Azidobenzene → (3S,4S)-tert-butyl 3-((3-carbamoyl-6-(1-phenyl-1H-1,2,3-triazol-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)amino)-4-ethylpyrrolidine-1-carboxylate

HRID 877806Notes

Reaction equation

HRID 877806 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].[N:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[N+:31]=[N-:32]>C1(C)C=CC=CC=1.CN(C=O)C>[C:1]([C:4]1[CH:9]=[N:8][N:7]2[CH:10]=[C:11]([C:13]3[N:32]=[N:31][N:30]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[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 2

HCID 69319AzidobenzeneHCID 86707904(3S,4S)-tert-butyl 3-((3-carbamoyl-6-ethynylpyrrolo[1,2-b]pyridazin-4-yl)amino)-4-ethylpyrrolidine-1-carboxylate

Product 1

HCID 68291098(3S,4S)-tert-butyl 3-((3-carbamoyl-6-(1-phenyl-1H-1,2,3-triazol-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)amino)-4-ethylpyrrolidine-1-carboxylateYield 44.3%

Reagents, catalysts & solvents 2

HCID 1140TolueneSolventHCID 6228DimethylformamideSolvent

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 of Example 292 (71 mg, 0.179 mmol) in toluene (2 mL) and DMF (0.2 mL) was added azidobenzene (149 mg, 1.250 mmol). The flask was purged with nitrogen, and the reaction solution was stirred at room temperature for 1 hour, then warmed to 95° C. After stirring over two nights, the reaction was cooled to room temperature. The volatiles were removed in vacuo and the residue was diluted with 3 mL DMF and purified by via preparative HPLC with the following conditions: Column: Phenomenex Luna C18, 21.5×250 mm, 5-μm particles; Mobile Phase A: 10:90 methanol:water with 0.1% trifluoroacetic acid; Mobile Phase B: 90:10 methanol:water with 0.1% trifluoroacetic acid; Gradient: 30-100% B over 14 minutes, then a 2-minute hold at 100% B; Flow: 25 mL/min. Fractions containing the desired product were combined and concentrated via centrifugal evaporation to remove the methanol. The solution was neutralized with 1N NaOH, and was then partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was dried over sodium sulfate. Filtration and evaporation afforded the title compound (41 mg, 42% yield). MS (ES+) m/z: 517.1 (M+H); LC retention time: 3.385 min (analytical LCMS Method J).

Workup

  1. customThe flask was purged with nitrogen
  2. temperaturewarmed to 95° C
  3. stirringAfter stirring over two nights
  4. temperaturethe reaction was cooled to room temperature
  5. customThe volatiles were removed in vacuo
  6. additionthe residue was diluted with 3 mL DMF
  7. custompurified by via preparative HPLC with the following conditions
  8. waitGradient: 30-100% B over 14 minutes
  9. customa 2-minute hold
  10. additionFractions containing the desired product
  11. concentrationconcentrated via centrifugal evaporation
  12. customto remove the methanol
  13. customwas then partitioned between ethyl acetate and saturated aqueous sodium bicarbonate
  14. dry with materialThe organic layer was dried over sodium sulfate
  15. filtrationFiltration and evaporation

Sources & evidence

ORD record
ord-4bc68c3559ba4f03af053802e97e75c0
Source dataset
uspto-grants-2015_03
Patent number
US08987268B2

Reaction notes

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