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

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1H NMR、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 = 2.6959(4) nm, b = 0.77245(13) nm, c = 1.6885(3) nm, α = 90? β = 109.320(2)? γ = 90? V = 3.3182(9) nm3, Z = 8, Dc = 1.455 Mg?m?3, μ = 0.23 mm?1, F(000) = 1504, R1 = 0.0579, wR2 = 0.1604。初步的生物活性测定实验表明，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HepG2和MCF-7细胞的抑制活性高于阳性对照样吉非替尼。

Abstract:

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-3-carbo-nitrile-tetrahydro[4,5]benzothieno[2,3-d]pyrimidine 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 according to the modified Gewald reaction with cyclohexanone, malononitrile and elemental sulfur as staring materials. The structures of these title compounds were confirmed by 1H NMR, IR, MS and elemental analysis. The crystal structure of compound IIIa was determined by single-crystal X-ray diffraction. The results show that this compound crystal belongs to monoclinic crystal system, space group C2/c with a = 2.6959(4) nm, b = 0.77245(13) nm, c = 1.6885(3) nm, α = 90? β = 109.320(2)? γ = 90? V = 3.3182(9) nm3, Z = 8, Dc = 1.455 Mg?m?3, μ = 0.23 mm?1, F(000) = 1504, R1 = 0.0579, wR2 = 0.1604. The preliminary bioassay results suggested that some of the title compounds exhibit good in vitro antitumor activity against HepG2 and MCF-7, especially the compounds IIIc, IIIf and IIIj exhibited higher inhibitory activity than the positive control gefitinib.