Potassium Phosphate, Tribasic → (R)-4-((R)-1-(3-(difluoromethyl)-6-(4-morpholinophenyl)-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)pyrrolidin-2-one

HRID 2209070노트

반응식

HRID 2209070 반응식
Cl[C:2]1[N:7]=[C:6]([O:8][C@@H:9]([C@H:11]2[CH2:15][NH:14][C:13](=[O:16])[CH2:12]2)[CH3:10])[C:5]2[N:17]([CH:20]([F:22])[F:21])[CH:18]=[N:19][C:4]=2[CH:3]=1.[O:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=2)[CH2:25][CH2:24]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.CCOC(C)=O.O.[Cl-].[Na+].O>[F:21][CH:20]([F:22])[N:17]1[C:5]2[C:6]([O:8][C@@H:9]([C@H:11]3[CH2:15][NH:14][C:13](=[O:16])[CH2:12]3)[CH3:10])=[N:7][C:2]([C:32]3[CH:31]=[CH:30][C:29]([N:26]4[CH2:25][CH2:24][O:23][CH2:28][CH2:27]4)=[CH:34][CH:33]=3)=[CH:3][C:4]=2[N:19]=[CH:18]1

참가 물질

8

반응물 3

HCID 62657Potassium Phosphate, TribasicHCID 2795359(4-(Morpholin-4-yl)phenyl)boronic acidHCID 117842863(R)-4-((R)-1-(6-chloro-3-(difluoromethyl)-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)pyrrolidin-2-one

생성물 1

HCID 117843265(R)-4-((R)-1-(3-(difluoromethyl)-6-(4-morpholinophenyl)-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)pyrrolidin-2-one

시약·촉매·용매 4

HCID 962Water용매2회HCID 8857Ethyl Acetate용매HCID 312751,4-Dioxane용매HCID 57417360Sodium chloride; water용매

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온도
100 °C

실험 절차

Intermediate 2.64 (24 mg, 0.073 mmol), 4-morpholinophenylboronic acid (33 mg, 0.16 mmol), Bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium(II) (1.7 mg, 0.0024 mmol) and K3PO4 (52 mg, 0.25 mmol) were taken up in 1,4-dioxane (0.9 mL) under Ar. Water (0.1 mL) was added and the resulting stirred mixture was heated to 100° C. After 1.75 h, the reaction mixture was cooled to r.t. and was diluted with EtOAc (2 mL), water (1 mL), and brine (1 mL). The phases were separated, and the aqueous phase was extracted with EtOAc (4×1.5 mL). The combined organic phase was dried over Na2SO4, filtered, and concentrated. The resulting crude residue was purified by silica gel chromatography (0% to 15% MeOH in DCM) to afford (R)-4-((R)-1-(3-(difluoromethyl)-6-(4-morpholinophenyl)-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)pyrrolidin-2-one 3.24. LCMS-ESI+ (m/z): [M+H]+ calcd for C23H26F2N5O3: 458.2; found 458.0. 1H NMR (400 MHz, Chloroform-d) δ 8.26 (s, 1H), 7.99-7.88 (m, 2H), 7.72 (s, 1H), 7.61 (t, J=61.1 Hz, 1H), 7.05-6.95 (m, 2H), 6.05 (s, 1H), 5.79-5.67 (m, 1H), 3.94-3.83 (m, 4H), 3.62-3.53 (m, 1H), 3.37 (dd, J=9.7, 6.2 Hz, 1H), 3.28-3.19 (m, 4H), 3.00-2.88 (m, 1H), 2.56 (dd, J=17.2, 9.3 Hz, 1H), 2.45 (dd, J=17.2, 7.4 Hz, 1H), 1.50 (d, J=6.2 Hz, 3H).

후처리

  1. temperaturethe reaction mixture was cooled to r.t.
  2. customThe phases were separated
  3. extractionthe aqueous phase was extracted with EtOAc (4×1.5 mL)
  4. dry with materialThe combined organic phase was dried over Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe resulting crude residue was purified by silica gel chromatography (0% to 15% MeOH in DCM)

출처 및 근거

ORD 기록
ord-779644eb89cb4fab97a6bf1fb2f14a22
출처 데이터셋
uspto-grants-2016_06
특허 번호
US09376441B2

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