Potassium Phosphate, Tribasic → acetic acid 2-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-6-{8-[5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-ylamino]-imidazo[1,2-b]pyridazin-6-yl}-benzyl ester

HRID 402934

반응식

HRID 402934 반응식
Cl[C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][N:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)=[CH:14][N:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[C:26]([O:29][CH2:30][C:31]1[C:36]([N:37]2[N:46]=[CH:45][C:44]3[C:39](=[C:40]([F:51])[CH:41]=[C:42]([C:47]([CH3:50])([CH3:49])[CH3:48])[CH:43]=3)[C:38]2=[O:52])=[CH:35][CH:34]=[CH:33][C:32]=1[B-](F)(F)F)(=[O:28])[CH3:27].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].O.C(O)CCC>[C:47]([C:42]1[CH:43]=[C:44]2[C:39](=[C:40]([F:51])[CH:41]=1)[C:38](=[O:52])[N:37]([C:36]1[CH:35]=[CH:34][CH:33]=[C:32]([C:2]3[CH:3]=[C:4]([NH:11][C:12]4[CH:17]=[CH:16][C:15]([CH2:18][N:19]5[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]5)=[CH:14][N:13]=4)[C:5]4[N:6]([CH:8]=[CH:9][N:10]=4)[N:7]=3)[C:31]=1[CH2:30][O:29][C:26](=[O:28])[CH3:27])[N:46]=[CH:45]2)([CH3:48])([CH3:49])[CH3:50]

참가 물질

8

반응물 4

HCID 62657Potassium Phosphate, TribasicHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 86686832(6-Chloro-imidazo[1,2-b]pyridazin-8-yl)-[5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-yl]-amineHCID 87134390potassium (2-(acetoxymethyl)-3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)phenyl)trifluoroborate

생성물 1

HCID 89611901acetic acid 2-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-6-{8-[5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-ylamino]-imidazo[1,2-b]pyridazin-6-yl}-benzyl ester

시약·촉매·용매 3

HCID 6505921(1E,4E)-1,5-diphenylpenta-1,4-dien-3-one; palladium촉매HCID 2631-Butanol용매HCID 962Water용매

반응 조건

온도
100 °C

실험 절차

In a 50 mL test tube, 6-chloro-N-(5((4-methylpiperazin-1-yl)methyl)pyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (170 mg, 475 μmol, Eq: 1.00) and potassium (2-(acetoxymethyl)-3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)phenyl)trifluoroborate (225 mg, 475 μmol, Eq: 1.00) were combined with BuOH (10 ml) to give an orange solution. Water (2.5 ml) was added. X-PHOS (22.6 mg, 47.5 μmol, Eq: 0.1) and potassium phosphate tribasic (202 mg, 950 μmol, eq: 2) were added. Bis(dibenzylideneacetone)palladium (13.7 mg, 23.8 μmol, Eq: 0.05) was added. The tube was purged with argon and sealed. The solution was warmed in an oil bath at 100° C. for 1.5 hours. The solution was cooled to room temperature. The reaction mixture was poured into 75 mL H2O and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 24 g, 50% to 100% (60:10:1 DCM:MeOH:NH4OH)/DCM gradient) to give a residue. The residue was triturated with Et2O. LC/MS analysis showed that the crude material was a mix of products: 12% 6-tert-butyl-8-fluoro-2-(2-hydroxymethyl-3-{8-[5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-ylamino]-imidazo[1,2-b]pyridazin-6-yl}-phenyl)-2H-phthalazin-1-one and 88% acetic acid 2-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-6-{8-[5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-ylamino]-imidazo[1,2-b]pyridazin-6-yl}-benzyl ester by UV. (157 mg, 48%). The mixture was taken into the next reaction “as is.” LC/MS-ESI observed [M+H]+ 648 and 690.

후처리

  1. customto give an orange solution
  2. customThe tube was purged with argon
  3. customsealed
  4. temperatureThe solution was cooled to room temperature
  5. additionThe reaction mixture was poured into 75 mL H2O
  6. extractionextracted with EtOAc
  7. dry with materialThe organic layer was dried over Na2SO4
  8. concentrationconcentrated in vacuo
  9. customThe crude material was purified by flash chromatography (silica gel, 24 g, 50% to 100% (60:10:1 DCM:MeOH:NH4OH)/DCM gradient)
  10. customto give a residue
  11. customThe residue was triturated with Et2O
  12. additiona mix of products
  13. customThe mixture was taken into the next reaction “

출처 및 근거

ORD 기록
ord-c814be499a254984a0c7f7e7796e116e
출처 데이터셋
uspto-grants-2014_06
특허 번호
US08742098B2

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