- Process Development of Febuxostat Using Palladium- and Copper-Catalyzed C-H Arylation
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There is significant interest in the development of process routes for active pharmaceutical ingredients using C-H arylation methodology. An efficient and practical synthetic route for febuxostat (1), which is the first non-purine-type xanthine oxidase inhibitor, was established via palladium- and copper-catalyzed C-H arylation of thiazole with aryl bromide. The catalyst loading was reduced to 0.1 mol percent for the intermolecular C-H arylation, and a three-step synthesis produced febuxostat in 89percent overall yield with excellent selectivity.
- Dohi, Masahiko,Kato, Yoshiaki,Komiyama, Masato,Kurokawa, Masayuki,Minamizono, Kunio,Sato, Yoshinori,Teramoto, Mitsuru,Tsuchiya, Hideyoshi,Tsuchiya, Naoki,Yajima, Naoki
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- Preparation method of febuxostat intermediate, and application thereof in preparation of febuxostat
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The invention provides a preparation method of a compound of structural formula II. The method comprises the following steps: 1) reacting a compound of structural formula VII under the action of an alkylating agent and an alkali to obtain a compound of structural formula VI; 2) reacting the compound of structural formula VI to obtain a compound of structural formula V; 3) reacting the compound ofthe structural formula V with urotropine under an acidic condition in the absence of a solvent to obtain a compound of structural formula IV; 4) reacting the compound of the structural formula IV withhydroxylamine hydrochloride in the presence of an alkali, and dehydrating the obtained reaction product to obtain a compound of structural formula III; and 5) performing a ring closing reaction on the compound of the structural formula III and the compound of the structural formula VIII to obtain the compound of structural formula II. The invention also provides an application of the preparationmethod in the synthesis of febuxostat. The method has the advantages of simplicity in operation, high yield, few side reactions and no highly toxic substances, and is suitable for industrial production as a novel method for preparing the febuxostat intermediate. R in the formulas is a C1-C4 alkyl group.
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- Facile one-pot transformation of arenes into aromatic nitriles under metal-cyanide-free conditions
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Electron-rich arenes bearing methyl or methoxy groups on the aromatic ring were treated with dichloromethyl methyl ether and ZnBr2, and then with molecular iodine and aq. ammonia to give the corresponding aromatic nitriles in good yields. Using this method, febuxostat was efficiently prepared from 4-bromophenol in four steps. The method can be used for the preparation of aromatic nitriles from arenes in one pot under metal-cyanide-free conditions. Various electron-rich arenes could be effectively converted into the corresponding aromatic nitriles in good yields, by treatment with ZnBr2 and dichloromethyl methyl ether, followed by reaction with molecular iodine and aq. ammonia.
- Tamura, Toshiyuki,Moriyama, Katsuhiko,Togo, Hideo
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p. 2023 - 2029
(2015/03/18)
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- Facile one-pot transformation of phenols into o-cyanophenols
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The treatment of phenols with paraformaldehyde in the presence of MgCl2 and Et3N in THF at 80 C, followed by reaction with molecular iodine and aq. ammonia at room temperature provided the corresponding o-cyanophenols in moderate to good yields. The present reaction is a one-pot transformation of phenols into o-cyanophenols using much less expensive reagents than are typically used; the reaction is free of both transition-metals and cyanide. The utility of this reaction was highlighted during our preparation of Febuxostat from p-bromophenol.
- Nakai, Yuhta,Moriyama, Katsuhiko,Togo, Hideo
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p. 6077 - 6083
(2015/03/30)
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- Direct oxidative conversion of methylarenes into aromatic nitriles
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A variety of methylarenes were successfully converted into the corresponding aromatic nitriles in good to moderate yields by the treatment with NBS or DBDMH in the presence of a catalytic amount of AIBN or BPO, followed by the reaction with molecular iodine in aq NH3 in a one-pot procedure. The present reaction is a useful and practical transition-metal-free method for the preparation of aromatic nitriles from methylarenes.
- Tsuchiya, Daisuke,Kawagoe, Yuhsuke,Moriyama, Katsuhiko,Togo, Hideo
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p. 4194 - 4197
(2013/09/12)
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- PROCESS FOR PRODUCING PHENYL-SUBSTITUTED HETEROCYCLIC DERIVATIVE THROUGH COUPLING USING TRANSITION METAL CATALYST
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A process for efficiently producing, through few steps either a xanthine oxidase inhibitor, which is a therapeutic agent for hyperuricemia, or an intermediate therefore. The process is a novel coupling process which comprises subjecting a compound represented by formula (1) to coupling reaction with a compound represented by formula (2) in the presence of a transition metal compound to thereby obtain a compound represented by formula (3).
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Page/Page column 18-19
(2012/01/13)
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- Nickel-catalyzed C-H arylation of azoles with haloarenes: Scope, mechanism, and applications to the synthesis of bioactive molecules
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Novel nickel-based catalytic systems for the C-H arylation of azoles with haloarenes and aryl triflates have been developed. We have established that Ni(OAc)2/bipy/LiOtBu serves as a general catalytic system for the coupling with aryl bromides and iodides as aryl electrophiles. For couplings with more challenging electrophiles, such as aryl chlorides and triflates, the Ni(OAc)2/dppf (dppf=1,1′-bis(diphenylphosphino)ferrocene) system was found to be effective. Thiazoles, benzothiazoles, oxazoles, benzoxazoles, and benzimidazoles can be used as the heteroarene coupling partner. Upon further investigation, we discovered a new protocol for the present coupling using Mg(OtBu)2 as a milder and less expensive alternative to LiOtBu. Attempts to reveal the mechanism of this nickel-catalyzed heterobiaryl coupling are also described. This newly developed methodology has been successfully applied to the syntheses of febuxostat (a xanthine oxidase inhibitor that is effective for the treatment of gout and hyperuricemia), tafamidis (effective for the treatment of TTR amyloid polyneuropathy), and texaline (a natural product having antitubercular activity). Copyright
- Yamamoto, Takuya,Muto, Kei,Komiyama, Masato,Canivet, Jerome,Yamaguchi, Junichiro,Itami, Kenichiro
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supporting information; experimental part
p. 10113 - 10122
(2011/10/08)
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- Nickel-catalyzed biaryl coupling of heteroarenes and aryl halides/triflates
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Ni-based catalytic systems for the arylation of heteroarenes with aryl halides and triflates have been established. Ni(OAc)2/bipy is a general catalyst for aryl bromides/iodides, and Ni(OAc)2/dppf is effective for aryl chlorides/triflates. Thiazole, benzothiazole, oxazole, benzoxazole, and benzimidazole are applicable as heteroarene coupling partners. A rapid synthesis of febuxostat, a drug for gout and hyperuricemia, is also demonstrated.
- Canivet, Jerome,Yamaguchi, Junichiro,Ban, Ikuya,Itami, Kenichiro
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supporting information; experimental part
p. 1733 - 1736
(2009/08/15)
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