Cesium carbonate → 8-(5-chloro-2-(1-methyl-1H-pyrazol-5-ylamino)pyridin-4-ylamino)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one

HRID 1045945노트

반응식

HRID 1045945 반응식
Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:18]=2[C:17](=[O:19])[N:16]([CH3:20])[CH2:15][CH2:14]3)[C:5]([Cl:21])=[CH:4][N:3]=1.[CH3:22][N:23]1[C:27]([NH2:28])=[CH:26][CH:25]=[N:24]1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:21][C:5]1[C:6]([NH:8][C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:18]=2[C:17](=[O:19])[N:16]([CH3:20])[CH2:15][CH2:14]3)=[CH:7][C:2]([NH:28][C:27]2[N:23]([CH3:22])[N:24]=[CH:25][CH:26]=2)=[N:3][CH:4]=1

참가 물질

7

반응물 4

HCID 10796Cesium carbonateHCID 1369272-Methyl-2H-pyrazol-3-ylamineHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 866551378-[(2,5-Dichloropyridin-4-yl)amino]-2-methyl-3,4-dihydroisoquinolin-1-one

생성물 1

HCID 446090408-(5-chloro-2-(1-methyl-1H-pyrazol-5-ylamino)pyridin-4-ylamino)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one수율 69.9%

시약·촉매·용매 2

HCID 167845palladium(II) acetate촉매HCID 312751,4-Dioxane용매

반응 조건

온도
100 °C

실험 절차

8-[(2,5-Dichloropyridin-4-yl)amino]-2-methyl-3,4-dihydroisoquinolin-1-one (100 mg, 0.31 mmol, example 3.23), 1-Methylpyrazol-5-amine (60.3 mg, 0.62 mmol), cesium carbonate (121 mg, 0.37 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (28.7 mg, 0.05 mmol) and palladium(II) acetate (5.57 mg, 0.02 mmol) were suspended in dioxane (2 mL) and sealed in a tube. The reaction was degased, purged with nitrogen and heated to 100° C. for 12 hours. The reaction mixture was filtered, washed with DCM and concentrated to dryness. The reaction mixture was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (5 microns silica, 30 mm diameter, 150 mm length) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions were evaporated to dryness to afford 8-(5-chloro-2-(1-methyl-1H-pyrazol-5-ylamino)pyridin-4-ylamino)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (83 mg, 69.8%) as a grey solid. 1H NMR spectrum (500 MHz, DMSO): 2.95 (t, 2H), 3.05 (s, 3H), 3.56 (t, 2H), 3.63 (s, 3H), 6.19 (d, 1H), 6.86 (s, 1H), 6.91 (dd, 1H), 7.29 (d, 1H), 7.42 (s, 1H), 7.43 (d, 1H), 8.02 (s, 1H), 8.68 (s, 1H), 11.26 (s, 1H); Mass spectrum: ESI+ MH+ 383.

후처리

  1. customsealed in a tube
  2. customThe reaction was degased
  3. custompurged with nitrogen
  4. filtrationThe reaction mixture was filtered
  5. washwashed with DCM
  6. concentrationconcentrated to dryness
  7. customThe reaction mixture was purified by preparative HPLC
  8. customThe fractions were evaporated to dryness

출처 및 근거

ORD 기록
ord-ea761b39e4154415b5a109134833248a
출처 데이터셋
uspto-grants-2013_10
특허 번호
US08569298B2

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