- NHC-palladium-catalyzed ionic liquid-accelerated regioselective oxyarylation of alkynes with diaryl ethers?
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The first NHC-palladium-catalyzed regioselective oxyarylation of oxime ether in a task-specific ionic liquid via C(sp3)-O and C(sp2)-O bond cleavage of two different types of ethers for the assembly of structurally diverse 4-arylisoxazoles is described. Both the basic ionic liquid [C3NH2mim]Br and NHC-Pd catalyst IPr-Pd-Im-Cl2 played an important role in this transformation. Notably, this new approach provides a practical and straightforward route to access a broad range of privileged 4-arylisoxazole structures with good yields and excellent regioselectivities. Significantly, this catalytic system can be recycled up to eight times without significant loss of catalytic activity.
- Cen, Liying,He, Dan,Jiang, Huanfeng,Li, Jianxiao,Lin, Zidong,Wu, Wanqing
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supporting information
p. 1983 - 1988
(2022/04/03)
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- Preparation method of parecoxib sodium intermediate 5-methyl-3,4-diphenyl isoxazole
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The invention relates to a preparation method of parecoxib sodium intermediate 5-methyl-3,4-diphenyl isoxazole. The preparation method comprises the following steps: step one, taking phenyl propinyl ketone as a starting material, firstly, carrying out condensation with methanol aminated hydrochloride to generate Z-type 1-phenyl-1-propinyl-3-methyl-oxime; step two, carrying out a cycloaddition reaction on the Z-type 1-phenyl-1-propinyl-3-methyl-oxime and iodine chloride to generate 3-phenyl-4-iodo-5-methyl isoxazole; and step three, carrying out a substitution reaction on the 3-phenyl-4-iodo-5-methyl isoxazole and phenylboronic acid to generate 5-methyl-3,4-diphenyl isoxazole.
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- Highly Site Selective Formal [5+2] and [4+2] Annulations of Isoxazoles with Heterosubstituted Alkynes by Platinum Catalysis: Rapid Access to Functionalized 1,3-Oxazepines and 2,5-Dihydropyridines
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Platinum-catalyzed formal [5+2] and [4+2] annulations of isoxazoles with heterosubstituted alkynes enabled the atom-economical synthesis of valuable 1,3-oxazepines and 2,5-dihydropyridines, respectively. Importantly, this Pt catalysis not only led to unique reactivity dramatically divergent from that observed under Au catalysis, but also proceeded via unprecedented α-imino platinum carbene intermediates.
- Shen, Wen-Bo,Xiao, Xin-Yu,Sun, Qing,Zhou, Bo,Zhu, Xin-Qi,Yan, Juan-Zhu,Lu, Xin,Ye, Long-Wu
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supporting information
p. 605 - 609
(2017/01/07)
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- Method for preparing parecoxib sodium key intermediates
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The invention relates to a method for preparing parecoxib sodium key intermediates, and belongs to the field of medicine synthesis. The method for preparing the parecoxib sodium key intermediates includes steps of firstly, preparing 1-(1-methyl-2-styrene)-pyrrolidine (a compound I); secondly, preparing 5-methyl-3, 4-diphenyl-5-(pyrrolidine-1-base)-4, 5-dihydro-isoxazole (a compound II); thirdly, preparing a crude product of 5-methyl-3, 4-diphenyl isoxazole (a compound III); fourthly, refining a crude product of 5-methyl-3, 4-diphenyl-5-isoxazole (a compound III). The shortcomings of existing synthesis methods can be overcome by the aid of the method. The method for preparing the parecoxib sodium key intermediates has the advantages of mild reaction conditions, inexpensive and easily available raw materials, simplicity in after-treatment operation, short production cycle and high product purity and yield. Besides, the novel method is provided for preparing the parecoxib sodium key intermediates.
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- Method for preparing parecoxib intermediate
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The invention discloses a method for preparing a parecoxib intermediate. The method includes subjecting 1, 2-diphenyl-2-acetyl ethyl ketone and ammonium acetate to contact reaction with the presence of iodobenzene diacetate and potassium iodide, performing organic-phase concentration and washing after reaction, performing ethyl alcohol recrystallization, and drying to obtain 5-methyl-3, 4-diphenyl isoxazole. The method for preparing the parecoxib intermediate has the advantages of simplicity in procedure and high yield.
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Paragraph 0016; 0021; 0022; 0023; 0025; 0027; 0029-0041
(2018/02/03)
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- A method of preparing intermediates handkerchief auspicious past cloth sodium
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The invention discloses a novel method for preparing a parecoxib sodium intermediate 5-methyl-3, 4-diphenyl isoxazole. The method comprises the following steps: performing rearrangement reaction on a compound in the formula I (referring to the Specification)under the action of a catalyst to prepare a compound in the formula II(referring to the Specification); and under the condition of a catalyst, reacting hydroxylammonium chloride with the compound in the formula II to prepare 5-methyl-3,4-diphenyl isoxazole. The method disclosed by the invention has the advantages of mild reaction condition, good simplicity and convenience for operation, low cost, environmental-friendliness and the like.
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Paragraph 0029; 0030; 0031
(2017/05/05)
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- A process for the preparation of sodium compound handkerchief auspicious past cloth and wherein the intermediate impurity, preparation method and application
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The invention provides parecoxib sodium which is prepared by controlling an intermediate impurity and in particular provides a preparation method of a parecoxib sodium compound as well as the intermediate impurity and an application of the parecoxib sodium compound. According to the preparation method provided by the invention, 3-methyl-4,5-diphenyl-4,5-dihydro-isoxazole-5-alcohol is used as an isomer impurity for preparing 5-methyl-3,4-diphenyl-4,5-dihydro-isoxazole-5-alcohol as an intermediate of the parecoxib sodium, the quality of the 3-methyl-4,5-diphenyl-4,5-dihydro-isoxazole-5-alcohol is controlled in the preparation of the parecoxib sodium, specifically, the impurity content is required not to be higher than 0.5 percent, and an important significance is provided for the product quality of the parecoxib sodium; by obtaining the 3-methyl-4,5-diphenyl-4,5-dihydro-isoxazole-5-alcohol as an isomer impurity of the important 5-methyl-3,4-diphenyl-4,5-dihydro-isoxazole-5-alcohol and further studying 3-methyl-4,5-diphenyl-4,5-dihydro-isoxazole-5-alcohol in the aspects of preparation process, detection process and purification process, important quality monitoring significance is provided for the process with the 5-methyl-3,4-diphenyl-4,5-dihydro-isoxazole-5-alcohol as an industrial production raw material.
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- Method for preparing parecoxib for treating postoperative pain
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The invention discloses a method for preparing parecoxib for treating postoperative pain. The method comprises the following steps: 1) conducting a contact reaction between 3,4-diphenyl-4-(1-pyrrolidyl)-3-butene-2-one and ammonium acetate in acetic acid; after the reaction, diluting dichloromethane; regulating the pH value to 6-7 with saturated sodium bicarbonate; concentrating the organic phase and washing; recrystallizing with ethanol; and drying to obtain 5-methyl-3,4-diphenyl isoxazole; 2) stirring the obtained 5-methyl-3,4-diphenyl isoxazole and chlorosulfonic acid for reacting; adding anion exchange resin, and dropwise adding saturated ammonium chloride and dichloromethane for extraction; washing and concentrating; and recrystallizing with ethanol to obtain valdecoxib; and 3) enabling the valdecoxib obtained in the step 2) to react with propionic anhydride in the presence of triethylamine to obtain parecoxib. The method for preparing parecoxib, disclosed by the invention, has the advantages of simple steps, mild conditions and high yield.
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Paragraph 0021; 0026; 0027; 0028`
(2017/01/12)
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- Preparation method of cyclooxygenase-2 inhibitor parecoxib
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The invention discloses a preparation method of a cyclooxygenase-2 inhibitor parecoxib. The method comprises the following steps that 1, benzaldoxime reacts with 1-phenylpropyne in the presence of tris(2-phenylpyridine)iridium (III), triethylamine and magnesium oxide under the illumination condition to obtain 5-methyl-3,4-diphenylisoxazole; 2, a stirring reaction is conducted on 5-methyl-3,4-diphenylisoxazole obtained in the first step and chlorosulfonic acid, dichloromethane extraction is conducted after the reaction is completed, a dichloromethane phase is directly added into ammonium hydroxide, an organic phase is separated, water washing, concentrating and ethanol recrystallization are conducted, and valdecoxib is obtained; 3, valdecoxib obtained in the second step reacts with propionic anhydride in the presence of triethylamine, and parecoxib is obtained. The preparation method of parecoxib is simple in step, high in yield and simple in posttreatment.
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Paragraph 0027; 0028; 0029
(2016/11/14)
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- Preparing method for parecoxib sodium
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The invention belongs to the field of medicine chemical industry and particularly relates to a preparing method for parecoxib sodium. According to the method, benzaldoxime (compound I) and 1-phenyl-1-propyne (compound II) are subjected to an addition reaction under existence of a catalyst and an acid-binding agent to construct an isoxazole ring to obtain a parecoxib sodium intermediate (compound III); the compound III is subjected to a sulfonation and sulfonylation reaction to obtain a compound IV, and the compound IV and propionic anhydride react to form salt to obtain parecoxib sodium (compound V). According to the method, the dipole ring addition reaction is creatively adopted for preparing the compound III, common safe and low-toxicity reagents chlorosulfuric chlorosulfonic acid and ammonia water with relative stable nature are used to be subjected to the sulfonylation reaction, and the method has the advantages that the reaction condition is mild, operation is reasonable, selectivity is high, and product quality is high; raw and auxiliary materials in the reaction are low in price, and the production cost is reduced.
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Paragraph 0061; 0062
(2016/10/08)
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- Preparation method of 5-methyl-3,4-diphenylisoxazole
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The invention discloses a preparation method of 5-methyl-3,4-diphenylisoxazole, which includes a step of performing a dehydration reaction to a compound (2) in methanol and water in the presence of an inorganic alkali to prepare the 5-methyl-3,4-diphenylisoxazole.
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Paragraph 0027; 0028; 0029; 0030; 0031; 0032; 0033-0040
(2017/07/20)
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- Oxime-mediated facile access to 5-methylisoxazoles and applications in the synthesis of valdecoxib and oxacillin
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A palladium-catalyzed efficient synthesis of 5-methylisoxazoles via oxime-mediated functionalization of unactivated olefins is described. The reaction affords a variety of 5-methylisoxazoles in moderate to good yields. To further demonstrate the utility of the method, the rapid synthesis of valdecoxib and oxacillin is reported. (Chemical Equation Presented).
- Dong, Kui-Yong,Qin, Hai-Tao,Bao, Xing-Xing,Liu, Feng,Zhu, Chen
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p. 5266 - 5268
(2015/01/09)
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- Application of [3+2]-cycloaddition in the synthesis of valdecoxib
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A large scale synthesis of valdecoxib 1 is described. Our work features potential application of [3+2]-dipolar cycloaddition involving enamine and in situ-generated nitrile oxide derivatives. Dr. Reddy's Laboratories Ltd.
- Reddy, Anumula Raghupathi,Goverdhan, Gilla,Sampath, Aalla,Mukkanti, Khagga,Reddy, Padi Pratap,Bandichhor, Rakeshwar
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p. 639 - 649
(2012/01/13)
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- Transition-metal-catalyzed uninterrupted four-step sequence to access trisubstituted isoxazoles
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We describe herein a novel uninterrupted four-step sequence to access trisubstituted isoxazoles from readily available propargylic alcohols using sequentially iron and palladium catalytic systems. The advantages of such a strategy are illustrated by the high overall yields and the time-saving procedure that are reported.
- Gayon, Eric,Quinonero, Ophelie,Lemouzy, Sebastien,Vrancken, Emmanuel,Campagne, Jean-Marc
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supporting information; experimental part
p. 6418 - 6421
(2012/02/01)
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- Functionalized diarylisoxazoles inhibitors of ciclooxygenase
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The present invention refers to isoxazole derivatives, in particular diarylisoxazole derivatives inhibitors of cyclooxygenase (COX), in particular cyclooxygenase-1 (COX-1), to their pharmaceutical compositions, the process for their preparation and their use for the chemoprevention and treatment of inflammatory syndromes and in the prevention and treatment of carcinomas, in particular intestinal, ovarian and cutaneous carcinomas, in the treatment of pain syndromes, in particular after surgery, and in the cardiovascular field as antithrombotics/vasoprotectives/cardioprotectives.
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Page/Page column 14
(2009/07/25)
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- Method for preparing 3,4-diphenyl-substituted isoxazole compounds
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The present invention relates to a process for preparing diaryl-substituted isoxazole using compounds of Formula (V) and Formula (VII): where Y is and to processes for preparing valdecoxib and parecoxib.
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Page/Page column 6; 8
(2008/06/13)
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- METHOD FOR THE PREPARATION OF DIARYLISOXAZOLE SULFONAMIDE COMPOUNDS AND INTERMEDIATES
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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.
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Page/Page column 29-30; 34-35
(2008/06/13)
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- ISOXAZOLE DERIVATIVES AND THEIR USE AS CYCLOOXYGENASE INHIBITORS
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The present invention refers to isoxazole derivatives, in particular 3,4-diaryl isoxazole derivatives, to their pharmaceutical compositions, the process for preparing them and their use as inhibitors of cycloosygenase, in particular of cycloosygenase 1 and 2 (COX-1) (COX-2). The present invention also refers to a process for determining the potential toxicity of compounds that inhibit cycloosygenase (COX), in particular cycloosygenase-2 (COX-2) isoform, and to the use of compounds that inhibit cycloosygenase (COX), in particular cycloosygenase-2 (COX-2) and their pharmaceutical compositions, in subjects for whom the potential cardiovascular toxicity of said compounds is reduced.
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Page/Page column 10; 14
(2010/02/13)
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- Isothiazole derivatives, process for the preparation thereof, and pharmaceutical composition including the same
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The present invention relates to an isothiazole derivative of the following formula 1 or nontoxic salt thereof: wherein, R1 is hydrogen, alkoxy group or halogen group; R2 is methyl or amino group. According to the present invention, isothiazole derivative or nontoxic salt thereof having antipyretic, analgesic and antiphlogistic activity and an improved side effect; process for the preparation thereof; and pharmaceutical composition including the same can be provided.
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Page/Page column 6-7
(2010/02/06)
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- ISOTHIAZOLE DERIVATIVES, PROCESS FOR THE PREPARATION THEREOF, AND PHARMACEUTICAL COMPOSITION INCLUDING THE SAME
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The present invention relates to an isothiazole derivative of the following formula 1 or nontoxic salt thereof: wherein, R1 is hydrogen, alkoxy group or halogen group; R2 is methyl or amino group. According to the present invention, isothiazole derivative or nontoxic salt thereof having antipyretic, analgesic and antiphlogistic activity and an improved side effect; process for the preparation thereof; and pharmaceutical composition including the same can be provided.
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- Novel synthesis of 3,4-diarylisoxazole analogues of valdecoxib: Reversal cyclooxygenase-2 selectivity by sulfonamide group removal
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3,4-Diarylisoxazole analogues of valdecoxib [4-(5-methyl-3-phenylisoxazol- 4-yl)-benzensulfonamide], a selective cyclooxygenase-2 (COX-2) inhibitor, were synthesized by 1,3-dipolar cycloaddition of arylnitrile oxides to the enolate ion of phenylacetone regioselectively prepared in situ with lithium diisopropylamide at 0 °C. The corresponding 3-aryl-5-methyl-4-phenyl- isoxazoles were easily generated by a dehydration/aromatization reaction under basic conditions of 3-aryl-5-hydroxy-5-methyl-4-phenyl-2-isoxazolines and further transformed into their benzenesulfonamide derivatives. The biochemical COX-1/COX-2 selectivity was evaluated in vitro by using the human whole blood assays of COX isozyme activity. Three compounds not bearing the sulfonamide group present in valdecoxib were selective COX-1 inhibitors.
- Di Nunno, Leonardo,Vitale, Paola,Scilimati, Antonio,Tacconelli, Stefania,Patrignani, Paola
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p. 4881 - 4890
(2007/10/03)
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- Method for preparing benzenesulfonyl compounds
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The present disclosure provides a method for the preparation of aromatic sulfonyl halides by contacting a substituted phenyl compound with a halosulfonic acid and trifluoroacetic acid. The present disclosure further provides a method for the preparation of 4-[5-methyl-3-phenylisoxazol-4-yl]benzenesulfonamide which is useful in treating cyclooxygenase-2 related disorders.
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- Substituted isoxazoles for the treatment of inflammation
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A class of substituted isoxazolyl compounds is described for use in treating inflammation and inflammation-related disorders. Compounds of particular interest are defined by Formula (III) wherein R7 is selected from hydroxyl, lower alkyl, carboxyl, halo, lower carboxylalkyl, lower alkoxycarbonylalkyl, lower alkoxyalkyl, lower carboxyalkoxyalkyl, lower haloalkyl, lower haloalkylsulfonyloxy, lower hydroxyalkyl, lower aryl (hydroxylalkyl), lower carboxyaryloxyalkyl, lower alkoxycarbonylaryloxyalkyl, lower cycloalkyl, lower cycloalkylalkyl, and lower aralkyl; and wherein R8 is one or more radicals independently selected from hydrido, lower alkylsulfinyl, lower alkyl, cyano, carboxyl, lower alkoxycarbonyl, lower haloalkyl, hydroxyl, lower hydroxyalkyl, lower haloalkoxy, amino, lower alkylamino, lower arylamino, lower aminoalkyl, nitro, halo, lower alkoxy, aminosulfonyl, and lower alkylthio; or a pharmaceutically-acceptable salt thereof.
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- Isoxazole compounds as cyclooxygenase inhibitors
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A class of substituted isoxazolyl compounds is described for use in treating cyclooxygenase-2 related disorders. Compounds of particular interest are defined by Formula I STR1 wherein R1, R2, and R3, are described in the specification.
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- Chemistry of Four-Membered Cyclic Nitrones. 3. Reaction with Nucleophilic Reagents and Stereospecific Conversion into 1-Hydroxyazetidines
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Four-membered cyclic nitrones (1) react with a variety of nucleophiles (MeMgI, CN-, OH-, MeO-, and H-) by stereospecific addition to the C=N bond.Reaction of 1a with potassium cyanide and with methylmagnesium iodide yields the 1-hydroxyazetidines 2a and 2b, respectively.Reduction of 1b with lithium aluminum hydride and with sodium borohydride affords the 1-hydroxyazetidine derivatives 3 and 4, respectively.Sodium hydroxide in methanol-water reacts with 1a to give a mixture of two isomeric 5-hydroxyisoxazolidines 5a and 5b, but under similar reaction conditions 1b and 1c rearrange to the oximes 6 and 7.In acetic acid at room temperature 6a cyclizes to the 6H-1,2-oxazin-6-one derivative 8, whereas 6b yields 5-methyl-3,4-diphenylisoxazole (9) after being refluxed in acetic acid, probably by carbon monoxide elimination from the intermediate oxazin-6-one derivative.Reaction of 1a with sodium hydroxide for 2 min gives exclusively the 1-hydroxy-4-methoxyazetidine 13a, whereas prolonged reaction gives the isomeric azetidine 13b together with 5 (mixture of 5a and 5b in a ratio 4:1).Single-crystal X-ray analysis of 13b reveals that all three relatively bulky substituents at C-2, C-3, and C-4 are on the same face of the azetidine ring.Treatment of 13b with acetic acid at room temperature gives the 5-methoxyisoxazolidine 15.The 1-hydroxyazetidines 2-4 are oxidized with yellow mercury(II) oxide to the corresponding four-membered cyclic nitrones 1b, 16 and 17.
- Pennings, Marcel L.M.,Reinhoudt, David N.,Harkema, Sybolt,Hummel, Gerrit J. van
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p. 4419 - 4425
(2007/10/02)
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- 3,4-Diarylisoxazol-5-acetic acids and process for making same
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3,4-Diarylisoxazol-5-acetic acids of the formula STR1 in which Ar1 and Ar2 are the same or different and are selected from phenyl and naphthyl, R1, R2, R3, and R4 are the same or different and are selected from hydrogen, halogen, trifluoromethyl, lower alkyl, and lower alkoxy, and R5 is selected from hydrogen, lower alkyl, and lower alkoxy. The compounds have anti-inflammatory, analgesic, and anti-pyretic activities and a low order of toxicity, and methods for their preparation and use are also disclosed.
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- Halogenation of Vinyl Ketoximes. Synthesis of Isoxazoles and Preparation and Silver Ion-Promoted Reactions of 4-Halo-2-isoxazolines
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Reaction of several α,β-unsaturated ketoximes with N-bromosuccinimide (NBS) gave isoxazoles, but yields were lower and the reaction less general than a similar transformation using iodine under basic conditions.With β,β-disubstituted oximes, 4-halo-5,5-disubstituted-2-isoxazolines were obtained using NBS, iodine, or N-chlorosuccinimide.Treatment of the 4-bromoisoxazolines with silver acetate or silver nitrate caused either elimination with rearrangement to give isoxazoles or substitution at C-4, depending upon the nature of the substituents at C-5.
- Hansen, John F.,Kim, Yong In,McCrotty, Stephen E.,Strong, Scott A.,Zimmer, Douglas E.
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p. 475 - 479
(2007/10/02)
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