Diisopropylamine → (3S,4S)-tert-butyl 3-((3-carbamoyl-6-ethynylpyrrolo[1,2-b]pyridazin-4-yl)amino)-4-ethylpyrrolidine-1-carboxylate

HRID 877802Notes

Reaction equation

HRID 877802 reaction equation
Br[C:2]1[CH:3]=[C:4]2[C:9]([NH:10][C@H:11]3[C@@H:15]([CH2:16][CH3:17])[CH2:14][N:13]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:12]3)=[C:8]([C:25](=[O:27])[NH2:26])[CH:7]=[N:6][N:5]2[CH:28]=1.[CH:29](NC(C)C)(C)[CH3:30].C([Si](C)(C)C)#C.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:25]([C:8]1[CH:7]=[N:6][N:5]2[CH:28]=[C:2]([C:29]#[CH:30])[CH:3]=[C:4]2[C:9]=1[NH:10][C@H:11]1[C@@H:15]([CH2:16][CH3:17])[CH2:14][N:13]([C:18]([O:20][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:19])[CH2:12]1)(=[O:27])[NH2:26]

Participants

9

Reactant 4

HCID 7912DiisopropylamineHCID 11430Potassium CarbonateHCID 66111TrimethylsilylacetyleneHCID 68290979(3S,4S)-tert-butyl 3-((6-bromo-3-carbamoylpyrrolo[1,2-b]pyridazin-4-yl)amino)-4-ethylpyrrolidine-1-carboxylate

Product 1

HCID 86707904(3S,4S)-tert-butyl 3-((3-carbamoyl-6-ethynylpyrrolo[1,2-b]pyridazin-4-yl)amino)-4-ethylpyrrolidine-1-carboxylateYield 57.9%

Reagents, catalysts & solvents 4

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418476HCID 178418476, compoundCatalystHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

A mixture of (3S,4S)-tert-butyl 3-((6-bromo-3-carbamoylpyrrolo[1,2-b]pyridazin-4-yl)amino)-4-ethylpyrrolidine-1-carboxylate (330 mg, 0.730 mmol), bis(triphenylphosphine)-palladium(II) chloride (154 mg, 0.219 mmol) and copper(I) iodide (41.7 mg, 0.219 mmol) in DMF (4 mL) was stirred and degassed by bubbling nitrogen through for 15 minutes. While maintaining positive nitrogen pressure, bis(isopropyl)amine (2.58 mL, 18.24 mmol) and ethynyltrimethylsilane (0.515 mL, 3.65 mmol) were added. The flask was immediately placed in a hot oil bath at 90° C. After stirring overnight at 90° C., the reaction was complete. The reaction was then cooled to room temperature and diluted with ethyl acetate (50 mL). This mixture was filtered through Celite, and was concentrated to an oil. This crude material was suspended in MeOH (5 mL) and potassium carbonate (121 mg, 0.876 mmol) was added. After stirring the mixture at room temperature for 1 h, the insoluble solids were removed by filtration, and the resulting solution was concentrated to an oil. This crude material was purified by flash chromatography, eluting with 0-100% EtOAc in hexanes. Concentration of the pure fractions afforded a brown solid as the title compound (168 mg, 56.7% yield). 1H NMR (400 MHz, DMSO-d6) δ 11.14 (t, J=9.0 Hz, 1H), 8.27 (s, 1H), 7.96 (d, J=1.3 Hz, 1H), 7.06 (s, 1H), 4.85-4.65 (m, 1H), 4.10 (d, J=1.8 Hz, 1H), 3.73-3.54 (m, 2H), 3.43-3.24 (m, 1H), 3.08-2.92 (m, 1H), 2.44-2.26 (m, 1H), 1.55-1.43 (m, 2H), 1.36 (d, J=15.4 Hz, 9H), 0.86 (t, J=7.4 Hz, 3H). MS (ES+) m/z: 398.2 (M+H); LC retention time: 2.993 min (analytical HPLC Method O).

Workup

  1. customdegassed
  2. customby bubbling nitrogen through for 15 minutes
  3. additionwere added
  4. customThe flask was immediately placed in a hot oil bath at 90° C
  5. stirringAfter stirring overnight at 90° C.
  6. filtrationThis mixture was filtered through Celite
  7. concentrationwas concentrated to an oil
  8. stirringAfter stirring the mixture at room temperature for 1 h
  9. customthe insoluble solids were removed by filtration
  10. concentrationthe resulting solution was concentrated to an oil
  11. customThis crude material was purified by flash chromatography
  12. washeluting with 0-100% EtOAc in hexanes

Sources & evidence

ORD record
ord-7cdd12a840eb44c5addd6fed3608b605
Source dataset
uspto-grants-2015_03
Patent number
US08987268B2

Reaction notes

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