WO2005123701A1

WO2005123701A1 - Method for the preparation of diarylisoxazole sulfonamide compounds and intermediates

Info

Publication number: WO2005123701A1
Application number: PCT/IB2005/001874
Authority: WO
Inventors: Leo J. Letendre; Cynthia K. Snoddy; George H. Klemm; Jon P. Lawson; Michael J. Bauer
Original assignee: Pharmacia Corporation
Priority date: 2004-06-14
Filing date: 2005-06-03
Publication date: 2005-12-29
Also published as: TW200616983A; AR049301A1

Abstract

The disclosure provides a method for the preparation of a diarylisoxazolé sulfonamide compound comprising contacting a deoxybenzoin with a secondary amine to form a diarylenamine compound; contacting the diarylenamine compound with an acetylating agent to form an acetyl diarylenamine compound; contacting the acetyl diarylenamine compound with a source of hydroxylamine to form an diaryl isoxazolol compound; eliminating water from the diaryl isoxazolol compound to form a diaryl isoxazole compound, chlorosulfonating the diarylisoxazole compound to form a chlorosulfonyl diaryl isoxazole compound; and contacting the chlorosulfonyl diaryl isoxazole compound with a source of ammonia to form the diarylisoxazole sulfonamide compound.

Description

METHOD FOR THE PREPARATION OF DIARYLISOXAZOLE SULFONAMIDE COMPOUNDS AND INTERMEDIATES

This application claims priority from U.S. Provisional Application Serial No. 60/579,591 filed June 14, 2004.

BACKGROUND OF THE INVENTION

Field of the Invention This invention relates to the preparation of compounds useful in the manufacture of pharmaceutical drugs. More specifically this invention relates to the preparation of diarylisoxazole compounds. This invention also relates to the manufacture of diarylisoxazole sulfonamide compounds useful as pharmaceutical drugs.

Description of Related Art The discovery of novel antiinflammatory drugs has been a goal of pharmaceutical research for decades. Significant among these drugs is the class of compounds now known as COX-2 inhibitors. Among the medically and commercially important COX-2 inhibitors are isoxazolyl benzenesulfonamide compounds. Many substituted isoxazolyl benzenesulfonamide compounds useful in treating inflammation are described in U.S. Patent 5,633,272. For example, among the substituted isoxazolyl benzenesulfonamide compounds described in that patent is valdecoxib, a potent COX-2 inhibitor sold under the brand name BEXTRA. Whereas the 5,633,272 patent describes small-scale preparations of valdecoxib and other compounds, such small-scale preparations are not directly amenable to large-scale manufacturing processes without additional development. Methods for preparing substituted isoxazol-4-yl benzenesulfonamide compounds are claimed in U.S. Patent 5,859,257. The methods in the 5,859,257 patent describe use a strong, water-reactive base (e.g., lithium diisopropylamide or n-butyllithium) to cyclize a diphenylethanone oxime compound to form the isoxazole moiety. Such water-reactive bases are inconvenient and sometimes cause safety and environmental concerns when used on a manufacturing scale. Alternatively the 5,859,257 patent describes the use iodine to achieve formation of the isoxazole moiety. Because of its volatility and reactivity, iodine is difficult to handle on a manufacturing scale and can be the source of significant safety concerns. Additional methods for preparing isoxazol-4-yl benzenesulfonamide compounds are described in U.S. Patent App. Pub. No. US 2003/0105334. Methods for preparing prodrugs of certain sulfonamide antiinflammatory compounds are described in U.S. Patent 5,932,598.

Summary of the Invention Among the several embodiments of the present invention may be noted the provision of an improved process for the preparation of diarylisoxazole sulfonamide compounds and intermediates for the making thereof. The present invention provides a novel method of preparing diarylenamine ketone compounds generally and 3,4-Diphenyl-4-pyrrolidin-1-yl-but-3-en-2-one specifically. The present invention further provides a novel method of preparing isoxazolylbenzenesulfonamide compounds, including 4-(5-methyl-3- phenyl-isoxazol-4-yl)-benzenesulfonamide and 4-(5-Methyl-3-phenyl-isoxazol-4-yl)-N-propionyl- benzenesulfonamide sodium salt. Briefly, therefore, the present invention is directed to a process for the preparation of a diarylhydroxyisoxazole compound having the structure of Formula!:

wherein the method comprises contacting a diarylenamine ketone compound having the structure of Formula 2:

with a source of hydroxylamine in the presence of a base, thereby forming the diarylhydroxyisoxazole compound, wherein: R¹ is selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, haloalkyl, haloalkenyl, haloalkynyl, and haioaryl; R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, and R¹¹ are each independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, alkylthio, halo, aminosulfonyl, acetoxy, protected hydroxyl, and a protected aminosulfonyl group; wherein the protected aminosulfonyl group has the structure of Formula 3:

R is a protected amino group; and R is a tertiary amino group. The invention is further directed to a method for the preparation of a diarylenamine ketone compound having the structure of Formula 2, wherein the method comprises contacting a diarylenamine compound having the structure of Formula 5:

with an acylating agent having the structure of Formula 6:

in the presence of a base, thereby forming the diarylenamine ketone compound, wherein: R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², and R¹³ are each independently are as defined above; and R¹⁴ is selected from the group consisting of halo and acyloxy. In another embodiment of the present invention is directed to a method for the preparation of a diarylisoxazole compound having the structure of Formula 7:

wherein the method comprises contacting a diarylhydroxyisoxazole compound having the structure of Formula 1 with an acid, thereby forming the diarylisoxazole compound, wherein: R¹ is selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, haloalkyl, haloalkenyl, haloalkynyl, and haioaryl; R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, and R¹³ are each independently as defined above; and wherein the protected aminosulfonyl group has the structure of Formula 3. Another embodiment of the present invention is directed to a method for the preparation of a diarylisoxazole sulfonamide compound having the structure of Formula 9:

wherein the method comprises contacting a diarylenamine ketone compound having the structure of Formula 11 :

with a source of hydroxylamine in the presence of a base, thereby forming a diarylhydroxyisoxazole compound having the structure of Formula 12:

optionally contacting the diarylhydroxyisoxazole compound with an acid, thereby forming a diarylisoxazole compound having the structure of Formula 13:

contacting the diarylhydroxyisoxazole compound or the diarylisoxazole compound with a halosulfonic acid to produce a halosulfonated product; and contacting the halosulfonated product with a source of ammonia to produce the diarylisoxazole sulfonamide compound; wherein: R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R¹⁰, R¹¹, and R¹² are each independently as defined above; and R¹⁵ is H. The present invention further provides a method for the preparation of a diarylisoxazole sulfonamide compound having the structure of Formula 9 wherein the method comprises contacting a diarylenamine ketone compound having the structure of Formula 25:

with a source of hydroxylamine in the presence of a base, thereby forming a diarylhydroxyisoxazole compound having the structure of Formula 26:

contacting the diarylhydroxyisoxazole compound with an acid, thereby forming a diarylisoxazole compound having the structure of Formula 27:

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R¹⁰, R¹¹, and R¹²are each as defined above. In yet another embodiment the present invention provides a method for the preparation of an N- acyl diarylisoxazole sulfonamide compound having the structure of Formula 10:

wherein the method comprises contacting a diarylenamine ketone compound having the structure of Formula 1! with a source of hydroxylamine in the presence of a base, thereby forming a diarylhydroxyisoxazole compound having the structure of Formula 12; optionally contacting the diarylhydroxyisoxazole compound with an acid, thereby forming a diarylisoxazole compound having the structure of Formula 13; contacting the diarylhydroxyisoxazole compound or the diarylisoxazole compound with a halosulfonic acid to produce a halosulfonated product; contacting the halosulfonated product with a source of ammonia to produce a diarylisoxazole sulfonamide compound having the structure of Formula 9; and contacting the diarylisoxazole sulfonamide compound with an acylating agent to form the N-acyl diarylisoxazole sulfonamide compound; wherein: R¹ is selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, haloalkyl, haloalkenyl, haloalkynyl, and haioaryl; R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R¹⁰, R¹¹, and R¹² are each independently as defined above; R¹⁵ is alkyl; and Rl-is H. In still another embodiment, the present invention provides a method for the preparation of an N- acyl diarylisoxazole sulfonamide compound having the structure of Formula 10, wherein the method comprises contacting a diarylenamine ketone compound having the structure of Formula 25 with a source of hydroxylamine in the presence of a base, thereby forming a diarylhydroxyisoxazole compound having the structure of Formula 26; contacting the diarylhydroxyisoxazole compound with an acid, thereby forming a diarylisoxazole compound having the structure of Formula 27; contacting the diarylisoxazole sulfonamide compound with an acylating agent to form the N-acyl diarylisoxazole sulfonamide compound; wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R¹⁰, R¹¹, R¹², and R¹⁵ are as defined above. In still another embodiment the present invention provides the compound 3,4-diphenyl-4- pyrrolidin-1 -yl-but-3-en-2-one. Further scope of the applicability of the present invention will become apparent from the detailed description provided below. However, it should be understood that the following detailed description and examples, while indicating useful 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 THE DRAWINGS Figure 1 describes a process for the conversion of 3,4-diphenyl-4-pyrrolidin-1 -yl-but-3-en-2-one

(16) into 5-methyl-3,4-diphenyl-4,5-dihydroisoxazol-5-ol (17). Figure 2 describes a process for the conversion of 1-(1,2-diphenylvinyl)pyrrolidine (15) into 3,4- diphenyl-4-pyrrolidin-1 -yl-but-3-en-2-one (16). Figure 3 describes an overall process and individual steps for the conversion of deoxybenzoin compound 8 into diarylisoxazole sulfonamide compound 9, diarylisoxazole compound 7, and N-acyl diarylisoxazole sulfonamide compound 10. Figure 4 describes an overall process and individual steps for the conversion of 1 ,2- diphenylethanone (14) to valdecoxib (19) and parecoxib sodium (20). Figure 5 describes an overall process and individual steps for the for the conversion of 4-(2-oxo-2- phenylethyl)benzenesulfonamide (21) to valdecoxib (19) and parecoxib sodium (20).

DETAILED DESCRIPTION

The following detailed description is provided to aid those skilled in the art in practicing the present invention. Even so, this detailed description should not be construed to unduly limit the present invention as modifications and variations in the embodiments discussed herein can be made by those of ordinary skill in the art without departing from the spirit or scope of the present inventive discovery. The contents of each of the references cited herein are herein incorporated by reference in their entirety.

a. Definitions The following definitions are provided in order to aid the reader in understanding the detailed description of the present invention: The term "protected aminosulfonyl group" means an aminosulfonyl group (or equivalent) which has been modified with a removable moiety which protects the aminosulfonyl group from chemical changes during the performance of a chemical reaction. For example a useful protected aminosulfonyl group is a 2,5-dimethylpyrrolylsulfonyl group. Additional protected aminosulfonyl groups are described in Protective Groups in Organic Synthesis. 3rd Ed., T.W. Greene and P.G.M. Wuts, John Wiley & Sons, Inc., New York, 1999. pp. 603-615 and 647-648, hereby incorporated by reference. The term "protected amino group" means an amino group which has been modified with a removable moiety which protects the amino group from chemical changes during the performance of chemical reactions. For example a useful protected amino group is a 2,5-dimethylpyrrolyl group. The term "protected amino group" in the context of this disclosure includes the protected amino functionalities described for protected aminosulfonyl groups, above. The term "protected hydroxyl group" means a hydroxyl group which has been modified with a removable moiety which protects the hydroxyl group from chemical changes during the performance of a chemical reaction. Some useful protected hydroxyl groups are described in Protective Groups in Organic Synthesis. 3rd Ed., T.W. Greene and P.G.M. Wuts, John Wiley & Sons, Inc., New York, 1999. pp. 246- 292, hereby incorporated by reference. The term "carboxylate base" means a conjugate base of a carboxylic acid. For example, the carboxylate base can be an alkylcarboxylate, an arylcarboxylate, or any other convenient conjugate base of a carboxylic acid. The term "carboxylate" means a -C0₂H group or a salt thereof. The symbol "H" means a hydrogen atom. "Alkyl", "alkenyl," and "alkynyl" unless otherwise noted are each straight chain or branched chain hydrocarbons of from one to twenty carbons for alkyl or two to twenty carbons for alkenyl and alkynyl in the present invention and therefore mean, for example, methyl, ethyl, propyl, butyl, pentyl or hexyl and ethenyl, propenyl, butenyl, pentenyl, or hexenyl and ethynyl, propynyl, butynyl, pentynyl, or hexynyl respectively and isomers thereof. "Aryl" means a fully unsaturated mono- or multi-ring carbocycle, including, but not limited to, substituted or unsubstituted phenyl, naphthyl, or anthracenyl. By "fully unsaturated" it is meant that the aryl moiety possesses 4n+2 pi electrons. "Heterocycle" means a saturated or unsaturated mono- or multi-ring carbocycle wherein one or more carbon atoms can be replaced by N, S, P, or O. This includes, for example, the following structures:

1 2 3 - - _ . _ . .. — - -_ _ _ . wherein Z, Z , Z or Z is a heteroatom selected from the group consisting of C, S, P, O, and N; with the 1 2 3 proviso that one of Z, Z , Z or Z is other than carbon, but is not O or S when attached to another Z atom by a double bond or when attached to another O or S atom; and further providing that at least one atom in the heterocycle ring is carbon. Furthermore, the optional substituents are understood to be attached to Z, 1 2 3

Z , Z or Z only when each is C. For example, the term "heterocyclyl" embraces each of the following groups, although this listing is not meant to limit the definition to these groups only: furanyl; thienyl; pyrrolyl; 2-isopyrrolyl; 3-isopyrrolyl; pyrazolyl; 2-isoimidazolyl; 1 ,2,3-triazolyl; 1 ,2,4-triazolyl; 1 ,2- dithiolyl; 1 ,3-dithiolyl; 1 ,2,3-oxathiolyl; isoxazolyl; oxazolyl; thiazolyl; isothiazolyl; 1 ,2,3-oxadiazolyl; 1 ,2,4-oxadiazolyl; 1 ,2,5-oxadiazolyl; 1 ,3,4-oxadiazolyl; 1 ,2,3,4-oxatriazolyl; 1 ,2,3,5-oxatriazolyl; 1 ,2,3- dioxazolyl; 1 ,2,4-dioxazolyl; 1 ,3,2-dioxazolyl; 1 ,3,4-dioxazolyl; 1 ,2,5-oxathiazolyl; 1 ,3-oxathiolyl; 1 ,2- pyranyl; 1 ,4-pyranyl; 1 ,2-pyranonyl; 1 ,4-pyranonyl; 1 ,2-dioxinyl; 1 ,3-dioxinyl; pyridyl; pyridazyl; pyrimidyl; pyrazinyl; piperazyl; 1 ,3,5-triazinyl; 1 ,2,4-triazinyl; 1 ,2,3-triazinyl; 1 ,2,4-oxazinyl; 1 ,3,2- oxazinyl; 1 ,3,6-oxazinyl; 1 ,2,6-oxazinyl; 1 ,4-oxazinyl; o-isoxazinyl; p-isoxazinyl; 1 ,2,5-oxathiazinyl; 1 ,4- oxazinyl; o-isoxazinyl; p-isoxazinyl; 1 ,2,5-oxathiainzyl; 1 ,2,6-oxathiainzyl; 1 ,4,2-oxadiainzyl; 1 ,3,5,2- oxadiainzyl; morpholino; azepinyl; oxepinyl; thiepinyl; 1 ,2,4-diazepinyl; benzofuranyl; isobenzofuranyl; benzothiofuranyl; isobenzothiofuranyl; indolyl; indoleninyl; 2-isobenzazolyl; 1 ,5-pyrindinyl; pyrano[3,4- bjpyrrolyl; isoindazolyl; indoxazinyl; benzoxazolyl; anthranilyl; 1 ,2-benzopyranyl; quinolyl; isoquinolyl; cinnolyl; quinazolyl; naphthyridyl; pyrido[3,4-b]pyridyl; pyrido[3,2-b]pyridyl; pyrido[4,3-b]pyridyl; 1 ,3,2- benzoxazyl; 1 ,4,2-benzoxazyl; 2,1 ,3-benzoxazyl; 3,1 ,4-benzoxazyl; 1 ,2-benzoisoxazyl; 1 ,4- benzoisoxazyl; carbazolyl; xanthenyl; acridinyl; purinyl; thiazolidyl; piperidyl; pyrrolidyl; 1 ,2- dihydroazinyl; 1 ,4-dihydroazinyl; 1 ,2,3,6-tetrahydro-1 ,3-diazinyl; perhydro-1 ,4-diazinyl; 1 ,2-thiapyranyl; and 1 ,4-thiapyranyl. The term "heteroaryl" means a fully unsaturated heterocycle. By "fully unsaturated" it is meant that the heteroaryl moiety possesses 4n+2 pi electrons. For example, the term "heteroaryl" embraces each of the following groups, although this listing is not meant to limit the definition to these groups only: furanyl; thienyl; pyrrolyl; pyrazolyl; 1 ,2,3-triazolyl; 1 ,2,4-triazolyl; isoxazolyl; oxazolyl; thiazolyl; isothiazolyl; 1 ,2,3-oxadiazolyl; 1 ,2,4-oxadiazolyl; 1 ,2,5-oxadiazolyl; 1 ,3,4-oxadiazolyl; 1 ,2,3,4- oxatriazolyl; 1 ,2,3,5-oxatriazolyl; 1 ,2-pyranonyl; 1 ,4-pyranonyl; pyridyl; pyridazyl; pyrimidyl; piperazyl; 1 ,3,5-triazinyl; 1 ,2,4-triazinyl; 1 ,2,3-triazinyl; benzofuranyl; isobenzofuranyl; benzothiofuranyl; isobenzothiofuranyl; indolyl; 1 ,5-pyrindinyl; pyrano[3,4-b]pyrrolyl; isoindazolyl; indoxazinyl; benzoxazolyl; anthranilyl; quinolyl; isoquinolyl; cinnolyl; quinazolyl; naphthyridyl; pyrido[3,4-b]pyridyl; pyrido[3,2-b]pyridyl; pyrido[4,3-b]pyridyl; carbazolyl; xanthenyl; acridinyl; purinyl; thiazolidyl; piperidyl; pyrrolidyl; 1 ,2-dihydroazinyl; 1 ,4-dihydroazinyl; 1 ,2,3,6-tetrahydro-1 ,3-diazinyl; perhydro-1 ,4-diazinyl; 1 ,2-thiapyranyl; and 1 ,4-thiapyranyl. In either "heterocycle" or "heteroaryl," the point of attachment to the molecule of interest can be at the heteroatom or elsewhere within the ring. The term "halo" or "halogen" means a fluoro, chloro, bromo or iodo group. The term "halide" means fluoride, chloride, bromide, or iodide. The term "haloalkyl" means alkyl substituted with one.or more halogens. _ .. The term "cycloalkyl" means a mono- or multi-ringed carbocycle wherein each ring contains three to ten carbon atoms, and wherein any ring can contain one or more double or triple bonds. Examples include radicals such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloalkenyl, and cycloheptyl. The term "cycloalkyl" additionally encompasses spiro systems. The term "oxo" means a doubly bonded oxygen. The term "aminosulfonyl" means a group having the structure -S0₂NH₂. When used in combination, for example "alkylaryl" or "arylalkyl," the individual terms listed above have the meaning indicated above. That is to say, the term "arylalkyl" means an aryl-substituted alkyl radical such as benzyl. The term "alkylarylalkyl" means an arylalkyl radical that is substituted on the aryl group with one or more alkyl groups. The term "alkoxy" an alkyl radical which is attached to the remainder of the molecule by oxygen, such as a methoxy radical. Among the useful alkoxy radicals are "lower alkoxy" radicals having one to six carbon atoms. Examples of such radicals include methoxy, ethoxy, propoxy, isopropoxy, butoxy and tert- butoxy. The term "alkylthio" means an alkyl radical which is attached to the remainder of the molecule by sulfur, such as a methylthio radical. The term "carboxy" means the carboxy group, -C0₂H, or its salts. The term "acyloxy" means an acyl group attached to the remainder of the molecule by oxygen, such as an acetoxy or a propionyloxy radical. The term "acyl" means an alkyl radical which is attached to the remainder of the molecule by a carbonyl group. The term "enamine" means a compound containing an amino group directly attached to a double bonded carbon which is doubly bonded to another carbon. The term "aromatic amine" means an amine wherein the nitrogen atom of the amine is part of an aromatic ring. The term "nitrile" means a compound containing a -CN group. The term "sulfonic acid" means a compound containing a -S03H group, or a salt thereof. The term "phosphonic acid" means a compound containing a -P0₃H₂ group, or a salt thereof. The term "ACN" means acetonitrile. The term "TFA" means trifluoroacetic acid. The term "mmHG" or "Torr" means millimeters of mercury. The term "HPLC" means high pressure liquid chromatography. The term "NaOAC" means sodium acetate. The term "IPA" means isopropyl alcohol. The symbol "g" means grams. The term "GCMS" means gas chromatography/mass spectrometry. The term "HRMS" means high resolution mass spectrometry. The term "EtOAc" means ethyl acetate. The term "mL" means milliliters. The term "GC" means gas chromatography. The term "Et" means ethyl. The term "Me" means methyl. The term "mmol" means millimoles. The term "wt%" means weight percent. The term "Ac" means acetyl or acetate. The term "eq." means equivalents. The compounds methods of the present invention also include tautomers. In the present description, a wavy line crossing a bond (for example, Formula 3)

means that the moiety depicted in the formula is attached to another chemical structure at that bond.

b. Process Details In accordance with the present invention, a process is now provided for the preparation of a diarylhydroxyisoxazole compound having the structure of Formula V.

with a source of hydroxylamine in the presence of a base, thereby forming the diarylhydroxyisoxazole compound, wherein: R is selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, haloalkyl, haloalkenyl, haloalkynyl, and haioaryl; R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, and R¹¹ are each independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, alkylthio, halo, aminosulfonyl, acetoxy, protected hydroxyl, and a protected aminosulfonyl group; wherein the protected aminosulfonyl group has the structure of Formula 3:

R is a protected amino group; and R is a tertiary amino group. In one embodiment, R¹² is a nitrogen-containing heterocycle optionally substituted with a moiety selected from the group consisting of alkyl, alkenyl, and alkynyl; and wherein a nitrogen atom of the nitrogen-containing heterocycle is part of the enamine structure of the diarylenamine ketone compound. In another embodiment, the nitrogen-containing heterocycle comprises a 3 to about 7-membered ring. In yet another embodiment, the nitrogen-containing heterocycle is selected from the group consisting of pyrrolidinyl, morpholinyl, piperidinyl, azetidinyl, and aziridinyl. In one embodiment the nitrogen-containing heterocycle is 1 -pyrrolidinyl. In another embodiment, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, and R¹¹ are each independently selected from the group consisting of H, alkyl, aminosulfonyl, and the protected aminosulfonyl group. Usefully, R², R³, R⁴, R^ε, R⁶, R⁷, R⁸, R⁹, R¹⁰, and R¹¹ are each independently selected from the group consisting of H, aminosulfonyl, and the protected aminosulfonyl group. In one embodiment, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, and R¹ are each H. In another embodiment, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R¹⁰, and R¹¹ are each H; and R⁹ is a protected aminosulfonyl group. In yet another embodiment, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R¹⁰, and R¹¹ are each H; and R⁹ is aminosulfonyl. When R⁹ is a protected aminosulfonyl group, R¹³ can for example have the structure of Formula 4:

In one embodiment R¹ is methyl; and R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, and R¹¹ are each H. In another embodiment, R¹ is methyl; and R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R¹⁰, and R¹¹ are each H; and R⁹ is aminosulfonyl. Among its many embodiments, therefore, the present invention provides a method for the preparation of 5-methyl-3,4-diphenyl-4,5-dihydroisoxazol-5-ol (17) wherein the method comprises contacting 3,4-diphenyl-4-pyrrolidin-1-yl-but-3-en-2-one (16) with a source of hydroxylamine optionally in the presence of a base other than hydroxylamine to form 17. In one alternative, hydroxylamine can serve as the base. In another alternative, a different base can be added to the reaction mixture. This reaction to form 17 is shown in Figure 1. Optionally, in the same reaction vessel or in a different reaction vessel, 17 can be further reacted to eliminate water. This elimination will form isoxazole 18. In one embodiment the base comprises one or more compounds selected from the group consisting of a carboxylate base, a hydroxide base, an aromatic amine base, a carbonate base, and an aliphatic amine. For example, when the base is an aliphatic amine, it can be a trialkyl amine such as triethylamine. In another embodiment, the base is a carboxylate base. Useful carboxylate bases can contain, for example, from 1 to about 10 carbon atoms, alternatively 1 to about 5 carbon atoms, and in another alternative 1 to about 3 carbon atoms. In one embodiment, the carboxylate base is an acetate base, for example an alkali metal acetate base. Alkali metal acetate bases useful in the present invention include, without limitation, sodium acetate or potassium acetate. For example, sodium acetate is a useful base. Alternatively, the acetate base can comprise one or more compounds selected from the group consisting of ammonium acetate and an N-substituted ammonium acetate. For example the acetate base can comprise, without intending to limit the scope of the invention, ammonium acetate, an alkylammonium acetate, a dialkylammonium acetate, a trialkylammonium acetate, or a tetraalkylammonium acetate, or any mixture thereof. By way of non-limiting example, the base can comprise methylammonium acetate, dimethylammonium acetate, trimethylammonium acetate, tetramethylammonium acetate, ethylammonium acetate, diethylammonium acetate, triethylammonium acetate, tetraethylammonium acetate, propylammonium acetate, dipropylammonium acetate, isopropylammonium acetate, diisopropylammonium acetate, or any mixture thereof. Alternatively, the base can comprise an alkali metal hydroxide base such as sodium hydroxide or potassium hydroxide. A useful base, for example, is sodium hydroxide. In another alternative, the base is an aromatic amine base. Useful aromatic amine bases include pyridine, lutidine, or collidine. The source of hydroxylamine in the present invention can vary widely. For example the source of hydroxylamine can be essentially neat hydroxylamine or it can be diluted hydroxylamine. The solvent with which the hydroxylamine can be diluted can vary widely. For example, the solvent for diluting hydroxylamine can comprise water, or it can comprise an organic solvent, or a mixture of water and an organic solvent. The solvent for diluting hydroxylamine can, for example, be the same solvent (if any) in which the contacting is performed. For example, the solvent can comprise propylene glycol, ethylene glycol, or glyme. Alternatively, the source of hydroxylamine can be a salt of hydroxylamine. The salt of hydroxylamine can comprise, for example, a hydroxylammonium halide, a hydroxylammonium carboxylic acid salt (herein, a "hydroxylammonium carboxylate"), hydroxylammonium sulfate, hydroxylammonium phosphate, or hydroxylammonium carbonate. In one embodiment the salt of hydroxylamine comprises a hydroxylammonium Cι to about C₅ alkyl carboxylate. For example, the salt of hydroxylamine can comprise hydroxylammonium acetate. In a further embodiment, the salt of hydroxylamine can comprise hydroxylammonium fluoride, hydroxylammonium chloride, hydroxylammonium bromide, or hydroxylammonium iodide. In another embodiment the salt of hydroxylamine comprises one or more compounds selected from the group consisting of hydroxylammonium chloride and hydroxylammonium bromide. For example the salt of hydroxylamine can comprise hydroxylammonium chloride. In a further embodiment of the present invention, the process for the preparation of a diarylhydroxyisoxazole compound can be performed under conditions in which the contacting of the diarylenamine ketone compound with the source of hydroxylamine is performed in the presence of a solvent. The contacting can also be performed, optionally, in the presence of a mixture of solvents. If a solvent is employed, it can comprise, for example one or more compounds selected form the group consisting of a nitrile, an aromatic solvent, an aliphatic hydrocarbon, an ether, an aromatic amine, water, a glycol, and an alcohol. Some useful glycols include ethylene glycol and propylene glycol. When the solvent includes an alcohol, exemplary useful alcohols include ethanol and methanol. In one embodiment the solvent comprises a nitrile; alternatively it comprises a C₂ to about C₇ nitrile; in another alternative a C₂ to about C₅ nitrile. For example the nitrile solvent can comprise acetonitrile or propionitrile, and in yet another embodiment it can comprise acetonitrile. As a useful alternative, the solvent can comprise an aromatic amine. For example the aromatic amine can comprise pyridine, lutidine (for example 2,6- lutidine), or collidine, or any mixture thereof; a useful aromatic amine is 2,6-lutidine. The contacting of the diarylenamine ketone compound with the source of hydroxylamine can be performed under a variety of conditions of temperature, pressure, and pH. In one embodiment the contacting is performed at a pH of about 1 to about 7; in another embodiment about 2 to about 5; and in still another embodiment about 3 to about 4. The pH can be maintained using a buffer or the pH can be maintained by manual or automated pH adjustments. A useful buffer is an acetate buffer. For example the buffer can comprise a mixture of sodium acetate and acetic acid. For the present inventive reaction, the molar ratio of the source of hydroxylamine to the diarylenamine compound can vary widely to useful end. For example the molar ratio of the source of hydroxylamine to the diarylenamine compound can be about 1 :10 to about 10:1 ; alternatively about 1 :5 to about 10:1 ; alternatively about 1 :1 to about 10:1 ; alternatively about 2:1 to about 5:1 ; and in yet another alternative about 3:1 to about 4:1. In one embodiment, the molar concentration of the source of hydroxylamine is higher than the molar concentration of the diarylenamine ketone compound under the conditions of the contacting. Conveniently, the reaction for the preparation of compound 1 from compound 2 can be performed under conditions in which the source of hydroxylamine is added to compound 2. In one embodiment, the various reactions described herein for the conversion of deoxybenzoin compound 8 to isoxazole compound 7 are carried out in a single reaction vessel, it is useful to perform the conversion of 1 to 2 in such a manner that compound 2 is in the reaction vessel when the source of hydroxylamine is added. For example, a mixture comprising the source of hydroxylamine and the base can be added to compound 2. Alternatively, the source of hydroxylamine can be added to a mixture of the base and compound 2. When the source of hydroxylamine is added to compound 2 (whether or not compound 2 has been isolated from the preceding reaction mixture), the addition rate of the source of hydroxylamine can vary widely. It is sometimes convenient to add the source of hydroxylamine at a rate such that the temperature of the reaction mixture can be maintained below about 35 to about 50°C, alternatively about 40 to about 45°C. It is convenient to maintain the reaction temperature mixture at about 45°C during the addition of the hydroxylamine. However, the reaction can be run at lower temperatures, as long as the reaction mixture is fluid and mixable. For example the reaction can be performed at a temperature of about 25°C or lower. Depending upon whether external cooling is applied to the reaction vessel, the source of hydroxylamine can be added rapidly or slowly. For example the source of hydroxylamine can be added to the diarylenamine ketone compound 2 in less than a minute or over a period of several hours. When diarylhydroxyisoxazole compound 1 is prepared, it can, if desired, be isolated (for example in the form of a wet cake). If the reaction for the preparation of 1 is performed in a solvent (for example, a solvent comprising water) from which 1 precipitates upon forming, compound 1_ can be filtered or centrifuged from the reaction mixture and washed with water (to remove solvent or water-soluble impurities), thereby producing the wet cake. Alternatively compound 1_ can be used in further reactions without isolation or without removal from the reaction vessel in which it was formed. One way to isolate compound 1 from the reaction mixture used to prepare it is to precipitate 1 by the addition of water to the reaction mixture. Another way is to remove solvent by distillation. Yet another way is to cool the reaction mixture. Still another way is to add seed crystals of . Any or all of the above techniques and conditions can be used in the preparation of compound 17. The invention is further directed to a method for the preparation of a diarylenamine ketone compound having the structure of Formula 2, wherein the method comprises contacting a diarylenamine compound having the structure of Formula 5:

with an acylating agent having the structure of Formula 6:

in the presence of a base, thereby forming the diarylenamine ketone compound, wherein: R through R¹³ each independently is as defined above; and R¹⁴ is selected from the group consisting of halo, acyloxy, imidazole, and a sulfonate leaving group. Useful sulfonate leaving groups include toluenesulfonate, methanesulfonate, and trifluoromethanesulfonate. In one embodiment, R¹⁴ is halo. For example, R¹⁴ usefully is chloro, bromo, or iodo. In another embodiment R¹⁴ is chloro. In an alternative embodiment R ⁴ is acyloxy. A wide range of acyloxy groups are useful in the present embodiment. For example R¹⁴ can be, if desired, C-_t to about C₇ acyloxy; alternatively C-i to about C₄ acyloxy; and in another alternative acetoxy. In another embodiment R¹⁴ is -OR¹⁷ wherein R¹⁷ is selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, alkylsulfonyl, arylsulfonyl, alkylarylsulfonyl, and haloalkylsulfonyl. For example R¹⁷ can be alkyl. In another example R¹⁷ can be Ci to about Cι₀ alkyl; alternatively C- to about C₅ alkyl; and alternatively d to about C₃ alkyl. For example R¹⁷ can be methyl. Alternatively, R¹⁷ can be ethyl. For example, the structure of Formula 6 can be ethyl acetate. The structure of Formula 6 can in another alternative be methyl acetate. Among its many embodiments, therefore, the present invention provides a method for the preparation of 3,4-diphenyl-4-pyrrolidin-1 -yl-but-3-en-2-one (16) from 1 -(1 ,2-diphenyl-vinyl)-pyrrolidine (15) according to the reaction shown in Figure 2. In one of the many embodiments of the present invention, the base used for the preparation of the diarylenamine ketone compound has a pK_a which is higher than the pK_a for the diarylenamine compound. For example, the base can comprise an aromatic amine, a tertiary amine, a nitrile, a carbonate salt, and a hydroxide base, or any combination thereof. In one embodiment the base comprises an aromatic amine. The aromatic amine can comprise, for example, pyridine, lutidine, pyrrolidine, or collidine, or any combination thereof. In another embodiment the base can comprise a tertiary amine such as a trialkylamine. For example, the tertiary amine can comprise a tri-(Cι to about C₅-alkyl)amine. Usefully, the tertiary amine comprises triethylamine. Alternatively the tertiary amine can comprise DBU. In yet another embodiment the base used for the preparation of the diarylenamine ketone compound can comprise a carbonate base. For example the base can comprise an alkali metal carbonate such as sodium carbonate or potassium carbonate. In one embodiment the carbonate base comprises potassium carbonate. Alternativelyihe.base can comprise sodium carbonate. In still another embodiment the base can comprise a hydroxide base such as sodium hydroxide or potassium hydroxide. The preparation of the diarylenamine ketone compound optionally can be performed in the presence of a solvent. The solvent can vary widely. For example, the solvent can comprise an ether, an alkylhalide, a nitrile, an aromatic amine, a tertiary amine, or an aromatic hydrocarbon, or a combination of the above. In one embodiment the solvent can comprise a nitrile (such as acetonitrile), or an aromatic amine (such as lutidine). In one embodiment, the solvent comprises a nitrile. For example the nitrile can comprise a C₂ to about C₇ nitrile; in another example a C₂ to about C₅ nitrile; in another example a C₂ to about C₃ nitrile; and in yet another example acetonitrile. Alternatively, the solvent can comprise an aromatic amine solvent such as pyridine, lutidine, or collidine. As another alternative, the solvent can comprise a tertiary amine. For example the tertiary amine can comprise a tri-(d to about C₅-alkyl)amine. For example the tertiary amine can comprise triethylamine. In another embodiment the solvent comprises an aromatic hydrocarbon, such as toluene. In one embodiment the solvent can serve as the base used for the preparation of the diarylenamine ketone compound, for example acetonitrile. The amount of solvent used in the preparation of the diarylenamine ketone compound can vary widely. In one embodiment, the amount of solvent is at least enough to solubilize the reactants. It is convenient to express the amount of solvent as a ratio of the weight of the diarylenamine compound (5) divided by the weight of solvent. Such ratio can vary widely. In one embodiment the ratio is less than 10, alternatively less than 2.0, alternatively less than 1.0, and alternatively 0.4. In the preparation of the diarylenamine ketone compound, the base and the acylating agent can be contacted with the diarylenamine compound at the same time, or sequentially. For example the base can be contacted with the diarylenamine compound first and the acylating agent can be contacted later. Alternatively, the acylating agent can be contacted with the diarylenamine compound first and the base can be contacted later. In another, the base and the acylating agent are contacted with the diarylenamine compound at substantially the same time. The term "at substantially the same time" in this context means the acylating agent and the base can be contacted with the diarylenamine compound simultaneously or within a matter of minutes or seconds of each other. When the base and the acylating agent are contacted with the diarylenamine compound at substantially the same time, the base can conveniently comprise an aromatic amine base. Under these conditions, it is convenient that the acylating agent comprise an acyl halide, for example a C-i to about C₇ acyl halide, alternatively a C-i to about C₅ acyl halide, alternatively a C₁ to about C₃ acyl halide, and in another alternative an acetyl halide. The acetyl halide can comprise, for example, acetyl chloride, acetyl bromide, or acetyl iodide. In one embodiment the acetyl halide comprises acetyl chloride. In a another embodiment of the present invention, the aromatic amine and the acyl halide are provided together in the form of an aromatic amine acyl halide salt when they are contacted with the diarylenamine compound. In other words, the preparation of the diarylenamine ketone compound can be performed under conditions in which the base and the acylating agent are contacted with the diarylenamine compound at the same time and in the form of an aromatic amine acyl halide salt. An example of such an aromatic amine acyl halide salt is 1 -acetyl pyridinium chloride. In another embodiment, the molar concentration of the acylating agent is higher than the molar concentration of the diarylenamine compound. Given the present teaching, a skilled artisan will find that the various embodiments are not necessarily exclusive of each other. For example the preparation of the diarylenamine ketone compound can be achieved by contacting the diarylenamine compound with an aromatic amine acyl halide salt in the presence of an excess of either the amine or the acyl halide. In the preparation of compound 2 from compound 5, it is sometimes useful to add the acylating agent and the base to a reaction vessel already containing compound 2. The addition rate of the acylating agent can vary widely in this flexible reaction. The actual rate of addition can vary significantly depending in part on whether there is external cooling applied to the reaction vessel. During the conversion of compound 5 into compound 2, it is useful to provide cooling to the reaction mixture. For example, it is useful to maintain a reaction temperature in a range of about 0°C to about 50°C, alternatively 0°C to about 40°C, alternatively about 5°C to about 35°C, and alternatively about 5°C to about 30°C. In one embodiment, the temperature is maintained at about 5°C. It is useful to maintain the temperature of the reaction mixture above a temperature at which the mixture will be fluid (e.g., a liquid or a slurry). The ratio of the diarylenamine compound 5 to the acylating agent can vary widely to useful effect in the present embodiment. This ratio can be conveniently expressed by dividing the number of miliimoles of the acetylating agent by the number of miliimoles of compound 5. This ratio can conveniently vary over any range under which the reagents are capable of reacting with each other to produce compound 2. For example it is convenient for this ratio to be in the range of about 0.25 to about 15, alternatively about 1 to about 10, alternatively 1.5 to about 8, and in another alternative about 2 to about 6. The contacting of the diarylenamine compound with the aromatic amine and the acyl halide can be performed under conditions of varying water concentration. In one embodiment the contacting is performed in a medium containing less than 0.2% by weight of water. In another embodiment the contacting is performed under essentially anhydrous conditions; or the contacting is performed under anhydrous conditions. In another embodiment of the present invention is directed to a method for the preparation of a diarylisoxazole compound having the structure of Formula 7:

wherein the method comprises contacting a diarylhydroxyisoxazole compound (having the structure of Formula 1) with an acid, thereby forming the diarylisoxazole compound, wherein: R¹ R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, and R¹¹ are each independently as defined above. The preparation of the diarylhydroxyisoxazole compound used in the preparation of the diarylisoxazole can be made, for example, by a method comprising contacting a diarylenamine ketone compound having the structure of Formula 2 with a source of hydroxylamine in the presence of a base, thereby forming the diarylhydroxyisoxazole compound. The diarylenamine ketone compound can, if desired, be prepared as described above. In one useful embodiment, Formula 7 has the structure of Formula 18. In another useful embodiment, Formula 7 has the structure of Formula 19. The diarylenamine compound (Formula 5) useful in the various embodiments of the present invention can be prepared by a method comprising contacting a deoxybenzoin compound having the structure of Formula 8:

with a secondary amine in the presence of an acid, thereby forming the diarylenamine compound; wherein R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, and R¹¹ are as defined above. The secondary amine can comprise for example a nitrogen-containing heterocycle optionally substituted with a variety of moieties including alkyl, alkenyl, alkynyl, and others. The nitrogen-containing heterocycle can be of any convenient size. For example, the nitrogen-containing heterocycle can comprise a 3 to about 7-membered ring. Nitrogen- containing heterocycles useful as the secondary amine in the present invention include, without limitation, pyrrolidinyl, morpholinyl, piperidinyl, azetidinyl, and aziridinyl. Alternatively, the secondary amine can comprise a dialkylamine. For example the secondary amine can contain two identical alkyl groups, for example two C-i to about C₇ alkyl groups, alternatively two Ci to about C₅ alkyl groups. Useful secondary aminesJncludejclimethylamine,-diethylamine,.di(prop-1_-yl)anime,-di(pr.op-2-yl)amine,_di(but-1-yl)amine, di(but-2-yl)amine, di(2-methylprop-1-yl)amine, and di(2-methylprop-2-yl)amine. The secondary amine can in another alternative contain two different alkyl groups. Among its many embodiments, therefore, the present invention provides a method for the preparation of 1-(1,2-diphenylvinyl)pyrrolidine (15) from 1 ,2-diphenylethanone (14) following the methods and procedures described above. The acid used in the preparation of the diarylenamine compound can very widely. For example, the acid can comprise a Lewis acid. Such Lewis acids include, for example, AICI₃, TiCI₄, BF₃, Al₂0₃, AI0₂, and mixtures thereof. In one embodiment the Lewis acid comprises TiCI₄. In another embodiment, the acid comprises a protic acid. For example the protic acid can comprises a mineral acid. Useful mineral acids include sulfuric acid, phosphoric acid, polyphosphoric acid, phosphorous acid, nitric acid, nitrous acid, hydrochloric acid, hydrobromic acid, hydriodic acid, and mixtures thereof. The protic acid can alternatively comprise an organic acid. Such organic acids include a carboxylic acid, a sulfonic acid, a phosphonic acid, carbonic acid, and mixtures thereof. In one embodiment the organic acid comprises a carboxylic acid or a sulfonic acid, for example a carboxylic acid. Examples of carboxylic acids useful in the present invention include acetic acid, propionic acid, butyric acid, isobutyric acid, trifluoroacetic acid, trichloroacetic acid, and mixtures thereof. In one embodiment the acid comprises acetic acid. Other useful acids include toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, and mixtures thereof. In one embodiment the acetic acid is added to the reaction mixture in the form of glacial acetic acid or aqueous acetic acid. In another embodiment, the acid comprises trifluoroacetic acid. In yet another embodiment, the acid comprises a sulfonic acid. For example the acid can comprise an alkylsulfonic acid or an arylsulfonic acid. If the acid comprises an alkylsulfonic acid, it can comprise, without limiting the scope or applicability of other embodiments, a C-i to about C₇ alkylsulfonic acid, alternatively a Ci to about C₅ alkylsulfonic acid, and in another alternative methanesulfonic acid or ethanesulfonic acid. Alternatively the acid can comprise an arylsulfonic acid. Useful arylsulfonic acids include, for example, benzenesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, and mixtures thereof. The process in which compound 8 is converted into compound 5 can be run, if desired, in the presence of a solvent. A wide range of solvents are useful in the present embodiment including aliphatic hydrocarbons, aromatic hydrocarbons, halogenated aliphatic hydrocarbons, aromatic amines, and others. For example the solvent can comprise an aliphatic hydrocarbon such as an alkane, an alkene, an alkyne, a cycloalkane, and a cycloalkene. A useful alkane includes an about C₅ to about C₁₅ alkane such as a pentane, a hexane, a heptane (e.g., N-heptane), an octane, a nonane, or a mixture thereof. Useful haloalkanes include methylene chloride. Alternatively the solvent can comprise an aromatic hydrocarbon such as benzene, toluene, mesitylene, or naphthalene. In one embodiment the solvent comprises cyclohexane. Alternative solvents include nitriles such as acetonitrile. The process can also be performed in any mixture of these solvents. Although not necessary, it is sometimes useful to run the process in which compound 8 is converted into compound 5 under such conditions that water is removed during the reaction. For example water can be removed using a Dean Stark trap or equivalent apparatus. In another example, water can -be-removed-using molecular sieve - - — The reaction under which compound 8 is converted into compound 5 can be conveniently speeded up or driven more toward completion by applying heat to the reaction mixture. It is convenient, for example, to heat the reaction mixture to reflux. Another embodiment of the present invention is directed to a method for the preparation of a diarylisoxazole sulfonamide compound having the structure of Formula 9:

dehydrating the diarylhydroxyisoxazole, thereby forming a diarylisoxazole compound having the structure of Formula 13:

contacting the diarylhydroxyisoxazole compound or the diarylisoxazole compound with a halosulfonic acid to produce a halosulfonated product; and contacting the halosulfonated product with a source of ammonia to produce the diarylisoxazole sulfonamide compound having the structure of Formula 9; wherein: R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R¹⁰, R¹¹ and R¹² are as defined above; and R¹⁶ is H. In one useful embodiment R is methyl; and R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, and R¹¹ are each H. The dehydration of 12 to 13 can be achieved by a variety of methods, for example by heating, by contacting with a base, by contacting with an acid, by contacting with silica gel, and other means. Some processes and methods useful for halosulfonating compound 13 are described in U.S. Pat. App. Pub. No. US 2003/0105334, hereby incorporated by reference. Some other processes and methods useful for halosulfonating compound 13 are described in U.S. Patent No. 5,633,272, hereby incorporated by reference. The present invention further provides a method for the preparation of a diarylisoxazole sulfonamide compound having the structure of Formula 9 wherein the method comprises contacting a diarylenamine ketone compound having the structure of Formula 25:

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R¹⁰, R¹¹, and R¹²are each as defined above. In one useful embodiment R¹ is methyl; and R², R³, R⁵, R⁴, R⁶, R⁷, R⁸, R⁹, R¹⁰, and R¹ are each H.

An overall process sequence showing the conversion of deoxybenzoin compound 8 into diarylisoxazole sulfonamide compound 9 is shown in Figure 3. This overall multi-step process can, if desired, be performed in a single reaction vessel. Alternatively, each individual step can be performed separately; for example, intermediates can be isolated or kept in the reaction mixture in which they were formed. In another alternative any two or more reaction steps can be performed in a single reaction vessel. This flexibility allows the storage, if desired, of raw or isolated reaction intermediates. One embodiment of the present overall process is shown in Figure 4. Figure 4 in part describes a process for the making of valdecoxib (5-methyl-3,4-diphenyl-isoxazo!e; compound 19) from 1 ,2- diphenylethanone (compound 14). Another embodiment of the present invention is shown in Figure 5. Figure 5 in part describes a process for the making of valdecoxib from 4-(2-oxo-2- phenylethyl)benzenesulf onam ide (21_) . In yet another embodiment the present invention provides a method for the preparation of an N- acyl diarylisoxazole sulfonamide compound having the structure of Formula 10:

wherein the method comprises contacting a diarylenamine ketone compound (having the structure of Formula H) with a source of hydroxylamine in the presence of a base, thereby forming a diarylhydroxyisoxazole compound having the structure of Formula 12; optionally contacting the diarylhydroxyisoxazole compound with an acid, thereby forming a diarylisoxazole compound having the structure of Formula 13; contacting the diarylhydroxyisoxazole compound or the diarylisoxazole compound with a halosulfonic acid to produce a halosulfonated product; contacting the halosulfonated product with a source of ammonia to produce a diarylisoxazole sulfonamide compound having the structure of Formula 9; and contacting the diarylisoxazole sulfonamide compound with an acylating agent to form the N-acyl diarylisoxazole sulfonamide compound; wherein: R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R¹⁰, R¹¹, R¹², and R¹⁶ are as defined above; and R¹⁵ is alkyl. Usefully R¹⁵ is Ci to about C₁₀ alkyl, in another embodiment C-i to about C₅ alkyl, and in another embodiment C-i to about C₃ alkyl. In one embodiment R¹⁵ is ethyl. In one useful embodiment, R¹ is methyl; R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R¹⁰, and R¹¹ are each H. Some useful acetylating agents and conditions are described in U.S. Pat. App. Pub. No. US

2003/0105334, hereby incorporated by reference. Some other useful acetylating agents and conditions are described in U.S. Patent No. 5,932,598, hereby incorporated by reference.

In still another embodiment, the present invention provides a method for the preparation of an N- acyl diarylisoxazole sulfonamide compound having the structure of Formula 10, wherein the method comprises contacting a diarylenamine ketone compound having the structure of Formula 25 with a source of hydroxylamine in the presence of a base, thereby forming a diarylhydroxyisoxazole compound having the structure of Formula 26; dehydrating the diarylhydroxyisoxazole compound, thereby forming a diarylisoxazole compound having the structure of Formula 27; contacting the diarylisoxazole sulfonamide compound with an acylating agent to form the N-acyl diarylisoxazole sulfonamide compound; wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R¹⁰, R¹¹, R¹², and R¹⁵ are as defined above. In one useful embodiment R¹ is methyl; and R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, and R ¹ are each H. The dehydration of 12 to 13 can be achieved by a variety of methods, for example by heating, by contacting with a base, by contacting with an acid, by contacting with silica gel, and other means.

The overall process sequence showing the conversion of deoxybenzoin compound 8 into diarylisoxazole sulfonamide compound 10 is shown in Figure 3. This overall multi-step process can, if desired, be performed in a single reaction vessel. Alternatively, each individual step can be performed separately; for example intermediates can be isolated or kept in the reaction mixture in which they were formed. In another alternative any two or more reaction steps can be performed in a single reaction vessel. This flexibility allows the storage, if desired, of raw or isolated reaction intermediates. Another embodiment of the present overall process is shown in Figure 4. Figure 4 describes a process for the making of parecoxib sodium (4-(5-methyl-3-phehylisoxazoi-4-yl)-N-propionyl- benzenesulfonamide sodium salt; compound 20) from 1 ,2-diphenylethanone (compound 14). Another embodiment of the present invention is shown in Figure 5. Figure 5 describes a process for the making of valdecoxib from 4-(2-oxo-2-phenylethyl)benzenesulfonamide (21). In still another embodiment the present invention provides the compound 3,4-diphenyl-4- pyrrolidin-1 -yl-but-3-en-2-one.

c. Detailed Preparative Methods The starting materials for use in the methods of preparation of the invention are known or can be prepared by conventional methods known to a skilled person or in an analogous manner to processes described in the art. Generally, the process methods of the present invention can be performed as follows.

Example 1, 5-Methyl-3,4-diphenyl-isoxazole (18):

14 15 1, 2-Diphenyl- 1- ( 1 , 2-Diphenyl- ethanone vinyl ) pyrrolidine

16 17 18 3,4-Diphenyl-4- 5-Methyl-3,4- 5-Methyl-3 , 4- pyrrolidin-1-yl- diphenyl-4, 5-dihydro- diphenyl isoxazole but-3-en-2-one isoxazol-5-ol

1a. 1-(1.2-Diphenylvinyl)pyrrolidine (15).

To a jacketed 250 mL reactor fitted with nitrogen blanket, overhead stirring, thermocouple, Dean/Stark trap, and condenser is charged 15.2 g (77mmol) 1 ,2-diphenylethanone 14, 40.6 g (482mmol, 6.3 eq.) cyclohexane, 17.0 g (234mmol, 3 eq.) pyrrolidine, and 0.52g (8.7mmol, 0.1 eq.) glacial acetic acid. The mixture is heated to reflux at atmospheric pressure, and water is collected in the Dean/Stark trap until reaction is complete (4 hours). The volatiles including cyclohexane, pyrrolidine, and acetic acid are stripped under reduced pressure (~10mm Hg, 70°C) to yield 19.6 g of orange oil 15. Yield 99.5% by area % GC. (column: 30 m x 0.25 mm DB-5, 0.25 micron film thickness; Detector: FID at 250°C) NMR (400MHz, CD3CN): D 7.4-6.6 mult 10H, □ 5.3 s 1H, D 3.0 mult 4H, D 1.9 mult 4H.

1b. 3,4-Diphenyl-4-pyrrolidin-1-yl-but-3-en-2-one (16).

The 1-(1,2-diphenyl-vinyl)-pyrroIidine (15) is dissolved in 62.4 g dry acetonitrile; 12.4 g (115.7mmol, 1.5 eq.) 2,6-lutidine are added, and the mixture is cooled to 5°C. A total of 23.6 g (301mmol, 3.9 eq.) acetyl chloride is added, in various portions over 24 hours at 5°C. Area % GC at this point indicated an enamine (15) to acetyl enamine (16) ratio of 1.5:98.5. NMR (400 MHz, CD3CN): α 6.8-7.1 mult 10H, D 2.9 br 4H, D 2.1 s 3H, D 1.7 br 4H.

1c. 5-Methyl-3.4-diphenyl-4.5-dihvdro-isoxazol-5-ol (17). To the previous reaction mixture containing 3,4-diphenyl-4-pyrrolidin-1-yl-but-3-en-2-one (16) was added over 3 minutes a mixture of 41.6 g (305.7mmol, 4 eq.) sodium acetate trihydrate (NaOAc.3H₂0), 43.5 g water (2425mmol, 31.6 eq.), and 21.3 g (306.5mnπol, 4 eq.) hydroxylamine hydrochloride (NH₂OH.HCI). The reaction was heated to 40°C. While stirring 1 hour, isoxazolol 17 precipitated from the reaction mixture as a fine solid. A total of 59 g of volatiles (acetonitrile, 2,6-lutidine, and water) were stripped from the reaction-mixture under reduced pressure, and the resulting slurry was filtered and washed with 157 g water to yield 28.8 g of isoxazolol 17 wet cake.

1d. 5-Methyl-3.4-diphenyl-isoxazole (18).

The isoxazolol 17 was charged back into the reactor with 21.4 g ethyl acetate and heated to 70°C. To the resulting slurry was charged 11.3 g (99mmol, 1.3 eq.) trifluoroacetic acid over 3 minutes. Reaction was complete by area % GC within 10 minutes. A total of 16.1 g isopropanol was added and the reaction mixture was cooled to 5°C to precipitate isoxazole 18. The product was filtered, washed with 20.0 g of 50 wt.% isopropanol in water, and dried in vacuo at 80°C to yield 13.3 g (74% yield) of isoxazole 18 assaying >99% by weight % HPLC (Column: YMC ODS-AQ, particle size 5 Dm, pore size 120 angstrom, length 4.6 x 250 mm; Mobile phase: isocratic at 70/30 (v/v) acetonitrile/water, containing 0.5% trifluoroacetic acid; Flow: 0.75 mlJmin; Detector: UV at 220 nm; Injection size: 10 DL; Column temperature: 40°C).

Example 2, 1-(1,2-diphenylvinyl)pyrrolidine (15):

14 15

A total of 62.6 g (880 mmol) pyrrolidine was dissolved in 150 mL toluene in a jacketed 1 liter reactor fitted with overhead stirrer, nitrogen blanket, dry ice condenser, and thermocouple. To this solution was added a total of 169 ml of 1.0M TiCI₄ (169 mmol, 0.19 eq.) over 2.4 hours while maintaining reaction temperature between 0-3°C. To this solution was added over 2 hours a solution of 39.3 g (200 mmol) 1,2- diphenylethanone (14) dissolved in 90 mL toluene, while maintaining reaction temperature between 0-3°C. The reaction mixture was warmed to 20°C and allowed to stir overnight (approximately 20 hours). Area % GC at this point indicated complete conversion (no starting material detected). The product was isolated by adding hexane, removing the solids by filtration, and stripping off hexane and excess pyrrolidine under reduced pressure. A total of 36.28 g (73% yield) of 1-(1,2-diphenylvinyl)pyrrolidine (15) was obtained as a yellow oil having the same GC retention time as the product of Example 1a.

Example 3, 5- ethyl-3,4-diphenyl-isoxazole (18):

3a. 3,4-Diphenyl-4-pyrrolidin-1-yl-but-3-en-2-one (16).

To a jacketed 250mL reactor fitted with nitrogen blanket, overhead stirring, thermocouple and reflux condenser was charged 19.0g (76mmol) of crude 1-(1 ,2-diphenyl-vinyl)-pyrrolidine (15) and 25.0 g dry acetonitrile, and the solution was cooled to 5°C. A total of 24.0 g (305.7 mmol, 4 equivalents) acetyl chloride was added dropwise over 20 minutes while maintaining temperature below 12°C. After cooling back to 5°C, a total of 12.35 g (114.7mmol, 1.5 eq.) 2,6-lutidine dissolved in 31.5 g acetonitrile was added to the reaction mixture over 2 hours, followed by an additional 15.1 g acetonitrile. The reaction mixture was stirred overnight (-16 hours) at 5°C then heated to 25°C. Area % GC at this point indicated an enamine 15 to acetyl enamine 16 ratio of 4:96.

3b. 5-Methyl-3,4-diphenyl-4.5-dihvdro-isoxazol-5-ol (17).

A mixture of 41.6 g (305.7mmol, 4 eq.) NaOAc.3H₂0, 43.5 g water (2425mmol, 31.6 eq.), and 18.6 g NH₂OH.HCI (267.5mmol, 3.5 eq.) was added to 3,4-diphenyl-4-pyrrolidin-1 -yl-but-3-en-2-one (16) from step 2a over 10 minutes while maintaining the temperature below 45°C. Precipitation of 5-methyl-3,4- diphenyl-4,5-dihydro-isoxazol-5-ol (17) occurred within 15 minutes. After stirring for 45 minutes, the pressure was reduced and a total of 60.6 g of acetonitrile and water were distilled out. To the remaining slurry was added 30.0 g ethyl acetate and 40.0 g water, and the mixture was heated to 68°C to dissolve all solids. The phases were separated and the lower (aqueous) phase was removed, leaving isoxazolol 17 dissolved in the organic phase.

3c. 5-Methyl-3,4-diphenyl-isoxazole (18).

To the remaining organic phase from the previous step was added 11.1 g (97mmol, 1.3 eq.) trifluoroacetic acid over 3 minutes at 68-70°C. After 10 minutes, dehydration of 17 to 18 was complete. A total of 49.9 g solvent was removed under reduced pressure, and 25.3 g ethyl acetate and 3.4 water were added at 70°C. A total of 16.1 g isopropanol was added then the reactor was cooled to 5°C to crystallize product. After stirring overnight (-16 hrs) at 5°C the product was filtered and washed with a 5°C solution of 50wt% aqueous solution of isopropanol, then dried in a vacuum oven at 80°C for 2.5 hrs to yield 12.65 g (70.4% yield) of isoxazole 18 assaying 96% by weight % HPLC.

Example 4:

4a. 3,4-Diphenyl-4-pyrrolidin-1-yl-but-3-en-2-one (16). To a jacketed 100mL reactor fitted with overhead stirrer, nitrogen blanket, thermocouple, condenser and addition funnel was charged 2.5 g (10mmol, 1 eq.) 1-(1,2-diphenyl-vinyl)-pyrrolidine (15), 15 mL acetonitrile, and 4.1 g (30 mmol, 3.0 eq.) anhydrous potassium carbonate. While stirring at 20-30°C, a total of 1.7 g (21 mmol, 2 eq.) of acetyl chloride was added and the mixture was stirred overnight. A total of 2.5 mL water was added to the reaction mixture, the phases were separated, and acetonitrile was -stripped -in -vaeuo.- Area % GC-at-this point indicated an enamine 15 to acetyl enamine-16 ratio of 1 :1.

4b. 5-Methyl-3,4-diphenyl-4,5-dihvdro-isoxazol-5-ol (17).

To the resulting crude 3,4-diphenyl-4-pyrrolidin-1-yl-but-3-en-2-one (16) from step 3a was added 15.0 g methanol, 15.0 g water, 0.7 g (5 mmol) anhydrous potassium carbonate, and 0.9 g (13 mmol) NH₂OH.HCI. The reaction mixture was pH adjusted from 7 to 5 with acetic acid. HPLC analysis of the resulting product indicated -53% isoxazolol 17.

Example 5:

5a. 3.4-Diphenyl-4-pyrrolidin-1-yl-but-3-en-2-one (16). To a 100 mL jacketed reactor fitted with overhead stirrer, thermocouple, nitrogen blanket, condenser, and addition funnel was charged 4.1 g (15mmol) of 1-(1,2-diphenyl-vinyl)-pyrrolidine (15), 15mL methylene chloride, and 3.43 g (33.5mmol) triethylamine. At 8°C a total of 2.6 g (33.1 mmol) acetyl chloride was added and the reaction mixture was warmed to 22°C. Area % GC at this point indicated an enamine 15 to acetyl enamine 16 ratio of 24:76.

5b. 5-Methyl-3,4-diphenyl-4,5-dihvdro-isoxazol-5-ol (17) and 5-Methyl-3,4-diphenyl-isoxazole (18).

To a 0.5g portion of stripped 3,4-diphenyl-4-pyrrolidin-1-yl-but-3-en-2-one (16) from step 4a was added 2 mL methanol and 0.1 g of 50% aqueous hydroxylamine. After stirring at ambient temperature for 2 days a sample analyzed by GCMS (Agilent model 6890N GC with 5873 MSD; Column: 30 m x 0.25 mm DB-5, 0.25 micron film thickness; Injector: split/splitless at 250°C, 50:1 split ratio; Column flow: He at 0.8 mL/minute) indicated 47% 5-methyl-3,4-diphenyl-isoxazole (18). Without being tied to a specific mechanism, it is believed that the formation of isoxazole 18 was due in whole or in part to dehydration of isoxazolol 17 in the hot (250°C) injection port.

Example 6: Deoxybenzoin-p-sulfonyl chloride (4-(2-Oxo-2-phenylethyl)benzenesulfonyl chloride) (28). Chlorosulfonic acid ("CSA," 305 mL, 532.2 g, 4.57 mole) was cooled to -16.3 °C in a 1-L jacketed two- piece reactor with a mechanical stirrer. The cooling medium was house glycol. The stirring rate was 150 rpm. Deoxybenzoin (1 ,2-diphenylethanone, 14, 90.51 g, 0.461 mole) was added in portions while the CSA was stirred, maintaining the pot temperature below -6.7 °C. The reaction was allowed to warm to -1.7 °C over 1 hour, after which the heating was speeded up by raising the jacket temperature to 22.9 °C. Within 10 minutes the pot temperature had risen to 24.3 °C. Hydrogen chloride evolution was noted. The reaction mass was maintained near ambient temperature (22-25 °C) until the gas evolution ceased, about 2 hours and 35 minutes. A sample of the reaction (1 drop, ca. 50 /A.) was diluted in dichloromethane (1 mL) and analyzed by TLC (Baker-flex® silica gel 1 B-F, J. T. Baker, Phillipsburg, NJ) by developing with ether to confirm the complete consumption of the starting deoxybenzoin. The reaction was cooled to - 16.7 °C and then slowly poured onto stirred, chipped ice, about 500 mL. The temperature of the quenching mixture was monitored and whenever it rose above 1 °C more ice was added. In this way the temperature was maintained between about -8 °C and 3.5°C during the quench. The total volume at the conclusion of the quench was about 2300 mL. Acetonitrile (700 mL) was added, after which the stirring was discontinued and the reaction was filtered through a 3-L Kimax 150C sintered glass funnel. The filtration took about 30 minutes. The cake was washed with 3 x 50 mL of water and removed from the funnel into a crystallizing dish. The wet cake (212.9 g) was dried at 100 Torr, 65 °C, with a nitrogen sweep overnight to give 108.1 g of a slightly gummy tan solid 28 (0.3677 mole, 79.6% yield based on deoxybenzoin not corrected for assay).

Example 7:

Deoxybenzoin-p-sulfonam ide (4-(2-Oxo-2-phenylethyl)benzenesulfonamide, 21).

Deoxybenzoin-p-sulfonyl chloride 28 (20.24 g, 68.7 mmol) was warmed in acetonitrile until it dissolved (80 mL) and filtered. Ammonium hydroxide (28 % in water, 8.61 g, 68.8 mmol) was added with stirring over a period of 10 minutes. The addition funnel was rinsed into the reaction with an additional 5 mL of water, followed by an additional 16 mL of water over 20 minutes. The reaction was filtered, washed with water (20 mL) and acetonitrile (10 mL), and air dried (9.99 g, 36.3 mmol, 52.8%, not corrected for assay). The solid was dried overnight at 100 Torr, 60 °C, with a nitrogen sweep. A total of 9.94 g (52.5%) of 2J. was recovered. NMR (400 MHz, CD₃COCD₃): δ 8.1 , d, 2H, J=8; δ 7.83, d, 2H, J=8; δ 7.63, dd, 1H, J=7; δ 7.51 , m, 5H; δ 4.55m s, 2H; δ 2.78, s, 2H.

Example 8: 8a. Deoxybenzoin-p-sulfonamide 2,5-dimethyl pyrrole

(2-(4-(2,5-Dimethyl-1 -pyrazolylsulfonyl)phenyl)-1 -phenylethanone, 29).

4-(2-Oxo-2-phenylethyl)benzenesulfonamide 21 (12.36 g, 44.9 mmol) was refluxed with acetonyl acetone (12.13 g, 106.3 mmol), p-toluene sulfonic acid monohydrate (1.06 g), and toluene (75 mL) overnight. The reaction was cooled and the remaining insoluble solid was filtered. The toluene solution was washed with 5% aqueous NaHC0₃ (100 mL) and then with water (100 mL). The solution was concentrated to dryness, giving 2-(4-(2,5-dimethyl-1 -pyrazolylsulfonyl)phenyl)-1 -phenylethanone (29) as a purple solid, 10.73 g (67.6%, not corrected for assay). NMR (400 MHz, CD₃COCD₃): δ 8.07, d, 2H, J=8; δ 7.73, d, 2H, J=8; δ 7.64, dd, 1 H, J=7; δ 7.55, m, 5H; δ 5.9, s 2H; δ 4.58, s, 2H; δ2.38, s, 6H.

8b. - 4-r4-(275-Dimethylpyrrole-1-sulfonyl)phenyll-5-methyl-3-phenylisoxazole-(30)-. - - -

4-[4-(2,5-Dimethylpyrrole-1-sulfonyl)phenyl]-5-methyl-3-phenylisoxazole (30) is prepared from 2-(4-(2,5- dimethyl-1 -pyrazolylsulfonyl)phenyl)-1 -phenylethanone (29) by the methods used in Examples 9 below for the conversion of 1 -(1 ,2-diphenylvinyl)pyrrolidine 15 to 5-methyl-3,4-diphenylisoxazole 18.

8c. Valdecoxib (19).

4-[4-(2,5-Dimethylpyrrole-1-sulfonyl)phenyl]-5-methyl-3-phenylisoxazole (30, 470 mg 1.2 mmol) was mixed with trifluoroacetic acid (1 mL) and water (1 mL) and heated in a 90 °C oil bath. The reaction was sampled and analyzed by TLC (silica gel 1 B-F 2.5 x 78.5 cm slide, J.T. Baker, Phillipsburg, NJ) developed with dichloromethane or ether. Compound 30 was approximately 50 % consumed. The reaction was left at ambient for 2 days (i.e. over the weekend) and then heating at 90 °C was resumed for an additional 2 hours and 45 minutes. The TLC at this point indicated that no more than a trace of the starting 30 remained. The reaction was concentrated to dryness under vacuum. The brown solid residue was crystallized from 2 mL of 50% aqueous methanol. The brown solid recovered was dried at ambient temperature, 100 Torr, with a nitrogen sweep. The nmr (CD₃OD) was identical to the nmr of a reference sample of valdecoxib.

Example 9: 5-Methyl-3,4-diphenylisoxazole (18).

9a. 1-(1.2-Diphenylvinyl)pyrrolidine (15). To a jacketed 250 mL reactor fitted with nitrogen blanket, overhead stirring, thermocouple, Dean/Stark trap, and condenser was charged 15.2 g (77mmol) deoxybenzoin 14 (1 ,2-diphenylethanone), 40.6 g (482mmol, 6.3 eq.) cyclohexane, 17.0 g (234mmol, 3 eq.) pyrrolidine, and 0.52g (8.7mmol, 0.1 eq.) glacial acetic acid. The mixture was heated to reflux at atmospheric pressure, and water was collected in the Dean/Stark trap until reaction was complete (4 hours). The volatiles including cyclohexane, pyrrolidine, and acetic acid were stripped under reduced pressure (-10mm Hg, 70°C) to yield 19.6 g of orange oil 15.

9b. 3,4-Diphenyl-4-pyrrolidin-1-yl-but-3-en-2-one (16). The 1 -(1 ,2-diphenylvinyl)pyrrolidine 15 was dissolved in 62.4 g dry acetonitrile; 12.4 g (115.7mmol, 1.5 eq.) 2,6-lutidine were added, and the mixture cooled to 5°C. A total of 23.6 g (301 mmol, 3.9 eq.) acetyl chloride were added, in various portions over 24 hours at 5°C. Area % GC at this point indicated an enamine 15 to acetyl enamine 16 ratio of 1.5:98.5.

9c. 5-Methyl-3.4-diphenyl-4.5-dihydroisoxazol-5-ol (17).

To the previous reaction mixture containing 16 was added over 3 minutes a mixture of 41.6 g (305.7mmol, 4 eq.) NaOAc.3H20, 43.5 g water (2425mmol, 31.6 eq.), and 21.3 g (306.5mmol, 4 eq.) NH20H.HCI. The reaction was heated to 40°C. While stirring 1 hour, isoxazolol 17 precipitated from the reaction mixture as a fine solid. A total of 59 g of volatiles (acetonitrile, 2,6-lutidine, and water) were stripped from the reaction mixture under reduced pressure, and the resulting slurry was filtered and washed with 157 g water to yield 28.8 g of isoxazolol 17 wet cake.

9d. 5-Methyl-3,4-diphenylisoxazole (18).

The 5-methyl-3,4-diphenyl-4,5-dihydroisoxazol-5-ol 17 was charged back into the reactor with 21.4 g ethyl acetate and heated to 70°C. To the resulting slurry was charged 11.3 g (99mmol, 1.3 eq.) trifluoroacetic acid over 3 minutes. Reaction was complete by area % GC within 10 minutes. A total of 16.1 g isopropanol was added and the reaction mixture was cooled to 5°C to crystallize isoxazole 18. The product was filtered, washed with 20.0 g of 50 wt% isopropanol in water, and dried in vacuo at 80°C to yield 13.3 g (74% yield) of 5-methyl-3,4-diphenylisoxazole 18 assaying >99% by weight % HPLC.

Example 10:

3.4-Diphenyl-4-pyrrolidin-1 -yl-but-3-en-2-one (16).

15 16

A total of 0.76 g (3.0 mmol) 1-(1 ,2-diphenylvinyl)pyrrolidine 15 was dissolved in 10 mL acetonitrile in a jacketed 100 mL Ace reactor fitted with overhead stirrer, nitrogen blanket, dry ice condenser, and thermocouple. To this solution was added a total of 2.72 g (17.3 mmol, 5.8 eq.) 1 -acetyl pyridinium chloride, prepared by adding acetyl chloride to a 30% molar excess of pyridine dissolved in cyclohexane, and filtering and washing with cyclohexane the resulting solid. The reaction mixture was heated to 60°C for a total of 2.5 hours and to 80°C for one hour. Area % GC at this point indicated an 2 to 3,4-diphenyl-4- pyrrolidin-1 -yl-but-3-en-2-one (16) ratio of about 1 :91.3.

-Example 11: -

NaOAc.3H₂0 NH₂OH.HCl water

17 18

11a.3,4-Diphenyl-4-pyrrolidin-1-yl-but-3-en-2-one (16).

To a jacketed 250mL reactor fitted with nitrogen blanket, overhead stirring, thermocouple and reflux condenser was charged 19.0g (76mmol) of crude 1 -(1 ,2-diphenylvinyl)pyrrolidine 15 and 25.0 g dry acetonitrile, and the solution was cooled to 5°C. A total of 24.0 g (305.7mmol, 4 equivalents) acetyl chloride was added dropwise over 20 minutes while maintaining temperature below 12°C. After cooling back to 5°C, a total of 12.35 g (114.7mmol, 1.5 eq) 2,6-lutidine dissolved in 31.5 g acetonitrile was added to the reaction mixture over 2 hours, followed by an additional 15.1 g acetonitrile. The reaction mixture was stirred overnight (-16 hours) at 5°C then heated to 25°C. Area % GC at this point indicated an enamine 15 to acetyl enamine 16 ratio of 4:96.

11b. 5-Methyl-3,4-diphenyl-4,5-dihvdroisoxazol-5-ol (17). A mixture of 41.6 g (305.7 mmol, 4 eq.) NaOAc.3H₂0, 43.5 g water (2425 mmol, 31.6 eq.), and 18.6 g NH₂OH.HCI (267.5 mmol, 3.5 eq.) was added to 3,4-diphenyl-4-pyrrolidin-1-yl-but-3-en-2-one 16 over 10 minutes while maintaining the temperature below 45°C. Precipitation of isoxazolol 17 occurred within 15 minutes. After stirring for 45 minutes, the pressure was reduced and a total of 60.6 g of acetonitrile and water were distilled out. To the remaining slurry was added 30.0 g ethyl acetate and 40.0 g water, and the mixture was heated to 68°C to dissolve all solids. The phases were separated and the lower (aqueous) phase was removed, leaving isoxazolol 17 dissolved in the organic phase.

11c. 5-Methyl-3,4-diphenylisoxazole (18).

To the remaining organic phase from step 9c was added 11.1 g (97mmol, 1.3 eq.) trifluoroacetic acid over 3 minutes at 68-70°C. After 10 minutes, dehydration of 17 to 18 was complete. A total of 49.9 g solvent was removed under reduced pressure, and 25.3 g ethyl acetate and 3.4 water were added at 70°C. A total of 16.1 g isopropanol was added then the reactor was cooled to 5°C to precipitate product. After stirring overnight (-16 hrs) at 5°C the product was filtered and washed with a 5°C solution of 50 wt% aqueous solution of isopropanol, then dried in a vacuum oven at 80°C for 2.5 hrs to yield 12.65 g (70.4% yield) of isoxazole 18 assaying 96% by weight % HPLC.

Example 12:

15 16 17

12a. 3,4-Diphenyl-4-pyrrolidin-1-yl-but-3-en-2-one (16).

To a jacketed 100mL reactor fitted with overhead stirrer, nitrogen blanket, thermocouple, condenser and addition funnel was charged 2.5 g (10mmol, 1 eq.) 1-(1 ,2-diphenylvinyl)pyrrolidine 15, 15mL acetonitrile, and 4.1 g (30 mmol, 3.0 eq.) anhydrous potassium carbonate. While stirring at 20-30°C, a total of 1.7 g (21 mmol, 2 eq.) of acetyl chloride was added and the mixture was stirred overnight. A total of 2.5 mL water was added to the reaction mixture, the phases were separated, and acetonitrile was stripped in vacuo. Area % GC at this point indicated an enamine 15 to acetyl enamine 16 ratio of 1 :1.

12b. 5-Methyl-3,4-diphenyl-4,5-dihvdroisoxazol-5-ol (17). To crude 3,4-diphenyl-4-pyrrolidin-1-yl-but-3-en-2-one 16 was added 15.0 g methanol, 15.0 g water, 0.7 g (5mmol) anhydrous potassium carbonate, and 0.9 g (13mmol) NH₂OH.HCI. The reaction mixture was pH adjusted from 7 to 5 with acetic acid. HPLC analysis of the resulting product indicated -53% isoxazolol

11-

Example 13: — - — - ._ . . - - _

15 16

17 18

13a. 3,4-Diphenyl-4-pyrrolidin-1-yl-but-3-en-2-one (16).

To a 100 mL jacketed reactor fitted with overhead stirrer, thermocouple, nitrogen blanket, condenser, and addition funnel was charged 4.1 g (15mmol) of 1-(1 ,2-diphenylvinyl)pyrrolidine 15, 15mL methylene chloride, and 3.43 g (33.5mmol) triethylamine. At 8°C a total of 2.6 g (33.1 mmol) acetyl chloride was added and the reaction mixture was warmed to 22°C. Area % GC at this point indicated an enamine 15 to acetyl enamine 16 ratio of 24:76.

13b. 5-Methyl-3.4-diphenylisoxazole (18).

To a 0.5g portion of stripped 3,4-diphenyl-4-pyrrolidin-1-yl-but-3-en-2-one 17 from the above reaction was added 2 mL methanol and 0.1 g of 50% aqueous hydroxylamine. After stirring at ambient temperature for 2 days a sample analyzed by GCMS indicated 47% desired 5-methyl-3,4-diphenylisoxazole 18 (due to dehydration of isoxazolol 17 in hot injection port).

Example 14: Preparation of 4-(5-methyl-3-phenyl-4- isoxazolvDbenzenesulfonyl chloride (28).

5-Methyl-3,4-diphenylisoxazole 18 (5.0 g, 0.0213 mol) was charged to a 100 mL jacketed reactor which was cooled with 0.2°C jacket fluid. Trifluoroacetic acid (3.5 mL, 0.045 mol) was charged to the solids to provide a solution at 3°C. Chlorosulfonic acid (13.3 mL, 0.201 mol) was added slowly while maintaining the reaction temperature below 20°C. The solution was heated to 60°C and held for 2.2 hours. The solution was then cooled to 6°C and transferred to a 60 mL addition funnel. Toluene (20 mL) and water (20 mL) were charged to the 100 mL jacketed reactor and cooled to 6°C. The reaction solution was then added slowly to the 100 mL jacketed reactor while maintaining the temperature below 16°C. The multi- phase mixture was transferred to 125 mL separatory funnel. Toluene (20 mL) and water (5 mL) were added and the mixture was shaken. Settling of the mixture resulted in two cloudy phases. The toluene phase was washed twice with 5 mL of water, transferred to a 125 mL flask with a 17 mL toluene rinse, and vacuum distilled to a semi-crystalline concentrate. The concentrate was dissolved in 100 mL of toluene and vacuum distilled to an oil. After initiating crystallization with a glass rod, heptane (11 mL) was added, and the mass broken up to produce an off white powder. The solids were collected by filtration. Portions of 25 mL of heptane were used to aid the transfer of solids to the filter. The cake was dried to provide 7.07 g (100 wt.% yield of 28) of the sulfonyl chloride as an 85:15 mixture of the para and meta isomers. HRMS Calculated for (M+1) C₁₆H₁₃N0₃CI: 334.0305; Found: (M+1): 334.0299.

Example 15:

Preparation of 4-(5-methyl-3-phenyl-4- isoxazolvDbenzenesulfonyl chloride (28).

4,5-Dihydro-5-methyl-3,4-diphenyl-5-isoxazolol 17 (13.0 grams, 0.0513 mol) was charged to a 200 mL jacketed flask which was cooled with 0.2°C jacket fluid. Trifluoroacetic acid (9.1 mL, 0.118 mol) was charged to the solids to provide a solution at 38.6°C. The solution was cooled to 2.1 °C and chlorosulfonic acid (34.7 mL, 0.522 mol) was added slowly while maintaining the temperature below 14°C. The solution was heated to 60°C, held for 2.5 hours, cooled to 20°C, and transferred to a 125 mL addition funnel. Toluene (52 mL) and water (52 mL) were charged to the 200 mL jacketed reactor, and cooled to 4°C. The reaction solution was then added slowly to the 200 mL jacketed reactor while maintaining the temperature below 20°C. The multi-phase mixture was warmed to 20°C, and transferred to a 250 mL separatory funnel. Toluene (50 mL) and water (10 mL) were added and the mixture was shaken. Settling of the mixture resulted in two cloudy phases. The toluene phase was washed twice with 15 mL of water, transferred to a 250 mL flask with a 20 mL toluene rinse, and vacuum distilled to 17.4 g of an oil. After initiating crystallization with a glass rod and cooling, heptane (20 mL) was added to the crystalline mass which was broken up to form a powder. The off white powder was collected by filtration. Portions of 50 mL of heptane were used to aid the transfer of solids to the filter. The cake was dried in a vacuum oven (35°C) to provide 13.6 g (79.4 wt% yield of 28) of the sulfonyl chloride as an 85:15 mixture of the para and meta isomers. HRMS Calculated for (M+1) C₁₆H₁₃N0₃CI: 334.0305; Found (M+1): 334.0309.

Example 16: 4-[3-Methyl-5-phenyl-4-isoxazolyllbenzenesulfonam ide (valdecoxib, 19).

A solution of 5-methyl-3,4-diphenyl isoxazole 18 (250 mg, 1.1 mmol) in chlorosulfonic acid (1 ml) was stirred at 0°C for 3 hours. The reaction was cautiously added to concentrated ammonium hydroxide (6 ml) in the cold (0°C). The resultant reaction mixture was stirred at 0°C for 1 hour. The reaction was cautiously diluted with water and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and the filtrate concentrated in vacuo to give the crude product. This material was chromatographed on silica gel using 25% ethyl acetate in toluene as the eluent to give the desired sulfonamide as a crystalline solid (110 mg, 40% yield of 19): mp 85° - 87°C. Anal. Calc'd. for C₁₆H₁₄N₂0₃ S: C, 61.13; H, 4.49; N, 8.91 ; S, 10.20. Found: C, 60.88; H, 4.61 ; N, 8.55; S, 10.40.

Example 17:

Preparation of Λ/-fr4-(5-methyl-3-phenyl-4-isoxazolyl)phenvπsulfonyllpropanamide (31 , parecoxib). 4-(5-methyl-3-phenyl-4-isoxazolyl)benzenesulfonamide 19 (10.0 g, 0.032 mol) and propionic anhydride (40 mL, 0.31 mol) were charged to the 500 mL reactor. The slurry was stirred and heated to 50°C. Sulfuric acid (40 DL, 0.8 mmol) was added in one portion. All the solids dissolved and the mixture warmed to 55.5°C within a 10 minute period after the addition was completed. The reaction mixture was then heated to 80°C and held for approximately 10 minutes. Heating was discontinued, and the mixture was allowed to cool to 50°C and held for about 60 minutes; solid started to crystallize from the reaction mixture at about 65°C. The mixture was slowly cooled to 0°C and was held at 0°C for about 60 minutes. The solid was collected by vacuum filtration. The wet cake was washed with two 45-mL portions of methyl tert-butyl ether and pulled dry at ambient temperature for about 15 minutes. The solid was further dried in a . vacuum oven with a nitrogen bleed at 60°C for 18 hours to give the solid product (8.72 g 75% yield of 31). DSC maximum endotherm for the high melting point parecoxib is 168.95. DSC maximum endotherm for the low melting point parecoxib is 147.44.

Example 18: Preparation of Λ/-fr4-(5-methyl-3-phenyl-4-isoxazolyl)phenyllsulfonyllpropanamide, sodium salt (parecoxib sodium. 20).

Λ/-[[4-(5-Methyl-3-phenyl-4-isoxazolyl)phenyl]sulfonyl]propanamide 31 (10.0 g, 0.026 mol) and 160 ml of absolute ethanol were charged to a 500 mL reactor. The slurry was heated to 45°C and held for 30 minutes and a solution of approximately 5 weight percent sodium hydroxide in ethanol (22.4 g, 0.028 mol) was added to the reaction vessel at 45°C. After addition was completed, the solution was seeded with N- [[4-(5-methyI-3-phenyl-4-isoxazolyl)phenyl]sulfonyl]propanamide, sodium salt, to initiate crystallization. The temperature of the reaction mixture was raised to 50°C and held for 30 min. The mixture was slowly cooled to 0°C and held for about 60 min. The solid was collected by vacuum filtration. The wet cake was washed twice with two 20-mL portions of absolute ethanol and was pulled dry under house vacuum with a purge of nitrogen. The solid was further dried in a vacuum oven with the nitrogen bleed at 120°C overnight to give the solid product (9.11g, 85% yield of 20). DSC maximum endotherm for the form I parecoxib sodium is 274.28°C

The examples herein can be performed by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples. The invention being thus described, it is apparent that the same can be varied in many ways. Such variations are not to be regarded as a departure from the spirit and scope of the present invention, and all such modifications and equivalents as would be obvious to one skilled in the art are intended to be included within the scope of the following claims.

Claims

What is claimed is:

A method for the preparation of a diarylhydroxyisoxazole compound having the structure of Formula 1 :

with hydroxylamine in the presence of a base, thereby forming the diarylhydroxyisoxazole compound, wherein: R¹ is selected from the group consisting of H and alkyl; R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, and R¹¹ are each independently selected from the group consisting of H, alkyl, aminosulfonyl, and a protected aminosulfonyl group; wherein the protected aminosulfonyl group has the structure of Formula 3:

R¹³ is a protected amino group; and R¹² is a nitrogen-containing heterocycle optionally substituted with a moiety selected from the group consisting of alkyl, alkenyl, and alkynyl; and wherein a nitrogen atom of the hitrageή-coήtaining^~h^~eterocycle is part of the enamine structure of the diarylenamine ketone compound.

2. The method of Claim 1 wherein the nitrogen-containing heterocycle is selected from the group consisting of pyrrolidinyl, morpholinyl, piperidinyl, azetidinyl, and aziridinyl.

3. The method of Claim 1 wherein R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, and R¹¹ are each H.

4. The method of Claim 1 wherein R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R¹⁰, and R¹¹ are each H; and R⁹ is a protected aminosulfonyl group.

5. The method of Claim 4 wherein R¹³ has the structure of Formula 4:

6. The method of Claim 1 wherein R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R ⁰, and R¹ are each H; and R⁹ is aminosulfonyl.

7. The method of Claim 1 wherein the base comprises one or more compounds selected from the group consisting of a carboxylate base, a hydroxide base, an aromatic amine base, a carbonate base, and an aliphatic amine.

8. The method of Claim 7 wherein the base comprises one or more compounds selected from the group consisting of sodium acetate, potassium acetate, sodium hydroxide, potassium hydroxide, and ammonium acetate.

9. The method of Claim 1 wherein the contacting is performed in the presence of at least one solvent.

10. The method of Claim 9 wherein the solvent comprises one or more compounds selected from the group consisting of a nitrile, an aromatic solvent, an aliphatic hydrocarbon, an ether, an aromatic amine, water, a glycol, and an alcohol.

11. The method of Claim 10 wherein the nitrile comprises acetonitrile.

12. The method of Claim 1 wherein the contacting is performed at a pH of about 3 to about 4.

13. The method of Claim 1 wherein: R¹ is methyl; and R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, and R¹¹ are each H.

14. The method of Claim 1 wherein: R is methyl; R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R¹⁰, and R¹¹ are each H; and R⁹ is aminosulfonyl.

15. A method for the preparation of a diarylisoxazole sulfonamide compound having the structure of Formula 9:

wherein the method comprises contacting a diarylenamine ketone compound having the structure of Formula 11:

contacting the diarylhydroxyisoxazole compound or the diarylisoxazole compound with a halosulfonic acid to produce a halosulfonated product; and contacting the halosulfonated product with a source of ammonia to produce the diarylisoxazole sulfonamide compound; wherein: R¹ is selected from the group consisting of H and alkyl; R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R¹⁰, and R¹¹ are each independently selected from the group consisting of H and alkyl; R¹² is a tertiary amino group; and R¹⁶ is H.

16. The method of Claim 15 wherein: R¹ is methyl; R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R¹⁰, and R¹¹ are each H; and R¹² is 1 -pyrrolidinyl.

17. A method for the preparation of a diarylisoxazole sulfonamide compound having the structure of Formula 9:

wherein the method comprises contacting a diarylenamine ketone compound having the structure of Formula 25:

wherein: R¹ is selected from the group consisting of H and alkyl; R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R¹⁰, and R¹¹ are each independently selected from the group consisting of H and alkyl; and R ₃12 is a tertiary amino group.

18. The method of Claim 17 wherein: R¹ is methyl; R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R¹⁰, and R¹¹ are each H; and R¹² is 1 -pyrrolidinyl.

19. A method for the preparation of an N-acyl diarylisoxazole sulfonamide compound having the structure of Formula 10:

optionally dehydrating the diarylhydroxyisoxazole compound, thereby forming a diarylisoxazole compound having the structure of Formula 13:

contacting the diarylhydroxyisoxazole compound or the diarylisoxazole compound with a halosulfonic acid to produce a halosulfonated product; contacting the halosulfonated product with a source of ammonia to produce a diarylisoxazole sulfonamide compound having the structure of Formula 9:

contacting the diarylisoxazole sulfonamide compound with an acylating agent to form the N-acyl diarylisoxazole sulfonamide compound; wherein: R¹ is selected from the group consisting of H and alkyl; R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R¹⁰, and R¹ are each independently selected from the group consisting of H and alkyl; R¹² is a tertiary amino group; R¹⁵ is alkyl; and R¹⁶ is H.

20. The method of Claim 19 wherein: R¹ is methyl; R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R¹⁰, and R¹¹ are each H R¹² is 1 -pyrrolidinyl; and R¹⁵ is ethyl.

21. A method for the preparation of an N-acyl diarylisoxazole sulfonamide compound having the structure of Formula 10:

contacting the diarylisoxazole sulfonamide compound with an acylating agent to form the N- acyl diarylisoxazole sulfonamide compound; wherein: R¹ is selected from the group consisting of H and alkyl; R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R¹⁰, and R¹¹ are each independently selected from the group consisting of H and alkyl; R¹² is a tertiary amino group; and The acylating agent is propionic anhydride.

22. The method of Claim 21 wherein: R¹ is methyl; R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R¹⁰, and R¹¹ are each H; and R¹² is 1 -pyrrolidinyl.

23. 3,4-Diphenyl-4-pyrroIidin-1-yl-but-3-en-2-one.