- Preparation method of (by machine translation)
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The invention relates to a novel process for preparing flutamipide by using a pharmaceutical active pharmaceutical ingredient, wherein ethyl acetoacetate is taken as a raw material and mixed with hydroxylamine hydrochloride to obtain fluticide. The process not only can better control the content of 3 - methyl isomers and 4 - trifluoromethylaniline in the baflunomide product, and is higher in yield and more concise. The industrial wastewater generated by the process is less in waste gas, environmentally friendly, capable of effectively reducing production cost and corrosion to equipment. (by machine translation)
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Paragraph 0040
(2020/06/24)
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- Microchannel continuous preparation method of 5-methylisoxazole-4-formic acid
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The invention relates to the field of organic synthesis, and in particular relates to a microchannel continuous preparation method of 5-methylisoxazole-4-formic acid, and the method comprises the following steps: dissolving 2-ethoxymethylacetoacetate in a polar organic solvent to obtain a solution A, dissolving hydroxylamine hydrochloride and an organic base in the polar organic solvent to obtaina solution B; respectively pumping the solution A and the solution B into a microchannel reactor simultaneously for reaction; after the reaction is completed, collecting the reaction liquid flowing out of the microchannel reactor, decompressing and desolventizing, adding sulfuric acid for heating hydrolysis, and performing recrystallization to obtain the 5-methyl isoxazole-4-formic acid. The method has high purity of the reaction process system, reduces the purification loss of products, enables the yield of the two-step reaction to reach more than 95%, reduces material consumption, saves cost, and provides high-quality raw materials for the production of leflunomide.
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Paragraph 0029-0036
(2020/01/25)
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- Synthesis and in vivo antifibrotic activity of novel leflunomide analogues
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Novel Leflunomide analogues were synthesized and evaluated in vivo against thioacetamide (TAA) induced liver fibrosis in rats. All the animals which were treated with the new analogues showed improved or comparable survival rates to those treated with Leflunomide. Animals which were treated with compounds 8d, 8e, 9 and 11 have shown improved liver parameters than Leflunomide treated animals. Histopathology of the liver has shown that compound 8a is the most active compound, which decreases fibrosis to a minimal level and compounds 8c, 8e and 11 are active compounds with fibrosis score 2-3 which is better than that of Leflunomide.
- Hamdi, Abdelrahman,Said, Eman,Farahat, Abdelbasset A.,El-Bialy, Serry A.A.,Massoud, Mohammed A.M.
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p. 912 - 920
(2016/10/31)
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- Synthesis and fungicidal activities of 1-(5-Methylisoxazoyl-4-carbonyl)-4- arylsulfonyl thiosemicarbazides
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1-(5-Methylisoxazoyl-4-carbonyl)-4-arylsulfonyl thiosemicarbazides, which were prepared by treatment of arylsulfonyl hydrazine with 5-methylisoxazole-4- carbonyl isothiocyanate in good yields. The structures of all compounds were confirmed by 1H NMR, MS and elemental analyses. The preliminary bioassays indicated that some compounds are comparable to the commercial fungicides. Some of these compounds also exhibit moderate fungicidal activities.
- Ye, Dong-Ju
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scheme or table
p. 1503 - 1506
(2012/04/10)
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- AN IMPROVED PROCESS FOR PREPARATION OF LEFLUNOMIDE
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This invention describes a process for the preparation of N-(4-trifluoromethyl)-5-methylisoxazole-4-carboxamide commonly known as leflunomide comprising : (a) reacting ethylaceto acetate, triethylorthoformate, and acetic anhydride with simultaneous distillation to form ethyl ethoxymethyleneacetoacetic ester; (b) reacting the ethyl ethoxymethyleneacetoacetic ester with aqueous hydroxylamine without using any external base and without any distillation to form ethyl-5-methylisoxazole-4-carboxylate; (c) reacting the ethyl-5-methylisoxazole-4-carboxylate with strong acid to form -5-methylisoxazole-4-carboxylic acid; (d) 5-methylisoxazole-4-carboxylic acid is reacted with thionyl chloride in presence of N, N-Dimethylformamide and equimolar of 4-trifluoromethylaniline without any external base to obtain highly pure Leflunomide.
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Page/Page column 5; 7
(2008/06/13)
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- Process for preparing 5-methylisoxazole-4-carboxylic- (4'-trifluoromethyl)-anilide
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A process for preparing 5-methylisoxazole-4-carboxylic-(4′-trifluoromethyl)-anilide comprising: (a) reacting ethylacetoacetate, triethylorthoformate, and acetic anhydride at a temperature of from about 75° C. to about 150° C., to form ethyl ethoxymethyleneacetoacetic ester; (b) combining the ethyl ethoxymethyleneacetoacetic ester with sodium acetate or a salt of trifluoroacetic acid in the presence of hydroxylamine sulfate at a temperature of from about ?20° C. to 10° C., to form ethyl-5-methylisoxazole-4-carboxylate; (c) reacting the ethyl-5-methylisoxazole-4-carboxylate with a strong acid to form 5-methylisoxazole-4-carboxylic acid; (d) reacting the crystallized 5-methylisoxazole-4-carboxylic acid with thionyl chloride to form 5-methylisoxazole-4-carbonyl chloride; and (e) reacting the 5-methylisoxazole-4-carbonyl chloride with trifluoromethyl aniline and an amine base at a temperature of from about 0° C. to about 50° C. to form 5-methylisoxazole-4-carboxylic-(4′-trifluoromethyl)-anilide. The process of the invention is especially advantageous for preparing 5-methylisoxazole-4-carboxylic-(4′-trifluoromethyl)-anilide, since the process: (1) eliminates or reduces the formation of the by-product 2-cyanoacetoacetic-1-(4′-trifluoromethyl)-anilide (CATA), generally as low as 0.0006%; (2) eliminates or reduces the formation of isomeric impurity ethyl-3-methyisoxazole-4-carboxylate and its corresponding acid as low as 0.1%, (3) produces a high quality of 5-methylisoxazole-4-carboxylic-(4′-trifluoromethyl)-anilide generally having 99.8-100% HPLC potency; and (4) does not require distillation of the isoxazole ester.
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- Reaction of 2-Dimethylaminomethylene-1,3-diones with Dinucleophiles. X. Synthesis of 5-Substituted Ethyl or Methyl 4-Isoxazolecarboxylates and Methyl 4-(2,2-Dimethyl-1-oxopropyl)-5-isoxazolecarboxylate
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Reaction of ethyl or methyl 2-dimethylaminomethylene-3-oxoalkanoates with hydroxylamine hydrochloride in methanol solution afforded in high yields the relative esters of 5-substituted 4-isoxazolecarboxylic acids II.These esters were hydrolyzed generally with concentrated hydrochloric acid-acetic acid mixtures to the corresponding carboxylic acids in satisfactory yields.Ethyl or methyl esters II isomerized with sodium ethoxide or methoxide, respectively, to the corresponding esters or hemiesters of 2-cyano-3-oxoalkanoic acids generally in excellent to satisfactory yields.Reaction of methyl 5,5-dimethyl-3-dimethylaminomethylene-2,4-dioxohexanoate with hydroxylamine hydrochloride afforded in moderate yield methyl 4-(2,2-dimethyl-1-oxopropyl)-5-isoxazolecarboxylate, which was converted by acid hydrolysis as above to 4-t-butyl-4-hydroxyfuroisoxazol-6-(4H)-one.
- Schenone, Pietro,Fossa, Paola,Menozzi, Giulia
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p. 453 - 457
(2007/10/02)
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- Pharmaceutical compounds
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Compounds of the following formula have pharmaceutical properties: STR1 in which X is R'(HO)C=C(CN)--, R1 (CO)--CH(CN)-- or STR2 R1 and R2 are each hydrogen or C1-6 alkyl, R3, R4, R5 and R6 are each hydrogen, hydroxy, halogen, nitro, cyano, carboxy, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, halo-substituted C1-4 alkyl, halo-substituted C1-4 alkoxy, halo-substituted C1-4 alkylthio, C2-5 alkoxycarbonyl, optionally substituted phenyl, optionally substituted phenoxy, R'R"N-- where R' and R" are each hydrogen or C1-4 alkyl or R'"CONH-- where R'" is C1-4 alkyl, or a group of the formula --CR7 R8 R9 in which R7, R8 and R9 are each C1-6 alkyl, halo-substituted C1-6 alkyl or optionally substituted phenyl, or R7 and R8, together with the carbon atom to which they are attached, form a cycloalkyl group containing 3 to 7 carbon atoms, or R7, R8 and R9 together with the carbon atom to which they are attached, form a bicycloalkyl group containing 4 to 9 carbon atoms, and Y is a 5- or 6-membered heterocyclic ring excluding pyrazole; and salts thereof.
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- N-phenyl amide compounds
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Compounds of the following formula have pharmaceutical properties: STR1 in which X is R1 (HO)C=C(CN)--, R1 (CO)--CH(CN)-- or STR2 R1 and R2 are each hydrogen or C1-6 alkyl, R3, R4 and R5 are each hydrogen, hydroxy, halogen, nitro, cyano, carboxy, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, halo-substituted C1-4 alkyl, halo-substituted C1-4 alkoxy, halo-substituted C1-4 alkylthio, C2-5 alkoxycarbonyl, optionally substituted phenyl, optionally substituted phenoxy, R'R"N- where R' and R" are each hydrogen or C1-4 alkyl R'"CONH-- where R'" is C1-4 alkyl, R6, R7 and R8 are each C1-6 alkyl, halo-substituted C1-6 alkyl or optionally substituted phenyl, or R6 and R7, together with the carbon atom to which they are attached, form a cycloalkyl group containing 3 to 7 carbon atoms, or R6, R7 and R8 together with the carbon atom to which they are attached, form a bicycloalkyl group containing 4 to 9 carbon atoms; and salts thereof.
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- Isoxazole-Oxazole Conversion by Beckmann Rearrangement
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A novel base-catalysed isoxazole-oxazole ring transformation was realized in the conversion of ethyl 5-hydroxy-3-(5-methylisoxazol-4-yl)isoxazole-4-carboxylate into 4-cyano-5-methyloxazol-2-ylacetic acid.A new process was developed for the preparation of t-4-amino-c-2-methyl-6-oxotetrahydropyran-r-3-carboxylic acid hydrochloride, a starting material for the synthesis of thienamycin.
- Doleschall, Gabor,Seres, Peter
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p. 1875 - 1880
(2007/10/02)
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