Potassium Phosphate, Tribasic → {2-[5-({5-[(2S,5R)-2,5-Dimethyl-4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-yl}amino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl]-4-fluoro-6-{6-oxo-8-thia-4,5-diazatricyclo[7.4.0.02,7]trideca-1(9),2(7),3-trien-5-yl]phenyl}methyl Acetate

HRID 1026474Notes

Reaction equation

HRID 1026474 reaction equation
Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][C@@H:21]([CH3:23])[N:20]([CH:24]4[CH2:27][O:26][CH2:25]4)[CH2:19][C@@H:18]3[CH3:28])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:29]([O:32][CH2:33][C:34]1[C:39](B2OC(C)(C)C(C)(C)O2)=[CH:38][C:37]([F:49])=[CH:36][C:35]=1[N:50]1[C:62](=[O:63])[C:61]2[S:60][C:59]3[CH2:58][CH2:57][CH2:56][CH2:55][C:54]=3[C:53]=2[CH:52]=[N:51]1)(=[O:31])[CH3:30].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[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.C(#N)C>[C:29]([O:32][CH2:33][C:34]1[C:35]([N:50]2[C:62](=[O:63])[C:61]3[S:60][C:59]4[CH2:58][CH2:57][CH2:56][CH2:55][C:54]=4[C:53]=3[CH:52]=[N:51]2)=[CH:36][C:37]([F:49])=[CH:38][C:39]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][C@@H:21]([CH3:23])[N:20]([CH:24]4[CH2:25][O:26][CH2:27]4)[CH2:19][C@@H:18]3[CH3:28])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:31])[CH3:30]

Participants

8

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 517045Sodium AcetateHCID 58043634(4-Fluoro-2-{6-oxo-8-thia-4,5-diazatricyclo[7.4.0.02,7]trideca-1(9),2(7),3-trien-5-yl}-6-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methyl acetateHCID 866837065-Bromo-3-(5-((2S,5R)-2,5-dimethyl-4-(oxetan-3-yl)piperazin-1-yl)-pyridin-2-ylamino)-1-methylpyridin-2(1H)-one

Product 1

HCID 86683747{2-[5-({5-[(2S,5R)-2,5-Dimethyl-4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-yl}amino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl]-4-fluoro-6-{6-oxo-8-thia-4,5-diazatricyclo[7.4.0.02,7]trideca-1(9),2(7),3-trien-5-yl]phenyl}methyl AcetateYield 34%

Reagents, catalysts & solvents 3

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

Procedure

A 25-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 5-bromo-3-(5-((2S,5R)-2,5-dimethyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-1-methylpyridin-2(1H)-one 104e (179 mg, 0.40 mmol), (4-fluoro-2-{6-oxo-8-thia-4,5-diazatricyclo[7.4.0.02,7]-trideca-1(9),2(7),3-trien-5-yl}-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methyl acetate 117d (200 mg, 0.40 mmol), Pd(dppf)Cl2 (29 mg, 0.04 mmol), K3PO4 (170 mg, 0.8 mmol), sodium acetate (66 mg, 0.8 mmol), acetonitrile (5 mL), water (1.0 mL). After three cycles of vacuum/argon flush, the mixture was heated at reflux for 2 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with 30:1 dichloromethane/methanol to afford 118a as yellow solid (100 mg, 34%). MS: [M+H]+ 740.3

Workup

  1. customA 25-mL single-neck round-bottomed 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 2 h
  5. filtrationfiltered
  6. concentrationThe filtrate was concentrated under reduced pressure
  7. customthe resulting residue was purified by silica-gel column chromatography
  8. washeluting with 30:1 dichloromethane/methanol

Sources & evidence

ORD record
ord-0adc1dfa9a9e415085d3d05cb7880594
Source dataset
uspto-grants-2014_05
Patent number
US08729072B2

Reaction notes

Loading…