反应详情

温度

60 °C

A 100-L, four-necked, round-bottomed flask was charged with the dimethyl 4-aminobenzene-1,2-dicarboxylate, K2CO3, KI (anhydrous), and 21.6 L of N,N-dimethylacetamide (DMAC, 200 ppm of water; however, the reaction can tolerate more water). Benzyl chloride (BnCl) was added in one portion, and the reaction mixture (brown slurry) was heated to 60° C. over 20 min using a steam bath. The steam bath was then shutoff, and the reaction temperature continued to increase to 76.8° C. over the next 30 min (exotherm). After cooling to 75° C., the reaction mixture was stirred at this temperature for 2 h and then stirred at 90° C. until <1.5% of the monobenzyl intermediate remained (ca. 8-12 h) (yellow/white slurry). [note, the reaction mixture gets very thick during the reaction]. The steam bath was turned off and the reaction mixture was allowed to cool to room temperature (18° C.), then diluted with 21.6 L (5 volumes) of methyl t-butyl ether (MTBE) and 43.2 L (10 volumes) of water. The resulting organic layer was separated, washed with water (2×28 L), and concentrated to ca. 18 L (ca. 3 volumes). The brown oil was then solvent-switched to THF (60 L) and concentrated to ca. 38 L (<1000 ppm water). The product mixture containing the title compound was used in the next step without further purification.

1. customhowever, the reaction
2. temperatureto increase to 76.8° C. over the next 30 min (exotherm)
3. temperatureAfter cooling to 75° C.
4. custom(ca. 8-12 h) (yellow/white slurry)
5. custom[note, the reaction mixture gets very thick during the reaction]
6. temperatureto cool to room temperature (18° C.)
7. customThe resulting organic layer was separated
8. washwashed with water (2×28 L)
9. concentrationconcentrated to ca. 18 L (ca. 3 volumes)
10. concentrationsolvent-switched to THF (60 L) and concentrated to ca. 38 L (<1000 ppm water)
11. additionThe product mixture containing the title compound
12. customwas used in the next step without further purification