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              Name Leflunomide;RS-34821;SU-101;HWA-486;Arava
              Chemical Name 5-Methyl-N-[4-(trifuoromethyl)phenyl]isoxazole-4-carboxamide
              CAS 75706-12-6
              Related CAS
              Formula C12H9F3N2O2
              Structure
              Formula Weight 270.21293
              Stage 上市-1998
              Company Aventis Pharma (Originator), Lepetit (Originator), Kyorin (Licensee), Sugen (Licensee)
              Activity/Mechanism Antiarthritic Drugs, Brain Cancer Therapy, Disease-Modifying Drugs, IMMUNOMODULATING AGENTS, Immunosuppressants, Oncolytic Drugs, Ovarian Cancer Therapy, Prostate Cancer Therapy, Psoriatic Arthritis, Treatment of , Rheumatoid Arthritis, Treatment of, TREATMENT OF MUSCULOSKELETAL & CONNECTIVE TISSUE DISEASES, Treatment of Transplant Rejection, Dihydroorotate Dehydrogenase Inhibitors, Inhibitors of Signal Transduction Pathways, PDGFR Inhibitors
              Syn. Route 1
              Route 1
              leflunomide can be obtained by several related ways:1) the reaction of diketene (i) with 4-(trifluoromethyl)-aniline (ii) in hot acetonitrile gives n-[4-(trifluoro-methyl) phenyl]acetoacetamide (iii) , which by reaction with triethyl orthoformate (iv) in refluxing acetic anhydride yields the corresponding ethoxymethylene derivative (v). finally, this compound is cyclized with hydroxylamine in refluxing ethanol/water.2) the reaction of ethyl acetoacetate (vi) with triethyl orthoformate (iv) as before gives the corresponding ethoxymethylene derivative (vii), which by cyclization with hydroxylamine as before affords 5-methylisoxazole-4-carboxylic acid ethyl ester (viii). the hydrolysis of (viii) under acidic conditions yields the free acid (ix), which is converted into the acid chloride (x) by standard methods. finally, this compound is condensed with 4-(trifluoro-methyl)aniline (ii) by means of triethylamine in acetonitrile.3) the formation of leflunomide from acid (ix) or its derivatives such as ethyl (viii) or other esters can also be performed through other standard procedures of amide formation.4) the n-[4-(trifluoromethyl)phenyl]acetoacetamide (iii) can also be obtained by reaction of 4-(trifluoro-methyl) aniline (ii) with 2,2,6-trimethyl-4h-1,3-dioxin-4-one (xi) in refluxing xylene.
              List of intermediates No.
              2-[6-nitro-4-oxo-2h-chromen-3(4h)-ylidene]acetic acid (i)
              5-[4-hydroxy-2-(3-hydroxypentyl)-3,5,6-trimethylphenoxy]-2,2-dimethylpentanoic acid (vi)
              (3r,4s,5s)-5-[(1s)-1,2-dihydroxyethyl]-3,4-dihydroxydihydro-2(3h)-furanone (xi)
              (4s)-6-(benzyloxy)-2,2-dimethyl-4,6a-dihydro-3ah-cyclopenta[d][1,3]dioxol-4-ol (ii)
              (4s)-6-(benzyloxy)-2,2-dimethyl-4-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-4,6a-dihydro-3ah-cyclopenta[d][1,3]dioxole; benzyl (6s)-2,2-dimethyl-6-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-6,6a-dihydro-3ah-cyclopenta[d][1,3]dioxol-4-yl ether (iii)
              1,3-propanedithiol; 3-sulfanylpropylhydrosulfide (v)
              n-(5-amino-6-chloro-4-pyrimidinyl)-n-[6-(benzyloxy)-2,2-dimethyl-4,6a-dihydro-3ah-cyclopenta[d][1,3]dioxol-4-yl]amine; n(4)-[6-(benzyloxy)-2,2-dimethyl-4,6a-dihydro-3ah-cyclopenta[d][1,3]dioxol-4-yl]-6-chloro-4,5-pyrimidinediamine (vii)
              9-[6-(benzyloxy)-2,2-dimethyl-4,6a-dihydro-3ah-cyclopenta[d][1,3]dioxol-4-yl]-6-chloro-9h-purine; benzyl 6-(6-chloro-9h-purin-9-yl)-2,2-dimethyl-6,6a-dihydro-3ah-cyclopenta[d][1,3]dioxol-4-yl ether (viii)
              9-[6-(benzyloxy)-2,2-dimethyl-4,6a-dihydro-3ah-cyclopenta[d][1,3]dioxol-4-yl]-9h-purin-6-amine; 9-[6-(benzyloxy)-2,2-dimethyl-4,6a-dihydro-3ah-cyclopenta[d][1,3]dioxol-4-yl]-9h-purin-6-ylamine (ix)
              4-(tert-butyl)phenol (x)
              methyl (2r)-2-[(tert-butoxycarbonyl)amino]-3-[3-[(diethoxyphosphoryl)methyl]-6,7-dimethyl-2-quinolinyl]propanoate (iv)
              Reference 1:
                  fossa, p.; schenone, p.; filippelli, w.; lucarelli, c.; menozzi, g.; russo, s.; marmo, e.; 5-substd. 4-isoxazolecarboxamides with platelet antiaggregating and other activities. farmaco 1991, 46, 6, 789-802.
              Reference 2:
                  kammerer, f.-j.; schleyerbach, r. (aventis sa); isoxazole deriv., process for its preparation, medicine containing it and intermediates required in the process. de 2854439; ep 0013376; us 4284786; us 4351841 .
              Reference 3:
                  treatment of platelet derived growth factor related disorders such as cancers using inhibitors of platelet derived growth receptor. ep 1000617; us 5700823; wo 9519169 .
              Reference 4:
                  gershon, n.; avrutov, i.; liberman, a. (teva pharmaceutical industries ltd.; teva pharmaceuticals usa, inc.); a method for synthesizing leflunomide. wo 0160363 .

              來源:藥化網

              作者:藥化小編

              摘要:本文合成路線介紹的是藥物中文名來氟米特;英文名Leflunomide;RS-34821;SU-101;HWA-486;Arava;CAS[75706-12-6]

               
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