设计了一条新路线合成选择性组蛋白去乙酰化酶6(HDAC6) 抑制剂ricolinostat(ACY-1215，1)。以2,5- 二氯嘧啶(2)为起始原料，与二苯胺反应得5- 氯-N,N- 二苯基嘧啶-2- 胺(3)，与氰化锌发生偶联反应得2- 二苯胺基嘧啶-5- 甲腈(4)，在硫酸溶液中水解得2- 二苯胺基嘧啶-5- 羧酸( 5)，与7- 氨基庚酸甲酯缩合后，再与盐酸羟胺在氢氧化钠作用下氨解得目标化合物1，总收率19.8％ ( 以2 计)。本路线中化合物3 和4 为未见文献报道的新化合物。
Abstract
A novel synthetic process of selective histone deacetylase 6 (HDAC6) inhibitor ricolinostat (ACY-1215, 1) was reported. 2,5-Dichloropyrimidine (2) reacted with diphenylamine to give 5-chloro-N,N-diphenylpyrimidin-2-amine (3). Then the latter reacted with zinc cyanide via a coupling reaction to afford 2-(diphenylamino)pyrimidine-5-carbonitrile (4), after hydrolysis in the solution of sulfuric acid, the key intermediate 2-(diphenylamino)pyrimidine-5-carboxylic acid (5) was obtained. Then compound 5 was subjected to condensation with methyl 7-aminoheptanoate and ammonolysis with hydroxylamine hydrochloride to give the target compound 1 with an overall yield of 19.8％(based on 2).New compounds 3 and 4 have not yet been reported in literature.
关键词
组蛋白去乙酰化酶 6 抑制剂 /
ricolinostat(ACY-1215) /
偶联反应 /
氰基水解
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Key words
histone deacetylase 6 inhibitor /
ricolinostat (ACY-1215) /
coupling reaction /
cyano hydrolysis
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参考文献
[1] Santo L, Hideshima T, Kung AL, et al. Preclinical activity,pharmacodynamic, and pharmacokinetic properties of a selective HDAC6 inhibitor, ACY-1215, in combination with bortezomib in multiple myeloma [J]. Blood, 2012, 119(11):2579—2589.
[2] Wang N, Bartlow P, Ouyang Q, et al. Recent advances in antimultiple myeloma drug development [J]. Pharm Pat Anal, 2014, 3(3): 261—277.
[3] Raje N, Hari PN, Dan TV, et al. Rocilinostat(ACY-1215), a selective HDAC6 inhibitor, alone and in combination with bortezomib in multiple myeloma: preliminary results from the
first-in-humans phase Ⅰ/Ⅱ study [J]. ASH Annual Meeting Abstracts, 2012, 120(21): 4061—4061.
[4] Vogl DT, Raje N, Jagannath S, et al. Ricolinostat, the first selective histone deacetylase 6 inhibitor, in combination with bortezomib and dexamethasone for relapsed or refractory
multiple myeloma [J]. Clin Cancer Res, 2017, 23(13):3307—3315.
[5] Van Duzer JH, Mazitschek R, Ogier W, et al. Reverse amide compounds as protein deacetylase inhibitors and methods of use thereof: WO, 2011091213 [P]. 2011-07-28.
[6] Castro AC, Evans CA, Liu T, et al. Heterocyclic compounds and uses thereof: US, 2013053362 [P]. 2013-02-28.
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脚注
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基金
贵州省普通高等学校化学药物研发工程中心项目(黔教合KY字[2014] 219)、贵州省化学合成药物研发利用工程技术研究中心(黔科合[2016]平台人才5402)
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