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-(2-methoxyethyl)-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl]amino}-1,2-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)pyridin-3-yl)methyl Acetate

HRID 1412100노트

반응식

HRID 1412100 반응식
Br[C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:24]=[C:15]3[CH2:16][N:17]([CH2:20][CH2:21][O:22][CH3:23])[CH2:18][CH2:19][N:14]3[N:13]=2)[C:5](=[O:10])[N:6]([CH3:9])[C:7]=1[CH3:8].[C:25]([O:28][CH2:29][C:30]1[C:31]([N:45]2[CH2:56][CH2:55][N:54]3[C:47](=[CH:48][C:49]4[CH2:50][C:51]([CH3:58])([CH3:57])[CH2:52][C:53]=43)[C:46]2=[O:59])=[N:32][CH:33]=[CH:34][C:35]=1B1OC(C)(C)C(C)(C)O1)(=[O:27])[CH3:26].[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:25]([O:28][CH2:29][C:30]1[C:31]([N:45]2[CH2:56][CH2:55][N:54]3[C:47](=[CH:48][C:49]4[CH2:50][C:51]([CH3:58])([CH3:57])[CH2:52][C:53]=43)[C:46]2=[O:59])=[N:32][CH:33]=[CH:34][C:35]=1[C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:24]=[C:15]3[CH2:16][N:17]([CH2:20][CH2:21][O:22][CH3:23])[CH2:18][CH2:19][N:14]3[N:13]=2)[C:5](=[O:10])[N:6]([CH3:9])[C:7]=1[CH3:8])(=[O:27])[CH3:26]

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 866845905-Bromo-3-(5-(2-methoxyethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-1,6-dimethylpyridin-2(1H)-one

생성물 1

HCID 86684591(2-{4,4-Dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}-4-(5-{[5-(2-methoxyethyl)-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl]amino}-1,2-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)pyridin-3-yl)methyl Acetate수율 45%

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
95 °C

실험 절차

A 25-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 327e (158 mg, 0.40 mmol), {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 (159 mg, 0.40 mmol), K3PO4 (170 mg, 0.80 mmol), sodium acetate (66 mg, 0.80 mmol), Pd(dppf)Cl2 (15 mg, 0.020 mmol), and acetonitrile/water (7/0.5 mL). After three cycles of vacuum/N2 flush, the mixture was heated at 95° C. for 1 h. LCMS analysis showed complete conversion to the desired product. The reaction mixture was cooled to room temperature, and diluted with dichloromethane (50 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 327f (120 mg, 45%) as a yellow solid. MS-ESI: [M+H]+ 668.8

후처리

  1. customA 25-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser
  2. customAfter three cycles of vacuum/N2 flush
  3. temperatureThe reaction mixture was cooled to room temperature
  4. additiondiluted with dichloromethane (50 mL) and water (30 mL)
  5. extractionThe water layer was extracted with dichloromethane (2×30 mL)
  6. extractionThe combined organic extract
  7. dry with materialwas dried over Na2SO4
  8. filtrationfiltered
  9. concentrationconcentrated under reduced pressure
  10. customThe dark residue was purified by silica-gel column chromatography
  11. washeluting with dichloromethane/methanol (80:1 to 30:1)

출처 및 근거

ORD 기록
ord-8aa182d33f5048ddb484909e9d8da249
출처 데이터셋
uspto-grants-2014_12
특허 번호
US08921353B2

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