帕比司他与苯并咪唑硫醚化合物的合成
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摘要
帕比司他是Novartis公司研制的异羟肟酸类小分子组蛋白去乙酰酶抑制剂,临床上作为罕见病用药,用于皮肤T细胞淋巴瘤的治疗。本文以苯肼和5-氯-2-戊酮为起始原料,经过缩合、分子内成环以及重排反应后得到关键中间体2-甲基色胺。以(E)-4-甲基肉桂酸甲酯为原料,经NBS溴化,得到另一中间体(E)-4-溴甲基肉桂酸甲酯。然后,2-甲基色胺与(E)-4-溴甲基肉桂酸甲酯发生N-烷基化反应,制得(E)-3-[4-[[2-(2-甲基-1H-吲哚-3-基)乙胺基]甲基]苯基]丙烯酸甲酯盐酸盐。最后,(E)-3-[4-[[2-(2-甲基-1H-吲哚-3-基)乙胺基]甲基]苯基]丙烯酸甲酯盐酸盐与过量的羟胺溶液发生胺解反应制得目标产物帕比司他,总收率30.6%。该工艺路线原料价廉易得,反应条件温和,有一定的应用价值。
2-(杂)芳甲基取代的苯并咪唑硫醚化合物骨架用于开发质子泵抑制剂类抗消化道溃疡药一直是药物化学家们的研究热点。本文以2-硝基苯胺类化合物为底物,碱性条件下,以水和低级醇为溶剂,经过一个连续的还原-环合-缩合三步一锅煮工艺合成了一系列的2-芳甲基取代苯并咪唑硫醚化合物,这种合成策略为本文首次报道,操作简便,环境友好,避免了合成过程中的分离损失,目标产物收率44.5%-85.9%。
中间体及目标产物的化学结构经MS、1H NMR确证,并讨论了影响反应的主要因素,从中得到合成帕比司他与苯并咪唑硫醚化合物较佳的反应条件。
Panobinostat, a novel class of small-molecule hydroxamic acid-based HDAC inhibitors developed by Novartis is now used for the treatment of CTCL as an orphan drug, It was prepared starting from phenylhydrazine,5-chloro-2-pentanone and methyl (E)-4-(methyl) cinnamate in 30.6% overall yield. Initially, the condensation of phenylhydrazine and 5-chloro-2-pentanone gave the corresponding hydrazone, ring formation of which and subsequent rearrangement afforded a key intermediate 2-methyltryptamine. Afterwards, another intermediate methyl (E)-4-(bromomethyl) cinnamate was obtained from methyl (E)-4-(methyl) cinnamate by bromination with NBS. Finally,2-methyltryptamine was performed N-alkylation with methyl (E)-4-(bromomethyl) cinnamate to give secondary amine, which was converted to the anticarcinogen drug panobinostat via aminolysis with hydroxylamine. The ready availability of raw materials and the mild conditions of this process make the route a valuable preparation for the drug.
2-(Hetero)arylmethylthiobenzimidazoles, a basic skeleton as novel proton pump inhibitors (PPIs) frequently used for ulcer treatment by medicinal chemists have been synthesized starting from 2-nitroanilines by a novel one-pot procedure in good to excellent yields. The procedure involves a continuous sequence of reduction, cyclization and condensation assisted with only H2O and MeOH as the solvents, and the compatible Na2S and KOH as the reagents. It is distinguished by simple manipulation, environmental benignancy, inexpensive reagents and higher yields, comparing to corresponding batch reaction.
The structures of all intermediates and products were confirmed by 1H NMR and MS. After optimization of reaction parameters with several experiments, the optimized reaction conditions for synthesis of panobinostat and benzimidazolyl sulfides were obtained.
2-(杂)芳甲基取代的苯并咪唑硫醚化合物骨架用于开发质子泵抑制剂类抗消化道溃疡药一直是药物化学家们的研究热点。本文以2-硝基苯胺类化合物为底物,碱性条件下,以水和低级醇为溶剂,经过一个连续的还原-环合-缩合三步一锅煮工艺合成了一系列的2-芳甲基取代苯并咪唑硫醚化合物,这种合成策略为本文首次报道,操作简便,环境友好,避免了合成过程中的分离损失,目标产物收率44.5%-85.9%。
中间体及目标产物的化学结构经MS、1H NMR确证,并讨论了影响反应的主要因素,从中得到合成帕比司他与苯并咪唑硫醚化合物较佳的反应条件。
Panobinostat, a novel class of small-molecule hydroxamic acid-based HDAC inhibitors developed by Novartis is now used for the treatment of CTCL as an orphan drug, It was prepared starting from phenylhydrazine,5-chloro-2-pentanone and methyl (E)-4-(methyl) cinnamate in 30.6% overall yield. Initially, the condensation of phenylhydrazine and 5-chloro-2-pentanone gave the corresponding hydrazone, ring formation of which and subsequent rearrangement afforded a key intermediate 2-methyltryptamine. Afterwards, another intermediate methyl (E)-4-(bromomethyl) cinnamate was obtained from methyl (E)-4-(methyl) cinnamate by bromination with NBS. Finally,2-methyltryptamine was performed N-alkylation with methyl (E)-4-(bromomethyl) cinnamate to give secondary amine, which was converted to the anticarcinogen drug panobinostat via aminolysis with hydroxylamine. The ready availability of raw materials and the mild conditions of this process make the route a valuable preparation for the drug.
2-(Hetero)arylmethylthiobenzimidazoles, a basic skeleton as novel proton pump inhibitors (PPIs) frequently used for ulcer treatment by medicinal chemists have been synthesized starting from 2-nitroanilines by a novel one-pot procedure in good to excellent yields. The procedure involves a continuous sequence of reduction, cyclization and condensation assisted with only H2O and MeOH as the solvents, and the compatible Na2S and KOH as the reagents. It is distinguished by simple manipulation, environmental benignancy, inexpensive reagents and higher yields, comparing to corresponding batch reaction.
The structures of all intermediates and products were confirmed by 1H NMR and MS. After optimization of reaction parameters with several experiments, the optimized reaction conditions for synthesis of panobinostat and benzimidazolyl sulfides were obtained.
引文
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[3]Esteller M. Cancer epigenomics:DNA methylomes and histonemodification maps[J]. Nat. Rev. Genet.2007,8:286-298.
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[5]Atadja P. Development of the pan-DAC inhibitor panobinostat (LBH589):successes and challenges[J]. Cancer. Letters.2009,280:233-241.
[6]檀琼,刘全海.组蛋白去乙酰酶抑制剂的研究进展[J].世界临床药物,2010,31(10)：616-620.
[7]王楠,阎征,刘娜.组蛋白去乙酰酶抑制剂的药理学研究进展[J].中国新药杂志,2004,13(7)：594-598.
[8]Bali P, Pranpat M, Bradner J. et al. Inhibition of histone deacetylase 6 acetylates and disrupts the chaperone function of heat shock protein 90:a novel basis for antileukemia activity of histone deacetylase inhibitors [J]. J. Biol. Chem.2005,280:26729-26734.
[9]Nakagawa M, Oda Y, Eguchi T. et al. Expression profile of class I histone deacetylases in human cancer tissues [J]. Oncol. Rep.2007,18:769-774.
[10]Glozak MA, Seto E. Histone deacetylases and cancer[J]. Oncogene.2007, (26):5420-5432.
[11]Kramer OH, Gottlicher M, Heinzel T. Histone deacetylase as a therapeutic target[J]. Trends. Endocrinol. Metab.2001,12(7):294-300.
[12]储卫华,冯华.组蛋白去乙酰基酶抑制剂抗肿瘤作用的研究进展[J].中国肿瘤临床与康复,2007,15(2)：186-188.
[13]Sasakawa Y, Naoe Y, Noto T. et al. Antitumor efficacy of FK228, a novel histone deacetylase inhibitor, depends on the effect on expression of angiogenesis factors[J]. Biochem. Pharmacol.2003,66(6):897-906.
[14]焦杰,徐文方.新型抗肿瘤药组蛋白脱乙酰基酶抑制剂的临床研究进展[J].中国新药与临床杂志,2009,28(3)：161-166.
[15]Null.抗癌药Panobinostat[J].药学进展,2007,31(9)：430.
[16]Novartis. Novartis phase Ⅱ LBH589 data show substantial disease control and tumor reduction in extensively pretreated Hodgkin lymphoma patients[EB/OL]. [2010-12-06]. http://www.novartis.com/newsroom/media-releases/en/2010/1469475.shtml.
[17]刘倩,江健安,冀亚飞.帕比司他的合成[J].中国医药工业杂志,2011,42(10)：725-727.
[18]Revill P, Mealy N, Serradell N, et al. Panobinostat:histone deacetylase (HDAC) inhibitor apoptosis inducer oncolytic[J]. Drugs. Future.2007,32(4):315-322.
[19]George P, Bali P, Annavarapu S. et al. Combination of the histone deacetylaase inhibitor LBH589 and hsp90 inhibitor 17-AAG is highly avtive against human CML-BC cells and AML cells with activating mutation of FLT-3[J]. Blood.2005,105(4):1768-1776.
[20]Maiso P, Carvajal VX, Ocio EM. et al. The histone deacetylase inhibitor LBH589 is a potent antimyeloma agent that overcomes drug resistance[J]. Cancer. Res.2006,66(11): 5781-5790.
[21]LaBonte MJ, Wilson PM, Fazzone W. et al. The effects of histone deacetylase inhibitors on epidermal growth factor receptor expression in colon cancer cell lines:Implications for combination therapy[J]. Proc. Am. Assoc. Cancer Res.2007,48:683.
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