化学合成。
医药中间体
合成路线 1（1. 合成：5271-67-0）
产率：90%
合成条件：Stage #1: With pyridine; disulfur dichloride In chlorobenzene at 20℃; for 1.75 h; Stage #2: With sulfuryl dichloride In chlorobenzene at 20 - 132℃; for 14.50 h;
实验步骤：在室温下搅拌的同时，向2-乙酰基噻吩（0.108ml，1.0mmol），吡啶（0.016ml，0.20mmol）和氯苯（0.35ml）的混合物中加入S2Cl 2（0.16ml，2.0mmol）。 搅拌1小时45分钟后，滴加SO 2 Cl 2（0.162ml，2.0mmol），将得到的混合物在室温下搅拌0.5小时。 然后将混合物在132℃下搅拌14小时。 将混合物用CDCl 3（2ml）稀释，加入内标（1BU 3 PO 4,0.0552ml，0.20mmol），并分析混合物。 1H NMR表明已形成2-噻吩碳酰氯，产率为90％。
参考文献：
- [1] Patent: WO2017/5606, 2017, A1. Location in patent: Page/Page column 31-32 [2] Journal of Organic Chemistry, 2015, vol. 80, # 20, p. 10370 - 10374 [3] Patent: WO2016/150937, 2016, A1. Location in patent: Page/Page column 27 [4] Patent: WO2016/202757, 2016, A1. Location in patent: Page/Page column 30; 31 [5] Patent: TW2017/36360, 2017, A
合成路线 2（2. 合成：5271-67-0）
产率：81%
合成条件：With thionyl chloride; N,N-dimethyl-formamide; sodium hydroxide In ethyl acetate at 58 - 65℃; for 2.50 h; Inert atmosphere
实验步骤：在该实验中，2-噻吩甲酸是来自实施例13的实验13.2和13.3的组合固体。将2-噻吩甲酸（63.1g，493mmol）的合并固体溶于乙酸乙酯（208g）中。一个三颈圆底烧瓶，配有热电偶，回流冷凝器和一个额外的漏斗，系统用氮气吹扫。回流冷凝器出口连接到含有水溶液的冷冻接收器。 NaOH（20％，250g）。加入催化量的二甲基甲酰胺（DMF）（0.2mL，0.005当量），并将所得反应混合物在搅拌下加热至65℃，然后缓慢加入亚硫酰氯（67.2,565mmol，1.15当量）。 。在添加过程中，释放诸如二氧化硫（SO 2）和氯化氢（HCl）的气体，并且反应温度降至约58℃。通过GC / MS在2.5小时内完成反应，没有可检测的未反应的2-噻吩甲酸。[0188]冷却后，在烧瓶上安装蒸馏头，在蒸馏过程中加入4-甲氧基苯酚（8.9mg）作为稳定剂。通过真空蒸馏（短路径），首先在较低真空（约60至125mmHg）下从混合物中蒸馏出乙酸乙酯和亚硫酰氯。将剩余的混合物冷却至室温并转换至更高的真空。在约63℃的蒸气温度下蒸馏（短程，约4mmHg），得到2-噻吩碳酰氯，为澄清的浅黄色油状物（56.5g，81％）。 GC-FID证实所得材料是2-噻吩碳酰氯，纯度> 98面积％。
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合成路线 3（3. 合成：5271-67-0）
产率：93%
合成条件：at 200℃; for 0.75 h;
实验步骤：装置：来自ISCO的活塞泵260D TeledyneDEVICE 1：管式反应器，长度为6米，内部容积为96.16毫升，外径为0.25英寸.DEVICE3：压力控制阀世伟洛克BPV-SS-07含有90％重量的混合物MIX1 摩尔比为2：1的草酰氯和噻吩的混合物MIX2和10％（重量）环丁砜（wtlcent，基于M1xi的总重量）由DEVICEO以2.14mL / min的速率通过装置1以averagePRESS进料。 80 bar中的1个，通过DEVICE3调整和保持。 通过加热流体将装置1保持在200℃的温度。 装置1中混合物的停留时间TIME1为45mm。 收集反应混合物的液体样品，并用内标二恶烷通过1H NMR分析，基于噻吩，噻吩-2-碳酰氯的产率为93％。
参考文献：
- [1] Patent: WO2017/76844, 2017, A1. Location in patent: Page/Page column 18; 19; 20; 21 [2] Journal fuer Praktische Chemie (Leipzig), 1956, vol. <4> 3, p. 137,142
