Water → 6-(3,4-dimethoxyphenyl)-4-((R)-1-((R)-5-oxopyrrolidin-3-yl)ethoxy)pyrazolo[1,5-a]pyrazine-3-carbonitrile

HRID 2209227노트

반응식

HRID 2209227 반응식
Cl[C:2]1[N:3]=[C:4]([O:13][C@@H:14]([C@@H:16]2[CH2:20][C:19](=[O:21])[NH:18][CH2:17]2)[CH3:15])[C:5]2[N:6]([N:8]=[CH:9][C:10]=2[C:11]#[N:12])[CH:7]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][C:29]=1[O:30][CH3:31].[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[CH3:22][O:23][C:24]1[CH:25]=[C:26]([C:2]2[N:3]=[C:4]([O:13][C@@H:14]([C@@H:16]3[CH2:20][C:19](=[O:21])[NH:18][CH2:17]3)[CH3:15])[C:5]3[N:6]([N:8]=[CH:9][C:10]=3[C:11]#[N:12])[CH:7]=2)[CH:27]=[CH:28][C:29]=1[O:30][CH3:31]

참가 물질

7

반응물 4

HCID 962WaterHCID 62657Potassium Phosphate, TribasicHCID 27347023,4-Dimethoxyphenylboronic acidHCID 1178433286-chloro-4-((R)-1-((R)-5-oxopyrrolidin-3-yl)ethoxy)pyrazolo[1,5-a]pyrazine-3-carbonitrile

생성물 1

HCID 1178437326-(3,4-dimethoxyphenyl)-4-((R)-1-((R)-5-oxopyrrolidin-3-yl)ethoxy)pyrazolo[1,5-a]pyrazine-3-carbonitrile

시약·촉매·용매 2

HCID 11714597Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)촉매HCID 312751,4-Dioxane용매

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온도
100 °C

실험 절차

Crude intermediate 5.65 from the previous step, (3,4-dimethoxyphenyl)boronic acid (34 mg, 0.19 mmol), K3PO4 (79 mg, 0.37 mmol) and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (3.3 mg, 0.005 mmol) were taken up in 1,4-dioxane (1.35 mL) and water (0.14 mL) under Ar. The stirred reaction mixture was heated to 100° C. After stirring 16 h, the reaction mixture was partitioned between EtOAc, water, and brine and the resulting emulsion was filtered through a pad of Celite. The Celite was washed with DCM to elute all product and the resulting filtrate was concentrated in vacuo. The concentrate was purified by silica gel chromatography (0-20% MeOH in DCM) to provide 6-(3,4-dimethoxyphenyl)-4-((R)-1-((R)-5-oxopyrrolidin-3-yl)ethoxy)pyrazolo[1,5-a]pyrazine-3-carbonitrile 5.66. LCMS-ESI+ (m/z): [M+H]+ calcd for C21H22N5O4: 408.2; found: 407.9. 1H NMR (400 MHz, DMSO-d6) δ 9.22 (s, 1H), 8.68 (s, 1H), 7.70 (dd, J=8.4, 2.1 Hz, 1H), 7.66 (d, J=2.1 Hz, 1H), 7.55 (s, 1H), 7.06 (d, J=8.5 Hz, 1H), 5.56-5.45 (m, 1H), 3.86 (s, 3H), 3.80 (s, 3H), 3.41-3.33 (m, 1H), 3.25-3.15 (m, 1H), 2.93-2.81 (m, 1H), 2.35-2.27 (m, 2H), 1.46 (d, J=6.2 Hz, 3H).

후처리

  1. customThe stirred reaction mixture
  2. customthe reaction mixture was partitioned between EtOAc, water, and brine
  3. filtrationthe resulting emulsion was filtered through a pad of Celite
  4. washThe Celite was washed with DCM
  5. washto elute all product
  6. concentrationthe resulting filtrate was concentrated in vacuo
  7. customThe concentrate was purified by silica gel chromatography (0-20% MeOH in DCM)

출처 및 근거

ORD 기록
ord-16ba2a468ec046d59cdf0e2dbfb8bcec
출처 데이터셋
uspto-grants-2016_06
특허 번호
US09376441B2

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