Diisopropylamine → HCID 59425630, compound

Temperature

-78 °C

To a solution of (i-Pr)2NH (1.35 mL, 9.65 mmol) in THF (30 mL) cooled to −78° C. was added n-BuLi (3.7 mL, 2.5M in hexanes, 9.21 mmol) in one portion. The acetone/dry ice bath was exchanged for ice/water bath and the solution was stirred further for 40 min. The solution was cooled to −78° C. and solution of 1-butyl-6-methoxy-1H-indole-3-carbonitrile, prepared as in example 1A (2.0 g, 8.77 mmol) in THF (10 mL) was added dropwise. This solution was stirred for 15 min at −78° C., following by 20 min at −20° C. Trimethyl borate (1.0 mL, 8.77 mmol) was added, the reaction mixture was stirred for 15 min at −20° C. after which the cooling bath was removed and this solution was stirred further at room temperature for 1 h. A solution of K3PO4 was added (11.7 mL, 3M aqueous solution, 35.1 mmol) followed by a solution of 4-iodoaniline (2.5 g, 11.40 mmol) and PdCl2dppf catalyst (640 mg, 0.88 mmol) in DMF (40 mL, plus a 5 mL rinse). The reaction mixture was stirred overnight (ca. 18 h.) and then water (80 mL) was added and the product was extracted with EtOAc (3×50 mL). The combined organic fractions were dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified via flush chromatography on silica gel (5→60% EtOAc/Hexanes as eluant) to afford the desired 2-(4-aminophenyl)-1-butyl-6-methoxy-1H-indole-3-carbonitrile as a tan solid (2.4 g, 86% yield).

1. additionwas added dropwise
2. stirringThis solution was stirred for 15 min at −78° C.
3. waitfollowing by 20 min at −20° C
4. stirringthe reaction mixture was stirred for 15 min at −20° C. after which the cooling bath
5. customwas removed
6. stirringthis solution was stirred further at room temperature for 1 h
7. additionA solution of K3PO4 was added (11.7 mL, 3M aqueous solution, 35.1 mmol)
8. washa 5 mL rinse)
9. stirringThe reaction mixture was stirred overnight (ca. 18 h.)
10. additionwater (80 mL) was added
11. extractionthe product was extracted with EtOAc (3×50 mL)
12. dry with materialThe combined organic fractions were dried over MgSO4
13. filtrationfiltered
14. concentrationconcentrated under reduced pressure
15. customThe crude product was purified
16. customvia flush chromatography on silica gel (5→60% EtOAc/Hexanes as eluant)

ORD record

ord-ab41c590fa694454862a8564ed056336

Source dataset

uspto-grants-2011_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08013006B2