拉帕替尼类似物的合成及抗肿瘤活性研究

以N'-(2-氰基-4-碘苯基)-N,N-二甲基甲脒为原料,经过Dimroth重排反应、Suzuki偶联、还原氨化3步反应合成了4种新型的拉帕替尼类似物。借助NMR、IR和HRMS对反应中间体和目标化合物进行结构表征,并采用MTT法在SW480、A549和A431人肿瘤细胞上进行了这些化合物抗肿瘤活性的初步体外评价。结果表明,以上4种化合物均具有明显的抑制肿瘤细胞生长作用,特别是化合物5a对所试肿瘤细胞均表现出良好的生长抑制活性(IC50:5.78~13.38μmol/L),与临床使用的抗肿瘤药物拉帕替尼的活性(IC50:4.80~14.90μmol/L)相当。     

Pd-PAN催化制备拉帕替尼中间体的研究

本文以N-(3-氯-4-((3-氟苯基)甲氧基)苯基)-6-碘喹唑啉-4-胺为起始原料,经自制聚苯胺负载钯催化剂(Pd-PAN)催化Suzuki偶联反应制备N-(3-氯-4-(3-氟苄氧基)苯基)-6-((5-甲酰基)呋喃-2-基)-4-喹唑啉胺。对Pd-PAN的结构和理化性能进行表征。通过正交实验确定最佳反应条件:80℃下,催化剂与底物质量比为1∶40,乙醇溶剂体系进行Suzuki偶联反应。Pd-PAN回收使用5次,产物的转化率保持在85%以上。以此中间体合成拉帕替尼,通过熔点测定、HPLC、质谱、~1H-NMR对终产物进行了结构确证。本工艺操作简单,产品质量稳定,适于工业扩大生产。     

厄洛替尼关键中间体的合成

间硝基苯甲醛与四溴化碳经Wittig反应、脱溴制得间硝基苯乙炔,经锌粉还原制得抗肿瘤药厄洛替尼关键中间体间氨基苯乙炔,总收率达69%以上。     

伊马替尼的合成及其中间体工艺优化

以3-乙酰基吡啶为起始原料,经环合、缩合、还原、酰胺化等六步反应制得抗肿瘤药物伊马替尼,并对其中间体N-(2-甲基-5-硝基苯基)-4-(3-吡啶基)嘧啶-2-胺的后处理工艺进行了优化,降低了成本和操作难度,有利于工业化。     

乐伐替尼的合成

以4-氨基-2-甲氧基苯甲酸甲酯为原料,与米氏酸、原甲酸三甲酯发生缩合得到4-[(2,2-二甲基-4,6-二氧代-1,3-二噁烷-5-亚甲基)氨基]-2-甲氧基苯甲酸甲酯(4),随后经环合、氯代、氨化反应生成4-氯-7-甲氧基喹啉-6-甲酰胺(7)。7与3-氯-4-氨基苯酚盐酸盐反应制得4-(4-氨基-3-氯苯氧基)-7-甲氧基喹啉-6-甲酰胺(8),最后与氯甲酸苯酯、环丙胺经一锅反应制得乐伐替尼。目标产物结构经核磁、质谱分析得到确证,总收率约34%(以4-氨基-2-甲氧基苯甲酸甲酯计)。改进后的工艺操作简单,降低了原料成本,且各步反应收率较高。     

靶向RET抑制剂塞尔帕替尼的合成进展

塞尔帕替尼是一种高选择性转染过程中重排(RET)受体酪氨酸激酶抑制剂,由Loxo Oncology公司研发于2020年5月在美国获批上市用于治疗RET融合阳性非小细胞肺癌、RET融合阳性甲状腺癌和RET突变甲状腺髓样癌。本文综述了目前报道的有关塞尔帕替尼的合成方法研究进展,并讨论了各方法的特点,以期对其工业化生产提供参考。     

抗肿瘤药物仑伐替尼合成研究进展

综述了仑伐替尼及其相关主要中间体的合成方法。首先对仑伐替尼逆合成分析,并着重讨论了喹啉环(原料1)以及终产物仑伐替尼的合成。原料1有四种合成方法,对这四种合成方法进行了详细对比与分析,指出第二种合成方法为最佳合成方法。总结了仑伐替尼最常用的两条合成路线并分析优缺点,第一条路线是汇聚式路线,反应时间短、能耗少、成本低、收率高,相比第二条路线更加适合工业化生产。     

吉非替尼的合成工艺改进

以3-羟基-4-甲氧基苯甲醛为原料,先与N-(3-氯丙基)吗啉缩合,后依次经过醛基转化为氰基、硝化、还原、与3-氯-4-氟苯胺环合等反应合成了抗肿瘤药物吉非替尼,总收率约50%。其结构经1H NMR,MS和元素分析表征。     

伊马替尼衍生物的合成及细胞毒活性研究

以3-乙酰基嘧啶、2-甲基-5-硝基苯胺为起始原料,经加成、缩合、环化、还原得到中间体伊马替胺(6),再与异氰酸酯和芳酰基异硫氰酸酯胺解得到脲类(7a~7e)和芳酰基硫脲类(8a~8g)共12个化合物。目标化合物经过IR、1H NMR、13C NMR、HRMS等结构确证。采用四甲基偶氮唑盐(MTT)法考察目标化合物细胞毒活性,结果显示,目标化合物对所选肿瘤细胞的增殖活性具有一定抑制作用,其中化合物7d、7e、8d对人白血病细胞(K562)和人肝癌细胞(Hep G2)的抑制活性接近伊马替尼。     

阿法替尼的合成工艺改进

以2-氨基-4-氯苯甲酸为原料,经环合、硝化、氯代和胺化后,采用一锅两步法制得关键中间体4-［(3-氯-4-氟苯基)氨基］-6-硝基-7-［(S)-四氢呋喃-3-基氧基]-喹唑啉(4); 4依次经还原、酰胺化、HWE反应合成阿法替尼,总收率55.7%,含量98%,其结构经¹H NMR和LC-MS确证。     

Synthesis and Structural Characterization of Some New Magnesium Formamidinates

[Mg(Form)₂(THF)] [Form = bis(2,6‐dimethylphenyl)formamidinate (XylForm) ( 1 ), bis(2,6‐diethylphenyl)formamidinate, (EtForm) ( 2 ), bis(2,6‐diisopropylphenyl)formamidinate (DippForm) ( 3 )] are conveniently synthesized by treating bis(2,6‐dimethylphenyl)formamidine, bis(2,6‐diethylphenyl)formamidine, or bis(2,6‐diisopropylphenyl)formamidine, respectively, with half an equivalent of dibutylmagnesium in THF. Compounds 1 – 3 are mononuclear species in the solid state with five coordinate central metal atoms. The ¹H NMR chemical shift of the formamidinate formyl proton exhibits a correlation with ligand sterics wherein increasing bulk leads to a shift to higher field.     

Synthesis of a novel magnetic nanocatalyst based on rhodium complex for transfer hydrogenation of ketone

A magnetic heterogeneous nanocatalyst based on novel rhodium complex is designed. The transfer hydrogenation of ketones with 2‐propanol as hydrogen donor and the rhodium complex as nanocatalyst was achieved. High yields of ketones under mild conditions were obtained from easily available precursors.     

酶解沉积放射性肿瘤药物前体的合成研究

放射性药物治疗肿瘤必须满足两个条件：一是肿瘤组织在短时间内对该药物有足够高的选择性摄取;二是放射性标记物进入肿瘤后有较好的体内稳定性,使放射性药物能充分的杀伤肿瘤细胞。     

考尼伐坦关键中间体的合成

合成考尼伐坦关键中间体2-甲基-6-(4-甲基苯磺酰基)-1,4,5,6-四氢咪唑[4,5-d][1]苯并氮杂卓并对其工艺优化。以氨茴酸甲酯为起始原料,经保护、烃化、环合、脱羧、溴化、烃化并缩合共六步反应合成考尼伐坦关键中间体。所得的目标化合物经核磁共振氢谱、质谱确认,总收率达49.06%。该关键中间体合成方法和工艺改进后,所用原料价格便宜、反应条件温和、反应周期缩短、产率提高,更加适合于工业化生产。     

一维链状配位聚合物[(C6H5)3SnO]n的合成和结构研究

在甲醇溶剂中利用(C6H5)3SnCl和三乙胺水解得到一种新型有机锡聚合物[(C6H5)3SnO]n。用元素分析、IR及X-射线衍射法表征配合物。晶体结构用直接法解出,并用全矩阵最小二乘法进行修正。该晶体属于正交晶系,空间群为P212121,晶胞参数为:a=0.8339(15)nm,b=1.040(2)nm,c=1.8067(4)nm,Z=4,V=1.5668(5)nm3,Mr=365.99,Dc=1.552g/cm3,mμ=1.623mm-1,F(000)=724,S=1.065,R=0.0278,wR=0.0511配合物的中心锡原子呈五配位畸变三角双锥构型。     

Synthesis of the Complex Fluoride LiBaF_3 through a Solvothermal Process

The complex fluoride LiBaF3 is solvothermally synthesized at 180℃ and characterized by means of X-ray powder diffraction, scanning electron microscopy, thermogravimetric analysis and infrared spectroscopy. In the solvothermal process, the solvents, mole ratios of initial mixtures and reaction temperature play important roles in the growth of the single crystal.     

Synthesis and crystal structure of a novel two-dimensional network complex [Mn(O_2CCH_2Cl)_2(phen)]_n

A novel two-dimensional network manganese(Ⅱ) polymer complex [Mn(O2CCH2CI)2-(phen)]n has been synthesized and characterized by elemental analysis and IR spectrum. The crystal structure of title complex has also been determined, which is in monoclinic of a space group P21/c with the following unit cell parameters at 294K: a =1.9738(4) nm, b =1.1384(2) nm, c =0.74915(14) nm, V=1.6795(5) nm3, Z= 2.     

Synthesis of sulfonamides promoted by alkyl iodide via a hypervalent iodine intermediate

Abstract

A new method for the preparation of sulfonamides from sodium sulfinates and amines is developed. A stoichiometric amount of m-chloroperbenzoic acid as oxidant and a catalytic amount of 1-iodopropane provides the corresponding sulfonamides in good yields under mild reaction conditions. In this protocol, 1-iodopropane is first oxidized by m-chloroperbenzoic acid into the corresponding hypervalent iodine intermediate iodosylpropane, which is highly unstable and decomposes at once to form hypoiodous acid. Then, the following reaction of the generated active hypoiodous acid with sodium sulfinates and amines results in the corresponding sulfonamides.     

Synthesis and Structure of a New Dinuclear Uranyl Complex

Dinuclear complexes have been widely investigated since 1970s when Robson proposed the conception of dinucleating ligand1,2. These compounds attracted much interests because of their applications as metal-enzemy model in bioinorganic chemistry or promising applications as functional materials. Most of these dinuclear complexes contain d transition metals as central ions. Few dinuclear U complexes have been reported. It is known, in most complexes of axial ion, five donors from ligands shou…