| 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. |
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