Cesium carbonate → tert-butyl 6-(6-(6-(2-(acetoxymethyl)-3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)phenyl)-2-methyl-3-oxo-2,3-dihydropyridazin-4-ylamino)pyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

HRID 449597Notes

Reaction equation

HRID 449597 reaction equation
Cl[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[CH:15][C:14]([N:17]3[CH2:30][C:19]4([CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20]4)[CH2:18]3)=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[C:31]([O:34][CH2:35][C:36]1[C:41](B2OC(C)(C)C(C)(C)O2)=[CH:40][CH:39]=[CH:38][C:37]=1[N:51]1[N:60]=[CH:59][C:58]2[C:53](=[C:54]([F:65])[CH:55]=[C:56]([C:61]([CH3:64])([CH3:63])[CH3:62])[CH:57]=2)[C:52]1=[O:66])(=[O:33])[CH3:32].C([O-])([O-])=O.[Cs+].[Cs+].O1CCOCC1>C(Cl)Cl.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Fe].O>[C:26]([O:25][C:23]([N:21]1[CH2:22][C:19]2([CH2:30][N:17]([C:14]3[CH:15]=[N:16][C:11]([NH:10][C:4]4[C:5](=[O:9])[N:6]([CH3:8])[N:7]=[C:2]([C:41]5[CH:40]=[CH:39][CH:38]=[C:37]([N:51]6[N:60]=[CH:59][C:58]7[C:53](=[C:54]([F:65])[CH:55]=[C:56]([C:61]([CH3:64])([CH3:62])[CH3:63])[CH:57]=7)[C:52]6=[O:66])[C:36]=5[CH2:35][O:34][C:31](=[O:33])[CH3:32])[CH:3]=4)=[CH:12][CH:13]=3)[CH2:18]2)[CH2:20]1)=[O:24])([CH3:29])([CH3:28])[CH3:27]

Participants

8

Reactant 4

HCID 10796Cesium carbonateHCID 312751,4-DioxaneHCID 594737692-(6-(tert-Butyl)-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetateHCID 66742401Tert-butyl 6-(6-(6-chloro-2-methyl-3-oxo-2,3-dihydropyridazin-4-ylamino)pyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

Product 1

HCID 66742494tert-butyl 6-(6-(6-(2-(acetoxymethyl)-3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)phenyl)-2-methyl-3-oxo-2,3-dihydropyridazin-4-ylamino)pyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

Reagents, catalysts & solvents 3

HCID 178477754HCID 178477754, compoundCatalyst2×HCID 962WaterSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
85 °C

Procedure

In a 250 mL round-bottomed flask, tert-butyl 6-(6-(6-chloro-2-methyl-3-oxo-2,3-dihydropyridazin-4-ylamino)pyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (300 mg, 693 μmol), 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate (445 mg, 901 μmol) and Cs2CO3 (677 mg, 2.08 mmol) were combined with dioxane (20 ml) and water (2.00 ml) to give a yellow suspension. The flask was evacuated and filled with argon and PdCl2(DPPF) (17.0 mg, 20.8 μmol) was added. The reaction mixture was heated to 85° C. and stirred for 3 h under argon. Additional PdCl2(DPPF) (17 mg, 20.8 μmol) was added and the reaction mixture was heated to 85° C. and stirred for 60 h. Cooled to 25° C. and diluted with DCM. The reaction mixture was filtered through celite and the filtrate was dried over Na2SO4. The crude reaction mixture was concentrated in vacuo. The brown solid was used crude in the subsequent reaction. (M+H)+=765 m/e.

Workup

  1. customto give a yellow suspension
  2. customThe flask was evacuated
  3. additionwas added
  4. temperaturethe reaction mixture was heated to 85° C.
  5. stirringstirred for 60 h
  6. temperatureCooled to 25° C.
  7. filtrationThe reaction mixture was filtered through celite
  8. dry with materialthe filtrate was dried over Na2SO4
  9. customThe crude reaction mixture
  10. concentrationwas concentrated in vacuo
  11. customin the subsequent reaction

Sources & evidence

ORD record
ord-c78c1f16b4cf41ff9804d758de94f43e
Source dataset
uspto-grants-2013_07
Patent number
US08481540B2

Reaction notes

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