Hydrochloric Acid → HCID 68499612, compound

Temperature

0 °C

To a mixture of 6-benzyloxy-1H-indole-2-carboxylic acid ethyl ester (10 g, 33.86 mmol) and iodomethane (2.32 mL, 37.10 mmol) in tetrahydrofuran (THF) (100 mL) and DMF (50 mL) was added 60% sodium hydride in oil (1.63 g, 40.75 mmol) under ice cooling and the mixture was stirred for 2 hours. After the addition of water and AcOEt, the organic layer was separated and washed with 1 M HCl and brine, dried over anhydrous magnesium sulfate and evaporated. To the residue in ethanol (EtOH) (100 mL) was added 5 M NaOH (20.3 mL, 101.5 mmol) and the mixture was refluxed for 2 hours. The reaction mixture was acidified with 6 M HCl under ice cooling and the precipitate was collected by filtration and dried. The filtrate was extracted with AcOEt and the organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated. To a solution of this residue and the precipitate in DMF (120 mL) was added piperazine-1-carboxylic acid tert-butyl ester (7.57 g, 40.63 mmol) and the mixture was cooled to 0° C. To the mixture was added 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (9.7 g, 50.60 mmol) and 1-Hydroxy-benzotiriazole monohydrate (6.1 g, 39.83 mmol) and the mixture was stirred at room temperature overnight. After the addition of water and saturated aqueous NaHCO3, the mixture was stirred for 1 hour. The precipitate was collected by filtration and dissolved in CH2Cl2. The solution was washed with 1 M HCl and water, dried over anhydrous magnesium sulfate and evaporated. To a solution of the residue in 1,4-dioxane (60 mL) was added a suspension of 10% palladium/carbon (Pd/C) (1.2 g) in EtOH (60 mL) under ice cooling. The mixture was stirred under a hydrogen atmosphere (1 atm) for 3 hours at 40° C. The catalyst was filtered off using celite and the filtrate was evaporated. The residue was purified by silica gel column chromatography (n-hexane:AcOEt=1:3, in ratio by volume; hereinafter the same) and crystallized with Et2O to afford the title compound (7.23 g) as a white powder.

1. customthe organic layer was separated
2. washwashed with 1 M HCl and brine
3. dry with materialdried over anhydrous magnesium sulfate
4. customevaporated
5. temperaturethe mixture was refluxed for 2 hours
6. filtrationthe precipitate was collected by filtration
7. customdried
8. extractionThe filtrate was extracted with AcOEt
9. washthe organic layer was washed with brine
10. dry with materialdried over anhydrous magnesium sulfate
11. customevaporated
12. stirringthe mixture was stirred at room temperature overnight
13. stirringthe mixture was stirred for 1 hour
14. filtrationThe precipitate was collected by filtration
15. dissolutiondissolved in CH2Cl2
16. washThe solution was washed with 1 M HCl and water
17. dry with materialdried over anhydrous magnesium sulfate
18. customevaporated
19. additionTo a solution of the residue in 1,4-dioxane (60 mL) was added
20. additiona suspension of 10% palladium/carbon (Pd/C) (1.2 g) in EtOH (60 mL) under ice cooling
21. stirringThe mixture was stirred under a hydrogen atmosphere (1 atm) for 3 hours at 40° C
22. filtrationThe catalyst was filtered off
23. customthe filtrate was evaporated
24. customThe residue was purified by silica gel column chromatography (n-hexane
25. customhereinafter the same) and crystallized with Et2O

ORD record

ord-d578263f071c426f970988234c0f5295

Source dataset

uspto-grants-2013_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08551999B2