5-氨基酮戊酸盐酸盐和曲沙他滨的合成研究
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摘要
本论文由以下两个部分组成：
Ⅰ5-氨基酮戊酸盐酸盐的合成
Ⅱ曲沙他滨的合成
第一部分：5-氨基酮戊酸(5-ALA)盐酸盐不仅是动物血红素和植物叶绿素生物合成的前体物质,而且是新一代光动力学治疗药物。近年来,5-ALA作为一种新型光动力化合物日益受到关注。在医学领域,5-ALA作为治疗癌症的光动力药物,可以用于皮肤癌、膀胱癌、消化道癌、肺癌的治疗；在农业领域,5-ALA可以作为无公害绿色除草剂、杀虫剂、落叶剂、植物生长调节剂等,具有广泛的用途。
本文对5-氨基酮戊酸盐酸盐作了简单的介绍,重点比较了5-氨基酮戊酸盐酸盐几种合成方法,进行了大量的对比实验和改进,得到一种适合工业化生产的合成路线。本文在得到目标化合物的过程中,对中间体2-(3-氯-2-氧代丙基)异吲哚啉-1,3-二酮的制备方法进行了大胆的改进：1.以环氧氯丙烷作为起始原料通过盖布瑞尔反应、开环、氧化获得；2.以1,3-二氯丙酮为起始原料通过与邻苯二甲酰亚胺钾盐在水相亲核取代完成。研究表明该方法具有原料便宜易得、总收率高、产物易分离纯化、后处理操作简单、总成本低等优点产品结构经1HNMR、13CNMR、MS验证。
第二部分：曲沙他滨,其化学名称为：4-氨基-1-[(2S)-2-(羟甲基)-1,3-二氧杂环戊-4-基]嘧啶-2-酮,是由Shire Biologics研制的一类抗癌药物。曲沙他滨是第一个dioxolane核苷类似物,作为抗癌药正处于临床研究阶段。本品是一个全DNA链终止子和DNA聚合酶抑制剂,通过将其自身掺入癌症细胞增长中的DNA链中,干扰其复制能力而起作用。
本文对曲沙他滨作了简单的介绍,讨论已有的合成方法,提出了一条新的合成路线。我们采用了具有光学活性的L-左旋薄荷醇为原料,经过酯化、脱水成环、氯代、耦合、还原得到目标产物曲沙他滨。由于使用手性辅助剂L-薄荷醇,立体构型保持完整,化合物分离简便,收率较高。产品结构经1HNMR、13CNMR、MS验证。
This paper is maked up of the synthesis of5-Aminolevulinic Acid Hydrochloride and Troxacitabine.
The first part is on the synthesis of5-Aminolevulinic Acid Hydrochloride, which is not only the biosynthesis precursor substance of a nimal heme and chlorophyll but also a new generation of photodynamic therapy. In recent years,5-Aminolevulinic Acid Hydrochloride has drawn more and more attention as a novel photodynamic compound in the medical field. It can be used for treatment of skin cancer, bladder cancer, gastrointestinal cancer and lung cancer as a photodynamic treatment of cancer drug; in the agricultural field, it has a wide range of uses such as a pollution-free green herbicides, insecticides, defoliants, and plant growth regulating agents.
The paper introduces5-Aminolevulinic Acid Hydrochloride simply.Through trying different reaction conditions; we obtained a suitable synthetic route for industrial production. In order to obtain the target compound, we have made the improvement of the synthesis of the compound2-(3-chloro-2-oxo-propyl) isoindoline-1,3-dione. In the first route, epichlorohydrin is used as a starting material by the Gabriel reaction, ring-opening, oxide to obtain it; in the second route,1,3-dichloroacetone is substituted by phthalimide potassium in water to obtain2-(3-chloro-2-oxo-propyl) isoindoline-1,3-dione. The results showed that the synthetic method has the advantages of materials being simply available, good overall yield, easily work-up and low cost.The structure of products was verficated by1HNMR,13CHMR and MS.
The second part is on the synthesis of Troxacitabine, whose chemical name is4-amino-1-[(2S)-2-(hydroxymethyl)-1,3-dioxol-4-yl] pyrimidin-2-one. Troxacitabine is the first dioxolane nucleoside analogues as anti-cancer drugs in the clinical research stage, which is developed by Shire Biologies. This drug is a DNA chain terminator and DNA polymerase inhibitor. It can interfere the action of DNA replication when it incorporates in the DNA chain in the growth of cancer cells.
We have compared about many synthesis routes of Troxacitabine and explored a new route to approach the terminate, which is used L-menthol with optically active as starting material. Through esterification, dehydration-condensation, chlorination, couoling and reduction, we get the target production Troxacitabine. Due to the use of the chiral auxiliary agent L-menthol, the compounds keep intact stereochemistry and the separation of the compound is simple, with high yield. The structure of products was verficated by1HNMR,13CHMR and MS.
Ⅰ5-氨基酮戊酸盐酸盐的合成
Ⅱ曲沙他滨的合成
第一部分：5-氨基酮戊酸(5-ALA)盐酸盐不仅是动物血红素和植物叶绿素生物合成的前体物质,而且是新一代光动力学治疗药物。近年来,5-ALA作为一种新型光动力化合物日益受到关注。在医学领域,5-ALA作为治疗癌症的光动力药物,可以用于皮肤癌、膀胱癌、消化道癌、肺癌的治疗；在农业领域,5-ALA可以作为无公害绿色除草剂、杀虫剂、落叶剂、植物生长调节剂等,具有广泛的用途。
本文对5-氨基酮戊酸盐酸盐作了简单的介绍,重点比较了5-氨基酮戊酸盐酸盐几种合成方法,进行了大量的对比实验和改进,得到一种适合工业化生产的合成路线。本文在得到目标化合物的过程中,对中间体2-(3-氯-2-氧代丙基)异吲哚啉-1,3-二酮的制备方法进行了大胆的改进：1.以环氧氯丙烷作为起始原料通过盖布瑞尔反应、开环、氧化获得；2.以1,3-二氯丙酮为起始原料通过与邻苯二甲酰亚胺钾盐在水相亲核取代完成。研究表明该方法具有原料便宜易得、总收率高、产物易分离纯化、后处理操作简单、总成本低等优点产品结构经1HNMR、13CNMR、MS验证。
第二部分：曲沙他滨,其化学名称为：4-氨基-1-[(2S)-2-(羟甲基)-1,3-二氧杂环戊-4-基]嘧啶-2-酮,是由Shire Biologics研制的一类抗癌药物。曲沙他滨是第一个dioxolane核苷类似物,作为抗癌药正处于临床研究阶段。本品是一个全DNA链终止子和DNA聚合酶抑制剂,通过将其自身掺入癌症细胞增长中的DNA链中,干扰其复制能力而起作用。
本文对曲沙他滨作了简单的介绍,讨论已有的合成方法,提出了一条新的合成路线。我们采用了具有光学活性的L-左旋薄荷醇为原料,经过酯化、脱水成环、氯代、耦合、还原得到目标产物曲沙他滨。由于使用手性辅助剂L-薄荷醇,立体构型保持完整,化合物分离简便,收率较高。产品结构经1HNMR、13CNMR、MS验证。
This paper is maked up of the synthesis of5-Aminolevulinic Acid Hydrochloride and Troxacitabine.
The first part is on the synthesis of5-Aminolevulinic Acid Hydrochloride, which is not only the biosynthesis precursor substance of a nimal heme and chlorophyll but also a new generation of photodynamic therapy. In recent years,5-Aminolevulinic Acid Hydrochloride has drawn more and more attention as a novel photodynamic compound in the medical field. It can be used for treatment of skin cancer, bladder cancer, gastrointestinal cancer and lung cancer as a photodynamic treatment of cancer drug; in the agricultural field, it has a wide range of uses such as a pollution-free green herbicides, insecticides, defoliants, and plant growth regulating agents.
The paper introduces5-Aminolevulinic Acid Hydrochloride simply.Through trying different reaction conditions; we obtained a suitable synthetic route for industrial production. In order to obtain the target compound, we have made the improvement of the synthesis of the compound2-(3-chloro-2-oxo-propyl) isoindoline-1,3-dione. In the first route, epichlorohydrin is used as a starting material by the Gabriel reaction, ring-opening, oxide to obtain it; in the second route,1,3-dichloroacetone is substituted by phthalimide potassium in water to obtain2-(3-chloro-2-oxo-propyl) isoindoline-1,3-dione. The results showed that the synthetic method has the advantages of materials being simply available, good overall yield, easily work-up and low cost.The structure of products was verficated by1HNMR,13CHMR and MS.
The second part is on the synthesis of Troxacitabine, whose chemical name is4-amino-1-[(2S)-2-(hydroxymethyl)-1,3-dioxol-4-yl] pyrimidin-2-one. Troxacitabine is the first dioxolane nucleoside analogues as anti-cancer drugs in the clinical research stage, which is developed by Shire Biologies. This drug is a DNA chain terminator and DNA polymerase inhibitor. It can interfere the action of DNA replication when it incorporates in the DNA chain in the growth of cancer cells.
We have compared about many synthesis routes of Troxacitabine and explored a new route to approach the terminate, which is used L-menthol with optically active as starting material. Through esterification, dehydration-condensation, chlorination, couoling and reduction, we get the target production Troxacitabine. Due to the use of the chiral auxiliary agent L-menthol, the compounds keep intact stereochemistry and the separation of the compound is simple, with high yield. The structure of products was verficated by1HNMR,13CHMR and MS.
引文
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[2]刘海灵,江换峰,王玉刚,刘鹏,光动力化合物5-氨基乙酰丙酸的简便全合成.有机化学,2005,25：1431-1434.
[3]Min-Seok, K.; Dong-Myung, K.; Jeong Sook, K.; Jin-Hyun, J. Synthesis of 5-[4,5-13C2]-and 5-[1,5-13C2] aminolevulinic acid. J. Label. Compd. Radiopharm,2002, 45:569-576.
[4]Hiroshi, K.; Takashi, E.; Hajime, M. New Synthesis of 5-Aminolevulinic Acid. Agric.Biol.Chem,1991,55:1687-1688.
[5]Diana, A.; Bruce, D.; Sung-Koo, L.; Young-Jin, H.; Hyun-Joon H.; Synthesis of analogues of 5-aminolaevulinic acid and inhibition of 5-aminolaevulinic acid dehydratase. J. Chem. Soc., Perkin Trans,1998,1:92-101.
[6]王俊卿,张肇铭.5-氨基乙酰丙酸及其衍生物对癌症的光动力治疗研究进展.细胞与分子免疫学杂志,2005,24：115-117.
[7]吕玲,刘宏.光敏剂5-氨基酮戊酸酯类衍生物的研究进展.中国药房,2011,25：2385-2397.
[8]王自明,张阳德,何剪太,林伶DFO、5-ALA联合诱导大肠癌细胞原卟啉Ⅸ聚积的时间动力学研究.中国现代医学杂志,2009,24：3753-3755.
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