Diisopropylethylamine → HCID 178436598, compound

HRID 1874891Notes

Reaction equation

HRID 1874891 reaction equation
[NH2:1][CH2:2][C:3]1[C:4]([F:21])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([CH:19]=[CH2:20])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.[Cl:22][C:23]1[N:24]=[CH:25][N:26](COCC[Si](C)(C)C)[C:27]=1[C:28](O)=[O:29].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[Cl:22][C:23]1[N:24]=[CH:25][NH:26][C:27]=1[C:28]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([O:10][C:11]2[CH:18]=[C:17]([CH:19]=[CH2:20])[CH:16]=[C:13]([C:14]#[N:15])[CH:12]=2)[C:4]=1[F:21])=[O:29]

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 684855334-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxylic acidHCID 684888433-{[3-(Aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-ethenylbenzonitrile

Product 1

HCID 178436598HCID 178436598, compoundYield 37.1%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-ethenylbenzonitrile (0.076 g, 0.251 mmol), 4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxylic acid (0.069 g, 0.251 mmol) and DIPEA (0.088 mL, 0.502 mmol) were combined in THF (2 mL) and treated with HATU (0.105 g, 0.276 mmol) at 25° C. overnight with stirring. The reaction mixture was concentrated to dryness, dissolved in DCM, washed with water, dried over MgSO4, filtered and concentrated to dryness. The residue was dissolved in DCM (2.5 mL) and treated with TFA (2.5 mL) at 25° C. for 3 days. The reaction mixture was concentrated to dryness and partitioned between EtOAc and saturated aqueous NaHCO3. The organic phase was isolated, dried over MgSO4, filtered and concentrated to dryness. The crude material was purified on an XTerra™ C-18 column eluted with 5 to 90% CH3CN/H2O (0.2% NH4OH buffer). Appropriate fractions were combined, concentrated to dryness, chased twice with ethanol and twice with toluene to remove residual water to give 4-chloro-N-({4-chloro-3-[(3-cyano-5-ethenyl phenyl)oxy]-2-fluorophenyl}methyl)-1H-imidazole-5-carboxamide (0.040 g, 0.093 mmol, 36.9% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.2 (br. s., 1H), 8.31 (br. s., 1H), 7.80 (s, 1H), 7.77 (s, 1H), 7.26-7.53 (m, 4H), 6.75 (dd, 1H), 6.04 (d, 1H), 5.44 (d, 1H), 4.53 (d, 2H). LC-MS (ES−) m/z 429.08, 431.11, 433.00 [M−1]. LC-MS (ES+) m/z 430.97, 432.95, 434.95 [M+H].

Workup

  1. concentrationThe reaction mixture was concentrated to dryness
  2. dissolutiondissolved in DCM
  3. washwashed with water
  4. dry with materialdried over MgSO4
  5. filtrationfiltered
  6. concentrationconcentrated to dryness
  7. dissolutionThe residue was dissolved in DCM (2.5 mL)
  8. additiontreated with TFA (2.5 mL) at 25° C. for 3 days
  9. concentrationThe reaction mixture was concentrated to dryness
  10. custompartitioned between EtOAc and saturated aqueous NaHCO3
  11. customThe organic phase was isolated
  12. dry with materialdried over MgSO4
  13. filtrationfiltered
  14. concentrationconcentrated to dryness
  15. customThe crude material was purified on an XTerra™ C-18 column
  16. washeluted with 5 to 90% CH3CN/H2O (0.2% NH4OH buffer)
  17. concentrationconcentrated to dryness
  18. customto remove residual water

Sources & evidence

ORD record
ord-bae22b02bc1746818918b64ae19a7188
Source dataset
uspto-grants-2012_11
Patent number
US08304419B2

Reaction notes

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