CN104530032A - 4-叔丁基-5-(1,2,4-三唑-1-基)-2-(2-羟基-3,5-二碘苄氨基)噻唑及其单晶结构 - Google Patents
4-叔丁基-5-(1,2,4-三唑-1-基)-2-(2-羟基-3,5-二碘苄氨基)噻唑及其单晶结构 Download PDFInfo
- Publication number
- CN104530032A CN104530032A CN201410474220.8A CN201410474220A CN104530032A CN 104530032 A CN104530032 A CN 104530032A CN 201410474220 A CN201410474220 A CN 201410474220A CN 104530032 A CN104530032 A CN 104530032A
- Authority
- CN
- China
- Prior art keywords
- thiazole
- triazol
- diiodo
- benzyl
- hydroxyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 239000013078 crystal Substances 0.000 title claims abstract description 41
- BRAFTHYEPFWOOU-UHFFFAOYSA-N 2-[[[4-tert-butyl-5-(1,2,4-triazol-1-yl)-1,3-thiazol-2-yl]amino]methyl]-4,6-diiodophenol Chemical compound C(C)(C)(C)C=1N=C(SC1N1N=CN=C1)NCC1=C(C(=CC(=C1)I)I)O BRAFTHYEPFWOOU-UHFFFAOYSA-N 0.000 title abstract description 7
- 206010008342 Cervix carcinoma Diseases 0.000 claims abstract description 4
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims abstract description 4
- 201000010881 cervical cancer Diseases 0.000 claims abstract description 4
- 239000003814 drug Substances 0.000 claims abstract description 3
- 150000003839 salts Chemical class 0.000 claims abstract description 3
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 47
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 41
- 229910052739 hydrogen Inorganic materials 0.000 claims description 16
- 239000001257 hydrogen Substances 0.000 claims description 16
- 238000002360 preparation method Methods 0.000 claims description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 5
- -1 2-hydroxyl-3,5-diiodo-benzyl Chemical group 0.000 claims description 4
- 238000002425 crystallisation Methods 0.000 claims description 4
- 230000008025 crystallization Effects 0.000 claims description 4
- 125000006850 spacer group Chemical group 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims 3
- 239000002798 polar solvent Substances 0.000 claims 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims 2
- 229940079593 drug Drugs 0.000 abstract 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 14
- 239000000523 sample Substances 0.000 description 6
- 230000000259 anti-tumor effect Effects 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- QGZCUOLOTMJILH-UHFFFAOYSA-N 2h-tetrazol-2-ium;bromide Chemical compound [Br-].C1=N[NH+]=NN1 QGZCUOLOTMJILH-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 108010019160 Pancreatin Proteins 0.000 description 2
- 239000012980 RPMI-1640 medium Substances 0.000 description 2
- 238000009825 accumulation Methods 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 229940041181 antineoplastic drug Drugs 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 239000006285 cell suspension Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000012937 correction Methods 0.000 description 2
- 238000002447 crystallographic data Methods 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 229940055695 pancreatin Drugs 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 150000003536 tetrazoles Chemical class 0.000 description 2
- RPAJSBKBKSSMLJ-DFWYDOINSA-N (2s)-2-aminopentanedioic acid;hydrochloride Chemical compound Cl.OC(=O)[C@@H](N)CCC(O)=O RPAJSBKBKSSMLJ-DFWYDOINSA-N 0.000 description 1
- RAIPHJJURHTUIC-UHFFFAOYSA-N 1,3-thiazol-2-amine Chemical compound NC1=NC=CS1 RAIPHJJURHTUIC-UHFFFAOYSA-N 0.000 description 1
- KJUGUADJHNHALS-UHFFFAOYSA-N 1H-tetrazole Substances C=1N=NNN=1 KJUGUADJHNHALS-UHFFFAOYSA-N 0.000 description 1
- DPSSUCFPNCLVKU-UHFFFAOYSA-N 2-benzyl-4-tert-butyl-1-imino-5-(1,2,4-triazol-1-yl)-1,3-thiazole Chemical compound C(C)(C)(C)C=1N=C(S(C=1N1N=CN=C1)=N)CC1=CC=CC=C1 DPSSUCFPNCLVKU-UHFFFAOYSA-N 0.000 description 1
- AZKSAVLVSZKNRD-UHFFFAOYSA-M 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide Chemical compound [Br-].S1C(C)=C(C)N=C1[N+]1=NC(C=2C=CC=CC=2)=NN1C1=CC=CC=C1 AZKSAVLVSZKNRD-UHFFFAOYSA-M 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 102000018832 Cytochromes Human genes 0.000 description 1
- 108010052832 Cytochromes Proteins 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000005260 alpha ray Effects 0.000 description 1
- 229950003476 aminothiazole Drugs 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 244000309466 calf Species 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 208000019065 cervical carcinoma Diseases 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004737 colorimetric analysis Methods 0.000 description 1
- LBJNMUFDOHXDFG-UHFFFAOYSA-N copper;hydrate Chemical group O.[Cu].[Cu] LBJNMUFDOHXDFG-UHFFFAOYSA-N 0.000 description 1
- 238000005336 cracking Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 229910002804 graphite Inorganic materials 0.000 description 1
- 239000010439 graphite Substances 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 230000035806 respiratory chain Effects 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 description 1
- 229910021642 ultra pure water Inorganic materials 0.000 description 1
- 239000012498 ultrapure water Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
本发明公开了4-叔丁基-5-(1,2,4-三唑-1-基)-2-(2-羟基-3,5-二碘苄氨基)噻唑:4-叔丁基-5-(1,2,4-三唑-1-基)-2-(2-羟基-3,5-二碘苄氨基)噻唑的晶体结构,其分子结构如附图所示。其单晶体属单斜晶系,空间群为P21/c,晶胞参数为: a = 7.91944(19) ?, b = 10.5250(3) ?, c = 24.4985(6) ?; Z =4, V =2041.66(9)?3, Dc =1.949 Mg/m3, F (000) =1152, μ =3.203 mm-1,3490个可观测点 [ I >2σ( I )],可观测点精修最终偏离因子 R = 0.0283, wR = 0.0592,(Δ/ σ )max =0.001, S = 1.12,( ? ρ )max = 0.569 e/?3,( ? ρ )min = – 0.916 e/?3。4-叔丁基-5-(1,2,4-三唑-1-基)-2-(2-羟基-3,5-二碘苄氨基)噻唑或其盐在制备抗人宫颈癌细胞药物中应用。
Description
技术领域
本发明涉及新化合物4-叔丁基-5-(1,2,4-三唑-1-基)-2-(2-羟基-3,5-二碘苄氨基)噻唑及其制备方法与单晶结构。
背景技术
胡艾希等[ZL200910043920.0,2011.3.16授权;ZL 200910226728.5,2011.5.18授权;ZL201010533798.8,2013.4.24授权;ZL201210528020.7,2014.7.23授权]描述了4-叔丁基-5-(1,2,4-三唑-1-基)-2-苄亚氨基噻唑、4-叔丁基-5-(1,2,4-三唑-1-基)-2-芳氨基噻唑和N-[4-叔丁基-5-(1,2,4-三唑-1-基)噻唑-2-基]苯甲酰胺的制备与生物活性。
发明内容
本发明的目的在于提供了化学结构式Ⅰ所示的4-叔丁基-5-(1,2,4-三唑-1-基)-2-(2-羟基-3,5-二碘苄氨基)噻唑:
Ⅰ
本发明的目的在于提供的4-叔丁基-5-(1,2,4-三唑-1-基)-2-(2-羟基-3,5-二碘苄氨基)噻唑的制备方法,其特征在于它的制备反应如下:
。
本发明的目的在于提供的4-叔丁基-5-(1,2,4-三唑-1-基)-2-(2-羟基-3,5-二碘苄氨基)噻唑或其盐在制备抗人宫颈癌细胞药物中应用。
本发明的目的在于提供了4-叔丁基-5-(1,2,4-三唑-1-基)-2-(2-羟基-3,5-二碘苄氨基)噻唑的单晶结构;原子编号如下:
其特征在于4-叔丁基-5-(1,2,4-三唑-1-基)-2-(2-羟基-3,5-二碘苄氨基)噻唑晶体属单斜晶系,空间群为P21/c,晶胞参数为:a = 7.91944(19) ?,b = 10.5250(3) ?,c = 24.4985(6) ?;Z=4,V=2041.66(9) ?3,D c =1.949 Mg/m3,F(000) =1152,μ=3.203 mm-1,3490个可观测点 [I>2σ(I)],可观测点精修最终偏离因子R = 0.0283,wR = 0.0592,(Δ/σ)max =0.001,S = 1.12,(?ρ)max = 0.569 e/?3,(?ρ)min = – 0.916 e/?3。
本发明的目的在于提供了4-叔丁基-5-(1,2,4-三唑-1-基)-2-(2-羟基-3,5-二碘苄氨基)噻唑的单晶体,其中含一分子结晶水,4-叔丁基-5-(1,2,4-三唑-1-基)-2-(2-羟基-3,5-二碘苄氨基)噻唑分子与水分子间存在3种分子间氢键:N—H…O氢键、O—H…O氢键和O—H…N分子间氢键。
本发明的目的在于提供了4-叔丁基-5-(1,2,4-三唑-1-基)-2-(2-羟基-3,5-二碘苄氨基)噻唑的单晶体,其特征在于单晶结构中在分子内形成了八元环的氢键:
。
本发明与现有技术相比具有如下优点:
(1)首次制得4-叔丁基-5-(1,2,4-三唑-1-基)-2-(2-羟基-3,5-二碘苄氨基)噻唑新化合物;4-叔丁基-5-(1,2,4-三唑-1-基)-2-(2-羟基-3,5-二碘苄氨基)噻唑较5-(1,2,4-三唑-1-基)-2-(2-羟基-3,5-二碘苄亚氨基)噻唑稳定;
(2)在作为抗肿瘤药物时,4-叔丁基-5-(1,2,4-三唑-1-基)-2-(2-羟基-3,5-二碘苄氨基)噻唑较5-(1,2,4-三唑-1-基)-2-(2-羟基-3,5-二碘苄亚氨基)噻唑的活性高。
附图说明
图 1 是4-叔丁基-5-(1,2,4-三唑-1-基)-2-(2-羟基-3,5-二碘苄氨基)噻唑晶体的分子结构。
图 2是4-叔丁基-5-(1,2,4-三唑-1-基)-2-(2-羟基-3,5-二碘苄氨基)噻唑晶体的氢键图。
图 3是4-叔丁基-5-(1,2,4-三唑-1-基)-2-(2-羟基-3,5-二碘苄氨基)噻唑晶体的晶体堆积图。
具体实施方式
以下实施例旨在说明本发明而不是对本发明的进一步限定。
实施例 1
4-叔丁基-5-(1,2,4-三唑-1-基)-2-(2-羟基-3,5-二碘苄氨基)噻唑的制备
1.16 g(2 mmol)4-叔丁基-5-(1,2,4-三唑-1-基)-2-(2-羟基-3,5-二碘苄亚氨基)噻唑[其制备方法见中国发明专利ZL200910043920.0]、20 mL乙醇,0.07 g(2 mmol)硼氢化钠,反应15 min,盐酸调节pH=6-7,倒入100 mL水中,固体析出,抽滤,干燥得到1.03 g白色固体4-叔丁基-5-(1,2,4-三唑-1-基)-2-(2-羟基-3,5-二碘苄氨基)噻唑,收率89%,m.p. 178~180℃;1H NMR (CDCl3,400 MHz) δ:1.21(d,J = 3.8 Hz,9H,3×CH3),4.48(s,2H,NCH2),7.46(s,1H,C2N3H2 3-H),7.98(s,1H,C2N3H2 5-H),8.09(d,J = 6.0 Hz,1H,C6H2 4-H),8.23(d,J = 6.0 Hz,1H,C6H2 6-H)。
实施例 2
4-叔丁基-5-(1,2,4-三唑-1-基)-2-(2-羟基-3,5-二碘苄氨基)噻唑的抗肿瘤活性
1. 抗肿瘤活性原理
MTT法生物活性测试又称MTT比色法,是一种检测细胞存活和生长的方法。MTT分析法以活细胞代谢物还原剂噻唑蓝[3-(4,5-二甲基-2-噻唑)-2,5-二苯基溴化四氮唑; 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide,MTT]为基础。MTT为黄色化合物,是一种接受氢离子的染料,可作用于活细胞线粒体中的呼吸链,在琥珀酸脱氢酶和细胞色素C的作用下四氮唑环(tetrazolium)开裂,生成蓝色水不溶性的甲瓒(Formazan)结晶并沉积在细胞中,甲瓒结晶的生成量仅与活细胞数目成正比(死细胞中琥珀酸脱氢酶消失,不能将MTT还原)。二甲基亚砜(DMSO)能溶解细胞中的甲瓒,用酶联免疫检测仪在570 nm波长处测定其光吸收值,可间接反映活细胞数量。在一定细胞数范围内,MTT结晶形成的量与细胞数成正比。
2. 抗肿瘤活性实验
试 样: 4-叔丁基-5-(1,2,4-三唑-1-基)-2-(2-羟基-3,5-二碘苄氨基)噻唑:
细胞系:宫颈癌细胞系Hela(中南大学湘雅医学院细胞库提供)。
试 剂:噻唑蓝(MTT)、RPMI 1640培养液、新生牛血清、抗生素(美国英杰生命技术公司);胰酶(美国AMRESCO公司);96孔培养板(美国英杰生命技术公司);二甲基亚砜(美国Sigma公司)。
仪 器:HFsafe-1500型超净工作台、HF151UV型CO2培养箱(上海力申科学仪器有限公司);XSP-15C型倒置显微镜(上海长方光学仪器有限公司);Multiskan MK3型酶标仪(美国Thermo公司);超纯水制备仪(美国Milli-Q公司)。
实验操作:试样对于hela细胞的测试。细胞的实验操作过程相同,一次实验过程中,每种试样设置5个浓度梯度,每个浓度四个平行试样,并通过空白组对照得出结论。
1)倒掉长满癌细胞的培养瓶中的培养基,加入5 mL PBS清洗,倒掉PBS,加入1 mL胰酶,放入37℃、5%CO2培养箱。
2)取出培养瓶,加入RPMI 1640培养基,用吸管反复吸打吹散细胞。
3)细胞悬液接种于96孔培养板,第1孔不加细胞悬液,其余每板100 μL(约10000个细胞),放入37℃、5%CO2培养箱中培养中48小时。
4) 试样配置。用DMSO作为溶剂,配置浓度梯度为1.0 μmol/mL、0.3 μmol/mL、0.1 μmol/mL、0.03 μmol/mL、0.01 μmol/mL的溶液。
5) 吸取每孔内的悬浮液,加入试样,放入37℃、5%CO2培养箱中培养中48小时。每组实验平行3次。
6) 取出上药48小时的96孔培养板,吸出每孔培养液,每孔120μL PBS清洗一次,加入每孔20μL 5 mg/mLMTT液,放入37℃、5%CO2培养箱中培养中3~4小时。
7) 吸出孔内MTT后,加入每孔150 μL DMSO液(包括第1空),将培养板置于微孔板扳荡器上振荡,使结晶物溶解。
8) 酶标仪检测各孔OD值(检测波长570 nm)。
3. 抗肿瘤活性评价
1) 细胞抑制率计算:
细胞抑制率(%)=(正常OD值-加药OD值)/正常OD值 × 100%
2) IC50值计算
试样浓度对数值与细胞抑制率线性回归,计算试样对细胞的半数抑制浓度IC50值。 4-叔丁基-5-(1,2,4-三唑-1-基)-2-(2-羟基-3,5-二碘苄氨基)噻唑和5-(1,2,4-三唑-1-基)-2-(2-羟基-3,5-二碘苄亚氨基)噻唑对于hela细胞的IC50分别为0.026 mmol/L和0.073 mmol/L。
测试结果显示,被测试的4-叔丁基-5-(1,2,4-三唑-1-基)-2-(2-羟基-3,5-二碘苄氨基)噻唑对于人宫颈癌细胞(hela细胞)具有良好的抑制活性,可用于制备抗肿瘤药物。
实施例 3
4-叔丁基-5-(1,2,4-三唑-1-基)-2-(2-羟基-3,5-二碘苄氨基)噻唑的单晶体的制备
2 g 4-叔丁基-5-(1,2,4-三唑-1-基)-2-(2-羟基-3,5-二碘苄氨基)噻唑溶入20 mL乙醇或甲醇中,室温放置,缓慢挥发,10~12天后析出4-叔丁基-5-(1,2,4-三唑-1-基)-2-(2-羟基-3,5-二碘苄氨基)噻唑晶体,选取质量好的单晶体。
实施例 4
4-叔丁基-5-(1,2,4-三唑-1-基)-2-(2-羟基-3,5-二碘苄氨基)噻唑的单晶体的制备
2 g 4-叔丁基-5-(1,2,4-三唑-1-基)-2-(2-羟基-3,5-二碘苄氨基)噻唑溶入20 mL丙酮中,室温放置,缓慢挥发,9~10天后析出4-叔丁基-5-(1,2,4-三唑-1-基)-2-(2-羟基-3,5-二碘苄氨基)噻唑晶体,选取质量好的单晶体。
实施例 5
4-叔丁基-5-(1,2,4-三唑-1-基)-2-(2-羟基-3,5-二碘苄氨基)噻唑的单晶结构
(1)X-射线结构测定
选取 0.41 mm×0.29 mm×0.18 mm单晶体,在BRUKER SMART APEX 1000 CCD 衍射仪上收集衍射数据,利用石墨单色器单色化了的Mo Kα 射线 (λ = 0.71073 ?),在152 K下以ω-φ扫描方式收集衍射数据,在2.69° ≤2θ ≤26.00°范围收集 10238个数据,其中独立衍射点4007个,可观测点3490个。然后运用 Bruker 的 SAINTPLUS 程序将数据还原,同时运用 SADABS 程序进行经验吸收校正。应用SHELXS-97 和 SHELXL-97 程序[Sheldrick,G. M. SHELXS97 and SHELXL97, University of G?ttingen, Germany, 1997] 直接法解析和精修结构。所有的非氢原子采用全矩阵最小二乘法进行结构精修。所有非氢原子都做各向异性精修。理论加氢,氢原子各向同性热参数修正。晶体数据与结构参数列入表 1。
表 1 4-叔丁基-5-(1,2,4-三唑-1-基)-2-(2-羟基-3,5-二碘苄氨基)噻唑的晶体数据与结构参数
(2)4-叔丁基-5-(1,2,4-三唑-1-基)-2-(2-羟基-3,5-二碘苄氨基)噻唑的晶体结构
4-叔丁基-5-(1,2,4-三唑-1-基)-2-(2-羟基-3,5-二碘苄氨基)噻唑的非氢原子坐标和热参数列于表 2,部分键长、键角和氢键列于表 3、表 4 和表 5。
表 2 4-叔丁基-5-(1,2,4-三唑-1-基)-2-(2-羟基-3,5-二碘苄氨基)噻唑晶体的原子坐标(×104 )和热参数(×103 ? 2)
Atom | x | y | z | U eq |
C(1) | 3889(5) | 8672(4) | 1438(2) | 24(1) |
C(2) | 4910(5) | 8263(4) | 676(2) | 20(1) |
C(3) | 6076(4) | 6132(3) | 923(1) | 16(1) |
C(4) | 7712(4) | 5766(3) | 912(1) | 14(1) |
C(5) | 9311(4) | 6552(3) | 980(1) | 17(1) |
C(6) | 10232(5) | 6155(4) | 1508(1) | 26(1) |
C(7) | 10448(5) | 6311(4) | 491(1) | 21(1) |
C(8) | 8950(5) | 7967(4) | 1011(2) | 29(1) |
C(9) | 6439(4) | 3884(3) | 778(1) | 16(1) |
C(10) | 7596(5) | 1725(3) | 705(1) | 17(1) |
C(11) | 8441(4) | 1533(3) | 1259(1) | 15(1) |
C(12) | 9959(4) | 2146(3) | 1391(1) | 14(1) |
C(13) | 10817(4) | 1829(3) | 1873(1) | 15(1) |
C(14) | 10151(5) | 957(3) | 2238(1) | 18(1) |
C(15) | 8607(4) | 400(3) | 2115(1) | 14(1) |
C(16) | 7752(4) | 679(3) | 1633(1) | 16(1) |
I(1) | 13175(1) | 2648(1) | 2048(1) | 23(1) |
I(2) | 7617(1) | -963(1) | 2643(1) | 22(1) |
N(1) | 4033(4) | 9149(3) | 921(1) | 23(1) |
N(2) | 4619(4) | 7586(3) | 1522(1) | 22(1) |
N(3) | 5298(4) | 7320(3) | 1022(1) | 16(1) |
N(4) | 7906(3) | 4466(3) | 827(1) | 13(1) |
N(5) | 6224(4) | 2640(3) | 696(1) | 18(1) |
O(1) | 10645(3) | 3003(2) | 1044(1) | 17(1) |
O(2) | 3032(3) | 1511(3) | 452(1) | 23(1) |
S(1) | 4689(1) | 4857(1) | 830(1) | 20(1) |
表 3 4-叔丁基-5-(1,2,4-三唑-1-基)-2-(2-羟基-3,5-二碘苄氨基)噻唑晶体的部分键长 (?)
Bond | Dist. | Bond | Dist. | Bond | Dist. |
C(1)-N(2) | 1.296(5) | C(5)-C(7) | 1.532(5) | C(13)-I(1) | 2.094(3) |
C(1)-N(1) | 1.370(5) | C(9)-N(4) | 1.317(4) | C(14)-C(15) | 1.385(5) |
C(1)-H(1) | 0.9500 | C(9)-N(5) | 1.335(5) | C(14)-H(14) | 0.9500 |
C(2)-N(1) | 1.314(5) | C(9)-S(1) | 1.730(4) | C(15)-C(16) | 1.382(5) |
C(2)-N(3) | 1.338(4) | C(10)-N(5) | 1.452(5) | C(15)-I(2) | 2.094(3) |
C(2)-H(2) | 0.9500 | C(10)-C(11) | 1.517(4) | C(16)-H(16) | 0.9500 |
C(3)-C(4) | 1.353(5) | C(10)-H(10A) | 0.9900 | N(2)-N(3) | 1.375(4) |
C(3)-N(3) | 1.417(5) | C(10)-H(10B) | 0.9900 | N(5)-H(5) | 0.80(4) |
C(3)-S(1) | 1.747(4) | C(11)-C(12) | 1.398(5) | O(1)-H(1A) | 0.83(4) |
C(4)-N(4) | 1.393(4) | C(11)-C(16) | 1.400(5) | O(2)-H(2A) | 0.77(4) |
C(4)-C(5) | 1.519(5) | C(12)-O(1) | 1.360(4) | O(2)-H(2B) | 0.812(10) |
C(5)-C(8) | 1.518(5) | C(12)-C(13) | 1.391(4) | ||
C(5)-C(6) | 1.531(5) | C(13)-C(14) | 1.392(5) |
表 4 4-叔丁基-5-(1,2,4-三唑-1-基)-2-(2-羟基-3,5-二碘苄氨基)噻唑晶体的部分键角(°)
Angle | (°) | Angle | (°) | Angle | (°) |
N(2)-C(1)-N(1) | 115.2(3) | N(4)-C(9)-S(1) | 115.1(3) | C(13)-C(14)-H(14) | 120.5 |
N(2)-C(1)-H(1) | 122.4 | N(5)-C(9)-S(1) | 119.4(3) | C(16)-C(15)-C(14) | 120.9(3) |
N(1)-C(1)-H(1) | 122.4 | N(5)-C(10)-C(11) | 114.8(3) | C(16)-C(15)-I(2) | 119.4(3) |
N(1)-C(2)-N(3) | 110.8(3) | N(5)-C(10)-H(10A) | 108.6 | C(14)-C(15)-I(2) | 119.7(2) |
N(1)-C(2)-H(2) | 124.6 | C(11)-C(10)-H(10A) | 108.6 | C(15)-C(16)-C(11) | 120.3(3) |
N(3)-C(2)-H(2) | 124.6 | N(5)-C(10)-H(10B) | 108.6 | C(15)-C(16)-H(16) | 119.9 |
C(4)-C(3)-N(3) | 132.4(3) | C(11)-C(10)-H(10B) | 108.6 | C(11)-C(16)-H(16) | 119.9 |
C(4)-C(3)-S(1) | 112.3(3) | H(10A)-C(10)-H(10B) | 107.5 | C(2)-N(1)-C(1) | 102.4(3) |
N(3)-C(3)-S(1) | 115.2(3) | C(12)-C(11)-C(16) | 119.3(3) | C(1)-N(2)-N(3) | 102.6(3) |
C(3)-C(4)-N(4) | 113.0(3) | C(12)-C(11)-C(10) | 120.6(3) | C(2)-N(3)-N(2) | 108.9(3) |
C(3)-C(4)-C(5) | 129.8(3) | C(16)-C(11)-C(10) | 120.0(3) | C(2)-N(3)-C(3) | 129.9(3) |
N(4)-C(4)-C(5) | 117.2(3) | O(1)-C(12)-C(13) | 119.7(3) | N(2)-N(3)-C(3) | 120.7(3) |
C(8)-C(5)-C(4) | 112.5(3) | O(1)-C(12)-C(11) | 120.9(3) | C(9)-N(4)-C(4) | 111.8(3) |
C(8)-C(5)-C(6) | 108.2(3) | C(13)-C(12)-C(11) | 119.4(3) | C(9)-N(5)-C(10) | 123.7(3) |
C(4)-C(5)-C(6) | 109.1(3) | C(12)-C(13)-C(14) | 121.2(3) | C(9)-N(5)-H(5) | 120(3) |
C(8)-C(5)-C(7) | 108.4(3) | C(12)-C(13)-I(1) | 119.7(3) | C(10)-N(5)-H(5) | 115(3) |
C(4)-C(5)-C(7) | 109.0(3) | C(14)-C(13)-I(1) | 119.1(2) | C(12)-O(1)-H(1A) | 102(3) |
C(6)-C(5)-C(7) | 109.7(3) | C(15)-C(14)-C(13) | 118.9(3) | H(2A)-O(2)-H(2B) | 112(4) |
N(4)-C(9)-N(5) | 125.5(3) | C(15)-C(14)-H(14) | 120.5 | C(9)-S(1)-C(3) | 87.77(17) |
表 5 4-叔丁基-5-(1,2,4-三唑-1-基)-2-(2-羟基-3,5-二碘苄氨基)噻唑晶体的氢键[?和°]
D—H...A | d(D—H) | d(H...A) | d(D...A) | ∠(DHA) |
O(2) —H(2B)...N(1)#1 | 0.812(10) | 2.069(18) | 2.844(4) | 160(4) |
O(2) —H(2A)...O(1)#2 | 0.77(4) | 2.10(4) | 2.871(4) | 173(4) |
O(1) —H(1A)...N(4) | 0.83(4) | 1.89(4) | 2.705(4) | 170(4) |
N(5) —H(5)...O(2) | 0.80(4) | 2.08(4) | 2.847(4) | 161(3) |
#1:x,y-1,z #2:x-1,y,z
4-叔丁基-5-(1,2,4-三唑-1-基)-2-(2-羟基-3,5-二碘苄氨基)噻唑晶体的分子结构如图1所示;氢键图如图2所示;晶胞堆积图如图3所示。
4-叔丁基-5-(1,2,4-三唑-1-基)-2-(2-羟基-3,5-二碘苄氨基)噻唑晶体属单斜晶系,空间群为P21/c。晶胞参数为:a = 7.91944(19) ?,b = 10.5250(3) ?,c = 24.4985(6) ?;Z=4,V=2041.66(9) ?3,D c =1.949 Mg/m3,F(000) =1152,μ=3.203 mm-1,3490个可观测点 [I>2σ(I)],可观测点精修最终偏离因子R = 0.0283,wR = 0.0592,(Δ/σ)max =0.001,S = 1.12,(?ρ)max = 0.569 e/?3,(?ρ)min = – 0.916 e/?3。
在4-叔丁基-5-(1,2,4-三唑-1-基)-2-(2-羟基-3,5-二碘苄氨基)噻唑晶体中,含一个结晶水,目标分子与1分子通过N—H…O、O—H…O和O—H…N分子间氢键作用结合,形成稳定的分子结构。
在4-叔丁基-5-(1,2,4-三唑-1-基)-2-(2-羟基-3,5-二碘苄氨基)噻唑晶体中存在八元环的分子内氢键:
Claims (7)
1.化学结构式Ⅰ所示的4-叔丁基-5-(1,2,4-三唑-1-基)-2-(2-羟基-3,5-二碘苄氨基)噻唑:
Ⅰ。
2.权利要求1所述的4-叔丁基-5-(1,2,4-三唑-1-基)-2-(2-羟基-3,5-二碘苄氨基)噻唑的制备方法,其特征在于它的制备反应如下:
。
3.权利要求1所述的4-叔丁基-5-(1,2,4-三唑-1-基)-2-(2-羟基-3,5-二碘苄氨基)噻唑或其盐在制备抗人宫颈癌细胞药物中应用。
4.权利要求1所述的4-叔丁基-5-(1,2,4-三唑-1-基)-2-(2-羟基-3,5-二碘苄氨基)噻唑的单晶体,其特征在于单晶体属单斜晶系,空间群为P21/c,晶胞参数为:a = 7.91944(19) ?,b = 10.5250(3) ?,c = 24.4985(6) ?;Z=4,V=2041.66(9)?3,D c =1.949 Mg/m3,F(000) =1152,μ=3.203 mm-1,3490个可观测点 [I>2σ(I)],可观测点精修最终偏离因子R = 0.0283,wR = 0.0592,(Δ/σ)max =0.001,S = 1.12,(?ρ)max = 0.569 e/?3,(?ρ)min = – 0.916 e/?3。
5.权利要求4所述的单晶体,其中含一分子结晶水,4-叔丁基-5-(1,2,4-三唑-1-基)-2-(2-羟基-3,5-二碘苄氨基)噻唑分子与水分子存在3种分子间氢键:N—H…O氢键、O—H…O氢键和O—H…N分子间氢键。
6.权利要求4所述的单晶体,其特征在于单晶结构中在分子内形成了八元环的氢键:
。
7.权利要求4所述的单晶体的制备方法,其特征在于4-叔丁基-5-(1,2,4-三唑-1-基)-2-(2-羟基-3,5-二碘苄氨基)噻唑在极性溶剂中缓慢结晶得到;极性溶剂是甲醇、乙醇、丙酮、四氢呋喃或乙酸乙酯中的一种或几种。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201410474220.8A CN104530032B (zh) | 2014-09-17 | 2014-09-17 | 4-叔丁基-5-(1,2,4-三唑-1-基)-2-(2-羟基-3,5-二碘苄氨基)噻唑及其单晶结构 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201410474220.8A CN104530032B (zh) | 2014-09-17 | 2014-09-17 | 4-叔丁基-5-(1,2,4-三唑-1-基)-2-(2-羟基-3,5-二碘苄氨基)噻唑及其单晶结构 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN104530032A true CN104530032A (zh) | 2015-04-22 |
CN104530032B CN104530032B (zh) | 2016-10-05 |
Family
ID=52845703
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201410474220.8A Expired - Fee Related CN104530032B (zh) | 2014-09-17 | 2014-09-17 | 4-叔丁基-5-(1,2,4-三唑-1-基)-2-(2-羟基-3,5-二碘苄氨基)噻唑及其单晶结构 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN104530032B (zh) |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101836979B (zh) * | 2009-12-25 | 2011-05-18 | 湖南大学 | 4-叔丁基-5-(1,2,4-三唑-1-基)-2-苄亚氨基噻唑的医药用途 |
CN103705511B (zh) * | 2014-01-14 | 2015-07-08 | 长沙理工大学 | N-[5-(1,2,4-三唑-1-基)噻唑-2-基]脂肪酰胺的医药用途 |
CN103830233B (zh) * | 2014-02-26 | 2016-08-17 | 长沙理工大学 | 5-(1,2,4-三唑-1-基)-2-苯乙酰氨基噻唑的医药用途 |
CN105440029B (zh) * | 2014-09-02 | 2018-05-22 | 湖南大学 | 5-(1,2,4-三唑-1-基)-2-苄氨基噻唑衍生物及其作为抗肿瘤药物的应用 |
-
2014
- 2014-09-17 CN CN201410474220.8A patent/CN104530032B/zh not_active Expired - Fee Related
Also Published As
Publication number | Publication date |
---|---|
CN104530032B (zh) | 2016-10-05 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN101845026B (zh) | 5-(4-氯苯甲基)-4-叔丁基噻唑衍生物及其制备方法与应用 | |
CN101805333B (zh) | 环丙鱼藤酮及其制备方法与应用 | |
CN101836979B (zh) | 4-叔丁基-5-(1,2,4-三唑-1-基)-2-苄亚氨基噻唑的医药用途 | |
CN104059092B (zh) | 一种苯并咪唑锌配合物及其制备方法 | |
CN102887892B (zh) | 4-叔丁基-2-(2-氟苯氨基)-5-(1,2,4-三唑-1-基)噻唑晶体 | |
CN104370892B (zh) | 1-(7-甲氧基苯并呋喃-5-基)-3-(2-甲氧基苯基)-2-(1,2,4-三唑-1-基)丙烯醇 | |
CN104530032A (zh) | 4-叔丁基-5-(1,2,4-三唑-1-基)-2-(2-羟基-3,5-二碘苄氨基)噻唑及其单晶结构 | |
CN104370893B (zh) | 1‑(7‑丙氧基苯并呋喃‑5‑基)‑3‑(2‑氯苯基)‑2‑(1,2,4‑三唑‑1‑基)丙烯酮 | |
CN106467498A (zh) | N-(噻唑-2-基)氨基酰胺衍生物及其制备方法与应用 | |
CN103214467B (zh) | 5-[[4-[(2,3-二甲基-2h-吲唑-6-基)甲氨基]-2嘧啶基]氨基]-2-甲基-苯磺酰胺衍生物及其制备方法与应用 | |
CN109666047B (zh) | 一种钌荧光探针及其制备方法、应用和应用产物 | |
CN105440029A (zh) | 5-(1,2,4-三唑-1-基)-2-苄氨基噻唑衍生物及其作为抗肿瘤药物的应用 | |
CN104876924A (zh) | 3-[5-(1,2,4-三唑-1-基)噻唑-2-基]苯并噁嗪酮及其制备方法与应用 | |
CN109627210B (zh) | 一种镓荧光探针及其制备方法、应用和应用产物 | |
CN101654459A (zh) | 吡咯[2,1-b]噻唑类化合物及其制备方法和抗肿瘤应用 | |
CN104387373B (zh) | 1‑(7‑丙氧基苯并呋喃‑5‑基)‑3‑(2‑甲氧基苯基)‑2‑(1,2,4‑三唑‑1‑基)丙烯酮 | |
CN106188034A (zh) | 5‑(3,4‑亚甲二氧基苄基)‑4‑叔丁基‑n‑(2‑甲基喹啉‑8‑基)噻唑‑2‑胺 | |
CN102516313B (zh) | 具有抗癌活性及双光子生物显影功能的类顺铂配合物及其制备方法 | |
Li et al. | Treatment effect of Co (II)-coordination polymers on postpartum depression by regulating 5-HT content | |
Wang et al. | Design, Synthesis, and Anti-Fungal Evaluation of Heterocyclic Benzoxazole Derivatives | |
Qin et al. | Identification of Photocatalytic Alkaloids from Coptidis Rhizome by an Offline HPLC/CC/SCD Approach | |
CN109796505B (zh) | 一种具抗肿瘤活性的酰胺类化合物的制备方法与应用 | |
CN102552274A (zh) | 动点马达蛋白小分子抑制剂在抑制肿瘤细胞增殖中的应用 | |
CN111138475B (zh) | 一种三(2-甲基-2-苯基丙基)锡3-甲基苯并呋喃甲酸酯配合物及其制备方法与应用 | |
CN102924356A (zh) | 2-取代苯甲醛缩肼基硫代甲酸苄酯席夫碱锌、镍配合物的制备方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20161005 Termination date: 20170917 |
|
CF01 | Termination of patent right due to non-payment of annual fee |