反应详情
EQUATION
反应方程式
REACTANTS
反应物
PRODUCTS
生成物
AUXILIARIES
试剂、催化剂与溶剂
CONDITIONS
反应条件
- 温度
- 65 °C
PROCEDURE
实验过程
To a 20 L temperature controlled reactor charge [(2R,3R,4S,5R,6R)-3,4,5-triacetoxy-6-[3-[(4-bromophenyl)methyl]-4-methyl-indol-1-yl]tetrahydropyran-2-yl]methyl acetate (1.37 moles; 1.18 kg; 73% purity), tert-butyl 8-[(E)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-enyl]-3,8-diazaspiro[5.5]undecane-3-carboxylate (1.79 moles; 776.46 g), potassium carbonate (3.85 moles; 532.03 g), THF (11.80 L) and water (1.18 L). Degas the mixture by subsurface nitrogen purge for 30 minutes and then add Pd(OAc)2 (54.99 mmoles; 12.35 g) and XPhos (54.99 mmoles; 26.22 g). Heat the mixture to 65° C. and stir overnight. Charge additional XPhos (13.75 mmoles; 6.55 g) and Pd(OAc)2 (13.75 mmoles; 3.09 g) and continue to stir at 65° C. for about 1 hour. Prepare a solution of tert-butyl 8-[(E)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-enyl]-3,8-diazaspiro[5.5]undecane-3-carboxylate (343.71 mmoles; 149.32 g) in THF (500 mL) and degas by subsurface purge with nitrogen for 5 mins. Add this solution to the main reaction mixture and continue stirring at 65° C. for about 3 hours. Cool the reaction mixture to room temperature and pump into a 50 L vessel equipped with a bottom outlet valve. Dilute the mixture with iso-hexane (11.80 L) and wash with brine (11.80 L). Separate the layers and filter the organic phase through a pad of silica gel (2.95 kg). Wash the pad twice with a mixture of THF (5.90 L) and iso-hexane (5.90 L). Concentrate the filtrate under reduced pressure to give the title compound (1.695 Kg; 62% purity as judged by quantative NMR; 88% yield), mass spectrum (m/z): 858.4 (M+1).
WORKUP
后处理
- customDegas the mixture by subsurface nitrogen
- custompurge for 30 minutes
- stirringto stir at 65° C. for about 1 hour
- customdegas by subsurface
- custompurge with nitrogen for 5 mins
- additionAdd this solution to the main reaction mixture
- stirringcontinue stirring at 65° C. for about 3 hours
- temperatureCool the reaction mixture to room temperature
- custompump into a 50 L vessel
- customequipped with a bottom outlet valve
- additionDilute the mixture with iso-hexane (11.80 L)
- washwash with brine (11.80 L)
- customSeparate the layers
- filtrationfilter the organic phase through a pad of silica gel (2.95 kg)
- washWash the pad
- additiontwice with a mixture of THF (5.90 L) and iso-hexane (5.90 L)
- concentrationConcentrate the filtrate under reduced pressure