Diisopropylethylamine → 4-(((3R,4R)-3-ethyl-1-((S)-2-hydroxybutanoyl)piperidin-4-yl)amino)-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide

HRID 877760Notes

Reaction equation

HRID 877760 reaction equation
[OH:1][C@@H:2]([CH2:6][CH3:7])[C:3](O)=[O:4].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:41]([C@H:43]1[C@H:48]([NH:49][C:50]2[C:51]3[N:52]([CH:59]=[C:60]([C:62]4[CH:63]=[N:64][N:65]([CH3:67])[CH:66]=4)[CH:61]=3)[N:53]=[CH:54][C:55]=2[C:56]([NH2:58])=[O:57])[CH2:47][CH2:46][NH:45][CH2:44]1)[CH3:42]>CN(C=O)C>[CH2:41]([C@H:43]1[C@H:48]([NH:49][C:50]2[C:51]3[N:52]([CH:59]=[C:60]([C:62]4[CH:63]=[N:64][N:65]([CH3:67])[CH:66]=4)[CH:61]=3)[N:53]=[CH:54][C:55]=2[C:56]([NH2:58])=[O:57])[CH2:47][CH2:46][N:45]([C:3](=[O:4])[C@@H:2]([OH:1])[CH2:6][CH3:7])[CH2:44]1)[CH3:42]

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 440864(S)-2-Hydroxybutyric acidHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 682916234-(((3R,4R)-3-ethylpiperidin-4-yl)amino)-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide

Product 1

HCID 682912724-(((3R,4R)-3-ethyl-1-((S)-2-hydroxybutanoyl)piperidin-4-yl)amino)-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazine-3-carboxamideYield 64%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a solution of (S)-2-hydroxybutanoic acid (3.54 mg, 0.034 mmol) in DMF (181 μl) were added DIEA (28.5 μl, 0.163 mmol) and HATU (25.9 mg, 0.068 mmol). After 15 minutes, 4-(((3R,4R)-3-ethylpiperidin-4-yl)amino)-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide (10 mg, 0.027 mmol) was added. The reaction was stirred at room temperature for 3 hrs. The product mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried with sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified via preparative HPLC (Column: Waters XBridge C18, 19×200 mm, 5-μm). The collected fractions were combined and dried via centrifugal evaporation to yield the title compound (7.9 mg, 0.017 mmol, 64.0% yield) as a white solid. 1H NMR (500 MHz, 1:1 Chloroform-d/Methanol-d4) δ 8.12-8.09 (m, 1H), 7.77 (d, J=2.5 Hz, 1H), 7.72 (d, J=3.5 Hz, 2H), 6.92-6.88 (m, 1H), 4.42-4.34 (m, 2H), 4.24-4.13 (m, 1H), 3.95 (s, 3H), 3.12-3.03 (m, 1H), 2.41-2.34 (m, 1H), 1.84-1.73 (m, 2H), 1.70-1.58 (m, 3H), 1.43-1.32 (m, 1H), 1.06-0.97 (m, 7H). LCMS (Method K) m/z 454.249 ([M+H]+). HPLC (Method F) Rt: 1.12 min.

Workup

  1. customThe product mixture was partitioned between ethyl acetate and water
  2. washThe organic layer was washed with brine
  3. dry with materialdried with sodium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated under reduced pressure
  6. customThe crude product was purified via preparative HPLC (Column: Waters XBridge C18, 19×200 mm, 5-μm)
  7. customdried via centrifugal evaporation

Sources & evidence

ORD record
ord-16b8356882bf4ae7adc01aa3633f3607
Source dataset
uspto-grants-2015_03
Patent number
US08987268B2

Reaction notes

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