抗癌药Lenvatinib的合成

  本文关键词：抗癌药Lenvatinib的合成，由笔耕文化传播整理发布。

        甲状腺癌是一种常见的内分泌腺恶性肿瘤。2013年，在美国约有60220甲状腺癌患者，其中1850例患者发生死亡。绝大多数(93%)甲状腺癌为分化型甲状腺癌(DTC)，其中包括乳头甲状腺癌(PTC)和滤泡样甲状腺癌(FTC)。另外甲状腺髓样癌(MTC)和未分化甲状腺癌(ATC)约分别占4%和2%。甲状腺癌多数是无症状的，一般是例行检查中偶然发现的，但只有5%的结节是恶性的。然而，约有3-15%的甲状腺癌患者伴随有远处的转移，另外有6-20%的患者在随访期间发现有远处转移。最常见的是转移到肺和骨骼中，但在诸如脑和皮肤的区域也会发现。据估计，被确诊的甲状腺癌病人前两年的花费可能会超过95000美元。一般情况下，分化型甲状腺癌的预后良好，10年内约有85%的疾病相关生存率。标准的治疗方法包括手术切除、促甲状腺激素疗法(TSH)和放射性碘消融法(RAI)。然而，对于不适合手术切除、RAI或者体外放疗的甲状腺癌患者的治疗仍是一种挑战，常规的化疗的效果一直都不理想。靶向分子药物的治疗的出现为这类患者带来了新的希望。Lenvatinib是由日本卫材公司发现和开发，2012年8月在日本被授予孤儿药(ODD)治疗甲状腺癌。Lenvatinib是一种口服的多酪氨酸激酶抑制剂，靶向的作用于血管内皮生长因子受体(VEGFR)1-3、成纤维细胞生长因子受体(FGFR)1-3、干细胞生长因子受体和β型的血小板衍生的生长因子受体(PDGFR)。Lenvatinib的临床Ⅰ期和Ⅱ期实验证明了其抗肿瘤的活性，并且其毒性是可以接受的。目前正在评估Lenvatinib对各种实体肿瘤的治疗效果，其中包括对放射性碘不能治疗的分化型甲状腺癌的Ⅲ期临床实验。Ⅲ期的临床实验表明Lenvatinib能增加甲状腺癌患者的生存率，与安慰剂的对照中，Lenvatinib在治疗放射性碘难治疗的甲状腺癌(RR-DTC)患者时,无进展生存时间(PFS)有显著的改善。初步的安全性表明，Lenvatinib五个比较常见的不良分别为高血压、腹泻、食欲下降、体重下降和恶心。基于这些临床结果，卫材将向日本、美国和欧洲卫生部门提交上市许可申请。如果获得批准，Lenvatinib将是由日本制药公司开发的第一个小分子靶向制剂。Lenvatinib的化学名：4-[3-氯-4-(环丙基氨基甲酰胺基)苯氧基]-7-甲氧基喹啉-6-甲酰胺目的：建立Lenvatinib的合成以及对Lenvatinib进行分析方法：Lenvatinib可由关键中间体7-甲氧基-4-氯-喹啉-6-甲酰胺(8)和1-(2-氯-4羟基苯基)-3-环丙基脲(12)反应得到。8的合成可以2-甲氧基-4-氨基苯甲酸甲酯(4)为原料，先与米氏酸(3)反应制得4-[(2,2-二甲基-4,6-二氧代-1,3-二恶唑烷-5-亚甲基)甲基氨基]-2-甲氧基苯甲酸甲酯(5)，5在二苯醚介导的高温条件下经环合得到7-甲氧基-4-氧代-1,4-二氢喹啉-6-羧酸甲酯(6),6经氯化亚砜氯代得到4-氯-7-甲氧基喹啉-6-羧酸甲酯(7)，7经过一步酯的氨解得到4-氯-7甲氧基喹啉-6-甲酰胺(8)。12的合成可以邻氯硝基苯(9)为原料，先与锌粉还原到邻氯苯羟胺，在酸性条件下转位得到4-氨基-3-氯苯酚(10),10与氯甲酸苯酯在碱性条件下反应制得N-(2-氯-4-羟基苯基)氨基甲酸苯酯(11)，11与环丙胺反应得到1-(2-氯-4-羟基苯基)-3-环丙基脲(12)。8和12在碱性条件下DMF做溶剂加热反应得到目标化合物Lenvatinib，通过熔点、质谱、红外、核磁等手段对各中间体和目标化合物进行鉴定，通过高效液相色谱法对目标物进行纯度测定。结果：成功合成了目标物Lenvatinib，性状为白色粉末，总收率为28%，mp.228~230℃，纯度99.8%。结论：本论文以2-甲氧基-4-氨基苯甲酸甲酯为原料，经过8步反应成功合成了目标化合物Lenvatinib。该法采用了价廉易得的原料，同时大大降低了原路线关键步骤的耗能、耗时，缩短了生产周期，，且反应条件温和，各步产品易于纯化。

    Thyroid cancer is the most common endocrine malignancy. In2013, therewas about60,220Americans diagnosed with thyroid cancer, and the diseaseaccounted for approximately1850deaths. The vast majority (93%) of thyroidcancers are considered differentiated thyroid cancers (DTC), which includepapillary thyroid carcinoma (PTC), follictalar thyroid carcinoma (FTC)subtypes. A substantially smaller proportion of thyroid cancers aremedullary(MTC) or anaplastic (ATC) thyroid cancers at4%and2%respectively. Thyroid cancer is usually asymptomatic and is often discoveredincidentally during a routine examination; only5%of nodules are malignant.Nevertheless,3–15%of thyroid cancer patients present with distant metastases,and another6–20%develop distant metastases during follow-up. Metastasesare most common in the lungs and bones, yet can also be found in areas suchas the brain and skin. Among patients with newly diagnosed metastatic thyroidcancer, it is estimated that healthcare costs can exceed$95,000per patient inthe two years after diagnosis alone. In general, the prognosis of patients withdifferentiated thyroid cancer is good, with a10-year disease-related survival of85%. Standard treatment usually includes primary surgery, thyroid-stimulatinghormone (TSH) suppressive therapy, and ablation of the thyroid remnant withradioactive iodine (RAI). Nonetheless, patients unsuitable for surgery, RAI, orexternal beam radiotherapy present a treatment challenge. Historically, theirresponses to conventional chemotherapy have been disappointing. Thedevelopment of molecular targeted therapy brings new hopes for thesepatients.Lenvatinib, discovered and developed by Eisai, was granted Orphan DrugDesignation (ODD) in Japan for thyroid cancer in August2012. Lenvatinib isan oral multi-tyrosine kinase inhibitor that targets vascular endothelial growthfactor receptors (VEGFR)1-3, fibroblas growth factor receptors (FGFR)1-3, RET, mast/stem cell growth factor receptor kit (SCFR), and platelet-derivedgrowth factor receptor (PDGFR) beta. Eisai’s lenvatinib increases survival inPhase Ⅲ study of thyroid cancer paients. Compared to placebo, lenvatinibshowed a highly statistically significant improvement in progression freesurvival (PFS) in patients with radioiodine-refractory differentiated thyroidcancer (RR-DTC). The preliminary safety analysis showed that the five mostcommon adverse reactions were hypertension, diarrhea appetite, decreasedweight and nausea. Based on these clinical results, Eisai will submit marketingauthorization application for lenvatinib to health authorities in Japan, the USand Europe. If approved, lenvatinib will be the first molecular-targeted smallmolecular agent developed by a Japanses pharmaceutical company.Lenvatinib:4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxy-quinoline-6-carboxamide.Objective: Establish the preparation and analysis method for Lenvatinib.Methods: Lenvatinib can be synthesized by the key intermediate:7-methoxy-4-chloro-quinoline-6-formamide(8) and1-(2-chloro-4-hydroxyphenyl)-3-cyclopropyl urea(12). With2-methoxy methyl-4-aminobenzoicacid(4) as raw material, by reaction with mie acid(3),4-[(2,2-dimethyl-1,3-dioxane-4,6-dione-5-methylene)methylamineo]-2-methoxybenzoate wasobtained (5). Under the high temperature condition and mediated by diphenyloxide,7-methoxy-4-oxygen generation-1,4-dihydro quinoline-6-carboxylicacid methyl ester(6) can be synthesized by cyclization.4-chlorine-7-methoxyquinoline-6-carboxylic acid methylester(7) was obtained on based of(6) bychlorinated with sulfoxide chloride chlorine.4-chloro-7-methoxyquinoline-6-formamide (8) can be obtained after futher ammonolysis of (7).With o-Chloronitrobenzene(9) as raw materials, reducting with zinc powder toobtained the Chlorobenzene hydroxylamine at first, under acid conditionChlorobenzene hydroxylamine turn into4-amino-3-chlorophenol(10),10reacting with chlorine formate benzene ester under alkaline conditionsobtained N-(2-chloro-4-hydroxy phenyl) phenyl carbamate(11),11reactingwith Cyclopropylamine to get1-(2-chloro-4-hydroxy phenyl)-3-cyclopropyl urea(12). Under the heating and alkaline condition of DMF, the target productsLenvatinib can be synthesized by8and12. The structure of intermediates andtarget products was confirmed by melting point, mass spectrum, infrared,nuclear magnetic. High performance liquid chromatography (HPLC) methodused for the purity determination of the target.Results: The targate compound Lenvatinib was successfully prepared, asa white powder with a total yield of28%, mp.228~230℃,99.8%.Conclusion: In this paper, Lenvatinib was successfully synthesized fromthe raw material2–Methoxy-4-amino-benzoic acid methylester through8steps.The method uses a more inexpensive and readily available raw materials,while significantly reducing the energy consumption of the original route ofthe key steps, time-consuming, shortening the generation cycle, and the mildreaction conditions, each step easily purified products.

抗癌药Lenvatinib的合成

中文摘要4-6ABSTRACT6-8前言9-10材料与方法10-21结果21-25附图25-39讨论39-41结论41参考文献41-43综述 抗甲状腺癌的研究进展43-55    参考文献51-55致谢55-56个人简历56

  本文关键词：抗癌药Lenvatinib的合成，由笔耕文化传播整理发布。