Triethylamine → (3S,4S)-tert-butyl 3-((3-carbamoyl-6-(3-methylisoxazol-5-yl)pyrrolo[1,2-b]pyridazin-4-yl)amino)-4-ethylpyrrolidine-1-carboxylate

HRID 877803Notes

Reaction equation

HRID 877803 reaction equation
[C:1]([C:4]1[CH:9]=[N:8][N:7]2[CH:10]=[C:11]([C:13]#[CH:14])[CH:12]=[C:6]2[C:5]=1[NH:15][C@H:16]1[C@@H:20]([CH2:21][CH3:22])[CH2:19][N:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:17]1)(=[O:3])[NH2:2].C(N(CC)CC)C.[OH:37]/[N:38]=[C:39](\Cl)/[CH3:40]>ClCCl>[C:1]([C:4]1[CH:9]=[N:8][N:7]2[CH:10]=[C:11]([C:13]3[O:37][N:38]=[C:39]([CH3:40])[CH:14]=3)[CH:12]=[C:6]2[C:5]=1[NH:15][C@H:16]1[C@@H:20]([CH2:21][CH3:22])[CH2:19][N:18]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[CH2:17]1)(=[O:3])[NH2:2]

Participants

5

Reactant 3

HCID 8471TriethylamineHCID 5464216N-hydroxyacetimidoyl chlorideHCID 86707904(3S,4S)-tert-butyl 3-((3-carbamoyl-6-ethynylpyrrolo[1,2-b]pyridazin-4-yl)amino)-4-ethylpyrrolidine-1-carboxylate

Product 1

HCID 68291147(3S,4S)-tert-butyl 3-((3-carbamoyl-6-(3-methylisoxazol-5-yl)pyrrolo[1,2-b]pyridazin-4-yl)amino)-4-ethylpyrrolidine-1-carboxylateYield 63.7%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Conditions

Temperature
40 °C

Procedure

To a solution of (3S,4S)-tert-butyl 3-((3-carbamoyl-6-ethynylpyrrolo[1,2-b]pyridazin-4-yl)amino)-4-ethylpyrrolidine-1-carboxylate from Step 2 (88 mg, 0.221 mmol) in dichloromethane (2 mL) and triethylamine (0.046 mL, 0.332 mmol) was added (Z)—N-hydroxyacetimidoyl chloride (25.9 mg, 0.277 mmol). The solution was stirred at 40° C. overnight. After stirring overnight, the reaction was cooled to room temperature and diluted with dichloromethane. This solution was washed once with aqueous potassium carbonate, and once with water. It was then dried over sodium sulfate, filtered and concentrated. The crude material was purified by flash chromatography, eluting with 0-100% ethyl acetate in hexanes. Concentration of the pure fractions afforded the title compound (64 mg, 60.4% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.20 (t, J=9.1 Hz, 1H), 8.31 (s, 1H), 8.24 (d, J=1.3 Hz, 1H), 7.30 (br. s., 1H), 6.72 (s, 1H), 5.01-4.74 (m, 1H), 3.81-3.58 (m, 2H), 3.48-3.34 (m, 1H), 3.10-2.96 (m, 1H), 2.42 (d, J=12.8 Hz, 1H), 2.28 (s, 3H), 1.60-1.46 (m, 2H), 1.37 (d, J=19.1 Hz, 9H), 0.96-0.75 (m, 3H). MS (ES+) m/z: 455.2 (M+H); LC retention time: 3.038 min (analytical HPLC Method O).

Workup

  1. stirringAfter stirring overnight
  2. temperaturethe reaction was cooled to room temperature
  3. washThis solution was washed once with aqueous potassium carbonate
  4. dry with materialIt was then dried over sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe crude material was purified by flash chromatography
  8. washeluting with 0-100% ethyl acetate in hexanes

Sources & evidence

ORD record
ord-77e4d9b62b23413195f316409e63a03b
Source dataset
uspto-grants-2015_03
Patent number
US08987268B2

Reaction notes

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