Tetrahydrofuran → 2-(6-tert-Butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-4-fluoro-6-(1-methyl-5-(5-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)benzaldehyde

HRID 407612Notes

Reaction equation

HRID 407612 reaction equation
Br[C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([N:11]2[N:20]=[CH:19][C:18]3[C:13](=[C:14]([F:25])[CH:15]=[C:16]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:17]=3)[C:12]2=[O:26])[C:3]=1[CH:4]=[O:5].[CH3:27][N:28]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[C:30]([NH:43][C:44]2[CH:49]=[CH:48][C:47]([N:50]3[CH2:55][CH2:54][N:53]([CH:56]4[CH2:59][O:58][CH2:57]4)[CH2:52][CH2:51]3)=[CH:46][N:45]=2)[C:29]1=[O:60].C1COCC1>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].O>[C:21]([C:16]1[CH:17]=[C:18]2[C:13](=[C:14]([F:25])[CH:15]=1)[C:12](=[O:26])[N:11]([C:6]1[CH:7]=[C:8]([F:10])[CH:9]=[C:2]([C:32]3[CH:31]=[C:30]([NH:43][C:44]4[CH:49]=[CH:48][C:47]([N:50]5[CH2:55][CH2:54][N:53]([CH:56]6[CH2:57][O:58][CH2:59]6)[CH2:52][CH2:51]5)=[CH:46][N:45]=4)[C:29](=[O:60])[N:28]([CH3:27])[CH:33]=3)[C:3]=1[CH:4]=[O:5])[N:20]=[CH:19]2)([CH3:24])([CH3:22])[CH3:23]

Participants

6

Reactant 3

HCID 8028TetrahydrofuranHCID 866839112-Bromo-6-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-4-fluorobenzaldehydeHCID 866839131-methyl-3-(5-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2(1H)-one

Product 1

HCID 866839122-(6-tert-Butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-4-fluoro-6-(1-methyl-5-(5-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)benzaldehydeYield 60%

Reagents, catalysts & solvents 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 962WaterSolvent

Conditions

Temperature
70 °C

Procedure

A round-bottomed flask was charged with 2-bromo-6-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-4-fluorobenzaldehyde 102b (100 mg, 0.24 mmol), 1-methyl-3-(5-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (131 mg, 0.28 mmol), PdCl2(dppf) (25 mg, 0.03 mmol), K3PO4.3H2O(149 mg, 0.56 mmol), THF (10 mL), and H2O (5 mL). After three cycles of vacuum/argon flash, the mixture was heated at 70° C. for 6 h. It was then filtered and the filtrate was evaporated in vacuo. The residue was purified on flash column chromatography eluting with 1:3 petroleum/ethyl acetate to afford 102c as a yellow solid (98 mg, 60%). LCMS: [M+H]+ 682

Workup

  1. filtrationIt was then filtered
  2. customthe filtrate was evaporated in vacuo
  3. customThe residue was purified on flash column chromatography
  4. washeluting with 1:3 petroleum/ethyl acetate

Sources & evidence

ORD record
ord-83fda043e686449a88123a7b546f07b0
Source dataset
uspto-grants-2014_06
Patent number
US08754077B2

Reaction notes

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