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

Reaktionsgleichung

Reaktionsgleichung von HRID 402934
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]

Komponenten

8

Edukt 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

Produkt 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

Reagenzien, Katalysatoren, Lösungsmittel 3

HCID 6505921(1E,4E)-1,5-diphenylpenta-1,4-dien-3-one; palladiumKatalysatorHCID 2631-ButanolLösungsmittelHCID 962WaterLösungsmittel

Reaktionsbedingungen

Temperatur
100 °C

Versuchsvorschrift

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.

Aufarbeitung

  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 “

Quellen und Nachweise

ORD-Eintrag
ord-c814be499a254984a0c7f7e7796e116e
Quelldatensatz
uspto-grants-2014_06
Patentnummer
US08742098B2

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