四氢苯并[4,5]噻吩并[2,3-d]嘧啶含氟衍生物的合成、晶体结构及抗肿瘤活性  

Synthesis,Crystal Structure and Antitumor Activity of Fluorinated Tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine Derivatives

作　　者：高慧[1] 付菊[1] 张磊[1,2] 杨平[1] 宋新建[1] 

机构地区：[1]湖北民族学院生物资源保护与利用湖北省重点实验室,湖北恩施445000 [2]常州大学石油化工学院,江苏常州213164

出　　处：《精细化工》2015年第8期895-900,共6页Fine Chemicals

基　　金：国家自然科学基金项目(21262012)~~

摘　　要：以环己酮、丙二腈和单质硫为起始原料,通过改良的Gewald反应合成2-氨基-3-氰基-4,5,6,7-四氢苯并[b]噻吩（Ⅰ）,再与三氟乙酸、三氯氧磷反应＂一锅法＂直接制得4-氯-2-三氟甲基-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶,然后与取代苄胺反应合成13个噻吩并[2,3-d]嘧啶类含氟衍生物,收率为69%~83%。目标化合物的结构经1HNMR、IR、MS和元素分析方法进行表征。并采用X射线单晶衍射测定化合物Ⅲa的晶体结构,结果表明,该化合物晶体属单斜晶系,空间群为C2/c,a=2.695 9（4）nm,b=0.772 45（13）nm,c=1.688 5（3）nm,α=90°,β=109.320（2）°,γ=90°,V=3.318 2（9）nm3,Z=8,Dc=1.455×106g·m-3,μ=0.23 mm-1,F（000）=1 504,R1=0.057 9,wR2=0.160 4。初步的生物活性实验表明,部分化合物表现出良好的抗肿瘤活性,其中化合物Ⅲc、Ⅲf和Ⅲj对Hep G2和MCF-7细胞的抑制活性高于阳性对照样吉非替尼。Thirteen fluorinated thieno [ 2,3-d ] pyrimidine derivatives were synthesized in the yields of 69 % - 83 % by the SNAr reaction of substituted benzylamines with 4-chloro-2-trifluoromethyl-5,6,7,8- tetrahydrobenzo [ 4,5 ] thieno [ 2,3-d ] pyridine, which was prepared directly from 2-amino-4,5,6,7- tetrahydrobenzo [ b ] thiophene-3-carbonitrile and trifluoroacetic acid （TFA） in the presence of phosphorous oxychloride via one-pot procedure. While 2-amino-4,5,6,7-tetrahydrobenzo [ b ] thiophene- 3-carbonitrile was first obtained through the modified Gewald reaction with cyclohexanone, malononitrile and elemental sulfur as raw materials. The structures of these title compounds were confirmed by 1HNMR,IR, MS and elemental analysis. The crystal structure of compound Ⅲ a was determined by single-crystal X-ray diffraction. The results show that this compound crystal belongs to monoclinic crystal system,the space group of which is C2/e,with a =2. 695 9（4） nm,b =0. 772 45（13） nm,c = 1. 688 5（3） nm,c =90° ,β = 109. 320（2）°,T =90°, V=3. 318 2（9） nm^3 ,Z =8 ,Dc = 1. 455 × 10^6 g · m^-3,μ =0. 23 mm^-1 ,F（000） = 1 504,R1 =0. 057 9,wR2 =0. 160 4. The preliminary bioassay results suggest that some of the title compounds exhibit good in vitro antitumor activity against HepG2 and MCF -7, and especially the compounds Ⅲ c, Ⅲ f and Ⅲ j exhibit higher inhibitory activity than thepositive control gefitinib.

关 键 词：噻吩并[2 3-d]嘧啶 含氟化合物 晶体结构 抗肿瘤活性 医药与日化原料 

分 类 号：R914.5[医药卫生—药物化学]