MXPA06009658A - Processes for the preparation of aryl-and heteroaryl-alkylsulfonyl halides - Google Patents

Abstract

The present invention provides processes for the preparation of arylalkylsulfonyl halides and heteroarylalkylsufonyl halides of Formula:Ar-R-SO2-X, that are useful as intermediates in the preparation of pharmaceuticals.

Description

PROCEDURES FOR THE PREPARATION OF HALOGENURS OF ARIL- AND HETEROARILALQUILSULFONILO FIELD OF THE INVENTION The present invention relates to processes for preparing arylalkylsufonyl halides and heteroarylalkylsulfonyl halides, useful as intermediates in the preparation of pharmaceutical agents, for example.

BACKGROUND OF THE INVENTION Sulfonyl chlorides are widely used in the chemical industry, for example for the preparation of dyes, lithographic protective substances and pharmaceutical agents. 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, for example, "Kirk-Othmer Encyclopedia of Chemical Technology". Sulfonamides are integral functional groups of a wide variety of small molecule drugs, such as antibacterial agents, diuretics and cPLA2 inhibitors. A typical sulfonyl chloride preparation includes the reaction of the sodium salt of a sulfonic acid with phosphorus pentachloride, sometimes in combination with phosphorus oxychloride or thionyl chloride, often with heating of the reaction mixture (see, for example. , March, "Advanced Organic Chemistry", 4th ed., John Wiley &Sons, 1992, p.499). These relatively harsh reaction conditions are not suitable for the preparation of sterically hindered sulfonyl chlorides, such as arylalkylsulfonyl chlorides and the like, which can produce low yields due to the removal of sulfur dioxide (Nakayama et al., Tet Lett., 1984). , 25, 4553-4556). A milder method rarely used for the synthesis of sulfonyl chlorides is the reaction of tetrabutylammonium salts of sulfonic acids with triphenylphosphine / sulfonyl chloride (Widlanski et al., Tet Lett., 1992, 33, 2657-2660), a method that has the disadvantage of a poor atomic efficiency. Many sterically hindered sulfonyl halides, such as (2,6-dimethylphenyl) methanesulfonyl chloride and other aryl- and heteroarylsulfonyl halides, are specifically useful in the preparation of cPLA2 inhibitors for the treatment of asthma or arthritic and rheumatic disorders, such as it is described, for example, in WO 2003/048122. As discussed above, it can be difficult to prepare these intermediates due to the loss of sulfur dioxide at high temperatures and the formation of significant amounts of impurities. In this way, new and improved methods of preparing these compounds are required, and the methods provided herein help to meet these and other needs.

BRIEF DESCRIPTION OF THE INVENTION In some embodiments, the present invention provides processes for preparing a compound of formula I: Ar-R-SO2-XI wherein: Ar is aryl or heteroaryl optionally substituted with one or more substituents, preferably up to five substituents, which are selected from the group consisting of halogen, C?-C6 alkyl, C3-C7 cycloalkyl, heterocycloalkyl, formyl, cyano, nitro, OH, d-Cß alkoxy, arylalkyloxy, C haloß haloalkyl, CrC 3 perhaloalkyl, Ci-Cß haloalkoxy , perhaloalkoxy of C C3l NR1R2, NR1COR3, aryl, aryloxy, heteroaryl and heteroaryloxy; R is C-C6 alkylenyl; R1 and R2 are each, independently, H, C? -C6 alkyl or C3-C7 cycloalkyl; or R1 and R2 together with the N atom to which they are attached form a 5- or 6-membered heterocycium; R3 is H, C -? - C-6 alkyl or C3-C7 cycloalkyl; and X is halogen; comprising: (a) reacting a compound of formula II: Ar-R-L wherein L is a leaving group, with a metal sulphite salt of group I or II, optionally in the presence of a phase transfer catalyst, for a time and under conditions sufficient to form a sulfonic acid salt compound of formula lll: (Ar-R-SO3"1) qM lll where M is a metal ion of group I or II, where q is 1 when M is a metal ion of group I, and q is 2 when M is a metal ion of group II. (b) reacting said compound of formula III with a protic acid, for a time and under conditions sufficient to form a sulfonic acid compound of formula IV: Ar-R-SO3H IV and (c) reacting said compound of formula IV with a halogen substitution reagent, for a time and under conditions sufficient to form said compound of formula I. In some embodiments, the reaction of step (a) is carried out in a solvent comprising water. In some embodiments, the reaction of step (a) is carried out without the presence of a phase transfer catalyst. In further embodiments, the reaction of step (a) is carried out in the presence of a phase transfer catalyst. In further embodiments, the reaction of step (a) is carried out in a solvent comprising water and in the presence of a phase transfer catalyst. In some embodiments, the compound of formula III is isolated, preferably by precipitating the compound of formula III and optionally filtering the resulting precipitate. In some embodiments, the precipitation of the compound of formula I is induced by (1) the addition of a water-soluble metal halide salt, which is preferably NaCl.; (2) the addition of a solvent that is substantially immiscible with water, which is preferably ethyl acetate; or both (1) and (2). In some embodiments, the protic acid of step (b) is an inorganic acid, which is preferably HCl, HBr, H3PO, HNO3, HCI04, or H2SO4, or a combination thereof. In some preferred embodiments, the protic acid from step (b) is HCl. In some embodiments, the protic acid is gaseous HCl added to the reaction mixture or to the solvent containing the compound of formula III. In some embodiments, the reaction of step (b) is carried out in a solvent comprising an alcohol, which is preferably methanol. In some embodiments, the compound of formula IV is isolated, preferably by precipitating the compound of formula IV, and optionally filtering the resulting precipitate. In some embodiments, the compounds of formula III and formula IV are isolated.

In some embodiments, the halogen substitution reagent is SOCI2, POCI3, CCI / triphenylphosphine, oxalyl chloride or oxalyl bromide, preferably oxalyl chloride. In some embodiments, the reaction of step (c) is carried out in the presence of an acyl transfer catalyst, which is preferably a tertiary amide, preferably N, N-dimethylformamide. In further embodiments, the invention provides processes for preparing a compound of formula IV: Ar-R-SO 3 H IV wherein: Ar and R are as defined above; which comprises: (a) reacting in a solvent a compound of formula II: Ar-RL II wherein L is as defined above, with a metal sulphite salt of group I or II, optionally in the presence of a phase transfer, for a time and under conditions sufficient to form a sulfonic acid salt of formula III: (Ar-R-SO3"1) qM lll where M and q are as defined above, and (b) react said compound of formula III with a protic acid, for a time and under conditions sufficient to form said compound of formula IV In some embodiments, the compound of formula III is isolated by precipitating the compound of formula III, and optionally filtering. preferred embodiments, precipitation is facilitated by (1) treating the reaction mixture of step (a) with a water-soluble metal halide salt, which is preferably NaCl, or (2) by adding to the reaction mixture of step (a) ) a solvent that which is substantially immiscible in water, which is preferably ethyl acetate; or both (1) and (2). In some embodiments, the reaction of step (a) is carried out in a solvent comprising water. In further embodiments, the reaction of step (a) is carried out in the presence of a phase transfer catalyst. In further preferred embodiments, the reaction of step (b) is carried out in a solvent comprising an alcohol, which is preferably methanol. In some preferred embodiments, the protic acid from step (b) is HCl, preferably gaseous HCl added to the solvent containing the compound of formula III. In additional embodiments, the present invention provides processes for preparing a compound of formula III: (Ar-R-SO3-1) qM lll wherein M is a metal ion of group I or II, where q is 1 when M is a metal ion of group I, and q is 2 when M is a metal ion of group II. Ar is aryl or heteroaryl optionally substituted with one or more substituents, preferably up to five substituents, which are selected from the group consisting of halogen, Ci-Cß alkyl, C 3 -C 7 cycloalkyl, heterocycloalkyl, formyl, cyano, nitro, OH, CI-CT alkoxy, arylalkyloxy, C-? -C-6 haloalkyl, C-C3 haloalkoxy Ci-C? haloalkoxy, CrC3 perhaloalkoxy, NR1R2, NR1COR3, aryl, aryloxy, heteroaryl and heteroaryloxy; R is alkylenyl of CrC6; R1 and R2 are each independently selected from the group consisting of H, C-pCß alkyl and C3-C7 cycloalkyl; or R1 and R2 together with the N atom to which they are attached form a 5- or 6-membered heterocycle; and R3 is selected from the group consisting of H, C6 alkyl, and C3-C7 cycloalkyl; comprising: reacting a compound of formula II: Ar-RL II wherein L is a leaving group, with a metal sulphite salt of group I or II, optionally in the presence of a phase transfer catalyst, for a time and under conditions sufficient to form a reaction mixture containing said compound of formula III; and isolating said compound of formula III by precipitating the compound of formula III from the reaction mixture. In some embodiments, precipitation is facilitated by (1) treating the reaction mixture with a water-soluble metal halide salt, which is preferably NaCl; or (2) adding to the reaction mixture a solvent that is substantially immiscible in water, which is preferably ethyl acetate; or both (1) and (2). In some embodiments, the reaction is carried out in a solvent comprising water, preferably in the presence of a phase transfer catalyst. In some embodiments of each of the above processes, the metal halide salt of water soluble metal is NaCl. In additional embodiments of each of the above processes, the phase transfer catalyst is tetrabutylammonium iodide. In additional embodiments of each of the above processes, the compound of formula II, for example 2,6-dimethylbenzyl chloride or 2,6-dimethylbenzyl bromide, is reacted with Na 2 SO 3. In additional embodiments of some of the above processes, the alcohol solvent to which the protic acid is added is methanol. In additional embodiments of some of the above processes, the protic inorganic acid is gaseous HCl. In further embodiments, the compound of formula IV is isolated by evaporation of the alcohol solvent. In some embodiments of the above processes, the reaction of the sulfonic acid species of formula IV, for example 2,6-dimethylbenzyl sulfonic acid, with the halogen substitution reagent, for example oxalyl chloride, is carried out at less than about - 10 ° C during the addition of oxalyl chloride. Suitable solvents for this reaction include, for example, an ether (for example tetrahydrofuran), or a mixture of ethers. In some embodiments of the above processes, Ar is phenyl optionally substituted with one or more substituents independently selected from halogen, C-pCβ alkyl, C3-C7 cycloalkyl, heterocycloalkyl, cyano, nitro, OH, Ci-Cß alkoxy, haloalkyl of C C6, haloCalkoxy of CrC6, NR1R2, NR1COR3, aryl and heteroaryl; preferably the substituents are independently selected from C6 alkyl, C6 alkoxy, halogen, CN, NO2, NR1R2 and NR1COR3. In some preferred embodiments, Ar is phenyl substituted with one or more halogen substituents, C? -C6 alkyl, CrC3 perhaloalkyl, formyl, or arylalkyloxy. In some embodiments, Ar is phenyl substituted with at least one substituent at the 2-position or the 6-position, or substituents at both the 2-position and the 6-position. In other embodiments, Ar is phenyl substituted at the 3-position and the position 4, such as for example 3,4-dichlorophenyl. In some additional embodiments of the above processes, R is C? -C alkylene or straight chain C6 alkylene, preferably methylene or ethylene, preferably methylene. In some embodiments of the above processes, L is independently halogen, OS02CH3, OSO2CF3 or OSO2-aryl, wherein aryl is a phenyl group optionally substituted with 1, 2 or 3 substituents, independently selected from d-C3 alkyl and halogen.

Preferably, L is Cl. In some embodiments of the above processes, M is the Na + or the K + ion, preferably the Na + ion. In some preferred embodiments of the above processes, X is Cl. In some further preferred embodiments of the above processes, Ar is phenyl optionally substituted with one or more substituents selected from halogen, Ci-Cß alkyl, C C3 perhaloalkyl, formyl, Arylalkyloxy, NR1R2 and NR1COR3; R is methylene or ethylene; R1 and R2 are each, independently, H or C-pCe alkyl; R3 is H or CrC6 alkyl; X is Cl; L is halogen; the metal sulphite salt of step (a) is Na2S03; the phase transfer catalyst of step (a) is present; the sulfonic acid salt compound of formula III has the formula NaSO 3 -R-Ar; step (a) also comprises isolating the compound of formula III; step (b) also comprises isolating the compound of formula IV; and the halogen substitution reagent of step (c) is oxalyl chloride. In other preferred embodiments of the methods of the present invention, step (a) is carried out without the presence of a phase transfer catalyst. In some of these embodiments, the Ar-R-L of formula II is 2,3-dichlorobenzyl chloride, and the compound of formula I is (2,3-dichlorophenyl) -methanesulfonyl chloride. In other preferred embodiments, the methods of the present invention are used to prepare (3,4-dichlorophenyl) -methanesulfonyl chloride, (2,6-dimethylphenyl) -methanesulfonyl chloride, (2-methylphenyl) -methanesulfonyl chloride , (2,6-difluorophenyl) -methanesulfonyl chloride, 2-fluoro-6- (trifluoromethylphenyl) -methanesulfonyl chloride, 2,6-bis (trifluoromethylphenyl) -methanesulfonyl chloride, (2-trifluoromethylphenyl) -methanesulfonyl chloride, (2-benzyloxyphenyl) -methanesulfonyl chloride, (2,3-dichlorophenyl) -methanesulfonyl chloride, or (2-formylphenyl) -methanesulfonyl chloride.

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a process for the preparation of aryl- and heteroarylalkylsulfonyl halides, which include (2,6-dimethyl-phenyl) -methanesulfonyl chloride, an intermediate in the synthesis of some cPLA2 inhibitors. In some embodiments, the methods generally include the formation of sulfonic acid prior to conversion to the sulfonyl halide. Scheme I gives a general outline of some embodiments of the methods of the present invention, wherein the constituent members of the compounds represented in formulas I, II, III and IV are as defined above.

SCHEME 1 Metal sulphite salt of group I or II Ar-R-L • * - (A? -R-SQ3) qM II? "» 1? Ll Step 2 Protic acid Step 3 Ar-R-S02-X - * - Ar-R-S03H 1 TV reagent halogenation As shown in scheme 1, the sulphonic acids of formula IV can be converted to sulfonyl halides by reaction with a halogen substitution reagent. Halogen substitution reagents, as used herein, are reagents that can convert a non-halogen substituent (such as for example H or OH) to a halogen substituent. The halogen substitution reagents of the present invention can convert, for example, a portion of sulfonic acid to a portion of sulfonyl halide. Many reagents capable of carrying out this conversion are known. Some preferred halogen substitution reagents include SOCI2, POCI3, CCI / triphenylphosphine, oxalyl chloride or oxalyl bromide. In some more preferred embodiments, the halogen substitution reagent is oxalyl chloride. The halogen substitution agent is preferably used in an excess amount, particularly if there is residual solvent in the starting material, solvents, or both. When oxalyl chloride is used as the halogen substitution agent, it can be used on a scale from about 1 to about 6 equivalents, from about 2 to about 4 equivalents, or from about 3 to about 3.5 equivalents, with respect to the amount of sulfonic acid reagent (the compound of formula IV). The person skilled in the art will recognize that the amount used of the halogen substitution agent will depend, among other things, on the amount of water in the starting material or solvent, and on the nature and reactivity of the starting material and the solvents. Suitable solvents for the halogen substitution reaction (e.g., step 3 of scheme I) include any organic solvent that can at least partially dissolve the compound of formula IV. Preferred solvents include non-polar or weakly polar solvents, including acetonitrile, aromatic hydrocarbons such as benzene and toluene, and halogenated solvents such as 1,2-dichloroethane and methylene chloride. The most preferred solvents are the ethers. Suitable ethers include tetrahydrofuran, dioxane, diethyl ether, dibutyl ether, diisopropyl ether, or mixtures thereof, and the like. A highly preferred ether is tetrahydrofuran. The halogen substitution reaction can be carried out at any suitable temperature. For example, in some preferred embodiments, the reaction can be carried out at about -40 ° C at room temperature. In some more preferred embodiments, the reaction can be carried out below about -10 ° C. The sulfonyl halide formation step of the methods of the invention (for example step 3 of scheme I) can also be carried out in the presence of an acyl transfer catalyst, such as a tertiary amide (for example dimethylformamide). The acyl transfer catalyst can be provided in an amount sufficient to accelerate the reaction rate. In preferred embodiments, the acyl transfer catalyst is present in an amount of less than about 1 equivalent with respect to the amount of sulfonic acid reagent. In more preferred embodiments, the acyl transfer catalyst is present in an amount of about 0.01 to about 0.5 equivalents; preferably from about 0.1 to about 0.2 equivalents with respect to the amount of sulfonic acid reagent. The compounds of formula I can be isolated from the reaction mixture by means of precipitation and filtration. Any method of the many known ones can be used to induce precipitation. In some preferred embodiments, an antisolvent such as water or a solvent containing water may be added to the reaction mixture to induce precipitation. It has been observed that the use of water as an antisolvent can reduce the rate of decomposition of the sulfonyl halide product, with respect to the rate of decomposition observed when an organic solvent such as heptane is used, producing better yields. In some more preferred embodiments, precipitation can be facilitated by reducing the temperature of the reaction mixture, for example, to less than about -20 ° C. As shown in scheme I, sulfonic acids of formula IV can be prepared by reacting sulfonic acid salts (sulfonate salts) of formula III with a protic acid. Suitable protic acids are of sufficient strength to convert a sulfonate salt to its corresponding acid according to the methods of the invention. For example, the protic acid may be a strong inorganic acid, such as HCl, HBr, H3PO4, HNO3, HCIO4, H2SO4, and the like. In other embodiments, the protic acid may be an organic acid. Examples of organic acids include formic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, trifluoroacetic acid and other organic acids. In some embodiments, protic acid is provided in gaseous form. In some preferred embodiments, the inorganic acid is HCl. In some more preferred embodiments, the inorganic acid is gaseous HCl which is added to the reaction solvent containing the sulfonate salt. In a preferred embodiment, the protic acid is provided in an excess of molar equivalents with respect to the sulfonic acid salt of formula III. The formation of the sulfonic acid compound of formula IV can be carried out in any suitable solvent. For example, organic solvents in which the compound of formula III is at least partially soluble are suitable. In some preferred embodiments, the solvent barely dissolves the metal halide salts, such as NaCl or KCl, thereby thermodynamically driving the reaction by precipitation of the metal halide salt. In additional preferred embodiments, the solvent may contain an alcohol such as methanol, ethanol, isopropanol and the like, or a mixture thereof. The solvent may also contain water. In still more preferred embodiments, the solvent contains methanol. The reaction temperature can be easily determined by the person skilled in the art. For example, the reaction can be carried out at a temperature below room temperature, for example from about -20 ° C to about 10 ° C. In some preferred embodiments, the reaction is carried out at a temperature from about 0 ° C to about 10 ° C. The sulfonic acid compound of formula IV can be isolated according to routine methods. The isolation can be effected, for example, by precipitating the product from the reaction mixture. Precipitation can be induced by any suitable means. In some preferred embodiments, precipitation can be induced by concentration of the reaction mixture (optionally made azeotropic), cooling (for example to less than about 10 ° C), addition of a non-polar organic solvent, such as an alkane (eg example heptane, hexane, pentane, etc.), or a mixture of these methods. The present invention also provides a process for preparing a sulfonic acid salt (sulfonate salt) of formula III, by reacting a compound of formula II: Ar-R-L (wherein Ar, R and L are as defined above), with a metal sulphite salt of group I or II, optionally in the presence of a phase transfer catalyst as shown in step 1 of scheme I above. Any metal sulphite salt of group I or II is suitable, for example and without limitation, Li2SO3, Na2SO3, K2SO3, MgSO3, CaSO3, and the like. Metal sulphite salts of group I or II can be supplied in a molar excess of for example about 2 eq to about 1 eq, with respect to the amount of compound of formula II. In some preferred embodiments, the metal salt is Na2SO3 or K2SO3, preferably Na2SO3. In a preferred embodiment, the formation of the sulfonate salt compounds of formula III can be carried out in the presence of a phase transfer catalyst. In some preferred embodiments, the phase transfer catalyst is a quaternary ammonium halide, preferably tetrabutylammonium iodide. The phase transfer catalyst can be provided in a suitable amount to accelerate the reaction rate. In some preferred embodiments, the phase transfer catalyst is present in an amount of 0.1% to 2%, or preferably 0.5% to 1% by weight. Any suitable solvent may be employed, such as a solvent which can at least partially dissolve the metal sulphite salts of group I or II. In some embodiments, the solvent contains water. In some preferred embodiments, the solvent contains more than about 50%, preferably about 75%, preferably more than about 90%, preferably more than about 95%, and most preferably more than about 99% of water. The reaction can be carried out at any suitable temperature. In some preferred embodiments, the temperature is high. In highly preferred embodiments, the reaction is carried out at 100 ° C. The isolation of the compound of formula III from the reaction mixture can be carried out by any routine method. In some embodiments, the compound of formula III is precipitated from the reaction mixture. In some preferred embodiments, precipitation is facilitated, for example, by treatment of the reaction mixture with a water-soluble inorganic salt. Although no particular theory is intended to be limited, it is believed that the addition of a sufficient amount of a water-soluble inorganic salt thermodynamically drives the compound of formula III out of solution, thus facilitating isolation and purification. In some preferred embodiments, the water soluble inorganic salt is NaCl or KCl, preferably NaCl. In further embodiments, the isolation of the compound of formula III can be further facilitated by adding an organic solvent substantially immiscible with water to the reaction mixture. Examples of suitable solvents include ethyl acetate, ethers (for example ethyl ether and the like), alkanes (for example hexane, petroleum ether, etc.), aromatics (for example benzene, toluene, xylene, etc.) and the like, with ethyl acetate being very preferred. Again, while it is not the intention to limit any particular theory, it is believed that the addition of an organic solvent helps to keep the impurities in solution when the compound of formula III is precipitated. In some preferred embodiments, the reaction mixture may also be cooled (e.g. to less than about 10 ° C), to help induce precipitation. Many advantages of the present invention will be apparent to the person skilled in the art. For example, the preparation of the sulfonic acid intermediate prior to the formation of the sulfonyl halide, allows to improve the yield, avoiding the loss of sulfur dioxide normally observed in the preparation of sterically hindered sulphonyl halides. Additionally, the preparation and isolation methods described herein help maximize yields. In some embodiments of the invention multi-step procedures are performed in a stepped manner, and each intermediary is isolated before proceeding to the next step. In other embodiments of the invention some of the intermediates are isolated and others are not. In other embodiments none of the intermediates is completely isolated, and not all reactions are carried out in a single reactor vessel. In the above generic description and for other groups described herein it is understood that, in each case, any variable group can be substituted independently with the admitted groups. Thus, for example, when describing a structure where two R2 groups are present simultaneously in the same compound, the two R2 groups may represent different groups. It is appreciated that some features of the invention, which for clarity are described in the context of separate embodiments, can also be provided combined in a single embodiment. Conversely, various features of the invention which for brevity are described in the context of a single embodiment, may also be provided separately or in any suitable subcombination. Unless otherwise indicated, the term "alkyl" employed is herein defined only as a straight or branched chain saturated hydrocarbon portion. In some embodiments, the alkyl portion contains from 1 to 12, from 1 to 10, from 1 to 8, from 1 to 6, or from 1 to 4 carbon atoms. Examples of saturated alkyl hydrocarbon portions include, without limitation, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, fer-butyl, isobutyl, sec-butyl; higher homologs such as n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. The term "alkylenyl" refers to a bivalent straight or branched chain alkyl group. 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, C F5, CCI3, C2CI5, and the like, and groups that have a minor substitution for perhalogen, such as CHF2, CHCI2, and the like. The term "perhaloalkyl" denotes an alkyl group in which all hydrogen atoms are replaced with halogen atoms. The term "alkoxy" used alone or in combination with other terms, unless otherwise indicated, is defined herein as -O-alkyl. Examples of alkoxy moieties include, without limitation, chemical groups such as methoxy, ethoxy, iopropoxy, sec-butoxy, tert-butoxy, and homologs, isomers, and the like. Unless otherwise indicated, the term "haloalkoxy", used alone or in combination with other terms, is defined herein as -O-haloalkyl. Examples of haloalkoxy moieties include, without limitation, chemical groups such as -OCF3 and the like. Unless otherwise indicated, the term "cycloalkyl", used alone or in combination with other terms, is defined herein as a monovalent portion of non-aromatic, monocyclic, bicyclic, tricyclic, fused, bridged, or spiro hydrocarbon, of 3-8 or 3-7 carbon atoms. Portions having one or more fused aromatic rings (that is, having a common bond) with the non-aromatic ring are also included in the definition of cycloalkyl. Any suitable ring position of the cycloalkyl portion can be covalently bound to the defined chemical structure. Examples of cycloalkyl portions include, without limitation, chemical groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, adamantyl, spiro [4.5] decanyl, and homologs, isomers, and the like. As used herein, "heterocycloalkyl" refers to a cycloalkyl group (e.g., 3-12 atoms) wherein one or more (e.g., up to 4 atoms) are replaced with a heteroatom, such as an O, S atom, N, or P. Also included in the definition of heterocycloalkyl are those portions having one or more (for example two) fused aromatic rings (that is, having a common bond) with the non-aromatic heterocyclic ring, eg, phthalimidyl , naphthalimidyl, pyromellitic, diimidyl, phthalanyl, and benzo derivatives of saturated heterocycles, such as the indolene and isoindolene groups. In some embodiments, the heterocycloalkyl is a group of 3-12 members having 1-4 identical or different heteroatoms selected from oxygen, nitrogen and sulfur, having one or two fused benzene rings, said group being attached via one atom carbon or nitrogen ring. Unless otherwise indicated, the terms "halo" or "halogen", used alone or in combination with other terms, are defined herein as fluorine, chlorine, bromine or iodine. Unless otherwise indicated, the term "aryl", used alone or in combination with other terms, is defined herein as an aromatic hydrocarbon of up to 14 carbon atoms, which may be a single ring (monocyclic) or multiple rings (bicyclic, up to three rings) fused or covalently linked. Any suitable ring position of the aryl portion can be covalently linked to the defined chemical structure. Examples of aryl moieties include, without limitation, chemical groups such as phenyl, 1-naphthyl, 2-naphthyl, dihydronaphthyl, tetrahydronaphthyl, biphenyl, anthryl, phenanthryl, fluorenyl, indanyl, biphenylenyl, acenaphthenyl, acenaphthylenyl, and the like. The term "aryloxy," as used herein, means a group of formula -O-aryl, wherein the term "aryl" has the previously described definition. Unless otherwise indicated, the term "arylalkyl" or "aralkyl", used alone or in combination with other terms, is defined herein as an alkyl as defined above, substituted with an aryl moiety as defined above. Examples of arylalkyl moieties include, without limitation, chemical groups such as benzyl, 1-phenylethyl, 2-phenylethyl, diphenylmethyl, 3-phenylpropyl, 2-phenylpropyl, fluorenylmethyl, and homologs, isomers, and the like. The term "arylalkyloxy", as used herein, means a group of formula -O-arylalkyl, wherein the term "arylalkyl" has the previously described definition. As used herein, the "heteroaryl" groups are monocyclic and polycyclic aromatic hydrocarbons (for example of three rings), having at least one ring member that is a heteroatom such as sulfur, oxygen or nitrogen. Heteroaryl groups include, without limitation, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrryl, oxazolyl, benzofuryl, benzothienyl, benzothiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,4-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, the heteroaryl groups may have from 1 to about 20 carbon atoms, and in additional embodiments from about 3 to about 20 carbon atoms. In some embodiments, heteroaryl groups have from 1 to about 4, from 1 to about 3, or 1 to 2 heteroatoms. In some embodiments, the heteroaryl is an aromatic group of 5-24 members, mono- or polycyclic (e.g., di- or tricyclic), having 1-4 identical or different heteroatoms, selected from oxygen, nitrogen and sulfur. As used herein, "heterocycle" refers to a heteroaryl or heterocycloalkyl group. The term "heteroaryloxy", as used herein, means a group of formula -O-heteroaryl, wherein the term "heteroaryl" has the definition described above. As used herein, the term "leaving group" refers to a portion that can be displaced by another portion during a chemical reaction, for example by means of a nucleophilic attack. The leaving groups are well known and include, for example, halides and OS02-R \ wherein R 'is for example alkyl, haloalkyl or aryl, optionally substituted with halogen, alkyl, alkoxy, amino and others. Some exemplary leaving groups include chlorine, bromine, iodine, mesylate, tosylate and other similar groups. As used herein, the term "react" refers to putting together the designated chemical reagents, such that a chemical transformation occurs that generates a compound different from any initially introduced into the system. The reaction can be carried out in the presence or absence of solvent. As used herein, the term "precipitate" has the known meaning and generally refers to the formation of a solid (for example a precipitate) of a solution that dissolves the solid. The solid can be amorphous or crystalline. Precipitation methods are well known and include, for example, increasing the proportion of the solvent in which a solute is insoluble, reducing the temperature, chemically transforming the solute so that it is no longer soluble in its solvent, and the like. The compounds of the present invention may contain an asymmetric atom and some of the compounds may contain one or more asymmetric atoms or centers, thus forming 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., and also other mixtures of the stereoisomers R and S, and pharmaceutically acceptable salts thereof. The optical isomers can be obtained in pure form by known standard procedures including, without limitation, diastereomer salt formation, kinetic resolution and asymmetric synthesis. It is also understood that this invention encompasses all possible regioisomers and their mixtures, which can be obtained in pure form by standard separation methods known to those skilled in the art including, without limitation, column chromatography, thin layer chromatography and high performance liquid chromatography. The compounds provided herein may also include their salts, formed for example from mineral or organic acid salts of basic residues such as amines; alkaline or organic salts of acidic residues such as carboxylic acids and the like. The invention includes acceptable salt forms formed from the addition reaction with organic or inorganic acids. In addition, this invention includes quaternary ammonium salts of the compounds, which can be prepared by reacting the nucleophilic amines with a suitably reactive alkylating agent, such as an alkyl halide or benzyl halide. In "Remington's Pharmaceutical Sciences," 17th ed., Mack Publishing Company, Easton, Pennsylvania, 1985, p. 1418, the description of which is incorporated herein by reference, lists of suitable salts are given. The compounds of the invention may also include all isotopes of the atoms that occur in the intermediates or the final compounds. Isotopes include atoms that have the same atomic number but different numbers of mass. For example, isotopes of hydrogen include tritium and deuterium.

The compounds of the invention may also include tautomeric forms, such as the keto-enol tautomers. The tautomeric forms may be in equilibrium or in a sterically blocked form by appropriate substitution. The methods described herein can be monitored according to any suitable known method. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (for example 1H or 13C), infrared spectroscopy, spectrophotometry (for example, UV-visible), or mass spectrometry, or by chromatography, such as high performance liquid chromatography (HPLC) or thin layer chromatography. The reactions of the processes described herein can be carried out in suitable solvents, which can be easily selected by an expert in organic synthesis. Suitable solvents may be substantially unreactive with the starting materials (reagents), intermediates, or products, at the temperatures at which the reactions are carried out, for example at temperatures that may vary from the freezing temperature of the solvent to the temperature of boiling the solvent. A given reaction can be carried out in a solvent or in a mixture of more than one solvent. Suitable solvents can be selected depending on the particular reaction step. In some embodiments, the reactions can be carried out in the absence of a solvent, for example when at least one of the reactants is a liquid or a gas. Exemplary solvents suitable for the described processes include halogenated hydrocarbons (for example methylene chloride), aromatic hydrocarbons (for example benzene, toluene, etc.), and ethers (for example diethyl ether, tetrahydrofuran, etc.). The reactions of the described processes can be carried out at appropriate temperatures, which can be easily determined by the person skilled in the art. The reaction temperatures will depend, for example, on the melting and boiling points of the reactants and the solvent, if present; of the thermodynamics of the reaction (for example, vigorously exothermic reactions are usually carried out at reduced temperatures); and the kinetics of the reaction (for example, a high activation energy barrier usually requires high temperatures). "High temperatures" refers to temperatures above room temperature (approximately 20 ° C) and "reduced temperatures" refers to temperatures below room temperature. The reactions of the described processes can be carried out in the air or under an inert atmosphere. Normally, reactions containing reagents or products that are substantially reactive with air can be effected using synthetic, air-sensitive techniques, which are well known to those skilled in the art. To prepare the compounds according to the methods described herein, the usual operations of isolation and purification, such as concentration, filtration, extraction, solid phase extraction, recrystallization, chromatography and the like, can be used to isolate the desired products. In some embodiments of the described methods, the following exemplary compounds can be prepared starting from their respective preparation materials, as shown in Table 1 and the following examples.

TABLE 1 TABLE 1 (Continued) The invention will be described in more detail by means of specific examples. The following examples are offered for illustrative purposes and are considered not to limit the invention in any way. Those skilled in the art will readily recognize a variety of non-critical parameters that can be changed or modified to produce essentially the same results.

EXAMPLES EXAMPLE 1 Preparation of (2,6-dimethyl-phenyD-methanesulfonyl chloride Step 1 Preparation of the sodium salt of (2,6-dimethyl-phenyl) methanesulfonic acid Sodium sulfite (442.4 g) was added to a stirred mixture of 2-chloromethyl-1,3-dimethyl-benzene (526.6 g), tetrabutylammonium iodide (6.4 g) and water (3.0 L). The mixture was refluxed for 1 h. As the mixture was cooled to room temperature, sodium chloride (526 g) and ethyl acetate (1.4 I) were added. The mixture was stirred and cooled to < 10 ° C. The product was collected by filtration and washed with ethyl acetate (250 mL) and acetone (500 mL). The product was dried under vacuum at 60 ° C to constant weight to give the sodium salt of the acid (2,6-dimethyl-phenyl) -methanesulfonic acid (634 g, 88%). 1 H NMR (300 MHz, DMSOdd): d 7.17-6.91 (m, 3 H, Ar H), 3.96 (s, 2 H, CH 2), and 2.29 (s, 6 H, CH 3).

Step 2 Preparation of (2,6-d-methyl-phenyl) -methanesulfonic acid Methanol (2.2 L) and the sodium salt of (2,6-dimethyl-phenyl) -methanesulfonic acid (185 g) were combined in a 5 L multi-neck flask equipped with overhead stirring. The mixture was cooled to 0 ° C and hydrogen chloride (112 g) was passed through the mixture, keeping the internal temperature at < 10 ° C. The mixture was stirred for 2 h and allowed to warm to room temperature. The mixture was clarified by filtration. The filtrate was concentrated to a volume of 600 mL at ambient pressure and azeotropically distilled with toluene (3X600 mL). Heptane (1.1 L) was added to the mixture as it was cooled to < 10 ° C. The solid product was collected by filtration and washed with heptane (100 mL). The product was dried at 40 ° C in vacuo to constant weight, to give the acid (2,6-dimethyl-phenyl) -methanesulfonic acid (149 g, 89%). 1 H NMR (300 MHz, DMSOd 6): d 7.0-6.91 (m, 3 H, Ar H), 4.40 (s, 2 H, CH 2), and 2.34 (s, 6 H, CH 3).

Step 3 Preparation of (2,6-dimethyl-phenyl) -methanesulfonyl chloride Tetrahydrofuran (3.0 L), (2,6-dimethyl-phenyl) -methanesulfonic acid (300 g, containing 12% water according to a KF analysis, or 266 g corrected for water content), and N, were combined. N-dimethylformamide (15 g), in a 5 L multi-neck flask equipped with overhead agitation. The reaction mixture was cooled to -20 ° C and oxalyl chloride (655.5 g) was added slowly over 1 h. The reaction mixture was clarified by filtration and concentrated to a volume of 1 L. The filtrate was transferred to a flask equipped with overhead stirring and cooled to -40 ° C. Water (900 mL) was added for 30 minutes, maintaining an internal temperature < -10 ° C. The product was collected by filtration, washed with water and heptane, and dried, to give (2,6-dimethyl-phenyl) -methanesulfonyl chloride (277 g, 96%). 1 H NMR (300 MHz, CDCl 3): d 7.25-7.04 (m, 3 H, Ar H), 5.17 (s, CH 2), and 2.50 (s, 6 H, CH 3).

EXAMPLE 2 Preparation of (2-methylphenyl) -methanesulfonyl chloride Step 1 Preparation of the sodium salt of (2-methylphen-P-methanesulfonic acid) Using the procedure described in example 1, step 1, a-bromo-o-xylene (100 g, 0.54 mol) produced the sodium salt of the acid (2-methylphenyl) -methanesulfonic acid (75 g, 66%), a white solid.A LC-MS showed the molecular ion of sulfonic acid (G8382-72, G8382-49).

Step 2 Preparation of (2-methylphenyl) -methanesulfonic acid Using the procedure described in the example, step 2, the (2-methylphenyl) -methanesulfonic acid sodium salt (12 g, 58 mmol) yielded the acid (2). -methylphenyl) -methanesulfonic acid (10.6 g, -100%), a pale yellow solid (L25213-78).

Step 3 Preparation of (2-methylphenyl) -methanesulfonyl chloride Using the procedure described in example 1, step 3, (2-methylphenyl) -methanesulfonic acid (10.6 g, 57 mmol) yielded (2-methylphenyl) chloride -methanesulfonyl (11.8 g, 100%). 1 H NMR (400 MHz, CDCl 3) d 2. 48 (s, 3 H), 4.97 (s, 2 H), 7.3 (d, J = 7.3 Hz, 2 H), 7.33-7.41 (m, 1 H), 7.45 (d, J = 7.6 Hz, 1 H) (L25213-80).

EXAMPLE 3 Preparation of (2,6-difluorophenyl) -methanesulfonyl chloride Step 1 Preparation of the sodium salt of the acid (2,6-difluoropheni-methanesulfonic acid) Using the procedure described in example 1, step 1, 2,6-difluorobenzyl bromide (50 g, 0.24 mol) yielded the sodium salt of (2,6-difluorophenyl) -methanesulfonic acid (38.9 g, 70%), a white solid (G8324-105).

Step 2 Preparation of (2,6-difluorophenyl) -methanesulfonic acid Using the procedure described in example 1, step 2, the sodium salt of (2,6-difluorophenyl) -methanesulfonic acid (10 g, 44 mmol) produced the (2,6-difluorophenyl) -methanesulfonic acid (9.5 g), a viscous orange oil, which was used without purification (L26913-131).

Step 3 Preparation of (2,6-difluorophenyl) -methanesulfonyl chloride Using the procedure described in example 1, step 3, (2,6-difluorophenyl) -methanesulfonic acid (9.5 g, 44 mmol) yielded the 2,6-difluorophenyl) -methanesulfonyl (1.3 g, 14%). 1 H NMR (400 MHz, CDCl 3) d 5.02 (s, 2 H), 7.00-7.11 (m, 2 H), 7.40-7.57 (m, 1 H) (L26913-136).

EXAMPLE 4 Preparation of 2-fluoro-6- (trifluoromethylphenyl) -methanesulfonyl chloride Step 1 Preparation of the sodium salt of 2-fluoro-6- (trifluoromethylphenyl) -methanesulfonic acid Using the procedure described in example 1, step 1, 2-fluoro-6- (trifluoromethylphenyl) benzyl bromide (15 g, 61 mmol) yielded the sodium salt of 2-fluoro-6- (trifluoromethylphenyl) -methanesulfonic acid (15 g, 89%), a white solid. 1 H NMR (400 MHz, DMSO-d 6) d 4.02 (s, 2 H), 7.26-7.66 (m, 3 H) (L26913-185).

Step 2 Preparation of 2-fluoro-6- (trifluoromethylphenyl) -methanesulfonic acid Using the procedure described in example 1, step 2, the sodium salt of 2-fluoro-6- (trifluoromethylphenyl) -methanesulfonic acid (15 g, 53 mmol) yielded 2-fluoro-6- (trifluoromethylphenyl) -methanesulfonic acid (15 g), a pale orange oil, which was used without further purification. 1 H NMR (400 MHz, DMSO-d 6) d 4.12 (s, 2 H), 7.39-7.73 (m, 3 H) (L26913-190).

Step 3 Preparation of 2-fluoro-6- (trifluoromethylpheni-methanesulfonyl chloride) Using the procedure described in example 1, step 3, 2-fluoro-6- (trifluoromethylphenyl) -methanesulfonic acid (15 g, 53 mmol) yielded 11 g of the crude product, which was purified by crystallization from hexane at low temperature, to obtain the 2-fluoro-6-chloride. - (trifluoromethylphenyl) -methanesulfonyl (9.0 g, 62%). 1 H NMR (400 MHz, CDCl 3) d 5.31 (s, 2 H), 7.38-7.51 (m, 1 H), 7.58-7.68 (m, 2 H) (L26913-192).

EXAMPLE 5 Preparation of 2,6-bis (trifluoromethylphenyl) -methanesulfonyl chloride Step l Preparation of 2,6-bis (trifluoromethyl) benzoyl fluoride Using the procedure described by W. Dmowski and K.

Piasecka-Maciejewska, Tetrahedron Lett. 1998, 54, 6781-6792, 7.0 g of 2,6-bis (trifluoromethyl) benzoic acid were converted to the acid fluoride (7.0 g, 100%), an orange solid. 1 H NMR (400 MHz, DMSO-d 6) d 8.17 (t, J = 8.0 Hz, 1 H), 8.40 (d, J = 8.0 Hz, 2 H) (L27132-12, 15).

Step 2 Preparation of 2,6-bis (trifluoromethylphenyl) -benzyl alcohol Using the procedure described by W. Dmowski and K. Piasecka-Maciejewska, Tetrahedron Lett. 1998, 54, 6781-6792, 7.0 g of 2,6-bis (trifluoromethyl) benzoyl fluoride were converted to alcohol (6.6 g, 100%), a pale yellow oil. 1 H NMR (400 MHz, CDCl 3) d 4.95 (s, 2 H), 7. 59 (t, J = 8.0 Hz, 1 H), 7.94 (d, J = 7.8 Hz, 2 H) (L27132-16).

Step 3 Preparation of 2,6-bis (trifluoromethylphenyl) -benzyl bromide To a solution of 2,6-bis (trifluoromethylphenyl) benzyl alcohol (6.6 g, 28 mmol) and 1,3-bis (diphenylphosphino) propane (6.9 g, 17 mmol) in CH2Cl2 (50 mL), at 0 ° C, was slowly added carbon tetrabromide (11 g, 33 mmol).

The mixture was stirred overnight at room temperature and then pipetted into 200 mL Et2O. The mixture was filtered through Celite® and concentrated. The yellow oil was suspended in 2% EtOAc-Hexane and filtered through a pad of SiO2l to yield the bromide (7.2 g, 84%), a colorless oil. 1 H NMR (400 MHz, CDCl 3) d 4.78 (s, 2 H), 7.59 (t, J = 7.9 Hz, 1 H), 7.92 (d, J = 7.9 Hz, 2 H) (L27132-7).

Step 4 Preparation of the sodium salt of 2,6-bis (trifluoromethylphenyl) -methanesulfonic acid Using the procedure described in example 1, step 1, 2,6-bis (trifluoromethylphenyl) benzyl bromide (7.2 g, 23 mmol) yielded the sodium salt of 2,6-bis (trifluoromethylphenyl) -methanesulfonic acid (3.2 g, 32%), a white solid ( L27132-19).

Step 5 Preparation of 2,6-bis (trifluoromethyl-phenyl) -methanesulfonic acid Using the procedure described in example 1, step 2, the sodium salt of 2,6-bis (trifluoromethylphenyl) -methanesulfonic acid (0.19 g, 0.44 mmol) yielded 2,6-bis (trifluoromethylphenyl) -methanesulfonic acid (0.14 g, 100%), an orange solid, which was used without further purification. 1 H NMR (400 MHz, DMSO-de) d 4.25 (s, 2 H), 7.64 (t, J = 8.5 Hz, 1 H), 7.96 (d, J = 7.8 Hz, 2 H) (L27132-21).

Step 6 Preparation of 2,6-bis (trifluoromethylpheni-methanesulfonyl chloride Using the procedure described in example 1, step 3, 2,6-bis (trifluoromethylphenyl) -methanesulfonic acid (0.14 g, 0.44 mmol) yielded 99 mg of crude product which was purified by crystallization from hexane at low temperature, to obtain the 2,6-bis chloride (trifluoromethylphenyl) -methanesulfonyl (33 mg, 23%), a white powder. 1 H NMR (400 MHz, CDCl 3) d 5.56 (s, 2 H), 7.70 (t, J = 8.0 Hz, 1 H), 7.97 (d, J = 8.0 Hz, 2 H) (L27132-23).

EXAMPLE 6 Preparation of (2-trifluoromethylphenyl) -methanesulfonyl chloride Step 1 Preparation of the sodium salt of (2-trifluoromethylphenyl) -methanesulfonic acid Using the procedure described in example 1, step 1, 2- (trifluoromethyl) benzyl bromide (25 g, 0.14 mol) produced the sodium salt of (2-trifluoromethylphenyl) -methanesulfonic acid (22.2 g, 60%), a white solid. An LC-MS showed the molecular ion of sulfonic acid (G9381-183).

Step 2 Preparation of (2-trifluoromethylphenyl) -methanesulfonic acid Using the procedure described in Example 1, Step 2, the sodium salt of (2-trifluoromethylphenyl) -methanesulfonic acid (22.2 g, 84 mmol) yielded the acid ( 2-trifluoromethylphenyl) -methanesulfonic acid (20.3 g, -100%), a pale yellow solid (G9381-183).

Step 3 Preparation of (2-trifluoromethylphenyl) -methanesulfonyl chloride Using the procedure described in example 1, step 3, (2-trifluoromethylphenyl) -methanesulfonic acid (20.3 g, 84 mmol) yielded (2-trifluoromethylphenyl) -methanesulfonyl chloride (19.6 g, 90%) as a white solid, after crystallization from petroleum ether. 1 H NMR (400 MHz, CDCl3) d 5.15 (s, 2 H), 7.60 (t, J = 7.6 Hz, 1 H), 7.66 (t, J = 7.4 Hz, 1H), 7.80 (dd, J = 7.5 and 2.8 Hz, 2 H) (G9381-184).

EXAMPLE 7 Preparation of (2-benzyloxy-phenyl) -methanesulfonyl chloride Step 1 Preparation of (2-benzyloxy-phenyl) -methanesulfonic acid Sodium sulfite (4.2 g) was added to a stirred mixture of 1-benzyloxy-2-bromomethyl-benzene (8.9 g), tetrabutylammonium iodide (59 mg) and water (150 ml). The mixture was heated to reflux overnight. As the mixture was cooled to 0 ° C, it was acidified with 6N HCl. It was extracted with ethyl acetate (100 ml x 6) (some remained in the aqueous layer). The combined organic phase was dried over MgSO. The filtrate was concentrated in vacuo. The product was triturated with ethyl ether to give (2-benzyloxy-phenyl) -methanesulfonic acid (678 mg, 8%). 1 H NMR (400 MHz, DMSO-d 6): d ppm 3.82 (s, 2 H) 5.09 (s, 2 H) 6.86 (t, J = 7.45 Hz, 1 H) 6.96 (d, J = 8.08 Hz, 1 H ) 7.14 (t, J = 7.83 Hz, 1 H) 7.32 (d, J = 7.33 Hz, 1 H) 7.38 (t, J = 7.33 Hz, 2 H) 7.46 (d, J = 9.09 Hz, 1 H) 7.52 (d, J = 7.07 Hz, 2 H).

Step 2 Preparation of (2-benzyloxy-phenyl) -methanesulfonyl chloride. Tetrahydrofuran (10 ml), (2-benzyloxy-phenyl) methanesulfonic acid (138 mg), and N, N-dimethylformamide (2 drops) were cooled to -78. ° C, oxalyl chloride (315 mg) was added slowly to the mixture. The reaction mixture was stirred for 3 h at -78 ° C to 0 ° C. The reaction mixture was clarified by filtration. The filtrate was washed with ice water and heptane and dried, to give (2-benzyloxy-phenyl) -methanesulfonyl chloride (114 mg, 77%). 1 H NMR (400 MHz, chloroform-D): d ppm 5.06 (s, 2 H) 5.15 (s, 2 H) 7.04 (m, 2 H) 7.42 (m, 7 H).

EXAMPLE 8 Preparation of (2,3-dichlorophenyl) -methanesulfonyl chloride Step 1 Preparation of the sodium salt of (2,3-dichlorophenyl) -methanesulfonic acid To a suspension of 2,3-dichlorobenzyl chloride (0.68 mL, 5.0 mmol) in 20 mL of water, sodium sulfite (630 mg) was added. , 5.0 mmol); the mixture was heated to reflux overnight. The reaction mixture was exhaustively evaporated on the rotary evaporator and dried under vacuum to give the sodium salt of (2,3-dichlorophenyl) -methanesulfonic acid as a white solid. 1 H NMR (400 MHz, DMSO-D 6) d ppm 3.97 (s, 2 H) 7.28 (t, J = 7.83 Hz, 1 H) 7.49 (m, 2 H).

Step 2 Preparation of (2,3-dichlorophenyl) -methanesulfonic acid The sodium salt of (2,3-dichlorophenyl) -methanesulfonic acid (5.0 mmo!) Was suspended in 50 mL of MeOH and stirred at 50 ° C for 1 hour; then it was cooled to -10 ° C. HCl was bubbled for several seconds and the resulting white suspension was stirred at -10X for 1 hour. The mixture was filtered through Celite® and evaporated. The resulting residue was triturated with 60 mL of dry acetone and filtered. The filtrate was evaporated to give a yellow semi-solid. This solid was triturated with 40 mL of etherphexane, 2: 1. The resulting solid was filtered and washed with hexane to give 902 mg of the (2,3-dichlorophenyl) -methanesulfonic acid. 1 H NMR (400 MHz, DMSO-D6) d ppm 3.96 (s, 2 H) 7.27 (t, J = 7.83 Hz, 1 H) 7.49 (m, 2 H).

Step 3 Preparation of (2,3-dichlorophenyl) -methanesulfonyl chloride. (2,3-Dichlorophenyl) -methanesulfonic acid (260 mg, 1.0 mmol) was dissolved in 5 mL of dry THF and cooled to 0 ° C. A catalytic drop of DMF was added, followed by oxalyl chloride (0.44 mL, 5.0 mmol). The reaction mixture was allowed to warm to room temperature for 90 minutes and then filtered through Celite®, rinsing the Celite® with 15 mL more dry THF. The filtrate was evaporated to a volume of about 5 mL and then 5 mL of water was added in small portions, cooling the vessel in a water bath. The mixture was extracted with 2 x 25 mL of EtOAc and the combined organic phase was washed with saturated sodium bicarbonate solution and brine, and dried (MgSO). Filtration and evaporation gave the crude product as a yellow oil. Chromatography on silica gel using a gradient of 5% EtOAc / Hexane, to 30% EtOAc / Hexane, gave 142 mg of (2,3-dichlorophenyl) -methanesulfonyl chloride as a white solid. 1 H NMR (400 MHz, chloroform-D) d ppm 5.09 (s, 2 H) 7.25 (t, J = 7.96 Hz, 1 H) 7.45 (m, 1 H) 7.53 (dd, J = 8.08, 1.52 Hz, 1 H).

EXAMPLE 9 Preparation of (2-formyl-phenyl) -methanesulfonyl chloride Step 1 Preparation of 2-bromomethyl-benzaldehyde DIBAL-H (1 M in hexane, 55 mL, 55 mmol) was added to a-bromo-o-tolunitrile (10 g, 51 mmol) in DCM, at 0 ° C, and the mixture The reaction mixture was stirred at the same temperature for 3.5 h before it was drained in a cold solution of 5% HBr. After stirring 15 min more, the layers were separated and the aqueous layer was extracted with DCM; The combined organic layer was washed with NaHCO3 and water, dried over MgSO and evaporated to yield a dark liquid (9.4 g). The material was used directly in the next step without further purification.

Step 2 Preparation of the sodium salt of (2-formyl-phenyl) -methanesulphonic acid Using the procedure described in example 1, step 1, 2-bromomethyl-benzaldehyde (1.58 g, 7.94 mol) yielded the sodium salt of (2-formyl-phenyl) -methanesulfonic acid (1.40 g, 80%), an off-white solid (L27234-72).

Step 3 Preparation of (2-formyl-phenyl) -methanesulfonic acid Using the procedure described in example 1, step 2, the sodium salt of (2-formyl-phenyl) -methanesulfonic acid (1.40 g, 6.30 mmol) produced the (2-formyl-phenyl) -methanesulfonic acid (418 mg, 33%), a pale yellow solid (L27234-73).

Step 4 Preparation of (2-formyl-phenyl) -methanesulfonyl chloride Using the procedure described in example 1, step 3, (2-formyl-phenyl) -methanesulfonic acid (418 mg, 2.09 mmol) yielded the ( 2-formyl-phenyl) -methanesulfonyl (367 mg, 80%). 1 H NMR (400 MHz, CDCI3) d 10.15 (s, 1 H), 7.92 (dd, 1 H), 7.74-7.61 (m, 3 H), 5.67 (s, 2 H) (L27234-74).

EXAMPLE 10 Preparation of (3,4-dichlorophenyl) -methanesulfonyl chloride The title compound can be prepared by the person skilled in the art with an appropriate modification of the procedure of example 8, for example by replacing the 2,3-dichlorobenzyl chloride with 3,4-dichlorobenzyl chloride as the starting material in step 1 Those skilled in the art will recognize that various changes or modifications may be made to the aspects or embodiments of this invention, and that such changes or modifications may be made without departing from the spirit of this invention. Therefore, it is considered that the appended claims cover all these equivalent variations within the spirit and scope of the invention. This application claims the priority benefit of the provisional application of E.U. Serial No. 60 / 547,600, filed on February 25, 2004, which is hereby incorporated by reference in its entirety. It is intended to incorporate as a reference in its entirety all patents, applications and printed publications, including the books mentioned in this patent document.

Claims (31)

1. NOVELTY OF THE INVENTION CLAIMS 1. - A process for preparing a compound of formula I: Ar-R-SO2-XI wherein: Ar is aryl or heteroaryl optionally substituted with one or more substituents selected from the group consisting of halogen, C-1-C6 alkyl, cycloalkyl of C3-C7, heterocycloalkyl, formyl, cyano, nitro, OH, CrC6 alkoxy, arylalkyloxy, Ci-Cß haloalkyl, C1-C3 perhaloalkyl, CrC6 haloalkoxy, C C3 perhaloalkoxy, NR1R2, NR1COR3, aryl, aryloxy, heteroaryl and heteroaryloxy; R is C-? -C6 alkylenyl; R1 and R2 are each independently selected from the group consisting of H, C? -C6 alkyl and C3-C7 cycloalkyl; or R1 and R2 together with the N atom to which they are attached form a 5- or 6-membered heterocycle; R3 is selected from the group consisting of H, CrC6 alkyl and C3-C cycloalkyl; and X is halogen; comprising: (a) reacting a compound of formula II: Ar-R-L wherein L is a leaving group, with a metal sulphite salt of group I or II, optionally in the presence of a phase transfer catalyst, to form a sulfonic acid salt compound of formula III: (Ar-R-) SO3"1) qM lll where M is a metal ion of group I or II, where q is 1 when M is a metal ion of group I, and q is 2 when M is a metal ion of group II; (b) reacting said compound of formula III with a protic acid to form a sulfonic acid compound of formula IV: Ar-R-SO3H IV and (c) reacting said compound of formula IV with a halogen substitution reagent for forming said compound of formula I.
2. 2. The process according to claim 1, fer characterized in that said reaction of step (a) is carried out in the presence of a phase transfer catalyst. claim 1 or claim 2, fer characterized by that step (a) comprises isolating said compound of formula III by precipitating said compound of formula III and optionally filtering the resulting precipitate. 4. The process according to any of claims 1 to 3, fer characterized in that said reaction of step (a) is carried out in a solvent comprising water. 5. The process according to claim 4, fer characterized in that said precipitation is facilitated: (1) by treating the reaction mixture of step (a) with a metal halide salt soluble in water; or (2) by adding to the reaction mixture of step (a) a solvent that is substantially immiscible in water; or both (1) and (2). 6. The process according to claim 5, fer characterized in that said metal halide salt soluble in water comprises NaCl. 7. The process according to claim 5 or claim 6, fer characterized in that said solvent that is substantially immiscible in water comprises ethyl acetate. 8. The process according to any of claims 1 to 7, fer characterized in that said protic acid of step (b) is selected from the group consisting of HCl, HBr, H3PO, HNO3, HCIO4, or H2SO, or a combination thereof. 9. The process according to claim 8, fer characterized in that said protic acid comprises HCl. 10. The method according to claim 9, fer characterized in that said protic acid comprises gaseous HCl. 11. The process according to any of claims 1 to 10, fer characterized in that said reaction of step (b) is carried out in a solvent comprising an alcohol. 12. The process according to claim 11, fer characterized in that said alcohol comprises methanol. 13. The method according to any of claims 1 to 12, fer characterized in that said step (b) also comprises isolating said compound of formula IV by precipitating said compound of formula IV, and optionally filtering the resulting precipitate. 14. The process according to any of claims 1 to 13, further characterized in that said halogen substitution reagent is selected from the group consisting of SOCI2, POCI3, CCI4 / triphenylphosphine, oxalyl chloride and oxalyl bromide. 15. The process according to claim 14, further characterized in that said halogen substitution reagent comprises oxalyl chloride. 16. The process according to any of claims 1 to 15, further characterized in that said reaction of step (c) is carried out in the presence of an acyl transfer catalyst. 17. The process according to claim 16, further characterized in that said acyl transfer catalyst comprises a tertiary amide. 18. The process according to claim 16, further characterized in that said acyl transfer catalyst comprises N, N-dimethylformamide. 19. The process according to any of claims 1 to 18, further characterized in that Ar is phenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, CrC6 alkyl, C3-C7 cycloalkyl, heterocycloalkyl, formyl, cyano, nitro, OH, C6-C6 alkoxy, arylalkyloxy, C6-C6 haloalkyl, C-1-C3 perhaloalkyl, d-Ce haloalkoxy, C-? -C3 perhaloalkoxy, NR1R2, NR1COR3, aryl , aryloxy, heteroaryl and heteroaryloxy. 20. The process according to claim 19, further characterized in that Ar is phenyl substituted with one or more substituents selected from the group consisting of halogen, CrC6 alkyl, C1-C3 perhaloalkyl, formyl and arylalkyloxy. 21. The process according to any of claims 1 to 20, further characterized in that R is alkylene of d-C4. 22. The process according to claim 21, further characterized in that R is methylene. 23. The process according to any of claims 1 to 22, further characterized in that L is selected from the group consisting of halogen, OSO2CH3, OSO2CF3, and OSO2-aryl ', wherein the aryl' is a phenyl group optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of d-C3 alkyl and halogen. 24. The method according to claim 23, further characterized in that L is Cl. 25.- The method according to any of claims 1 to 24, further characterized in that M is an on Na + or an on K +. 26. - The method according to any of claims 1 to 25, further characterized in that X is Cl. 27.- The process according to claim 1, further characterized in that: Ar is phenyl optionally substituted with one or more substituents selected from the group consisting of halogen, C6 alkyl, perhaloalkyl of dd, formyl, arylalkyloxy, NR1R2 and NR1COR3; R is methylene or ethylene; R1 and R2 are each, independently, H or d-d alkyl; R3 is H or d-d alkyl; X is Cl; L is halogen; said metal sulfite salt of step (a) is Na2S03; said phase transfer catalyst of step (a) is present; said sulfonic acid salt compound of formula III has the formula NaSO 3 -R-Ar; said step (a) also comprises isolating said compound of formula III; said step (b) also comprises isolating said compound of formula IV; and said halogen substitution reagent of step (c) is oxalyl chloride. 28. The process according to claim 1, further characterized in that the compound of formula I is (3,4-dichlorophenyl) -methanesulfonyl chloride, (2,6-dimethylphenyl) -methanesulfonyl chloride, chloride of (2-methylphenyl) -methanesuifonyl, (2,6-difluorophenii) -methanesulfonyl chloride, 2-fluoro-6- (trifluoromethylphenyl) -methanesulfonyl chloride, 2,6-bis (trifluoromethylphenyl) -methanesulfonyl chloride, (2-trifluoromethylphenyl) -methanesulfonyl, (2-benzyloxyphenyl) -methanesulfonyl chloride, (2,3-dichlorophenyl) -methanesulfonyl chloride, or (2-formylphenyl) -methanesulfonyl chloride. 29. - The method according to any of claims 1 to 18, further characterized in that the compound of formula I, Ar, R and X are selected according to the following table: 30. - A process for preparing a compound of formula IV: Ar-R-SO 3 H IV wherein Ar is aryl or heteroaryl optionally substituted with one or more substituents selected from the group consisting of halogen, dd alkyl, C 3 -C 7 cycloalkyl, heterocycloalkyl , formyl, cyano, nitro, OH, dd alkoxy, arylalkyloxy, dd haloalkyl, d-C3 perhaloalkyl, dd haloalkoxy, C C3 perhaloalkoxy, NR1R2, NR1COR3, aryl, aryloxy, heteroaryl, and heteroaryloxy; R is alkylenyl of d-C6; R1 and R2 are each independently selected from the group consisting of H, C3-C7-C-alkyl and cycloalkyl; or R1 and R2 together with the N atom to which they are attached form a 5- or 6-membered heterocycle; and R3 is selected from the group consisting of H, d-d alkyl and C3-C cycloalkyl; said process comprises: (a) reacting a compound of formula II in a solvent: Ar-R-L II wherein L is a leaving group, with a metal sulphite salt of! group I or II, optionally in the presence of a phase transfer catalyst, to form a sulfonic acid salt compound of formula III: (Ar-R-SO3-1) qM lll wherein M is a metal ion of group I or II , where q is 1 when M is a metal ion of group I, and q is 2 when M is a metal ion of group II; and (b) reacting said compound of formula III with a protic acid to form said compound of formula IV. 31. A process for preparing a compound of formula III: (Ar-R-SO3"1) qM lll where M is a metal ion of group I or II, where q is 1 when M is a metal ion of group I, and q is 2 when M is a metal ion of group II; Ar is aryl or heteroaryl optionally substituted with one or more substituents selected from the group consisting of halogen, dd alkyl, C3-C7 cycloalkyl, heterocycloalkyl, formyl, cyano, nitro, OH, C-alkoxy C6, arylalkyloxy, haloalkyl of C C6, perhaloalkyl of d-d, haloalkoxy of CrC6, perhaloalkoxy of d-d, NR1R2, NR1COR3, aryl, aryloxy, heteroaryl and heteroaryloxy; R is CrCe alkylenyl; R1 and R2 are each independently selected from the group consisting of H, Crd alkyl and C3-C7 cycloalkyl; or R1 and R2 together with the N atom to which they are attached form a 5- or 6-membered heterocycle; and R3 is selected from the group consisting of H, d-d alkyl and C3-C7 cycloalkyl; said method comprises: (a) reacting a compound of formula II: Ar-RL II wherein L is a leaving group, with a metal sulphite salt of group I or II, optionally in the presence of a phase transfer catalyst , to form a reaction mixture containing said compound of formula III; and isolating said compound of formula III; wherein said isolation is carried out by precipitating said compound of formula III of said reaction mixture; wherein said precipitation is facilitated: (1) treating said reaction mixture with a metal halide salt soluble in water; or (2) adding to said reaction mixture a solvent that is substantially immiscible in water; or both (1) and (2).