Potassium Carbonate → 2-(5-Fluoro-2-(hydroxymethyl)-3-(3-methyl-7-(5-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-3H-benzo[d]imidazol-5-yl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one

HRID 1024044Notes

Reaction equation

HRID 1024044 reaction equation
Cl[C:2]1[CH:3]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][N:22]([CH:25]4[CH2:28][O:27][CH2:26]4)[CH2:21][CH2:20]3)=[CH:15][N:14]=2)[C:5]2[N:9]=[CH:8][N:7]([CH3:10])[C:6]=2[CH:11]=1.C([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[CH2:62][CH2:61][N:53]2[C:54]3[CH2:55][CH2:56][CH2:57][CH2:58][C:59]=3[CH:60]=[C:52]2[C:51]1=[O:63])(=O)C.C(=O)([O-])[O-].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:49][C:37]1[CH:38]=[C:39]([C:2]2[CH:3]=[C:4]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH2:20][CH2:21][N:22]([CH:25]5[CH2:26][O:27][CH2:28]5)[CH2:23][CH2:24]4)=[CH:15][N:14]=3)[C:5]3[N:9]=[CH:8][N:7]([CH3:10])[C:6]=3[CH:11]=2)[C:34]([CH2:33][OH:32])=[C:35]([N:50]2[CH2:62][CH2:61][N:53]3[C:54]4[CH2:55][CH2:56][CH2:57][CH2:58][C:59]=4[CH:60]=[C:52]3[C:51]2=[O:63])[CH:36]=1

Participants

6

Reactant 4

HCID 11430Potassium CarbonateHCID 75806TricyclohexylphosphineHCID 580442052-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-4-fluoro-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzyl AcetateHCID 866841396-Chloro-1-methyl-N-(5-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)-1H-benzo[d]imidazol-4-amine

Product 1

HCID 715569822-(5-Fluoro-2-(hydroxymethyl)-3-(3-methyl-7-(5-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-3H-benzo[d]imidazol-5-yl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-oneYield 14%

Reagents, catalysts & solvents 1

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalyst

Conditions

Temperature
110 °C

Procedure

A microwave vial equipped with a magnetic stirrer was charged with 109e (300 mg, 0.75 mmol), 4-fluoro-2-(1-oxo-3,4,6,7,8,9-Hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate 101l (545 mg, 1.13 mmol), potassium carbonate (414 mg, 3.0 mmol), tris(dibenzylideneacetone)dipalladium(0) (68 mg, 0.075 mmol), and tricyclohexylphosphine (210 mg, 0.75 mmol). After bubbling nitrogen through the suspension for 5 minutes, the reaction was heated at 110° C. for overnight. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 109 as a white solid (71 mg, 14%). LCMS: [M+H]+ 677.3. 1H NMR (500 MHz, DMSO) δ 8.64 (s, 1H), 8.23 (d, J=1.0, 1H), 8.18 (s, 1H), 7.88 (d, J=2.5, 1H), 7.38-7.39 (m, 1H), 7.33-7.35 (m, 1H), 7.24 (d, J=9.0, 1H), 7.18-7.19 (m, 2H), 6.52 (s, 1H), 4.85 (bs, 1H), 4.56 (t, J=6.0, 2H), 4.46 (t, J=6.0, 2H), 4.29 (s, 2H), 4.16-4.18 (m, 3H), 3.93-3.94 (m, 1H), 3.84 (s, 3H), 3.44-3.45 (m, 1H), 3.07 (t, J=4.0, 4H), 2.61-2.62 (m, 2H), 2.47 (t, J=6.0, 2H), 2.39 (t, J=4.0, 4H), 1.79-1.80 (m, 2H), 1.70-1.71 (m, 2H)

Workup

  1. customA microwave vial equipped with a magnetic stirrer
  2. customAfter bubbling nitrogen through the suspension for 5 minutes
  3. temperatureIt was then cooled to room temperature
  4. filtrationfiltered
  5. concentrationThe filtrate was concentrated under reduced pressure
  6. customthe residue was purified by reverse-phase prep-HPLC

Sources & evidence

ORD record
ord-d3edfe1f584645c5ae797015d4ca1c4c
Source dataset
uspto-grants-2014_05
Patent number
US08722676B2

Reaction notes

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