Potassium Phosphate, Tribasic → 2-(5-(5-(2-Ethyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-fluoro-6-(1-oxo-3,4,6,7,8,9-hexahydropyrido[3,4-b]indolizin-2(1H)-yl)benzyl Acetate

HRID 519375Notes

Reaction equation

HRID 519375 reaction equation
[C:1]([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:24][CH2:23][C:22]3[N:21]4[C:16]([CH2:17][CH2:18][CH2:19][CH2:20]4)=[CH:15][C:14]=3[C:13]2=[O:25])=[CH:10][C:9]([F:26])=[CH:8][C:7]=1Br)(=[O:3])[CH3:2].[CH2:28]([C@H:30]1[CH2:35][N:34]([CH:36]2[CH2:39][O:38][CH2:37]2)[CH2:33][CH2:32][N:31]1[C:40]1[CH:41]=[CH:42][C:43]([NH:46][C:47]2[C:48](=[O:63])[N:49]([CH3:62])[CH:50]=[C:51](B3OC(C)(C)C(C)(C)O3)[CH:52]=2)=[N:44][CH:45]=1)[CH3:29].[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].C(#N)C.O>[C:1]([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:24][CH2:23][C:22]3[N:21]4[C:16]([CH2:17][CH2:18][CH2:19][CH2:20]4)=[CH:15][C:14]=3[C:13]2=[O:25])=[CH:10][C:9]([F:26])=[CH:8][C:7]=1[C:51]1[CH:52]=[C:47]([NH:46][C:43]2[CH:42]=[CH:41][C:40]([N:31]3[CH2:32][CH2:33][N:34]([CH:36]4[CH2:37][O:38][CH2:39]4)[CH2:35][CH:30]3[CH2:28][CH3:29])=[CH:45][N:44]=2)[C:48](=[O:63])[N:49]([CH3:62])[CH:50]=1)(=[O:3])[CH3:2]

Participants

8

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 517045Sodium AcetateHCID 866837002-Bromo-4-fluoro-6-(1-oxo-3,4,6,7,8,9-hexahydropyrido[3,4-b]-indolizin-2(1H)-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 866837592-(5-(5-(2-Ethyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-fluoro-6-(1-oxo-3,4,6,7,8,9-hexahydropyrido[3,4-b]indolizin-2(1H)-yl)benzyl AcetateYield 53.7%

Reagents, catalysts & solvents 3

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

Conditions

Temperature
100 °C

Procedure

A 100-mL single-neck round-bottomed flask was charged with 2-bromo-4-fluoro-6-(1-oxo-3,4,6,7,8,9-hexahydropyrido[3,4-b]indolizin-2(1H)-yl)benzyl acetate 101h (120 mg, 0.27 mmol), (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 122a (158.4 mg, 0.32 mmol), Pd(dppf)Cl2 (24.5 mg, 0.03 mmol), K3PO4 (114.5 mg, 0.54 mmol), sodium acetate.trihydrate (73.4 mg, 0.54 mmol), water (0.5 mL), and acetonitrile (20 mL). The system was evacuated and refilled with N2. The reaction mixture was heated at 100° 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 25:1 dichloromethane/methanol to afford 123a (105 mg, 53%) as a yellow brown solid. MS: [M+H]+ 724.3.

Workup

  1. customThe system was evacuated
  2. additionrefilled with N2
  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 25:1 dichloromethane/methanol

Sources & evidence

ORD record
ord-ba4182b46c1f4d1aaeab382220f15a23
Source dataset
uspto-grants-2015_08
Patent number
US09115152B2

Reaction notes

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