降血脂药阿托伐他汀钙的合成
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摘要
阿托伐他汀钙是新一代羟甲戊二酰辅酶A(HMG-CoA)还原酶抑制剂(他汀类降血脂药)。
阿托伐他汀钙既能降低胆固醇,又能降低甘油三酯,其作用远比辛伐他汀、普伐他汀、氟伐
他汀和洛伐他汀强。口服10mg/d可使低密度脂蛋白胆固醇降低40%;20～40mg/d可使甘油
三酯下降30%,并可减少冠心病临床事件和降低冠心病死亡率。
本论文主要进行了阿托伐他汀钙的合成工艺研究,合成阿托伐他汀钙主要有线性和会聚
两种策略,会聚的合成策略较为实用。分别对4-氟-α-[2-甲基-1-氧丙基-γ-氧代-N,β-
二苯基苯丁酰胺(主环)和(4R,6R)-6-胺乙基-2,2-二甲基-1,3-二氧己环-4-乙酸叔丁酯(侧
链)的合成进行了综述,认为从丙二酸合成母环和L-苹果酸合成侧链较为方便。讨论了具体
的各步反应机理利反应条件的优化。分别合成山土环和侧链,再将它们进行Paal-Knorr’s缩
合得到缩合物固体,在脱保护基后得到阿托伐他汀钠,再用醋酸钙成钙盐。文献总收率为
7.56%(以主环计),实验室收率为9.35%。
在主环的合成中,合成了噻唑催化剂用于Stetter反应,并对此反应进行了优化,降低
了催化剂的用量。主环收率16.4%,与文献报道16.8%相当。土环合成中有一中间体4-异丁
酰基-2,2-二甲基-1,3-二噁炕-4,6-二酮(ATS-2)不稳定,对收率和质量都有很人的影响,
改进工艺将ATS-2碱水解得到固体4-甲基-3-羰基丁酸钠。
在侧链的合成中用自制的硼烷还原L-苹果酸二甲酯得到(S)-3,4-二羟基丁酸甲酯,再
经过磺酰化,氰基取代制得关键中间体(R)-4-氰基-3-羟基丁酸甲酯。为了延长两个碳原子,
侧链的合成中还需要两个低温反应,以及强碱二异丙胺基锂和选择性还原β-羟基酮为顺
1,3-二醇的甲氧基二乙基硼,此两试剂无国产化供应,且价格较贵,实验室合成了此两试剂,
用于合成效果很好。为了进行质量控制,单独合成出关键中间体(4S,6R)-6-氰甲基-2,2-_二甲
基-1,3-二氧己环-4-乙酸叔丁酯(ATS-8的差向异构体),经过高效液相-质谱确证,合成的
侧链光学纯度较高,重结晶后无手性异构体。侧链文献收率50.2%,实验室收率57.5%。
缩合反应研究了主环和侧链投料比,从1:1.3降至1:l,提高了缩合水解成盐的收率,
从文献报道的45%提高至57%。
经过元素分析,核磁共振,红外,质谱,热重分析,水分分析,合成的阿托伐他汀钙与
结构符合。氢谱数据与文献报道一致。比旋度与文献报道相符。
Atorvastatin is a new generation of HMG-CoA reductase inhibitors (blood lipid lowering agent of statins class). Not only cholesterol but also triglyceride(TG) can be lowered by the agent and it is more effective than other statins such as simvastatin, pravastatin, fluvastatin and lovastatin .With a daily oral dose of 10 mg/d LDL-C can be lowered by 40%; with a 20~40mg/d daily dose TG can be lowered by 30%, and the event of coronary heart disease and its mortality can also be decreased .This paper is a study about the synthesis of atorvastatin. There are two strategy,one is liner synthesis and the other is convergent synthesis. The convergent is more practical. The synthesis of 4-Fluro- α -[2-methyl-l-oxopropyl]- Y -oxo-N, β -diphenylbenzenebutaneamide(mother nucleus) and (4R,6R) 1,1 -dimethylethyl-6-(2-aminoethyl)-2,2-dimethyI-1,3-dioxane-4-acetate(side chain) is reviewed in detail. The convenient routes start from malonic acid to mother nucleus and from L-malic acid to side chain.The mechanism and optimization of every step has been discussed. With the fully functionalized,stereochemically pure side chain and the fully substituted mother nucleus in hand.they are reacted under Paal-Knorr's condensation.Deprotection and formation of the hemi-calcium salt produced atorvastatin calcium in high-yielding and commercially viable manner. From malonic acid the overall yield of atorvastatin calcium is 9.35% .(7.56% of reference)In the course of the synthesis of the mother nucleus ,the amount of N-ehtylthiazolium catalyst is cut down. The total yield of the mother nucleus is 16.4%,which is correspond to 16.8% of the reference.In order to improve stability of acylated meldrum's acid (AST-2), hydrolyzing it to 4-methyl-3-carbonyl butyrate sodium salt as a solid is studied.In the course of the synthesis of the side chain , the L-malic acid dimethyl ester is reducted to (S)-3,4-dihydroxybutane acid methyl ester with the use of self-made borane-dimethyl sulfide,followed by sulfonylation and cyan displacement, then the key intermediate (R)-4-cyano-3-hydroxybutane acid methyl ester is obtained. Lithium diisopropylamine and methoxydiethylborane ,which are used in the reactions of the side chain, are very expensive and can not be produced in our country.These two reagents are synthesized and used directly in our reactions. In order to control optical purity, (4S,6R)-1,1 -dimethylethyl-6-cyanomethyl-2 , 2-dimethyl-l,3-dioxane-4-acetate (the isomer of ATS-8) is synthesized.With the prove of
HPLC-MS ,the synthesized ATS-8's optical purity is highly ,and there is no epimeric isomer after recrystallization. The total yield of side chain is improved from 50.2% of the reference to 57.5% of experiment.In the condensation reaction the ratio of mother nucler to side chain is decreased from 1:1.3 to 1 :l,and the total yield is increased from 45% of the reference to 57%.Atorvastatin calcium has been confirmed by element analysis, MS, NMR,IR,TGA and water analysis ,rotation and 'H-NMR are in accord with the reference.
阿托伐他汀钙既能降低胆固醇,又能降低甘油三酯,其作用远比辛伐他汀、普伐他汀、氟伐
他汀和洛伐他汀强。口服10mg/d可使低密度脂蛋白胆固醇降低40%;20～40mg/d可使甘油
三酯下降30%,并可减少冠心病临床事件和降低冠心病死亡率。
本论文主要进行了阿托伐他汀钙的合成工艺研究,合成阿托伐他汀钙主要有线性和会聚
两种策略,会聚的合成策略较为实用。分别对4-氟-α-[2-甲基-1-氧丙基-γ-氧代-N,β-
二苯基苯丁酰胺(主环)和(4R,6R)-6-胺乙基-2,2-二甲基-1,3-二氧己环-4-乙酸叔丁酯(侧
链)的合成进行了综述,认为从丙二酸合成母环和L-苹果酸合成侧链较为方便。讨论了具体
的各步反应机理利反应条件的优化。分别合成山土环和侧链,再将它们进行Paal-Knorr’s缩
合得到缩合物固体,在脱保护基后得到阿托伐他汀钠,再用醋酸钙成钙盐。文献总收率为
7.56%(以主环计),实验室收率为9.35%。
在主环的合成中,合成了噻唑催化剂用于Stetter反应,并对此反应进行了优化,降低
了催化剂的用量。主环收率16.4%,与文献报道16.8%相当。土环合成中有一中间体4-异丁
酰基-2,2-二甲基-1,3-二噁炕-4,6-二酮(ATS-2)不稳定,对收率和质量都有很人的影响,
改进工艺将ATS-2碱水解得到固体4-甲基-3-羰基丁酸钠。
在侧链的合成中用自制的硼烷还原L-苹果酸二甲酯得到(S)-3,4-二羟基丁酸甲酯,再
经过磺酰化,氰基取代制得关键中间体(R)-4-氰基-3-羟基丁酸甲酯。为了延长两个碳原子,
侧链的合成中还需要两个低温反应,以及强碱二异丙胺基锂和选择性还原β-羟基酮为顺
1,3-二醇的甲氧基二乙基硼,此两试剂无国产化供应,且价格较贵,实验室合成了此两试剂,
用于合成效果很好。为了进行质量控制,单独合成出关键中间体(4S,6R)-6-氰甲基-2,2-_二甲
基-1,3-二氧己环-4-乙酸叔丁酯(ATS-8的差向异构体),经过高效液相-质谱确证,合成的
侧链光学纯度较高,重结晶后无手性异构体。侧链文献收率50.2%,实验室收率57.5%。
缩合反应研究了主环和侧链投料比,从1:1.3降至1:l,提高了缩合水解成盐的收率,
从文献报道的45%提高至57%。
经过元素分析,核磁共振,红外,质谱,热重分析,水分分析,合成的阿托伐他汀钙与
结构符合。氢谱数据与文献报道一致。比旋度与文献报道相符。
Atorvastatin is a new generation of HMG-CoA reductase inhibitors (blood lipid lowering agent of statins class). Not only cholesterol but also triglyceride(TG) can be lowered by the agent and it is more effective than other statins such as simvastatin, pravastatin, fluvastatin and lovastatin .With a daily oral dose of 10 mg/d LDL-C can be lowered by 40%; with a 20~40mg/d daily dose TG can be lowered by 30%, and the event of coronary heart disease and its mortality can also be decreased .This paper is a study about the synthesis of atorvastatin. There are two strategy,one is liner synthesis and the other is convergent synthesis. The convergent is more practical. The synthesis of 4-Fluro- α -[2-methyl-l-oxopropyl]- Y -oxo-N, β -diphenylbenzenebutaneamide(mother nucleus) and (4R,6R) 1,1 -dimethylethyl-6-(2-aminoethyl)-2,2-dimethyI-1,3-dioxane-4-acetate(side chain) is reviewed in detail. The convenient routes start from malonic acid to mother nucleus and from L-malic acid to side chain.The mechanism and optimization of every step has been discussed. With the fully functionalized,stereochemically pure side chain and the fully substituted mother nucleus in hand.they are reacted under Paal-Knorr's condensation.Deprotection and formation of the hemi-calcium salt produced atorvastatin calcium in high-yielding and commercially viable manner. From malonic acid the overall yield of atorvastatin calcium is 9.35% .(7.56% of reference)In the course of the synthesis of the mother nucleus ,the amount of N-ehtylthiazolium catalyst is cut down. The total yield of the mother nucleus is 16.4%,which is correspond to 16.8% of the reference.In order to improve stability of acylated meldrum's acid (AST-2), hydrolyzing it to 4-methyl-3-carbonyl butyrate sodium salt as a solid is studied.In the course of the synthesis of the side chain , the L-malic acid dimethyl ester is reducted to (S)-3,4-dihydroxybutane acid methyl ester with the use of self-made borane-dimethyl sulfide,followed by sulfonylation and cyan displacement, then the key intermediate (R)-4-cyano-3-hydroxybutane acid methyl ester is obtained. Lithium diisopropylamine and methoxydiethylborane ,which are used in the reactions of the side chain, are very expensive and can not be produced in our country.These two reagents are synthesized and used directly in our reactions. In order to control optical purity, (4S,6R)-1,1 -dimethylethyl-6-cyanomethyl-2 , 2-dimethyl-l,3-dioxane-4-acetate (the isomer of ATS-8) is synthesized.With the prove of
HPLC-MS ,the synthesized ATS-8's optical purity is highly ,and there is no epimeric isomer after recrystallization. The total yield of side chain is improved from 50.2% of the reference to 57.5% of experiment.In the condensation reaction the ratio of mother nucler to side chain is decreased from 1:1.3 to 1 :l,and the total yield is increased from 45% of the reference to 57%.Atorvastatin calcium has been confirmed by element analysis, MS, NMR,IR,TGA and water analysis ,rotation and 'H-NMR are in accord with the reference.
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