KRAS^(G12C)共价抑制剂ARS-1620的合成工艺研究

Study on the Synthetic Process of KRAS^(G12C) Covalent Inhibitor ARS-1620

本研究改进了抗肿瘤药物ARS-1620的合成工艺。以N-(3-溴-2-氟苯基)-2(羟基亚氨基)乙酰胺(2)为起始原料,经桑德迈尔靛红合成法、碱性水解开环、氯代、环合、氯代,叔丁氧羰基哌嗪取代得到重要中间体4-(7-溴-6-氯-8-氟喹唑啉-4-基)哌嗪-1-羧酸叔丁酯(9);以2-氟-6-甲氧基苯硼酸(I)为原料经脱甲基化反应合成中间体2-氟-6-羟基苯硼酸(13);中间体7与13经Suzuki偶联反应、脱Boc保护基、酯水解、手性柱色谱分离得到目标化合物ARS-1620(1)。以N-(3-溴-2-氟苯基)-2(羟基亚氨基)乙酰胺计,ARS-1620合成总收率为33%,终产物HPLC纯度为98.8%(HPLC面积归一化法);目标物及关键中间体的结构经MS、^(1)H-NMR确证。该方法与原路线相比总收率较高,反应条件相对温和,后处理操作简便,适合大量制备,可为ARS-1620的生产及其衍生物的合成提供参考。

In this study,the synthesis process of ARS-1620 was improved.Tertbutyl 4-(7-bromo-6-chloro-8-fluoroquinazolin-4-yl)piperazine-1-carboxylate(9),an important intermediate,was synthesized from n-(3-bromo-2-fluorophenyl)-2(hydroxyimino)acetamide(2)via Sandmeyer's indigo synthesis,alkaline hydrolysis,ring opening,chlorination,cyclization,chlorination,and substitution of TERT butoxycarbonyl piperazine with_(2)-fluoro-6-methoxyphenylboric acid(I)by demethylation.The intermediate 2-fluoro-6-hydroxyphenylboronic acid(II)was synthesized.The target compound ARS-1620(1)was obtained by Suzuki coupling reaction between intermediate 7 and Ⅱ,deprotection of BOC,ester hydrolysis and chiral column chromatography.Based on N-(3-bromo-2-fluorophenyl)-2(hydroxyimino)acetamide,the total yield of ARS-1620 was 33%,and the purity of the final product was 98.8%(HPLC area normalization).The structures of the target compound and its key intermediates were confirmed by MS and 1H-NMR.The starting materials and 2-fluoro-6-methoxyphenylboronic acid used in this method are cheap and easy to obtain.The total yield is high.The reaction conditions are relatively mild and the post-treatment operation is simple.It is suitable for large-scale preparation.It can provide a theoretical reference for the production of ARS-1620 and the synthesis of its derivatives.