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. is added n-BuLi (3.7 mL, 2.5M in hexanes, 9.21 mmol) in one portion. The acetone/dry ice bath is exchanged for ice/water bath and the solution is stirred further for 40 min. The solution is 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) is added dropwise. This solution is stirred for 15 min at −78° C., following by 20 min at −20° C. Trimethyl borate (1.0 mL, 8.77 mmol) is added, the reaction mixture is stirred for 15 min at −20° C. after which the cooling bath is removed and this solution is stirred further at room temperature for 1 h. A solution of K3PO4 is 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 is stirred overnight (ca. 18 h) and then water (80 mL) is added and the product is extracted with EtOAc (3×50 mL). The combined organic fractions are dried over MgSO4, filtered and concentrated under reduced pressure. The crude product is 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. additionis added dropwise
2. stirringThis solution is stirred for 15 min at −78° C.
3. waitfollowing by 20 min at −20° C
4. stirringthe reaction mixture is stirred for 15 min at −20° C. after which the cooling bath
5. customis removed
6. stirringthis solution is stirred further at room temperature for 1 h
7. additionA solution of K3PO4 is added (11.7 mL, 3M aqueous solution, 35.1 mmol)
8. washa 5 mL rinse)
9. stirringThe reaction mixture is stirred overnight (ca. 18 h)
10. additionwater (80 mL) is added
11. extractionthe product is extracted with EtOAc (3×50 mL)
12. dry with materialThe combined organic fractions are dried over MgSO4
13. filtrationfiltered
14. concentrationconcentrated under reduced pressure
15. customThe crude product is purified
16. customvia flush chromatography on silica gel (5-60% EtOAc/Hexanes as eluant)

ORD record

ord-108b5c89e68146bdbbf55e8f7b3441f0

Source dataset

uspto-grants-2011_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07868037B2