Acetonitrile → 4-[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]-2-[(1S,11R)-7-oxo-3,6-diazatetracyclo[9.2.1.02,10.03,8]tetradeca-2(10),8-dien-6-yl]pyridine-3-carbaldehyde

HRID 592743Notes

Reaction equation

HRID 592743 reaction equation
C(#N)C.Cl[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([N:11]2[C:23](=[O:24])[C:22]3[N:14]([C:15]4[C@@H:16]5[CH2:25][C@H:19]([C:20]=4[CH:21]=3)[CH2:18][CH2:17]5)[CH2:13][CH2:12]2)[C:6]=1[CH:26]=[O:27].[CH3:28][N:29]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[C:31]([NH:44][C:45]2[CH:50]=[CH:49][C:48]([N:51]3[CH2:56][CH2:55][N:54]([CH:57]4[CH2:60][O:59][CH2:58]4)[CH2:53][C@@H:52]3[CH3:61])=[CH:47][N:46]=2)[C:30]1=[O:62].C([O-])(=O)C.[K+]>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>[CH3:28][N:29]1[C:30](=[O:62])[C:31]([NH:44][C:45]2[CH:50]=[CH:49][C:48]([N:51]3[CH2:56][CH2:55][N:54]([CH:57]4[CH2:58][O:59][CH2:60]4)[CH2:53][C@@H:52]3[CH3:61])=[CH:47][N:46]=2)=[CH:32][C:33]([C:5]2[CH:10]=[CH:9][N:8]=[C:7]([N:11]3[C:23](=[O:24])[C:22]4[N:14]([C:15]5[C@@H:16]6[CH2:25][C@H:19]([C:20]=5[CH:21]=4)[CH2:18][CH2:17]6)[CH2:13][CH2:12]3)[C:6]=2[CH:26]=[O:27])=[CH:34]1

Participants

7

Reactant 4

HCID 6342AcetonitrileHCID 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 866842944-Chloro-2-[(1S,11R)-7-oxo-3,6-diazatetracyclo[9.2.1.02,10.03,8]tetradeca-2(10),8-dien-6-yl]pyridine-3-carbaldehyde

Product 1

HCID 866843044-[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]-2-[(1S,11R)-7-oxo-3,6-diazatetracyclo[9.2.1.02,10.03,8]tetradeca-2(10),8-dien-6-yl]pyridine-3-carbaldehydeYield 29%

Reagents, catalysts & solvents 2

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

Conditions

Temperature
80 °C

Procedure

A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with acetonitrile (30 mL), 4-chloro-2-[(1S,11R)-7-oxo-3,6-diazatetracyclo[9.2.1.02,10.03,8]tetradeca-2(10),8-dien-6-yl]pyridine-3-carbaldehyde 167g (170 mg, 0.50 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 130f (336 mg, 0.70 mmol), water (3 mL), and potassium acetate (147 mg, 1.5 mmol). After bubbling argon through the suspension for 30 minutes, 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II) (408 mg, 0.05 mmol) was added. The system was subjected to three cycles of vacuum/argon flush and heated at 80° C. for 3 h. It was then cooled to room temperature and filtered. The solid was washed with dichloromethane (2×100 ml). The combined filtrate was concentrated under reduced pressure and the residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (50:1 to 30:1) to afford 171a (95 mg, 29%) as a light yellow solid. MS-ESI: [M+H]+ 661.3

Workup

  1. customA 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser
  2. customAfter bubbling argon through the suspension for 30 minutes
  3. customflush
  4. temperatureIt was then cooled to room temperature
  5. filtrationfiltered
  6. washThe solid was washed with dichloromethane (2×100 ml)
  7. concentrationThe combined filtrate was concentrated under reduced pressure
  8. customthe residue was purified by silica-gel column chromatography
  9. washeluting with dichloromethane/methanol (50:1 to 30:1)

Sources & evidence

ORD record
ord-823e7cc88c8c400e9b377834477460c9
Source dataset
uspto-grants-2016_01
Patent number
US09238655B2

Reaction notes

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