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

HRID 1910072Notes

Reaction equation

Br[C:2]1[C:10]2[C:9]([NH2:11])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH:3]=1.CC1(C)C(C)(C)OB([C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[N:30]([C:34](=[O:46])[CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:45])([F:44])[F:43])[CH:37]=2)[CH2:29][CH2:28]3)O1.O1CCOCC1.C([O-])(O)=O.[Na+]>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:15][CH:14]([CH3:16])[CH2:13][CH2:12][N:4]1[C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH2:11])[C:10]=2[C:2]([C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[N:30]([C:34](=[O:46])[CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:45])([F:43])[F:44])[CH:37]=2)[CH2:29][CH2:28]3)=[CH:3]1

Participants

Conditions

Temperature: 100 °C

Procedure

To 5-bromo-7-(3-methylbutyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (75 mg, 0.265 mmol) and 5-(4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indole (160 mg, 0.371 mmol) were added 1,4-Dioxane (2 mL) and saturated NaHCO3 (1 mL) in a 5 ml sealable vessel. The mixture was then bubbled with N2 gas for 5 minutes then Pd(Ph3P)4 (30.6 mg, 0.026 mmol) was added and the vessel was capped. The reaction was then 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 crude was dissolved in 3 mL of DMSO and the product 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, 40% ACN/H2O, 0.1% TFA to 65% ACN/H2O, 0.1% TFA) with UV detection at 254 nm). Product fractions were combined and the volume was reduced to remove most of the MeCN. The water left behind was added saturated NaHCO3 and then extracted with EtOAc (3×15 mL). The organics were combined and washed with saturated NaCl solution, dried over MgSO4, filtered and concentrated. The material was transferred to a 40 mL vial with MeCN then water was added and the solution was freeze-dried. to afford 7-(3-methylbutyl)-5-(1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (67 mg, 0.132 mmol, 49.8% yield) as a white solid. LC-MS (ES) m/z=508.5 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.15 (s, 1H), 8.11 (d, J=8.34 Hz, 1H), 7.69 (s, 1H), 7.56-7.66 (m, 3H), 7.33 (s, 2H), 7.24 (d, J=8.34 Hz, 1H), 6.10 (br. s., 2H), 4.27 (t, J=8.46 Hz, 2H), 4.18 (t, J=7.33 Hz, 2H), 4.03 (s, 2H), 3.26 (t, J=8.34 Hz, 2H), 1.69 (q, J=6.99 Hz, 2H), 1.50 (dt, J=6.69, 13.39 Hz, 1H), 0.93 (d, J=6.57 Hz, 6H).

Workup

customThe mixture was then bubbled with N2 gas for 5 minutes
customthe vessel was capped
extractionthen extracted with EtOAc (3×3 ml)
washwashed with brine
dry with materialdried over MgSO4
filtrationfiltered
concentrationconcentrated
dissolutionThe crude was dissolved in 3 mL of DMSO
customthe product purified by HPLC
custom7.3-minute
customto remove most of the MeCN
waitThe water left behind
additionwas added saturated NaHCO3
extractionextracted with EtOAc (3×15 mL)
washwashed with saturated NaCl solution
dry with materialdried over MgSO4
filtrationfiltered
concentrationconcentrated
additionwater was added
customthe solution was freeze-dried

Sources & evidence

ORD record: ord-c6adf0e6a5e34738bd803123671631f4
Source dataset: uspto-grants-2013_12
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08598156B2

Reaction notes

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