Potassium Phosphate, Tribasic → 4-(1-methyl-5-(5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl-amino)-6-oxo-1,6-dihydropyridin-3-yl)-2-(1-oxo-5,6,7,8-tetrahydro-1H-pyrrolo[3,4-b]indolizin-2(3H)-yl)nicotinaldehyde

HRID 592960Notes

Reaction equation

HRID 592960 reaction equation
Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([N:10]2[CH2:21][C:20]3[N:19]4[C:14]([CH2:15][CH2:16][CH2:17][CH2:18]4)=[CH:13][C:12]=3[C:11]2=[O:22])[N:5]=[CH:4][CH:3]=1.[CH3:23][N:24]1[CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=[C:26]([NH:39][C:40]2[CH:45]=[CH:44][C:43]([N:46]3[CH2:51][CH2:50][N:49]([CH:52]4[CH2:55][O:54][CH2:53]4)[CH2:48][C@@H:47]3[CH3:56])=[CH:42][N:41]=2)[C:25]1=[O:57].C([O-])(=O)C.[Na+].[O-]P([O-])([O-])=O.[K+].[K+].[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.C(#N)C>[CH3:23][N:24]1[C:25](=[O:57])[C:26]([NH:39][C:40]2[CH:45]=[CH:44][C:43]([N:46]3[CH2:51][CH2:50][N:49]([CH:52]4[CH2:53][O:54][CH2:55]4)[CH2:48][CH:47]3[CH3:56])=[CH:42][N:41]=2)=[CH:27][C:28]([C:2]2[C:7]([CH:8]=[O:9])=[C:6]([N:10]3[CH2:21][C:20]4[N:19]5[C:14]([CH2:15][CH2:16][CH2:17][CH2:18]5)=[CH:13][C:12]=4[C:11]3=[O:22])[N:5]=[CH:4][CH:3]=2)=[CH:29]1

Participants

8

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 517045Sodium 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 866844524-Chloro-2-(1-oxo-5,6,7,8-tetrahydro-1H-pyrrolo[3,4-b]indolizin-2(3H)-yl)nicotinaldehyde

Product 1

HCID 866844534-(1-methyl-5-(5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl-amino)-6-oxo-1,6-dihydropyridin-3-yl)-2-(1-oxo-5,6,7,8-tetrahydro-1H-pyrrolo[3,4-b]indolizin-2(3H)-yl)nicotinaldehydeYield 30%

Reagents, catalysts & solvents 3

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

Conditions

Temperature
85 °C

Procedure

A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 238e (150 mg, 0.48 mmol, 1.0 eq.), (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 191j (459 mg, 0.95 mmol, 2.0 eq.), Pd(dppf)Cl2 (39 mg, 0.048 mmol, 0.1 eq.), sodium acetate (78 mg, 0.95 mmol, 2.0 eq.), K3PO4 (202 mg, 0.95 mmol, 2.0 eq.), acetonitrile (10 mL), and water (1 mL). After three cycles of vacuum/argon flush, the mixture was heated at 85° C. 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 40:1 dichloromethane/ethanol to afford 238f (90 mg, 30%) as a yellow solid. MS-ESI: [M+H]+ 635.3.

Workup

  1. customA 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser
  2. customAfter three cycles of vacuum/argon flush
  3. temperatureIt was then cooled to room temperature
  4. filtrationfiltered
  5. concentrationThe filtrate was concentrated under reduced pressure
  6. customthe resulting residue was purified by silica-gel column chromatography
  7. washeluting with 40:1 dichloromethane/ethanol

Sources & evidence

ORD record
ord-baaaab8531854a38a7811708f4524547
Source dataset
uspto-grants-2016_01
Patent number
US09238655B2

Reaction notes

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