Potassium Phosphate, Tribasic → (S)-2-(6-tert-Butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-4-(5-(5-(2-ethyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)nicotinaldehyde

HRID 1185054Notes

Reaction equation

HRID 1185054 reaction equation
[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[N:24]=[CH:23][CH:22]=[C:21](Cl)[C:18]=1[CH:19]=[O:20])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[CH2:26]([C@H:28]1[CH2:33][N:32]([CH:34]2[CH2:37][O:36][CH2:35]2)[CH2:31][CH2:30][N:29]1[C:38]1[CH:39]=[CH:40][C:41]([NH:44][C:45]2[C:46](=[O:61])[N:47]([CH3:60])[CH:48]=[C:49](B3OC(C)(C)C(C)(C)O3)[CH:50]=2)=[N:42][CH:43]=1)[CH3:27].[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC([O-])=O.[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].O.CC#N>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[N:24]=[CH:23][CH:22]=[C:21]([C:49]3[CH:50]=[C:45]([NH:44][C:41]4[CH:40]=[CH:39][C:38]([N:29]5[CH2:30][CH2:31][N:32]([CH:34]6[CH2:35][O:36][CH2:37]6)[CH2:33][C@@H:28]5[CH2:26][CH3:27])=[CH:43][N:42]=4)[C:46](=[O:61])[N:47]([CH3:60])[CH:48]=3)[C:18]=1[CH:19]=[O:20])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2]

Participants

8

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 517045Sodium AcetateHCID 86683743(S)-3-(5-(2-Ethyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-oneHCID 866839152-(6-tert-Butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-4-chloronicotinaldehyde

Product 1

HCID 86683931(S)-2-(6-tert-Butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-4-(5-(5-(2-ethyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)nicotinaldehydeYield 49%

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 962WaterSolventHCID 6342AcetonitrileSolvent

Conditions

Temperature
100 °C

Procedure

A 50-mL round bottom flask was charged with 2-(6-tert-butyl-8-fluoro-1-oxo-phthalazin-2(1H)-yl)-4-chloronicotinaldehyde 103b (150 mg, 0.43 mmol), (S)-3-(5-(2-ethyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (206 mg, 0.43 mmol), PdCl2(dppf) (33 mg, 0.04 mmol), K3PO4 (202 mg, 0.86 mmol), NaOAc (71 mg, 0.86 mmol), and CH3CN (10 mL), H2O (2 mL). After three cycles of vacuum/argon flush, the mixture was heated at 100° C. for 3 h. It was then filtered and the filtrate was evaporated in vacuo. The residue was purified by flash column chromatography eluting with 1:3 petroleum/ethyl acetate to afford 112a as a yellow solid (146 mg, 49%). LCMS: [M+H]+ 693

Workup

  1. customAfter three cycles of vacuum/argon flush
  2. filtrationIt was then filtered
  3. customthe filtrate was evaporated in vacuo
  4. customThe residue was purified by flash column chromatography
  5. washeluting with 1:3 petroleum/ethyl acetate

Sources & evidence

ORD record
ord-797177c96d2c41078bba7f23b9f019f7
Source dataset
uspto-grants-2014_03
Patent number
US08669251B2

Reaction notes

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