Water → HCID 66641326, compound

HRID 73706Notes

Reaction equation

HRID 73706 reaction equation
Br[C:2]1[C:3]([CH3:20])=[C:4]([CH2:12][N:13]2[CH2:19][CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[N:5]2[C:10]=1[C:9]([NH2:11])=[N:8][CH:7]=[N:6]2.[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=1[NH:32][C:33]([NH:35][C:36]1[CH:41]=[CH:40][C:39](B2OC(C)(C)C(C)(C)O2)=[CH:38][CH:37]=1)=[O:34].C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:11][C:9]1[C:10]2=[C:2]([C:39]3[CH:38]=[CH:37][C:36]([NH:35][C:33]([NH:32][C:23]4[CH:24]=[C:25]([C:28]([F:29])([F:31])[F:30])[CH:26]=[CH:27][C:22]=4[F:21])=[O:34])=[CH:41][CH:40]=3)[C:3]([CH3:20])=[C:4]([CH2:12][N:13]3[CH2:19][CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:5]2[N:6]=[CH:7][N:8]=1

Participants

7

Reactant 4

HCID 962WaterHCID 11430Potassium CarbonateHCID 161252301-(2-Fluoro-5-(trifluoromethyl)phenyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ureaHCID 579551855-Bromo-6-methyl-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

Product 1

HCID 66641326HCID 66641326, compoundYield 15%

Reagents, catalysts & solvents 2

HCID 11979704Tetrakis(triphenylphosphine)palladiumCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
90 °C

Procedure

To a stirred solution of 5-bromo-6-methyl-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (100 mg, 0.29 mmol) and tetrakis(triphenylphosphine)-palladium(0) (101 mg, 0.088 mmol), in degassed 1,4 dioxane (4.0 mL), was added Intermediate AAN (1-[2-fluoro-5-(trifluoromethyl)phenyl]-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea) (248 mg, 0.59 mmol), K2CO3 (162 mg, 1.18 mmol), and H2O (0.4 mL). The mixture was degassed and heated (90° C.) for 17 h and then cooled to rt. The mixture was partitioned between ethyl acetate (25 mL) and saturated aqueous Na2CO3 solution (25 mL). The layers were separated and the organic phase was washed, dried (Na2SO4), and concentrated to dryness. The residue was purified by preparative HPLC using a gradient elution from 10% to 70% acetonitrile to obtain 24 mg (15%) of the desired product. 1H-NMR (DMSO-d6) δ 9.36 (s, 1H), 8.98-8.97 (m, 1H), 8.63 (dd, J=2.4, 7.2 Hz, 1H), 7.85 (s, 1H), 7.60-7.47 (m, 3H), 7.41-7.33 (m, 1H), 7.33 (d, J=8.7 Hz, 2H), 3.95 (s, 2H), 3.66 (t, J=6.0 Hz, 2H), 3.59-3.56 (m, 2H), 3.31 (m, 2H), 2.68-2.62 (m, 4H), 2.10 (s, 3H), 1.83-1.75 (m, 2H); MS [M+H]+=558.1; LCMS RT=2.94.

Workup

  1. customThe mixture was degassed
  2. temperaturecooled to rt
  3. customThe mixture was partitioned between ethyl acetate (25 mL) and saturated aqueous Na2CO3 solution (25 mL)
  4. customThe layers were separated
  5. washthe organic phase was washed
  6. dry with materialdried (Na2SO4)
  7. concentrationconcentrated to dryness
  8. customThe residue was purified by preparative HPLC
  9. washa gradient elution from 10% to 70% acetonitrile

Sources & evidence

ORD record
ord-a8a08fe6325044eb8540bce5e4fc8638
Source dataset
uspto-grants-2014_09
Patent number
US08829185B2

Reaction notes

Loading…