Trimethylaluminum → N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]-4-[(3R,5S)-3,5-dimethylpiperazin-1-yl]benzamide

HRID 16799Notes

Reaction equation

HRID 16799 reaction equation
C[Al](C)C.[CH3:5][C@H:6]1[NH:11][C@@H:10]([CH3:12])[CH2:9][N:8]([C:13]2[CH:23]=[CH:22][C:16]([C:17]([O:19]CC)=O)=[CH:15][CH:14]=2)[CH2:7]1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH2:34][O:35][C:36]2[CH:37]=[C:38]([NH2:41])[NH:39][N:40]=2)[CH:29]=[C:30]([O:32][CH3:33])[CH:31]=1>C1(C)C=CC=CC=1>[CH3:33][O:32][C:30]1[CH:29]=[C:28]([CH2:34][O:35][C:36]2[CH:37]=[C:38]([NH:41][C:17](=[O:19])[C:16]3[CH:15]=[CH:14][C:13]([N:8]4[CH2:9][C@H:10]([CH3:12])[NH:11][C@H:6]([CH3:5])[CH2:7]4)=[CH:23][CH:22]=3)[NH:39][N:40]=2)[CH:27]=[C:26]([O:25][CH3:24])[CH:31]=1

Participants

5

Reactant 3

HCID 16682925TrimethylaluminumHCID 23381002Ethyl 4-((3S,5R)-3,5-dimethylpiperazin-1-yl)benzoateHCID 574403815-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-amine

Product 1

HCID 66589904N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]-4-[(3R,5S)-3,5-dimethylpiperazin-1-yl]benzamideYield 41.1%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent2×

Conditions

Temperature
60 °C

Procedure

A 2M solution of trimethylaluminium in toluene (1.875 mL, 3.75 mmol) was added dropwise to a stirred suspension of ethyl 4-((3R,5S)-3,5-dimethylpiperazin-1-yl)benzoate (0.394 g, 1.50 mmol) and 5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-amine (0.374 g, 1.5 mmol) in toluene (10 mL) at 20° C., over a period of 5 mins under nitrogen. The resulting solution was stirred at 60° C. for 5 h. The reaction mixture was cooled and the reaction quenched by diluting with acetone (100 ml) and excess damp sodium sulphite added in portions. This was stirred for 60 mins. The resulting solid filtered off, washed with 10% methanol in DCM. The filtrate was evaporated to give crude product. The crude product was purified by silica column chromatography, eluting with a gradient of 0 to 5% 2M ammonia/MeOH in DCM. Pure fractions were evaporated to dryness to afford the title compound (0.287 g, 41.1%) as a white solid. 1H NMR (500.13 MHz, DMSO-d6) δ 1.08 (6H, d), 2.31 (2H, t), 3.70-3.73 (2H, m), 3.78 (6H, s), 5.10 (2H, s), 5.64 (1H, s), 6.46 (1H, t), 6.62 (2H, d), 6.95-6.97 (2H, m), 7.83-7.85 (2H, m), 10.21 (1H, s), 11.09 (1H, s). MS: m/z 466 (MH+).

Workup

  1. temperatureThe reaction mixture was cooled
  2. customthe reaction quenched
  3. additionby diluting with acetone (100 ml) and excess damp sodium sulphite
  4. additionadded in portions
  5. stirringThis was stirred for 60 mins
  6. filtrationThe resulting solid filtered off
  7. washwashed with 10% methanol in DCM
  8. customThe filtrate was evaporated
  9. customto give crude product
  10. customThe crude product was purified by silica column chromatography
  11. washeluting with a gradient of 0 to 5% 2M ammonia/MeOH in DCM
  12. customPure fractions were evaporated to dryness

Sources & evidence

ORD record
ord-a3c7ae5a9b7e485491ba818273103dc6
Source dataset
uspto-grants-2010_06
Patent number
US07737149B2

Reaction notes

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