【合成方法】氯代嘧啶，2位活性高还是4位活性高？如何控制选择性取代？

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嘧啶类杂环是有机合成中非常常见的一类杂环，很多天然产物和药物中都含有嘧啶结构，因此嘧啶类化合物也是一类非常重要的医药中间体。一直以来， 2,4-二氯嘧啶类化合物2/4位选择性上对于合成路线的选择至关重要， 根据以往文献报道和实验的验证，我们通常认为 2,4-二氯嘧啶类化合物的4-位反应活性高于2-位。

【图片来源：】

2006年，默克公司的Zhi-Hui Peng等人就报道了2,4-二氯嘧啶胺基化的选择性问题，SNAr机理条件下，主要是4-位产物，但选择性不高，4位产物: 2位产物在2:1到4:1之间。在钯催化的偶联条件下，可以高产物率的得到4-位胺基化产物。【Org. Lett. 2006, 8, 395–398】

2016年，麻省理工Stephen L. Buchwald教授报道了5位TMS取代的2,4-二氯嘧啶进行可以高选择性得到2-位胺基化的产物。但是其他类型的2,4-二氯嘧啶还是只能通过迂回路线得到2-位胺基化的产物。【Org. Lett. 2016, 18, 2180–2183】

有没有嘧啶在4-位氯存在下，直接选择性在2-位取代的方法呢？

2022年，Biogen公司的Chaomin Li等人，在《 Org. Process Res. Dev. 》上报道了一篇名为 “通过砜取代实现大规模生产4‑氯‑N‑(1-甲基‑1H‑吡唑-4-基)嘧啶-2-二胺” 的文章。通过 4-氯- 2-甲砜基嘧啶代替 2,4 -二氯嘧啶，甲酰基吡唑胺代替吡唑胺进行SNAr反应可以选择性得到2-位取代的产物。【 Org. Process Res. Dev. 2022 , 26, 137−143】

利用 2,4 -二氯嘧啶作为原料， 常规路线制备 4‑氯‑N‑(1-甲基‑1H‑吡唑-4-基)嘧啶-2-二胺，总产率只有21%。

改用4-氯- 2-甲砜基嘧啶直接与1-甲基-1H-吡唑-4-胺在碱性条件下进行SNAr反应，发现4-位的活性还是更高，或者产率很低，没有取得很好的效果。

利用 4-氯- 2-甲砜基嘧啶和 N-(1-甲基-1H-吡唑-4-基)甲酰胺在强碱性条件下反应，明显2-位的反应活性更高，其中叔戊醇钠的反应效果更好。

作者对反应条件进行了进一步优化。得出最优反应条件：两个原料1:1当量，1.5eq叔戊醇钠，0℃下反应3小时。

放大生产：利用4-氯-2-甲硫基嘧啶和1-甲基-1H-吡唑-4-胺（4a）作为起始原料，两个原料并行推进，以总产率58%得到最终产物1。而且此路线不涉及钯催化反应，无腐蚀性试剂，无需柱层析纯化，经济和环境效益更高。

机理研究：

作者利用现在非常流行的密度泛函理论 (DFT)对砜的SNAr反应的区域选择性反应进行理论计算。

对三种亲核试剂：甲酰化吡唑胺（10），甲酰化吡唑胺负离子和吡唑胺（4）分别进行计算。从反应能垒图可以看出，只有甲酰化吡唑胺负离子和化合物7的SNAr反应，2-位甲磺酰基反应能垒明显低于4-位氯，甲酰化吡唑胺（10）对2位进行SNAr的反应能垒虽然也低于4位，但是区别不是很明显，导致选择性不高，另外10的亲核性较差，能垒相对于另外两个亲核试剂更高，反应活性更差。

反应操作

Synthesis of Formamide 10. Compound 4a (174 kg, 1.31 kmol) was added to HCOOH (488 kg, 10.6 kmol, 8.10 equiv) at 25 °C under a N2 atmosphere. The mixture was stirred at 100−110 °C (jacket temperature of 130−140 °C) for 12 h, at which point it was complete by HPLC analysis (0.78% of 4a remaining). The reaction mixture was concentrated at 60−70°C to give a residue, which was dissolved in acetone (250 L). K2CO3 (200 kg) was added at 25 °C, and the reaction mixture was stirred for 12 h. The resulting slurry was filtered, and the filtrate was concentrated to obtain a residue. The residue was redissolved in CH2Cl2/acetone = 1:1 (200 L), filtered to remove K2CO3, the filtrate was concentrated to give a residue, which was redissolved in CH2Cl2 (200 L), filtered, and the filtrate was concentrated to give compound 10 (135 kg, 1.08kmol, 83% yield) as a black oil. The crude formamide was used directly for the next step without further purification.

Preparation of Sulfone 7. Caution! The reaction safety was evaluated by DSC/TSU/RC1. A strong exotherm was observed from the calorimetry with a ΔT of 122 °C. The safe operation temperature is very close to the reaction temperature by the test of TSU. We strongly recommend to please ensure that the engineering control is in place to strictly follow the parameters in the procedure. Ammonium molybdate tetrahydrate (43.9 kg, 35.5 mol, 0.03 equiv) was added to H2O2 (439 kg, 27.5 wt %, 3.55 kmol, 3 equiv). After the mixture was cooled to 10 °C, the solution was slowly charged to a stirred solution of compound 11 (190 kg, 1.19 kmol, 1 equiv) in EtOH (950 L) precooled to 10 °C while maintaining <40 °C reaction temperature. The reaction was stirred at 37 °C for 12 h, at which point complete consumption of 11 was observed. The reaction mixture was cooled to 7 °C and filtered. The filtrate was directly transferred to another reactor in which 3 volumes of the saturated sodium sulfite solution was used to quench the residual H2O2 while controlling the temperature under 20 °C. The filter cake was washed with ice water (8 × 50 L) and dried in a double conical rotary dryer at 40 °C for 12 h to give compound 7 (199.3 kg,1.03 kmol, 87% yield) as a white solid.

Synthesis of 1. To a mixture of compounds 7 (199 kg, 1.03kmol, 1 equiv) and 10 (129 kg, 1.03 kmol, 1 equiv) in anhydrous THF (1000 L) was added NaOtAm solution, which was prepared by dissolving 119 kg (1.08 kmol, 1.05 equiv) of NaOtAm in 600 L of THF at −10−5 °C under an inert atmosphere of N2. The mixture was stirred at −10−5 °C for 3

h, at which point complete consumption of 7 was observed; 4.0V of 1 M NaOH (796 L) was added slowly to the mixture for 2h at 10 °C and stirred for an additional 1 h. To the reaction mixture were charged 500 L of water and 600 L of ethyl acetate, and the phases were separated. The aqueous layer was extracted with ethyl acetate (600 L). The combined organic phases were washed with brine (100 L), filtered, andconcentrated to give a residue. The residue was triturated with ethyl acetate (200 L) at 15 °C for 30 min and filtered to give 179 kg of crude product. The crude product was further triturated with ethyl acetate/H2O/MTBE (1:1:5 (v/v/v), 1050 L) at 25 °C for 1 h and filtered. After drying in a doubletapered rotary dryer at 40 °C for 12 h, 144 kg of compound 1(66% yield, 99% purity) was obtained as a yellow solid.

参考资料

1、Org. Lett. 2006, 8, 395–398；

2、Org. Lett. 2016, 18, 2180–2183；

3、Org. Process Res. Dev. 2022, 26, 137−143。