Isobutylene oxide → HCID 66548285, compound

HRID 877775Notes

Reaction equation

HRID 877775 reaction equation
[CH3:1][C@H:2]1[CH2:6][N:5]([S:7]([CH3:10])(=[O:9])=[O:8])[CH2:4][C@H:3]1[NH:11][C:12]1[C:13]2[N:14]([CH:21]=[C:22]([C:24]3[CH:25]=[N:26][NH:27][CH:28]=3)[CH:23]=2)[N:15]=[CH:16][C:17]=1[C:18]([NH2:20])=[O:19].C1CCN2C(=NCCC2)CC1.[CH3:40][C:41]1([CH3:44])[CH2:43][O:42]1>C(#N)C.CO>[OH:42][C:41]([CH3:44])([CH3:43])[CH2:40][N:26]1[CH:25]=[C:24]([C:22]2[CH:23]=[C:13]3[C:12]([NH:11][C@H:3]4[C@@H:2]([CH3:1])[CH2:6][N:5]([S:7]([CH3:10])(=[O:8])=[O:9])[CH2:4]4)=[C:17]([C:18]([NH2:20])=[O:19])[CH:16]=[N:15][N:14]3[CH:21]=2)[CH:28]=[N:27]1

Participants

6

Reactant 3

HCID 11208Isobutylene oxideHCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 68291544HCID 68291544, compound

Product 1

HCID 66548285HCID 66548285, compoundYield 31.9%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 6342AcetonitrileSolvent

Conditions

Temperature
60 °C

Procedure

To slurry of 4-((3S,4S)-4-methyl-1-(methylsulfonyl)pyrrolidin-3-ylamino)-6-(1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide (Example 211, 40 mg, 0.099 mmol) in acetonitrile (0.3 mL) was added DBU (0.060 mL, 0.397 mmol) and 2,2-dimethyloxirane (25.02 mg, 0.347 mmol) and the resulting mixture was heated at 60° C. for ˜16 h. The mixture was cooled, diluted with MeOH, and was purified via preparative reverse-phase HPLC (method B). Fractions which contained the major product were combined and concentrated to give an aqueous solution which was lyophilized to afford a near white solid. This solid was triturated with 1 mL of aq sat. NaHCO3, sonicated, and the resulting solid was collected, rinsed with water and dried on the filter to afford 15 mg (30%) of the title compound as an off-white solid. HPLC (method B) retention time=2.57 min. LCMS (M+1)=476.2. 1HNMR (400 MHz, METHANOL-d4) δ 8.18 (s, 1H), 7.99 (s, 1H), 7.88 (d, J=1.5 Hz, 1H), 7.85 (s, 1H), 7.10 (d, J=1.5 Hz, 1H), 4.98-4.93 (m, 1H), 4.15 (s, 2H), 3.85 (dd, J=10.8, 4.4 Hz, 1H), 3.75 (dd, J=9.8, 7.8 Hz, 1H), 3.58 (dd, J=10.9, 1.7 Hz, 1H), 3.25 (t, J=10.1 Hz, 1H), 2.88 (s, 3H), 2.86-2.77 (m, 1H), 1.27-1.22 (m, 9H).

Workup

  1. temperatureThe mixture was cooled
  2. customwas purified via preparative reverse-phase HPLC (method B)
  3. concentrationconcentrated
  4. customto give an aqueous solution which
  5. customto afford a near white solid
  6. customThis solid was triturated with 1 mL of aq sat. NaHCO3
  7. customsonicated
  8. customthe resulting solid was collected
  9. washrinsed with water
  10. customdried on the
  11. filtrationfilter

Sources & evidence

ORD record
ord-e302a83e4f204e7daf75f75348577aed
Source dataset
uspto-grants-2015_03
Patent number
US08987268B2

Reaction notes

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