本文關鍵詞：抗癌藥Lenvatinib的合成，由筆耕文化傳播整理發(fā)布。

        甲狀腺癌是一種常見的內分泌腺惡性腫瘤。2013年，在美國約有60220甲狀腺癌患者，其中1850例患者發(fā)生死亡。絕大多數(shù)(93%)甲狀腺癌為分化型甲狀腺癌(DTC)，其中包括乳頭甲狀腺癌(PTC)和濾泡樣甲狀腺癌(FTC)。另外甲狀腺髓樣癌(MTC)和未分化甲狀腺癌(ATC)約分別占4%和2%。甲狀腺癌多數(shù)是無癥狀的，一般是例行檢查中偶然發(fā)現(xiàn)的，但只有5%的結節(jié)是惡性的。然而，約有3-15%的甲狀腺癌患者伴隨有遠處的轉移，另外有6-20%的患者在隨訪期間發(fā)現(xiàn)有遠處轉移。最常見的是轉移到肺和骨骼中，但在諸如腦和皮膚的區(qū)域也會發(fā)現(xiàn)。據(jù)估計，被確診的甲狀腺癌病人前兩年的花費可能會超過95000美元。一般情況下，分化型甲狀腺癌的預后良好，10年內約有85%的疾病相關生存率。標準的治療方法包括手術切除、促甲狀腺激素療法(TSH)和放射性碘消融法(RAI)。然而，對于不適合手術切除、RAI或者體外放療的甲狀腺癌患者的治療仍是一種挑戰(zhàn)，常規(guī)的化療的效果一直都不理想。靶向分子藥物的治療的出現(xiàn)為這類患者帶來了新的希望。Lenvatinib是由日本衛(wèi)材公司發(fā)現(xiàn)和開發(fā)，2012年8月在日本被授予孤兒藥(ODD)治療甲狀腺癌。Lenvatinib是一種口服的多酪氨酸激酶抑制劑，靶向的作用于血管內皮生長因子受體(VEGFR)1-3、成纖維細胞生長因子受體(FGFR)1-3、干細胞生長因子受體和β型的血小板衍生的生長因子受體(PDGFR)。Lenvatinib的臨床Ⅰ期和Ⅱ期實驗證明了其抗腫瘤的活性，并且其毒性是可以接受的。目前正在評估Lenvatinib對各種實體腫瘤的治療效果，其中包括對放射性碘不能治療的分化型甲狀腺癌的Ⅲ期臨床實驗。Ⅲ期的臨床實驗表明Lenvatinib能增加甲狀腺癌患者的生存率，與安慰劑的對照中，Lenvatinib在治療放射性碘難治療的甲狀腺癌(RR-DTC)患者時,無進展生存時間(PFS)有顯著的改善。初步的安全性表明，Lenvatinib五個比較常見的不良分別為高血壓、腹瀉、食欲下降、體重下降和惡心�；谶@些臨床結果，衛(wèi)材將向日本、美國和歐洲衛(wèi)生部門提交上市許可申請。如果獲得批準，Lenvatinib將是由日本制藥公司開發(fā)的第一個小分子靶向制劑。Lenvatinib的化學名：4-[3-氯-4-(環(huán)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的合成以及對Lenvatinib進行分析方法：Lenvatinib可由關鍵中間體7-甲氧基-4-氯-喹啉-6-甲酰胺(8)和1-(2-氯-4羥基苯基)-3-環(huán)丙基脲(12)反應得到。8的合成可以2-甲氧基-4-氨基苯甲酸甲酯(4)為原料，先與米氏酸(3)反應制得4-[(2,2-二甲基-4,6-二氧代-1,3-二惡唑烷-5-亞甲基)甲基氨基]-2-甲氧基苯甲酸甲酯(5)，5在二苯醚介導的高溫條件下經環(huán)合得到7-甲氧基-4-氧代-1,4-二氫喹啉-6-羧酸甲酯(6),6經氯化亞砜氯代得到4-氯-7-甲氧基喹啉-6-羧酸甲酯(7)，7經過一步酯的氨解得到4-氯-7甲氧基喹啉-6-甲酰胺(8)。12的合成可以鄰氯硝基苯(9)為原料，先與鋅粉還原到鄰氯苯羥胺，在酸性條件下轉位得到4-氨基-3-氯苯酚(10),10與氯甲酸苯酯在堿性條件下反應制得N-(2-氯-4-羥基苯基)氨基甲酸苯酯(11)，11與環(huán)丙胺反應得到1-(2-氯-4-羥基苯基)-3-環(huán)丙基脲(12)。8和12在堿性條件下DMF做溶劑加熱反應得到目標化合物Lenvatinib，通過熔點、質譜、紅外、核磁等手段對各中間體和目標化合物進行鑒定，通過高效液相色譜法對目標物進行純度測定。結果：成功合成了目標物Lenvatinib，性狀為白色粉末，總收率為28%，mp.228~230℃，純度99.8%。結論：本論文以2-甲氧基-4-氨基苯甲酸甲酯為原料，經過8步反應成功合成了目標化合物Lenvatinib。該法采用了價廉易得的原料，同時大大降低了原路線關鍵步驟的耗能、耗時，縮短了生產周期，，且反應條件溫和，各步產品易于純化。

    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.

抗癌藥Lenvatinib的合成

中文摘要4-6ABSTRACT6-8前言9-10材料與方法10-21結果21-25附圖25-39討論39-41結論41參考文獻41-43綜述 抗甲狀腺癌的研究進展43-55    參考文獻51-55致謝55-56個人簡歷56

  本文關鍵詞：抗癌藥Lenvatinib的合成，由筆耕文化傳播整理發(fā)布。