Water → HCID 136079973, compound

HRID 481083Notes

Reaction equation

HRID 481083 reaction equation
[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].C[Al](C)C.C([O:15][C:16]([C:18]1[C:27]2[C:26]3=[N:28][N:29]([CH3:31])[CH:30]=[C:25]3[CH2:24][CH2:23][CH2:22][C:21]=2[NH:20][CH:19]=1)=O)C.O>C(Cl)Cl.[NH4+].[Cl-].CCOCC>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:16]([C:18]1[C:27]2[C:26]3=[N:28][N:29]([CH3:31])[CH:30]=[C:25]3[CH2:24][CH2:23][CH2:22][C:21]=2[NH:20][CH:19]=1)=[O:15]

Participants

8

Reactant 4

HCID 962WaterHCID 95842-FluoroanilineHCID 16682925TrimethylaluminumHCID 136079971HCID 136079971, compound

Product 1

HCID 136079973HCID 136079973, compoundYield 60.1%

Reagents, catalysts & solvents 3

HCID 3283Diethyl EtherSolventHCID 6344DichloromethaneSolventHCID 25517Ammonium ChlorideSolvent

Procedure

To a solution of 2-fluoroaniline (103 mg, 0.926 mmol) in CH2Cl2 (2.0 mL) at 0° C. under N2 is slowly added AlMe3 (0.46 mL, 2.0 M in toluene). The resulting solution is stirred at room temperature for 1 h. Next, 2-methyl-4,5,6,7-tetrahydro-2H-1,2,7-triaza-cyclopenta[e]azulene-9-carboxylic acid ethyl ester (60 mg, 0.231 mmol) is added in one portion. The resulting mixture is then stirred at reflux for 2 h. After cooling, the reaction mixture is carefully diluted with saturated aq NH4Cl (˜5 mL) and some H2O. The mixture is stirred vigorously for 30 min. and then extracted three times with CH2Cl2(containing some (˜5%) MeOH). The combined extracts are dried over K2CO3 and concentrated. The crude material is purified by flash chromatography on silica gel. Elution with 40:1 CHCl3-MeOH followed by 30:1 CHCl3-MeOH and finally 20:1 CHCl3-MeOH afforded, after concentration of the fractions containing pure product, a residue, which is then granulated with Et2O. The suspension is filtered, and the solid washed with Et2O and dried, affording 45 mg (60%) of 2-methyl-4,5,6,7-tetrahydro-2H-1,2,7-triaza-cyclopenta[e]azulene-9-carboxylic acid (2-fluoro-phenyl)-amide as an off-white solid. Electrospray mass spectrum: m/z 325 [M+1].

Workup

  1. customat 0° C.
  2. stirringThe resulting mixture is then stirred
  3. temperatureat reflux for 2 h
  4. temperatureAfter cooling
  5. stirringThe mixture is stirred vigorously for 30 min.
  6. extractionextracted three times with CH2Cl2(
  7. additioncontaining some (˜5%) MeOH)
  8. dry with materialThe combined extracts are dried over K2CO3
  9. concentrationconcentrated
  10. customThe crude material is purified by flash chromatography on silica gel
  11. washElution with 40:1 CHCl3-MeOH
  12. customafforded
  13. additionafter concentration of the fractions containing pure product
  14. filtrationThe suspension is filtered
  15. washthe solid washed with Et2O
  16. customdried

Sources & evidence

ORD record
ord-16be2a3197b842919eb876bcd65d6345
Source dataset
uspto-grants-2003_11
Patent number
US06653471B2

Reaction notes

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