反应详情

温度

20 °C

To a solution of physostigmine (290 g) in dry THF (2.3 L) at 15° C. under a nitrogen atmosphere was treated with KOtBu (126.4 g), added over 0.05 hour. The mixture was kept at 15° C. for 0.5 hour, then treated with glacial HOAc (64.1 mL, 1 equiv., pH=10) to give a mixture containing physostigmine (II) and eseroline (III) in a 1/99 HPLC ratio. Addition of 1,1'-carbonyldiimidazole (195.8 g, 1.15 equiv) in 10 (0.1 equiv.) and 3 (0.05 equiv.) portions at -30° C. over 2 hours gave the following HPLC ratios of imidazolecarbonyl intermediate (V) and eseroline after 1.0, 1.1 and 1.15 equiv.: 92/8, 98/2 and 99/1. Addition of glacial HOAc (482 mL, 8 equiv., pH-5) followed by 1,2,3,4-tetrahydroisoquinoline (175 g, 1.25 equiv., added over 1.5 hours at - 10° C.) and warming to 20° C. for 15 hours gave a mixture containing (3aS-cis)- 1,2,3,3a,8,8a-hexahydro- 1,3a,8-trimethylpyrrolo-[2,3-b]indol-5-yl 3,4-dihydro-2(1H)-isoquinolinecarboxylate and eseroline in a 99/1 HPLC ratio. Addition of water (500 mL), cooling to -10° C., partial neutralization to pH=8 with 50% NaOH (471 g, 0.7 equiv based in HOAc), concentration of the THF under 30° C., toluene extraction (1×1L and 2×0.5L) of the residue, washing with water (500 mL), 5% NaCl (500 mL) and concentration under reduced pressure at 50° C. gave 370 g of crude product. This material was further purified by silica gel chromatography using ethyl acetate/methanol to give 346 g of 99% pure product in 89% yield from physostigmine. Recrystallization from methanol/water gave 321 g of crystalline product in 99% PHLC purity and 84 % yield.

1. customgave a mixture
2. temperaturecooling to -10° C.
3. washwashing with water (500 mL), 5% NaCl (500 mL) and concentration under reduced pressure at 50° C.
4. customgave 370 g of crude product
5. customThis material was further purified by silica gel chromatography