Cabozantinib (1, Scheme 1) marketed as CometriqR is a small molecule inhibitor of the tyrosine kinases c-Met and VEGFR2. It was developed by Exelixis Inc. and was approved by the U.S. FDA in 2012 for medullary thyroid cancer and advanced renal cell carcinoma in people who have received prior anti-angiogenic therapy. Two synthetic routes of cabozantinib have been developed so far. With regard to preparation of the key intermediate 6,7-dimethoxyquinolin-4-ol (6), there are two kinds of approaches, as shown in Scheme 1. A common route to prepare 6 is based on Gould-Jacobs methodology, in which the Meldrum's acid derivative 4 is heated with Dowtherm A at > 230 C for several hours to give 6. This method is short, but the main problem is that the high reaction temperature leads to a complex and tedious procedure. Dowtherm A is a high boiling solvent which is difficult to recover, is harmful to the environment and may cause allergic reactions in workers, an effect which we have seen in our own experience. Alternatively, 1-(2-aminophenyl)ethan-1-one 5 reacts with ethyl formate under strong alkaline conditions to give the intermediate 6 in 55% yield. Generally, MeONa or BuONa and anhydrous solvents are used in the reaction. We consider the overall yield to be unsatisfactory. 4-Chloro-6,7-dimethoxyquinoline (7) was then reacted successively with 4-aminophenol (8) and 1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carbonyl chloride (10) to give the final product cabozantinib (1) in about 60% over-all yield from compound 6. We developed a new and practical synthetic route, as shown in Scheme 2. A reduction cyclization process was adopted to prepare the key 6,7-dimethoxyquinolin-4-ol (6) from 1-(4,5-dimethoxy-2-nitrophenyl)-3-(dimethylamino) prop-2-en-1-one (13). Commercially available 1-(3,4-dimethoxyphenyl)ethan-1-one (11) was nitrated in HOAc/HNO3 to give 1-(4,5-dimethoxy-2-nitrophenyl)ethan-1-one (12) in 86% isolated yield. Compound 12 was then reacted with N,N-dimethylformamide dimethyl acetal (DMF-DMA) in toluene to obtain 13 in 79% yield. Through nucleophilic substitution

中文翻译：

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卡博替尼的新合成

卡博替尼（1，方案 1）作为 CometriqR 销售，是酪氨酸激酶 c-Met 和 VEGFR2 的小分子抑制剂。它由 Exelixis Inc. 开发，并于 2012 年被美国 FDA 批准用于先前接受过抗血管生成治疗的甲状腺髓样癌和晚期肾细胞癌。迄今为止，已经开发了两种卡博替尼的合成路线。关于关键中间体6,7-二甲氧基喹啉-4-醇(6)的制备，有两种途径，如Scheme 1所示。制备6的常用途径是基于Gould-Jacobs方法，其中Meldrum的酸衍生物4与Dowtherm A在> 230°C下加热数小时得到6。该方法很短，但主要问题是反应温度高导致过程复杂和乏味。Dowtherm A 是一种高沸点溶剂，难以回收，对环境有害，并可能引起工人过敏反应，我们在自己的经验中已经看到了这种影响。或者，1-(2-氨基苯基)ethan-1-one 5 在强碱性条件下与甲酸乙酯反应，以 55% 的产率得到中间体 6。通常，反应中使用MeONa或BuONa和无水溶剂。我们认为整体收益并不理想。然后将 4-氯-6,7-二甲氧基喹啉 (7) 依次与 4-氨基苯酚 (8) 和 1-((4-氟苯基) 氨基甲酰基) 环丙烷-1-碳酰氯 (10) 反应，得到最终产物卡博替尼 ( 1) 化合物6的总收率约为60%。我们开发了一条实用的新合成路线，如Scheme 2所示。采用还原环化工艺制备关键6，7-二甲氧基喹啉-4-醇 (6) 来自 1-(4,5-二甲氧基-2-硝基苯基)-3-(二甲氨基) prop-2-en-1-one (13)。市售的 1-(3,4-二甲氧基苯基)ethan-1-one (11) 在 HOAc/HNO3 中硝化得到 1-(4,5-二甲氧基-2-硝基苯基)ethan-1-one (12) 在 86 % 分离产率。然后将化合物 12 与 N,N-二甲基甲酰胺二甲基乙缩醛 (DMF-DMA) 在甲苯中反应，以 79% 的产率获得 13。通过亲核取代