1,4-Dioxane → 7-[2-(4-morpholinyl)ethyl]-5-(1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

Temperature

100 °C

To 5-bromo-7-[2-(4-morpholinyl)ethyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (50 mg, 0.153 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indole (93 mg, 0.215 mmol) were added 1,4-Dioxane (2 mL) and sat. NaHCO3 (1 mL) in a 5 ml sealable vessel. The mixture was then bubbled with N2 gas for 5 minutes then added Pd(Ph3P)4 (17.71 mg, 0.015 mmol) and the reaction was capped and heated at 100° C. overnight. The reaction was then diluted with water (2 ml) then extracted with EtOAc (3×3 ml). The organics were then combined and washed with brine, dried over MgSO4, filtered, and concentrated. The residue was dissolved in 3 mL of DMSO and then purified by HPLC: (HPLC condition: Gilson using Trilution software with a Sunfire 5u C18(2) 100A. 50×30.00 mm 5 micron. 7.3-minute run (47 ml/min, 18% ACN/H2O, 0.1% TFA to 43% ACN/H2O, 0.1% TFA) with UV detection at 220 nm). Product fractions were combined and the volume was reduced to remove most of the MeCN. To the water left behind was added saturated NaHCO3 and then the mixture was extracted with EtOAc (3×15 mL). The organics were combined, washed with saturated NaCl solution, dried over MgSO4, filtered and concentrated. Then the product was transferred into a 40 mL vial with MeCN then added water and freeze-dried to give 7-[2-(4-morpholinyl)ethyl]-5-(1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (35 mg, 41.5% yield) as a white solid. LC-MS (ES) m/z=551.5 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.10-8.15 (m, 2H), 7.69 (s, 1H), 7.56-7.66 (m, 3H), 7.33 (s, 2H), 7.24 (d, J=8.34 Hz, 1H), 6.06 (br. s., 2H), 4.24-4.31 (m, 4H), 4.04 (s, 2H), 3.54 (br. s., 4H), 3.22-3.29 (m, J=7.83 Hz, 2H), 2.71 (br. s., 2H), 2.46 (br. s., 4H).

1. customThe mixture was then bubbled with N2 gas for 5 minutes
2. extractionthen extracted with EtOAc (3×3 ml)
3. washwashed with brine
4. dry with materialdried over MgSO4
5. filtrationfiltered
6. concentrationconcentrated
7. dissolutionThe residue was dissolved in 3 mL of DMSO
8. custompurified by HPLC
9. custom7.3-minute
10. customto remove most of the MeCN
11. waitTo the water left behind
12. additionwas added saturated NaHCO3
13. extractionthe mixture was extracted with EtOAc (3×15 mL)
14. washwashed with saturated NaCl solution
15. dry with materialdried over MgSO4
16. filtrationfiltered
17. concentrationconcentrated
18. dry with materialadded water and freeze-dried

ORD record

ord-cb415febf2cc48ef92e389c2a2dfe3df

Source dataset

uspto-grants-2013_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08598156B2