WO2005123701A1 - Procedes destines la preparation d'un compose de diarylisoxazole sulfonamide et d'intermediaires - Google Patents

Procedes destines la preparation d'un compose de diarylisoxazole sulfonamide et d'intermediaires Download PDF

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WO2005123701A1
WO2005123701A1 PCT/IB2005/001874 IB2005001874W WO2005123701A1 WO 2005123701 A1 WO2005123701 A1 WO 2005123701A1 IB 2005001874 W IB2005001874 W IB 2005001874W WO 2005123701 A1 WO2005123701 A1 WO 2005123701A1
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compound
formula
diarylisoxazole
group
contacting
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PCT/IB2005/001874
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English (en)
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Leo J. Letendre
Cynthia K. Snoddy
George H. Klemm
Jon P. Lawson
Michael J. Bauer
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Pharmacia Corporation
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/04—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms

Definitions

  • 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.
  • COX-2 inhibitors are isoxazolyl benzenesulfonamide compounds.
  • isoxazolyl benzenesulfonamide compounds useful in treating inflammation are described in U.S. Patent 5,633,272.
  • valdecoxib a potent COX-2 inhibitor sold under the brand name BEXTRA.
  • 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.
  • 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.
  • the present invention is directed to a process for the preparation of a diarylhydroxyisoxazole compound having the structure of Formula!:
  • R 1 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, haloalkyl, haloalkenyl, haloalkynyl, and haioaryl
  • R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 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:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 are each independently are as defined above; and R 14 is selected from the group consisting of halo and acyloxy.
  • R 14 is selected from the group consisting of halo and acyloxy.
  • the method comprises contacting a diarylhydroxyisoxazole compound having the structure of Formula 1 with an acid, thereby forming the diarylisoxazole compound, wherein: R 1 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, haloalkyl, haloalkenyl, haloalkynyl, and haioaryl; R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 13 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:
  • diarylhydroxyisoxazole compound optionally contacting the diarylhydroxyisoxazole compound with an acid, thereby forming a diarylisoxazole compound having the structure of Formula 13:
  • 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:
  • diarylhydroxyisoxazole compound having the structure of Formula 27:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 10 , R 11 , and R 12 are each as defined above.
  • the present invention provides a method for the preparation of an N- acyl diarylisoxazole sulfonamide compound having the structure of Formula 10:
  • 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: R 1 is selected from the group consisting of H, alkyl, al
  • 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 R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 10 , R 11 , R 12 , and R 15 are as defined above.
  • the present invention provides the compound 3,4-diphenyl-4- pyrrolidin-1 -yl-but-3-en-2-one.
  • 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).
  • 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.
  • 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.
  • 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.
  • a useful protected amino group is a 2,5-dimethylpyrrolyl group.
  • protected amino group in the context of this disclosure includes the protected amino functionalities described for protected aminosulfonyl groups, above.
  • 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.
  • carboxylate base means a conjugate base of a carboxylic acid.
  • the carboxylate base can be an alkylcarboxylate, an arylcarboxylate, or any other convenient conjugate base of a carboxylic acid.
  • carboxylate means a -C0 2 H group or a salt thereof.
  • the symbol "H” means a hydrogen atom.
  • Alkyl alkenyl
  • alkynyl 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:
  • 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.
  • the optional substituents are understood to be attached to Z, 1 2 3
  • 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-o
  • heteroaryl means a fully unsaturated heterocycle. By “fully unsaturated” it is meant that the heteroaryl moiety possesses 4n+2 pi electrons.
  • 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
  • halo or halogen means a fluoro, chloro, bromo or iodo group.
  • halide means fluoride, chloride, bromide, or iodide.
  • haloalkyl means alkyl substituted with one.or more halogens. _ ..
  • 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.
  • cycloalkyl additionally encompasses spiro systems.
  • oxo means a doubly bonded oxygen.
  • aminosulfonyl means a group having the structure -S0 2 NH 2 .
  • alkylarylalkyl means an arylalkyl radical that is substituted on the aryl group with one or more alkyl groups.
  • alkoxy an alkyl radical which is attached to the remainder of the molecule by oxygen, such as a methoxy radical.
  • 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.
  • alkylthio means an alkyl radical which is attached to the remainder of the molecule by sulfur, such as a methylthio radical.
  • carboxy means the carboxy group, -C0 2 H, or its salts.
  • acyloxy means an acyl group attached to the remainder of the molecule by oxygen, such as an acetoxy or a propionyloxy radical.
  • acyl means an alkyl radical which is attached to the remainder of the molecule by a carbonyl group.
  • enamine means a compound containing an amino group directly attached to a double bonded carbon which is doubly bonded to another carbon.
  • aromatic amine means an amine wherein the nitrogen atom of the amine is part of an aromatic ring.
  • nitrile means a compound containing a -CN group.
  • sulfonic acid means a compound containing a -S03H group, or a salt thereof.
  • phosphonic acid means a compound containing a -P0 3 H 2 group, or a salt thereof.
  • ACN means acetonitrile.
  • TFA means trifluoroacetic acid.
  • mmHG or “Torr” means millimeters of mercury.
  • HPLC means high pressure liquid chromatography.
  • NaOAC means sodium acetate.
  • IPA means isopropyl alcohol.
  • g means grams.
  • GCMS means gas chromatography/mass spectrometry.
  • HRMS means high resolution mass spectrometry.
  • EtOAc means ethyl acetate.
  • mL means milliliters.
  • GC means gas chromatography.
  • Et means ethyl.
  • Me means methyl.
  • mmol means millimoles.
  • wt% means weight percent.
  • Ac means acetyl or acetate.
  • 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.
  • R is selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, haloalkyl, haloalkenyl, haloalkynyl, and haioaryl;
  • R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 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.
  • R 12 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.
  • the nitrogen-containing heterocycle comprises a 3 to about 7-membered ring.
  • the nitrogen-containing heterocycle is selected from the group consisting of pyrrolidinyl, morpholinyl, piperidinyl, azetidinyl, and aziridinyl.
  • the nitrogen-containing heterocycle is 1 -pyrrolidinyl.
  • R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 are each independently selected from the group consisting of H, alkyl, aminosulfonyl, and the protected aminosulfonyl group.
  • R 2 , R 3 , R 4 , R ⁇ , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 are each independently selected from the group consisting of H, aminosulfonyl, and the protected aminosulfonyl group.
  • R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 1 are each H.
  • R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 10 , and R 11 are each H; and R 9 is a protected aminosulfonyl group.
  • R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 10 , and R 11 are each H; and R 9 is aminosulfonyl.
  • R 13 can for example have the structure of Formula 4:
  • R 1 is methyl; and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 are each H. In another embodiment, R 1 is methyl; and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 10 , and R 11 are each H; and R 9 is aminosulfonyl.
  • 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.
  • hydroxylamine can serve as the base.
  • a different base can be added to the reaction mixture.
  • This reaction to form 17 is shown in Figure 1.
  • 17 can be further reacted to eliminate water. This elimination will form isoxazole 18.
  • 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.
  • a carboxylate base when it is an aliphatic amine, it can be a trialkyl amine such as triethylamine.
  • 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.
  • 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.
  • sodium acetate is a useful base.
  • the acetate base can comprise one or more compounds selected from the group consisting of ammonium acetate and an N-substituted ammonium acetate.
  • 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.
  • 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.
  • the base can comprise an alkali metal hydroxide base such as sodium hydroxide or potassium hydroxide.
  • a useful base for example, is sodium hydroxide.
  • 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.
  • 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.
  • 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.
  • the solvent can comprise propylene glycol, ethylene glycol, or glyme.
  • 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.
  • the salt of hydroxylamine comprises a hydroxylammonium C ⁇ to about C 5 alkyl carboxylate.
  • the salt of hydroxylamine can comprise hydroxylammonium acetate.
  • the salt of hydroxylamine can comprise hydroxylammonium fluoride, hydroxylammonium chloride, hydroxylammonium bromide, or hydroxylammonium iodide.
  • the salt of hydroxylamine comprises one or more compounds selected from the group consisting of hydroxylammonium chloride and hydroxylammonium bromide.
  • the salt of hydroxylamine can comprise hydroxylammonium chloride.
  • 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.
  • a solvent 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.
  • exemplary useful alcohols include ethanol and methanol.
  • the solvent comprises a nitrile; alternatively it comprises a C 2 to about C 7 nitrile; in another alternative a C 2 to about C 5 nitrile.
  • the nitrile solvent can comprise acetonitrile or propionitrile, and in yet another embodiment it can comprise acetonitrile.
  • the solvent can comprise an aromatic amine.
  • 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.
  • the buffer can comprise a mixture of sodium acetate and acetic acid.
  • the molar ratio of the source of hydroxylamine to the diarylenamine compound can vary widely to useful end.
  • 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.
  • 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.
  • 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.
  • 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.
  • a mixture comprising the source of hydroxylamine and the base can be added to compound 2.
  • the source of hydroxylamine can be added to a mixture of the base and compound 2.
  • 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.
  • 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.
  • the source of hydroxylamine can be added rapidly or slowly.
  • 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.
  • diarylhydroxyisoxazole compound 1 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.
  • a solvent for example, a solvent comprising water
  • 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:
  • R through R 13 each independently is as defined above; and R 14 is selected from the group consisting of halo, acyloxy, imidazole, and a sulfonate leaving group.
  • Useful sulfonate leaving groups include toluenesulfonate, methanesulfonate, and trifluoromethanesulfonate.
  • R 14 is halo.
  • R 14 usefully is chloro, bromo, or iodo.
  • R 14 is chloro.
  • R 4 is acyloxy. A wide range of acyloxy groups are useful in the present embodiment.
  • R 14 can be, if desired, C- t to about C 7 acyloxy; alternatively C-i to about C 4 acyloxy; and in another alternative acetoxy.
  • R 14 is -OR 17 wherein R 17 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, alkylsulfonyl, arylsulfonyl, alkylarylsulfonyl, and haloalkylsulfonyl.
  • R 17 can be alkyl.
  • R 17 can be Ci to about C ⁇ 0 alkyl; alternatively C- to about C 5 alkyl; and alternatively d to about C 3 alkyl.
  • R 17 can be methyl.
  • R 17 can be ethyl.
  • the structure of Formula 6 can be ethyl acetate.
  • the structure of Formula 6 can in another alternative be methyl acetate.
  • 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.
  • 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.
  • the base can comprise an aromatic amine, a tertiary amine, a nitrile, a carbonate salt, and a hydroxide base, or any combination thereof.
  • the base comprises an aromatic amine.
  • the aromatic amine can comprise, for example, pyridine, lutidine, pyrrolidine, or collidine, or any combination thereof.
  • the base can comprise a tertiary amine such as a trialkylamine.
  • the tertiary amine can comprise a tri-(C ⁇ to about C 5 -alkyl)amine.
  • the tertiary amine comprises triethylamine.
  • the tertiary amine can comprise DBU.
  • the base used for the preparation of the diarylenamine ketone compound can comprise a carbonate base.
  • the base can comprise an alkali metal carbonate such as sodium carbonate or potassium carbonate.
  • the carbonate base comprises potassium carbonate.
  • 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.
  • 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.
  • the solvent can comprise a nitrile (such as acetonitrile), or an aromatic amine (such as lutidine).
  • the solvent comprises a nitrile.
  • the nitrile can comprise a C 2 to about C 7 nitrile; in another example a C 2 to about C 5 nitrile; in another example a C 2 to about C 3 nitrile; and in yet another example acetonitrile.
  • the solvent can comprise an aromatic amine solvent such as pyridine, lutidine, or collidine.
  • the solvent can comprise a tertiary amine.
  • the tertiary amine can comprise a tri-(d to about C 5 -alkyl)amine.
  • the tertiary amine can comprise triethylamine.
  • the solvent comprises an aromatic hydrocarbon, such as toluene.
  • 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.
  • the base and the acylating agent can be contacted with the diarylenamine compound at the same time, or sequentially.
  • the base can be contacted with the diarylenamine compound first and the acylating agent can be contacted later.
  • the acylating agent can be contacted with the diarylenamine compound first and the base can be contacted later.
  • 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.
  • the base can conveniently comprise an aromatic amine base.
  • the acylating agent comprise an acyl halide, for example a C-i to about C 7 acyl halide, alternatively a C-i to about C 5 acyl halide, alternatively a C 1 to about C 3 acyl halide, and in another alternative an acetyl halide.
  • the acetyl halide can comprise, for example, acetyl chloride, acetyl bromide, or acetyl iodide.
  • the acetyl halide comprises acetyl chloride.
  • 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.
  • 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.
  • the molar concentration of the acylating agent is higher than the molar concentration of the diarylenamine compound.
  • 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.
  • 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.
  • 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.
  • the temperature is maintained at about 5°C.
  • 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:
  • the method comprises contacting a diarylhydroxyisoxazole compound (having the structure of Formula 1) with an acid, thereby forming the diarylisoxazole compound, wherein: R 1 R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 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.
  • Formula 7 has the structure of Formula 18.
  • 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:
  • 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.
  • 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.
  • the secondary amine can comprise a dialkylamine.
  • the secondary amine can contain two identical alkyl groups, for example two C-i to about C 7 alkyl groups, alternatively two Ci to about C 5 alkyl groups.
  • Useful secondary aminesJn cludejclimethylamine,-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.
  • 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.
  • the acid can comprise a Lewis acid.
  • Lewis acids include, for example, AICI 3 , TiCI 4 , BF 3 , Al 2 0 3 , AI0 2 , and mixtures thereof.
  • the Lewis acid comprises TiCI 4 .
  • the acid comprises a protic acid.
  • 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.
  • the organic acid comprises a carboxylic acid or a sulfonic acid, for example a carboxylic acid.
  • carboxylic acids useful in the present invention include acetic acid, propionic acid, butyric acid, isobutyric acid, trifluoroacetic acid, trichloroacetic acid, and mixtures thereof.
  • the acid comprises acetic acid.
  • Other useful acids include toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, and mixtures thereof.
  • the acetic acid is added to the reaction mixture in the form of glacial acetic acid or aqueous acetic acid.
  • the acid comprises trifluoroacetic acid.
  • the acid comprises a sulfonic acid.
  • 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 C 7 alkylsulfonic acid, alternatively a Ci to about C 5 alkylsulfonic acid, and in another alternative methanesulfonic acid or ethanesulfonic acid.
  • the acid can comprise an arylsulfonic acid.
  • 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.
  • solvents are useful in the present embodiment including aliphatic hydrocarbons, aromatic hydrocarbons, halogenated aliphatic hydrocarbons, aromatic amines, and others.
  • 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 C 5 to about C 15 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.
  • the solvent can comprise an aromatic hydrocarbon such as benzene, toluene, mesitylene, or naphthalene.
  • the solvent comprises cyclohexane.
  • Alternative solvents include nitriles such as acetonitrile.
  • the process can also be performed in any mixture of these solvents.
  • water can be removed using a Dean Stark trap or equivalent apparatus.
  • 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:
  • R is methyl; and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 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:
  • diarylhydroxyisoxazole compound having the structure of Formula 27:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 10 , R 11 , and R 12 are each as defined above.
  • R 1 is methyl; and R 2 , R 3 , R 5 , R 4 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 1 are each H.
  • FIG. 3 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.
  • Figure 4 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_) .
  • the present invention provides a method for the preparation of an N- acyl diarylisoxazole sulfonamide compound having the structure of Formula 10:
  • 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: R 1 , R 2 , R 3 , R 4
  • R 15 is Ci to about C 10 alkyl, in another embodiment C-i to about C 5 alkyl, and in another embodiment C-i to about C 3 alkyl. In one embodiment R 15 is ethyl. In one useful embodiment, R 1 is methyl; R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 10 , and R 11 are each H. Some useful acetylating agents and conditions are described in U.S. Pat. App. Pub. No. US
  • 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 R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 10 , R 11 , R 12 , and R 15 are as defined above.
  • R 1 is methyl; and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , 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.
  • each individual step can be performed separately; for example intermediates can be isolated or kept in the reaction mixture in which they were formed.
  • 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).
  • Figure 5 describes a process for the making of valdecoxib from 4-(2-oxo-2-phenylethyl)benzenesulfonamide (21).
  • the present invention provides the compound 3,4-diphenyl-4- pyrrolidin-1 -yl-but-3-en-2-one.
  • 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): ⁇ 6.8-7.1 mult 10H, D 2.9 br 4H, D 2.1 s 3H, D 1.7 br 4H.
  • 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.
  • 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.
  • 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.
  • TLC Boker-flex® silica gel 1 B-F, J. T. Baker, Phillipsburg, NJ
  • 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).
  • 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).
  • Example 8 8a. Deoxybenzoin-p-sulfonamide 2,5-dimethyl pyrrole
  • 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 NaHC0 3 (100 mL) and then with water (100 mL).
  • 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.
  • 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 (CD 3 OD) was identical to the nmr of a reference sample of valdecoxib.
  • 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.
  • 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.
  • step 9c 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.
  • 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.
  • 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.
  • Example 16 4-[3-Methyl-5-phenyl-4-isoxazolyllbenzenesulfonam ide (valdecoxib, 19).
  • 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 ⁇ /-fr4-(5-methyl-3-phenyl-4-isoxazolyl)phenyllsulfonyllpropanamide, sodium salt (parecoxib sodium. 20).

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Abstract

L'invention concerne un procédé destiné à la préparation d'un composé à base de diarylisoxazole sulfonamide, qui consiste à mettre en contact une désoxybenzoïne avec une amine secondaire pour former un composé de diarylenamine; à mettre en contact le composé de diarylenamine avec un agent d'acétylation pour former un composé d'acétyl de diarylenamine; à mettre en contact le composé d'acétyl de diarylenamine avec une source d'hydroxylamine pour former un composé de diaryle isoxazolole; à éliminer l'eau du composé de diaryle isoxazolole pour former un composé de diaryle isoxazolole; à chlorosulfonater le composé de diarylisoxazole pour former un composé de chlorosulfonyle diaryle isoxazole; et à mettre en contact le composé de chlorosulfonyle diaryle isoxazole avec une source d'ammoniac pour former un composé de diarylisoxazole sulfonamide.
PCT/IB2005/001874 2004-06-14 2005-06-03 Procedes destines la preparation d'un compose de diarylisoxazole sulfonamide et d'intermediaires WO2005123701A1 (fr)

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