Npc164516 → 3-(5-Methoxy-benzo[b]thiophen-2-yl)-8-methyl-8-aza-bicyclo[3.2.1]oct-2-ene

Temperature

-70 °C

5-Methoxy-benzo[b]thiophene (3.20 g, 19.5 mmol) was solved in diethylether (50 ml). n-BuLi (8.58 ml, 21.45 mmol) was added to the mixture at a temperature below 20° C. The cooling was removed and the mixture was allowed to stir for 30 minutes. The mixture was cooled to −70° C. Tropinone (2.71 g, 19.5 mmol) solved in diethylether (50 ml) was added during 20 minutes. The temperature was kept below −60° C. Precipitation occurred. The mixture was stirred for 2 hours. Aqueous sodium hydroxide (20 ml, 1 M) was added. The mixture was stirred for 10 minutes. The solid intermediate product (endo/exo-3-(5-methoxy-benzo-[b]thiophen-2-yl)-8-methyl-8-aza-bicyclo[3.2.1]octan-3-ol) was filtered and washed with water and diethylether. Yield 3.97 g (67%). The intermediate product was combined with acetic acid (20 ml) and hydrochloric acid (7 ml). The mixture was stirred at reflux for 1 hour. The mixture was poured out on ice. The mixture was made alkaline by adding ammonia and extracted with dichloromethane and washed with water. The crude mixture was purified by column chromatography using a mixture of dichloromethane, methanol and aqueous ammonia (6:1:1%). Yield 2.28 g, (61%).

1. customThe cooling was removed
2. additionwas added during 20 minutes
3. customwas kept below −60° C
4. customPrecipitation
5. stirringThe mixture was stirred for 2 hours
6. additionAqueous sodium hydroxide (20 ml, 1 M) was added
7. stirringThe mixture was stirred for 10 minutes
8. filtrationThe solid intermediate product (endo/exo-3-(5-methoxy-benzo-[b]thiophen-2-yl)-8-methyl-8-aza-bicyclo[3.2.1]octan-3-ol) was filtered
9. washwashed with water and diethylether
10. stirringThe mixture was stirred
11. temperatureat reflux for 1 hour
12. additionThe mixture was poured out on ice
13. additionby adding ammonia
14. extractionextracted with dichloromethane
15. washwashed with water
16. customThe crude mixture was purified by column chromatography
17. additiona mixture of dichloromethane, methanol and aqueous ammonia (6:1:1%)

ORD record

ord-7820bb9b139945bcae79312c806723ce

Source dataset

uspto-grants-2014_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08633218B2