3-Methyl-5-isoxazolecarboxylic acid → HCID 24955179, compound

HRID 1801612Notes

Reaction equation

HRID 1801612 reaction equation
[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]([OH:9])=O)[CH:3]=1.C(N(C(C)C)CC)(C)C.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([NH:28][C@@H:29]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=2)[CH3:30])[CH3:27])=[CH:22][C:21]=1[NH2:38].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O.CCOC(C)=O>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([NH:28][C@@H:29]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=2)[CH3:30])[CH3:27])=[CH:22][C:21]=1[NH:38][C:7]([C:4]1[CH:3]=[C:2]([CH3:1])[O:6][N:5]=1)=[O:9]

Participants

8

Reactant 4

HCID 769473-Methyl-5-isoxazolecarboxylic acidHCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 59803155HCID 59803155, compound

Product 1

HCID 24955179HCID 24955179, compoundYield 70.3%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

A solution of 5-methylisoxazole-3-carboxylic acid (8.6 mg, 68 μmol), diisopropylethylamine (12 μL, 68 μmol), and 2-chloro-5-(1-((R)-1-(3-chlorophenyl)ethylamino)ethyl)benzenamine 109 (21 mg, 68 μmol) in DMF was stirred under N2 and chilled to 0° C. HATU (26 mg, 68 μmol) was then added to the solution. The reaction was allowed to warm to room temperature and stirred for 3 h. Afterwards, the reaction was diluted with water and EtOAc. The organic solution was extracted with saturated NaHCO3, water, and brine. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography using a 5% to 60% gradient of EtOAc in hexanes as the eluent. The desired fractions were combined and concentrated to give N-(2-chloro-5-(1-((R)-1-(3-chlorophenyl)ethylamino)ethyl)phenyl)-5-methylisoxazole-3-carboxamide 110 (20 mg, 70% yield) as a colorless oil and as a mixture of diastereomers. 1H NMR (400 MHz, MeOH) δ ppm 1.60-1.66 (m, 6H) 2.53 (s, 3H) 4.19 (m, 2H) 6.61 (s, 1H) 7.19 (dd, J=8.31, 2.05 Hz, 1H) 7.30 (m, 1H) 7.40 (s, 1H) 7.48 (d, J=4.89 Hz, 2H) 7.63 (d, J=8.41 Hz, 1H) 8.09 (s, 1H). Mass spectrum: calculated for C21H21Cl2N3O2 418.3. found 418.4 (M++1).

Workup

  1. temperatureto warm to room temperature
  2. extractionThe organic solution was extracted with saturated NaHCO3, water, and brine
  3. dry with materialThe organic layer was dried over MgSO4
  4. filtrationfiltered
  5. concentrationconcentrated in vacuo
  6. customThe crude material was purified by silica gel chromatography
  7. concentrationconcentrated

Sources & evidence

ORD record
ord-bcb331e99667401d9259f76949562c73
Source dataset
uspto-grants-2013_01
Patent number
US08349831B2

Reaction notes

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