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

HRID 1910069Notes

Reaction equation

Br[C:2]1[C:10]2[C:9]([NH2:11])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH:12]2[CH2:15][O:14][CH2:13]2)[CH:3]=1.CC1(C)C(C)(C)OB([C:24]2[CH:25]=[C:26]3[C:30](=[CH:31][CH:32]=2)[N:29]([C:33](=[O:45])[CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:44])([F:43])[F:42])[CH:36]=2)[CH2:28][CH2:27]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>[O:14]1[CH2:15][CH:12]([N:4]2[C:5]3[N:6]=[CH:7][N:8]=[C:9]([NH2:11])[C:10]=3[C:2]([C:24]3[CH:25]=[C:26]4[C:30](=[CH:31][CH:32]=3)[N:29]([C:33](=[O:45])[CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:44])([F:42])[F:43])[CH:36]=3)[CH2:28][CH2:27]4)=[CH:3]2)[CH2:13]1

Participants

Conditions

Temperature: 100 °C

Procedure

To 5-bromo-7-(3-oxetanyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (50 mg, 0.186 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indole (112 mg, 0.260 mmol) were added 1,4-Dioxane (2 mL) and sat. NaHCO3 (1 mL) into a 5 ml sealable. The mixture was then bubbled with N2 gas for 5 minutes. Pd(Ph3P)4 (21.47 mg, 0.019 mmol) was added and the vessel was capped and heated at 100° C. overnight. The reaction was then diluted with water (2 ml) and extracted with EtOAc (3×3 ml). The organics were then combined and washed with brine, dried over MgSO4, filtered, concentrated. The crude was dissolved in 3 mL of DMSO and 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, 20% ACN/H2O, 0.1% TFA to 45% 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. To the water left behind was added saturated NaHCO3 and then the mixture was extracted with EtOAc (3×15 mL). The organics were combined wash with saturated NaCl solution, dried over MgSO4, filtered and concentrated. The material was transferred into a 40 mL vial with MeCN then water was added and the solution was freeze-dried to give 7-(3-oxetanyl)-5-(1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (46 mg, 50.2% yield) as a white solid. LC-MS (ES) m/z=494.4 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.11-8.17 (m, 2H), 7.67-7.72 (m, 2H), 7.56-7.67 (m, 3H), 7.40 (s, 1H), 7.29 (d, J=8.08 Hz, 1H), 6.16 (br. s., 2H), 5.88 (quin, J=7.14 Hz, 1H), 4.95-5.04 (m, 4H), 4.28 (t, J=8.34 Hz, 2H), 4.04 (s, 2H), 3.27 (t, J=8.34 Hz, 2H).

Workup

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

Sources & evidence

ORD record: ord-73457994e53e4723b284cc9533258b83
Source dataset: uspto-grants-2013_12
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08598156B2

Reaction notes

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