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

HRID 1843214Notes

Reaction equation

HRID 1843214 reaction equation
[CH2:1]([C@H:3]1[CH2:8][N:7]([CH:9]2[CH2:12][O:11][CH2:10]2)[CH2:6][CH2:5][N:4]1[C:13]1[CH:14]=[CH:15][C:16]([NH:19][C:20]2[C:21](=[O:36])[N:22]([CH3:35])[CH:23]=[C:24](B3OC(C)(C)C(C)(C)O3)[CH:25]=2)=[N:17][CH:18]=1)[CH3:2].[C:37]([O:40][CH2:41][C:42]1[C:47]([N:48]2[CH2:59][CH2:58][N:57]3[C:50](=[CH:51][C:52]4[CH2:53][C:54]([CH3:61])([CH3:60])[CH2:55][C:56]=43)[C:49]2=[O:62])=[CH:46][C:45]([F:63])=[CH:44][C:43]=1B1OC(C)(C)C(C)(C)O1)(=[O:39])[CH3:38].[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:37]([O:40][CH2:41][C:42]1[C:43]([C:24]2[CH:25]=[C:20]([NH:19][C:16]3[CH:15]=[CH:14][C:13]([N:4]4[CH2:5][CH2:6][N:7]([CH:9]5[CH2:10][O:11][CH2:12]5)[CH2:8][C@@H:3]4[CH2:1][CH3:2])=[CH:18][N:17]=3)[C:21](=[O:36])[N:22]([CH3:35])[CH:23]=2)=[CH:44][C:45]([F:63])=[CH:46][C:47]=1[N:48]1[CH2:59][CH2:58][N:57]2[C:50](=[CH:51][C:52]3[CH2:53][C:54]([CH3:61])([CH3:60])[CH2:55][C:56]=32)[C:49]1=[O:62])(=[O:39])[CH3:38]

Participants

8

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 517045Sodium AcetateHCID 670162322-(7,7-dimethyl-1-oxo-3,4,7,8-tetrahydro-1H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2(6H)-yl)-4-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl 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)-one

Product 1

HCID 86683742(2-{4,4-Dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}-6-[5-({5-[(2S)-2-ethyl-4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-yl}amino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl]-4-fluorophenyl)methyl AcetateYield 39%

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 114f (180 mg, 0.40 mmol), (2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}-4-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methyl acetate 103g (198 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), and 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 114g as a yellow solid (115 mg, 39%). MS: [M+H]+ 738.4

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-92b597cf501f48b8bbce17590d011aa4
Source dataset
uspto-grants-2015_02
Patent number
US08946213B2

Reaction notes

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