Potassium Phosphate, Tribasic → (2-{4,4-Dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}-4-(5-{[5-(1-methoxypropan-2-yl)-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl]amino}-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)pyridin-3-yl)methyl Acetate

HRID 1022167노트

반응식

HRID 1022167 반응식
[C:1]([O:4][CH2:5][C:6]1[C:7]([N:21]2[CH2:32][CH2:31][N:30]3[C:23](=[CH:24][C:25]4[CH2:26][C:27]([CH3:34])([CH3:33])[CH2:28][C:29]=43)[C:22]2=[O:35])=[N:8][CH:9]=[CH:10][C:11]=1B1OC(C)(C)C(C)(C)O1)(=[O:3])[CH3:2].Br[C:37]1[CH:38]=[C:39]([NH:45][C:46]2[CH:59]=[C:49]3[CH2:50][N:51]([CH:54]([CH3:58])[CH2:55][O:56][CH3:57])[CH2:52][CH2:53][N:48]3[N:47]=2)[C:40](=[O:44])[N:41]([CH3:43])[CH:42]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C.O>[C:1]([O:4][CH2:5][C:6]1[C:7]([N:21]2[CH2:32][CH2:31][N:30]3[C:23](=[CH:24][C:25]4[CH2:26][C:27]([CH3:34])([CH3:33])[CH2:28][C:29]=43)[C:22]2=[O:35])=[N:8][CH:9]=[CH:10][C:11]=1[C:37]1[CH:38]=[C:39]([NH:45][C:46]2[CH:59]=[C:49]3[CH2:50][N:51]([CH:54]([CH3:58])[CH2:55][O:56][CH3:57])[CH2:52][CH2:53][N:48]3[N:47]=2)[C:40](=[O:44])[N:41]([CH3:43])[CH:42]=1)(=[O:3])[CH3:2]

참가 물질

7

반응물 4

HCID 62657Potassium Phosphate, TribasicHCID 517045Sodium AcetateHCID 86684419(2-(7,7-dimethyl-1-oxo-3,4,7,8-tetrahydro-1H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2(6H)-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)methyl acetateHCID 866845465-Bromo-3-(5-(1-methoxypropan-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]-pyrazin-2-ylamino)-1-methylpyridin-2(1H)-one

생성물 1

HCID 86684547(2-{4,4-Dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}-4-(5-{[5-(1-methoxypropan-2-yl)-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl]amino}-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)pyridin-3-yl)methyl Acetate수율 50%

시약·촉매·용매 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)촉매HCID 18373917Acetonitrile--water (1/1)용매

반응 조건

온도
100 °C

실험 절차

A 50-mL round bottomed flask equipped with a reflux condenser was charged with {3-[(acetyloxy)methyl]-2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyridin-4-yl}boronic acid 199e (238 mg, 0.60 mmol), 300c (240 mg, 0.80 mmol), K3PO4 (254 mg, 1.2 mmol), sodium acetate (98 mg, 1.6 mmol), Pd(dppf)Cl2 (22 mg, 0.030 mmol), and acetonitrile/water (12/0.5 mL). The system was subjected to three cycles of vacuum/nitrogen flush and heated at 100° C. under N2 protection for 1 h. Analysis of the reaction mixture by LCMS showed complete conversion to the desired product. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was partitioned between dichloromethane (30 mL) and water (30 mL). The water layer was extracted with dichloromethane (2×30 mL). The combined organic extract was dried over Na2SO4, filtered, and concentrated under reduced pressure. The dark residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (80/1 to 30/1) to afford 300d (200 mg, 50%) as yellow solid. MS-ESI: [M+H]+ 669.4

후처리

  1. customA 50-mL round bottomed flask equipped with a reflux condenser
  2. customflush
  3. temperatureThe reaction mixture was cooled to room temperature
  4. filtrationfiltered
  5. concentrationThe filtrate was concentrated under reduced pressure
  6. customThe residue was partitioned between dichloromethane (30 mL) and water (30 mL)
  7. extractionThe water layer was extracted with dichloromethane (2×30 mL)
  8. extractionThe combined organic extract
  9. dry with materialwas dried over Na2SO4
  10. filtrationfiltered
  11. concentrationconcentrated under reduced pressure
  12. customThe dark residue was purified by silica-gel column chromatography
  13. washeluting with dichloromethane/methanol (80/1 to 30/1)

출처 및 근거

ORD 기록
ord-734bbd62df47412d8a4691bca40d8a7d
출처 데이터셋
uspto-grants-2014_05
특허 번호
US08716274B2

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