Potassium Phosphate, Tribasic → 2-{4,4-Dimethyl-9-oxo-7-thia-10,11-diazatricyclo[6.4.0.02,6]dodeca-1(8),2(6),11-trien-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 1843283Notes

Reaction equation

HRID 1843283 reaction equation
Br[C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([N:11]2[N:22]=[CH:21][C:20]3[C:19]4[CH2:18][C:17]([CH3:24])([CH3:23])[CH2:16][C:15]=4[S:14][C:13]=3[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].[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].O1CCCC1>[CH3:24][C:17]1([CH3:23])[CH2:16][C:15]2[S:14][C:13]3[C:12](=[O:25])[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])[N:22]=[CH:21][C:20]=3[C:19]=2[CH2:18]1

Participants

7

Reactant 3

HCID 62657Potassium Phosphate, TribasicHCID 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 866837822-Bromo-6-{4,4-dimethyl-9-oxo-7-thia-10,11-diazatricyclo[6.4.0.02,6]dodeca-1(8),2(6),11-trien-10-yl}-4-fluorobenzaldehyde

Product 1

HCID 866837842-{4,4-Dimethyl-9-oxo-7-thia-10,11-diazatricyclo[6.4.0.02,6]dodeca-1(8),2(6),11-trien-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 80%

Reagents, catalysts & solvents 3

HCID 962WaterCatalystHCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 8028TetrahydrofuranSolvent

Procedure

A 50-mL round bottom flask equipped with a magnetic stirrer and a reflux condenser was charged with 131i (421 mg, 1.0 mmol), (S)-1-methyl-3-(5-(2-methyl-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 113f (580 mg, 1.2 mmol), Pd(dppf)Cl2 (59 mg, 0.080 mmol), K3PO4.trihydrate (360 mg, 1.6 mmol), water (6 drops), and tetrahydrofuran (20 mL). After three cycles of vacuum/argon flush, the mixture was heated at reflux for 6 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the residue was washed with 1:1 petroleum ether/ethyl acetate (20 mL) to afford 131j as a white solid (556 mg, 80%). MS-ESI: [M+H]+ 696.3

Workup

  1. customA 50-mL round bottom flask equipped with a magnetic stirrer and a reflux condenser
  2. customAfter three cycles of vacuum/argon flush
  3. temperaturethe mixture was heated
  4. temperatureat reflux for 6 h
  5. filtrationfiltered
  6. concentrationThe filtrate was concentrated under reduced pressure
  7. washthe residue was washed with 1:1 petroleum ether/ethyl acetate (20 mL)

Sources & evidence

ORD record
ord-f278956f75b64d37b03d4000c6bdab86
Source dataset
uspto-grants-2015_02
Patent number
US08946213B2

Reaction notes

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