7-氮杂吲哚衍生物的合成

7-氮杂吲哚：氮氧化物的氯代，MsCl为氯代试剂

已有文献报道

化合物3，选择性氯代得到化合物2；

化合物4，选择性溴代得到化合物2

化合物2，硝化得到化合物1

收率不高，选择性不是很好，原料3和原料4的制备也面临卤素的选择性

合成化合物1的设计路线

化合物6先氯代，再硝化，最后溴代

设计路线的研究

1.氯代化合物4的合成

化合物6先用m-CPBA进行氧化得到氮氧化物7，然后采用甲磺酰氯作为氯代试剂（也可以采用三氯氧磷，但是本案例中，甲磺酰氯效果更好），进行氯代。

2.氯代的选择性

选择性很好，4-位是主产物，6-位和3-位作为杂质，相对含量不高，后处理分离后，主产物97.5%。

3.硝化化合物5的合成

淬灭条件是水的正淬灭A和反淬灭B，选择性还是不错的，吲哚的3-位。

4.溴代化合物1的合成

NBS被选择为溴代试剂，溶剂选择醋酸

添加剂的研究发现，加入醋酸钠，醋酸钾，磷酸氢二钾等弱碱性盐，收率可以明显提高。工艺最后选择醋酸钠，用量0.5mol.

实验没有发现杂质1a，但是发现了杂质8，推测是没有发现的杂质1a转化

数据信息

50kg规模，4步反应，总收率46%，相比已有文献报道的条件，有所改善。

氧化操作

To a solution of 6 (65.3 kg, 553 mol, 100 mol %) in EtOAc (655 kg) was added m-CPBA (85 wt %, 146 kg, 130 mol %) in portions below 20 °C. The resulting suspension was stirred at 25 °C for 2 h and filtered. The resulting solids were washed with EtOAc/petroleum ether (40/60, w/w, 243 kg ×2) and dried at below 40 °C under reduced pressure to provide 7- hydroxy-1H-pyrrolo[2,3-b]pyridin-7-ium 3-chlorobenzoate (148 kg, 92% yield) as a light yellow solid. To a mixture of 7-hydroxy-1H-pyrrolo[2,3-b]pyridin-7-ium 3-chlorobenzoate and water (528 kg) was added 2 M aqueous K3PO4 solution (317 kg) to adjust the pH to 10 at 10−15 °C. The suspension was stirred at 0 °C for 1 h and filtered. The solid was washed with cold water (176 kg) and dried under reduced pressure at 50 °C to afford 6 as a light pink solid (63.3 kg, 85% yield)

氯代操作

To a solution of 7 (63.0 kg, 470 mol, 100mol %) in DMF (302 kg) was added MsCl (179 kg, 333 mol%) at 60−75 °C over 1 h. The reaction mixture was stirred at 70 °C for 5 h, cooled to 40 °C, and transferred into cold water (1280 kg) over 1 h while maintaining the batch temperature below 15 °C. To the resulting suspension was added aqueous NaOH solution (500 kg, 30 wt %). The suspension was stirred at 10 °C for 0.5 h and filtered. The resulting solids were washed with water (380 kg) and dried under reduced pressure at 50 °C to afford 4 as a light yellow solid (52.0 kg, 73% yield）

溴代操作

Into a suspension of 5 (53.2 kg, 94.5 wt %, 254 mol, 100 mol %) and sodium acetate (11.0 kg, 50 mol %) in acetic acid (336.1 kg) was added NBS (73.8 kg, 160 mol %) in portions19 at 25 °C. The reaction mixture was stirred at 25 °C for 18 h. Into the reaction mixture was added 5 wt % aqueous sodium sulfite solution (694 kg) over 1 h. The suspension was stirred at 25 °C for 2 h and filtered. The resulting solid was washed with water (347 kg) and dried under reduced pressure at 70 °C to afford  1 as a tan solid(66.4 kg, 96.2 wt %, 90% yield）

参考文献

Org. Process Res. Dev. 2017, 21, 664−668