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 2209070ノート

反応式

HRID 2209070 の反応式
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

参加物

8

反応物 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

生成物 1

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

試薬・触媒・溶媒 4

HCID 962Water溶媒2 回HCID 8857Ethyl Acetate溶媒HCID 312751,4-Dioxane溶媒HCID 57417360Sodium chloride; water溶媒

反応条件

温度
100 °C

実験手順

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).

後処理

  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)

出典と根拠

ORDレコード
ord-779644eb89cb4fab97a6bf1fb2f14a22
出典データセット
uspto-grants-2016_06
特許番号
US09376441B2

反応ノート

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