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(11) EP 1 907 355 B1

(12) EUROPEAN PATENT SPECIFICATION

(45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C07C 303/22 (2006.01) C07C 303/38 (2006.01) 05.08.2015 Bulletin 2015/32 C07D 209/22 (2006.01) C07D 209/18 (2006.01)

(21) Application number: 06800157.7 (86) International application number: PCT/US2006/028182 (22) Date of filing: 20.07.2006 (87) International publication number: WO 2007/013974 (01.02.2007 Gazette 2007/05)

(54) PROCESS FOR THE SYNTHESIS OF SULFONYL HALIDES AND SULFONAMIDES FROM SULFONIC ACID SALTS VERFAHREN FÜR DIE SYNTHESE VON SULFONYLHALIDEN UND SULFONAMIDEN AUS SULFONSÄURESALZEN PROCÉDÉ DE SYNTHÈSE D’HALOGÉNURES DE SULFONYLE ET DE SULFONAMIDES À PARTIR DE SELS D’ACIDE SULPHONIQUE

(84) Designated Contracting States: • D. BRUNDISH ET AL.: "Design and Synthesis of AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Thrombin Inhibitors: Analogues of MD-805 with HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI Reduced Stereogenicity and Improved Potency" SK TR J. MED. CHEM., vol. 42, no. 22, 1999, pages 4584-4603, XP002414353 (30) Priority: 21.07.2005 US 701158 P • R. A. ABRAMOVITCH ET AL.: "Solution and Flash Vacuum Pyrolysis of Some 2,6- (43) Date of publication of application: Disubstituted .beta.-Phenethylsulfonyl Azides 09.04.2008 Bulletin 2008/15 and of .beta.-Styrenesulfonyl Azide" J. ORG. CHEM., vol. 50, no. 12, 1985, pages 2066-2073, (73) Proprietor: Ziarco Pharma Ltd XP002414354 Canterbury • "Houben-Weyl: Methoden der Organischen Kent CT1 2NF (GB) Chemie, 4. ed." 1955, GEORG THIEME VERLAG , STUTTGART DE , XP002414355 page 563, last (72) Inventors: paragraph, first two lines • MICHALAK, Ronal, Stanley • DATABASE BEILSTEIN BEILSTEIN INSTITUTE Congers, NY 10920 (US) FORORGANIC CHEMISTRY, FRANKFURT- MAIN, • HELOM, Jean Louise DE; XP002414363 Database accession no. BRN Hillsdale, NJ 07642 (US) 5427164 & J. ZINCZUK ET AL.: J. HETEROCYCL. • ZELDIS, Joseph CHEM., vol. 29, no. 4, 1992, pages 859-866, New City, NY 10956 (US) • DATABASE BEILSTEIN BEILSTEIN INSTITUTE FORORGANIC CHEMISTRY, FRANKFURT- MAIN, (74) Representative: Rutt, Jason Edward et al DE; XP002414364 Database accession no. BRN Rouse IP Limited 2717732 & R. EGLI; C.H. EUGSTER: HEL. CHIM. 11th Floor, Exchange Tower ACTA, 58, 1975, pages 2321-2346, 1 Harbour Exchange Square • DATABASE BEILSTEIN BEILSTEIN INSTITUTE London E14 9GE (GB) FORORGANIC CHEMISTRY, FRANKFURT- MAIN, DE; XP002414365 Database accession no. BRN (56) References cited: 1747453 & FRANCHIMONT; KLOBBIE: RECL. WO-A2-03/048122 US-A- 2 507 408 TRAV. CHIM. PAYS-BAS, 5, 1886, page 277, US-A- 2 888 486

Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 1 907 355 B1

Printed by Jouve, 75001 PARIS (FR) (Cont. next page) EP 1 907 355 B1

• DATABASE BEILSTEIN BEILSTEIN INSTITUTE • DATABASE BEILSTEIN BEILSTEIN INSTITUTE FORORGANIC CHEMISTRY, FRANKFURT- MAIN, FORORGANIC CHEMISTRY, FRANKFURT- MAIN, DE; XP002414366 Database accession no. BRN DE; XP002414369 Database accession no. BRN 2697078 & H. L. YALE; J. T. SHEEHAN: J.ORG. 2639938 & V. BRAUN ET AL.: CHEM. BER. 63, CHEM., vol. 26, 1961, pages 4315-4325, 1930, page 2847, 2861, • DATABASE BEILSTEIN BEILSTEIN INSTITUTE FORORGANIC CHEMISTRY, FRANKFURT- MAIN, DE; XP002414367 Database accession no. BRN 2703228, 2702138 & FEIT: ACTA CHEM. SCAN., 16, 1962, page 275, 277, • DATABASE BEILSTEIN BEILSTEIN INSTITUTE FORORGANIC CHEMISTRY, FRANKFURT- MAIN, DE; XP002414368 Database accession no. BRN 3255360 & TRUCE, MILIONIS: J. AM. CHEM. SOC., vol. 74, 1952, page 974, 975,

2 EP 1 907 355 B1

Description

[0001] This application claims benefit of priority to US provisional patent application serial no. 60/701,158 filed on July 21, 2005. 5 FIELD OF THE INVENTION

[0002] The present invention relates to processes for the preparation of sulfonyl halides and sulfonamides useful as intermediates in the preparation of, for example, pharmaceuticals and for the preparation of sulfonamides useful as 10 pharmaceuticals.

BACKGROUND OF THE INVENTION

[0003] Sulfonyl chlorides are widely used in the chemical industry such as for the preparation of dyes, lithographic 15 resists, and pharmaceuticals. They can be further transformed into other functional groups such as aromatic sulfones (by Friedel-Crafts sulfonylation of aromatic substrates) or sulfonamides (by reaction with amines) (see, e.g., Kirk-Othmer Encyclopedia of Chemical Technology). Sulfonamides are integral functional groups of a wide variety of therapeutic small molecule drugs such as antibacterial agents, diuretics, and cPLA 2 inhibitors. [0004] A typical preparation of sulfonyl chlorides involves reaction of the sodium salt of a sulfonic acid with phosphorus 20 pentachloride, sometimes in combination with phosphorus oxychloride or thionyl chloride, frequently with heating of the reaction mixture (see, e.g., March, Advanced Organic Chemistry, 4th ed., John Wiley & Sons, 1992, p.499). These relatively harsh reaction conditions are unsuitable for the preparation of sterically hindered sulfonyl chlorides, such as arylalkylsulfonyl chlorides and the like, which can result in low yields due to the elimination of sulfur dioxide (Nakayama et al., Tet Lett., 1984, 25, 4553-4556). A milder, infrequently used method for the synthesis of sulfonyl chlorides is the 25 reaction of tetrabutylammonium salts of sulfonic acids with triphenylphosphine/sulfuryl chloride (Widlanski et al., Tet. Lett., 1992, 33, 2657-2660), a method that suffers from the disadvantage of poor atom efficiency. [0005] Numerous sterically hindered sulfonyl halides such as (2-trifluoromethylphenyl)-methanesulfonyl chloride and other aryl- and heteroaryl-alkylsulfonyl halides are specifically useful in the preparation of cPLA2 inhibitors for the treat- ment of asthma or arthritic and rheumatic disorders as described in, for example, WO 2003/048122. As discussed above, 30 these intermediates can be difficult to prepare due to loss of sulfur dioxide at higher temperatures and formation of significant amounts of impurities. Thus, new and improved methods for making these compounds, and the corresponding sulfonamides, are needed. The methods provided herein help meet these and other needs.

SUMMARY OF THE INVENTION 35 [0006] In some embodiments, the present invention provides a synthetic process comprising reacting a compound of Formula II:

-1 [Ar-(R)z-SO3 ]qM II 40 wherein:

Ar is phenyl substituted with one perhaloalkyl group at the 2 position thereof; R is methylene;

45 M is a Group I or II metal ion;

q is 1 where M is Group I metal ion;

or q is 2 where M is a Group II metal ion; and 50 z is 1 ;

with a halogen substitution reagent in the presence of a catalytic amount of water and in the presence of a co-catalyst for a time and under conditions sufficient to form a compound of Formula III: 55

Ar-(R)2-SO2-X III

wherein X is halogen.

3 EP 1 907 355 B1

[0007] In some embodiments, the synthetic processes of the present invention further include reacting the compound of Formula III with an amine reagent, optionally in the presence of a base, for a time and under conditions sufficient to form a compound of Formula I:

5 4 5 Ar-(R)2-SO2-NR R I

wherein:

4 5 R and R are each, independently, H, C1-C18 alkyl, C2-C18 alkenyl, C2-C18 alkynyl, C3-C18 cycloalkyl, heterocy- 10 cloalkyl, aryl or heteroaryl, each optionally substituted by up to five substituents independently selected from the

group consisting of halogen, C 1-C6 alkyl, C 3-C7 cycloalkyl, heterocycloalkyl, cyano, nitro, OH, C 1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloaikoxy, aryl and heteroaryl;

or R4 and R5 together with the N atom to which they are attached can form a 5- or 6-membered heterocycle. 15 DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTION

[0008] Described is a process for the preparation of sulfonyl halides and sulfonamides, such as aryl- and heteroaryl- alkylsulfonyl halides and aryl- and heteroaryl-alkylsulfonamides, including (2-trifluoromethylphenyl)- methanesulfonyl 20 chloride and (2-trifluoromethylphenyl)-methanesulfonamide, which are intermediates in the synthesis of certain CPLA2 inhibitors. In some embodiments, the processes involve the formation of the intermediate sulfonic acid prior to conversion to the sulfonyl halide. [0009] Described is a synthetic process that includes reacting a compound of Formula II:

25 -1 [Ar-(R)2-SO3 ]qM II

wherein:

Ar is C1-C18 alkyl, C2-C18 alkenyl, C2-C18 alkynyl, C3-C18 cycloalkyl, heterocycloalkyl, aryl or heteroaryl, each 30 optionally substituted by up to five substituents independently selected from the group consisting of halogen, C 1-C6 alkyl, C3-C7 cycloalkyl, heterocycloalkyl, cyano, nitro, OH, C 1-C6 haloalkyl, C 1-C3 perhaloalkyl, C 1-C6 alkoxy, C 1-C6 1 2 1 3 3 3 3 haloalkoxy, C1-C3 perhaloalkoxy, NR R , NR COR , COR , COOR , OCOR , aryloxy, heteroaryloxy, arylalkyloxy, heteroarylalkyloxy, cycloalkylalkyl, arylalkyl, heteroarylalkyl, aryl and heteroaryl; R is C1-C6 alkylenyl; 35 1 2 each R and R is independently selected from the group consisting of H, C 1-C6 alkyl and C3-C7 cycloalkyl; or any R1 and R2, together with the nitrogen atom to which they are attached, can form a 5- or 6- membered heterocycle; 3 each R is independently selected from the group consisting of H, C 1-C6 alkyl and C3-C7 cycloalkyl; M is a Group I or II metal ion; 40 q is 1 where M is Group I metal ion; or q is 2 where M is a Group II metal ion; and z is 0 or 1;

with a halogen substitution reagent in the presence of a catalytic amount of water and in the presence of a co-catalyst 45 for a time and under conditions sufficient to form a compound of Formula III:

Ar-(R)z-SO2-X III

wherein X is halogen. 50 [0010] In some embodiments, the process of the present invention further include reacting the compound of Formula III with an amine reagent, optionally in the presence of a base, for a time and under conditions sufficient to form a compound of Formula I:

4 5 Ar-(R)z-SO2-NR R I 55 wherein:

4 5 R and R are each, independently, H, C1-C18 alkyl, C2-C18 alkenyl, C2-C18 alkynyl, C3-C18 cycloalkyl, heterocy-

4 EP 1 907 355 B1

cloalkyl, aryl or heteroaryl, each optionally substituted by up to five substituents independently selected from the group consisting of halogen, C 1-C6 alkyl, C 3-C7 cycloalkyl, heterocycloalkyl, cyano, nitro, OH, C 1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, aryl and heteroaryl; or R4 and R 5, together with the nitrogen atom to which they are attached, can form a 5- or 6- membered heterocycle. 5 [0011] In some embodiments of the processes of the present invention, the compound of Formula I is formed without isolation of the compound of Formula III. [0012] The compound of Formula III is useful as a chemical intermediate to prepare cPLA2 inhibitors, including, for example, 4-{3-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic ac- 10 id, 4-(3-{5-chloro-1-(diphenylmethyl)-2-[2-({[2-(trifluoromethyl)benzyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}propyl)benzoic acid , 4-(3-{5-chloro-1-(diphenylmethyl)-2-[2-({[2-fluoro-6-(trifluoromethyl)benzyl]sulfonyl}amino)ethyl]-1H-indol-3-yl} propyl)benzoic acid and 4-(3-{5-chloro-1-(diphenylmethyl)-2-[2-({[2-(trifluoromethoxy)benzyl]sulfonyl}amino) ethyl]-

1H-indol-3-yl}propyl)benzoic acid. Exemplary cPLA2 inhibitors and methods and intermediates useful for making them are disclosed and claimed in the following applications: PCT/US2002/038311, filed December 02, 2002 (published as 15 WO 2003/048122); PCT/US2004/023247, filed July 19, 2004 (published as WO 2005/012238); PCT/US2004/038335, filed November 16, 2004 (published as WO 2005/049566); PCT/US2005/005624, filed February 23, 2005 (published as WO 2005/082843); PCT/US2005/009746, filed March 14, 2005 (published as WO 2005/097727); PCT/US2005/029338, filed August 18, 2005 (published as WO 2006/023611); US Patent Application Serial No. 10/930,534 (filed August 31, 2004); US Patent Application Serial No. 10/948,004 (filed September 23, 2004); and US Patent Application Serial No. 20 11/442,199 (filed May 26, 2006). [0013] In some embodiments, the present invention provides processes for preparing such cPLA2 inhibitors which comprise preparing a compound of Formula III in accordance with a process of the invention and converting the compound

of Formula III into the cPLA2 inhibitor. In some embodiments, the cPLA 2 inhibitors include 4-{3-[1-benzhydryl-5-chloro- 2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid, 4-(3-{5-chloro-1-(diphenylmethyl)- 25 2-[2-({[2-(trifluoromethyl)benzyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}propyl)benzoic acid , 4-(3-{5-chloro-1-(diphenylmethyl)-2-[2-({[2-fluoro-6-(trifluoromethyl)benzyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}propyl)benzoic acid and 4-(3-{5-chloro-1-(diphenylmethyl)-2-[2-({[2-(trifluoromethoxy)benzyl]sulfonyl}amino) ethyl]-1H-indol-3-yl}propyl)benzoic acid. [0014] In some embodiments, the present invention provides processes for the preparation of cPLA 2 inhibitors having Formula (A1): 30

35

40

45

wherein:

Ar, R and z are as defined in claim 1; 50 10 R is selected from the formulae -(CH 2)n-A, -(CH2)n-S-A, or -(CH2)n-O-A, wherein A is selected from the moieties:

55

5 EP 1 907 355 B1

wherein:

D is C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, -CF3 or-(CH2)1-3-CF3; B and C are independently selected from phenyl, pyridinyl, pyrimidinyl, furyl, thienyl and pyrrolyl groups, each 5 optionally substituted by from 1 to 3, preferably 1 to 2, substituents selected independently from H, halogen,

-CN, -CHO, -CF3, -OCF3, - OH, -C1-C6 alkyl, C1-C6 alkoxy, -NH2, -N(C1-C6 alkyl)2, -NH(C1-C6 alkyl), -N- C(O)-(C1-C6 alkyl), -NO2, or by a 5- or 6-membered heterocyclic or heteroaromatic ring containing 1 or 2 heteroatoms selected from O, N or S; n is an integer from 0 to 3; 10 n1 is an integer from 1 to 3; n3 is an integer from 0 to 3; n4 is an integer from 0 to 2 2 X is selected from -O-, -CH2-, -S-, -SO-, -SO2- -NH-, -C(O)-,

15

20

25

30

R12 is a ring moiety selected from phenyl, pyridinyl, pyrimidinyl, furyl, thienyl or pyrrolyl groups, the ring moiety 35 being substituted by a group of the formula -(CH2)n4-CO2H or a pharmaceutically acceptable acid mimic or mimetic; and also optionally substituted by 1 or 2 additional substituents independently selected from H, halogen,

-CN, -CHO, -CF3, -OCF3, -OH, -C1-C6 alkyl, C 1-C6 alkoxy, C1-C6 thioalkyl, - NH 2, -N(C1-C6 alkyl)2, -NH(C1-C6 alkyl), -N-C(O)-(C1-C6 alkyl), or -NO2; 13 R is selected from H, halogen, -CN, -CHO, -CF3, -OCF3, -OH, -C1-C6 alkyl, C1-C6 alkoxy, C1-C6 thioalkyl, 40 -NH2, -N(C1-C6 alkyl)2, -NH(C1-C6 alkyl), -N-C(O)-(C1-C6 alkyl), or -NO2; 14 R is selected from H, halogen, -CN, -CHO, -CF3, -OCF3, -OH, -C1-C6 alkyl, C1-C6 alkoxy, C1-C6 thioalkyl, -NH2, -N(C1-C6 alkyl)2, -NH(C1-C6 alkyl), -N-C(O)-(C1-C6 alkyl), -NO2, -N-C(O)-N(C1-C3 alkyl)2, -N- C(O)-NH(C1-C3 alkyl), -N-C(O)-O-(C 1-C3 alkyl), -SO 2-C1-C6alkyl, -S-C 3-C6cycloalkyl, -S-CH 2-C3-C6 cycloalkyl, -SO2-C3-C6 cycloalkyl, , -SO2-CH2-C3-C6 cycloalkyl, C3-C6 cycloalkyl, -CH2-C3-C6 cycloalkyl, -O-C3-C6 45 cycloalkyl, , -O-CH2-C3-C6 cycloalkyl, phenyl, benzyl, benzyloxy, morpholino or other heterocycles such as pyrrolidino, piperidine, piperizine furan, thiophene, imidazole, tetrazole, pyrazine, pyrazolone, pyrazole, imidazole, oxazole or isoxazole, the rings of each of these R 14 groups each being optionally substituted by from 1 to 3 substituents selected from the group of H, halogen, -CN, -CHO, -CF 3, -OH, -C1-C6 alkyl, C1-C6 alkoxy, -NH2, -N(C1-C6 alkyl)2, -NH(C1-C6 alkyl), -N-C(O)-(C1-C6 alkyl), - NO2, -SO2(C1-C3 alkyl), -SO2NH(C1-C3 alkyl), 50 10 -SO2N(C1-C3 alkyl)2, or OCF3; or a pharmaceutically acceptable salt form thereof. In some embodiments, R is diphenylmethyl.

[0015] In some embodiments, the compound having Formula (A1) or a pharmaceutically acceptable salt thereof is prepared by the compound having formula III is reacted with a compound having Formula (B1): 55

6 EP 1 907 355 B1

5

10

15 wherein R12 is a ring moiety selected from phenyl, pyridinyl, pyrimidinyl, furyl, thienyl or pyrrolyl groups, the ring moiety being substituted by a group of the formula - (CH2)n4-CO2H wherein the carboxy group is optionally protected by a protecting group and the ring moiety being also optionally substituted by 1 or 2 additional substituents independently selected from H, halogen, -CN, -CHO, -CF3, -OCF3, -OH, -C1-C6 alkyl, C1-C6 alkoxy, C1-C6 thioalkyl, -NH2, -N(C1-C6 10 13 14 2 alkyl)2, -NH(C1-C6 alkyl), -N-C(O)-(C1-C6 alkyl), or -NO2; and R , R , R , X , n1, n3 and n4 are as defined above to 20 give a sulfonamide and, if the carboxy group is protected by a protecting group, the protecting group is removed from the resultant sulfonamide. -1 [0016] The compounds having the formula II: [Ar-(R)2-SO3 ]qM where Ar, R, and q are as defined above and z is 1 may be prepared as described in WO 2005/082843, which is incorporated herein by reference in its entirety. [0017] A general outline of some embodiments of the processes of the present invention is provided in Scheme I, 25 where constituent members of the depicted compounds of Formulas I, II and III are defined hereinabove.

30

35

40

45 [0018] As shown in Step 1 of Scheme I, sulfonic acid salts of Formula II can be converted to sulfonyl halides of Formula III by reaction with a halogen substitution reagent in the presence of a catalytic amount of water and in the presence of a co-catalyst such as N,N-dimethylformamide. [0019] Halogen substitution reagents, as used herein, are reagents that can convert a non-halogen substituent of the 50 compound of Formula II (such as, for example, H, OH or OM) to a halogen substituent. Halogen substitution reagents of the present invention can, for example, convert a sulfonic acid salt moiety or sulfonic acid moiety to a sulfonyl halide moiety. Numerous reagents capable of carrying out the conversion of sulfonyl acid to sulfonyl halide are known in the

art. Some preferred halogen substitution reagents include SOCl 2, POCl3, CCl4/triphenylphosphine, oxalyl chloride and oxalyl bromide. In some more preferred embodiments, the halogen substitution reagent is oxalyl chloride. Generally, 55 the halogen substitution reagent is used in a molar excess, relative to the compound of Formula II. Preferably, the halogen substitution reagent is employed in an amount of about 1.2 equivalents or greater, relative to the amount of compound of Formula II. For example, oxalyl chloride can be used as the halogen substitution reagent in molar excess, for example from about 1.2 to about 4 equivalents; about 2 to about 3 equivalents or about 2.1 to about 2.6 equivalents

7 EP 1 907 355 B1

with respect to the amount of sulfonic acid salt reagent (compound of Formula II). One skilled in the art will recognize that the amount of halogen substitution reagent used will depend, inter alia, on the amount of solvent and the nature and reactivity of the starting materials and solvents. [0020] As shown in step 1 of Scheme 1, the reaction of the compound of Formula II and the halogen substitution 5 reagent is carried out in the presence of a catalytic amount of water. While not wishing to be bound by any particular theory, it is believed that the catalytic amount of water facilitates the formation of the sulfonyl chloride from the sodium salt by first forming the corresponding protonated sulfonic acid, which is easier to convert to the sulfonyl chloride and can be done under milder conditions, such as by using oxalyl chloride at room temperature or below. The molar ratio of the catalytic amount of water to the compound of Formula II is generally less than about 0.5:1, or from about 0.2:1 to 10 about 0.4:1, or about 0.3:1. [0021] Generally, the reaction of the compound of Formula II with the halogen substitution reagent is carried out in the presence of a co-catalyst. While not wishing to be bound by any particular theory, it is believed that the co-catalyst facilitates the formation of the sulfonyl chloride. Suitable co-catalysts include N, N-dialkylformamides, for example N,N- dimethylformamide, as well as other reagents useful as co-catalysts for sulfonic acid halogenation reactions, for example 15 triphenylphosphine oxide. The co-catalyst is generally provided in an amount sufficient to accelerate the reaction rate. In some embodiments, the co-catalyst is present in less than about one equivalent relative to the amount of sulfonic acid salt reagent. In some preferred embodiments, the co-catalyst is present in an amount of about 0.01 to about 0.5 equivalents, or about 0.1 to about 0.2 equivalents, relative to the amount of sulfonic acid salt reagent. One skilled in the art will recognize that the amount of the co-catalyst used will depend, inter alia, on the amount of solvent and the nature 20 and reactivity of the starting materials and solvents. [0022] In some embodiments, the reacting of the compound of Formula II with the halogen substitution reagent is carried out in a solvent system that includes at least one organic solvent. In some embodiments, the solvent system can include two or more solvents. Solvents suitable for inclusion in the solvent system include aprotic organic solvents, polar aprotic organic solvents, nonpolar aprotic organic solvents, water-miscible aprotic organic solvents, and water-immiscible 25 aprotic organic solvents. In some embodiments, the solvent system includes one or more of tetrahydrofuran, acetonitrile, N,N-dimethylformamide, dioxane, acetone, toluene, methylene chloride, 1,2-di-chloroethane, methyl t-butyl ether and ethyl ether. In some preferred embodiments, the solvent system includes or consists of tetrahydrofuran. [0023] The halogen substitution reaction can be carried out at any suitable temperature. Generally, the reaction is performed at a temperature below room temperature. For example, in some embodiments, the reaction can be carried 30 out at or below about 5°C, for example at a temperature of from about 0 °C to about 5 °C. [0024] In accordance with some embodiments of the invention, and as shown in Step 2 of Scheme I, the sulfonyl halides of Formula III can react with an amine reagent, optionally in the presence of a base, for a time and under conditions sufficient to form a compound of Formula I:

35 4 5 Ar-(R)z-SO2-NR R

where the constituent variables are as defined herein. [0025] Advantageously, in accordance with some embodiments of the invention, the sulfonyl halide of Formula III need not be isolated prior to reaction with the amine reagent. 40 [0026] Generally, where excess halogen substitution reagent is employed for the reaction with the compound of Formula II, it is advantageous that the excess halogen substitution reagent remaining after the reaction be either removed or destroyed, prior to reaction of the sulfonyl halide with the amine reagent, to prevent the formation of impurities. In some embodiments, the excess halogen substitution reagent can be destroyed by adding a chemical reagent, for example asmall amount of water. Preferably, aminimum amount ofwater should be used todestroy the excess halogen substitution 45 reagent, such as oxalyl chloride, when the sulfonyl halides of Formula III, such as (2-trifluoromethyl-phenyl)-methanesulfonyl chloride, are sensitive to hydrolysis. Alternatively, the excess halogen substitution reagent can be removed, for example by one or more of distillation; distillation under reduced pressure; distillation further facilitated by adding a co- solvent; or distillation under reduced pressure further facilitated by adding a co-solvent. When the excess halogen substitution reagent is removed by distillation, it is not necessary that the distillation be continued to dryness. 50 [0027] As used herein, the term "amine reagent" is intended to mean a reagent that either is an amine capable of participating in the reaction with the compound of Formula III to produce a sulfonamide of Formula I, or a reagent that provides such an amine. In some embodiments, the amine reagent has the Formula HNR 4R5, where R4 and R5 are as defined supra. Thus, amine reagents include ammonia, primary and secondary amines, as well as reagents that are 4 5 capable of liberating or producing an amine of the Formula HNR R , such as NH 4OH. In some embodiments, the amine 55 reagent can be in a pure form such as gaseous ammonia or dimethylamine. In some preferred embodiments, the amine reagent is gaseous ammonia, or NH4OH. [0028] In the amination step of Scheme 1, when excess amount of the amine reagent is used, an ammonium halide inorganic salt can be formed. Such ammonium halide inorganic salts can be conveniently removed from the reaction

8 EP 1 907 355 B1

solution by standard techniques, for example by filtration. [0029] The amination of the compound of Formula III (as shown in Step 2 of Scheme 1) can be carried out in a solvent system that can include one or more organic solvents; for example a single organic solvent, or a mixture of two or more organic solvents. Suitable solvents for inclusion in the solvent system include one or more of tetrahydrofuran, acetonitrile, 5 N,N-dimethylformamide, dioxane, acetone, toluene, methylene chloride, 1,2-di-chloroethane, methyl t-butyl ether and ethyl ether. [0030] In some embodiments, the solvent system for the amination includes, in addition to any organic solvents, a small amount of water. It is believed that the presence of a small amount of water in the solvent system facilitates the dissolving the amine reagent. It is advantageous to keep the amount of water in the solvent system at a minimum if the 10 sulfonyl halides of Formula III, such as (2-trifluoromethylphenyl)-methanesulfonyl chloride, are sensitive to hydrolysis. For example, in some embodiments, the amount of water is present in less than about one equivalent relative to the amount of sulfonyl halide reagent. One preferred solvent system includes a small amount of water and tetrahydrofuran. [0031] In some embodiments, the reaction of the compound of Formula III and the amine reagent is performed in the

presence of a base. Suitable bases include ammonia, lower (i.e., C1-6) trialkyl amines, pyridine, or an inorganic base 15 such as metallic carbonates or bicarbonates. In many instances, it is preferred that the amine reagent also function as the base, particularly where the amine reagent is ammonia, or relatively small in size, for example a lower (i.e., C1-6) mono- or di-alkyl amine. [0032] The reaction of the compound of Formula III with the amine reagent can be carried out at any suitable temperature.Generally, the reactionis performed ata temperature belowroom temperature.For example, in some embodiments, 20 the reaction can be carried out at a temperature of less than about -10 °C. In some preferred embodiments, the reaction can be carried out at a temperature of from about -20 °C to about -10 °C. [0033] The sulfonic acid salts of Formula II can be any of a variety of organic sulfonic acid salts. In some embodiments, Ar in the compound of Formula III is phenyl optionally substituted by up to five substituents independently selected from

the group consisting of halogen, C 1-C6 alkyl, C 3-C7 cycloalkyl, heterocycloalkyl, cyano, nitro, OH, C 1-C6 haloalkyl, C 1-C3 25 1 2 1 3 3 3 3 perhaloalkyl, C1-C6 alkoxy, C 1-C6 haloalkoxy, C 1-C3 perhaloalkoxy, NR R , NR COR , COR , COOR , OCOR , aryloxy, heteroaryloxy, arylalkyloxy, heteroalkyloxy, cycloalkylalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, arylalkyl, heteroarylalkyl, aryl and heteroaryl. [0034] In some embodiments, Ar in the compound of Formula III is phenyl substituted by up to five substituents

independently selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C1-C3 perhaloalkyl, C1-C6 alkoxy, 30 1 2 1 3 C1-C6 haloalkoxy, C1-C3 perhaloalkoxy, halogen, CN, NO2, NR R and NR COR . [0035] In some embodiments, Ar in the compound of Formula III is a disubstituted phenyl group bearing substituents in the 2- and 6- positions; or a disubstituted phenyl group bearing substituents in the 3- and 4- positions; or a monosub- stituted phenyl group bearing a substituent in the 2-position. In some embodiments, the substituents are independently selected from halogen, for example chlorine, C1-6 alkyl, for example methyl, C1-6 alkoxy, for example methoxy, C1-3 35 perhaloalkyl, for example trifluoromethyl and C1-3 perhaloalkoxy, for example trifluoromethoxy. [0036] In some embodiments, Ar in the compound of Formula III is phenyl substituted by up to three groups independ-

ently selected from C1-C6 haloalkyl, C1-C3 perhaloalkyl and C1-3 perhaloalkoxy. In some embodiments, Ar in the compound of Formula III is phenyl substituted with one perhaloalkyl group at the 2 position thereof. In some embodiments, Ar in the compound of Formula III is 2-trifluoromethylphenyl. In other embodiments, Ar in the compound of Formula III 40 is phenyl substituted with one perhaloalkoxy group at the 2 position thereof, for example, 2-trifluoromethoxyphenyl. In still other embodiments, Ar in the compound of Formula III is phenyl substituted with two halogens at the 3 and 4 positions thereof, for example, 3,4-dichlorophenyl. In further embodiments, Ar in the compound of Formula III is phenyl substituted with groups in the 2 and 6 positions thereof, for example, 2-fluoro-6-(trifluoromethyl)phenyl. [0037] In some embodiments, z is 1. In some further embodiments, z is 1, and R is1 -CC4 alkylene, for example 45 methylene. [0038] In some embodiments, X is Cl. In some embodiments, M is Na + ion or K+ ion, preferably Na+ ion. [0039] In some embodiments, Ar is phenyl substituted with one perhaloalkyl group at the 2 position thereof; R is methylene or ethylene; M is Na+ ion or K+ ion; X is Cl; q is 1; and z is 1. [0040] In some embodiments of the synthetic process of the present invention, the co-catalyst is N,N-dimethylforma- 50 mide; the halogen substitution reagent is oxalyl chloride; and the molar ratio of the catalytic amount of water to the compound of Formula II is of a value of between about 0.2 to about 0.4. [0041] In some embodiments of the synthetic process of the present invention, Ar is phenyl substituted with one perhaloalkyl group at the 2 position thereof; R is methylene or ethylene; M is Na + ion or K+ ion; X is Cl; q is 1; z is 1; the co-catalyst is N,N-dimethylformamide; the halogen substitution reagent is oxalyl chloride; the molar ratio of the halogen 55 substitution reagent to the compound of Formula II is at a value of about 2 to about 3; and the molar ratio of the catalytic amount of water to the compound of Formula II is of a value of between about 0.2 to about 0.4. [0042] In some embodiments of the process of forming the compound of Formula I, the amine reagent is gaseous ammonia, and the reacting of the compound of Formula III with the amine reagent is carried out in a solvent system

9 EP 1 907 355 B1

comprising an organic solvent and a small amount of water. [0043] In some embodiments of the process of forming the compound of Formula I, the process of the present invention further comprises isolating the compound of Formula I. [0044] In some embodiments of the processes of the invention, Ar is phenyl substituted with one perhaloalkyl group 5 at the 2 position thereof; R is methylene or ethylene; M is Na + ion or K+ ion; X is Cl; q is 1; z is 1; the co-catalyst is N,N- dimethylformamide; the halogen substitution reagent is oxalyl chloride; the molar ratio of the halogen substitution reagent to the compound of Formula II is at a value of about 2 to about 3; the molar ratio of the catalytic amount of water to the compound of Formula II is of a value of between about 0.2 to about 0.4; and the compound of Formula I is formed without isolation of said compound of Formula III. In some further embodiments, Ar is 2-trifluoromethylphenyl. 10 [0045] In some embodiments, the processes of the present invention further include a) removing excess the halogen substitution reagent; and c) isolating the compound of Formula I. [0046] In some embodiments, of each of the processes of the invention, the compound of Formula I is formed without isolation of the compound of Formula III. [0047] The compounds of Formula I can be isolated from the reaction mixture by any routine method such as precip- 15 itation and filtration. Any of numerous well known methods for inducing precipitation can be used. In some embodiments, the reaction mixture can be cooled (e.g., less than about 10 °C) to help induce precipitation. In some embodiments, an anti-solvent such as water or a solvent containing water can be added to the reaction mixture to induce precipitation. In some embodiments, precipitation can be facilitated by lowering the temperature of the reaction mixture to, for example, below about 5°C. 20 [0048] Numerous advantages of the present invention are apparent to the art-skilled. For example, preparation of sulfonyl halide at a moderate temperautre allows for improved yields by avoiding the hydrolysis of sulfonyl halides in the presence of water. Additionally, the preparation and isolation methods described herein help maximize yields. [0049] In some embodiments of the invention, multi-step processes are carried out stepwise and each intermediate is isolated before proceeding to the next step. In other embodiments of the invention, some of the intermediates are 25 isolated and others are not. In yet other embodiments, none of the intermediates are completely isolated and all of the reactions take place in a single reactor vessel. [0050] It is understood in the generic description above and for other groups described herein that, in each instance any variable group may be independently substituted by their allowed groups. Thus, for example, where a structure is described wherein two substituents selected from a same group are simultaneously present on the same compound, 30 the two substituents can be different members of the same group. [0051] It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination. 35 [0052] The term "alkyl", employed alone, is defined herein as, unless otherwise stated, either a straight-chain or branched saturated hydrocarbon moiety. In some embodiments, the alkyl moiety contains 1 to 18, 1 to 12, 1 to 10, 1 to 8, 1 to 6, or 1 to 4 carbon atoms. Examples of saturated hydrocarbon alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl; higher homologs such as n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. 40 [0053] The term "alkylenyl" refers to a bivalent straight-chained or branched alkyl group. [0054] As used herein, "alkenyl" refers to an alkyl group having one or more carbon-carbon double bonds. Nonlimiting examples of alkenyl groups include ethenyl, propenyl, and the like. [0055] As used herein, "alkynyl" refers to an alkyl group having one or more carbon-carbon triple bonds. Nonlimiting examples of alkynyl groups include ethynyl, propynyl, and the like. 45 [0056] As used herein, "haloalkyl" refers to an alkyl group having one or more halogen substituents, up to and including perhalogenated species. Thus, examples of haloalkyl groups include perhaloalkyl groups such as CF3, C2F5, CCl3, C2Cl5, and the like, as well as groups having less than perhalo substitution, such as CHF 2, CHCl2 and the like. The term "perhaloalkyl" is intended to denote an alkyl group in which all of the hydrogen atoms are replaced with halogen atoms. [0057] The term "alkoxy", employed alone or in combination with other terms, is defined herein as, unless otherwise 50 stated, -O-alkyl. Examples of alkoxy moieties include, but are not limited to, chemical groups such as methoxy, ethoxy, isopropoxy, sec-butoxy, tert-butoxy, and the like. [0058] The term "haloalkoxy", employed alone or in combination with other terms, is defined herein as, unless otherwise

stated, -O-haloalkyl. Examples of haloalkoxy moieties include, but are not limited to, chemical groups such -OCF 3, and the like. 55 [0059] The term "cycloalkyl", employed alone or in combination with other terms, is defined herein as, unless otherwise stated, a monocyclic, bicyclic, tricyclic, fused, bridged, or spiro monovalent non-aromatic hydrocarbon moiety of 3-18 or 3-7 carbon atoms. Also included in the definition of cycloalkyl are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the nonaromatic ring. Any suitable ring position of the cycloalkyl moiety can be

10 EP 1 907 355 B1

covalently linked to the defined chemical structure. Examples of cycloalkyl moieties include, but are not limited to, chemical groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, adamantyl, spiro[4.5]de- canyl, and the like. [0060] As used herein, "heterocycloalkyl" refers to a cycloalkyl group (e.g. of 3-12 atoms) wherein one or more (e.g., 5 up to 4 atoms) are replaced by a heteroatom such as an O, S, N or P atom. Also included in the definition of heterocycloalkyl are moieties that have one or more (e.g., two) aromatic rings fused (i.e., having a bond in common with) to the nonaromatic heterocyclic ring, for example phthalimidyl, naphthalimidyl pyromellitic diimidyl, phthalanyl, and benzo derivatives of saturated heterocycles such as indolene and isoindolene groups. In some embodiments, heterocycloalkyl groups are 3-12 membered groups having 1-4 heteroatoms independently selected from oxygen, nitrogen and sulfur, and optionally 10 having one or two benzene rings fused thereto, where the group is bonded via a ring carbon or a nitrogen atom. [0061] The terms "halo" or "halogen", employed alone or in combination with other terms, is defined herein as, unless otherwise stated, fluoro, chloro, bromo, or iodo. [0062] The term "aryl", employed alone or in combination with other terms, is defined herein as, unless otherwise stated, an aromatic hydrocarbon of up to 14 carbon atoms, which can be a single ring (monocyclic) or multiple rings 15 (bicyclic, up to three rings) fused together or linked covalently. Any suitable ring position of the aryl moiety can be covalently linked to the defined chemical structure. Examples of aryl moieties include, but are not limited to, chemical groups such as phenyl, 1-naphthyl, 2-naphthyl, dihydronaphthyl, tetrahydronaphthyl, biphenyl, anthryl, phenanthryl, fluorenyl, indanyl, biphenylenyl, acenaphthenyl, acenaphthylenyl, and the like. [0063] The term "aryloxy" as used herein means a group of formula -O-aryl, where the term "aryl" has the definition 20 as previously described herein. [0064] The term "arylalkyl" or "aralkyl," employed alone or in combination with other terms, is defined herein as, unless otherwise stated, an alkyl group as herein before defined, that is substituted with an aryl moiety as defined herein. Examples of arylalkyl moieties include, but are not limited to, chemical groups such as benzyl, 1-phenylethyl, 2-phenylethyl, diphenylmethyl, 3-phenylpropyl, 2-phenylpropyl, fluorenylmethyl, and the like. 25 [0065] The term "arylalkyloxy" as used herein means a group of formula -O-arylalkyl, where the term "arylalkyl" has the definition as previously described herein. [0066] As used herein, "heteroaryl" groups are monocyclic and polycyclic (e.g., two or three rings) aromatic hydrocar- bons that have at least one heteroatom ring member such as sulfur, oxygen, or nitrogen. Heteroaryl groups include, without limitation, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thi- 30 azolyl, indolyl, pyrryl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indaz olyl, 1,2,4-thiadiazolyl, isothiazolyl, benzothienyl, purinyl, carbazolyl, benzimidazolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl-S-oxide, 2,3-dihydrobenzothienyl-S-dioxide, benzoxazolin-2-on-yl, indolinyl, benzodioxolanyl, benzodioxane, and the like. In some embodiments, heteroaryl groups can have from 1 to about 20 carbon atoms, and in further embodiments from about 3 to about 20 carbon atoms. In some embodiments, heteroaryl 35 groups have 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms. In some embodiments, heteroaryl is an aromatic 5-24 membered mono- or poly- (e.g., di- or tri-) cyclic group having 1-4 heteroatoms the same or different selected from oxygen, nitrogen and sulfur. [0067] The term "heteroarylalkyl," employed alone or in combination with other terms, is defined herein as, unless otherwise stated, an alkyl group as herein before defined, substituted with a heteroaryl moiety as defined herein. Examples 40 of heteroarylalkyl moieties include, but are not limited to, chemical groups such as pyridylmethyl. [0068] The term "heteroarylalkyloxy" as used herein means a group of formula -O-heteroarylalkyl, where the term "heteroarylalkyl" has the definition as previously described herein. [0069] As used herein, "heterocycle" refers to a heteroaryl or heterocycloalkyl group. [0070] The term "heteroaryloxy" as used herein means a group of formula -O-heteroaryl, where the term "heteroaryl" 45 has the definition as previously described herein. [0071] As used herein, the term "reacting" refers to the bringing together of designated chemical reactants such that a chemical transformation takes place generating a compound different from any initially introduced into the system. Reacting can take place in the presence or absence of solvent. [0072] As used herein, the term "precipitating" is used as known in the art and generally refers to the formation of solid 50 (e.g., precipitate) from a solution in which the solid is dissolved. The solid can be amorphous or crystalline. Methods of precipitation are well known in the art and include, for example, increasing the proportion of solvent in which a solute is insoluble, decreasing temperature, chemically transforming the solute such that it becomes no longer soluble in its solvent, and the like. [0073] The compounds of the present invention can contain an asymmetric atom, and some of the compounds can 55 contain one or more asymmetric atoms or centers, which can thus give rise to optical isomers (enantiomers) and diastereomers. The present invention includes such optical isomers (enantiomers) and diastereomers (geometric isomers), as well as, the racemic and resolved, enantiomerically pure R and S stereoisomers, as well as, other mixtures of the R and S stereoisomers and pharmaceutically acceptable salts thereof. Optical isomers can be obtained in pure form by

11 EP 1 907 355 B1

standard procedures known to those skilled in the art, and include, but are not limited to, diastereomeric salt formation, kinetic resolution, and asymmetric synthesis. It is also understood that this invention encompasses all possible regioi- somers, and mixtures thereof, which can be obtained in pure form by standard separation procedures known to those skilled in the art, and include, but are not limited to, column chromatography, thin-layer chromatography, and high- 5 performance liquid chromatography. [0074] Compounds of the invention can also include all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium. [0075] Compounds of the invention can also include tautomeric forms, such as keto-enol tautomers. Tautomeric forms 10 can be in equilibrium or sterically locked into one form by appropriate substitution. [0076] The processes described herein can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., 1H or 13C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), or mass spectrometry, or by chromatography such as high performance liquid chromatography (HPLC) or thin layer chromatography. 15 [0077] The reactions of the processes described herein can be carried out in air or under an inert atmosphere. Typically, reactions containing reagents or products that are substantially reactive with air can be carried out using air-sensitive synthetic techniques that are well known to the skilled artisan. [0078] Upon carrying out preparation of compounds according to the processes described herein, the usual isolation and purification operations such as concentration, filtration, extraction, solid-phase extraction, recrystallization, chroma- 20 tography, and the like may be used to isolate the desired products. [0079] The invention will be described in greater detail by way of specific examples.

EXAMPLE 1

25 Synthesis of (2-Trifluoromethyl-phenyl)-methanesulfonamide

[0080] A vessel of suitable size was charged with tetrahydrofuran (THF, 250 mL), water (1 mL), DMF (2 mL), and (2- trifluoromethyl-phenyl)-methanesulfonic acid, sodium salt (50 g, 0.190 mol). The mixture was stirred under a nitrogen blanket and cooled to 0-5 °C. Oxalyl chloride (63 g, 0.496 mol) was added dropwise to the reaction mixture. The mixture 30 was stirred at 0-5 °C for 16 hours. In-process analysis (HPLC) showed a 99% conversion to (2-(trifluoromethyl)phenyl)methanesulfonyl chloride. The reaction mixture was concentrated to 107 g, then diluted with THF (200 mL). The mixture was stirred and cooled to -10 to -20 °C. Water (3.0 mL) was added dropwise. Ammonia (gas, 13 g, 0.765 mol) was added via subsurface tubing to the reaction mixture. The reaction mixture was basic to pH paper. In-process testing (HPLC) showed complete 35 conversion of the sulfonyl chloride to the sulfonamide with ∼5% of the sulfonic acid. The mixture was filtered to remove inorganic salts. Water (135 mL) was added to the filtrate. The filtrate was concentrated to 190 g. The mixture was stirred at 0-5 °C for 30 min. The solid product was collected by filtration and dried to constant weight to give 33.2 g (73%) of 1 the title compound. HNMR(300 MHz, CDCl3): δ 7.81-7.52 (m, 4H, ArH), 4.60 (s, 2H, CH 2), and 4.52 (br s, 2H, NH 2).

40 EXAMPLE 2

Synthesis of 4-(3-{5-chloro-1-(diphenylmethyl)-2-[2-({[2(trifluoromethyl)benzyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}propyl)benzoic acid

45 [0081] Step1: Toa suspension of4-{3-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoic acid (prepared as described in U.S. Patent No. 6797708, incorporated herein by reference in its entirety) (10.0 g, 19 mmol) in

CH3CN (100 mL) and MeOH (25 mL) was added (trimethylsilyl)diazomethane (2.0 M soln. in hexanes, 9.6 mL, 19 mmol). After 16 h the mixture was filtered and concentrated to afford the methyl 4-{3-[2-(2-aminoethyl)-1-benzhydryl-5-chloro- 1H-indol-3-yl]propyl}benzoate (8.8 g, ca. 86%), an orange foam, which was used without purification. 50 [0082] Step 2: Methyl 4-{3-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate (Example 2, Step 1, 9.1 g, 17 mmol) was treated with (2-(trifluoromethyl)phenyl)methanesulfonyl chloride (4.8 g, 17 mmol, obtainable according to example 1 above) and sat. NaHCO 3 in CH 2Cl2. The mixture was poured into saturated sodium bicarbonate and extracted with CH 2Cl2. The combined organic phase was washed with brine, dried over sodium sulfate and purified by column chromatography to afford 6.1 g of 4-(3-{5-chloro-1-(diphenylmethyl)-2-[2-({[2-(trifluoromethyl)benzyl]sulfonyl} 55 1 amino)ethyl]-1H-indol-3-yl}propyl)benzoic acid methyl ester as a white foam (47% yield). H NMR (400 MHz, CDCl3) δ 1.88 - 2.00 (m, 2 H), 2.64 - 2.77 (m, 6 H), 2.83 - 2.95 (m, 2 H), 3.90 (s, 3 H), 4.05 (t, J=5.9 Hz, 1 H), 4.33 (s, 2 H), 6.49 (d, J=8.8 Hz, 1 H), 6.70 - 6.88 (m, 2 H), 7.04 (dd, J=6.4, 2.7 Hz, 4 H), 7.24 (s, 1 H), 7.28 - 7.35 (m, 7 H), 7.36 - 7.49 (m, 3 H), 7.55 - 7.71 (m, 2 H), 7.95 (d, J=8.1 Hz, 2 H).

12 EP 1 907 355 B1

[0083] Step 3: The resulting ester (2.6 g, 3.4 mmol) was hydrolyzed by stirring with 1 N NaOH in THF and enough MeOH to produce a clear solution. The reaction was monitored by TLC for the disappearance of starting material. When the reaction was complete, the mixture was concentrated, diluted with H 2O, and acidified to pH 2-4 using 1 M HCl. The aqueous phase was extracted with EtOAc and the organic phase was washed with brine, dried over sodium sulfate, and 5 1 concentrated to afford 2.25 g (88%) of the title product, a yellow solid. H NMR (400 MHz, DMSO-d6) δ 1.81 - 1.97 (m, 2 H), 2.66 - 2.79 (m, 4 H), 2.95 (s, 4 H), 4.41 (s, 2 H), 6.45 (d, J=8.8 Hz, 1 H), 6.78 (dd, J=8.8, 2.0 Hz, 1 H), 7.01 - 7.14 (m, 5 H), 7.24 - 7.42 (m, 8 H), 7.46 (d, J=2.0 Hz, 1 H), 7.50 - 7.66 (m, 4 H), 7.73 (d, J=7.8 Hz, 1 H), 7.85 (d, J=8.3 Hz, 1+ 2 H), 12.77 (s, 1 H); HRMS: calcd for C 41H36ClF3N2O4S + H+, 745.21092; found (ESI-FTMS, [M+H] ), 745.2132; Anal. Calcd for C41H36ClF3N2O4S: C, 66.08; H, 4.87; N3.76. Found: C, 66.07; H, 4.57; N, 3.67. 10

Claims

1. A synthetic process comprising reacting a compound of Formula II: 15 -1 [Ar-(R)z-SO3 ]qMII

wherein:

20 Ar is phenyl substituted with one perhaloalkyl group at the 2 position thereof; R is methylene; M is a Group I or II metal ion; q is 1 where M is Group I metal ion; or q is 2 where M is a Group II metal ion; and 25 z is 1;

with a halogen substitution reagent in the presence of a catalytic amount of water and in the presence of a co- catalyst comprising N,N-dimethylformamide at a temperature below room temperature for a time sufficient to form a compound of Formula III: 30

Ar-(R)z-SO2-X III

wherein X is halogen and Ar, R and z are as defined above.

35 2. The process of claim 1 wherein said reaction of said compound of Formula II with said halogen substitution reagent is carried out in a solvent system comprising a solvent selected from the group consisting of an aprotic organic solvent.

3. The process of claim 2 wherein said solvent system comprises one or more of tetrahydrofuran, acetonitrile, N,N- dimethylformamide, dioxane, acetone, toluene, methylene chloride, 1,2-di-chloroethane, methyl t-butyl ether, or 40 ethyl ether.

4. The process of claim 2 wherein said solvent system comprises tetrahydrofuran.

5. The process of claim 1, 2, 3 or 4, wherein said reaction of said compound of Formula II with said halogen substitution 45 reagent is carried out at a temperature of less than 5 °C.

6. The process of claim 1, 2, 3, 4 or 5, wherein the molar ratio of said catalytic amount of water to said compound of Formula II is less than 0.5:1.

50 7. The process of claim 1, 2, 3, 4, 5 or 6, wherein the molar ratio of said catalytic amount of water to said compound of Formula II is of a value of from 0.2 to 0.4.

8. The process of claim 1, 2, 3, 4, 5, 6 or 7, wherein the molar ratio of said catalytic amount of water to said compound of Formula II is 0.3. 55

9. The process of any one of claims 1 to 8, wherein said halogen substitution reagent comprises SOCl2, POCl3, CCl4/triphenylphosphine, oxalyl chloride or oxalyl bromide.

13 EP 1 907 355 B1

10. The process of any one of claims 1 to 9, wherein said halogen substitution reagent comprises oxalyl chloride.

11. The process of any one of claims 1 to 10, wherein the molar ratio of said halogen substitution reagent to said compound of Formula II is 1.2 or greater. 5 12. The process of any one of claims 1 to 11, wherein Ar is 2-trifluoromethylphenyl.

13. The process of any one of claims 1 to 12, wherein X is Cl.

10 14. The process of any one of claims 1 to 13, wherein M is Na+ ion or K+ ion.

15. The process of any one of claims 1 to 14, wherein M is Na+ ion.

16. The process of any one of claims 1 to 15, wherein: 15 said co-catalyst is N,N-dimethylformamide; said halogen substitution reagent is oxalyl chloride; and the molar ratio of said catalytic amount of water to said compound of Formula II is of a value of between 0.2 to 0.4.

20 17. The process of claim 1 further comprising reacting said compound of Formula III with an amine reagent optionally in the presence of a base for a time and under conditions sufficient to form a compound of Formula I:

4 5 Ar-(R)z-SO2-NR R I

25 wherein:

4 5 R and R are each, independently, H, C1-C18 alkyl, C2-C18 alkenyl, C2-C18 alkynyl, C3-C18 cycloalkyl, heterocycloalkyl, aryl or heteroaryl, each optionally substituted by up to five substituents independently selected from

the group consisting of halogen, C 1-C6 alkyl, C 3-C7 cycloalkyl, heterocycloalkyl, cyano, nitro, OH, C 1-C6 alkoxy, 30 C1-C6 haloalkyl, C1-C6 haloalkoxy, aryl and heteroaryl; orR 4and R 5,together with thenitrogen atomto which they are attached,can form a 5- or 6-memberedheterocycle and Ar, R and z are as defined in claim 1.

18. The process of claim 17 further comprising removing or destroying excess halogen substitution reagent prior to 35 reaction of said compound of Formula III with said amine reagent.

19. The process of claim 18 wherein said destroying of said excess halogen substitution reagent is fac ilitated by adding a chemical reagent; wherein said chemical reagent is water.

40 20. The process of any one of claims 17 to 19 wherein said reaction of said compound of Formula III with said amine reagent is carried out at a temperature of less than -10 °C.

21. The process of any one of claims 17 to 20, wherein the amine reagent has the Formula HNR4R5, wherein R4 and R5 are as defined in claim 17. 45

22. The process of any one of claims 17 to 21, wherein said amine reagent is NH3 or NH4OH.

23. The process of claim 22, wherein said amine reagent is gaseous ammonia, and said reaction of said compound of Formula III with said amine reagent is carried out in a solvent system comprising an organic solvent and a small 50 amount of water.

24. The process of any one of claims 17 to 23, further comprising isolating said compound of Formula I.

25. The process of any one of claims 17 to 24, wherein said compound of Formula I is formed without isolation of said 55 compound of Formula III.

26. A process for the preparation of a compound of Formula (A1):

14 EP 1 907 355 B1

5

10

15

wherein:

20 Ar, R and z are as defined in claim 1; R10 is selected from the formulae -(CH2)n-A, -(CH2)n-S-A, or -(CH2)n-O-A, wherein A is selected from the moieties:

25

30

wherein:

D is C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, -CF3 or -(CH2)1-3-CF3; 35 B and C are independently selected from phenyl, pyridinyl, pyrimidinyl, furyl, thienyl or pyrrolyl groups, each optionally substituted by from 1 to 3, preferably 1 to 2, substituents selected independently from H, halogen, -CN, -CHO, -CF3, -OCF3, -OH,-C1-C6 alkyl, C1-C6 alkoxy, -NH2, -N(C1-C6 alkyl)2, -NH(C1-C6 alkyl), -N- C(O)-(C1-C6 alkyl), -NO2, or by a 5- or 6-membered heterocyclic or heteroaromatic ring containing 1 or 2 heteroatoms selected from O, N or S; 40 n is an integer from 0 to 3;

n1 is an integer from 1 to 3; n3 is an integer from 0 to 3; n4 is an integer from 0 to 2 2 X is selected from -O-, -CH2-, -S-, -SO-, -SO2-, -NH-, -C(O)-, 45

50

55

15 EP 1 907 355 B1

5

R12 is a ring moiety selected from phenyl, pyridinyl, pyrimidinyl, furyl, thienyl or pyrrolyl groups, the ring 10 moiety being substituted by a group of the formula -(CH2)n4-CO2H or a pharmaceutically acceptable acid mimic or mimetic; and also optionally substituted by 1 or 2 additional substituents independently selected from H, halogen, - CN, -CHO, -CF 3, -OCF3, -OH, -C 1-C6 alkyl, C 1-C6 alkoxy, C 1-C6 thioalkyl, -NH 2, -N(C1-C6 alkyl)2, -NH(C1-C6 alkyl), -N-C(O)-(C1-C6 alkyl), or -NO2; 13 R is selected from H, halogen, -CN, -CHO, -CF 3, -OCF3, -OH, -C 1-C6 alkyl, C 1-C6 alkoxy, C 1-C6 thioalkyl, 15 -NH2, -N(C1-C6 alkyl)2, -NH(C1-C5 alkyl), -N-C(O)-(C1-C6 alkyl), or -NO2; 14 R is selected from H, halogen, -CN, -CHO, -CF 3, -OCF3, -OH, -C 1-C6 alkyl, C 1-C6 alkoxy, C 1-C6 thioalkyl, -NH2, -N(C1-C6 alkyl)2, -NH(C1-C6 alkyl), -N-C(O)-(C1-C6 alkyl), -NO2, -N-C(O)-N(C1-C3 alkyl)2, -N- C(O)-NH(C1-C3 alkyl), -N-C(O)-O-(C1-C3 alkyl), -SO2-C1-C6 alkyl, -S-C3-C6 cycloalkyl, -S-CH2-C3-C6 cycloalkyl, -SO2-C3-C6 cycloalkyl, , -SO2-CH2-C3-C6 cycloalkyl, C3-C6 cycloalkyl, -CH 2-C3-C6 cycloalkyl, -O- 20 C3-C6 cycloalkyl, , -O-CH2-C3-C6 cycloalkyl, phenyl, benzyl, benzyloxy, morpholino or other heterocycles such as pyrrolidino, piperidine, piperizine furan, thiophene, imidazole, tetrazole, pyrazine, pyrazolone, pyrazole, imidazole, oxazole or isoxazole, the rings of each of these R 14 groups each being optionally substituted by from 1 to 3 substituents selected from the group of H, halogen, -CN, -CHO, -CF3, -OH, -C1-C6 alkyl, C1-C6 alkoxy, -NH2, -N(C1-C6 alkyl)2, -NH(C1-C6 alkyl), -N-C(O)-(C1-C6 alkyl), -NO2, -SO2(C1-C3 alkyl), 25 -SO2NH(C1-C3 alkyl), -SO2N(C1-C3 alkyl)2, or OCF3;

or a pharmaceutically acceptable salt form thereof; which comprises reacting a compound of Formula II:

30 -1 [Ar-(R)z-SO3 ]qMII

wherein:

Ar, R and z are as defined in claim 1; 35 M is a Group I or II metal ion; q is 1 where M is Group I metal ion; or q is 2 where M is a Group II metal ion; and with a halogen substitution reagent in the presence of a catalytic amount of water and in the presence of a co-catalyst comprising N,N-dimethylformamide at a temperature below room temperature for a time and 40 under conditions sufficient to form a compound of Formula III:

Ar-(R)z-SOz-X III

wherein X is halogen and Ar, R and z are as defined in claim 1; and converting the compound of Formula 45 III into the compound of Formula (A1) or a pharmaceutically acceptable salt form thereof, by reacting the compound of formula III with a compound of Formula (B1):

50

55

16 EP 1 907 355 B1

5

10

15 wherein R12 is a ring moiety selected from phenyl, pyridinyl, pyrimidinyl, furyl, thienyl or pyrrolyl groups, the ring moiety being substituted by a group of the formula -(CH2)n4-CO2H wherein the carboxy group is optionally protected by a protecting group and the ring moiety being also optionally substituted by 1 or 2 additional substituents independently selected from H, halogen, -CN, -CHO, -CF3, -OCF3, -OH, -C1-C6 20 alkyl, C1-C6 alkoxy, C1-C6 thioalkyl, -NH2, -N(C1-C6 alkyl)2, -NH(C1-C6 alkyl), -N-C(O)-(C1-C6 alkyl), or 10 13 14 2 -NO2; and R , R , R , X , n1, n3 and n4 are as defined above in relation to formula (A1) to give a sulfonamide and, if the carboxy group is protected by a protecting group, the protecting group is removed from the resultant sulfonamide.

25 27. A process according to claim 26, wherein R 10 is diphenylmethyl.

28. A process according to claim 26 or 27 carried out to prepare 4-(3-{5-chloro-1-(diphenylmethyl)-2-[2-({[2-(trifluoromethyl)benzyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}propyl)benzoic acid or a pharmaceutically acceptable salt thereof.

30 Patentansprüche

1. Synthetisches Verfahren, welches das Reagieren einer Verbindung der Formel II:

35 -1 [Ar- (R)z-SO3 ]qMII

wobei:

Ar Phenyl substituiert mit einer Perhaloalkyl-Gruppe an Position 2 davon ist; 40 R Methylen ist; M ein Metallion der Gruppe I oder II ist; q 1 ist, wenn M ein Metallion der Gruppe I ist; oder q 2 ist, wenn M ein Metallion der Gruppe II ist; und z 1 ist; 45 mit einem Halogen-Substitutionsreagens in Gegenwart einer katalytischen Menge an Wasser und in Gegenwart eines Co-Katalysators, welcher N,N-Dimethylformamid umfasst, bei einer Temperatur unter Raumtemperatur für eine Zeit, die ausreichend ist für die Bildung einer Verbindung der Formel III:

Ar-(R)z-SO2-X III 50 wobei X Halogen ist und Ar, R und z wie oben definiert sind, umfasst.

2. Verfahren nach Anspruch 1, wobei die Reaktion der Verbindung der Formel II mit dem Halogen-Substitutionsreagens in einem Lösemittelsystem ausgeführt wird, welches ein Lösemittel ausgewählt aus der Gruppe bestehend aus 55 einem aprotischen organischen Lösemittel umfasst.

3. Verfahren nach Anspruch 2, wobei das Lösemittelsystem eines oder mehrere aus Tetrahydrofuran, Acetonitril, N,N- Dimethylformamid, Dioxan, Aceton, Toluol, Methylenchlorid, 1,2-Dichlorethan, Methyl-t-butylether oder Ethylether

17 EP 1 907 355 B1

umfasst.

4. Verfahren nach Anspruch 2, wobei das Lösemittelsystem Tetrahydrofuran umfasst.

5 5. Verfahren nach Anspruch 1, 2, 3 oder 4, wobei die Reaktion der Verbindung der Formel II mit dem Halogen- Substitutionsreagens bei einer Temperatur von weniger als 5 °C ausgeführt wird.

6. Verfahren nach Anspruch 1, 2, 3, 4 oder 5, wobei das Molverhältnis der katalytischen Menge an Wasser zu der Verbindung der Formel II weniger als 0,5:1 beträgt. 10 7. Verfahren nach Anspruch 1, 2, 3, 4, 5 oder 6, wobei das Molverhältnis der katalytischen Menge an Wasser zu der Verbindung der Formel II einen Wert von 0,2 bis 0,4 hat.

8. Verfahren nach Anspruch 1, 2, 3, 4, 5, 6 oder 7, wobei das Molverhältnis der katalytischen Menge an Wasser zu 15 der Verbindung der Formel II 0,3 beträgt.

9. Verfahren nach einem der Ansprüche 1 bis 8, wobei das Halogen-Substitutionsreagens SOCl2, POCl3, CCl4/Tri- phenylphosphin, Oxalylchlorid oder Oxalylbromid umfasst.

20 10. Verfahren nach einem der Ansprüche 1 bis 9, wobei das Halogen-Substitutionsreagens Oxalylchlorid umfasst.

11. Verfahren nach einem der Ansprüche 1 bis 10, wobei das Molverhältnis des Halogen-Substitutionsreagens zu der Verbindung der Formel II 1,2 oder höher ist.

25 12. Verfahren nach einem der Ansprüche 1 bis 11, wobei Ar 2-Trifluormethylphenyl ist.

13. Verfahren nach einem der Ansprüche 1 bis 12, wobei X Cl ist.

14. Verfahren nach einem der Ansprüche 1 bis 13, wobei M ein Na+-Ion oder ein K+-Ion ist. 30 15. Verfahren nach einem der Ansprüche 1 bis 14, wobei M ein Na+-Ion ist.

16. Verfahren nach einem der Ansprüche 1 bis 15, wobei:

35 der Co-Katalysator N,N-Dimethylformamid ist; das Halogen-Substitutionsreagens Oxalylchlorid ist; und das Molverhältnis der katalytischen Menge an Wasser zu der Verbindung der Formel II einen Wert zwischen 0,2 und 0,4 hat.

40 17. Verfahren nach Anspruch 1, welches ferner das Reagieren der Verbindung der Formel III mit einem Aminreagens, wahlweise in Gegenwart einer Base, für eine Zeit und unter Bedingungen, die ausreichend sind für die Bildung einer Verbindung der Formel I:

4 5 Ar- (R)z-SO2NR R I 45 wobei:

4 5 R und R jeweils unabhängig H, C1-C18-Alkyl, C2-C18-Alkenyl, C2-C18-Alkinyl, C3-C18-Cycloalkyl, Heterocyc- loalkyl, Aryl oder Heteroaryl sind, jeweils wahlweise substituiert durch bis zu fünf Substituenten unabhängig 50 ausgewählt aus der Gruppe bestehend aus Halogen, C 1-C6-Alkyl, C3-C7-Cycloalkyl, Heterocycloalkyl, Cyano, Nitro, OH, C1-C6-Alkoxy, C1-C6-Haloalkyl, C1-C6-Haloalkoxy, Aryl und Heteroaryl; oder R4 und R5, zusammen mit dem Stickstoffatom, an welches sie gebunden sind, einen 5- oder 6-gliedrigen Heterocyclus bilden können, und Ar, R und z wie in Anspruch 1 definiert sind, umfasst. 55 18. Verfahren nach Anspruch 17, welches ferner das Entfernen oder Zerstören von überschüssigem Halogen-Substi- tutionsreagens vor der Reaktion der Verbindung der Formel III mit dem Aminreagens umfasst.

18 EP 1 907 355 B1

19. Verfahren nachAnspruch 18,wobei das Zerstören desüberschüssigen Halogen-Substitutionsreagens durch Zugabe eines chemischen Reagens vereinfacht wird; wobei das chemische Reagens Wasser ist.

20. Verfahren nach einem der Ansprüche 17 bis 19, wobei die Reaktion der Verbindung der Formel III mit dem Amin- 5 reagens bei einer Temperatur von weniger als -10 °C ausgeführt wird.

21. Verfahren nach einem der Ansprüche 17 bis 20, wobei das Aminreagens die Formel HNR4R5 aufweist, wobei R4 und R5 wie in Anspruch 17 definiert sind.

10 22. Verfahren nach einem der Ansprüche 17 bis 21, wobei das Aminreagens NH3 oder NH4OH ist.

23. Verfahren nach Anspruch 22, wobei das Aminreagens gasförmiger Ammoniak ist und die Reaktion der Verbindung der Formel III mit dem Aminreagens in einem Lösemittelsystem ausgeführt wird, welches ein organisches Lösemittel und eine kleine Menge Wasser umfasst. 15 24. Verfahren nach einem der Ansprüche 17 bis 23, welches ferner das Isolieren der Verbindung der Formel I umfasst.

25. Verfahren nach einem der Ansprüche 17 bis 24, wobei die Verbindung der Formel I ohne Isolierung der Verbindung von Formel III gebildet wird. 20 26. Verfahren zur Herstellung einer Verbindung der Formel (A1) :

25

30

35

40 wobei:

Ar, R und z wie in Anspruch 1 definiert sind;

R10 ausgewählt ist aus den Formeln -(CH 2)n-A, -(CH2)n-S-A oder -(CH2)n-O-A, wobei A ausgewählt ist aus den Resten: 45

50

wobei: 55

D C1-C6-Alkyl, C1-C6-Alkoxy, C3-C6-Cycloalkyl, -CF3 oder -(CH2)1-3-CF3 ist; B und C unabhängig ausgewählt sind aus Phenyl-, Pyridinyl-, Pyrimidinyl-, Furyl-, Thienyl- oder Pyrrolyl-Grup- pen, jeweils wahlweise substituiert durch 1 bis 3, vorzugsweise 1 bis 2, Substituenten unabhängig ausgewählt

19 EP 1 907 355 B1

aus H, Halogen, -CN, -CHO, 3, -CF -OCF3, -OH, 1 -C-C6-Alkyl, C1-C6-Alkoxy, -NH2, -N(C1-C6-Al- kyl)2,-NH(C1-C6-Alkyl), -N-C(O) -(C1-C6-Alkyl), -NO2, oder durch einen 5- oder 6-gliedrigen heterocyclischen oder heteroaromatischen Ring, der 1 oder 2 Heteroatome ausgewählt aus 0, N oder S enthält; n eine ganze Zahl von 0 bis 3 ist; 5 n1 eine ganze Zahl von 1 bis 3 ist; n3 eine ganze Zahl von 0 bis 3 ist; n4 eine ganze Zahl von 0 bis 2 ist; 2 X ausgewählt ist aus -0-, -CH2, -S-, -SO-, -SO2, -NH-, -C(O)-,

10

15

20

25

30

R12 ein Ringelement ausgewählt aus Phenyl-, Pyridinyl-, Pyrimidinyl-, Furyl-, Thienyl- oder Pyrrolyl-Gruppen 35 ist, wobei das Ringelement substituiert ist durch eine Gruppe der Formel -(CH 2)n4-CO2H oder ein/en pharmazeutisch akzeptablen/s Säureimitator oder - mimetikum; und auch wahlweise substituiert ist durch 1

oder 2 zusätzliche Substituenten, unabhängig ausgewählt aus H, Halogen, -CN, -CHO, -CF 3, -OCF3, -OH, -C1-C6-Alkyl,C 1-C6-Alkoxy, C 1-C6-Thioalkyl,-NH 2,-N(C 1-C6-Alkyl)2, -NH(C 1-C6-Alkyl), -N-C (0) - (C 1-C6-Al- kyl) oder - NO2; 40 13 R ausgewählt ist aus H, Halogen, -CN, -CHO, -CF 3,-OCF3, -OH, -C1-C6-Alkyl, C1-C6-Alkoxy, C1-C6-Thi- oalkyl,-NH2, -N(C1-C6-Alkyl)2, -NH(C1-C6-Alkyl), -N-C(O)-(C1-C6-Alkyl) oder -NO2; 14 R ausgewählt ist aus H, Halogen, -CN, -CHO, -CF 3,-OCF3, -OH, -C1-C6-Alkyl, C1-C6-Alkoxy, C1-C6-Thi- oalkyl,-NH2, -N(C1-C6-Alkyl)2, -NH(C1-C6-Alkyl), -N-C(O) -(C1-C6-Alkyl), -NO2, -N-C(O) -N(C1-C3-Alkyl)2, -N-C(O)-NH(C1-C3-Alkyl), -N-C(O)-O-(C1-C3-Alkyl), -SO2-C1-C6-Alkyl, -S-C3-C6-Cycloalkyl, -S- 45 CH2-C3-C6-Cycloalkyl, -SO2C3-C6-Cycloalkyl, -SO2-CH2-C3-C6-Cycloalkyl, 3-C C6-Cycloalkyl,- CH2-C3-C6-Cycloalkyl, -O-C 3-C6-Cycloalkyl, -O-CH 2C3-C6-Cycloalkyl, Phenyl, Benzyl, Benzyloxy, Morpho- lino oder anderen Heterocyclen, wie z.B. Pyrrolidino, Piperidin, Piperizinfuran, Thiophen, Imidazol, Tetrazol, Pyrazin, Pyrazolon, Pyrazol, Imidazol, Oxazol oder Isoxazol, wobei die Ringe jeder dieser 14R -Gruppen jeweils wahlweise substituiert sind durch 1 bis 3 Substituenten ausgewählt aus der Gruppe bestehend aus 50 H, Halogen, - CN, -CHO, -CF 3, -OH, -C 1-C6-Alkyl, C1-C6-Alkoxy, -NH2,-N(C1-C6-Alkyl)2, -NH(C1-C6-Alkyl), -N-C (0) - (C1-C6-Alkyl), -NO2, -SO2(C1-C3-Alkyl), -SO2NH(C1-C3-Alkyl),-SO2N(C1-C3-Alkyl2 oder OCF3; oder einer pharmazeutisch akzeptablen Salzform davon; welches das Reagieren einer Verbindung der Formel II:

55 -1 [Ar- (R)z-SO3 ]qMII

wobei:

20 EP 1 907 355 B1

Ar, R und z wie in Anspruch 1 definiert sind; M ein Metallion der Gruppe I oder II ist; q 1 ist, wenn M ein Metallion der Gruppe I ist; oder q 2 ist, wenn M ein Metallion der Gruppe II ist; und 5 mit einem Halogen-Substitutionsreagens in Gegenwart einer katalytischen Menge an Wasser und in Gegenwart eines Co-Katalysators, welcher N,N-Dimethylformamid umfasst, bei einer Temperatur unter Raumtemperatur für eine Zeit und unter Bedingungen, die ausreichend sind für die Bildung einer Ver- bindung der Formel III:

10 Ar-(R)z-SO2-X III

wobei X Halogen ist und Ar, R und z wie in Anspruch 1 definiert sind; und das Umwandeln der Verbindung der Formel III in die Verbindung der Formel (A1) oder eine pharmazeutisch akzeptable Salzform davon durch Reagieren der Verbindung der Formel III mit einer Ver- 15 bindung der Formel (B1) :

20

25

30

wobei R12 ein Ringelement ausgewählt aus Phenyl-, Pyridinyl-, Pyrimidinyl-, Furyl-, Thienyl- oder Pyr- 35 rolyl-Gruppen ist, wobei das Ringelement substituiert ist durch eine Gruppe der Formel -(CH 2)n4-CO2H, wobei die Carboxygruppe wahlweise geschützt ist durch eine Schutzgruppe, und das Ringelement auch wahlweise substituiert ist durch 1 oder 2 zusätzliche Substituenten, unabhängig ausgewählt aus

H, Halogen, - CN, -CHO, -CF3, -OCF3, -OH, -C1-C6-Alkyl, C1-C6-Alkoxy, C1-C6-Thioalkyl, -NH2, 10 13 14 2 -N(C1-C6-Alkyl)2, -NH(C1-C6-Alkyl), -N-C (0) - (C1-C6-Alkyl) oder -NO2; und R , R , R , X , n1, n3 40 und n4 wie oben in Bezug auf Formel (A1) definiert sind, um ein Sulfonamid zu ergeben, und, wenn die Carboxygruppe durch eine Schutzgruppe geschützt ist, das Entfernen der Schutzgruppe aus dem resultierenden Sulfonamid umfasst.

27. Verfahren nach Anspruch 26, wobei R10 Diphenylmethyl ist. 45 28. Verfahren nach Anspruch 26 oder 27, ausgeführt zum Herstellen von 4-(3-{5-Chlor-1-(diphenylmethyl)- 2-[2-({[2-(trifluormethyl)benzyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}propyl)benzoesäure oder eines pharmazeutisch akzeptablen Salzes davon.

50 Revendications

1. Processus synthétique comprenant la réaction d’un composé de Formule II :

55 -1 [Ar- (R)z-SO3 ]qMII

dans laquelle :

21 EP 1 907 355 B1

Ar est du phényle substitué par un seul groupe perhaloalkyle à la position de 2 ce dernier ; R est du méthylène ; M est un ion métallique du Groupe I ou II ; q vaut 1 si M est un ion métallique du Groupe I ; 5 ou q vaut 2 si M est un ion métallique du Groupe II ; et z vaut 1 ; avec un réactif de substitution d’halogène en présence d’une quantité catalytique d’eau et en présence d’un co-catalyseur comprenant du N,N-diméthylformamide à une température au-dessous de la température ambiante pendant un temps suffisant pour former un composé de Formule III : 10

Ar-(R)z-SO2-X III

dans laquelle X est de l’halogène et Ar, R et z sont tels que précédemment définis.

15 2. Processus selon la revendication 1, dans lequel ladite réaction dudit composé de Formule II avec ledit réactif de substitution d’halogène est effectuée dans un système de solvant comprenant un solvant sélectionné à partir du groupe constitué par un solvant organique aprotique.

3. Processus selon la revendication 2, dans lequel ledit système de solvant comprend un ou plusieurs de tétrahydro- 20 furanne, acétonitrile, N,N-diméthylformamide, dioxane, acétone, toluène, chlorure de méthylène, 1,2-di-chloroétha- ne, éther méthylique de t-butyle, ou éther éthylique.

4. Processus selon la revendication 2, dans lequel ledit système de solvant comprend du tétrahydrofuranne.

25 5. Processus selon la revendication 1, 2, 3 ou 4, dans lequel ladite réaction dudit composé de Formule II avec ledit réactif de substitution d’halogène est effectuée à une température de moins de 5 °C.

6. Processus selon la revendication 1, 2, 3, 4 ou 5, dans lequel le rapport de molaire de ladite quantité catalytique d’eau sur ledit composé de Formule II est inférieur à 0,5:1. 30 7. Processus selon la revendication 1, 2, 3, 4, 5 ou 6, dans lequel le rapport molaire de ladite quantité catalytique d’eau sur ledit composé de Formule II a une valeur de 0,2 à 0,4.

8. Processus selon la revendication 1, 2, 3, 4, 5, 6 ou 7, dans lequel le rapport de molaire de ladite quantité catalytique 35 d’eau sur ledit composé de formule II est 0,3.

9. Processus selon n’importe laquelle des revendications 1 à 8, dans lequel ledit réactif de substitution d’halogène comprend du SOCl2, POCl3, CCl4/triphénylphosphine, chlorure d’oxalyle ou bromure d’oxalyle.

40 10. Processus selon n’importe laquelle des revendications 1 à 9, dans lequel ledit réactif de substitution d’halogène comprend du chlorure d’oxalyle.

11. Processus selon n’importe laquelle des revendications 1 à 10, dans lequel le rapport molaire dudit réactif de substitution d’halogène sur ledit composé de Formule II est de 1,2 ou plus élevé. 45 12. Processus selon n’importe laquelle des revendications 1 à 11, dans lequel Ar est du 2-trifluorométhylphényle.

13. Processus selon n’importe laquelle des revendications 1 à 12, dans lequel X est du Cl.

50 14. Processus selon n’importe laquelle des revendications 1 à 13, dans lequel M est un ion Na + ou un ion K+.

15. Processus selon n’importe laquelle des revendications 1 à 14, dans lequel M est un ion Na +.

16. Processus selon n’importe laquelle des revendications 1 à 15, dans lequel : 55 ledit co-catalyseur est du N,N-diméthylformamide ; ledit réactif de substitution d’halogène est du chlorure d’oxalyle ; et le rapport molaire de ladite quantité catalytique d’eau sur ledit composé de Formule II a une valeur entre 0,2 et 0,4.

22 EP 1 907 355 B1

17. Processus selon la revendication 1 comprenant en outre la réaction dudit composé de Formule III avec un réactif d’amine de manière facultative en présence d’une base pendant un temps et sous des conditions suffisantes pour former un composé de Formule I :

5 4 5 Ar- (R)z-SO2-NR R I

dans laquelle :

4 5 R et R sont chacun, indépendamment, H, alkyle en C 1-C16, alcényle en C 2-C13, alcynyle en C 2-C13, cycloalkyle 10 en C3-C13, hétérocycloalkyle, aryle ou hétéroaryle, chacun remplacé de manière facultative par jusqu’à cinq substituants indépendamment sélectionnés à partir du groupe constitué par l’halogène, alkyle en 1C-C6, cycloalkyle en C 3-C7, hétérocycloalkyle, cyano, nitro, OH, alcoxy en C 1-C6, halogénoalkyle en C 1-C6, halogénoal- coxy en C1-C6, aryle et hétéroaryle ; ou R4 et R 5, ensemble avec l’atome d’azote auquel ils sont attachés, peuvent former un composé hétérocyclique 15 à 5 ou à 6 éléments et Ar, R et z sont tels que définis dans la revendication 1.

18. Processus selon la revendication 17 comprenant en outre l’enlèvement ou la destruction du réactif de substitution d’halogène en excès avant la réaction dudit composé de Formule III avec ledit réactif d’amine.

20 19. Processus selon la revendication 18, dans lequel ladite destruction dudit réactif de substitution d’halogène en excès est facilitée en ajoutant un réactif chimique ; dans lequel ledit réactif chimique est de l’eau.

20. Processus selon n’importe laquelle des revendications 17 à 19, dans lequel ladite réaction dudit composé de Formule III avec ledit réactif d’amine est effectuée à une température de moins de -10 °C. 25 21. Processus selon n’importe laquelle des revendications 17 à 20, dans lequel le réactif d’amine a la Formule HNR 4R5, dans lequel R4 et R5 sont tels que définis dans la revendication 17.

22. Processus selon n’importe laquelle des revendications 17 à 21, dans lequel ledit réactif d’amine est du NH3 ou 30 NH4OH.

23. Processus selon la revendication 22, dans lequel ledit réactif d’amine est de l’ammoniac gazeux, et ladite réaction dudit composé de Formule III avec ledit réactif d’amine est effectuée dans un système de solvant comprenant un solvant organique et une petite quantité d’eau. 35 24. Processus selon n’importe laquelle des revendications 17 à 23, comprenant en outre l’isolement dudit composé de Formule I.

25. Processus selon n’importe laquelle des revendications 17 à 24, dans lequel ledit composé de Formule I est formé 40 sans isolement dudit composé de Formule III.

26. Processus pour la préparation d’un composé de Formule (A1) :

45

50

55

23 EP 1 907 355 B1

5

10

15

20 dans laquelle :

Ar, R et z sont tels que définis dans la revendication 1 ; R10 est sélectionné à partir des formules -(CH 2)n-A, -(CH2)n-S-A, ou -(CH 2)n-O-A, dans lesquelles A est sélec- 25 tionné à partir des fractions :

30

35

dans lesquelles :

D est alkyle en C1-C6, alcoxy en C1-C6, cycloalkyle en C3-C6, -CF3 ou -(CH2)1-3-CF3 ; 40 B et C sont indépendamment sélectionnés à partir de groupes phényle, pyridinyle, pyrimidinyle, furyle, thiényle ou pyrrolyle, chacun remplacé de manière facultative par de 1 à 3, de préférence 1 à 2, substituants

sélectionnés indépendamment à partir de H, halogène, -CN, -CHO, -CF3, -OCF3, -OH, alkyle en C1-C6, alcoxy en C1-C6, -NH2, -N (alkyle en C1-C6)2, -NH(alkyle en C1-C6), -N-C(O)-(alkyle en C1-C6), -NO2, ou par un composé hétérocyclique ou hétéroaromatique à 5 ou à 6 éléments contenant 1 ou 2 hétéroatomes 45 sélectionnés à partir de 0, N ou S ; n est un entier de 0 à 3 ;

n1 est un entier de 1 à 3 ; n3 est un entier de 0 à 3 ; n4 est un entier de 0 à 2 ; 50 2 X est sélectionné à partir de -O-, -CH 2-, -S-, -SO-, -SO2-, -NH-, -C(O)-,

55

24 EP 1 907 355 B1

5

10

15

20 R12 est une fraction de noyau sélectionnée à partir de groupes phényle, pyridinyle, pyrimidinyle, furyle, 2 thiényle ou pyrrolyle, la fraction de noyau étant substituée par un groupe de la formule -(CH )n4-CO2H ou un mimique ou un mimétique d’acide acceptable d’un point de vue pharmaceutique ; et également substitué de manière facultative par 1 ou 2 substituants supplémentaires indépendamment sélectionnés à partir de

H, halogène, -CN, -CHO, -CF3, -OCF3, -OH, alkyle en C1-C6, alcoxy en C1-C6, thioalkyle en C1-C6, -NH2, 25 -N (alkyle en C1-C6)2, -NH (alkyle en C1-C6), -N-C(O)-(alkyle en C1-C6), ou -NO2 ; 13 R est sélectionné à partir de H, halogène, -CN, -CHO, -CF3, -OCF3, -OH, alkyle en C1-C6, alcoxy en C1-C6, thioalkyle en C 1-C6, -NH2, -N (alkyle en C 1-C6)2, -NH (alkyle en C 1-C6), -N-C(O)- (alkyle en C 1-C6), ou -N02 ; 14 R est sélectionné à partir de H, halogène, -CN, -CHO, -CF3, -OCF3, -OH, alkyle en C1-C6, alcoxy en 30 C1-C6, thioalkyle en C1-C6, -NH2, -N (alkyle en C 1-C6)2, -NH (alkyle en C1-C6), -N-C(O)-(alkyle en C1-C6), -NO2, -N-C(O)-N(alkyle en C 1-C3)2, -N-C(O)-NH (alkyle en C 1-C3), -N-C(O)-O-(alkyle en C 1-C3), -SO 2-alkyle en C1-C6, -S-cycloalkyle en C3-C6, -S-CH2-cycloalkyle en C3-C6, -SO2-cycloalkyle en C3-C6, -SO2-CH2- cycloalkyle en C 3-C6, cycloalkyle en C 3-C6, -CH2- cycloalkyle en C 3-C6, -O-cycloalkyle en C 3-C6, -OCH2-cycloalkyle en C 3-C6, phényle, benzyle, benzyloxy, morpholino ou d’autres composés hétérocycliques comme 35 pyrrolidino, pipéridine, pipérazine, furanne, thiofène, imidazole, tétrazole, pyrazine, pyrazolone, pyrazole, imidazole, oxazole ou isoxazole, les noyaux de chacun de ces groupes R14 étant chacun substitués de manière facultative par de 1 à 3 substituants sélectionnés à partir du groupe de H, halogène, -CN, -CHO, -CF3, -OH, alkyle en C1-C6, alcoxy en C1-C -NH2, -N (alkyle en C1-C6)2, -NH (alkyle en C1-C6), -N-C(O)- (alkyle en C1-C6), -NO2, -SO2(alkyle en C1-C3), -SO2NH (alkyle en C1-C3), -SO2N (alkyle en C1-C3)2, ou 40 OCF3 ; ou une forme de sel de ceux-ci acceptable d’un point de vue pharmaceutique ; qui comprend la réaction d’un composé de Formule II :

-1 [Ar-(R)z-SO3 ]qMII 45 dans laquelle :

Ar, R et z sont tels que définis dans la revendication 1 ; M est un ion métallique du Groupe I ou II ; 50 q vaut 1 si M est un ion métallique du Groupe I ; ou q vaut 2 si M est un ion métallique du Groupe II ; et

avec un réactif de substitution d’halogène en présence d’une quantité catalytique d’eau et en présence d’un co-catalyseur comprenant du N,N-diméthylformamide à une température au-dessous de la température 55 ambiante pendant un temps et sous des conditions suffisantes pour former un composé de Formule III :

Ar-(R)z-SO2-X II

25 EP 1 907 355 B1

dans laquelle X est de l’halogène et Ar, R et z sont tels que définis dans la revendication 1 ; et la transformation du composé de Formule III en composé de Formule (A1) ou une forme de sel de ce dernier acceptable d’un point de vue pharmaceutique, en faisant réagir le composé de formule III avec un composé de Formule (B1) : 5

10

15

20

25 dans laquelle R12 est une fraction de noyau sélectionnée à partir des groupes phényle, pyridinyle, pyrimidinyle, furyle, thiényle ou pyrrolyle, la fraction de noyau étant substituée par un groupe de la formule

-(CH2)n4-CO2H dans laquelle le groupe carboxy est protégé de manière facultative par un groupe de protection et la fraction de noyau étant également substituée de manière facultative par 1 ou 2 substituants 30 supplémentaires indépendamment sélectionnés à partir de H, halogène, -CN, -CHO, -CF3, -OCF3, -OH, alkyle en C1-C6, alcoxy en C1-C6, thioalkyle en C1-C6, -NH2, -N (alkyle en C1-C6)2, -NH (alkyle en C1-C6), 10 13 14 2 -N-C(O)-(alkyle en C1-C6), ou -NO2 ; et R , R , R , X , n1, n3 et n4 sont tels que précédemment définis en relation à la formule (A1) pour donner un sulfamide et, si le groupe carboxy est protégé par un groupe de protection, le groupe de protection est enlevé du sulfamide résultant. 35 27. Processus selon la revendication 26, dans lequel R 10 est du diphénylméthyle.

28. Processus selon la revendication 26 ou 27 effectué pour préparer de l’acide 4-(3-{5-chloro-1-(diphénylméthyl)- 2-[2-({[2-(trifluorom éthyl)benzyl]sulfonyl}amino)éthyl]-1H-indol-3-yl}propyl)benzoïque ou un sel de ce dernier ac- 40 ceptable d’un point de vue pharmaceutique.

45

50

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26 EP 1 907 355 B1

REFERENCES CITED IN THE DESCRIPTION

This list of references cited by the applicant is for the reader’s convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.

Patent documents cited in the description

• US 70115805 P [0001] • US 2005009746 W [0012] • WO 2003048122 A [0005] [0012] • WO 2005097727 A [0012] • US 2002038311 W [0012] • US 2005029338 W [0012] • US 2004023247 W [0012] • WO 2006023611 A [0012] • WO 2005012238 A [0012] • US 93053404 A [0012] • US 2004038335 W [0012] • US 94800404 A [0012] • WO 2005049566 A [0012] • US 44219906 A [0012] • US 2005005624 W [0012] • US 6797708 B [0081] • WO 2005082843 A [0012] [0016]

Non-patent literature cited in the description

• MARCH. Advanced Organic Chemistry. John Wiley • WIDLANSKI et al.Tet. Lett., 1992, vol. 33, & Sons, 1992, 499 [0004] 2657-2660 [0004] • NAKAYAMA et al. Tet Lett.,1984, vol. 25, 4553-4556 [0004]

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