由于微信更改了訂閱號的推送規則，很多朋友不能快速找到我們，其實我們每天都在推送！您可以將有機合成設置為星標（點擊右上方“...", 設為星標），就能在微信訂閱號中快速找到我們，查看每天訂閱。

嘧啶類雜環是有機合成中非常常見的一類雜環，很多天然產物和藥物中都含有嘧啶結構，因此嘧啶類化合物也是一類非常重要的醫藥中間體。一直以來， 2,4-二氯嘧啶類化合物2/4位選擇性上對于合成路線的選擇至關重要， 根據以往文獻報道和實驗的驗證，我們通常認為 2,4-二氯嘧啶類化合物的4-位反應活性高于2-位。

【圖片來源：】

2006年，默克公司的Zhi-Hui Peng等人就報道了2,4-二氯嘧啶胺基化的選擇性問題，SNAr機理條件下，主要是4-位產物，但選擇性不高，4位產物: 2位產物在2:1到4:1之間。在鈀催化的偶聯條件下，可以高產物率的得到4-位胺基化產物。【Org. Lett. 2006, 8, 395–398】

2016年，麻省理工Stephen L. Buchwald教授報道了5位TMS取代的2,4-二氯嘧啶進行可以高選擇性得到2-位胺基化的產物。但是其他類型的2,4-二氯嘧啶還是只能通過迂回路線得到2-位胺基化的產物?！綩rg. Lett. 2016, 18, 2180–2183】

有沒有嘧啶在4-位氯存在下，直接選擇性在2-位取代的方法呢？

2022年，Biogen公司的Chaomin Li等人，在《 Org. Process Res. Dev. 》上報道了一篇名為 “通過砜取代實現大規模生產4?氯?N?(1-甲基?1H?吡唑-4-基)嘧啶-2-二胺” 的文章。通過 4-氯- 2-甲砜基嘧啶代替 2,4 -二氯嘧啶，甲?；吝虬反孢吝虬愤M行SNAr反應可以選擇性得到2-位取代的產物?！?Org. Process Res. Dev. 2022 , 26, 137?143】

利用 2,4 -二氯嘧啶作為原料， 常規路線制備 4?氯?N?(1-甲基?1H?吡唑-4-基)嘧啶-2-二胺，總產率只有21%。

改用4-氯- 2-甲砜基嘧啶直接與1-甲基-1H-吡唑-4-胺在堿性條件下進行SNAr反應，發現4-位的活性還是更高，或者產率很低，沒有取得很好的效果。

利用 4-氯- 2-甲砜基嘧啶和 N-(1-甲基-1H-吡唑-4-基)甲酰胺在強堿性條件下反應，明顯2-位的反應活性更高，其中叔戊醇鈉的反應效果更好。

作者對反應條件進行了進一步優化。得出最優反應條件：兩個原料1:1當量，1.5eq叔戊醇鈉，0℃下反應3小時。

放大生產：利用4-氯-2-甲硫基嘧啶和1-甲基-1H-吡唑-4-胺（4a）作為起始原料，兩個原料并行推進，以總產率58%得到最終產物1。而且此路線不涉及鈀催化反應，無腐蝕性試劑，無需柱層析純化，經濟和環境效益更高。

機理研究：

作者利用現在非常流行的密度泛函理論 (DFT)對砜的SNAr反應的區域選擇性反應進行理論計算。

對三種親核試劑：甲?；吝虬罚?strong>10），甲?；吝虬坟撾x子和吡唑胺（4）分別進行計算。從反應能壘圖可以看出，只有甲?；吝虬坟撾x子和化合物7的SNAr反應，2-位甲磺?；磻軌久黠@低于4-位氯，甲酰化吡唑胺（10）對2位進行SNAr的反應能壘雖然也低于4位，但是區別不是很明顯，導致選擇性不高，另外10的親核性較差，能壘相對于另外兩個親核試劑更高，反應活性更差。

反應操作

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.

參考資料

1、Org. Lett. 2006, 8, 395–398；

2、Org. Lett. 2016, 18, 2180–2183；

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