Potassium Phosphate, Tribasic → (S)-4-(4,4-dimethylpyrrolidin-3-ylamino)-6-(2-methoxypyridin-4-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide

HRID 877810노트

반응식

HRID 877810 반응식
Br[C:2]1[CH:3]=[C:4]2[C:9]([NH:10][CH:11]3[CH2:15][N:14](C(OCC4C=CC=CC=4)=O)[CH2:13][C:12]3([CH3:27])[CH3:26])=[C:8]([C:28](=[O:30])[NH2:29])[CH:7]=[N:6][N:5]2[CH:31]=1.[CH3:32][O:33][C:34]1[CH:39]=[C:38](B(O)O)[CH:37]=[CH:36][N:35]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+].I[Si](C)(C)C>O1CCOCC1.CCOCC>[CH3:27][C:12]1([CH3:26])[CH2:13][NH:14][CH2:15][C@H:11]1[NH:10][C:9]1[C:4]2[N:5]([CH:31]=[C:2]([C:38]3[CH:37]=[CH:36][N:35]=[C:34]([O:33][CH3:32])[CH:39]=3)[CH:3]=2)[N:6]=[CH:7][C:8]=1[C:28]([NH2:29])=[O:30]

참가 물질

8

반응물 5

HCID 62657Potassium Phosphate, TribasicHCID 85247Trimethylsilyl iodideHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 23546919(2-Methoxypyridin-4-yl)boronic acidHCID 68291595Benzyl 4-((6-bromo-3-carbamoylpyrrolo[1,2-b]pyridazin-4-yl)amino)-3,3-dimethylpyrrolidine-1-carboxylate

생성물 1

HCID 68290815(S)-4-(4,4-dimethylpyrrolidin-3-ylamino)-6-(2-methoxypyridin-4-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide수율 41.7%

시약·촉매·용매 2

HCID 3283Diethyl Ether용매HCID 312751,4-Dioxane용매

반응 조건

온도
100 °C

실험 절차

A solution of benzyl 4-((6-bromo-3-carbamoylpyrrolo[1,2-b]pyridazin-4-yl)amino)-3,3-dimethylpyrrolidine-1-carboxylate (35 mg, 0.072 mmol) in 1,4-dioxane (0.3 mL), was added (2-methoxypyridin-4-yl)boronic acid (14.3 mg, 0.094 mmol), X-Phos (3.43 mg, 7.2 μmol) and potassium phosphate (2 M, 0.115 mL, 0.23 mmol). The reaction vial was purged with nitrogen, sealed and heated at 100° C. for 18 h. The reaction was diluted with ethyl acetate (50 mL), washed with aq. sodium bicarbonate and brine. The organic layer was dried and concentrated. The residue was suspended in acetonitrile (5 mL), was added iodotrimethylsilane (36.0 mg, 0.180 mmol) at 0° C., stirred at rt for 1 h. To the suspension was added ether (30 mL), stirred for additional 2 h, filtered and rinsed the collected solid with ether and dried to give the hydroiodide salt of the title compound (15 mg, 0.030 mmol, 41.0% yield) as a yellow solid. 1H NMR (500 MHz, METHANOL-d4) δ 8.15 (s, 1H), 8.09 (d, J=5.4 Hz, 1H), 8.01 (d, J=1.5 Hz, 1H), 7.58 (s, 3H), 7.31 (d, J=1.5 Hz, 1H), 7.25 (dd, J=5.4, 1.5 Hz, 1H), 7.09 (d, J=1.0 Hz, 1H), 4.61-4.54 (m, 1H), 4.30 (br. s., 1H), 3.94 (s, 3H), 3.73 (dd, J=11.9, 6.9 Hz, 1H), 3.12-3.04 (m, 2H), 1.97 (s, 2H), 1.24 (d, J=14.4 Hz, 6H), MS (ES+) m/z: 380.2, 381.3 (M+H); LC retention time: 0.84 min (analytical HPLC Method I).

후처리

  1. customThe reaction
  2. customvial was purged with nitrogen
  3. customsealed
  4. additionThe reaction was diluted with ethyl acetate (50 mL)
  5. washwashed with aq. sodium bicarbonate and brine
  6. customThe organic layer was dried
  7. concentrationconcentrated
  8. stirringstirred for additional 2 h
  9. filtrationfiltered
  10. washrinsed the collected solid with ether
  11. customdried

출처 및 근거

ORD 기록
ord-4e8a25466e114db8ab083f6d236cb1df
출처 데이터셋
uspto-grants-2015_03
특허 번호
US08987268B2

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