巴多昔芬的合成工艺改进
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摘要
为了改进巴多昔芬的合成工艺,以4-苄氧基苯肼盐酸盐和4-苄氧基苯丙酮为起始原料,经过Fischer吲哚合成法得到母体。吲哚化合物3与侧链缩合后,经水解、取代、还原、氢解6步得到目标化合物。结果表明,目标化合物经质谱、核磁共振确证其结构。总产率可达44%,产品HPLC法获得纯度可达99.3%以上。改进后的工艺反应条件温和,步骤大大缩短,副产物很少,后处理简单,适合工业化生产。
To improve the synthetic process of bazedoxifene, the stemnucleus was obtained by fischer indole synthesis taking 4-methoxyphenylhydrazine hydrochloride and 4-benzyloxypropiophenone as starting ma-terials. The indole compound 3 and the side chain were condensed and process byhydrolysis, replace, reduc-tion and, hydrogenolysis to get the target compound via total six steps. The results showed that: The structure of the target compound was confirmed by ESI-MS and ~1H-NMR. The total yield was 44%, and HPLC purity was more than 99.3%. The improved process conditions are mild, the steps are greatly shortened, the byproducts are greatly reduced, the post-treatment is simple and suitable for industrial production.
To improve the synthetic process of bazedoxifene, the stemnucleus was obtained by fischer indole synthesis taking 4-methoxyphenylhydrazine hydrochloride and 4-benzyloxypropiophenone as starting ma-terials. The indole compound 3 and the side chain were condensed and process byhydrolysis, replace, reduc-tion and, hydrogenolysis to get the target compound via total six steps. The results showed that: The structure of the target compound was confirmed by ESI-MS and ~1H-NMR. The total yield was 44%, and HPLC purity was more than 99.3%. The improved process conditions are mild, the steps are greatly shortened, the byproducts are greatly reduced, the post-treatment is simple and suitable for industrial production.
引文
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[7]JOSHI S,BHUTA S,TALUKDAR S,et al.Processes for the synthesis of bazedoxifene acetate and intermediates thereof:WO,2010118997[P].2010-10-21.
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[9]RAKESHWAR B,REDDY L A,PRANAB H,et al.Prepatation of Bazedoxifene and its salts:WO,2011022596[P].2011-02-24.
[10]WAGAW S,YANG B H,BUCHWALD S L.A Palladium-Catalyzed Strategy for the Preparation of Indoles:A Novel Entry into the Fischer Indole Synthesis[J].Cheminform,1998,120(26):6 621-6 622.
[11]LEKKALA A R,HALDAR P,MYLAVARAPU A K,et al.Preparation of bazedoxifene and its salts:WO,2011022596A2[P].2001-02-24.
[12]THEODOROU V,PARASKEVOPOULOS G,SKOBRIDIS K.A mild alkaline hydrolysis of N-and N,N-substituted amides and nitriles[J].Archive for Organic Chemistry,2015,7:101-112.
[13]LARRIVEE-ABOUSSAFY C,JONES B P,PRICE K E,et al.DBU-Catalysis of N,N'Carbonyldiimidazole-Mediated Amidations[J].Organic Letters,2010,12(2):324-327.
[14]CHO Sudong,PARK Yongdae,KIM Jeumjong,et al.Facile Reduction of Carboxylic Acids,Esters,Acid Chlorides,Amides and Nitriles to Alcohols or Amines Using Na BH4/BF3·Et2O[J].Bull Korean Chem Soc,2004,25(3):407-409.
[15]LUTHRA P K,BHUTA S,NAIR R,et al.Novel Salt Intermediates for the Synthesis of Bazedoxifene Acetate and Process Thereof:WO,2013001511[P].2013-01-03.
[2]STOCH S A,ZAJIC S,STONE J,et al.Effect of the cathepsin Kinhibitor odanacatib on bone resorption biomarkers in healthy postmenopausal women:two double-blind,randomized,placebo-controlled phase I studies[J].Clinical Pharmacology and Therapeutics,2009,86:175-182.
[3]赵文丽.FDA批准用于治疗绝经后潮热和预防骨质疏松症药物[J].国际药学研究杂志,2013,40(6):806.
[4]CHRIS P M,MICHAEL D C,BACH D T.2-Phenly-1-[4-(2-aminoethoxy)-benzyl]-indoles as estrogenic agents:US,5998402[P].1999-12-07.
[5]JAMES H P,BARRY S K.2-Phenly-1-[4-(2-amino-ethoxy)-benzyl]-indoles and estrogen formulation:US,6479535[P].2002-11-12.
[6]陈姗,刘相奎,俞雄,等.醋酸巴多昔芬的合成[J].中国新药杂志,2013,22(13):1 571-1 573.
[7]JOSHI S,BHUTA S,TALUKDAR S,et al.Processes for the synthesis of bazedoxifene acetate and intermediates thereof:WO,2010118997[P].2010-10-21.
[8]薛琛琛,裴叔宸,胥涛,等.巴多昔芬有关物质的合成[J].中国医药工业杂志,2014,45(12):1 112-1 116.
[9]RAKESHWAR B,REDDY L A,PRANAB H,et al.Prepatation of Bazedoxifene and its salts:WO,2011022596[P].2011-02-24.
[10]WAGAW S,YANG B H,BUCHWALD S L.A Palladium-Catalyzed Strategy for the Preparation of Indoles:A Novel Entry into the Fischer Indole Synthesis[J].Cheminform,1998,120(26):6 621-6 622.
[11]LEKKALA A R,HALDAR P,MYLAVARAPU A K,et al.Preparation of bazedoxifene and its salts:WO,2011022596A2[P].2001-02-24.
[12]THEODOROU V,PARASKEVOPOULOS G,SKOBRIDIS K.A mild alkaline hydrolysis of N-and N,N-substituted amides and nitriles[J].Archive for Organic Chemistry,2015,7:101-112.
[13]LARRIVEE-ABOUSSAFY C,JONES B P,PRICE K E,et al.DBU-Catalysis of N,N'Carbonyldiimidazole-Mediated Amidations[J].Organic Letters,2010,12(2):324-327.
[14]CHO Sudong,PARK Yongdae,KIM Jeumjong,et al.Facile Reduction of Carboxylic Acids,Esters,Acid Chlorides,Amides and Nitriles to Alcohols or Amines Using Na BH4/BF3·Et2O[J].Bull Korean Chem Soc,2004,25(3):407-409.
[15]LUTHRA P K,BHUTA S,NAIR R,et al.Novel Salt Intermediates for the Synthesis of Bazedoxifene Acetate and Process Thereof:WO,2013001511[P].2013-01-03.