KR20070018857A - Processes for the preparation of aryl?and heteroaryl?alkylsulfonyl halides - Google Patents

Abstract

The present invention provides methods for the preparation of arylalkylsulfonyl halides and heteroarylalkylsulfonyl halides of the formulas useful as intermediates in the manufacture of a medicament:

Ar-R-SO ₂ -X

Description

Process for producing aryl- and heteroaryl-alkylsulfonyl halides {PROCESSES FOR THE PREPARATION OF ARYL-AND HETEROARYL-ALKYLSULFONYL HALIDES}

The present invention relates to methods of preparing arylalkylsulfonyl halides and heteroarylalkylsulfonyl halides which are useful, for example, as intermediates in the manufacture of medicaments.

Sulfonyl chlorides are widely used in the chemical industry, such as in the manufacture of dyes, lidograph resists, and pharmaceuticals. They may further be converted to 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 range of therapeutic small molecule drugs such as antibacterial agents, diuretics and cPLA ₂ inhibitors.

Typical preparations of sulfonyl chloride often involve the reaction of the phosphorus pentachloride with the sodium salt of sulfonic acid, often in combination with phosphorus oxychloride or thionyl chloride (see, for example, March , Advanced Organic Chemistry, 4th Edition, John Wiley & Sons, 1992, p. 499). Their relatively stringent reaction conditions are unsuitable for the preparation of sterically hindered sulfonyl chlorides such as arylalkylsulfonyl chlorides, etc., which can result in low yields due to the removal of sulfur dioxide (Nakayama et al., Tet Lett , 1984, 25, 4553-4556). A more mild method, which is not often used for sulfonyl chloride synthesis, is the reaction of the tetrabutylammonium salt of sulfonic acid with triphenylphosphine / sulfuryl chloride (Widlanski et al., Tet. Lett., 1992, 33, 2657-2660), This has the disadvantage of low atomic efficiency.

Many hindered sulfonyl halides such as (2,6-dimethylphenyl) -methanesulfonyl chloride and other aryl- and heteroaryl-sulfonyl halides are particularly useful for asthma or arthritis as described, for example, in WO 2003/048122. And cPLA ₂ inhibitors for the treatment of rheumatic disorders. As discussed above, the intermediates can be difficult to manufacture due to the loss of sulfur dioxide at high temperatures and the formation of significant amounts of impurities. Accordingly, there is a need for new and improved methods for preparing such compounds, and the methods provided herein will help meet these and other needs.

Summary of the Invention

In some embodiments, the present invention provides a process for preparing a compound of formula I, comprising the following steps a) to c):

Ar-R-SO ₂ -X

[In meals:

Ar is halogen, C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, heterocycloalkyl, formyl, cyano, nitro, OH, C ₁ -C ₆ alkoxy, arylalkyloxy, C ₁ -C ₆ halo Alkyl, C ₁ -C ₃ perhaloalkyl, C ₁ -C ₆ haloalkoxy, C ₁ -C ₃ perhaloalkoxy, NR ¹ R ² , NR ¹ COR ³ , aryl, aryloxy, heteroaryl and heteroaryloxy Aryl or heteroaryl which may be substituted with one or more, preferably up to 5 substituents selected from the group consisting of;

R is C ₁ -C ₆ alkylenyl;

R ¹ and R ² are each independently H, C ₁ -C ₆ alkyl or C ₃ -C ₇ cycloalkyl; Or R ¹ and R ² together with the N atom to which they are attached form a 5- or 6-membered heterocycle;

R ³ is H, C ₁ -C ₆ alkyl or C ₃ -C ₇ cycloalkyl;

X is halogen]:

a) preparing a sulfonate compound of formula III by reaction of a compound of formula II with a group I or group II metal sulfite salt under sufficient time and conditions, optionally in the presence of a phase transfer catalyst:

Ar-R-L

[Wherein L is a leaving group];

(Ar-R-S0 ₃ ^-1 ) _q M

[Wherein M is a Group I or Group II metal ion, q is 1 when M is a Group I metal ion, and q is 2 when M is a Group II metal ion];

b) preparing a sulfonic acid compound of formula IV by reaction of said compound of formula III with a protic acid under sufficient time and conditions:

Ar-R-SO ₃ H

And

c) preparing the compound of formula I by reaction of said compound of formula IV with a halogen substituent under sufficient time and conditions.

In some embodiments, the reaction of step a) is carried out in a solvent containing water. In some embodiments, the reaction of step a) is carried out in the absence of phase transfer catalyst. In a further embodiment, the reaction of step a) is carried out in the presence of a phase transfer catalyst. In a further embodiment, the reaction of step a) is carried out in the presence of a solvent containing water and a phase transfer catalyst.

In some embodiments, the compound of formula III is preferably separated by precipitation of the compound of formula III and optional filtration of the precipitate obtained. In some embodiments, the precipitation of the compound of formula III comprises (1) addition of a water soluble metal halide salt, preferably NaCl; (2) addition of a solvent that is not substantially miscible with water, preferably ethyl acetate; Or by both (1) and (2).

In some embodiments, the protic acid of step (b) is an inorganic acid, preferably HCl, HBr, H ₃ PO ₄ , HNO ₃ , HCl 0 ₄ or H ₂ SO ₄ , or a combination thereof. In some preferred embodiments, the protic acid of step (b) is HCl. In some embodiments, the protic acid is gaseous HCl added to a solvent or reaction mixture comprising a compound of Formula III.

In some embodiments, the reaction of step b) is carried out in a solvent containing alcohol, preferably methanol.

In some embodiments, the compound of formula IV is preferably separated by precipitation of the compound of formula IV and optional filtration of the precipitate obtained. In some embodiments, both compounds of Formula III and Formula IV are isolated.

In some embodiments, the halogen substituent is SOCl ₂ , POCl ₃ , CCl ₄ / 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, preferably tertiary amine, preferably N, N-dimethylformamide.

In a further embodiment, the present invention provides a process for the preparation of a compound of formula IV comprising the following steps a) to b):

[Formula IV]

Ar-R-SO ₃ H

[In meals:

Ar and R are as defined above;

a) preparing a sulfonic acid salt of formula III by reaction of a compound of formula II with a group I or group II sulfite salt under sufficient time and conditions, optionally in the presence of a phase transfer catalyst:

[Formula II]

Ar-R-L

Wherein L is as defined above;

[Formula III]

(Ar-R-S0 ₃ ^-1 ) _q M

Wherein M and q are as defined above; And

b) preparing a compound of formula IV by reaction of a compound of formula III with a protic acid under sufficient time and conditions.

In some embodiments, the compound of formula III is separated by precipitation of the compound of formula III, followed by optional filtration. In some preferred embodiments, the precipitation comprises treating the reaction mixture of step (a) with a water soluble metal halide salt, preferably NaCl; Or (2) adding a solvent, preferably ethyl acetate, which is not substantially miscible with water to the reaction mixture in step (a); Or both (1) and (2). In some embodiments, the reaction in step (a) is carried out in a solvent comprising water. In a further embodiment, the reaction of step (a) is carried out in the presence of a phase transfer catalyst. In a further preferred embodiment, the reaction of step (b) is carried out in a solvent comprising an alcohol, preferably methanol. In some preferred embodiments, the protic acid of step (b) is HCl, preferably gaseous HCl, added to a solvent comprising a compound of Formula III.

In a further embodiment, the present invention provides a process for the preparation of a compound of formula III comprising the following steps:

[Formula III]

(Ar-R-S0 ₃ ^-1 ) _q M

[In meals:

M is a Group I or II metal ion, q is 1 when M is a Group I metal ion, and q is 2 when M is a Group II metal ion;

Ar is halogen, C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, heterocycloalkyl, formyl, cyano, nitro, OH, C ₁ -C ₆ alkoxy, arylalkyloxy, C ₁ -C ₆ halo Alkyl, C ₁ -C ₃ perhaloalkyl, C ₁ -C ₆ haloalkoxy, C ₁ -C ₃ perhaloalkoxy, NR ¹ R ² , NR ¹ COR ³ , aryl, aryloxy, heteroaryl and heteroaryloxy Aryl or heteroaryl, which may be substituted with one or more, preferably up to 5 substituents selected from the group consisting of;

R is C ₁ -C ₆ alkylenyl;

R ¹ and R ² are each independently selected from the group consisting of H, C ₁ -C ₆ alkyl and C ₃ -C ₇ cycloalkyl; Or R ¹ and R ² together with the N atom to which they are attached form a 5- or 6-membered heterocycle;

R ³ is selected from the group consisting of H, C ₁ -C ₆ alkyl and C ₃ -C ₇ cycloalkyl;

Under sufficient time and conditions, optionally in the presence of a phase transfer catalyst, reacting a compound of Formula II with a Group I or Group II metal sulfite salt to produce a reaction mixture comprising said compound of Formula III:

[Formula II]

Ar-R-L

[Wherein L is a leaving group]; And

Precipitating the compound of formula III from the reaction mixture to separate said compound of formula III from the mixture. In some embodiments, precipitation may comprise (1) treating the reaction mixture with a water soluble metal halide salt, preferably NaCl; Or (2) adding to the reaction mixture a solvent which is not substantially miscible with water, preferably ethyl acetate; Or by treating 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 methods, the water soluble metal halide salt is NaCl. In further embodiments of each of these methods, the phase transfer catalyst is tetrabutyl ammonium iodide. In a further embodiment of each of these methods, the compound of formula II, for example 2,6-dimethyl benzyl chloride or 2,6-dimethyl benzyl bromide, is reacted with Na ₂ SO ₃ . In some further embodiments of the above methods, the alcohol solvent to which the protic acid is added is methanol. In some further embodiments of the above methods, the protic acid is gaseous HCl. In further embodiments, the compound of formula IV is separated through evaporation of the alcohol solvent.

In some embodiments of the method, the reaction of the sulfonic acid species of formula IV, for example 2,6-dimethylbenzyl sulfonic acid, with a halogen substituent, for example oxalyl chloride, is carried out at less than about −10 ° C. during oxalyl chloride addition. Is performed. Suitable solvents for the reaction include, for example, ethers (eg tetrahydrofuran) or mixtures of ethers.

In some embodiments of the method, Ar is halogen, C ₁ -C ₆ Alkyl, C ₃ -C ₇ cycloalkyl, heterocycloalkyl, cyano, nitro, OH, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, NR ¹ R ² , NR ¹ phenyl optionally substituted with one or more substituents independently selected from COR ³ , aryl and heteroaryl, preferably said substituent is C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, CN, NO ₂ , NR ¹ R ² and NR ¹ COR ³ are independently selected. In some preferred embodiments, Ar is phenyl substituted with one or more halogen, C ₁ -C ₆ alkyl, C ₁ -C ₃ perhaloalkyl, formyl or arylalkyloxy substituents. In some embodiments, Ar is in 2 or 6 position; Or phenyl substituted with one or more substituents at both the 2 and 6 positions. In other embodiments, Ar is phenyl substituted at the 3 and 4 positions, such as 3,4-dichloro phenyl. In some further embodiments of the process, R is C ₁ -C ₄ alkylene, or C ₁ -C ₆ straight chain alkylene, preferably methylene or ethylene, more preferably methylene.

In some embodiments of the method, L is independently halogen, OSO ₂ CH ₃ , OSO ₂ CF ₃ or OSO ₂ -aryl 'wherein aryl' is 1, independently selected from C ₁ -C ₃ alkyl and halogen Phenyl group optionally substituted with 2 or 3 substituents. Preferably L is Cl.

In some embodiments of the method, M is Na ⁺ ions or K ⁺ ions, preferably Na ⁺ ions.

In some embodiments of the method, X is Cl.

In some further preferred embodiments of the above methods, Ar is selected from halogen, C ₁ -C ₆ alkyl, C ₁ -C ₃ perhaloalkyl, formyl, arylalkyloxy, NR ¹ R ² and NR ¹ COR ³ Phenyl optionally substituted with one or more substituents; R is methylene or ethylene; R ¹ and R ² are each independently H or C ₁ -C ₆ Alkyl; R ³ is H or C ₁ -C ₆ alkyl; X is Cl; L is halogen; The metal sulfite salt of step (a) is Na ₂ SO ₃ ; The phase transfer catalyst of step (a) is present; Sulfonate compounds of Formula III have formula NaSO ₃ -R-Ar; Step (a) further comprises separation of the compound of formula III; Step (b) further comprises separation of the compound of formula IV; The halogen substituent of step (c) is oxalyl chloride.

In another preferred embodiment of the process of the invention, step (a) is carried out in the absence of a phase transfer catalyst. In some embodiments of the above, 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 process of the invention comprises (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 Used to prepare methanesulfonyl chloride.

Of the present invention Implementation  details

The present invention provides a process for the preparation of aryl- and heteroaryl-alkylsulfonyl halides comprising (2,6-dimethyl-phenyl) -methanesulfonyl chloride which is an intermediate in the synthesis of certain cPLA ₂ inhibitors. In some embodiments, the method generally involves the formation of sulfonic acid prior to conversion to sulfonyl halides.

A general overview of some embodiments of the process of the invention is shown in Scheme I, wherein the members of the compounds represented by Formulas I, II, III and IV have been defined above.

As shown in Scheme I, sulfonic acids of formula IV can be converted to sulfonyl halides by reaction with halogen substituents. Halogen substituents are reagents that can convert non-halogen substituents (eg H or OH) into halogen substituents herein. Halogen substituents of the present invention can, for example, convert sulfonic acid moieties to sulfonyl halide moieties. Many reagents capable of carrying out such conversions are known in the art. Some preferred halogen substituents include SOCl ₂ , POCl ₃ , CCl ₄ / triphenylphosphine, oxalyl chloride or oxalyl bromide. In some more preferred embodiments, the halogen substituent is oxalyl chloride. Halogen substituents are preferably used in excess, especially when there are residual solvents in the starting material, solvent or both. When oxalyl chloride is used as the halogen substituent, about 1 to about 6 equivalents relative to the amount of sulfonic acid reagent (compound of formula IV); It may be used in the range of about 2 to about 4 equivalents or about 3 to about 3.5 equivalents. One skilled in the art will recognize that the amount of halogen substituents used depends in particular on the amount of water in the starting material or solvent and on the properties and reactivity of the starting material and solvent.

Suitable solvents for the halogen substitution reaction (eg, step 3 in Scheme I) include any organic solvent capable of at least partially dissolving the compound of Formula IV. Preferred solvents include apolar or weak polar solvents including acetonitrile, aromatic hydrocarbons such as benzene and toluene, and halogenated solvents such as 1,2-dichloroethane and methylene chloride. More preferred solvent is ether. Suitable ethers include tetrahydrofuran, dioxane, diethyl ether, dibutyl ether, diisopropyl ether or mixtures thereof and the like. More 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 performed at about −40 ° C. to about room temperature. In some preferred embodiments, the reaction can be carried out below -10 ° C.

The sulfonyl halide-forming step (eg, step 3 of Scheme I) of the process of the present invention may also be carried out in the presence of an acyl transfer catalyst such as tertiary amide (eg dimethyl formamide). Acyl transfer catalyst may be provided in an amount sufficient to accelerate the reaction rate. In a preferred embodiment, the acyl transfer catalyst is present in less than about 1 equivalent relative to the amount of sulfonic acid reagent. In a more preferred embodiment, the acyl transfer catalyst comprises about 0.01 to 0.5 equivalents relative to the amount of sulfonic acid reagent; More preferably, in an amount of about 0.1 to about 0.2 equivalents.

Compounds of formula (I) can be separated from the reaction mixture by precipitation and filtration. Any number of well known precipitation induction methods can be used. In some preferred embodiments, anti-solvents such as water or solvents containing water may be added to the reaction mixture to induce precipitation. The use of water as an antisolvent is observed to reduce the rate of decomposition of the sulfonyl halide product relative to the rate of degradation observed when using organic solvents such as heptane, providing improved yields. In some preferred cases, precipitation may be facilitated by lowering the temperature of the reaction mixture, for example below about −20 ° C.

As shown in Scheme I, sulfonic acids of formula IV can be prepared by reacting sulfonic acid salts of formula III (sulfonate salts) with protic acids. Suitable protic acids are those having sufficient strength to convert the sulfonate salts to their corresponding acids according to the process of the invention. For example, the protic acid can be a strong inorganic acid such as HCl, HBr, H ₃ PO ₄ , HNO ₃ , HCl0 ₄ , H ₂ SO ₄ , and the like. In other embodiments, the protic acid can be an organic acid. Exemplary organic acids include form methanesulfonic acid, p-toluene sulfonic acid, benzenesulfonic acid, trifluoroacetic acid and other strong organic acids. In some embodiments, the 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 added to the reaction solvent comprising a sulfonate salt. In a preferred embodiment, the protic acid is provided in an molar amount relative to the sulfonic acid 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 is almost insoluble in metal halide salts, such as NaCl or KCl, so that the reaction can be thermodynamically driven by precipitation of the metal halide salt. In even more preferred embodiments, the solvent may comprise alcohols such as methanol, ethanol, isopropanol, and the like, or mixtures thereof. The solvent may also include water. In even more preferred embodiments, the solvent comprises methanol. The reaction temperature can be easily determined by one skilled in the art. For example, the reaction can be performed at a temperature below room temperature, such as from about -20 to about 10 ° C. In some preferred embodiments, the reaction can be carried out at about 0 or below about 10 ° C.

The sulfonic acid compounds of formula IV can be separated according to routine methods. Separation can be carried out, for example, by precipitation of the product from the reaction mixture. Precipitation can be induced by any suitable means. In some preferred embodiments, the precipitation is nonpolar organic, such as concentration of the reaction mixture (optionally azeotropic distillation), cooling (eg, below about 10 ° C.), and alkanes (eg, heptane, hexane, pentane, etc.). May be derived from any of the addition of solvents or combinations thereof.

The present invention also provides compounds of Formula II, optionally in the presence of a phase transfer catalyst as set forth in step 1 of Scheme 1 above:

[Formula II]

Ar-R-L

Wherein Ar, R and L are as defined above

Provided is a process for preparing sulfonic acid salts (sulfonate salts) of compounds of formula III by reacting with Group I or Group II metal sulfite salts. Any Group I or II metal sulfite salt is suitable, including but not limited to Li ₂ SO ₃ , Na ₂ SO ₃ , K ₂ SO ₃ , MgSO ₃ , CaS0 _3, and the like. The Group I or Group II metal sulfite salt may be provided in an excess molar amount, for example from about 2 equivalents to about 1 equivalent, relative to the amount of the compound of formula II. In some preferred embodiments, the metal salt is Na ₂ SO ₃ or K ₂ SO ₃ , more preferably Na ₂ S0 ₃ .

In a preferred embodiment, the formation of the sulfonate salt compound 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 tetrabutyl ammonium iodide. The phase transfer catalyst may be provided in an amount suitable to accelerate the reaction rate. In some preferred embodiments, the phase transfer catalyst is present at about 0.1 to 2 weight percent or more preferably 0.5 to 1 weight percent.

Any suitable solvent may be used, such as a solvent capable of at least partially dissolving Group I or Group II sulfite salts. In some embodiments, the solvent comprises water. In some preferred embodiments, the solvent contains at least about 50%, more preferably at least about 75%, even more preferably at least about 90%, even more preferably at least about 95%, even more preferably at least about 99% water. Include. The reaction can also be carried out at any suitable temperature. In some preferred embodiments, the temperature is raised. In even more preferred embodiments, the reaction is carried out at about 100 ° C.

Separation of the compound of formula III from the reaction mixture can be carried out in any routine manner. In some embodiments, the compound of formula III is precipitated from the reaction mixture. In some preferred embodiments, precipitation is facilitated by, for example, treating the reaction mixture with a water soluble inorganic salt. Without being bound by theory, it is believed that the addition of a sufficient amount of water-soluble inorganic salts thermodynamically drives the compound of formula III in solution, thereby facilitating separation and purification. In some preferred embodiments, the water soluble inorganic salt is NaCl or KCl, more preferably NaCl. In a further embodiment, the separation of the compound of formula III can be further facilitated by adding a mixture of organic solvents which are not substantially miscible with water to the reaction mixture. Examples of suitable solvents include ethyl acetate, ethers (eg, ethyl ether, etc.), alkanes (eg, hexane, petroleum ethers, etc.), aromatics (eg, benzene, toluene, xylene, etc.), and the like. Ethyl acetate is most preferred. Without wishing to be bound by theory, it is believed that the addition of an organic solvent helps to maintain impurities in the solvent when precipitating the compound of formula III. In some preferred embodiments, the reaction mixture may also be cooled (eg, below about 10 ° C.) to help induce precipitation.

Many advantages of the invention are apparent to those skilled in the art. For example, the preparation of sulfonic acid intermediates prior to sulfonyl halide formation allows for improved yields by avoiding the sulfur dioxide losses typically observed in the preparation of hindered sulfonyl halides. In addition, the preparation and separation methods described herein assist in maximum yields.

In some embodiments of the invention, the multistep method is performed step by step, with each intermediate being separated before proceeding to the next step. In other embodiments of the invention, certain intermediates are separated but the rest are not. In another embodiment, neither intermediate is completely separated and all the reactions take place in a single reaction vessel.

With respect to the above general description and the other groups described herein, it will be understood that in each case any of the various groups may be independently substituted by its permissible groups. Thus, for example, when a structure is described in which two R ₂ groups are simultaneously present in the same compound; The two R ₂ groups may represent different groups.

While features of the invention are described in the context of individual embodiments for clarity, it is contemplated that they may be provided in combination in a single embodiment. Conversely, various features of the invention may be provided separately or in any suitable subcombination, although are described in the context of a single embodiment for the sake of brevity.

The term "alkyl", when used alone, is defined herein as a straight-chain or branched saturated hydrocarbon moiety unless stated otherwise. In some embodiments, the alkyl moiety comprises 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.

The term "alkylenyl" refers to a divalent straight or branched chain alkyl group.

As used herein, "haloalkyl" refers to haloalkyl comprising perhalogenated species with up to one or more halogen substituents. Accordingly, examples of haloalkyl groups include perhaloalkyl groups such as CF ₃ , C ₂ F ₅ , CCl ₃ , C ₂ Cl _5, and the like, as well as groups having perhalo substituents such as CHF ₂ , CHCl _2, and the like. The term "perhaloalkyl" is intended to mean an alkyl group in which all of the hydrogen atoms are substituted with halogen atoms.

The term "alkoxy", used alone or in combination with other terms, is defined herein as -O-alkyl, unless stated otherwise. Examples of the alkoxy moiety include, but are not limited to, methoxy, ethoxy, isopropoxy, sec-butoxy, tert-butoxy and their homologues, isomers and the like.

The term "haloalkoxy", used alone or in combination with other terms, is defined as -O-haloalkyl unless stated otherwise herein. Examples of haloalkoxy moieties include, but are not limited to, chemical groups such as -OCF ₃ and the like.

The term "cycloalkyl", used alone or in combination with other terms, unless stated otherwise, refers to monocyclic, bicyclic, tricyclic, fused, bridged or spiro monovalent non-aromatic hydrocarbon moieties having from 3 to 8 or 3 to 7 carbon atoms. Is defined. The definition of cycloalkyl includes moieties having one or more aromatic rings fused to the non-aromatic ring (ie, having a common bond). Any suitable ring position of the cycloalkyl moiety may be covalently linked to the defined chemical structure. Examples of cycloalkyl moieties include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, adamantyl, spiro [4.5] decanyl and homologues, isomers, and the like.

As used herein, "heterocycloalkyl" refers to a cycloalkyl group (eg, 3 to 3, wherein one or more (eg, up to 4 atoms) is substituted with a heteroatom such as an O, S, N or P atom 12 atoms). Definitions of heterocycloalkyl also include moieties having at least one (eg, two) aromatic rings fused (ie, having a common bond) to a non-aromatic heterocyclic ring, for example phthalimidyl, naphthalimi Diphenyl pyromellitic acid diimidyl, phthalanyl and saturated heterocyclic benzo derivatives such as indole and isoindole groups. In some embodiments, heterocycloalkyl is a 3-12 membered group having the same or different 1-4 heteroatoms selected from oxygen, nitrogen and sulfur, wherein one or two benzene rings are fused therein, wherein the group It is bonded via a carbon or nitrogen atom of the ring.

The term "halo" or "halogen", used alone or in combination with other terms, means fluoro, chloro, bromo or iodo herein, unless stated otherwise.

The term "aryl", used alone or in combination with other terms, is defined herein as an aromatic hydrocarbon of up to 14 carbon atoms, unless stated otherwise, which is a monocyclic (monocyclic) or fused or covalently bonded to each other. It may be a multi-ring (bicyclic, up to 3 rings) connected by. Any suitable ring position of the aryl moiety may 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.

The term "aryloxy" as used herein, means a group of the formula -O-aryl, wherein the term "aryl" has the same definition as described above.

As used herein, alone or in combination with other terms, the term “arylalkyl” or “aralkyl” herein refers to alkyl, as defined above, substituted with an aryl moiety as defined above, unless stated otherwise. Is defined. Examples of arylalkyl moieties include, but are not limited to, chemistry such as benzyl, 1-phenylethyl, 2-phenylethyl, diphenylmethyl, 3-phenylpropyl, 2-phenylpropyl, fluorenylmethyl, and homologues, isomers, and the like. Groups are included.

The term "arylalkyloxy" as used herein, means a group of the formula -O-arylalkyl, wherein the term "arylalkyl" has the definitions described herein above.

As used herein, a "heteroaryl" group is a monocyclic and polycyclic (eg three ring) aromatic hydrocarbon having one or more heteroatom ring members such as sulfur, oxygen or nitrogen. Heteroaryl groups include, but are not limited to, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyryl , Oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, benzothienyl, fury Nyl, carbazolyl, benzimidazolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl-S-oxide, 2,3- Dihydrobenzothienyl-S-dioxide, benzoxazolin-2-one-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 can have from about 3 to about 20 carbon atoms. In some embodiments, the heteroaryl group has 1 to about 4, 1 to about 3 or 1 or 2 heteroatoms. In some embodiments, the heteroaryl is an aromatic 5 to 24 membered mono- or poly- (eg, di- or tri-) cyclic having the same or different 1-4 heteroatoms selected from oxygen, nitrogen and sulfur. It is.

As used herein, “heterocycle” means a heteroaryl or heterocycloalkyl group.

The term "heteroaryloxy" as used herein refers to a group of the formula -0-heteroaryl, and the term "heteroaryl" has the same meaning as described above herein.

As used herein, the term “leaving group” means a moiety that can be replaced with another moiety by a nucleophilic attack during a chemical reaction. Leaving groups are well known in the art, for example halides and OS0 ₂ -R 'wherein R' is optionally substituted with, for example, alkyl, haloalkyl, or halo, alkyl, alkoxy, amino, and the like. Aryl). Certain exemplary leaving groups include chloro, bromo, iodo, mesylate, tosylate and other similar groups.

As used herein, the term "reaction" means that a chemical reactant is brought together to define a chemical reactant to form a compound that is different from any initially introduced into the system. The reaction can occur in the presence or absence of a solvent.

As used herein, the term “precipitation” is used as known in the art and generally refers to the formation of a solid (eg, a precipitate) from a solution in which the solid is dissolved. The solid is amorphous or crystalline. Precipitation methods are well known in the art and include, for example, an increase in the proportion of solvents in which the solute is insoluble, a decrease in temperature, a chemical conversion that no longer becomes soluble in the solvent, and the like.

The compounds of the present invention may comprise asymmetric atoms, and some compounds may comprise one or more asymmetric atoms or centers, which may thus provide optical isomers (enantiomers) and diastereomers. The present invention includes the optical isomers (enantiomers) and diastereomers (geoisomers) as well as racemates, and as enantiomers, pure R and S stereoisomers, as well as other mixtures of R and S stereoisomers and pharmaceutical agents thereof Includes academically acceptable salts. Optical isomers can be obtained in pure form by standard procedures known to those skilled in the art, including but not limited to diastereomeric salt formation, kinetic cleavage and asymmetric synthesis. It will be appreciated that the present invention encompasses all possible regioisomers and mixtures thereof, which may be obtained in pure form by standard separation procedures known to those skilled in the art, including but not limited to column chromatography, thin layer chromatography and High performance liquid chromatography.

Compounds provided herein also include, for example, inorganic or organic salts of basic residues such as amines; Alkali or organic salts of acidic residues such as carboxylic acids; Salts thereof formed from the back and the like. The present invention includes acceptable salts formed by addition reactions with inorganic or organic acids. Additionally, the present invention includes quaternary ammonium salts of the compounds herein, which may be prepared by reaction of nucleophilic amines with a suitable reactive alkylating agent such as an alkyl halide or benzyl halide. A list of suitable salts is described in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is incorporated herein by reference.

The present invention includes all isotopic compounds occurring in intermediates or final compounds. Isotopes include those having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.

Compounds of the invention also include tautomeric forms such as keto-enol tautomers. Tautomeric forms may be equilibrated or sterically locked to one form by suitable substituents.

The methods described herein can be monitored according to any suitable method known in the art. For example, product formation may be performed by spectroscopic means such as nuclear magnetic resonance spectrometers (eg, ¹ H or ¹³ C), infrared spectrometers, spectrophotometers (eg, UV-visible) or mass spectrometers, or high performance liquids It can be monitored by chromatography, such as chromatography (HPLC) or thin layer chromatography.

The reactions of the methods described herein can be carried out in a suitable solvent that can be readily selected by one skilled in the art of organic synthesis. Suitable solvents may be substantially unreactive with the starting material (reactant), intermediate, or product at the temperature at which the reaction is carried out, for example at a temperature that may range from the freezing point of the solvent to the boiling point of the solvent. The presented reaction can be carried out in one solvent or in a mixture of one or more solvents. Depending on the particular reaction stage, a solvent suitable for the particular reaction stage can be selected. In some embodiments, the reactions can be carried out in the absence of a solvent, such as when one or more of the reactants is a liquid or a gas. Some exemplary solvents suitable for the methods described herein include halogenated hydrocarbons (eg methylene chloride), aromatic hydrocarbons (eg benzene, toluene and the like) and ethers (eg diethyl ether, tetrahydrofuran and the like). Included.

The reaction of the methods described herein can be carried out at a suitable temperature that can be readily determined by one skilled in the art. The reaction temperature can be, for example, the melting and boiling points of the reactants and the solvent, if present; Thermodynamics of the reaction (eg very exothermic reactions are generally carried out at lowered temperatures); It will depend on the kinetics of the reaction (eg, high activation energy barriers generally require elevated temperatures). “Elevated temperature” means a temperature above room temperature (about 20 ° C.), and “decreased temperature” means a temperature below room temperature.

The reaction of the methods described herein can be carried out in air or under an inert atmosphere. In general, reactions involving reagents or products that are substantially reactive with air can be performed using air-sensitive synthesis techniques well known to those skilled in the art.

In carrying out the preparation of the compounds according to the methods described herein, general separation and purification operations such as concentration, filtration, extraction, solid phase extraction, recycle, chromatography and the like can be used to separate the desired products.

In some embodiments of the methods described herein, the following exemplified compounds may be prepared from their respective preparative materials, as shown in Table 1 and Examples below.

The invention will be explained in more detail by specific examples. The following examples are provided for illustrative purposes and are not intended to limit the invention in any way. Those skilled in the art will readily recognize various variable parameters that can be modified or modified to provide essentially the same results.

Example 1

Preparation of (2,6-dimethyl-phenyl) -methanesulfonyl chloride

Step 1: Preparation of (2,6-dimethyl-phenyl) -methanesulfonic acid sodium salt

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 heated to reflux for 1 hour. Sodium chloride (526 g) and ethyl acetate (1.4 l) were added while cooling the mixture to room temperature. The mixture was stirred and cooled to below 10 ° C. The product was collected by filtration and washed with ethyl acetate (250 mL) and acetone (500 mL). The product was dried in vacuo to 60 ° C. until constant mass to give (2,6-dimethyl-phenyl) -methanesulfonic acid sodium salt (634 g, 88%).

및

And

Step 2: Preparation of (2,6-dimethyl-phenyl) -methanesulfonic acid

Methanol (2.2 L) and (2,6-dimethyl-phenyl) -methanesulfonic acid sodium salt (185 g) were placed in a multi-necked 5 L flask equipped with an overhead stirrer. The mixture was cooled to 0 ° C, hydrogen chloride (112 g) was passed through the mixture while keeping the internal temperature below 10 ° C. The mixture was stirred for 2 hours and warmed to room temperature. The mixture was filtered off. The filtrate was concentrated to a volume of 600 mL at room temperature, and azeotropically distilled with toluene (3 x 600 mL). Heptane (1.1 L) was added to the mixture while cooling below 10 ° C. The solid product was collected by filtration and washed with heptane (100 mL). The product was dried at 40 ° C. in vacuo until constant mass to give (2,6-dimethyl-phenyl) -methanesulfonic acid (149 g, 89%).

및

And

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 KF analysis, or 266 g water when calibrated with water content) and N, N -Dimethylformamide (15 g) was placed in a 5 L multineck flask equipped with an overhead stirrer. The reaction mixture was cooled to -20 ° C and oxalyl chloride (655.5 g) was added slowly over 1 hour. The reaction mixture was purified by filtration and concentrated to 1 L of volume. The filtrate was transferred to a flask equipped with an overhead stirrer and cooled to -40 ° C. Water (900 mL) was added over 30 minutes while maintaining the internal temperature below -10 ° C. The product was collected by filtration, washed with water and heptane and dried to give (2,6-dimethyl-phenyl) -methanesulfon chloride (277 g, 96%).

및

And

Example 2

Preparation of (2-methylphenyl) -methanesulfonyl chloride

Step 1: Preparation of (2-methylphenyl) -methanesulfonic acid sodium salt

Using the procedure described in Example 1, Step 1, α-bromo-o-xylene (100 g, 0.54 mol) is a white solid of (2-methylphenyl) -methanesulfonic acid sodium salt (75 g, 66%) Provided. LC-MS showed molecular ions of sulfonic acid. (G8382-72, G8382-49)

Step 2: Preparation of (2-methylphenyl) -methanesulfonic acid

Using the procedure described in Example 1, step 2, the (2-methylphenyl) -methanesulfonic acid sodium salt (12 g, 58 mmol) is a pale yellow solid (2-methylphenyl) -methanesulfonic acid (10.6 g, -100%). ) (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) provided (2-methylphenyl) -methanesulfonyl chloride (11.8 g, 100%).

Example 3

Preparation of (2,6-difluorophenyl) -methanesulfonyl chloride

Step 1: Preparation of (2,6-difluorophenyl) -methanesulfonic acid sodium salt

Using the procedure described in Example 1, Step 1, 2,6-difluorobenzyl bromide (50 g, 0.24 mol) is a white solid of (2,6-difluorophenyl) -methanesulfonic acid sodium salt (38.9 g, 70%). (G8324-105)

Step 2: Preparation of (2,6-difluorophenyl) -methanesulfonic acid

Using the procedure described in Example 1, Step 2, (2,6-difluorophenyl) -methanesulfon sodium salt (10 g, 44 mmol) is a viscous orange oil (2,6-difluoro Phenyl) -methanesulfonic acid (9.5 g) was provided and 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) was obtained from (2,6-difluorophenyl) -methanesulfonyl chloride ( 1.3 g, 14%).

Example 4

Preparation of 2-fluoro-6- (trifluoromethylphenyl) -methanesulfonyl chloride

Step 1: Preparation of 2-Fluoro-6- (trifluoromethylphenyl) -methanesulfonic acid sodium salt

Using the procedure described in Example 1, Step 1, 2-fluoro-6- (trifluoromethylphenyl) benzyl bromide (15 g, 61 mmol) is a white solid 2-fluoro-6- (trifluoro Methylphenyl) -methanesulfonic acid sodium salt (15 g, 89%) was provided.

Step 2: Preparation of 2-fluoro-6- (trifluoromethylphenyl) -methanesulfonic acid

Using the procedure described in Example 1, Step 2, 2-fluoro-6- (trifluoromethylphenyl) -methanesulfonic acid sodium salt (15 g, 53 mmol) is 2-fluoro-6- which is a pale orange oil. (Trifluoromethylphenyl) -methanesulfonic acid (15 g) was provided and used without further purification.

Step 3: Preparation of 2-fluoro-6- (trifluoromethylphenyl) -methanesulfonyl chloride

Using the procedure described in Example 1, Step 3, 2-fluoro-6- (trifluoromethylphenyl) -methanesulfonic acid (15 g, 53 mmol) gave 11 g of crude product, which was obtained from hexane Purification by low temperature crystallization gives 2-fluoro-6- (trifluoromethylphenyl) -methanesulfonyl chloride (9.0 g, 62%).

Example 5

Preparation of 2,6-bis (trifluoromethylphenyl) -methanesulfonyl chloride

Step 1: Preparation of 2,6-bis (trifluoromethyl) benzoyl fluoride

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 an orange solid acid chloride (7.0 g, 100%).

Step 2: Preparation of 2,6-bis (trifluoromethylphenyl) benzyl alcohol

W. Dmowski and K. Piasecka- Maciejewska, Tetrahedron Lett. 1998,54, 6781-6792 was used to convert 7.0 g of 2,6-bis (trifluoromethyl) benzoyl fluoride to an alcohol (6.6 g, 100%) which was a cloudy yellow oil.

Step 3: Preparation of 2,6-bis (trifluoromethylphenyl) benzyl bromide

로 여과시키고 농축했다. 황색 오일을 2% EtOAc-Hex 에 현탁시키고, Si0₂ 의 패드를 통해 여과하여 무색 오일인 브로마이드 (7.2 g, 84%) 를 수득했다.CH ₂ Cl ₂ of 2,6-bis (trifluoromethylphenyl) benzyl alcohol (6.6 g, 28 mmol) and 1,3-bis (diphenylphosphino) propane (6.9 g, 17 mmol) at 0 ° C. ( 50 mL) was slowly added carbon tetrabromide (11 g, 33 mmol). The mixture was stirred overnight at room temperature, then 200 mL Et ₂ 0 was added by pipette. Celite Mixture

Filtered and concentrated. The yellow oil was suspended in 2% EtOAc-Hex and filtered through a pad of Si0 ₂ to give a colorless oil, bromide (7.2 g, 84%).

Step 4: Preparation of 2,6-bis (trifluoromethylphenyl) -methanesulfonic acid sodium salt

Using the procedure described in Example 1, Step 1, 2,6-bis (trifluoromethylphenyl) benzyl bromide (7.2 g, 23 mmol) was a white solid 2,6-bis (trifluoromethylphenyl) -methane Sodium sulfonic acid salt (3.2 g, 32%) was provided. (L27132-19)

Step 5: Preparation of 2,6-bis (trifluoromethylphenyl) -methanesulfonic acid

Using the procedure described in Example 1, Step 2, 2,6-bis (trifluoromethylphenyl) -methanesulfonic acid sodium salt (0.19 g, 0.44 mmol) is an orange oil, 2,6-bis (trifluoromethylphenyl ) -Methanesulfonic acid (0.14 g, 100%) was provided and used without further purification.

Step 6: Preparation of 2,6-bis (trifluoromethylphenyl) -methanesulfonyl chloride

Using the procedure described in Example 1, step 3, 2,6-bis (trifluoromethylphenyl) -methanesulfonic acid (0.14 g, 0.44 mmol) provided 99 mg of crude product, which was cold crystallization from hexanes. Purification with 2 gave 2,6-bis (trifluoromethylphenyl-) methanesulfonyl chloride (33 mg, 23%) as a white powder.

Example 6

Preparation of (2-trifluoromethylphenyl) -methanesulfonyl chloride

Step 1: Preparation of (2-trifluoromethylphenyl) -methanesulfonic acid sodium salt

Using the procedure described in Example 1, Step 1, 2- (trifluoromethyl) benzyl bromide (25 g, 0.14 mol) is a white solid of (2-trifluoromethylphenyl) -methanesulfonic acid sodium salt (22.2 g , 60%). LC-MS showed molecular ions of sulfonic acid. (G9381-183)

Step 2: Preparation of (2-trifluoromethylphenyl) -methanesulfonic acid

Using the procedure described in Example 1, Step 2, the (2-trifluoromethylphenyl) -methanesulfonic acid sodium salt (22.2 g, 84 mmol) is a pale yellow solid (2-trifluoromethylphenyl) -methanesulfonic acid ( 20.3 g, -100%). (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) was crystallized from petroleum ether and was then a white solid (2-trifluoromethylphenyl). Methanesulfonyl chloride (19.6 g, 90%) was provided.

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. The mixture was acidified with 6N HCl while cooling to 0 ° C. Extraction with ethyl acetate (100 ml x 6) was performed (some remaining in the aqueous layer). The combined organic layer was dried over MgSO ₄ . The filtrate was concentrated in vacuo. The product was triturated with ethyl ether to give (2-benzyloxy-phenyl) -methanesulfonic acid (678 mg, 8%).

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 and oxalyl chloride (315 mg) Was added slowly. The reaction mixture was stirred for 3 h from -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%).

Example 8

Preparation of (2,3-dichlorophenyl) -methanesulfonyl chloride

Step 1: Preparation of (2,3-dichlorophenyl) -methanesulfonic acid sodium salt

To a suspension in 20 mL water of 2,3-dichlorobenzyl chloride (0.68 mL, 5.0 mmole) was added sodium sulfite (630 mg, 5.0 mmole) and the mixture was heated to reflux overnight. The reaction mixture was evaporated completely on a rotary evaporator and dried under vacuum to give the sodium salt of (2,3-dichlorophenyl) -methanesulfonic acid as a white solid.

Step 2: Preparation of (2,3-dichlorophenyl) -methanesulfonic acid

로 여과시키고 증발시켰다. 수득한 잔사를 60 mL 의 무수 아세톤으로 분쇄하고 여과했다. 여과액을 증발시켜 황색 반고체를 수득했다. 상기 고체를 40 mL 의 2:1 에테르:헥산으로 분쇄했다. 수득한 고체를 여과하고 헥산으로 세척하여 902 mg 의 (2,3-디클로로페닐)-메탄술폰산을 수득했다. The sodium salt of (2,3-dichlorophenyl) -methanesulfonic acid (5.0 mmole) was suspended in 50 mL MeOH, stirred at 50 ° C. for 1 hour and then cooled to −10 ° C. HCl gas was bubbled for several seconds, and the obtained white suspension was stirred at -10 ° C for 1 hour. Celite Mixture

Filtered and evaporated. The obtained residue was triturated with 60 mL of anhydrous acetone and filtered. The filtrate was evaporated to yield a yellow semisolid. The solid was triturated with 40 mL of 2: 1 ether: hexanes. The obtained solid was filtered and washed with hexane to give 902 mg of (2,3-dichlorophenyl) -methanesulfonic acid.

Step 3: Preparation of (2,3-dichlorophenyl) -methanesulfonyl chloride

로 여과하고, 추가의 15 mL 무수 THF 로 Celite

를 헹구어냈다. 여과액을 약 5 mL 의 부피로 증발시킨 후, 5 mL 의 물을 소량씩 첨가하고, 수조에서 용기를 냉각시켰다. 혼합물을 2 ×25 mL EtOAc 로 추출하 고, 유기물을 조합해, 포화 중탄산나트륨, 식염수로 세척하고, 건조시켰다 (MgS0₄). 여과 및 증발로 미정제 생성물을 황색 오일로서 수득했다. 5% EtOAc/헥산에서 30% EtOAc/헥산으로의 구배를 이용한 실리카 겔 상의 크로마토그래피는 142 mg 의 (2,3-디클로로페닐)-메탄술포닐 클로라이드를 백색 고체로서 제공했다. (2,3-dichlorophenyl) -methanesulfonic acid (260 mg, 1.0 mmole) was dissolved in 5 mL anhydrous THF and cooled to 0 ° C. A catalytic addition of DMF was added followed by oxalyl chloride (0.44 mL, 5.0 mmole). The reaction mixture is allowed to come to room temperature over 90 minutes and then Celite

Filter with Celite and additional 15 mL anhydrous THF

Rinse off. After the filtrate was evaporated to a volume of about 5 mL, 5 mL of water was added in small portions and the vessel was cooled in a water bath. The mixture was extracted with 2 x 25 mL EtOAc and the organics combined and washed with saturated sodium bicarbonate, brine and dried (MgS0 ₄ ). Filtration and evaporation gave the crude product as a yellow oil. Chromatography on silica gel using a gradient from 5% EtOAc / hexanes to 30% EtOAc / hexanes provided 142 mg of (2,3-dichlorophenyl) -methanesulfonyl chloride as a white solid.

Example 9

Preparation of (2-formyl-phenyl) -methanesulfonyl chloride

Step 1: Preparation of 2-bromomethyl-benzaldehyde

To α-bromo-o-tolunitrile (10 g, 51 mmol) in DCM is added DIBAL-H (1 M in hexane, 55 mL, 55 mmol) at 0 ° C. and the reaction mixture is stirred for 3.5 hours at the same temperature. After stirring for a while, a solution of cold 5% HBr was poured. After stirring for an additional 15 minutes, the layers were separated, the aqueous layer was extracted with DCM and the combined organic layers were washed with NaHCO ₃ and water, dried over MgSO ₄ and evaporated to give a dark liquid (9.4 g). The material was used directly in the next step without further purification.

Step 2: Preparation of (2-formyl-phenyl) -methanesulfonic acid sodium salt

Using the procedure described in Example 1, Step 1, 2-bromomethyl-benzaldehyde (1.58 g, 7.94 mol) is a near white solid (2-formyl-phenyl) -methanesulfonic acid sodium salt (1.40 g, 80%). (L27234-72)

Step 3: Preparation of (2-formyl-phenyl) -methanesulfonic acid

Using the procedure described in Example 1, Step 2, (2-formyl-phenyl) -methanesulfonic acid sodium salt (1.40 g, 6.30 mmol) is a pale yellow solid (2-formyl-phenyl) -methanesulfonic acid (418 mg, 33%). (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) was (2-formyl-phenyl) -methanesulfonyl chloride (367 mg, 80 %) Provided.

Example 10

Preparation of (3,4-dichlorophenyl) -methanesulfonyl chloride

The title compound can be prepared by one skilled in the art by appropriate modification of the procedure described in Example 8, such as replacing 2,3-dichlorobenzyl chloride as starting material in Step 1 with 3,4-dichlorobenzyl chloride.

Those skilled in the art will recognize that various changes and / or modifications may be made to the aspects or embodiments of the invention, and that such changes and / or modifications may be made without departing from the spirit of the invention. Accordingly, the appended claims imply that all such equivalent variations are within the scope of the present invention. This application was previously filed on February 25, 2004 in U.S. Pat. Provisional Application No. 60 / 547,600 is claimed as a priority, which is incorporated herein by reference in its entirety. All printed publications, including each patent, application, and book mentioned in the above patent documents, are incorporated herein by reference in their entirety.

Claims (31)

A process for preparing a compound of formula (I) comprising the following steps (a) to (c) [Formula I] Ar-R-S0 ₂ -X [In meals: Ar is halogen, C ₁ -C ₆ alkyl, C ₃ -C ₇ Cycloalkyl, heterocycloalkyl, formyl, cyano, nitro, OH, C ₁ -C ₆ alkoxy, arylalkyloxy, C ₁ -C ₆ haloalkyl, C ₁ -C ₃ perhaloalkyl, C ₁ -C ₆ Aryl or heteroaryl optionally substituted with one or more substituents selected from the group consisting of haloalkoxy, C ₁ -C ₃ perhaloalkoxy, NR ¹ R ² , NR ¹ COR ³ , aryl, aryloxy, heteroaryl and heteroaryloxy Is; R is C ₁ -C ₆ alkylenyl; R ¹ and R ² are each independently selected from the group consisting of H, C ₁ -C ₆ alkyl and C ₃ -C ₇ cycloalkyl; Or R ¹ and R ² together with the N atom to which they are attached form a 5- or 6-membered heterocycle; R ³ is selected from the group consisting of H, C ₁ -C ₆ alkyl and C ₃ -C ₇ cycloalkyl; X is halogen; (a) reacting a compound of formula II with a group I or group II metal sulfite salt, optionally in the presence of a phase transfer catalyst, to produce a sulfonic acid salt compound of formula III: [Formula II] Ar-R-L [Wherein L is a leaving group]; [Formula III] (Ar-R-SO ₃ ^-1 ) _q M [Wherein M is a Group I or Group II metal ion; Q is 1 when M is a Group I metal ion; Q is 2 when M is a Group II metal ion; (b) reacting the compound of Formula III with a protic acid to prepare a sulfonic acid compound of Formula IV: [Formula IV] Ar-R-SO ₃ H And (c) reacting the compound of Formula IV with a halogen substituent to prepare a compound of Formula I. The process of claim 1 wherein the reaction of step (a) is carried out in the presence of a phase transfer catalyst. The process according to claim 1 or 2, wherein step (a) further comprises separation of the compound of formula III by precipitation of the compound of formula III and optional filtration of the precipitate obtained. The process according to claim 1, wherein the reaction of step (a) is carried out in a solvent comprising water. The method of claim 4 wherein said precipitation is promoted by: (1) treating the reaction mixture of step (a) with a water soluble metal halide salt; or (2) adding a solvent that is substantially immiscible with water to the reaction mixture of step (a); or Both (1) and (2). 6. The method of claim 5 wherein said water soluble metal halide salt comprises NaCl. 7. The process of claim 5 or 6 wherein said solvent that is not substantially miscible with water comprises ethyl acetate. The group according to claim 1, wherein the protic acid of step (b) consists of HCl, HBr, H ₃ PO ₄ , HNO ₃ , HCl 0 ₄ and H ₂ SO ₄ , or a combination thereof. Selected from. The method of claim 8, wherein the protic acid comprises HCl. 10. The method of claim 9, wherein said protic acid comprises gaseous HCl. The process according to claim 1, wherein said reaction of step (b) is carried out in a solvent comprising an alcohol. The method of claim 11, wherein the alcohol comprises methanol. 13. The process according to any one of claims 1 to 12, wherein step (b) further comprises the separation of the compound of formula IV by precipitation of the compound of formula IV and optional filtration of the precipitate obtained. The process of claim 1, wherein the halogen substituent is selected from the group consisting of SOCl ₂ , POCl ₃ , CCl ₄ / triphenylphosphine, oxalyl chloride and oxalyl bromide. 15. The method of claim 14, wherein said halogen substituent comprises oxalyl chloride. The process according to any one of claims 1 to 15, wherein said reaction of step (c) is carried out in the presence of an acyl transfer catalyst. The method of claim 16, wherein the acyl transfer catalyst comprises a tertiary amine. The method of claim 16, wherein the acyl transfer catalyst comprises N, N-dimethylformamide. 19. The compound of any of claims 1-18, wherein Ar is halogen, C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, heterocycloalkyl, formyl, cyano, nitro, OH, C _1- C ₆ alkoxy, arylalkyloxy, C ₁ -C ₆ haloalkyl, C ₁ -C ₃ perhaloalkyl, C ₁ -C ₆ haloalkoxy, C ₁ -C ₃ perhaloalkoxy, NR ¹ R ² , NR ¹ COR ³ , aryl, aryloxy, heteroaryl and heteroaryloxy, phenyl optionally substituted with one or more substituents independently selected from the group consisting of. 20. The method of claim 19, wherein Ar is phenyl substituted with one or more substituents selected from the group consisting of halogen, C ₁ -C ₆ alkyl, C ₁ -C ₃ perhaloalkyl, formyl and arylalkyloxy. 21. The method of any one of claims 1 to 20, wherein R is C ₁ -C ₄ alkylene. The method of claim 21, wherein R is methylene. 23. The compound of any of claims 1 to 22, wherein L is halogen, OSO ₂ CH ₃ , OSO ₂ CF ₃ and OS0 ₂ -aryl ', wherein aryl is composed of C ₁ -C ₃ alkyl and halogen A phenyl group optionally substituted with 1, 2 or 3 substituents independently selected from the group. The method of claim 23, wherein L is Cl. The method of claim 1, wherein M is Na ⁺ ions or K ⁺ ions. 26. The method of any one of claims 1 to 25, wherein X is Cl. The method of claim 1, Ar is phenyl optionally substituted with one or more substituents selected from the group consisting of halogen, C ₁ -C ₆ alkyl, C ₁ -C ₃ perhaloalkyl, formyl, arylalkyloxy, NR ¹ R ² and NR ¹ COR ³ Is; R is methylene or ethylene; R ¹ and R ² are each independently H or C ₁ -C ₆ alkyl; R ³ is H or C ₁ -C ₆ alkyl; X is Cl; L is halogen; The metal sulfite of step (a) is Na ₂ SO ₃ ; The phase transfer catalyst of step (a) is present; The sulfonic acid salt compound of formula III has formula NaSO ₃ -R-Ar; Said step (a) further comprises the separation of said compound of formula III; Step (b) further comprises separation of the compound of formula IV; Wherein said halogen substituent of step (c) comprises oxalyl chloride. A compound according to claim 1, wherein the compound of formula I is selected from (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-benzyloxy-phenyl) -methanesulfonyl chloride, (2,3-dichlorophenyl) -methanesulfonyl chloride or (2-formylphenyl ) -Methanesulfonyl chloride. 19. The method of any one of claims 1 to 18, wherein in the compounds of formula I, Ar, R and X are selected from the table below:

A process for preparing a compound of formula IV comprising the following steps a) to b): [Formula IV] Ar-R-SO ₃ H [In meals: Ar is halogen, C ₁ -C ₆ alkyl, C ₃ -C ₇ Cycloalkyl, heterocycloalkyl, formyl, cyano, nitro, OH, C ₁ -C ₆ alkoxy, arylalkyloxy, C ₁ -C ₆ haloalkyl, C ₁ -C ₃ perhaloalkyl, C ₁ -C ₆ Aryl or heteroaryl optionally substituted with one or more substituents selected from the group consisting of haloalkoxy, C ₁ -C ₃ perhaloalkoxy, NR ¹ R ² , NR ¹ COR ³ , aryl, aryloxy, heteroaryl and heteroaryloxy Is; R is C ₁ -C ₆ alkylenyl; R ¹ and R ² are each independently selected from the group consisting of H, C ₁ -C ₆ alkyl and C ₃ -C ₇ cycloalkyl; Or R ¹ and R ² together with the N atom to which they are attached form a 5- or 6-membered heterocycle; R ³ is selected from the group consisting of H, C ₁ -C ₆ alkyl and C ₃ -C ₇ cycloalkyl; a) preparing a sulfonic acid salt compound of formula III by reaction of a compound of formula II with a group I or group II metal sulfite salt, optionally in the presence of a phase transfer catalyst: [Formula II] Ar-R-L [Wherein L is a leaving group]; [Formula III] (Ar-R-SO ₃ ^-1 ) _q M [Wherein M is a group I or group II metal ion, Q is 1 when M is a Group I metal ion, and q is 2 when M is a Group II metal ion; And b) reacting the compound of formula III with a protic acid to prepare a compound of formula IV. A process for preparing a compound of formula III comprising the steps of [Formula III] (Ar-R-SO ₃ ^-1 ) _q M [Wherein M is a Group I or Group II metal ion, q is 1 when M is a Group I metal ion, and q is 2 when M is a Group II metal ion; Ar is halogen, C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, heterocycloalkyl, formyl, cyano, nitro, OH, C ₁ -C ₆ alkoxy, arylalkyloxy, C ₁ -C ₆ halo Alkyl, C ₁ -C ₃ perhaloalkyl, C ₁ -C ₆ haloalkoxy, C ₁ -C ₃ perhaloalkoxy, NR ¹ R ² , NR ¹ COR ³ , aryl, aryloxy, heteroaryl and heteroaryloxy Aryl or heteroaryl optionally substituted with one or more substituents independently selected from the group consisting of; R is C ₁ -C ₆ alkylenyl; R ¹ and R ² are each independently selected from the group consisting of H, C ₁ -C ₆ alkyl and C ₃ -C ₇ cycloalkyl; Or R ¹ and R ² together with the N atom to which they are attached form a 5- or 6-membered heterocycle; R ³ is selected from the group consisting of H, C ₁ -C ₆ alkyl and C ₃ -C ₇ cycloalkyl; Reacting a compound of formula II with a group I or group II metal sulfite salt, optionally in the presence of a phase transfer catalyst, to produce a reaction mixture comprising the compound of formula III: [Formula II] Ar-R-L [Wherein L is a leaving group]; And Separating the compound of formula III; Wherein said separation is performed by precipitating said compound of formula III from said reaction mixture: The precipitation is promoted by: (1) treating the reaction mixture with a water soluble metal halide salt; or (2) adding a solvent that is not substantially miscible with water to the reaction mixture; or Both of (1) and (2).