Dimethylformamide → HCID 22722264, compound

Temperature

0 °C

Sodium hydride (10 mmol) is added to 1-(1H-Indole-4-yl)-ethanol(4 mmol) in DMF (7 mL). After stirring 20 minutes, iodomethane (10 mmol) is added and the mixture stirred an additional 2 hours. The reaction is then partitioned between water and ethyl acetate, the layers are separated, the ethyl acetate phase removed in vacuo, and the product dried under high vacuum. The residue is then dissolved in a small amount of alcohol, and 4-(1-methoxy-ethyl)-1-methyl-1H-indole isolated by chromatography on silica gel using chloroform-methanol as eluent. This product (2 mmol) is dissolved in ether (40 mL), oxalyl chloride (8 mmol) added dropwise and the mixture stirred 8 h at 24° C. The reaction vessel is then equipped with a Dewar condenser, chilled to 0° C., and anhydrous ammonia bubbled through the mixture during 1.5 h. The gas and solvent are removed in vacuo. The resulting solid is dissolved in ethyl acetate, extracted with brine, and the ethyl acetate phase dried with magnesium sulfate and evaporated. The material is dissolved in THF (15 mL) and treated with borane-THF (3 mL of 1 M solution) 16 h at 25° C. The reaction is neutralized with sodium bicarbonate and extracted with ethyl acetate. The ethyl acetate extract is next dried in vacuc, redissolved in ethanol (10 mL) and refluxed in the presence of cesium fluoride (380 mg) and sodium carbonate (350 mg). The mixture is filtered through Celite, evaporated and the residue chromatographed on silica gel using chloroform-methanol-ammonia (9:1:0.1) as eluent affording 2-[4-(1-methoxy-ethyl)-1-methyl-1H-indol-3-yl]-ethylamine. This material is dissolved in pyridine (6 mL) and treated with acetic anhydride (3 mL) to provide N-{2-[4-(1-methoxy-ethyl)-1-methyl-1H-indol-3-yl]ethyl}-acetamide. After drying 24 h at <0.1 mmHg, the compound (1 mmol) is taken into dichloromethane (2 mL). Ammonium nitrate (1.7 mmol) is added followed by trifluoroacetic anhydride (3 mmol)). The mixture is stirred overnight, then partitioned between cold, saturated sodium bicarbonate and chloroform. The organic phase is washed with water, dried with magnesium sulfate and evaporated to dryness. The N-{2-[4-(1-methoxy-ethyl)-1-methyl-5-nitro-1H-indol-3-yl]-ethyl}-acetamide is isolated by chromatography on silica gel using ethyl acetate-hexane as eluent, and finally transformed into the title compound by hydrogenation and formation of the methyl carbamate as described in previous examples.

1. stirringthe mixture stirred an additional 2 hours
2. customThe reaction is then partitioned between water and ethyl acetate
3. customthe layers are separated
4. customthe ethyl acetate phase removed in vacuo
5. customthe product dried under high vacuum
6. dissolutionThe residue is then dissolved in a small amount of alcohol, and 4-(1-methoxy-ethyl)-1-methyl-1H-indole
7. customisolated by chromatography on silica gel
8. stirringthe mixture stirred 8 h at 24° C
9. customThe reaction vessel is then equipped with a Dewar condenser
10. customanhydrous ammonia bubbled through the mixture during 1.5 h
11. customThe gas and solvent are removed in vacuo
12. dissolutionThe resulting solid is dissolved in ethyl acetate
13. extractionextracted with brine
14. dry with materialthe ethyl acetate phase dried with magnesium sulfate
15. customevaporated
16. dissolutionThe material is dissolved in THF (15 mL)
17. additiontreated with borane-THF (3 mL of 1 M solution) 16 h at 25° C
18. extractionextracted with ethyl acetate
19. extractionThe ethyl acetate extract
20. customis next dried in vacuc
21. dissolutionredissolved in ethanol (10 mL)
22. temperaturerefluxed in the presence of cesium fluoride (380 mg) and sodium carbonate (350 mg)
23. filtrationThe mixture is filtered through Celite
24. customevaporated
25. customthe residue chromatographed on silica gel

ORD record

ord-d8f5dd47325f42ba888a50f7b1719e74

Source dataset

uspto-grants-2004_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06730707B2