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曲格列酮

曲格列酮

CAS号:97322-87-7
英文名:Troglitazone
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化合物简介
Troglitazone (Rezulin, Resulin, Romozin, Noscal) is an antidiabetic and anti-inflammatory drug, and a member of the drug class of the thiazolidinediones. It was prescribed for patients with diabetes mellitus type 2. It was developed by Daiichi Sankyo (Japan). In the United States, it was introduced and manufactured by Parke-Davis in the late 1990s, but turned out to be associated with an idiosyncratic reaction leading to drug-induced hepatitis. The F.D.A. medical officer assigned to evaluate troglitazone, John Gueriguian, did not recommend its approval due to potential high liver toxicity; Parke-Davis complained to the FDA and Guerigian was subsequently removed from his post. A full panel of experts approved it in January 1997. Once the prevalence of adverse liver effects became known, troglitazone was withdrawn from the British market in December 1997, from the United States market in 2000, and from the Japanese market soon afterwards. It did not get approval in the rest of Europe.
基本信息
编号系统
物化性质
安全信息
生产方法及用途
生产方法
将940g 6-羟基-2-羟甲基-2,5,7,8-四甲基色满溶于3.5L DMF中,在冰浴冷却和搅拌下,分批加入96g 95%的NaIt,搅拌1h后,加入460ml苯甲酰氯在2.0L甲苯中的溶液。移去冰浴,搅拌过夜。加入5kg冰,用1.5L乙酸乙酯萃取3次。萃取液干燥后浓缩,剩余物溶于200ml乙酸乙酯,加入4L异己烷,在室温下搅拌。过滤收集析出的沉淀,用异己烷洗,在40℃真空干燥,得1167g 6-苯甲酰氧基-2-羟甲基-2,5,7,8-四甲基色满,mp73~74℃,收率90%。 将326.4g 6-苯甲酰氧基-2-羟甲基-2,5,7,8-四甲基色满溶于1.6L无水吡啶,在冰浴冷却和搅拌下,滴加164.1ml三氟甲磺酸酐。滴毕,在此温度下搅拌1h。加入1.5kg冰,用稀盐酸调至Ph值3,然后用1.5L乙酸乙酯萃取2次。萃取液干燥后浓缩,剩余物加入2L异己烷。过滤收集析出的沉淀,得320.1g 6-苯甲酰氧基-2-(三氟甲磺酰氧基甲基)-2,5,7,8-四甲基色满,mp 89~90℃,收率70%。 91.7g 6-苯甲酰氧基-2-(三氟甲磺酰氧基甲基)-2,5,7,8-四甲基色满和24.4g 4-羟基苯甲醛溶于200rnl DMF,加入54g碳酸钾,在室温搅拌过夜。加入1kg冰,用2mol/L盐酸酸化,乙酸乙酯萃取。萃取液干燥后浓缩,得83.5g油状的化合物(Ⅰ),收率97%。 121g化合物(Ⅰ)、39.5g 2,4-噻唑烷二酮和86.1g无水乙酸钠,在150℃加热2h。冷却后加入500rnl水,用1L乙酸乙酯萃取2次。萃取液干燥后浓缩,剩余物溶于200ml甲醇,一起加热,冷却析出沉淀,过滤收集,在50℃干燥。得136g化合物(Ⅱ),mp 145~147℃,收率91%。 119g化合物(Ⅱ)溶于1L THF和1L甲醇的混合液中,在室温加入53.5g镁屑,可加入小量碘以激发反应。在35℃反应2h后,再回流1h。浓缩,剩余物溶于500ml水,酸化,用300ml乙酸乙酯萃取2次。萃取液干燥后浓缩,剩余物悬浮于500ml水中,搅拌2h。过滤收集沉淀,将其溶于1:1的异己烷和乙酸乙酯混合液中,并以此作为展开剂在硅胶柱上进行层析。得到的结晶在50℃干燥,得99.6g化合物(Ⅲ),mp 97~100℃,收率83%。 53g化合物(Ⅲ)和265g吡啶盐酸盐,一起在150℃加热60min至全溶。冷却后加入100ml水,用50ml 2mol/L用100ml乙酸乙酯萃取3次,干燥,浓缩。用丙酮和异己烷结晶,得38.4g曲格列酮,mp 183-186℃,收率87%。
用途
噻唑烷酮类口服抗高血糖药。用于因产生耐受而单独使用胰岛素难控制的Ⅱ型糖尿病。
上游原料
(6-t-butyldimethylsilyloxy-2,5,7,8-tetramethyl-3,4-dihydro-2H-1-benzo[1,2-b]pyran-2yl)methanol 4-[6-benzyloxy-2,5,7,8-tetramethylchroman-2-ylmethoxy]benzaldehyde 3,4-二氢-2-羟基甲基-2,5,7,8-四甲基-2H-苯并吡喃-6-醇 2,5,7,8-tetramethyl-6-acetoxy-2-(4-nitrophenyloxy)methylchroman 乙二醇甲醚 2-hydroxymethyl-6-methoxymethoxy-2,5,7,8-tetramethylchroman 6-(Methoxymethoxy)-2,5,7,8-tetramethyl-2-[(4-nitrophenoxy)methyl]chroman [2-[(4-aminophenoxy)methyl]-2,5,7,8-tetramethyl-4-oxo-3H-chromen-6-yl] acetate carbonic acid tert-butyl ester 2-{4-[2,4-dioxo-thiazolidin-(5Z)-ylidenemethyl]phenoxymethyl}-2,5,7,8-tetramethyl-chroman-6-yl ester carbonic acid tert-butyl ester 2-hydroxymethyl-2,5,7,8-tetramethyl-chroman-6-yl ester thiourea Troglitazone glucuronide (+/-)-5-[4-(6-hydroxy-2,5,7,8-tetramethyl-2H-chromen-2-ylmethoxy)benzyl]thiazolidine-2,4-dione carbonic acid tert-butyl ester 2-(4-formylphenoxymethyl)-2,5,7,8-tetramethyl-chroman-6-yl ester ethyl 6-hydroxy-2,5,7,8-tetramethyl-3,4-dihydro-2H-chromene-2-carboxylate 对氟苯甲醛 Ethyl 3-(4-((6-acetoxy-2,5,7,8-tetramethylchroman-2-yl)methoxy)phenyl)-2-chloropropionate 6-tert-butyl(dimethyl)silyloxy-2,5,7,8-tetramethyl-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid 4-((6-((tert-butyldimethylsilyl)oxy)-2,5,7,8-tetramethylchroman-2-yl)methoxy)benzaldehyde 6-羟基-2,5,7,8-四甲基色满-2-羧酸 (6-Benzyloxy-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)methanol carbonic acid tert-butyl ester 2-{4-[2,4-dioxothiazolidin-5-ylmethyl]phenoxymethyl}-2,5,7,8-tetramethylchroman-6-yl ester TG-12 5-[4-(6-Benzyloxy-2,5,7,8-tetramethyl-chroman-2-ylmethoxy)-benzyl]-thiazolidine-2,4-dione 6-tert-butoxycarbonyloxy-2,5,7,8-tetramethyl-chroman-2-carboxylic acid ethyl ester 6-Hydroxy-2,5,7,8-tetramethyl-2-[(4-nitrophenoxy)methyl]chroman