2-Chloroethanol → 1-Azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol

Participants

Reaction Conditions

Reaction Steps

Ethyl isonipecotate (600 g) and DBU (600 ml) were dissolved in toluene (3000 ml) and heated to 100° C. 2-Chloroethanol (330 ml) was added over 2 hours and the mixture stirred at 109° C. for a further 4.5 hours. The temperature was adjusted to 55-65° C. and thionyl chloride (378 ml) added. After stirring for 1 hour the mixture was cooled to 30° C. and water (1800 ml) and 40% w/w aqueous potassium carbonate (3350 g) were added. The layers were separated and the aqueous layer extracted with toluene (3000 ml). The combined organic layers were washed with water (600 ml) and dried by addition of toluene (2000 ml) and concentration to 6000 ml by vacuum distillation. A solution assay showed 94% conversion from ethyl isonipecotate. 0.5M Potassium hexamethyldisilazide in toluene (8400 ml) was added at 45-50° C. and the mixture stirred for 2 hours. Further 0.5M potassium hexamethyldisilazide in toluene (1260 ml) was added and the mixture stirred for 30 minutes. Ethanol (390 ml) was added and the mixture concentrated to 8400 ml by vacuum distillation. Acetic acid (850 ml) was added and the mixture stirred at 45° C. for 15 hours. A 26% w/w aqueous potassium carbonate solution (8110 g) was added and the layers separated. The aqueous layer was extracted with toluene (4800 ml). The combined organic layers were split in two halves and filtered using filter aid (38 g of Celite or Harborlite), recombined and concentrated to 6000 ml by vacuum distillation. The solution was cooled to 0-5° C. and 2M phenyl lithium in dibutyl ether (3840 ml) added. After one hour, water (3000 ml) and n-butanol (3960 ml) were added and the mixture heated to 83° C. The aqueous layer was removed and the organic layer washed with water (3000 ml). The organic phase was concentrated to 12000 ml by distillation with addition of toluene, then cooled to 20° C. and stirred overnight. The product was filtered, washed with toluene (2×1200 ml) and dried under vacuum at 70° C. to give a white solid (561 g, 50%). EI-MS m/z 294 (M+H+) Rt (3.7 min).

Provenance & Evidence