Diisopropylethylamine → HCID 44464039, compound

HRID 2381455Notes

Reaction equation

HRID 2381455 reaction equation
[CH:1]1([CH2:5][CH:6]([N:10]2[C:15](=[O:16])[CH:14]=[C:13]([O:17][C:18]3[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=3[F:25])[CH:12]=[N:11]2)[C:7](O)=[O:8])[CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:62][C:63]1[CH:67]=[CH:66][N:65]([CH2:68][C:69]([CH3:72])([OH:71])[CH3:70])[N:64]=1>CN(C)C=O.C(OCC)(=O)C>[CH:1]1([CH2:5][CH:6]([N:10]2[C:15](=[O:16])[CH:14]=[C:13]([O:17][C:18]3[C:19]([F:25])=[CH:20][CH:21]=[CH:22][C:23]=3[F:24])[CH:12]=[N:11]2)[C:7]([NH:62][C:63]2[CH:67]=[CH:66][N:65]([CH2:68][C:69]([OH:71])([CH3:70])[CH3:72])[N:64]=2)=[O:8])[CH2:4][CH2:3][CH2:2]1

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 151348Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphateHCID 57919282HCID 57919282, compound2×HCID 593449381-(3-amino-1H-pyrazol-1-yl)-2-methylpropan-2-ol2×

Product 1

HCID 44464039HCID 44464039, compoundYield 51%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
25 °C

Procedure

A solution of 3-cyclobutyl-2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid (Intermediate 29, 151.8 mg, 0.43 mmol) in N,N-dimethylformamide (1.67 mL, 0.26M) at 25° C. was treated with N,N-diisopropylethylamine (0.21 mL, 1.29 mmol), (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (0.28 g, 0.64 mmol) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1, 0.08 g, 0.51 mmol). The reaction was stirred at 25° C. overnight. After this time, the reaction was diluted with ethyl acetate (100 mL) and was washed with a saturated aqueous ammonium chloride solution (1×150 mL), a saturated aqueous sodium bicarbonate solution (1×150 mL) and a saturated aqueous sodium chloride solution (1×150 mL), dried over sodium sulfate, filtered, rinsed and concentrated in vacuo. Silica gel column chromatography (AnaLogix 12 g, 75-100% gradient ethyl acetate/hexanes) afforded 3-cyclobutyl-2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide (107 mg, 51%) as an off-white solid; ES+-HRMS m/e calcd for C24H27N5O4F2 [M+H+] 488.2104 found 488.2103. 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.06 (br s, 3H) 1.07 (br s, 3H) 1.45-1.66 (m, 1H) 1.69-1.89 (m, 4H) 1.88-2.03 (m, 1H) 2.02-2.41 (m, 3H) 3.90 (s, 2H) 4.67 (s, 1H) 5.35 (dd, J=10.1, 4.4 Hz, 1H) 6.02 (d, J=2.9 Hz, 1H) 6.40 (d, J=2.1 Hz, 1H) 7.34-7.44 (m, 2H) 7.44-7.51 (m, 1H) 7.53 (d, J=2.1 Hz, 1H) 8.27 (d, J=2.9 Hz, 1H) 10.83 (s, 1H).

Workup

  1. washwas washed with a saturated aqueous ammonium chloride solution (1×150 mL)
  2. dry with materiala saturated aqueous sodium bicarbonate solution (1×150 mL) and a saturated aqueous sodium chloride solution (1×150 mL), dried over sodium sulfate
  3. filtrationfiltered
  4. washrinsed
  5. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-e95d634aa71848a0ba2ba709a2807f18
Source dataset
uspto-grants-2012_09
Patent number
US08258134B2

Reaction notes

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