吉非替尼的合成研究

以3-羟基-4-甲氧基苯甲醛为起始原料合成了抗肿瘤药吉非替尼.先将3-羟基-4-甲氧基苯甲醛的醛基转化成氰基,再与N-(3-氯丙基)吗啉缩合,依次经硝化、还原、与DMF-DMA反应、与3-氯-4-氟苯胺反应合成得到吉非替尼,总收率约33%.     

吉非替尼的合成

以3-羟基-4-甲氧基苯甲醛为起始原料,经缩合,氰基化,硝化,还原,合环等七步反应制得4-(3-氯-4-氟苯胺基)-7-甲氧基-6-[3-(4-吗啉基)丙氧基]喹唑啉(吉非替尼,ZD1839),其结构经IR、1H-NMR、13C-NMR和MS确认,总收率31.81%。     

4-氯-7-甲氧基-6-（3-氯丙氧基）喹唑啉的合成

以3-羟基-4-甲氧基苯甲酸为初始原料,经过6步反应,合成了喹唑啉类酪氨酸激酶抑制剂Gefitinib及-系列衍生物的关键中间体4-氟-7-甲氧基-6-（3-氯丙氧基）喹唑啉,其中涉及到喹唑啉环的合成、羟基的合理保护等,反应总收率为44．56％;产物结构经HNMR确证。该方法反应条件温和,原料易得操作简便,适合于工业化生产。     

马来酸阿法替尼合成工艺研究

以7-氟-6-硝基-4-羟基喹唑啉(原料A)和(S)-3-羟基四氢呋喃为起始原料,经取代反应得到中间体(S)-6-硝基-7-((四氢-3-呋喃基)氧基)-4-喹唑啉酮.该中间体经铁粉还原后的中间体再依次与二乙基磷乙酸、二甲氨基乙醛缩二乙醇和3-氯-4-氟苯胺经发生缩合反应得到阿法替尼碱,所得阿法替尼碱与马来酸成盐得到马...     

N-（3-氯-4-（3-氟苯甲氧基）苯基）-6-碘喹唑啉-4-胺盐酸盐的合成

以2-氯-4-硝基苯酚为原料,经Williamson反应得3-氯-4-（3-氟苯甲氧基）硝基苯,硝基还原后与4-氯-6-碘喹唑啉缩合得到抗肿瘤药物拉帕替尼的重要中间体N-（3-氯-4-（3-氟苯甲氧基）苯基）-6-碘喹唑啉-4-胺盐酸盐,总收率约62％。中间体及目标产物结构经1HNMR和MS得以证实。     

波齐替尼合成工艺研究

本研究改进了表皮生长因子受体(EGFR)酪氨酸激酶抑制剂波齐替尼(Poziotinib,1)的合成工艺。以价廉易得的3,4-二氢-7-甲氧基-4-氧代喹唑啉-6-醇乙酸酯(5)为起始原料,经氯化、取代、酯水解反应得到中间体4-(3,4-二氯-2-氟苯氨基)-7-甲氧基喹唑啉-6-醇(14);化合物14与4-(甲苯-4-磺酰氧)哌啶-1-羧酸叔丁酯(11)经酯化、脱保护得中间体N-(3,4-二氯-2-氟苯基)-7-甲氧基-6-(哌啶-4-氧基)喹唑啉-4-胺(10);化合物10再与丙烯酰氯经酰化反应得到目标产物EGFR酪氨酸激酶抑制剂Poziotinib(1)。终产物HPLC纯度为99.46%(面积归一化法),以3,4-二氢-7-甲氧基-4-氧代喹唑啉-6-醇乙酸酯(5)计,总收率为43.2%。目标终产物及关键中间体的结构经HRMS和1H NMR确证。该方法与原研专利相比,缩短了合成路线,总收率较高,后处理简单,适合工业化生产,本研究可为Poziotinib(1)的生成及其衍生物的合成提供理论参考。     

拉帕替尼合成工艺的研究进展

拉帕替尼(Lapatinib)是一种口服的新型小分子表皮生长因子酪氨酸激酶抑制剂(TKIs),临床治疗Ⅱ型人表皮生长因子受体过度表达引起的晚期或转移性乳腺癌。本文回顾了近十年以来有关拉帕替尼生产及应用的文献及专利,介绍了拉帕替尼的主要工艺合成路线,系统阐述其3种关键中间体(包括3-氯-4-(3-氟苄氧基)苯胺(2)、N-(3-氯-4-(3-氟苄氧基)苯基)-6-碘喹唑啉-4-胺(3)和5-[4-[3-氯-4-[(3-氟苄氧基)苯基]氨基]-6-喹唑啉]-2-呋喃甲醛(4))和两种关键原料(苯并嘧啶和2-甲砜基乙胺盐酸盐)的合成工艺,研究了各种路线之间的异同与特点,比较各条路线的优劣,指出了各种关键中间体、原料和终产物拉帕替尼的最优合成工艺。     

凡德他尼重要中间体7-羟基-4-(4-溴-2-氟苯胺基)-6-甲氧基喹唑啉的合成

以4-羟基-3-甲氧基苯甲酸为起始原料,经过酯化、保护羟基、硝化、还原、环合、氯化、与4-溴-2-氟苯胺缩合、钯碳脱保护合成凡德他尼(Vandetanib)的重要中间体7-羟基-4-(4-溴-2-氟苯胺基)-6-甲氧基喹唑啉,总收率42.6%。     

微波促进下N-(3-氯-4-氟苯基)-7-氟-6-硝基-4-喹唑啉胺的合成

以2-溴-4-氟-5-硝基苯甲腈为原料,CuI为催化剂,在微波促进下与3-氯-4-氟苯胺进行加成反应后,再与甲酰胺发生串联的胺化和缩合环化反应合成抗癌药Afatinib(阿法替尼)和Dacomitinib(达克替尼)的关键中间体N-(3-氯-4-氟苯基)-7-氟-6-硝基-4-喹唑啉胺,并对反应条件进行了优化。结果表明:在Cu I用量为20%(以2-溴-4-氟-5-硝基苯甲腈的物质的量为基准,下同)和微波促进下,n(2-溴-4-氟-5-硝基苯甲腈):n(3-氯-4-氟苯胺)=1:1,回流反应20 min,制备得到2-溴-N-(3-氯-4-氟苯基)-4-氟-5-硝基苯甲脒,收率93.8%;在Cu I与4-羟基-L-脯氨酸用量均为10%〔以2-溴-N-(3-氯-4-氟苯基)-4-氟-5-硝基苯甲脒的物质的量为基准,下同〕和微波促进下,n〔2-溴-N-(3-氯-4-氟苯基)-4-氟-5-硝基苯甲脒〕:n(甲酰胺)=1:2,80℃反应10min,以96.4%的收率得到目标产物N-(3-氯-4-氟苯基)-7-氟-6-硝基-4-喹唑啉胺。     

抗肿瘤药乐伐替尼相关杂质的合成

为了控制乐伐替尼的质量,本文以4-氨基-3-氯苯酚为起始原料,经酰化、成脲得到中间体1-(2-氯-4羟基苯基)-3-环丙基脲(4),然后该中间体与4-氯-7-甲氧基喹啉-6-甲酰胺(5)发生亲核取代反应得到乐伐替尼的有关杂质4,4'-[4,4'-羰基双(脲二基)双(3-氯-4,1-次苯基)]双(氧)双(7-甲氧基喹啉-6-羧酰胺),该杂质为工艺杂质,其结构经核磁、质谱和元素分析确证。同时,对该杂质产生的原因及机理进行了分析,为今后乐伐替尼的工业化生产提供指导。     

含亚胺结构片段的喹唑啉酮衍生物的合成与抗肿瘤活性研究

设计并合成了一系列含亚胺结构片段的新型喹唑啉酮衍生物,最终的15个化合物结构经¹HNMR、¹³CNMR和HR-MS确证,并评价了它们对野生型表皮生长因子受体酪氨酸激酶(EGFR^wt)和两种人癌细胞株(A549、HepG2)的体外抗肿瘤活性。结果表明,部分化合物具有良好的活性,特别是化合物(E)-2-((4-((3,4-二氟亚苄基)氨基)苯氧基)甲基)-3-甲基喹唑啉-4(3 H)-酮对EGFR^wt激酶的IC₅₀达到0.037μmol/L,对A549和HepG2两种肿瘤细胞的IC₅₀值优于吉非替尼。     

Derivatives of Iressa, a specific epidermal growth factor receptor inhibitor, are powerful apoptosis inducers in PC3 prostatic cancer cells

The tyrosine kinase activity of the epidermal growth factor receptor (EGFR) is widely involved in signaling pathways and often deregulated in cancer. Its role in the development of prostate cancer is well established, and therapeutic strategies such as blockade of the intracellular tyrosine kinase domain with small-molecule tyrosine kinase inhibitors have been proposed. Herein we describe the synthesis and in vitro pharmacological properties of C6- and C7-substituted 4-anilinoquinazolines, analogues of Iressa and powerful proapoptotic inducers in hormone-independent prostate cancer PC3 cell lines.     

2-甲氧基-4'-三氟甲基苯乙酮的合成

以4-三氟甲基苯甲酸甲酯和甲氧基乙酸甲酯为原料,在碱性条件下进行交叉酯缩合反应,然后经水解、脱羧得到产品2-甲氧基-4′-三氟甲基苯乙酮,总收率达85％以上。实验获得了较佳工艺条件：原料配比4-三氟甲基苯甲酸甲酯／甲氧基乙酸甲酯为1／1．5(mol／mol),酯缩合的反应温度为30℃、反应时间为12h,适宜的溶剂为DMSO：水解、脱羧反应时间为15h;并采用^1HNMR及IR对产品进行了表征。     

Fluorine‐18 Radiolabeling and Radiopharmacological Characterization of a Benzodioxolylpyrimidine‐based Radiotracer Targeting the Receptor Tyrosine Kinase EphB4

Members of the Eph receptor tyrosine kinase family play essential roles in the pathogenesis of cancer and are therefore promising candidates for molecular imaging by positron emission tomography (PET), for example. In this regard, radiochemical access to novel PET radiotracers derived from potent inhibitors that target the EphB4 kinase domain and which bear a benzodioxolylpyrimidine structural motif was developed. A synthetic route was established for a new fluorine‐18‐containing radiotracer and for the desired precursor based on a high‐affinity benzodioxolylpyrimidine receptor tyrosine kinase inhibitor lead structure. The radiotracer [¹⁸F] 15 was obtained in 16 % radiochemical yield with a specific activity of ～7 GBq μmol^?1 and >95 % radiochemical purity. Due to the implication of EphB4, particularly in the progression, angiogenesis, and metastasis of melanoma, EphB4‐overexpressing human melanoma cells were generated and used as a novel in vitro model for radiopharmacological evaluation of the radiotracer. We demonstrate that the corresponding non‐radioactive reference compound regained its functionality as an inhibitor for both EphB4 receptor tyrosine kinase and Src kinase. EphB4 was significantly inhibited at compound concentrations >1 μM . Cellular uptake studies with [¹⁸F] 15 revealed substantial uptake in both EphB4‐overexpressing and control cells. Moreover, NMRI nu/nu mice bearing both EphB4‐overexpressing tumors and control tumors were used for radiopharmacological characterization by biodistribution studies ex vivo and by dynamic small‐animal PET experiments in vivo. Despite the high metabolic stability of the novel radiotracer observed in vivo, no substantial binding or accumulation in EphB4‐overexpressing and control tumors was observed. Nevertheless, we point out that the approach presented herein gives convenient access to novel ¹⁸F‐labeled benzodioxolylpyrimidines and is a promising strategy for the further development of novel radiotracers for imaging Eph receptor tyrosine kinases in cancer.     

Kinome Array Profiling of Patient-Derived Pancreatic Ductal Adenocarcinoma Identifies Differentially Active Protein Tyrosine Kinases

Pancreatic cancer remains one of the most difficult malignancies to treat. Minimal improvements in patient outcomes and persistently abysmal patient survival rates underscore the great need for new treatment strategies. Currently, there is intense interest in therapeutic strategies that target tyrosine protein kinases. Here, we employed kinome arrays and bioinformatic pipelines capable of identifying differentially active protein tyrosine kinases in different patient-derived pancreatic ductal adenocarcinoma (PDAC) cell lines and wild-type pancreatic tissue to investigate the unique kinomic networks of PDAC samples and posit novel target kinases for pancreatic cancer therapy. Consistent with previously described reports, the resultant peptide-based kinome array profiles identified increased protein tyrosine kinase activity in pancreatic cancer for the following kinases: epidermal growth factor receptor (EGFR), fms related receptor tyrosine kinase 4/vascular endothelial growth factor receptor 3 (FLT4/VEGFR-3), insulin receptor (INSR), ephrin receptor A2 (EPHA2), platelet derived growth factor receptor alpha (PDGFRA), SRC proto-oncogene kinase (SRC), and tyrosine kinase non receptor 2 (TNK2). Furthermore, this study identified increased activity for protein tyrosine kinases with limited prior evidence of differential activity in pancreatic cancer. These protein tyrosine kinases include B lymphoid kinase (BLK), Fyn-related kinase (FRK), Lck/Yes-related novel kinase (LYN), FYN proto-oncogene kinase (FYN), lymphocyte cell-specific kinase (LCK), tec protein kinase (TEC), hemopoietic cell kinase (HCK), ABL proto-oncogene 2 kinase (ABL2), discoidin domain receptor 1 kinase (DDR1), and ephrin receptor A8 kinase (EPHA8). Together, these results support the utility of peptide array kinomic analyses in the generation of potential candidate kinases for future pancreatic cancer therapeutic development.     

去甲基文拉法辛中间体的制备方法

以4-[2-氨基-1-(1-羟基环己基)乙基]苯酚为原料,经氨基保护、缩合、水解、甲基化得到去甲基文拉法辛中间体,总收率在64.8％,色谱纯度99.5％以上,操作简单,副产物少,适合工业化放大.     

2-正丁基-4-氯-5-甲酰基咪唑合成新工艺

以戊腈为原料,经加成、取代得到脒（2）,再与乙二醛缩合、脱一分子水得到眯唑啉酮化合物（3）,最后经氯代、氧化后得到2-正丁基-4-氯-5-甲酰基咪唑,收章40．5％。该工艺具有原料易得,反应条件温和,合成路线短,易于工业化生产等特点,是-条新的2-正丁基-4-氯-5-甲酰基咪唑（1）合成路线。     

4,4′-二甲氧基二苯甲酰甲烷的合成

以对羟基苯甲酸甲酯为原料,经醚化、克莱森酯缩合两步反应制得4,4’-二甲氧基二苯甲酰甲烷。采用4因素3水平正交实验优化醚化条件,单因素实验法考察克莱森酯缩合反应的各种影响因素,得到了较佳的工艺条件：以DMSO和THF为混合溶剂,NaH作催化剂,n（对甲氧基苯乙酮）∶n（对甲氧基苯甲酸甲酯）∶n（氢化钠）=1∶2∶4,反应温度30℃,反应时间90 min,收率达78.2%。应用IR与1H NMR光谱进行了结构表征。     

Dual Inhibition of EGFR and IGF-1R Signaling Leads to Enhanced Antitumor Efficacy against Esophageal Squamous Cancer

Both the epidermal growth factor receptor (EGFR) and insulin-like growth factor 1 receptor (IGF-1R) have been implicated in the development of cancers, and the increased expression of both receptors has been observed in esophageal cancer. However, the tyrosine kinase inhibitors of both receptors have thus far failed to provide clinical benefits for esophageal cancer patients. Studies have confirmed the complicated crosstalks that exist between the EGFR and IGF-1R pathways. The EGFR and IGF-1R signals act as mutual compensation pathways, thereby conveying resistance to EGFR or IGF-1R inhibitors when used alone. This study evaluated the antitumor efficacy of the EGFR/HER2 inhibitors, gefitinib and lapatinib, in combination with the IGF-1R inhibitor, linsitinib, on the esophageal squamous cell carcinoma (ESCC). Gefitinib or lapatinib, in combination with linsitinib, synergistically inhibited the proliferation, migration, and invasion of ESCC cells, caused significant cell cycle arrest, and induced marked cell apoptosis. Their combination demonstrated stronger inhibition on the activation of EGFR, HER2, and IGF-1R as well as the downstream signaling molecules. In vivo, the addition of linsitinib to gefitinib or lapatinib also potentiated the inhibition effects on the growth of xenografts. Our results suggest the next clinical exploration of the combination of gefitinib or lapatinib with linsitinib in the treatment of ESCC patients.