WO2011011598A1

WO2011011598A1 - Process for preparing 4- { (s) -2- (4-(4-chlorophenoxy) phenoxymethyl) pyrrolidin-1-yl) } butyric acid and salts thereof

Info

Publication number: WO2011011598A1
Application number: PCT/US2010/042901
Authority: WO
Inventors: Livia A. Enache; Isaac Kennedy; David Sullins; Glenn L. Stahl; Wei Chen; Douglas F. Fry
Original assignee: Decode Genetics Ehf
Priority date: 2009-07-24
Filing date: 2010-07-22
Publication date: 2011-01-27

Abstract

The present invention relates to a process for preparing 4-{(S)-2-[4-(4-chlorophenoxy)phenoxymethyl]pyrrolidin-1-yl}butyric acid and its salts.

Description

PROCESS FOR PREPARING 4- { ( S ) -2 - ( 4 - ( 4 -CHLOROPHENOXY) PHENOXYMETHYL ) PYRROLIDIN-1-YL ) } BUTYRIC ACID AND SALTS THEREOF

FIELD OF THE INVENTION

[0001] The present invention relates to a process for preparing 4-{(5)-2-[4-(4- chlorophenoxy)phenoxymethyl]pyrrolidin-l-yl} butyric acid and its salts.

BACKGROUND OF THE INVENTION

[0002] 4-{(5')-2-[4-(4-Chlorophenoxy)phenoxymethyl]pyrrolidin-l-yl}butyric acid is an inhibitor of LTA4H (leukotriene A4 hydrolase) which has been disclosed in US patent 7,402,684 to be useful for the treatment and prophylaxis of inflammatory diseases and disorders.

SUMMARY OF THE INVENTION

[0003] The present invention involves processes for preparing 4-{(5)-2-[4-(4- chlorophenoxy)phenoxymethyl]pyrrolidin-l-yl}butyric acid and its salts. These improved processes result in higher yields of the desired product, less expensive reagents, fewer steps, increased efficiencies in purification, and reduced processing time than previously disclosed processes.

[0004] One embodiment of the invention enables preparation of 4-{2-[4-(4- chlorophenoxy)phenoxymethyl]pyrrolidin-l-yl}butyric acid (CPPBA) of formula I

[0005] The process comprises the steps of: reacting a compound of formula II

in the presence of potassium tert-butoxide with a compound of formula III

to obtain a compound of formula IV

followed by converting the compound of formula IV to the compound of formula I.

[0006] Further, the step of converting the compound of formula IV to a compound of formula I is accomplished by:

reacting the compound of formula IV with a mineral acid in dioxane to obtain a compound of formula V

followed by reacting the compound of formula V with ethyl 4-bromobutyrate and a base selected from potassium carbonate, cesium carbonate, sodium carbonate, diazabicyclooctane and l,8-diazabicyclo[5.4.0]undec-ene to obtain a compound of formula VI

followed by reacting the compound of formula VI with aqueous alkali metal hydroxide, such as sodium hydroxide, potassium hydroxide or lithium hydroxide, in alkanol to obtain the alkali metal salt of the compound of formula I, and acidifying.

[0007] In one embodiment the invention relates to a process for preparing CPPBA

(I):

comprising the steps of

a) reacting 4-bromochlorobenzene with 4-methoxyphenol in the presence of cesium carbonate, N,N-dimethylglycine hydrochloride and Cu(I)I in 1,4-dioxane to obtain 1 -(4-methoxyphenoxy)-4-chlorobenzene;

b) reacting l-(4-methoxyphenoxy)-4-chlorobenzene with sodium iodide and chlorotrimethylsilane in acetonitrile to obtain formula II

c) reacting Boc-(«S)-(-)-2-pyrrolidinemethanol and base withp- toluenesulfonyl chloride to obtain a compound of formula III

in; d) reacting a compound of formula II in the presence of potassium tert- butoxide with a compound of formula III to obtain compound of formula IV

e) reacting the compound of formula IV with a mineral acid in a moderately polar aprotic solvent, such as ethyl acetate, diethyl ether or dioxane, to obtain a compound of formula V

f) reacting the compound of formula V with potassium carbonate and ethyl 4-bromobutyrate in acetonitrile to obtain a compound of formula VI

g) reacting the compound of formula VI with aqueous alkali metal hydroxide in alkanol to obtain the alkali metal salt of the compound of formula I, and acidifying.

[0008] In another embodiment, the invention is a process for preparing a compound of formula VII

VII comprising reacting a compound of formula VI

with aqueous sodium hydroxide, potassium hydroxide or lithium hydroxide in alkanol followed by acidification withp-toluenesulfonic acid monohydrate.

[0009] In a particular embodiment, the invention relates to a process for preparing a compound of formula VII

comprising the steps of:

a) reacting N-Boc-L-prolinol andp-toluenesulfonyl chloride in

acetonitrile/toluene in the presence of triethylamine and one or both of dimethylaminopyridine or trimethylamine;

b) treating 4-(4-chlorophenoxy)phenol in dimethylformamide with potassium tert-butoxide in tert-butanol;

c) combining the mixtures from steps a) and b) to obtain (S)-2-[4-(4- chlorophenoxy)phenoxymethyl)pyrrolidine- 1 -carboxylic acid tert-butyl ester;

d) treating the (S)-2-[4-(4-chlorophenoxy)phenoxymethyl)pyrrolidine- 1 - carboxylic acid tert-butyl ester with hydrogen chloride in ethyl acetate, diethylether or 1,4-dioxane to obtain (S)-2-[4-(4- chlorophenoxy)phenoxymethyl)pyrrolidine hydrochloride; e) basifying the (S)-2-[4-(4-chlorophenoxy)phenoxymethyl)pyrrolidine hydrochloride and taking the (S)-2-[4-(4- chlorophenoxy)phenoxymethyl)pyrrolidine into acetonitrile;

f) adding ethyl 4-bromobutyrate and potassium carbonate to obtain 4-{(S)-2- [4-(4-chlorophenoxy)phenoxymethyl]pyrrolidine-lyl} butyric acid ethyl ester;

g) treating 4- {(S)-2-[4-(4-chlorophenoxy)phenoxymethyl]pyrrolidine- lyl} butyric acid ethyl ester with sodium hydroxide in ethanol and water to obtain 4- {(S)-2-[4-(4-chlorophenoxy)phenoxymethyl]pyrrolidin- 1 - yl} butyric acid; and

h) adding p-toluene sulfonic acid monohydrate to obtain a compound of formula VII.

[0010] In another embodiment, the invention relates to a process for preparing (S)-CPPBA of formula I

comprising the steps of:

a) reacting N-Boc-L-prolinol andp-toluenesulfonyl chloride in

b) dissolving 4-(4-chlorophenoxy)phenol in dimethyl formamide with

potassium tert-butoxide in tert-butanol;

g) treating 4- {(S)-2-[4-(4-chlorophenoxy)phenoxymethyl]pyrrolidine- lyl} butyric acid ethyl ester with sodium hydroxide and water and acidifying to obtain 4-{(S)-2-[4-(4- chlorophenoxy)phenoxymethyl]pyrrolidin- 1 -yl} butyric acid.

[0011] These processes are advantageous in that they result in higher yields of the desired product while using less expensive reagents. Additionally, fewer steps are required, there are increased efficiencies in purification, and the processing time is reduced when compared with previously disclosed processes. Further, the sequence can be further streamlined by deleting the intermediate isolation steps.

DETAILED DESCRIPTION OF THE INVENTION

[0012] Throughout this application, various references are cited. The disclosures of each of these publications in their entireties are hereby incorporated by reference as if written herein.

Definitions

[0013] The terms and substituents are defined when introduced and retain their definitions throughout.

[0014] Alkyl is intended to include linear, branched, or cyclic hydrocarbon structures and combinations thereof. Lower alkyl refers to alkyl groups of from 1 to 6 carbon atoms. Examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, s-and t-butyl and the like. Preferred alkyl and alkylene groups are those of C₂0 or below. Cycloalkyl is a subset of alkyl and includes cyclic hydrocarbon groups of from 3 to 8 carbon atoms. Examples of cycloalkyl groups include c-propyl, c-butyl, c-pentyl, norbornyl, adamantyl and the like. When not otherwise restricted, the term alkyl or cycloalkyl refers to alkyl of 10 or few carbons. Preferred alkyl and alkylene groups are those of Cio or below (e.g. Ci, C₂, C3, C₄, C5,

[0015] Ci to C₂₀ Hydrocarbon includes alkyl, cycloalkyl, alkenyl, alkynyl, aryl and combinations thereof. Examples include benzyl, phenethyl, cyclohexylmethyl, camphoryl and naphthylethyl.

[0016] Alkanol describes a linear or branched alkyl group containing a hydroxyl group. Examples of alkanols include, but are not limited to, methanol, ethanol, 1- or 2-propanol, 2-methylpropan-2-ol (t-butanol), 1- or 2-butanol, etc. Preferred alkanols contain from 1 to 6 carbon atoms.

[0017] A mineral acid is an inorganic acid. Examples of mineral acids include, but are not limited to, sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid and nitric acid.

[0018] "Taking...into" describes a process whereby a substance is ultimately in solution in a solvent. It can come about by direct dissolution of a solid or semi-solid into a solvent, or it can come about by changeover from solution in one solvent to solution in another. For instance, "...taking the (S)-2-[4-(4- chlorophenoxy)phenoxymethyl) pyrrolidine into acetonitrile..." describes the action of exchanging the ethyl acetate that the (S)-2-[4-(4- chlorophenoxy)phenoxymethyl)pyrrolidine-l-carboxylic acid tert-butyl ester had been dissolved in with acetonitrile. This can be accomplished by removing (stripping) the first solvent and redissolving the solid (or semisolid) residue in a second solvent, or by partially removing the first solvent and then displacing the remaining portion of it via repeated additions of the second solvent followed each time by partial evaporation or distillation until the compound of interest (in this example (S)-2-[4-(4- chlorophenoxy)phenoxymethyl)pyrrolidine- 1 -carboxylic acid tert-butyl ester) ends up as a solute in the second solvent, so that a solid phase never appears.

[0019] A copper complexing ligand is defined as an additive ligand that can form a complex with copper. Representative copper complexing ligands include, but are not limited to, NN-dimethylglycine, 1 , 10-phenanthroline, 2,9-dimethyl-l,10- phenanthroline, NN'-dimethylethylenediamine, proline, 1,1,1- tris(hydroxymethyl)ethane, ethyleneglycol, DMAP, pyrrolidine-2-phosphonic acid phenyl monoester, and 2,2,6,6-tetramethylheptane-3,5-dione. Copper complexing amines can be used as free bases or salts.

[0020] The compound described herein contains an asymmetric center and may thus give rise to enantiomers. The chiral center may be defined, in terms of absolute stereochemistry, as (R)- or (S)-. Except where a single enantiomer is clearly designated, the present invention is meant to include all such possible isomers, as well as, their racemic and optically pure forms. Optically active (R)- and (S)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.

[0021] The graphic representations of racemic, ambiscalemic and scalemic or enantiomerically pure compounds used herein are taken from Maehr J₁ Chem. Ed. 62, 114-120 (1985), solid and broken wedges are used to denote the absolute

configuration of a chiral element; wavy lines and single thin lines indicate disavowal of any stereochemical implication which the bond it represents could generate; and wedge outlines and dotted or broken lines denote enantiomerically pure compounds of indeterminate absolute configuration.

[0022] Terminology related to "protecting", "deprotecting" and "protected" functionalities occurs throughout this application. Such terminology is well understood by persons of skill in the art and is used in the context of processes which involve sequential treatment with a series of reagents. In that context, a protecting group refers to a group which is used to mask a functionality during a process step in which it would otherwise react, but in which reaction is undesirable. The protecting group prevents reaction at that step, but may be subsequently removed to expose the original functionality. The removal or "deprotection" occurs after the completion of the reaction or reactions in which the functionality would interfere. Thus, when a sequence of reagents is specified, as it is in the processes of the invention, the person of ordinary skill can readily envision those groups that would be suitable as "protecting groups". Suitable groups for that purpose are discussed in standard textbooks in the field of chemistry, such as Protective Groups in Organic Synthesis by T.W.Greene [John Wiley & Sons, New York, 1991], which is incorporated herein by reference. Particular attention is drawn to the chapters entitled "Protection for the Hydroxyl Group, Including 1,2- and 1,3-Diols" (pages 10-86) and to "Protection for the Amino Group (pages 494-653)".

[0023] The abbreviations Me, Et, Ph, Tf, Ts and Ms represent methyl, ethyl, phenyl, trifluoromethanesulfonyl (triflate), toluenesulfonyl and methanesulfonyl respectively. T-BOC or boc represents tert-butoxycarbonyl. TEA represents triethylamine. MTBE represents methyl tert-butyl ether. DMAP represents A- Dimethylaminopyridine. DMF represents dimethylformamide. MEK represents methyl ethyl ketone (2-butanone), and MIBK represents methyl isobutyl ketone (4- methyl-2-pentanone). A comprehensive list of abbreviations utilized by organic chemists (i.e. persons of ordinary skill in the art) appears in the first issue of each volume of the Journal of Organic Chemistry. The list, which is typically presented in a table entitled "Standard List of Abbreviations," is incorporated herein by reference.

[0024] In the specification and claims various amines are described. In many cases the amine is commercially available as its acid addition salt and such salts are often easier to manipulate than the free base. For example, the person of skill in the art will understand that trimethylamine (TMA) can be furnished as a base or as an acid addition salt, and that for many applications the amine can be generated in situ. For the purpose of the present application, reference to the use of a trialkyl amine will be understood to include its salt. For instance, TMA can be free or derived from trimethylamine hydrochloride.

[0025] Potassium tert -butoxide is commonly provided as a solution in a solvent such as tert-butanol.

[0026] A compound of formula I can be prepared by reacting a compound of formula

II

with a compound of formula III

in the presence of potassium tert-butoxide. This results in a

compound of formula IV

. The compound of formula IV can then be converted to a compound of formula I.

[0027] One method of converting a compound of formula IV to a compound of formula I involves reacting the compound of formula IV with a mineral acid in dioxane to obtain a compound of formula V

In some embodiments of the invention, the mineral acid is hydrochloric acid. The compound of formula V is then reacted with ethyl 4-bromobutyrate and a base to obtain a compound of formula VI

. In some embodiments of the invention, the compound of formula V is reacted with ethyl 4-bromobutyrate in acetonitrile. In some embodiments, the base is potassium carbonate. In other embodiments, the base is cesium carbonate. In still other embodiments the base is sodium carbonate. In yet other embodiments, the base is diazabicyclooctane or 1,8- diazabicyclo[5.4.0]undec-ene. This step is followed by reacting the compound of formula VI with sodium hydroxide, alkanol and water to obtain the sodium salt of the compound of formula I, and acidifying.

[0028] In an embodiment of the invention, a compound of formula II is prepared by reacting 4-bromochlorobenzene with 4-methoxyphenol in the presence of a base, a copper complexing ligand; and Cu(I)I to obtain l-(4-methoxyphenoxy)-4- chlorobenzene. In some embodiments, the copper complexing ligand is N,N- dimethylglycine hydrochloride. In some embodiments, the base is cesium carbonate. In other embodiments, the base is potassium carbonate. In still other embodiments, the base is sodium carbonate. In some embodiments of the invention, the A- bromochlorobenzene is reacted with 4-methoxyphenol in 1,4-dioxane.

[0029] This step is followed by reacting l-(4-methoxyphenoxy)-4-chlorobenzene with iodotrimethylsilane to obtain a compound of formula II. The

iodotrimethylsilane can be generated in situ from sodium iodide and

chlorotrimethylsilane. In some embodiments, the 1 -(4-methoxyphenoxy)-4- chlorobenzene is reacted with iodotrimethylsilane or sodium iodide and

chlorotrimethylsilane in acetonitrile.

[0030] In one embodiment of the invention, CPPBA can be prepared by reacting A- bromochlorobenzene with 4-methoxyphenol and 1,4-dioxane in the presence of cesium carbonate, N,N-dimethylglycine hydrochloride and Cu(I)I to obtain l-(4- methoxyphenoxy)-4-chlorobenzene. This step is followed by reacting l-(4- methoxyphenoxy)-4-chlorobenzene with iodotrimethylsilane or sodium iodide and chlorotrimethylsilane in acetonitrile to obtain a compound of formula II. Boc-(«S)-(-)- 2-pyrrolidinemethanol and base is reacted withp-toluenesulfonyl chloride to obtain a compound of formula III. In some embodiments, the base is triethylamine. In other embodiments, triethylamine is combined with dimethylaminopyridine. In still other embodiments, triethylamine is combined with trimethylamine. Compounds II and III are reacted in the presence of potassium tert-butoxide to obtain a compound of formula IV. The compound of formula IV is reacted with a mineral acid in dioxane to obtain a compound of formula V. In some embodiments, the mineral acid is hydrochloric acid. The compound of formula V is reacted with potassium carbonate and ethyl 4-bromobutyrate in acetonitrile to obtain a compound of formula VI.

Finally, the compound of formula VI is reacted with sodium hydroxide, ethanol and water and acidified to obtain a compound of formula I. In some embodiments, the base is triethylamine optionally combined with dimethylaminopyridine or trimethylamine and the mineral acid is hydrochloric acid. [0031] In some embodiments, the invention relates to a process of preparing a

compound of formula VII

. This process comprises reacting a compound of formula VI

O"

with aqueous alkali metal hydroxide in alkanol followed by acidification withp-toluenesulfonic acid monohydrate. In one embodiment, the alkali metal hydroxide is sodium hydroxide. In another

embodiment, alkali metal hydroxide is potassium hydroxide. In still another embodiment, alkali metal hydroxide is lithium hydroxide.

[0032] In one embodiment, the invention relates to a process of preparing a

compound of formula VII

. This process comprises reacting N-Boc-L-prolinol andp-toluenesulfonyl chloride in acetonitrile/toluene in the presence of triethylamine and one or both of

dimethylaminopyridine or trimethylamine. 4-(4-Chlorophenoxy)phenol is treated in dimethylformamide with potassium tert-butoxide in tert-butanol. These two mixtures are combined to obtain (S)-2-[4-(4-chlorophenoxy)phenoxymethyl)pyrrolidine-l- carboxylic acid tert-butyl ester. In one embodiment, the (S)-2-[4-(4- chlorophenoxy)phenoxymethyl)pyrrolidine-l-carboxylic acid tert-butyl ester is treated with hydrogen chloride in ethyl acetate to obtain (S)-2-[4-(4- chlorophenoxy)phenoxymethyl)pyrrolidine hydrochloride. In another embodiment, the (S)-2-[4-(4-chlorophenoxy)phenoxymethyl)pyrrolidine-l-carboxylic acid tert- butyl ester is treated with hydrogen chloride in diethylether to obtain (S)-2-[4-(4- chlorophenoxy)phenoxymethyl)pyrrolidine hydrochloride. In still another embodiment, the (S)-2-[4-(4-chlorophenoxy)phenoxymethyl)pyrrolidine- 1 -carboxylic acid tert-butyl ester is treated with hydrogen chloride in 1,4-dioxane to obtain (S)-2- [4-(4-chlorophenoxy)phenoxymethyl)pyrrolidine hydrochloride. The (S)-2-[4-(4- chlorophenoxy)phenoxymethyl)pyrrolidine hydrochloride is then basified and the resulting (S)-2-[4-(4-chlorophenoxy)phenoxymethyl)pyrrolidine is taken into acetonitrile. Ethyl 4-bromobutyrate and potassium carbonate are added to obtain 4- {(S)-2-[4-(4-chlorophenoxy)phenoxymethyl]pyrrolidine-lyl}butyric acid ethyl ester. The 4-{(S)-2-[4-(4-chlorophenoxy)phenoxymethyl]pyrrolidine-lyl}butyric acid ethyl ester is treated with sodium hydroxide in ethanol and water to obtain 4-{(S)-2-[4-(4- chlorophenoxy)phenoxymethyl]pyrrolidin-l-yl} butyric acid, which is converted to formula VII by the addition of p-toluem sulfonic acid monohydrate.

[0033] In an embodiment, the invention relates to a process for preparing a compound of formula Ia [the (S)-enantiomer of the compound of formula I]:

. This process comprises reacting N-Boc-L-prolinol andp-toluenesulfonyl chloride in acetonitrile/toluene in the presence of triethylamine and one or both of dimethylaminopyridine or

trimethylamine. 4-(4-chlorophenoxy)phenol is treated in dimethylformamide with potassium tert-butoxide in tert-butanol. These two mixtures are combined to obtain (S)-2-[4-(4-chlorophenoxy)phenoxymethyl)pyrrolidine- 1 -carboxylic acid tert-butyl ester. In one embodiment, the (S)-2-[4-(4- chlorophenoxy)phenoxymethyl)pyrrolidine-l -carboxylic acid tert-butyl ester is treated with hydrogen chloride in ethyl acetate to obtain (S)-2-[4-(4- chlorophenoxy)phenoxymethyl)pyrrolidine hydrochloride. In another embodiment, the (S)-2-[4-(4-chlorophenoxy)phenoxymethyl)pyrrolidine-l -carboxylic acid tert- butyl ester is treated with hydrogen chloride in diethylether to obtain (S)-2-[4-(4- chlorophenoxy)phenoxymethyl)pyrrolidine hydrochloride. In still another embodiment, the (S)-2-[4-(4-chlorophenoxy)phenoxymethyl)pyrrolidine- 1 -carboxylic acid tert-butyl ester is treated with hydrogen chloride in 1,4-dioxane to obtain (S)-2- [4-(4-chlorophenoxy)phenoxymethyl)pyrrolidine hydrochloride. The (S)-2-[4-(4- chlorophenoxy)phenoxymethyl)pyrrolidine hydrochloride is then basified and the resulting (S)-2-[4-(4-chlorophenoxy)phenoxymethyl)pyrrolidine is taken into acetonitrile. Ethyl 4-bromobutyrate and potassium carbonate are added to obtain 4- {(S)-2-[4-(4-chlorophenoxy)phenoxymethyl]pyrrolidine-lyl}butyric acid ethyl ester. The 4-{(S)-2-[4-(4-chlorophenoxy)phenoxymethyl]pyrrolidine-lyl}butyric acid ethyl ester is treated with sodium hydroxide in ethanol and water followed by acidification to obtain 4-{(S)-2-[4-(4-chlorophenoxy)phenoxymethyl]pyrrolidin-l-yl}butyric acid.

EXPERIMENTAL

[0034] (5)-2-(p-Toluenesulfonyloxymethyl)pyrrolidine-l-carboxylic acid tert- butyl ester (Formula III) (TV-Bo c-L-prolinol tosylate). A solution of Boc-(«S)-(-)-2- pyrrolidinemethanol (N-Boc-L-prolinol) (1.43 kg, 7.10 mol) and DMAP (86.40 g, 0.71 mol) in dichloromethane (11 L) in a 22 L round bottom flask was cooled to 5 ⁰C. />-Toluenesulfonyl chloride (1.49 kg, 7.81 mol) was added in portions, with stirring, while maintaining the temperature at 0-5 ⁰C. The resulting mixture was stirred while allowing it to warm up to ambient temperature overnight, after which it was quenched with 6 L water. The organic layer was separated, washed with 6 L water, 4x5 L 0.3 M aqueous HCl, 2x6 L water, and 4 L brine, after which it was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford the desired product (2.42 kg, 96%). The purity (96.3% by HPLC) was suitable for the material to be used in the following step without further purification. This material maintained an acceptable quality when stored refrigerated (2 - 8 ⁰C), under inert atmosphere, for up to two weeks; ¹H ΝMR (CDCI3) δ [ppm] 1.36 and 1.41 (two singlets without baseline separation, 9 H), 1.75 - 2.05 (m, 4 H), 2.44 (s, 3 H), 3.23 - 3.40 (m, 2 H), 3.85 - 4.15 (m, 3 H), 7.35 (m, 2 H), 7.78 (d, 2 H, J= 8.0 Hz).

[0035] 4-(4-Chlorophenoxy)phenol (Formula II). 4-Bromochlorobenzene (4.89 kg, 25.5 mol) and 4-methoxyphenol (4.87 kg, 39.2 mol) were dissolved in 1,4-dioxane (34.8 L) in a 100 L reactor. Cesium carbonate (17.10 Kg, 52.5 mol), Ν,Ν- dimethylglycine hydrochloride (1.07 kg, 7.7 mol) and Cu(I)I (0.49 kg, 2.6 mol) were added with stirring, and the mixture was de-gassed by bubbling nitrogen for 45 minutes. The stirred suspension was warmed to 104-110 ⁰C. Stirring was continued for 60 minutes around 105 ⁰C and then the reaction mixture was allowed to cool to ambient temperature. MTBE (30 L) followed by water (30 L) were added with stirring. The layers were separated and the aqueous layer was extracted with MTBE (10 L). The combined organic layers were washed with water (12 L), 10% aqueous sodium hydroxide solution (2 x 15 L), and brine (15 L), dried over anhydrous sodium sulfate and concentrated to afford crude 4-(4-chlorophenoxy)anisole (5.24 Kg, 88.4% crude yield) as an oil that solidified upon standing and could be used as such in the next step. ¹H NMR (CDCl₃) δ [ppm] 3.80 (s, 3 H), 6.86 (d, 2 H, J= 9.2 Hz), 6.88 (d, 2 H, J= 9.2 Hz), 6.96 (d, 2 H, J= 9.2 Hz), 7.24 (d, 2 H, J= 9.2 Hz).

[0036] Acetonitrile (22 L) and sodium iodide (16.54 kg, 110.4 mol) were charged to a 100 L reactor and stirred. Chlorotrimethylsilane (11.99 kg, 110.4 mol) was added over 40 minutes to the mixture to form a white to pale yellow suspension which was allowed to stir for 30 minutes after which the crude 4-(4-chlorophenoxy)anisole (5.18 Kg) was added in one portion, dissolved in acetonitrile (8 L). The mixture was stirred for 20 minutes and then brought to reflux. Mild refluxing was continued overnight, and then the mixture was allowed to cool to 23 ⁰C. Water (20L) was added carefully to the reaction mixture and stirring continued for 40 minutes. Isopropyl acetate (IPAC, 25L) was added with stirring, the layers were separated and the aqueous layer was extracted with IPAC (7L). The combined organic layers were washed with water (10 L), 10% aqueous sodium thiosulfate solution (3 x 10 L) and brine (10 L), dried over anhydrous sodium sulfate, filtered, and concentrated to afford crude 4-(4- chlorophenoxy)phenol (4.80 Kg). This material was re-crystallized from heptane (4 L) to afford the purified product as white to off-white solid of 98.3% purity (3.80 Kg, 68.3% yield over two steps). ¹H NMR (CDCl₃) δ [ppm] 4.96 (s, 1 H), 6.83 (d, 2 H, J = 9.0 Hz), 6.88 (d, 2 H, J= 9.0 Hz), 6.92 (d, 2 H, J= 9.0 Hz), 7.25 (d, 2 H, J= 9.0 Hz). ¹³C NMR (CDCl₃) δ [ppm] 116.44, 118.80, 120.97, 127.45, 129.55, 149.95, 151.86, 157.04. mp 81 - 83 ⁰C.

[0037] (5)-2-[4-(4-Chlorophenoxy)phenoxymethyl)pyrrolidine-l-carboxylic acid tert-butyl ester (Formula IV). A 200 L reactor under nitrogen purge was charged with DMF (55 L) and 4-(4-chlorophenoxy) phenol (4.29 kg, 19.43 mol). With continuous stirring, potassium tert-butoxide (2.36 kg, 21.03 mol) was added and the resulting brown mixture was stirred at ambient temperature for 1 hr. With continuous stirring, N-Boc-L-prolinol tosylate (6.22 kg, 17.50 mol) was added with 12 L DMF to form a pale green, thick mixture. The reaction mixture was heated to 55 ⁰C for 18 hours. The heating was turned off, the reaction mixture was diluted with heptane (50 L) and water (31 L) with continuous stirring at 30 ±5 ⁰C. Stirring was continued for 10 min, then the layers were allowed to separate. The aqueous layer was extracted with heptane (50 L) at 30 ±5 ⁰C. The combined organic layers, maintained at 30 ±5 ⁰C, were washed with 5 % sodium hydroxide solution (2 x 31 L), water (31 L) and brine (31 L). Concentration by rotary evaporation afforded 6.58 kg of off-white solids that were suspended in heptane (20 L), stirred at ambient temperature overnight, cooled to 5 ±5 ⁰C for 2 hours, and filtered with suction. The solids were washed with cold heptane (2 x 3 L) and dried in vacuo at 40 C for 17 hours to afford 99.7% pure product as a white solid (5.84 kg, 82.7 %).

[0038] (5)-2-[4-(4-Chlorophenoxy)phenoxymethyl]pyrrolidine (Formula V). A

100 L reactor under nitrogen purge was charged with 1,4-dioxane (27 L) and (S)-2-[4- (4-chlorophenoxy)phenoxymethyl)pyrrolidine-l-carboxylic acid tert-butyl ester (5.84 kg, 14.46 mol). To this solution, 4M HCl/ 1,4-dioxane (18 L) was added over 35 minutes. The reaction mixture was stirred overnight at ambient temperature. The reaction mixture was degassed by bubbling nitrogen and concentrated under vacuum. The residue (4.99 kg off-white solid) was dissolved in water (29 L) and washed with MTBE (3 x 22 L). Potassium carbonate (2.1 kg, 15.19 mol) was added in portions to the aqueous phase to bring the pH to ca. 10. The resulting white, thick mixture was stirred for 3 h and allowed to separate. The aqueous layer was extracted with isopropyl acetate (IPAC, 2 x 20 L). The combined organic layers were washed with brine (40 L), dried over sodium sulfate (6.40 kg), filtered and concentrated in vacuo to a thick, yellow oil that solidified upon standing to afford the desired product as an off- white solid (4.37 kg, 99.5 %) of 99.1% purity. ¹H NMR (CDCl₃) δ [ppm] 1.53 - 1.63 (m, 1 H), 1.73 - 1.90 (m, 2 H), 1.90 - 2.00 (m, 1 H), 2.58 (br s, 1 H), 2.93 - 3.08 (m, 2 H), 3.53 (ddd, 1 H, J= 14.0, 6.8, 5.2 Hz), 3.86 (dd, 1 H, J= 9.2, 6.8 Hz), 3.92 (dd, 1 H, J= 9.2, 5.2 Hz), 6.86 (d, 2 H, J= 8.8 Hz), 6.89 (d, 2 H, J= 9.2 Hz), 6.94 (d, 2 H, J = 9.2 Hz), 7.24 (d, 2 H, J= 8.8 Hz). [0039] 4-{(S)-2-[4-(4-Chlorophenoxy)phenoxymethyl]pyrrolidin-l-yl}butyric acid ethyl ester (Formula VI). A 22 L round bottom flask under nitrogen purge was charged with anhydrous acetonitrile (27 L) and (S)-2-[4-(4- chlorophenoxy)phenoxymethyl]pyrrolidine (4.36 kg, 14.38 mol). To the resulting mixture were added anhydrous potassium carbonate (4.00 kg, 28.96 mol) and ethyl 4- bromobutyrate (3.11 kg, 15.97 mol). The reaction mixture was stirred at 55 ±5 ⁰C, overnight. Anhydrous potassium carbonate, (1.59 kg, 11.51 mol) and ethyl-4- bromobutyrate (1.12 kg, 5.75 mol) were added and stirring continued at 55 ±5 ⁰C. After a total of 68 hours at 55 ±5 ⁰C, the reaction was complete. The reaction mixture was cooled to 29 ⁰C, water (27 L) was added, and the mixture was allowed to separate. The organic phase was concentrated in vacuo to afford the crude product as a light brown oil of 93.0% purity by HPLC (7.30 kg, 121.4 %) that still contained some ethyl 4-bromobutyrate but could be used as such in the next step. ¹H NMR (CDCl₃) δ [ppm] 1.24 (t, 3 H, J= 7.0 Hz), 1.66 - 1.75 (m, 1 H), 1.75 - 1.87 (m, 4 H), 1.95 - 2.04 (m, 1 H), 2.22 - 2.47 (m, 4 H), 2.82 - 2.92 (m, 2 H), 3.16 (m, 1 H), 3.76 (dd, 1 H, J= 9.0, 6.8 Hz), 3.90 (dd, 1 H, J= 9.0, 5.0 Hz), 4. 11 (q, 2 H, J= 7.0 Hz), 6.86 (d, 2 H, J= 8.5 Hz), 6.88 (d, 2 H, J= 9.0 Hz), 6.94 (d, 2 H, J= 9.0 Hz), 7.24 (d, 2 H, J= 8.5 Hz).

[0040] 4-{(.S)-2-[4-(4-Chlorophenoxy)phenoxymethyl]pyrrolidin-l-yl}butyric acid hydrochloride (Formula I). A mixture of crude 4-{(S)-2-\4-(4- chlorophenoxy)phenoxymethyl]pyrrolidin-l-yl} butyric acid ethyl ester (1193.00 g crude material containing some residual ethyl 4-bromobutyrate and maximum 860.96 g (2.06 mol) of 4-{(5')-2-[4-(4-chlorophenoxy)phenoxymethyl]pyrrolidin-l-yl}butyric acid ethyl ester), ethanol (3.5 L), sodium hydroxide (165.00 g, 4.12 mol), and water (2.0 L) was stirred at ambient temperature for 21 h in a 22 L round bottom flask. The mixture was concentrated in vacuo to a paste that was dissolved in water (5.0 L). The aqueous solution was acidified (pH 1) using concentrated hydrochloric acid (550 mL), while maintaining the temperature below 30 ⁰C. Sodium chloride (500.00 g) was added and the mixture was extracted twice with 2-butanone (MEK, 3 L, then 1 L). To the combined organic extracts was added 4-methyl-2-pentanone (MIBK, 1 L) and the resulting mixture was concentrated using a rotary evaporator. The solid residue was stirred with MEK (4 L) at 50 ⁰C for 3 h. Most solids were dissolved. The resulting mixture was filtered through a Celite bed. The Celite cake was rinsed with more MEK (2 x 150 mL) and the combined MEK filtrate was stirred for 20 h at ambient temperature. A suspension formed that was cooled to 5 ⁰C, diluted with MIBK, and stirred 3 h at 5 ⁰C. The precipitated solids were isolated by filtration, rinsed on filter with cold (5 ⁰C) MIBK (2 x 250 mL) and dried to afford 626.00 g (71.3%) of product 4- {(5')-2-[4-(4-Chlorophenoxy)phenoxymethyl]pyrrolidin- 1 -yljbutyric acid hydrochloride as a white solid of 99.4% purity. ¹H NMR (DMSOd₆) δ [ppm] 1.81 (m, 1 H), 1.86 - 2.10 (m, 4 H), 2.25 (m, 1 H), 2.40 (m, 1 H), 3.06 - 3.24 (m, 2 H), 3.53 (m, 1 H), 3.65 (m, 1 H), 3.89 (m, 1 H), 4.32 (dd, 1 H, J= 10.5, 3.8 Hz), 4.50 (m, 1 H), 6.96 (d, 2 H, J= 9.5 Hz), 7.05 (d, 2 H, J= 9.0 Hz), 7.07 (d, 2 H, J= 9.5 Hz), 7.40 (d, 2 H, J= 9.0 Hz), 11.26 (br s, IH), 12.34 (br s, I H). ¹³C NMR (DMSO-d₆) δ [ppm] 20.42, 21.87, 26.53, 30.81, 53.75, 65.82, 66.90, 116.11, 118.94, 120.78, 126.34, 129.68, 149.63, 154.22, 156.81, 173.48. IR [cm^"1] 3436, 2950, 2599, 2525, 1729, 1610, 1592, 1503, 1484, 1404, 1389, 1279, 1220, 1162, 1086, 1056, 1009, 958, 874, 846, 824, 765, 720, 510, 500. MS (APCI+) m/z 390.2. Anal, calcd. for

C_2IH₂₅Cl₂NO₄: C, 59.16; H, 5.91; Cl, 16.63; N, 3.29. Found: C, 58.86; H, 6.08; Cl, 16.93; N, 3.47. mp 99.6 - 103.9 ⁰C.

[0041] 4-{(S)-2-[4-(4-Chlorophenoxy)phenoxymethyl]pyrrolidin-l-yl}butyric acid /j-toluenesulf onate (Formula VII).

A. From crude 4-{(5)-2-[4-(4-chlorophenoxy)phenoxymethyl]pyrrolidin-l- yl}butyric acid ethyl ester. A 200 L reactor was charged with ethanol (30 L) and crude 4- {(5')-2-[4-(4-chlorophenoxy)phenoxymethyl]pyrrolidin- 1 -yljbutyric acid ethyl ester (7.30 kg crude material containing some residual ethyl 4-bromobutyrate and maximum 6.00 kg (14.37 mol) of 4-{(S>2-[4-(4- chlorophenoxy)phenoxymethyl]pyrrolidin-l-yl} butyric acid ethyl ester. A solution of sodium hydroxide (1.44 kg, 36.08 mol) in water (17.2 L) was added with stirring and the resulting mixture was stirred at ambient temperature for 16 h (the reaction was complete after 5 h). The reaction mixture was concentrated in vacuo to 11.90 kg residue that was transferred back to the 200 L reactor and dissolved in water (52 L) at 30 ⁰C. The resulting solution was cooled to 20 ⁰C, thenp- toluenesulfonic acid monohydrate (10.97 kg, 57.67 mol) was added in two portions (6.87 kg, then 4.10 kg) with stirring at ambient temperature. The temperature was maintained below 25 ⁰C. The mixture was stirred at ambient temperature for 1 h. The resulting white suspension was extracted with 3: 1 (v/v) MIBK /MEK (1 x 44 L, 1 x 15 L). The combined organic layers were washed with water (2 x 16 L). The organic extract was concentrated in vacuo to 21.50 kg suspension that was transferred to a 72 L round bottom flask and heated with MIBK (36 L) at 50 ⁰C for 30 min. The mixture was allowed to cool to ambient temperature spontaneously. The precipitated solids were isolated by filtration, washed on filter with MIBK (3 x 8 L), suction dried, then dried at 55 ⁰C for 19 h to afford 6.85 kg (84.8%) of product as a white solid of 99.9% purity. ¹H NMR (DMSOd₆) δ [ppm] 1.83 (m, 1 H), 1.86 - 1.95 (m, 2 H), 2.03 (m, 1 H), 2.23 (m, 1 H), 2.28 (s, 3H), 2.37 (m, 2 H), 3.12 - 3.24 (m, 2 H), 3.47 (m, 1 H), 3.64 (m, 1 H), 3.94 (m, 1 H), 4.17 (m, 1 H), 4.30 (dd, 2 H, J= 11.0 Hz), 6.94 (d, 2 H, J= 9.0 Hz), 7.06 (s, 4 H), 7.11 (d, 2 H, J= 8.5 Hz), 7.40 (d, 2 H, J= 9.0 Hz), 7.48 (d, 2 H, J= 8.5 Hz), 9.48 (br s, IH), 12.31 (br s, 1 H). ¹³C NMR (DMSO-d₆) δ [ppm] 20.59, 20.72, 22.39, 26.15, 30.41, 39.76, 54.36, 66.19, 66.79, 116.00, 118.95, 120.80, 125.44, 126.39, 128.03, 129.71, 137.66, 145.54, 149.71, 154.15, 156.80, 173.51. IR [cm^"1] 2986, 2919, 2718, 2680, 2637, 2551, 1721, 1504, 1484, 1455, 1403, 1221, 1195, 1151, 1120, 1106, 1084, 1055, 1033, 1009, 843, 824, 814, 681, 565. MS (APCI+) m/z 390.2. Anal, calcd. for C₂₈H₃₂ClNO₇S: C, 59.83; H, 5.74; Cl, 6.31; N, 2.49; S, 5.70. Found: C, 60.03; H, 5.81; Cl, 6.07; N, 2.41; S, 5.90. mp 115.0 - 116.4 ⁰C.

B. From iV-Boc-L-prolinol, without intermediate isolation

In a 500-gal GLS reactor, N-Boc-L-prolinol (58.0 kg, 288.2 mol) and trimethylamine hydrochloride (2.7 kg, 28.3 mol) were dissolved in 166 L of 1 : 1 (v/v) mixture of acetonitrile and toluene. Triethylamine (62.1 kg, 613.7 mol) was added while maintaining the temperature below 30 ⁰C. The solution was cooled to 15 ⁰C and/>- toluenesulfonyl chloride (TsCl, 65.9 kg, 345.7 mol) was added as a solution in 144 L of 1 : 1 (v/v) mixture of acetonitrile and toluene and the resulting mixture was stirred 2 h at ambient temperature. The reaction was quenched by addition of water (290.9 L) with stirring at temperature below 25 ⁰C. The layers were allowed to separate. The organic layer was washed with 25% sodium chloride solution (2 x 293 L), after which a Karl Fischer analysis showed that it contained less than 1% water. In a 500-gal GLS reactor, 4-(4-chlorophenoxy)phenol (70.2 kg, 318.1 mol) was dissolved in DMF (423.0 L). A solution of 15 % potassium tert-butoxide in tert-butanol (299.9 kg, 400.9 mol) was added with stirring at 20 - 25 ⁰C. After 30 min stirring, to the resulting potassium 4-(4-chlorophenoxy)phenoxide solution was added the N-Boc-L- prolinolp-toluenesulfonate previously prepared, with stirring at 20 -22 ⁰C. The resulting reaction mixture was heated to 60 ⁰C over 6 h, then held at that temperature for 27 h, cooled to 22 ⁰C, quenched by addition of water (76.4 L), diluted under continuous stirring with more water (695 L) and heptanes (772 L), and allowed to separate. The organic layer was washed sequentially with 1 M citric acid (1 x 826 L), 0.5 N sodium hydroxide (2 x 786 L), and water (771 L), after which the bulk of the solvents was removed by vacuum distillation and the remaining solvents were exchanged to ethyl acetate by repeated (3x) vacuum concentration from ethyl acetate. The amount of dissolved crude (5)-2-[4-(4- chlorophenoxy)phenoxymethyl)pyrrolidine- 1 -carboxylic acid tert-butyl ester was determined by concentration of a small aliquot to be 89.4 kg and to the ethyl acetate solution was added the necessary ethyl acetate to adjust the concentration to 21 wt%. Through this solution, kept at 15 - 20 ⁰C under stirring, was slowly bubbled gaseous HCl (40.3 kg, 1105.3 mol) over 4.4 h. Water (558 L) was added, the mixture was stirred 30 min, and the layers were allowed to separate. The aqueous layer was extracted with ethyl acetate (193 L). The combined organic extracts were washed with 50% aqueous potassium carbonate solution (480 kg), after which the bulk of the ethyl acetate was removed by vacuum distillation and the remaining ethyl acetate was exchanged to acetonitrile by repeated (3x) vacuum concentration from acetonitrile. The amount of dissolved crude (5)-2-[4-(4- chlorophenoxy)phenoxymethyl)pyrrolidine was determined by concentration of a small aliquot to be 63.7 kg and to the acetonitrile solution was added the necessary acetonitrile to adjust the concentration to 17.4 wt%. To the resulting solution were added ethyl 4 bromobutyrate (47.5 kg, 243.5 mol) and potassium carbonate (67.5 kg, 488.4 mol). The mixture was stirred at 52 ⁰C for 10.8 h, cooled to 25 ⁰C, stirred for 30 min with water (398 L), and the layers were allowed to separate. The organic layer was vacuum distilled to remove most of the acetonitrile, after which the remaining acetonitrile was exchanged to ethanol by repeated (3x) vacuum concentration from ethanol. The amount of dissolved crude 4- {(5)-2-[4-(4- chlorophenoxy)phenoxymethyl]pyrrolidin-l-yl}butyric acid ethyl ester was determined by concentration of a small aliquot to be 94.7 kg and to the ethanol solution was added the necessary ethanol to adjust the concentration to 18.7 wt%. The resulting solution was stirred with a solution of aqueous 10.5% sodium hydroxide (198.9 kg solution, 522.1 mol) for 6 h at 21 - 25 ⁰C, after which it was concentrated to 39% of the original volume to remove most of the ethanol, diluted with 214 L water and partially concentrated again, then diluted with 183 L water. The aqueous solution (containing 0.6 wt% ethanol) was stirred withp-toluene sulfonic acid monohydrate (159.4 kg, 838.0 mol) for 30 min at 20 ⁰C, then extracted repeatedly with MIBK/MEK mixtures (1 x (3: 1, v/v), 578 L; 1 x (1 : 1, v/v), 288 L; 8 x (1:2, v/v), 285 L each). The combined organic extracts were washed with water (2 x 264 L), vacuum concentrated to remove the bulk of MEK, then concentrated again from MIBK (438 L) until the resulting suspension in MIBK contained 19.2 wt% 4-{(5>2-[4-(4- Chlorophenoxy)phenoxymethyl]pyrrolidin- 1 -yljbutyric acid p-toluenesulfonate. The slurry was cooled to 25 ⁰C and the solid product was isolated by filtration, rinsed with MIBK (428 L; 396 L), and dried 23 h at 50 ⁰C to afford 71 kg (43.8%) 4- {(S>2-[4-(4- Chlorophenoxy)phenoxymethyl]pyrrolidin- 1 -yljbutyric acid p-toluenesulfonate of 99.9 area% purity (98.4% assay). More 4-{(S>2-[4-(4-

Chlorophenoxy)phenoxymethyl]pyrrolidin-l-yl}butyric acidp-toluenesulfonate (15 kg; 99.5 area% purity; 98.9% assay) could be isolated from the aqueous mother liquors that remained after the MIBK/MEK extractions (further diluted with 1 vol water) by one more extraction with 3 : 1 (v/v) MIBK/MEK, thus achieving a cumulated yield of 53%.

Claims

1. A process for preparing a compound of formula I

comprising the steps of:

a) reacting a compound of formula II

in the presence of potassium tert-butoxide with a compound of formula III

to obtain compound of formula IV

b) followed by converting said compound of formula IV to the compound of formula I.

2. A process according to claim 1 wherein the step of converting said compound of formula IV to a compound of formula I is accomplished by

a) reacting the compound of formula IV with a mineral acid in dioxane to obtain a compound of formula V

b) followed by reacting the compound of formula V with ethyl 4- bromobutyrate and a base selected from potassium carbonate, cesium carbonate, sodium carbonate, diazabicyclooctane and 1,8- diazabicyclo[5.4.0]undec-ene to obtain a compound of formula VI

c) followed by reacting the compound of formula VI with sodium hydroxide or potassium hydroxide in alkanol and water to obtain the sodium or potassium salt of the compound of formula I, and acidifying.

3. A process according to claim 2 wherein the mineral acid is hydrochloric acid.

4. A process according to claim 2 wherein the compound of formula V is reacted with ethyl 4-bromobutyrate in acetonitrile.

5. A process according to claim 1 wherein a compound of formula II is prepared by a) reacting 4-bromochlorobenzene with 4-methoxyphenol in the presence of a base chosen from cesium carbonate, potassium carbonate and sodium carbonate; a copper complexing ligand; and Cu(I)I to obtain l-(4- methoxyphenoxy)-4-chlorobenzene;

b) followed by reacting 1 -(4-methoxyphenoxy)-4-chlorobenzene with iodotrimethylsilane or sodium iodide and chlorotrimethylsilane to obtain a compound of formula II.

6. A process according to claim 5 wherein 4-bromochlorobenzene is reacted with

4-methoxyphenol in 1,4-dioxane.

7. A process according to claim 5 wherein 1 -(4-methoxyphenoxy)-4- chlorobenzene is reacted with iodotrimethylsilane or sodium iodide and chlorotrimethylsilane in acetonitrile. A process according to claim 5 wherein said copper complexing ligand is

N,N-dimethylglycine hydrochloride.

9. A process for preparing a compound of formula I

comprising the steps of

a) reacting 4-bromochlorobenzene with 4-methoxyphenol and 1,4- dioxane in the presence of cesium carbonate, N,N-dimethylglycine hydrochloride and Cu(I)I tO obtain l-(4-methoxyphenoxy)-4-chlorobenzene;

b) reacting 1 -(4-methoxyphenoxy)-4-chlorobenzene with

iodotrimethylsilane or sodium iodide and chlorotrimethylsilane in acetonitrile to obtain formula II

c) reacting Boc-(,S)-(-)-2-pyrrolidinemethanol and base wύ^' hp- toluenesulfonyl chloride to obtain a compound of formula III

d) reacting a compound of formula II in the presence of potassium tert- butoxide with a compound of formula III to obtain compound of formula IV

e) reacting the compound of formula IV with a mineral acid in dioxane to obtain a compound of formula V

g) reacting the compound of formula VI with sodium hydroxide in ethanol and water and acidifying to obtain a compound of formula I.

10. A process according to claim 9 wherein the base is triethylamine optionally combined with dimethylaminopyridine or trimethylamine and the mineral acid is hydrochloric acid.

11. A process for preparing a compound of formula VII

comprising reacting a compound of formula VI

12. A process for preparing a compound of formula VII

comprising the steps of:

a) reacting N-Boc-L-prolinol andp-toluenesulfonyl chloride in acetonitrile/toluene in the presence of triethylamine and one or both of

dimethylaminopyridine or trimethylamine;

b) treating 4-(4-chlorophenoxy)phenol in dimethylformamide with potassium tert-butoxide;

d) treating said (S)-2-[4-(4-chlorophenoxy)phenoxymethyl)pyrrolidine-l- carboxylic acid tert-butyl ester with hydrogen chloride in ethyl acetate, diethylether or 1,4-dioxane to obtain (S)-2-[4-(4-chlorophenoxy)phenoxymethyl)pyrrolidine hydrochloride;

e) basifying said (S)-2-[4-(4-chlorophenoxy)phenoxymethyl)pyrrolidine hydrochloride and taking the (S)-2-[4-(4-chlorophenoxy)phenoxymethyl)pyrrolidine into acetonitrile;

f) adding ethyl 4-bromobutyrate and potassium carbonate to obtain 4- {(S)-2-[4-(4-chlorophenoxy)phenoxymethyl]pyrrolidine-lyl}butyric acid ethyl ester; g) treating 4- {(S)-2-[4-(4-chlorophenoxy)phenoxymethyl]pyrrolidine- lyljbutyric acid ethyl ester with sodium hydroxide in ethanol and water to obtain 4- {(S)-2-[4-(4-chlorophenoxy)phenoxymethyl]pyrrolidin- 1 -yljbutyric acid; and

13. A process for preparing a compound of formula I

comprising the steps of:

dimethylaminopyridine or trimethylamine;

c) combining the mixtures from steps a) and b) to obtain (S)-2-[4-(4- chlorophenoxy)phenoxymethyl)pyrrolidine-l-carboxylic acid tert-butyl ester;

f) adding ethyl 4-bromobutyrate and potassium carbonate to obtain 4- {(S)-2-[4-(4-chlorophenoxy)phenoxymethyl]pyrrolidine-lyl}butyric acid ethyl ester; g) treating 4- {(S)-2-[4-(4-chlorophenoxy)phenoxymethyl]pyrrolidine- lyl} butyric acid ethyl ester with sodium hydroxide in ethanol and water and acidifying to obtain 4-{(S)-2-[4-(4-chlorophenoxy)phenoxymethyl]pyrrolidin-l- yl} butyric acid.