Potassium Phosphate, Tribasic → 2-{4,4-Dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}-4-fluoro-6-[1-methyl-5-({5-[(2S)-2-methyl-4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-yl}amino)-6-oxo-1,6-dihydropyridin-3-yl]benzaldehyde

HRID 1026512Notes

Reaction equation

HRID 1026512 reaction equation
Br[C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([N:11]2[CH2:22][CH2:21][N:20]3[C:13](=[CH:14][C:15]4[CH2:16][C:17]([CH3:24])([CH3:23])[CH2:18][C:19]=43)[C:12]2=[O:25])[C:3]=1[CH:4]=[O:5].[CH3:26][N:27]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[C:29]([NH:42][C:43]2[CH:48]=[CH:47][C:46]([N:49]3[CH2:54][CH2:53][N:52]([CH:55]4[CH2:58][O:57][CH2:56]4)[CH2:51][C@@H:50]3[CH3:59])=[CH:45][N:44]=2)[C:28]1=[O:60].C([O-])(=O)C.[K+].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O.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].C(#N)C>[CH3:23][C:17]1([CH3:24])[CH2:16][C:15]2[CH:14]=[C:13]3[N:20]([CH2:21][CH2:22][N:11]([C:6]4[CH:7]=[C:8]([F:10])[CH:9]=[C:2]([C:31]5[CH:30]=[C:29]([NH:42][C:43]6[CH:48]=[CH:47][C:46]([N:49]7[CH2:54][CH2:53][N:52]([CH:55]8[CH2:56][O:57][CH2:58]8)[CH2:51][C@@H:50]7[CH3:59])=[CH:45][N:44]=6)[C:28](=[O:60])[N:27]([CH3:26])[CH:32]=5)[C:3]=4[CH:4]=[O:5])[C:12]3=[O:25])[C:19]=2[CH2:18]1

Participants

8

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 517044Potassium AcetateHCID 866837011-methyl-3-((5-((2S)-2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-oneHCID 866837722-Bromo-6-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}-4-fluorobenzaldehyde

Product 1

HCID 866837742-{4,4-Dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}-4-fluoro-6-[1-methyl-5-({5-[(2S)-2-methyl-4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-yl}amino)-6-oxo-1,6-dihydropyridin-3-yl]benzaldehydeYield 77%

Reagents, catalysts & solvents 3

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

Conditions

Temperature
100 °C

Procedure

A 50-mL round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 128a (303 mg, 0.75 mmol), 1-methyl-3-({5-[(2S)-2-methyl-4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-yl}amino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxa-borolan-2-yl)-1,2-dihydropyridin-2-one 113f (385 mg, 0.80 mmol), Pd(dppf)Cl2 (68.6 mg, 0.075 mmol), potassium acetate (147 mg, 1.50 mmol), K3PO4 (327 mg, 1.50 mmol), acetonitrile (15 mL), and water (6 drops). After three cycles of vacuum/argon flush, the mixture was heated at 100° C. for 2 h. After this time the reaction was cooled to room temperature. It was then filtered and the filtrate was evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 15:1 ethyl acetate/methanol to afford 128b (382 mg, 77%) as a black solid. MS-ESI: [M+H]+ 680.3

Workup

  1. customA 50-mL round-bottomed flask equipped with a magnetic stirrer and a reflux condenser
  2. customAfter three cycles of vacuum/argon flush
  3. temperatureAfter this time the reaction was cooled to room temperature
  4. filtrationIt was then filtered
  5. customthe filtrate was evaporated under reduced pressure
  6. customThe residue was purified by silica-gel column chromatography
  7. washeluting with 15:1 ethyl acetate/methanol

Sources & evidence

ORD record
ord-5c2734626e99433e9dfced66f8271955
Source dataset
uspto-grants-2014_05
Patent number
US08729072B2

Reaction notes

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