii) optionally, isolating a compound of formula (XII).

[0018] In keeping with an embodiment of the invention, a process for preparing a compound of formula (S)-(VII) comprises ix) removing the nitrogen protecting group Q of compound of formula (XII), to obtain a compound of formula (S)-(VII).

[0019] In some embodiments, a process of the invention comprises x) optionally, if R¹ is

-CN, converting the -CN to -CONH₂, by reacting compound of formula (S)-(VH) with a hydrolyzing agent.

[0020] In some embodiments, a process of the invention comprises xi) optionally, isolating a compound of formula (S)-(VII).

[0021] By way of example, illustrative nitrogen protecting groups suitable in a process of the invention are arylalkyl and sulfonyl, e.g., arylsulfonyl groups. In a preferred embodiment, the nitrogen protecting group, Q, is selected from the group consisting of benzyl, j5-toulenesulfonyl (tosyl), and/?-nitrobenzenesulfonyl (nosyl).

[0022] In preferred embodiments, the reaction of (S)-malic acid of formula (S)-(VIII) with a compound of formula (XIV) further comprises a non-oxidizing acid in catalytic amounts. In more preferred embodiments, the non-oxidizing acid is an aryl sulfonic acid, such as, for example, /?-toluenesulfonic acid.

[0023] By way of example, illustrative solvents suitable as a first organic solvent in step i) of processes of the invention include one or more aromatic hydrocarbons. In a preferred embodiment, the first organic solvent comprises a xylene.

[0024] By way of example, illustrative reducing agents suitable as a carbonyl reducing agent in processes of the invention include any suitable reducing agent capable of reducing the carbonyl groups of a compound of formula (IX) in step iii) to obtain a compound of formula (X) such as, for example, a hydride. In a preferred embodiment, the hydride is provided by a metal hydride agent such as, for example, lithium aluminium hydride.

[0025] By way of example, illustrative solvents suitable as a second organic solvent in step iii) of processes of the invention include polar, aprotic ether solvents. In a preferred embodiment, the second organic solvent comprises tetrahydrofuran. [0026] By way of example, illustrative oxygen activating agents suitable for step v) in processes of the invention include any suitable oxygen activating agent capable of converting the hydroxyl group of a compound of formula (X) into a leaving group. In a preferred embodiment, the oxygen activating agent is a sulfonyl compound, more preferably the oxygen activating agent is a/?-toluenesulfonyl chloride.

[0027] By way of example, illustrative solvents suitable as a third organic solvent in step v) of processes of the invention include one or more aromatic heterocyclic solvents. In a preferred embodiment, the third organic solvent comprises pyridine.

[0028] By way of example, illustrative bases suitable in step v) of processes of the invention include any base capable of catalyzing the reaction of a compound of formula (X) with an oxygen activating agent.

[0029] In preferred embodiments, the solvent and base of step v) of processes of the invention are the same and comprise pyridine.

[0030] By way of example, illustrative bases suitable in step vii) of processes of the invention are any bases capable of catalyzing the reaction of a compound of formula (XI) with a compound of formula (XV) to obtain a compound of formula (XII). In a preferred embodiment, the base of step vii) is selected from the group consisting of an alkali metal hydride, an alkali metal hydroxide, and an alkaline-earth metal hydroxide, more preferably the base of step vii) is sodium hydride.

[0031] By way of example, illustrative solvents suitable as a fourth organic solvent in step vii) of processes of the invention include one or more aromatic hydrocarbon solvents. In a preferred embodiment, the fourth solvent comprises toluene.

[0032] In keeping with certain embodiments of the invention, processes of the invention comprise removing a nitrogen protecting group Q of a compound of formula (XII) to obtain a compound of formula (.S)-(VII).

[0033] In embodiments when the nitrogen protecting group Q is benzyl, preferably Q is removed by hydrogenating a compound of formula (XII) with a hydrogen donor compound in the presence of palladium on carbon catalyst and in an alcohol solvent.

[0034] By way of example, illustrative hydrogen donor compounds suitable for processes of the invention include formate salts. In a preferred embodiment, the hydrogen donor compound is ammonium formate. [0035] In embodiments when the nitrogen protecting group Q is tosyl, preferably Q is removed by reacting a compound of formula (XII) with a concentrated acid and a reducing agent.

[0036] In embodiments when the nitrogen protecting group Q is nosyl, preferably Q is removed by reacting a compound of formula (XII) with samarium iodide or tributyltin hydride, a concentrated acid, and a reducing agent.

[0037] In some embodiments, R¹ of a compound of formula (S)-(VII) is converted from

-CN to -CONH₂ using a hydrolyzing agent.

[0038] By way of example, illustrative hydrolyzing agents of step x) of processes of the invention include any suitable hydrolyzing agent capable of converting a -CN of a compound of formula (S)-(VII) to a -CONH₂. In a preferred embodiment, the hydrolyzing agent is aqueous acid such as aqueous sulphuric acid.

[0039] In some embodiments, processes of the invention further comprise preparing a salt of compound of formula (S)-(VII). Preferably, the salt of compound of formula (S)-(VII) is the L-tartrate salt of compound of formula (S)-(VII). In keeping with the invention, the

L-tartrate salt of compound of formula (S)-(VII) is prepared by reacting a compound of formula (S)-(VII) with L-tartaric acid in an alcohol solvent.

[0040] In a particular embodiment, the present invention provides an improved process for the preparation of 3 -substituted pyrrolidine compounds of formula (VII) (e.g., a compound of formula (S)-(VIIa) and a compound of formula (S)-(VIIb) or salts thereof according to Scheme 3.

Scheme 3 [0041] In the present invention, applicants have observed that when the (5)-enantiomer of malic acid is used as a starting compound (compound of formula (S)- VIII), the (S)- enantiomer of the 3 -substituted pyrrolidines of formula (VII) or salts thereof is obtained.

[0042] Accordingly, starting from the (i?)-enantiomer of malic acid, the (i?)-enantiomer of the 3 -substituted pyrrolidines (VII) or salts thereof is obtained.

[0043] Accordingly, starting from racemic malic acid, the racemic 3 -substituted pyrrolidine (VII) or salts thereof will be obtained.

[0044] In some embodiments, the present invention provides a process for preparing darifenacin, or pharmaceutically acceptable salts thereof, using a compound of formula (VII), or a salt thereof, which has been prepared in accordance with a process of the invention. In a preferred embodiment, the L-(+)-tartrate salt of (S)-(VIIb) obtained according to the process of the invention is used for preparing darifenacin or a pharmaceutically acceptable salt thereof.

[0045] In keeping with embodiments of the invention, the process for preparing darifenacin can be any suitable process for preparing darifenacin or a pharmaceutically acceptable salt thereof from a compound of formula (VII).

[0046] In some embodiments, the invention provides an improved process for preparing darifenacin or a pharmaceutically acceptable salt thereof, comprising a) reacting the compound of formula (iS)-(VII), or a salt thereof, with a compound of formula (XIII):

wherein Z is a leaving group, in the presence of an organic solvent and with a base, to obtain a compound of formula (XVI):

[0047] Suitable leaving groups, Z, of processes of the invention include, for example, halogens and sulfonate esters. Illustrative halogen leaving groups are fluoride, chloride, bromide, and iodide. Illustrative sulfonate esters leaving groups are methanesulfonate or mesylate, j7-toluenesulfonate or tosylate, /7-nitrobenzenesulfonate or nosylate, and p-bromobenzenesulfonate or brosylate. In a preferred embodiment, the leaving group is bromide. [0048] In some embodiments, R¹ of a compound of formula (XVI) is -CONH₂ (i.e., a compound of formula (XVI) is darifenacin base).

[0049] In some embodiments, R¹ of a compound of formula (XVI) is -CN. In these embodiments, a compound of formula (XVI) is reacted with a hydrolyzing agent to convert the -CN to -CONH₂, thereby obtaining darifenacin base.

[0050] In a preferred embodiment, the hydrolyzing agent is aqueous sulphuric acid.

[0051] In some embodiments, darifenacin base is converted to a pharmaceutically acceptable salt. In a preferred embodiment, darifenacin base is reacted with hydrogen bromide to obtain darifenacin hydrobromide of formula (I).

[0052] In a preferred embodiment, the compound of formula (S)-(VU), or a salt thereof, is the L-(+)-tartrate salt of (S)-(VII) wherein R¹ is -CONH₂ (i.e., a compound of formula

(S)-VIIb), which is obtained according to the process of the invention, and which is reacted with a compound of formula (XIII) to obtain darifenacin base, which is converted to the hydrobromide salt.

[0053] In other embodiments, the present invention provides a pharmaceutical composition comprising darifenacin obtained according to the process of the invention.

[0054] The following examples further illustrate the invention but, of course, should not be construed as in any way limiting its scope.

EXAMPLES

[0055] Example 1 : Preparation of (3S)-./V-benzyl-3-hydroxysuccinimide (i.e., a compound of formula (IX)).

[0056] This example demonstrates a process for preparing a compound of formula (IX) in accordance with an embodiment of the invention.

[0057] A four-neck round bottom flask equipped with a Dean-Stark, was charged with 50.00 g (372.9 mmol) of (S)-malic acid, 50.00 g (466.6 mmol) of benzylamine, 0.50 g (2.90 mmol) of/?-toluenesulfonic acid, and xylene (500 mL). The mixture was stirred at reflux (about 140 °C) for about 6 h. After removal of xylene and crystallization from benzene, 41.32 g (54.00% yield) of (35)-N-benzyl-3-hydroxysuccinimide (IX) as a pale yellow solid was obtained.

[0058] Example 2: Preparation of (35)-N-benzyl-3-hydroxypyrrolidine (i.e., compound of formula (X)). [0059] This example demonstrates a process for preparing a compound of formula (X) in accordance with an embodiment of the invention.

[0060] A four-neck round bottom flask, was charged with 25.00 g (121.8 mmol) of (35)- iV-benzyl-3-hydroxysuccinimide from Example 1 and tetrahydrofuran (650 mL). The mixture was cooled to 15-20 °C and lithium aluminium hydride (14 g, 368.9 mmol) was added portionwise over a period of 1.5 h. The reaction mixture was heated to reflux and stirred at this temperature for 4 h. The reaction mixture was cooled (20-25 °C). Water (50 mL) and 4 N NaOH (12 mL) were added. The resulting suspension was filtered and the filtrate was concentrated, to obtain 7.52 g (87.04% yield) of (3S)-N-benzyl-3- hydroxypyrrolidine (X) as an oil.

[0061] Example 3: Preparation of (35)-N-benzyl-3-hydroxysuccinimide (i.e., compound of formula (IX)).

[0062] This is another example demonstrating a process for preparing a compound of formula (IX) in accordance with an embodiment of the invention.

[0063] A four-neck round bottom flask equipped with a Dean-Stark was charged with

100.0 g (745.8 mmol) of (5)-malic acid, 100.0 g (933.2 mmol) of benzylamine, 1.00 g (5.80 mmol) of/7-toluenesulfonic acid, and xylene (1000 mL). The mixture was stirred at reflux for 7 h. The mixture was cooled to room temperature and stirred overnight. The mixture was filtered and the resulting cake was washed with ethyl acetate (800 mL). The mother liquors were concentrated in vacuum and the remaining residue was recrystallized with ethyl acetate

(150 mL) and petroleum oil (150 mL). After filtration and drying, 92.00 g (60.12% yield) of

(35)-N-benzyl-3-hydroxysuccinimide (IX) was obtained as an off-white powder.

[0064] Example 4: Preparation of (35)-N-benzyl-3-hydroxypyrrolidine (i.e., compound of formula (X)).

[0065] This is another example demonstrating a process for preparing a compound of formula (X) in accordance with an embodiment of the invention.

[0066] A four-neck round bottom flask was charged with 9.20 g (242.4 mmol) of lithium aluminium hydride and 100 mL of tetrahydrofuran. A solution of 17.00 g (82.84 mmol) of

(3S)-iV-benzyl-3-hydroxysuccinimide in tetrahydrofuran (80 mL) was added dropwise at 0-

10 ⁰C. The mixture was heated to reflux and stirred at this temperature for 6 h. The mixture was cooled to 10-20 °C and water (40 mL) and 4 N sodium hydroxide solution (10 mL) were added. The mixture was filtered and the resulting cake was washed with ethyl acetate (2 x

200 mL). The mother liquors were concentrated in vacuum. The remaining residue was dissolved in ethyl acetate (400 mL) and then washed with brine. The organic layer was dried with anhydrous sodium sulfate and concentrated in vacuum to obtain 18.00 g (quantitative yield) of (35)-N-benzyl-3-hydroxypyrrolidine as an oil.

[0067] Example 5: Preparation of (3iS)-7V-benzyl-3-tosylpyrrolidine (i.e., compound of formula (XI)).

[0068] This example demonstrates a process for preparing a compound of formula (XI) in accordance with an embodiment of the invention.

[0069] A four-neck round bottom flask was charged with (3<S)-./V-benzyl-3- hydroxypyrrolidine from Example 4 (18.00 g) and pyridine (150 mL). The mixture was cooled to 0 °C and/>-toluenesulfonyl chloride (18.99 g, 99.61 mmol) was added in portions.

After addition, the mixture was stirred at 0 ⁰C overnight and concentrated under vacuum.

The remaining residue was dissolved in methylene chloride (300 mL) and then washed with

10% hydrochloric acid (100 mL), 10% sodium hydroxide (120 mL) and brine (200 mL). The organic layer was dried with anhydrous sodium sulfate and concentrated in vacuum. The residue was crystallized from a mixture of ethyl acetate (12 mL) and methanol (8 mL). After filtration and drying, 11.00 g (52.01% yield) of (35)-N-benzyl-3-tosylpyrrolidine (XI) as a powder was obtained.

[0070] Example 6: Preparation of 2,2-diphenyl-2-[(35)-N-benzyl-pyrrolidin-3- yl]acetonitrile (i.e., compound of formula (XII)).

[0071] This example demonstrates a process for preparing a compound of formula (XII) in accordance with an embodiment of the invention.

[0072] A four-neck round bottom flask was charged with sodium hydride 60% (3.00 g,

75.00 mmol), 2,2-diphenylacetonitrile (6.88 g, 35.60 mmol) and toluene (200 mL). The mixture was heated to reflux. After stirring at reflux for 2 h, (3S)-N-benzyl-3- tosylpyrrolidine (9.6 g, 37.60 mmol) was added and the mixture was stirred at reflux for 3 h.

Toluene (60 mL) was added and the mixture was washed with water (2 x 100 mL), 5% sodium hydroxide (2 x 100 mL) and brine (2 x 100 mL), dried with anhydrous sodium sulfate and concentrated in vacuum to obtain 13.00 g (quantitative yield) of 2,2-diphenyl-2-[(3S)-7V- benzyl-pyrrolidin-3-yl]acetonitrile (XII) as an oil.

[0073] Example 7: Preparation of 2,2-diphenyl-2-[(3S)-pyrrolidin-3-yl]acetonitrile (i.e., compound of formula (<!?)-(VIIa)).

[0074] This example demonstrates a process for preparing a compound of formula (S)-

(VIIa) in accordance with an embodiment of the invention. [0075] A four-neck round bottom flask was charged with 2,2-diphenyl-2-[(3S)-iV-benzyl- pyrrolidin-3-yl]acetonitrile from Example 6 (13.00 g), 10% palladium on charcoal (1% wet, 2.00 g), ammonium formate (10.30 g, 163.34 mmol) and methanol (60 mL). The mixture was heated to reflux, stirred at this temperature for 5 h, filtered, and concentrated in vacuum. The residue was purified by column chromatography (ethyl acetate/triethylamine = 1 :0.02) to obtain 1.80 g (19.27% yield) of 2,2-diphenyl-2-[(3S)-pyrrolidin-3-yl]acetonitrile (S)-(VIIa) as a semi-solid.

[0076] Example 8: Preparation of 2,2-diphenyl-2-[(55)-pyrrolidin-3-yl]acetamide (i.e., compound of formula (S)-(VIIb)).

[0077] This example demonstrates a process for preparing a compound of formula (S)- VIIb) in accordance with an embodiment of the invention.

[0078] A four-neck round bottom flask was charged with 2,2-diphenyl-2-[(3S)- pyrrolidin-3-yl]acetonitrile (1.80 g, 6.86 mmol) and 80% sulfuric acid (30 mL). The mixture was heated to 85-90 ⁰C and stirred at this temperature for 14 h. The pH of the mixture was adjusted to 12 with ammonia at 10 °C and the mixture was extracted with methylene chloride (2 x 100 mL). The combined organic layers were washed with water (3 x 100 mL) and brine, dried with anhydrous sodium sulfate and concentrated in vacuum to obtain 2.00 g (quantitative yield) of 2,2-diphenyl-2-[(3S)-pyrrolidin-3-yl]acetamide (S)-(VIIb) as an oil. [0079] Example 9: Preparation of 2,2-diphenyl-2-[(3S)-pyrrolidin-3-yl]acetamide L-(+)- tartrate (i.e., L-(+)-tartrate salt of compound of formula (S)-(VIIb)). [0080] This example demonstrates a process for preparing a compound of formula (S)- VIIb) in accordance with an embodiment of the invention.

[0081] A 4-neck round bottom flask was charged with 2,2-diphenyl-2-[(3S)-pyrrolidin-3- yljacetamide from Example 8 (2.00 g), L-(+)-tartaric acid (1.03 g, 6.86 mmol) and ethanol (25 mL). The mixture was heated to reflux and stirred at this temperature for 10 min. The mixture was then cooled to 0-5 ⁰C and stirred at this temperature for 2 h. The suspension was filtered and the resulting cake was recrystallized with methanol (12 mL) to obtain 0.50 g (16.95% yield) of 2,2-diphenyl-2-[(3S)-pyrrolidin-3-yl]acetamide L-(+)-tartrate as a powder. [0082] The use of the terms "a" and "an" and "the" and similar referents in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The terms "comprising," "having," "including," and "containing" are to be construed as open-ended terms (i.e., meaning "including, but not limited to,") unless otherwise noted. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "such as") provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

[0083] Preferred embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Variations of those preferred embodiments may become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

Claims

CLAIM(S):

1. A process for preparing a compound of formula (S)-(VII):

wherein R¹ is selected from the group consisting of -CN and -CONH₂, said process comprising: i) reacting (5)-malic acid of formula (iS)-(VIH):

with a compound of formula (XIV):

H₂N-Q (_XIV)₅

wherein Q is a nitrogen protecting group, in a first organic solvent, to obtain a compound of formula (IX),

ii) optionally, isolating a compound of formula (IX); iii) reacting compound of a formula (IX) with a carbonyl reducing agent, in a second organic solvent, to obtain a compound of formula (X):

HO,

^^Q (X); iv) optionally, isolating a compound of formula (X); v) converting the hydroxyl group of compound of formula (X) into a leaving group by reacting a compound of formula (X) with an oxygen activating agent, in a third organic solvent and a base, to obtain a compound of formula (XI): YO

(^NQ

(XI), wherein -OY is a leaving group; vi) optionally, isolating a compound of formula (XI); vii) reacting a compound of formula (XI) with a compound of formula (XV):

Ph

CH-R¹ Ph (XV), wherein R¹ is selected from the group consisting of -CN and -CONH₂, with a base, and in a fourth organic solvent, to obtain a compound of formula (XII):

viii) optionally, isolating a compound of formula (XII); ix) removing the nitrogen protecting group Q of compound of formula (XII), to obtain a compound of formula (S)-(VII); x) optionally, if R¹ is -CN, converting the -CN to -CONH₂, by reacting compound of formula (S)-(VII) with a hydrolyzing agent; and xi) optionally, isolating a compound of formula (S)-(VII).

2. The process of claim 1, wherein Q is selected from the group consisting of benzyl, tosyl, and nosyl.

3. The process of claim 1 , wherein the reaction of step i) further comprises a non-oxidizing acid in catalytic amounts.

4. The process of claim 3, wherein the non-oxidizing acid is p-toluenesulfonic acid.

5. The process of claim 1, wherein the first organic solvent comprises a xylene.

6. The process of claim 1, wherein the carbonyl reducing agent is a hydride agent.

7. The process of claim 6, wherein the hydride agent is lithium aluminium hydride.

8. The process of claim 1, wherein the second organic solvent comprises tetrahydrofuran.

9. The process of claim 1, wherein the oxygen activating agent is a sulfonyl compound.

10. The process of claim 9, wherein the sulfonyl compound is /7-toluenesulfonyl chloride.

11. The process of claim 1 , wherein the third organic solvent and the base of step v) are the same and comprise pyridine.

12. The process of claim 1, wherein the base of step vii) is selected from the group consisting of an alkali metal hydride, an alkali metal hydroxide, and an alkaline-earth metal hydroxide.

13. The process of claim 1, wherein the fourth organic solvent comprises toluene.

14. The process of claim 2, wherein removing the nitrogen protecting group Q of a compound of formula (XII) comprises:

(a) if the nitrogen protecting group Q is benzyl, hydrogenating a compound of formula (XII) with a hydrogen donor compound, in the presence of palladium on carbon catalyst, and in an alcohol solvent; or

(b) if the nitrogen protecting group Q is tosyl, reacting a compound of formula (XII) with a concentrated acid and a reducing agent; or

(c) if the nitrogen protecting group Q is nosyl, reacting a compound of formula (XII) with samarium iodide or tributyltin hydride.

15. The process of claim 14, wherein the hydrogen donor compound is ammonium formate.

16. The process of claim 1, wherein the hydrolyzing agent is aqueous sulphuric acid.

17. The process of any one of claims 1 to 16, said process further comprising preparing a salt of compound of formula (S)-(VII).

18. The process of claim 17, wherein the salt of compound of formula (S)-(VII) is the L-tartrate salt.

19. The process of claim 18, wherein the process comprises reacting a compound of formula (S)-(VII) with L -tartaric acid in an alcohol solvent.

20. The process of any one of claims 1 to 19, said process further comprising:

a) reacting the compound of formula (S)-(VII), or a salt thereof, with a compound of formula (XIII):

wherein Z is a leaving group, in the presence of an organic solvent and a base, to obtain a compound of formula (XVI):

wherein, if R¹ is -CONH₂, the compound of formula (XVI) is darifenacin base; b) if R¹ is -CN, reacting the compound of formula (XVI) with a hydrolyzing agent, to obtain darifenacin base; and c) optionally, reacting the darifenacin base with hydrogen bromide to obtain darifenacin hydrobromide salt of formula (I):

(i).

21. The process of claim 20, wherein the compound of formula (S)-(WU), or a salt thereof, of step i) is the L-tartrate salt compound of formula (.S)-(VII) wherein R¹ is -CONH₂.

22. The process of claim 20, wherein Z is selected from the group consisting of halogens and sulfonate esters.

23. The process of claim 22, wherein Z is bromide.

24. The process of claim 20, wherein the hydrolyzing agent of step b) is aqueous sulphuric acid.