HK1069578B

HK1069578B - Method for preparing benzenesulfonyl compounds

Info

Publication number: HK1069578B
Application number: HK05102121.3A
Authority: HK
Inventors: L．J．勒滕迪尔; S．A．昆达; D．J．伽拉赫尔; L．M．肖尼; K．麦克劳格林
Original assignee: 法玛西雅公司
Priority date: 2001-10-02
Filing date: 2002-10-02
Publication date: 2007-09-07

Description

Process for preparing benzenesulfonyl compounds

background

Technical Field

The present invention relates to a process for the preparation of aromatic sulfonyl chlorides and isoxazolyl benzenesulfonamides. The process is particularly directed to a process for the preparation of valdecoxib, parecoxib, sodium parecoxib and 4- [ 5-methyl-3-phenylisoxazol-4-yl ] benzenesulfonyl chloride.

Description of related Art

Substituted isoxazole compounds useful for treating inflammation are described in U.S. Pat. No. 5,633,272. A process for preparing substituted isoxazol-4-yl benzenesulfonamide compounds is described in U.S. Pat. No. 5,859,257. Methods for preparing prodrugs of COX-2 inhibitors are described in U.S. Pat. No. 5,932,598. Ullmann's Encyclopedia of Industrial chemistry, 5th edition Vol.A3 page 513 describes the preparation of aromatic sulfonyl chlorides using excess chlorosulfonic acid. Ullmann's Encyclopedia also describes the preparation of aromatic sulfonamides from aromatic sulfonyl chlorides.

In the chlorosulfonation reaction, secondary reactions such as sulfone formation and polychlorinated sulfonation can be minimized by utilizing a large excess of chlorosulfonic acid by diluting with a solvent or adding a sulfone formation inhibiting substance, as described in U.S. patent 5,136,043. The addition of an additional chlorinating agent, such as thionyl chloride (EP115,328) complicates the process because of the incorporation of additional operations, complicating waste disposal, while not solving the reactivity problem due to the insolubility of the reactants. The use of chlorinated solvents such as carbon tetrachloride, chloroform or methylene chloride, although partially solving some of the solubility problems, complicates the process operation by generating two-phase reactants, creates employee contamination problems due to the volatility and toxicity of these solvents, and introduces these chlorinated solvents into the waste stream. Japanese patent application No. JP06-145227 describes the reaction of High Density Polyethylene (HDPE) with sulfonyl chloride in trifluoroacetic acid in the presence of AIBN (group forming agent) to give chlorosulfonated polyethylene, which is used in the manufacture of rubber.

Summary of The Invention

The synthesis of aromatic sulfonamides and the use of isoxazolyl benzenesulfonamide compounds in the treatment of inflammation are working on meeting the ongoing need for economical, practical and environmentally acceptable methods of preparing these compounds.

The present invention provides novel general preparations of aromatic sulfonyl halide compounds and corresponding isoxazolyl benzenesulfonamide compounds, N- [ [4- (3-phenylisoxazol-4-yl) benzeneBase of]Sulfonyl radical]Propionamide compound and N- [ [4- (3-phenylisoxazol-4-yl) phenyl group]Sulfonyl radical]A method for preparing propionamide sodium salt compound. Mention may be made, in several embodiments of the invention, of processes for the preparation of aromatic sulfonyl halide compounds; preparation of [ isoxazol-4-yl]Benzenesulfonamide compounds, N- [ [4- (3-phenylisoxazol-4-yl) phenyl]Sulfonyl radical]Propionamide compound and N- [ [4- (3-phenylisoxazol-4-yl) phenyl group]Sulfonyl radical]A method for preparing propionamide sodium salt compound. In one embodiment of the present invention, the present invention provides a process for preparing a compound having formula (I)1Of the structure [ isoxazol-4-yl]Method of benzenesulfonamide compound:

wherein the process comprises reacting a compound selected from the group consisting of formula (la) and (lb) in the presence of trifluoroacetic acid2And formula3The precursor compound of (a):

contacting with halosulfonic acid to produce a halosulfonated product; and contacting the halosulfonated product with a source of ammonia to produce a product having formula1Of the structure [ isoxazol-4-yl]A benzenesulfonamide compound (valdecoxib).

In another embodiment of the invention, the invention provides a process for the preparation of N- [ [4- (3-phenylisoxazol-4-yl) phenyl ] sulfonyl ] propanamide (paleachoxib) having the structure of formula 1 a:

wherein the process comprises reacting a compound selected from the group consisting of formula (la) and (lb) in the presence of trifluoroacetic acid2And contacting the precursor compound of formula 3 with a halosulfonic acid to form a halosulfonated product; and contacting the halosulfonated product with a source of ammonia to form [ isoxazol-4-yl]A benzenesulfonamide; and make sulfurContacting the amide with a propionating agent to produce a compound having the formula1aN- [ [4- (3-phenylisoxazol-4-yl) phenyl ] of structure]Sulfonyl radical]Propionamide compounds.

In another embodiment of the invention, the invention provides a process for preparing N- [ [4- (3-phenylisoxazol-4-yl) phenyl ] sulfonyl ] propanamide sodium salt (sodium paleachoxib) having the structure of formula 1 b:

wherein the process comprises reacting a compound selected from the group consisting of formula (la) and (lb) in the presence of trifluoroacetic acid2And formula3Contacting the precursor compound of (a) with a halosulfonic acid to form a halosulfonated product; and contacting the halosulfonated product with a source of ammonia to form [ isoxazol-4-yl]A benzenesulfonamide; and contacting the sulfonamide with a propionating agent to form N- [ [4- (3-phenylisoxazol-4-yl) phenyl]Sulfonyl radical]Propionamide; and contacting the propionamide with a sodium base to produce a compound having the formula1bN- [ [4- (3-phenylisoxazol-4-yl) phenyl ] of structure]Sulfonyl radical]Propionamide sodium salt compound.

In another embodiment of the invention, the invention provides a process for preparing a compound of formula (I)1N- [ [4- (3-phenylisoxazol-4-yl) phenyl ] of structure]Sulfonyl radical]A method of sulfonamides, wherein the method comprises contacting 1, 2-diphenylethanone with a source of hydroxylamine to form a diphenylethanone oxime derivative; and contacting the oxime compound with a strong base and an acetylating agent to produce a diphenylisoxazoline derivative compound; and contacting the diphenylisoxazoline derivative compound with trifluoroacetic acid and a halosulfonic acid to produce a halosulfonated product; and contacting the halosulfonated product with a source of ammonia to produce a product having formula1Of the structure [ isoxazol-4-yl]A benzenesulfonamide compound.

In another embodiment, the invention provides a process for preparing a compound of formula (I)1aN- [ [4- (3-phenylisoxazol-4-yl) phenyl ] of structure]Sulfonyl radical]A method of propionamide, wherein the method comprises reacting 1, 2-diphenylethanone with a hydroxy groupContacting an amine source to produce a diphenylethanone oxime derivative compound; contacting the oxime compound with a strong base and an acetylating agent to produce a diphenylisoxazoline derivative compound; contacting a diphenylisoxazoline derivative with trifluoroacetic acid and a halosulfonic acid to produce a halosulfonated product; contacting the halosulfonated product compound with a source of ammonia to produce a catalyst having the formula1Of the structure [ isoxazol-4-yl]A benzenesulfonamide compound; and contacting the sulfonamide compound with a propionating agent to produce a compound having the formula1aN- [ [4- (3-phenylisoxazol-4-yl) phenyl ] of structure]Sulfonyl radical]Propionamide compounds.

In another embodiment, the invention provides a process for preparing a compound of formula (I)1bN- [ [4- (3-phenylisoxazol-4-yl) phenyl ] of structure]Sulfonyl radical]A process for the production of a propionamide sodium salt compound, wherein the process comprises contacting 1, 2-diphenylethanone with a source of hydroxylamine to produce a diphenylethanone oxime derivative compound; contacting the oxime derivative compound with a strong base and an acetylating agent to produce a diphenylisoxazoline derivative; contacting a diphenylisoxazoline derivative with trifluoroacetic acid and a halosulfonic acid to produce a halosulfonated product; contacting the halosulfonated product with a source of ammonia to produce a product having formula1Of the structure [ isoxazol-4-yl]A benzenesulfonamide; contacting a sulfonamide with a propionating agent to produce a compound having the formula1aN- [ [4- (3-phenylisoxazol-4-yl) phenyl ] of structure]Sulfonyl radical]Propionamide compounds; and contacting the propionamide compound with a sodium base to produce a compound having the formula1bN- [ [4- (3-phenylisoxazol-4-yl) phenyl ] of structure]Sulfonyl radical]Propionamide sodium salt compound.

In another embodiment, the invention provides a process for preparing a compound of formula (I)4A method of making a benzenesulfonyl halide compound of structure:

wherein X is a halogen atom, R¹、R²、R³、R⁴And R⁵Independently selected from hydrogen, alkyl, chainAlkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, alkoxy, alkylamino, alkylthio, acyl; wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl is optionally substituted with one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, alkoxy, alkylamino, alkylthio, acyl, halo, haloalkylaryl, alkoxyaryl, haloalkyl, and alkoxyhaloalkyl;

wherein the process comprises reacting a compound having the formula5A substituted phenyl compound of structure:

with a halosulfonic acid, thereby producing a benzenesulfonyl halide compound.

In another embodiment, the invention provides a process for preparing 5-phenylisoxazol-4-ylbenzenesulfonyl halides wherein the process comprises contacting a 4, 5-diphenylisoxazole compound with a halosulfonic acid in the presence of trifluoroacetic acid, thereby producing a compound having the formula6A 5-phenylisoxazol-4-ylphenylsulfonyl halide compound of structure:

further areas of applicability of the present invention will become apparent from the detailed description provided hereinafter. It should be understood, however, that the detailed description and the examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.

Brief Description of Drawings

FIG. 1 shows that compounds of formula (II a) can be prepared 14- [ 5-methyl-3-phenylisoxazol-4-yl of structure]A process for the preparation of benzenesulfonamides.

FIG. 2 shows a compound represented by the formula1Preparation of a Compound of the structure1aAnd1ba method of a compound of structure (la).

Description of The Preferred Embodiment

The following detailed description is provided to assist those skilled in the art in carrying out the invention. In this regard, such detailed description is not to be construed as unduly limiting the invention since modifications and variations may be made in the embodiments discussed herein by those of ordinary skill in the art without departing from the spirit or scope of the present discovery.

The contents of each reference cited herein, including the references cited within these original references, are hereby incorporated by reference in their entirety.

a. Definition of

To assist the reader in understanding the detailed description of the invention, the following definitions are provided.

"alkyl", "alkenyl" and "alkynyl" are in the present invention unless otherwise noted, each straight or branched chain hydrocarbon radical having from one to about twenty carbons for alkyl, or from two to about twenty carbons for alkenyl and alkynyl, and thus for example represent methyl, ethyl, propyl, butyl, pentyl or hexyl, and ethenyl, propenyl, butenyl, pentenyl or hexenyl, and ethynyl, propynyl, butynyl, pentynyl or hexynyl and isomers thereof, respectively.

"cycloalkyl" is a monocyclic or polycyclic carbocyclic ring wherein each ring contains three to ten carbon atoms, and wherein any ring may contain one or two double or triple bonds. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloalkenyl, and cycloheptyl.

"aryl" means a fully unsaturated monocyclic or polycyclic carbocyclic ring including, but not limited to, substituted or unsubstituted phenyl, naphthyl, or anthracenyl.

"heterocyclyl" means a saturated or unsaturated monocyclic or polycyclic carbocyclic ring in which one or more carbon atoms may be replaced by N, S, P or O. This includes, for example, the following structures:

z, Z therein¹、Z²Or Z³Is C, S, P, O or N, provided that it is Z, Z¹、Z²Or Z³One is not carbon, but is not O or S when attached to another Z atom or to another O or S atom by a double bond. Further, only when each is C, the optional substituents are understood to be attached to Z, Z¹、Z²Or Z³. The attachment point of the molecule of interest may be a heteroatom or elsewhere within the ring.

The term "alkoxy" denotes a group comprising an alkyl group bonded to an oxygen atom, for example a methoxy group. More preferred alkoxy groups are "lower alkoxy" groups having one to ten carbon atoms. Examples of such groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy and tert-butoxy.

The term "alkylamino" denotes a group comprising an alkyl group bonded to a nitrogen atom, for example an N-methylamino group. More preferred groups are "lower alkylamino" groups having from one to ten carbon atoms. Examples of such groups include N-methylamino, N-dimethylamino, N-ethylamino, N-diethylamino, N-dipropylamino, N-butylamino and N-methyl-N-ethylamino.

The term "alkylthio" denotes a group comprising an alkyl group bonded to a sulfur atom, such as a methylthio group. More preferred alkylthio groups are "lower alkylthio" groups having from one to ten carbon atoms. Examples of such groups include methylthio, ethylthio, propylthio and butylthio.

The term "acyl" denotes a group comprising an alkyl or aryl group bonded to a carboxyl group, for example a carboxymethyl group. More preferred acyl groups are "carboxy lower alkyl" groups and carboxyphenyl groups having one to ten carbon atoms. Examples of such groups include carboxymethyl, carboxyethyl and carboxypropyl.

The term "halogen" denotes a fluoro, chloro, bromo or iodo group.

The term "haloalkyl" denotes an alkyl group substituted with one or more halogens. Examples of such groups include chloromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, dichloromethyl, and trichloromethyl.

When used in combination, for example, "haloalkylaryl", "alkoxyaryl" or "alkoxyhaloalkyl", the above-listed terms have the meanings indicated above.

As used herein, Me represents a methyl group, Et represents an ethyl group, Pr represents a propyl group, i-Pr or PrⁱEach represents isopropyl, Bu represents butyl, t-Bu or Bu^tEach represents a tert-butyl group.

The weak acid is an acid of such a strength as to form sufficient protonated hydroxylamine to react with the diphenylethanone compound to form a diphenylethanone oxime derivative.

A strong base is one that upon contact with the oxime derivative compound generates sufficient dianionic species to further react with the acetylating agent.

The deprotonating base is one which reacts with a hydroxylamine salt to form sufficient hydroxylamine for further reaction with the diphenylethanone compound to form a diphenylethanone oxime derivative.

Propionating agent means an agent having the formula1The benzene sulfonamide compound with the structure generates the sulfonyl propionamide compound. The propionating agent may include active esters, such as propionyl anhydrides, propionyl mixed anhydrides, propionyl thioestersPropionyl carbonate, and the like. Propionating agents also include propionyl halides, preferably propionyl chloride; active amides such as N-propionylimidazole, N-alkyl-N-alkoxypropionamide and the like. Further active propionating agents are described in M.Bodanszky, Principles of Peptide Synthesis 14-61(second review section, Springer Verlag 1993).

The acylating agent is one which upon contacting the 1, 2-diphenylethanone derivative oxime in the presence of a strong base produces a compound having the formula2And/or3Isoxazolyl compounds or isoxazole compounds of the structure. The acylating agent may comprise acetic anhydride, preferably diacetic anhydride. The acylating agent may also comprise an acyl halide, preferably acetyl chloride. The acylating agent may also comprise a C1 to about C6 alkyl acetate selected from the group consisting of methyl acetate, ethyl acetate, propyl acetate and butyl acetate, more preferably ethyl acetate.

A sodium base is a base once reacted with a compound having the formula1aThe contact of the benzene acrylamide compound with the structure generates a sulfonyl propionamide sodium salt compound. The sodium base may comprise sodium hydroxide, sodium alkoxide, for example sodium ethoxide or sodium methoxide. The sodium base may also be sodium hydride or sodium carbonate.

A protecting group is a chemical moiety that is capable of protecting the chemical functionality of a molecule while the molecule undergoes chemical reactions at different positions on the molecule. Preferably, the protecting group may be removed after the chemical reaction to expose the original chemical functionality. For example, a hydroxyl protecting group can protect a hydroxyl group. The protected hydroxymethyl group comprises a hydroxymethyl group wherein the hydroxyl group is protected by a protecting group. Useful protecting groups can vary widely in chemical nature. A number of hydroxyl protecting Groups are described in Theodora W.Greene and Peter G.M.WutsProtective Groups in Organic Chemistry 86-97(Third Edition, John Wiley & Sons, 1999). Examples of the protected hydroxymethyl group include an inactivated benzyloxymethyl group and the like.

b. Details of the method

According to the present invention there is now provided the preparation of benzenesulfonyl derivativesBiological processes, in particular of the formula64- [ 5-methyl-3-phenylisoxazol-4-yl of structure]Benzenesulfonyl chlorides of formula14- [ 5-methyl-3-phenylisoxazol-4-yl of structure]Benzenesulfonamide (valdecoxib) having the formula1aN- [ [4- (5-methyl-4-phenylisoxazol-4-yl) phenyl ] of structure]Sulfonyl radical]Propionamide (palecoxib) and compounds of formula1bN- [ [4- (5-methyl-4-phenylisoxazol-4-yl) phenyl ] of structure]Sulfonyl radical]Propionamide sodium salt (paleacoxib sodium). Figure 1 provides a schematic representation of the process for preparing valdecoxib using the present invention. FIG. 2 provides a schematic representation of the process for preparing paleachoxib and paleachoxib sodium from valdecoxib using the present invention.

In one embodiment, the invention provides a process for preparing a compound having the formula1Of the structure [ isoxazol-4-yl]A process for the preparation of a benzenesulfonamide compound, which comprises reacting a compound selected from the group consisting of the following formulae in the presence of trifluoroacetic acid2And formula3By contacting the precursor compound of (a) with a halosulfonic acid to form a halosulfonated product, and contacting the halosulfonated product with an ammonia source to form a catalyst having the formula1Of the structure [ isoxazol-4-yl]A benzenesulfonamide compound. The halosulfonic acid used in the various embodiments of the invention may be, for example, any suitable halosulfonic acid. Preferably, the halosulfonic acid is selected from the group consisting of bromosulfonic acid and chlorosulfonic acid, more preferably chlorosulfonic acid. The ammonia source used in various embodiments of the present invention may be selected from, for example, ammonium hydroxide and anhydrous ammonia. More preferred sources of ammonia comprise ammonium hydroxide. In another preferred embodiment, the source of ammonia comprises anhydrous ammonia.

In another embodiment, the invention provides a process for preparing a compound of formula (I)1aN- [ [4- (3-phenylisoxazol-4-yl) phenyl ] of structure]Sulfonyl radical]A process for preparing propionamide compounds comprising reacting a compound selected from the group consisting of formula (la) in the presence of trifluoroacetic acid2And formula3By contacting the precursor compound of (a) with a halosulfonic acid to form a halosulfonated product, and contacting the halosulfonated product with an ammonia source to form a catalyst having the formula1Of the structure [ isoxazol-4-yl]Benzenesulfonamide compound, [ isoxazol-4-yl]Contacting the benzenesulfonamide compound with a propionating agent to produce a compound having the formula 1aN- [ [4- (3-phenylisoxazol-4-yl) phenyl ] of structure]Sulfonyl radical]Propionamide compounds. The propionating agent used in the various embodiments of the present invention may be selected from the group consisting of anhydrides of propionic acid, propionyl halides, propionyl thioesters, propionyl carbonates, and N-propionyl imidazole, for example. Preferably, the propionating agent is an anhydride of propionic acid, more preferably propionic anhydride, even more preferably a propionyl halide, even more preferably propionyl chloride.

In another embodiment, the invention provides a process for preparing a compound of formula (I)1bN- [ [4- (3-phenylisoxazol-4-yl) phenyl ] of structure]Sulfonyl radical]A process for the preparation of a propionamide sodium salt compound comprising contacting a precursor compound selected from the group consisting of formula 2 and formula 3 with a halosulfonic acid in the presence of trifluoroacetic acid to form a halosulfonated product and contacting the halosulfonated product with an ammonia source to form a compound having the formula1Of the structure [ isoxazol-4-yl]Benzenesulfonamide compound, [ isoxazol-4-yl]Contacting the benzenesulfonamide compound with a propionating agent to produce a compound having the formula1aN- [ [4- (3-phenylisoxazol-4-yl) phenyl ] of structure]Sulfonyl radical]Propionamide compounds, further compounds of formula1aContacting the compound with a sodium base to form a compound having the formula1bN- [ [4- (3-phenylisoxazol-4-yl) phenyl ] of structure]Sulfonyl radical]Propionamide sodium salt compound. The sodium base used in various embodiments of the present invention is selected from, for example, sodium hydroxide, sodium alkoxide, sodium hydride, and sodium carbonate. Preferably, the sodium base is sodium methoxide, more preferably, the sodium base is sodium hydroxide.

In another embodiment, the present invention provides a method for preparing [ isoxazol-4-yl ] having the structure of formula 1]A process for making a benzenesulfonamide compound comprising contacting 1, 2-diphenylethanone with a source of hydroxylamine to form a diphenylethanone oxime-derived compound, contacting the oxime-derived compound with a strong base and an acetylating agent to form a diphenylisoxazoline derivative, contacting the diphenylisoxazoline derivative with trifluoroacetic acid and a halosulfonic acid to form a halosulfonated product, and contacting the halosulfonated product with a source of ammonia to form a compound having the formula1Of the structure [ isoxazol-4-yl]A benzenesulfonamide compound. Sources of hydroxylamine for use in various embodiments of the present invention may be, for example, aqueous solutions containing hydroxylamineAnd (4) liquid. Preferably, the source of hydroxylamine is an aqueous solution comprising hydroxylamine and a weak acid, wherein the weak acid is a carboxylic acid, and preferably an alkyl carboxylic acid, and even more preferably the alkyl carboxylic acid is selected from formic acid, acetic acid and propionic acid, more preferably acetic acid. Most preferably, the source of hydroxylamine is an aqueous solution of hydroxylamine and acetic acid.

The source of hydroxylamine may also comprise an aqueous solution of hydroxylamine and a conjugate base of a weak acid. The weak acid conjugate base is sodium acetate.

The source of hydroxylamine may also comprise a hydroxylamine salt and a deprotonating base. The hydroxylamine salt is selected from hydroxylamine hydrochloride, hydroxylamine sulfate and hydroxylamine acetate. The hydroxylamine salt is preferably hydroxylamine hydrochloride. The deprotonating base is selected from sodium hydroxide, potassium hydroxide and sodium acetate. The deprotonating base is preferably sodium acetate. Another more preferred source of hydroxylamine comprises hydroxylamine hydrochloride and sodium acetate.

The strong base that may be used in various embodiments of the present invention in contact with the oxime derivative may preferably be selected from, for example, lithium dialkylamides, aryl lithiums, aryl alkyllithiums, and alkyllithiums. The strong base may be lithium dialkyl amide and is preferably lithium diisopropylamide. More preferably, the strong base is C₁To about C₁₀The alkyl lithium is more preferably selected from butyl lithium, hexyl lithium, heptyl lithium, octyl lithium, and still more preferably butyl lithium or hexyl lithium.

The acetylating agent used in the various embodiments of the present invention may be selected from the group consisting of, for example, alkyl acetates, acetic anhydrides, N-alkyl-N-alkoxyacetamides, and acetyl halides. The acetylating agent may be an acetic anhydride, and preferably is acetic anhydride, or may be an acetyl halide, and preferably is acetyl chloride, more preferably is C₁To about C₆Alkyl acetates selected from methyl acetate, ethyl acetate, propyl acetate and butyl acetate, more preferably ethyl acetate.

In another embodiment, the invention provides a process for preparing a compound of formula (I)1aN- [ [4- (3-phenylisoxazol-4-yl) phenyl ] of structure]Sulfonyl radical]A process for propionamide comprising contacting a 1, 2-diphenylethanone compound with a source of hydroxylamine to form a diphenylethanone oxime derivative compound, contacting the oxime derivative compound with a strong base andcontacting an acetylating agent to form a diphenylisoxazoline derivative, contacting the diphenylisoxazoline derivative with trifluoroacetic acid and a halosulfonic acid to form a halosulfonated product, and contacting the halosulfonated product with a source of ammonia to form a compound having the formula1Of the structure [ isoxazol-4-yl]Benzenesulfonamide compound, [ isoxazol-4-yl]Contacting the benzenesulfonamide compound with a propionating agent to produce a compound having the formula1aN- [ [4- (3-phenylisoxazol-4-yl) phenyl ] of structure]Sulfonyl radical]Propionamide compounds.

In another embodiment, the invention provides a process for preparing a compound of formula (I)1bN- [ [4- (3-phenylisoxazol-4-yl) phenyl ] of structure]Sulfonyl radical]A process for the production of a propionamide sodium salt compound comprising contacting a 1, 2-diphenylethanone compound with a source of hydroxylamine to produce a diphenylethanone oxime derivative compound, contacting the oxime derivative compound with a strong base and an acetylating agent to produce a diphenylisoxazoline derivative compound, and contacting the diphenylisoxazoline derivative with trifluoroacetic acid and a halosulfonic acid to produce a halosulfonated product, and contacting the halosulfonated product with a source of ammonia to produce a compound having the formula1Of the structure [ isoxazol-4-yl]Benzenesulfonamide compound, [ isoxazol-4-yl]Contacting the benzenesulfonamide compound with a propionating agent to produce a compound having the formula1aN- [ [4- (3-phenylisoxazol-4-yl) phenyl ] of structure]Sulfonyl radical]A propionamide compound and further contacting the compound of formula 1a with a sodium base to form a compound having the formula1bN- [ [4- (3-phenylisoxazol-4-yl) phenyl ] of structure]Sulfonyl radical]Propionamide sodium salt compound.

wherein X is a halogen atom, R¹、R²、R³、R⁴And R⁵Independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroCyclyl, alkoxy, alkylamino, alkylthio, acyl; wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl is optionally substituted with one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, alkoxy, alkylamino, alkylthio, acyl, halogen, haloalkylaryl, alkoxyaryl, haloalkyl, protected hydroxymethyl, aralkoxymethyl, and alkoxyhaloalkyl;

with a halosulfonic acid, thereby producing a benzenesulfonyl halide compound.

A more preferred embodiment of the present invention provides such a process wherein R³Is heterocyclyl, optionally substituted with one or more groups selected from alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, alkoxy, alkylamino, alkylthio, acyl, halo, haloalkylaryl, alkoxyaryl, haloalkyl, alkoxycarbonyl, protected hydroxymethyl, arylalkoxymethyl and alkoxyhaloalkyl; r¹、R²、R⁴And R⁵Is hydrogen. Further preferred is a process wherein R³Selected from isoxazolyl and pyrazolyl, wherein R³Optionally substituted with one or more groups selected from alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, alkoxy, alkylamino, alkylthio, acyl, halo, haloalkylaryl, alkoxyaryl, haloalkyl, alkoxycarbonyl, protected hydroxymethyl, arylalkoxymethyl and alkoxyhaloalkyl; r¹、R²、R⁴And R⁵Is hydrogen.

In another embodiment, the present invention provides for the production of 5-phenylisoxazolesA process for preparing an oxazol-4-yl benzenesulfonyl halide, wherein the process comprises contacting 4, 5-diphenylisoxazole with a halosulfonic acid in the presence of trifluoroacetic acid, thereby producing a compound having the formula6A 5-phenylisoxazol-4-ylphenylsulfonyl halide compound of structure:

in another embodiment, the invention provides a process for preparing 5-phenylisoxazol-4-ylphenylsulfonyl halide, wherein the process comprises reacting a compound selected from the group consisting of2And formula3With a halosulfonic acid, thereby producing a compound having the formula6A 5-phenylisoxazol-4-ylphenylsulfonyl halide compound of structure (la).

As provided herein, trifluoroacetic acid is the solvent for halosulfonation of aromatic compounds to provide the corresponding arylsulfonyl halide. The use of trifluoroacetic acid provides for the solubilization of many solid substrates. Trifluoroacetic acid has a higher boiling point than dichloromethane, enabling the halosulfonation reaction to be carried out at higher temperatures, which may have the benefit of shorter reaction times. In addition, trifluoroacetic acid can be used to pre-dissolve the solid aromatic substrate, making it easier and safer to transfer the substrate from the filtration device to the halosulfonation reactor. The use of trifluoroacetic acid also eliminates the release of chlorinated hydrocarbons into the air and the discharge of waste liquids.

Compound (I)2、 3And5reaction generating structure4And6the halosulfonation reaction of (a) to (b) is carried out in the presence of trifluoroacetic acid.

The ratio of trifluoroacetic acid used and the reaction time may vary, as shown in the following table.

TFA equivalent	Temperature of	Reaction time hours (h)	Completion time	Valdecoxib¹
TFA equivalent	Temperature of	Reaction time hours (h)	Completion time	Valdecoxib¹	2.0	70	2	＜30min	78
2.0	40	6	3.3h	80	2.0	70	2	＜30min	78
2.0	40	6	3.3h	80	3.0	60	3	50min	76
4.0	70	2.5	1h	87	3.0	60	3	50min	76
4.0	70	2.5	1h	87	4.0	40	4	4h	77

¹End point mol% values from treated samples quenched with acetonitrile, water, and ammonium hydroxide mixtures

Preferably, sufficient trifluoroacetic acid is used to ensure fluid reaction mass. Then is turned on2And3to the direction of6The amount of trifluoroacetic acid for the conversion of (a) may be from about 1.5 to about 4 weight equivalents relative to2And3in other words. In a preferred embodiment, the weight equivalent of trifluoroacetic acid is equal to2And3the weight of (c).

The halosulfonation reaction can be carried out at a temperature range, preferably in the range of-20 ℃ to 100 ℃, more preferably about 30 ℃ to 70 ℃, and even more preferably about 55 ℃ to 65 ℃. The chlorosulfonation reaction may be carried out at atmospheric pressure or under pressure, preferably at atmospheric pressure, below the boiling point of trifluoroacetic acid. Chlorosulfonation can be carried out at higher temperatures, under sufficient pressure, depending on the reactor system, to prevent losses due to volatilization.

c. Detailed preparation method

The starting materials for use in the preparation process of the present invention are known or can be prepared by conventional methods known to those skilled in the art or in a manner analogous to the methods described in the art. The following examples are intended to illustrate many embodiments of the invention and are not meant to limit the scope thereof.

In general, the process of the invention can be carried out as follows. Larger scale preparations can be made, for example, by increasing the amount of the ingredients proportionally.

Example 1

4- (5-methyl-3-phenyl-4-isoxazolyl) benzenesulfonamide (valdecoxib,1) Preparation of

Step 1: preparation of 1, 2-diphenylethanone oxime 7

To a solution of deoxybenzoin (2.3kg, 11.7mol), acetic acid (669mL, 11.7mol), and ethanol 3A (8.05L, 190 proof (proof)) was added 50 weight percent hydroxylamine (800mL, 13.3mol) via an addition funnel at 70 ℃. The addition funnel was rinsed with water (460mL) and the reaction mixture was held at 70 ℃ for 1 hour. The reaction was monitored by HPLC for completion. Water (2.87L) was added to the reactor and the temperature was reduced to 50 ℃. An aliquot (250mL) was removed from the reactor, cooled, and allowed to crystallize. The mixture was reintroduced into the reactor to seed the initiation of crystallization. Seeding is not necessary, but if used, helps to increase the bulk density of the oxime product, thereby improving the handling properties of the resulting oxime. After stirring for 1 hour, water (8.78L) was added over 2.5 hours and the mixture was cooled to 20 ℃. The mixture is filtered under pressure; the filter cake was washed with 2: 1 water/ethanol 3A (10.8L) and water (4.5L). The filter cake is treated with N₂Blow dry overnight to give a white solid (2.34kg, 95% yield, 96: 4E/Z oxime isomer). High resolution MS (ES) M/z (M + H)⁺Calculated values: 212.1075, respectively; measured value: 212.1085.

step 1 (alternative process): preparation of 1, 2-diphenylethanone oxime 7

To a solution of deoxybenzoin (75.0g, 0.382mol), sodium acetate (34.5g, 0.420mol), and ethanol 3A (267mL, 190 proof) was added 35 weight percent hydroxylamine hydrochloride (72.0mL, 0.420mol) via a syringe pump at 70 ℃. The reaction mixture was maintained at 70 ℃ for 1 hour and the reaction was monitored by HPLC for completion. Water (75.0mL) was added to the reactor and the temperature was reduced to 50 ℃. An aliquot (0.5mL) was removed from the reactor, cooled, and allowed to crystallize. The mixture was reintroduced into the reactor to seed the initiation of crystallization. Seeding is not necessary, but if used, helps to increase the bulk density of the oxime product, thereby improving the handling properties of the resulting oxime. After stirring for 1 hour, water (274mL) was added over 1 hour and the mixture was cooled to 20 ℃. Filtering the mixture; the filter cake was washed with 2: 1 water/ethanol 3A (188mL) and water (100 mL). The filter cake was dried in a vacuum oven at 50 ℃ for 16 hours to give a white solid (76.39g, 95% yield, 97: 3E/Z oxime isomer).

Step 2: preparation of 4, 5-dihydro-5-methyl-3, 4-diphenyl-5-isoxazolol, 2

To a 500mL jacketed reactor equipped with a magnetic stirrer, a thermocouple, and a positive pressure nitrogen inlet was added 1, 2-diphenylethanone oxime (31.4 g). Tetrahydrofuran (THF) (160mL) was added while stirring to dissolve the solid. The reaction was cooled using a jacket temperature of-15 ℃. A solution of n-hexyllithium in hexane (131mL, 2.3M) was added to the reaction vessel while maintaining the temperature below 10 ℃. After the addition was complete, the mixture was stirred for 30 minutes using a jacket temperature of-15 ℃. Ethyl acetate (120mL) was added, maintaining the temperature below 10 ℃. The reaction mixture was then transferred via a catheter to a mixture of sodium chloride (14.0g) and water (160mL) cooled to 5 ℃. The reaction vessel was flushed with 40ml of hf and the mixture was transferred to a quench flask. The quenched mixture was warmed to 20 ℃ and the layers were separated. The organic layer was washed with sodium bicarbonate (NaHCO)₃) Solution (9.6g NaHCO)₃160mL of water). Toluene (120mL) was added to the organic layer and the mixture was distilled until the pot temperature reached 90.2 ℃. Heptane (439mL) was added and the mixture was cooled at 0.5 deg.C/min to 5 deg.C, during which time crystals formed. The mixture was filtered through a polypropylene screen and the solid filter cake was washed with 100mL 50: 50 (v/v) heptane: toluene. The solid was dried overnight in a 50 ℃ vacuum oven with nitrogen flow. The product was obtained as a white solid (19.75g, 52% yield). C₁₆H₁₆NO₂Calculated high resolution mass spectra of: 254.1193(M + H)⁺(ii) a Measured value: 254.1181.

step 2 (alternative process): preparation of 4, 5-dihydro-5-methyl-3, 4-diphenyl-5-isoxazolol, 2

To a 500mL jacketed reactor equipped with a magnetic stirrer, a thermocouple, and a positive pressure nitrogen inlet was added 1, 2-diphenylethanone oxime (31.4 g). Tetrahydrofuran (THF) (209mL) was added while stirring to dissolve the solid. The reaction was cooled until a batch temperature of-15 ℃ was obtained. A solution of n-hexyllithium in hexane (131mL, 2.3M) was added to the reaction vessel while maintaining the temperature below 10 ℃. After the addition was complete, the mixture was cooled to a batch temperature of-15 ℃. Ethyl acetate (80mL) was added as rapidly as possible. The reaction mixture was adjusted to 0 ℃ and then transferred to a mixture of sodium chloride (14.0g) and water (160mL) cooled to < 5 ℃. The mixture was kept below 15 ℃ during the quenching process. The reaction vessel was rinsed with 40mL of ethyl acetate and the mixture was transferred to a quench flask. The quenched mixture was warmed to 20 ℃ and the layers were separated. The organic layer was washed with sodium bicarbonate (NaHCO)₃) Solution (9.6g NaHCO)₃160mL of water). Toluene (120mL) was added to the organic layer and the mixture was distilled until 67% of the can contents were removed (temperature-90-93 ℃). Heptane (439mL) was added and the mixture was cooled at 0.5 deg.C/min to 5 deg.C, during which time crystals formed. The mixture was filtered and the solid filter cake was washed with 100mL 50: 50 (vol/vol) heptane: toluene. The solid was dried overnight in a 50 ℃ vacuum oven with nitrogen flow. The product was obtained as a white solid (typical manufacturing yield 59%). C₁₆H₁₆NO₂Calculated high resolution mass spectra of: 254.1193(M + H)⁺(ii) a Measured value: 254.1181.

and step 3: preparation of 4- (5-methyl-3-phenyl-4-isoxazolyl) benzenesulfonamide (valdecoxib, 1)

To a 500mL reactor that had been cooled to 5 ℃ was added 4, 5-dihydro-5-methyl-3, 4-diphenyl-5-isoxazolol (50.0g, 0.197 mol). Trifluoroacetic acid (38.3mL, 0.496mol) was added to the reactor while stirring and the 35 ℃ solution was cooled to-5 ℃. Chlorosulfonic acid (232g, 1.99mol) was added slowly, the evolution of hydrogen chloride (HCl) being controlled during the addition and maintained at < 25 ℃. The reaction solution was then heated to 60 ℃ and held at 60 ℃ for 2.5 hours. After cooling the reaction solution to 0 ℃, it was slowly added to a stirred mixture of toluene (172mL) and water (150mL) at 2 to 25 ℃. The reactor was rinsed with a mixture of toluene (18.4mL) and water (50mL) and then added to the quench mixture. The toluene layer was extracted with water (50mL) and cooled to 0.2 ℃. Concentrated ammonium hydroxide (62mL, 1.60mol) was added slowly while cooling to maintain-10 to 15 ℃ during the addition. The mixture was slowly warmed to 35 ℃ and held at that temperature for-40 minutes. Isopropanol (240mL) was added and the reaction mixture was reheated to 35 ℃ and held at 35 ℃ for 90 minutes. The crystalline mixture was slowly cooled to 20 ℃ and the crude product was filtered and washed with isopropanol (100mL) and water (100 mL). The wet cake was transferred to a 500mL crystallizer and dissolved in methanol (350mL) at-58 ℃. Water (92mL) was added to the methanol solution and the solution was heated to-70 ℃. The solution was slowly cooled to 50 ℃, held for 60 minutes, and then cooled to 5 ℃. After 1 hour at 5 ℃, the crystalline product was collected by filtration, and the filter cake was washed with 75% methanol-water (100mL) and dried under vacuum at-70 ℃. Melting points were measured using Differential Scanning Calorimetry (DSC) at 171 to 174 ℃ (measured at 10 ℃/min).

Example 2

Preparation of N- [ [4- (5-methyl-3-phenyl-4-isoxazolyl) phenyl ] sulfonyl ] propanamide (paleachoxib, 1a)

To a 500mL reactor was added 4- (5-methyl-3-phenyl-4-isoxazolyl) benzenesulfonamide (10.0g, 0.032mol) and propionic anhydride (40mL, 0.31 mol). The slurry was stirred and heated to 50 ℃. Sulfuric acid (40. mu.L, 0.8mmol) was added in one portion. After the addition was complete all solids dissolved and the mixture was warmed to 55.5 ℃ over 10 minutes. The reaction mixture was then heated to 80 ℃ for about 10 minutes. Discontinuing the heating and allowing the mixture to cool to 50 ℃ for about 60 minutes; the solid began to crystallize out of the reaction mixture at about 65 ℃. The mixture was slowly cooled to 0 ℃ and held at 0 ℃ for about 60 minutes. The solid was collected by vacuum filtration. The wet cake was washed with two 45mL portions of methyl tert-butyl ether and blotted dry at ambient temperature for about 15 minutes. The solid was further dried in a vacuum oven at 60 ℃ for 18 hours with nitrogen flow to give the product as a solid (8.72g, 75% yield). The DS maximum endotherm of the high melting point paleachoxide was 168.95. The DSC maximum endotherm for the low melting point paleacoxib was 147.44.

Example 3

Preparation of N- [ [4- (5-methyl-3-phenyl-4-isoxazolyl) phenyl ] sulfonyl ] propanamide sodium salt (paleachoxib sodium, 1b)

To a 500mL reactor was added N- [ [4- (5-methyl-3-phenyl-4-isoxazolyl) phenyl ] sulfonyl ] propionamide (10.0g, 0.026mol) and 160mL absolute ethanol. The slurry was heated to 45 ℃ for 30 minutes and approximately 5 weight percent sodium hydroxide in ethanol (22.4g, 0.028mol) was added to the reaction vessel at 45 ℃. After the addition was completed, the solution was inoculated with N- [ [4- (5-methyl-3-phenyl-4-isoxazolyl) phenyl ] sulfonyl ] propionamide sodium salt to initiate crystallization. The temperature of the reaction mixture was raised to 50 ℃ and maintained for 30 minutes. The mixture was slowly cooled to 0 ℃ for about 60 minutes. The solid was collected by vacuum filtration. The wet cake was washed twice with two 20mL portions of absolute ethanol, blotted dry under vacuum, and purged with nitrogen. The solid was further dried overnight in a 120 ℃ vacuum oven with nitrogen flow to give the product as a solid (9.11g, 85% yield). The DSC maximum endotherm for form I sodium paleacetate is 274.28 ℃.

Example 4

Preparation of 5-methyl-3, 4-diphenylisoxazole 3

A250 mL flask was charged with 4, 5-dihydro-5-methyl-3, 4-diphenyl-5-isoxazolol (15.0g, 0.059 mol). Trifluoroacetic acid (10.5mL) was added with stirring and an exotherm to 44 ℃ was observed. The solution was heated between 44 and 57 ℃ for 60 minutes, cooled to room temperature and distilled under vacuum to remove trifluoroacetic acid. The residue was dissolved in 100mL of toluene and distilled under vacuum. The process is repeated a second time to obtain a semi-crystalline concentrate. The concentrate was dissolved in 250mL hot heptane, decanted into a 500mL flask, cooled to room temperature, and held for 18 hours. The crystallized filter cake is broken up and the crystals are collected by filtration. The filter cake was dried to yield 10.19g (73 wt% yield) of the desired product. The DSC melting point was measured at 10 ℃/min in an unsealed pan to be 95.55-96.24 ℃.

Example 5

Preparation of 4- (5-methyl-3-phenyl-4-isoxazolyl) benzenesulfonyl chloride 6

A200 mL jacketed flask was charged with 4, 5-dihydro-5-methyl-3, 4-diphenyl-5-isoxazolol (13.0g, 0.0513mol) and the flask was cooled with 0.2 ℃ jacket fluid. Trifluoroacetic acid (9.1mL, 0.118mol) was added to the solid to give a solution at 38.6 ℃. The solution was cooled to 2.1 ℃ and chlorosulfonic acid (34.7mL, 0.522mol) was added slowly while maintaining the temperature below 14 ℃. The solution was heated to 60 ℃ for 2.5 hours, cooled to 20 ℃ and transferred to a 125mL addition funnel. Toluene (52mL) and water (52mL) were added to a 200mL jacketed reactor and cooled to 4 ℃. The reaction solution was then slowly added to a 200mL jacketed reactor while maintaining the temperature below 20 ℃. The heterogeneous mixture was warmed to 20 ℃ and transferred to a 250mL separatory funnel. Toluene (50mL) and water (10mL) were added and the mixture was shaken. The mixture settled, resulting in two turbid phases. The toluene phase was washed twice with 15mL of water, transferred to a 250mL flask, rinsed with 20mL of toluene, and distilled under vacuum to give 17.4g of an oil. After initiation of crystallization with a glass rod and cooling, heptane (20mL) was added to the crystals, which crashed into a powder. The milky white powder was collected by filtration. Heptane was used to help transfer the solids to the filter with 50mL aliquots. The filter cake was dried in a vacuum oven (35 ℃ C.) to give 13.6g (79.4 wt%) of sulfonyl chloride as an 85: 15 mixture of para and meta isomers. C₁₆H₁₃NO₃HRMS calcd for Cl (M + 1): 334.0305, respectively; found (M + 1): 334.0309.

example 6

Preparation of 4- (5-methyl-3-phenyl-4-isoxazolyl) benzenesulfonyl chloride 6

A100 mL jacketed flask was charged with 5-methyl-3, 4-diphenylisoxazole (5.0g, 0.0213mol) and cooled with 0.2 deg.C jacket fluid. Trifluoroacetic acid (3.5mL, 0.045mol) was added to the solid at 3 ℃ to give a solution. Chlorosulfonic acid (13.3mL, 0.201mol) was added slowly while maintaining the reaction temperature below 20 ℃. Heating the solution to 6The temperature was maintained at 0 ℃ for 2.2 hours. The solution was then cooled to 6 ℃ and transferred to a 60mL addition funnel. Toluene (20mL) and water (20mL) were added to a 100mL jacketed reactor and cooled to 6 ℃. The reaction solution was then slowly added to a 100mL jacketed reactor while maintaining the temperature below 16 ℃. The heterogeneous mixture was transferred to a 125mL separatory funnel. Toluene (20mL) and water (5mL) were added and the mixture was shaken. The mixture settled, resulting in two turbid phases. The toluene phase was washed twice with 5mL of water, transferred to a 125mL flask, washed with 17mL of toluene and distilled under vacuum to give a semi-crystalline concentrate. The concentrate was dissolved in 100mL of toluene and distilled under vacuum to give an oil. After initiation of crystallization with a glass rod, heptane (11mL) was added and the crystals were broken up into an opalescent powder. The solid was collected by filtration. Heptane was used to help transfer the solids to the filter with 25mL portions. The filter cake was dried to give 7.07g (100 wt%) of sulfonyl chloride as an 85: 15 mixture of para and meta isomers. C₁₆H₁₃NO₃HRMS calcd for Cl (M + 1): 334.0305, respectively; found (M + 1): 334.0299.

example 5

Preparation of 4- (5-methyl-3-phenyl-4-isoxazole) benzenesulfonic acid

To a 1L flask was added 4- (5-methyl-3-phenylisoxazole) benzenesulfonyl chloride (39.6g, 0.11mol), water (99.5mL, 5.5mol), and tetrahydrofuran (558mL), and the mixture was heated under reflux overnight. After cooling to ambient temperature, the solvent was removed under pressure. The residual yellow oil was further dried under high vacuum. The resulting solid was covered with toluene (500mL) and heated to reflux. After about 30 minutes, the solids melted and pooled at the bottom of the flask. The mixture was stirred at reflux temperature for 4 hours, cooled to room temperature and stirred overnight. The solid was collected by filtration, briefly air-dried, and ground into a powder. The powder was suspended in toluene (500mL), heated to reflux temperature, and re-solidified during cooling to room temperature. The solid was collected by filtration and dried to give 23.8g of product having a melting point of 174-.

Claims

1. A process for preparing an [ isoxazol-4-yl ] benzenesulfonamide compound having the structure of formula 1:

comprises the following steps:

reacting a precursor compound selected from the group consisting of formula 2 and formula 3:

contacting with halosulfonic acid to produce a halosulfonated product;

and contacting the halosulfonated product with a source of ammonia to produce an [ isoxazol-4-yl ] benzenesulfonamide compound having the structure of formula 1.

2. The method of claim 1, wherein the halosulfonic acid is selected from the group consisting of bromosulfonic acid and chlorosulfonic acid.

3. The method of claim 1, wherein the halosulfonic acid is chlorosulfonic acid.

4. The method of claim 1, wherein the ammonia source is selected from the group consisting of ammonium hydroxide and anhydrous ammonia.

5. The method of claim 1, wherein the source of ammonia is ammonium hydroxide.

6. The method of claim 1, wherein the source of ammonia is anhydrous ammonia.

7. A process for the preparation of N- [ [4- (3-phenylisoxazol-4-yl) phenyl ] sulfonyl ] propanamide compounds having the structure of formula 1 a:

comprises the following steps:

contacting with halosulfonic acid to produce a halosulfonated product;

contacting the halosulfonated product with a source of ammonia to produce an [ isoxazol-4-yl ] benzenesulfonamide compound having the structure of formula 1:

and contacting the [ isoxazol-4-yl ] benzenesulfonamide compound with a propionating agent to produce an N- [ [4- (3-phenylisoxazol-4-yl) phenyl ] sulfonyl ] propionamide compound having the structure of formula 1 a.

8. The method of claim 7, wherein the halosulfonic acid is selected from the group consisting of bromosulfonic acid and chlorosulfonic acid.

9. The method of claim 7, wherein the halosulfonic acid is chlorosulfonic acid.

10. The method of claim 7, wherein the ammonia source is selected from the group consisting of ammonium hydroxide and anhydrous ammonia.

11. The method of claim 7, wherein the source of ammonia is ammonium hydroxide.

12. The method of claim 7, wherein the source of ammonia is anhydrous ammonia.

13. The method of claim 7 wherein the propionating agent is selected from the group consisting of an anhydride of propionic acid, a propionyl halide, a propionyl thioester, a propionyl carbonate, and a N-propionyl imidazole.

14. The method of claim 13 wherein the propionating agent is a propionyl halide.

15. The method of claim 14 wherein the propionating agent is a propionyl chloride.

16. The method of claim 13 wherein the propionating agent is an anhydride of propionic acid.

17. The method of claim 13, wherein the anhydride of propionic acid is propionic anhydride.

18. A process for the preparation of a compound of the sodium salt of N- [ [4- (3-phenylisoxazol-4-yl) phenyl ] sulfonyl ] propanamide having the structure of formula 1 b:

comprises the following steps:

contacting with halosulfonic acid to produce a halosulfonated product;

and contacting the [ isoxazol-4-yl ] benzenesulfonamide compound having the structure of formula 1 with a propionating agent to produce a N- [ [4- (3-phenylisoxazol-4-yl) phenyl ] sulfonyl ] propionamide compound having the structure of formula 1 a:

and further contacting the compound of formula 1a with a sodium base to produce a compound of N- [ [4- (3-phenylisoxazol-4-yl) phenyl ] sulfonyl ] propanamide sodium salt having the structure of formula 1 b.

19. The method of claim 18, wherein the halosulfonic acid is selected from the group consisting of bromosulfonic acid and chlorosulfonic acid.

20. The method of claim 18, wherein the halosulfonic acid is chlorosulfonic acid.

21. The method of claim 18, wherein the ammonia source is selected from the group consisting of ammonium hydroxide and anhydrous ammonia.

22. The method of claim 18, wherein the source of ammonia is ammonium hydroxide.

23. The method of claim 18, wherein the source of ammonia is anhydrous ammonia.

24. The method of claim 18 wherein the propionating agent is selected from the group consisting of an anhydride of propionic acid, a propionyl halide, a propionyl thioester, a propionyl carbonate, and a N-propionyl imidazole.

25. The method of claim 24 wherein the propionating agent is a propionyl halide.

26. The method of claim 25 wherein the propionating agent is a propionyl chloride.

27. The method of claim 24 wherein the propionating agent is an anhydride of propionic acid.

28. The method of claim 24, wherein the anhydride of propionic acid is propionic anhydride.

29. The process of claim 18, wherein the sodium base is selected from the group consisting of sodium hydroxide, sodium alkoxide, sodium hydride, and sodium carbonate.

30. The method of claim 29, wherein the sodium base is sodium hydroxide.

31. A process for preparing an [ isoxazol-4-yl ] benzenesulfonamide compound having the structure of formula 1:

comprises the following steps:

contacting a 1, 2-diphenylethanone compound with a source of hydroxylamine to produce a diphenylethanone oxime derivative;

contacting a diphenylethanone oxime derivative with a strong base and an acetylating agent to produce a diphenylisoxazoline derivative;

contacting a diphenylisoxazoline derivative with trifluoroacetic acid and a halosulfonic acid to produce a halosulfonated product;

contacting the halosulfonated product with a source of ammonia to produce an [ isoxazol-4-yl ] benzenesulfonamide compound having the structure of formula 1.

32. The method of claim 31, wherein the source of hydroxylamine is an aqueous solution comprising hydroxylamine.

33. The method of claim 31, wherein the source of hydroxylamine is an aqueous solution comprising hydroxylamine and a weak acid.

34. The method of claim 33, wherein the weak acid is a carboxylic acid.

35. The method of claim 34, wherein the carboxylic acid is an alkyl carboxylic acid.

36. The method of claim 35, wherein the alkyl carboxylic acid is selected from the group consisting of formic acid, acetic acid, and propionic acid.

37. The method of claim 35, wherein the alkyl carboxylic acid is acetic acid.

38. The method of claim 31, wherein the source of hydroxylamine is an aqueous solution comprising hydroxylamine and a conjugate base of a weak acid.

39. The method of claim 38, wherein the conjugate base of a weak acid is sodium acetate.

40. The method of claim 31, wherein the source of hydroxylamine comprises a hydroxylamine salt and a deprotonating base.

41. The method of claim 40, wherein the hydroxylamine salt is selected from the group consisting of hydroxylamine hydrochloride, hydroxylamine sulfate and hydroxylamine acetate.

42. The method of claim 41, wherein the hydroxylamine salt is hydroxylamine hydrochloride.

43. The method of claim 40, wherein the deprotonating base is selected from the group consisting of sodium hydroxide, potassium hydroxide, and sodium acetate.

44. The method of claim 40, wherein the deprotonating base is sodium acetate.

45. The method of claim 40, wherein the source of hydroxylamine comprises hydroxylamine hydrochloride and sodium acetate.

46. The process of claim 31 wherein the strong base is selected from the group consisting of lithium dialkylamides, aryl lithiums, arylalkyl lithiums, and alkyl lithiums.

47. The method of claim 31, wherein the strong base is lithium dialkylamide.

48. The method of claim 47 wherein the strong base is lithium diisopropylamide.

49. The method of claim 46, wherein the strong base is C₁To C₁₀An alkyl lithium.

50. The method of claim 31, wherein the strong base is butyl lithium.

51. The method of claim 31, wherein the strong base is hexyl lithium.

52. The method of claim 31, wherein the strong base is heptyl lithium.

53. The method of claim 31, wherein the strong base is octyl lithium.

54. The method of claim 31 wherein the acetylating agent is selected from the group consisting of alkyl acetates, acetic anhydride, N-alkyl-N-alkoxy acetamides and acetyl halides.

55. The method of claim 54 wherein the acetylating agent is C₁To C₆Alkyl acetate ester.

56. The method of claim 31, wherein the acetylating agent is selected from the group consisting of methyl acetate, ethyl acetate, propyl acetate and butyl acetate.

57. The method of claim 56, wherein the alkyl acetate is ethyl acetate.

58. The method of claim 31, wherein the acetylating agent is an acetyl halide.

59. The method of claim 58, wherein the acetyl halide is acetyl chloride.

60. The method of claim 31, wherein the acetylating agent is acetic anhydride.

61. The method of claim 31, wherein the halosulfonic acid is selected from the group consisting of bromosulfonic acid and chlorosulfonic acid.

62. The method of claim 31, wherein the halosulfonic acid is chlorosulfonic acid.

63. The method of claim 31, wherein the ammonia source is selected from the group consisting of ammonium hydroxide and anhydrous ammonia.

64. The method of claim 31, wherein the source of ammonia is ammonium hydroxide.

65. The method of claim 31, wherein the ammonia source is anhydrous ammonia.

66. A process for the preparation of N- [ [4- (3-phenylisoxazol-4-yl) phenyl ] sulfonyl ] propanamide compounds having the structure of formula 1 a:

comprises the following steps:

and contacting the [ isoxazol-4-yl ] benzenesulfonamide compound of formula 1 with a propionating agent to produce an N- [ [4- (3-phenylisoxazol-4-yl) phenyl ] sulfonyl ] propionamide compound having the structure of formula 1 a.

67. The method of claim 66, wherein the source of hydroxylamine is an aqueous solution comprising hydroxylamine.

68. The method of claim 66, wherein the source of hydroxylamine is an aqueous solution comprising hydroxylamine and a weak acid.

69. The method of claim 68, wherein the weak acid is a carboxylic acid.

70. The method of claim 69, wherein the carboxylic acid is an alkyl carboxylic acid.

71. The method of claim 70, wherein the alkyl carboxylic acid is selected from the group consisting of formic acid, acetic acid, and propionic acid.

72. The method of claim 70, wherein the alkyl carboxylic acid is acetic acid.

73. The method of claim 66, wherein the source of hydroxylamine is an aqueous solution comprising hydroxylamine and a conjugate base of a weak acid.

74. The method of claim 73, wherein the conjugate base of a carboxylic acid is sodium acetate.

75. The method of claim 66, wherein the source of hydroxylamine comprises a hydroxylamine salt and a deprotonating base.

76. The method of claim 75, wherein the hydroxylamine salt is selected from the group consisting of hydroxylamine hydrochloride, hydroxylamine sulfate and hydroxylamine acetate.

77. The method of claim 76, wherein the hydroxylamine salt is hydroxylamine hydrochloride.

78. The method of claim 75, wherein the deprotonating base is selected from the group consisting of sodium hydroxide, potassium hydroxide, and sodium acetate.

79. The method of claim 75, wherein the deprotonating base is sodium acetate.

80. The method of claim 75, wherein the source of hydroxylamine comprises hydroxylamine hydrochloride and sodium acetate.

81. The method of claim 66, wherein the strong base is selected from the group consisting of lithium dialkylamides, aryl lithiums, aryl alkyllithiums, and alkyllithiums.

82. The method of claim 66, wherein the strong base is lithium dialkylamide.

83. The method of claim 82 wherein the strong base is lithium diisopropylamide.

84. The method of claim 81, wherein the strong base is C₁To C₁₀An alkyl lithium.

85. The method of claim 66, wherein the strong base is butyl lithium.

86. The method of claim 66, wherein the strong base is hexyl lithium.

87. The method of claim 66, wherein the strong base is heptyl lithium.

88. The method of claim 66, wherein the strong base is octyl lithium.

89. The method of claim 66 wherein the acetylating agent is selected from the group consisting of alkyl acetates, acetic anhydride, N-alkyl-N-alkoxyacetamides and acetyl halides.

90. The method of claim 89, wherein said acetylating agent is C₁To C₆Alkyl acetate ester.

91. The method of claim 66, wherein the acetylating agent is selected from the group consisting of methyl acetate, ethyl acetate, propyl acetate and butyl acetate.

92. The method of claim 91, wherein the alkyl acetate is ethyl acetate.

93. The method of claim 66, wherein the acetylating agent is an acetyl halide.

94. The method of claim 93, wherein the acetyl halide is acetyl chloride.

95. The method of claim 66, wherein the acetylating agent is acetic anhydride.

96. The method of claim 66, wherein the halosulfonic acid is selected from the group consisting of bromosulfonic acid and chlorosulfonic acid.

97. The method of claim 66, wherein the halosulfonic acid is chlorosulfonic acid.

98. The method of claim 66, wherein the ammonia source is selected from the group consisting of ammonium hydroxide and anhydrous ammonia.

99. The method of claim 66, wherein the ammonia source is ammonium hydroxide.

100. The method of claim 66, wherein the ammonia source is anhydrous ammonia.

101. The method of claim 66 wherein the propionating agent is selected from the group consisting of an anhydride of propionic acid, a propionyl halide, a propionyl thioester, a propionyl carbonate and a N-propionyl imidazole.

102. The method of claim 101 wherein the propionating agent is a propionyl halide.

103. The method of claim 102 wherein the propionating agent is a propionyl chloride.

104. The method of claim 101 wherein the propionating agent is an anhydride of propionic acid.

105. The method of claim 104, wherein the anhydride of propionic acid is propionic anhydride.

106. A process for the preparation of a compound of the sodium salt of N- [ [4- (3-phenylisoxazol-4-yl) phenyl ] sulfonyl ] propanamide having the structure of formula 1 b:

comprises the following steps:

contacting an [ isoxazol-4-yl ] benzenesulfonamide compound with a propionating agent to produce an N- [ [4- (3-phenylisoxazol-4-yl) phenyl ] sulfonyl ] propionamide compound having the structure of formula 1 a:

and contacting the N- [ [4- (3-phenylisoxazol-4-yl) phenyl ] sulfonyl ] propanamide compound with a sodium base to produce the N- [ [4- (3-phenylisoxazol-4-yl) phenyl ] sulfonyl ] propanamide sodium salt compound having the structure of formula 1 b.

107. The method of claim 106, wherein the source of hydroxylamine is an aqueous solution comprising hydroxylamine.

108. The method of claim 106 wherein the source of hydroxylamine is an aqueous solution comprising hydroxylamine and a weak acid.

109. The method of claim 108, wherein the weak acid is a carboxylic acid.

110. The method of claim 109, wherein the carboxylic acid is an alkyl carboxylic acid.

111. The method of claim 110, wherein the alkyl carboxylic acid is selected from the group consisting of formic acid, acetic acid, and propionic acid.

112. The process of claim 110, wherein the alkyl carboxylic acid is acetic acid.

113. The method of claim 106 wherein the source of hydroxylamine is an aqueous solution comprising hydroxylamine and a conjugate base of a weak acid.

114. The method of claim 113, wherein the conjugate base of a carboxylic acid is sodium acetate.

115. The method of claim 106, wherein the source of hydroxylamine comprises a hydroxylamine salt and a deprotonating base.

116. The method of claim 106, wherein the hydroxylamine salt is selected from the group consisting of hydroxylamine hydrochloride, hydroxylamine sulfate and hydroxylamine acetate.

117. The method of claim 116, wherein the hydroxylamine salt is hydroxylamine hydrochloride.

118. The method of claim 115, wherein the deprotonating base is selected from the group consisting of sodium hydroxide, potassium hydroxide and sodium acetate.

119. The method of claim 115, wherein the deprotonating base is sodium acetate.

120. The method of claim 115, wherein the source of hydroxylamine comprises hydroxylamine hydrochloride and sodium acetate.

121. The method of claim 106 wherein the strong base is selected from the group consisting of lithium dialkylamides, aryl lithiums, aryl alkyllithiums, and alkyllithiums.

122. The method of claim 106 wherein the strong base is lithium dialkylamide.

123. The method of claim 122 wherein the strong base is lithium diisopropylamide.

124. The method of claim 121, wherein the strong base is C₁To C₁₀An alkyl lithium.

125. The method of claim 106, wherein the strong base is butyl lithium.

126. The method of claim 106, wherein the strong base is hexyl lithium.

127. The method of claim 106, wherein the strong base is heptyl lithium.

128. The method of claim 106, wherein the strong base is octyl lithium.

129. The method of claim 106 wherein the acetylating agent is selected from the group consisting of alkyl acetates, acetic anhydride, N-alkyl-N-alkoxy acetamides and acetyl halides.

130. The method of claim 129, wherein the acetylating agent is C₁To C₆Alkyl acetate ester.

131. The method of claim 106, wherein the acetylating agent is selected from the group consisting of methyl acetate, ethyl acetate, propyl acetate and butyl acetate.

132. The method of claim 131, wherein the alkyl acetate is ethyl acetate.

133. The method of claim 106 wherein the acetylating agent is an acetyl halide.

134. The method of claim 133, wherein the acetyl halide is acetyl chloride.

135. The method of claim 106 wherein the acetylating agent is acetic anhydride.

136. The method of claim 106, wherein the halosulfonic acid is selected from the group consisting of bromosulfonic acid and chlorosulfonic acid.

137. The method of claim 106, wherein the halosulfonic acid is chlorosulfonic acid.

138. The method of claim 106, wherein the ammonia source is selected from the group consisting of ammonium hydroxide and anhydrous ammonia.

139. The method of claim 106, wherein the ammonia source is ammonium hydroxide.

140. The method of claim 106, wherein the ammonia source is anhydrous ammonia.

141. The method of claim 106 wherein the propionating agent is selected from the group consisting of an anhydride of propionic acid, a propionyl halide, a propionyl thioester, a propionyl carbonate, and a N-propionyl imidazole.

142. The method of claim 141 wherein the propionating agent is a propionyl halide.

143. The method of claim 142 wherein the propionating agent is a propionyl chloride.

144. The method of claim 141 wherein the propionating agent is an anhydride of propionic acid.

145. The method of claim 144, wherein the anhydride of propionic acid is propionic anhydride.

146. The method of claim 106, wherein the sodium base is selected from the group consisting of sodium hydroxide, sodium alkoxide, sodium hydride, and sodium carbonate.

147. The method of claim 146, wherein the sodium base is sodium hydroxide.

148. A method of preparing a benzenesulfonyl halide compound having the structure of formula 4:

wherein:

x is a halogen atom;

R¹、R²、R⁴and R⁵Is hydrogen;

R³selected from isoxazolyl and pyrazolyl, wherein R³Unsubstituted or substituted with one or more groups selected from alkyl, alkenyl, alkynyl, cycloalkyl, alkaryl, aryl, heterocyclyl, alkoxy, alkylamino, alkylthio, acyl, halogen, haloalkylaryl, alkoxyaryl, alkoxysubstituted with one or more groups selected from alkyl, alkenyl, alkynyl, cycloalkyl, alkaryl, aryl, heterocyclyl, alkoxy, alkylamino, alkylthio, acyl, halogen, haloalkylaryl, alkoxyaryl, alkoxy,Haloalkyl, protected hydroxymethyl, arylalkoxymethyl and alkoxyhaloalkyl;

wherein the process comprises reacting a substituted phenyl compound having the structure of formula 5:

and a halosulfonic acid, thereby producing a benzenesulfonyl halide compound having the structure of formula 4.

149. The method of claim 148, wherein the halosulfonic acid is selected from the group consisting of bromosulfonic acid and chlorosulfonic acid.

150. The method of claim 148 wherein the halosulfonic acid is chlorosulfonic acid.

151. The method of claim 148, wherein the benzenesulfonyl halide compound is 4- [ 5-methyl-3-phenylisoxazol-4-yl ] benzenesulfonyl chloride compound having the structure of formula 6: