反应详情

温度

110 °C

A mixture of 2-(azetidin-3-yl)-3-chloropyrazine hydrochloride (8) (163 g, 0.79 mol), 2-bromoquinoline (164 g, 0.79 mol, 1 eq., Combi-Blocks) and cesium carbonate (772 g, 2.37 mol, 3 eq., Aldrich) in anhydrous DMF (6.5 L) was heated to 110° C. and stirred for 19 h. After cooling to RT, the mixture was transferred to 50 L separatory funnel and diluted with water (13 L). Then it was extracted with ethyl acetate (20 L×2) and the organic extracts were combined, washed with water (8 L), brine (8 L), dried and concentrated. The resulting residue was purified by column chromatography (eluting with hexanes/ethyl acetate=9:1 to 3:1). All fractions containing desired compound were combined and concentrated. The obtained solid was triturated with MTBE (250 mL), washed with MTBE (100 mL×2) and dried to obtain 100 g of 2-(3-(3-chloropyrazin-2-yl)azetidin-1-yl)quinoline (9) with >99% purity. The mother liquor was concentrated and purified by column chromatography and trituration with MTBE again to give 4.5 g of 2-(3-(3-chloropyrazin-2-yl)azetidin-1-yl)quinoline (9) with >99% purity. Yield: 45% for two steps.

1. temperatureAfter cooling to RT
2. customthe mixture was transferred to 50 L separatory funnel
3. extractionThen it was extracted with ethyl acetate (20 L×2)
4. washwashed with water (8 L), brine (8 L)
5. customdried
6. concentrationconcentrated
7. customThe resulting residue was purified by column chromatography (eluting with hexanes/ethyl acetate=9:1 to 3:1)
8. additionAll fractions containing desired compound
9. concentrationconcentrated
10. customThe obtained solid was triturated with MTBE (250 mL)
11. washwashed with MTBE (100 mL×2)
12. customdried