Tris(hydroxymethyl)aminomethane → (S)-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)isoxazole-3-carboxamide

HRID 872492Notes

Reaction equation

HRID 872492 reaction equation
[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[O:11][N:10]=[C:9]([C:12]([OH:14])=O)[CH:8]=2)[CH:4]=[N:3]1.C1C=CC2N(O)N=NC=2C=1.N=C=N.[NH2:28][C@@H:29]([CH3:45])[CH2:30][N:31]1[CH:35]=[CH:34][C:33]([C:36]2[CH:43]=[CH:42][C:39]([C:40]#[N:41])=[C:38]([Cl:44])[CH:37]=2)=[N:32]1.C(O)C(N)(CO)CO>CN(C=O)C.C(Cl)Cl>[Cl:44][C:38]1[CH:37]=[C:36]([C:33]2[CH:34]=[CH:35][N:31]([CH2:30][C@@H:29]([NH:28][C:12]([C:9]3[CH:8]=[C:7]([C:5]4[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=4)[O:11][N:10]=3)=[O:14])[CH3:45])[N:32]=2)[CH:43]=[CH:42][C:39]=1[C:40]#[N:41]

Participants

8

Reactant 5

HCID 6503Tris(hydroxymethyl)aminomethaneHCID 757711-HydroxybenzotriazoleHCID 160435CarbodiimideHCID 31611225-(1-methyl-1H-pyrazol-4-yl)-1,2-oxazole-3-carboxylic acidHCID 67170882(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile

Product 1

HCID 70656419(S)-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)isoxazole-3-carboxamideYield 13.8%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Procedure

5-(1-methyl-1H-pyrazol-4-yl)isoxazole-3-carboxylic acid (57.9 mg, 0.3 mmol), HOBt (46 mg, 0.340 mmol) and PS-carbodiimide (364 mg), DCM (4 ml) and DMF (0.4 ml) were mixed in a glass vial. The mixture was shaken for 10 min. (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (51 mg, 0.2 mmol) was added and the mixture was stirred for 24 h. The solids were filtered off PS-Trisamine (333 mg, 1.0 mmol) was added to the filtrate. The mixture was shaken for 4 h and filtered. The filtrate was concentrated and purified by flash chromatography (gradient of DCM:MeOH) to give 12 mg of the title compound. 1H-NMR (400 MHz; CDCl3): δ 1.25 (d, 3H), 4.00 (s, 3H), 4.23-4.31 (m, 1H), 4.42-4.48 (m, 1H), 4.55-4.66 (m, 1H), 6.63 (d, 1H), 6.66 (s, 1H), 7.50 (d, 1H), 7.69 (d, 1H), 7.79-7.94 (m, 4H), 8.07 (m, 1H).

Workup

  1. additionwas added
  2. additionwas added to the filtrate
  3. stirringThe mixture was shaken for 4 h
  4. filtrationfiltered
  5. concentrationThe filtrate was concentrated
  6. custompurified by flash chromatography (gradient of DCM:MeOH)

Sources & evidence

ORD record
ord-2145a086836346bb902f4ec9f4cccc51
Source dataset
uspto-grants-2015_03
Patent number
US08975254B2

Reaction notes

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