Cesium carbonate → 2-[3-(Hydroxymethyl)-4-[8-[[5-[4-(oxetan-3-yl)piperazin-1-yl]-2-pyridyl]amino]imidazo[1,2-a]pyridin-6-yl]-2-pyridyl]-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1-one

HRID 1024094Notes

Reaction equation

HRID 1024094 reaction equation
Cl[C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][N:21]([CH:24]4[CH2:27][O:26][CH2:25]4)[CH2:20][CH2:19]3)=[CH:14][N:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.C([O:31][CH2:32][C:33]1[C:34]([N:48]2[CH2:60][CH2:59][N:51]3[C:52]4[CH2:53][CH2:54][CH2:55][CH2:56][C:57]=4[CH:58]=[C:50]3[C:49]2=[O:61])=[N:35][CH:36]=[CH:37][C:38]=1B1OC(C)(C)C(C)(C)O1)(=O)C.P(C1CCCCC1)(C1CCCCC1)C1CCCCC1.C([O-])([O-])=O.[Cs+].[Cs+]>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].O.O1CCOCC1>[OH:31][CH2:32][C:33]1[C:34]([N:48]2[CH2:60][CH2:59][N:51]3[C:52]4[CH2:53][CH2:54][CH2:55][CH2:56][C:57]=4[CH:58]=[C:50]3[C:49]2=[O:61])=[N:35][CH:36]=[CH:37][C:38]=1[C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][N:21]([CH:24]4[CH2:25][O:26][CH2:27]4)[CH2:20][CH2:19]3)=[CH:14][N:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1

Participants

8

Reactant 4

HCID 10796Cesium carbonateHCID 75806TricyclohexylphosphineHCID 86684122HCID 86684122, compoundHCID 86684143(2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)methyl acetate

Product 1

HCID 715574722-[3-(Hydroxymethyl)-4-[8-[[5-[4-(oxetan-3-yl)piperazin-1-yl]-2-pyridyl]amino]imidazo[1,2-a]pyridin-6-yl]-2-pyridyl]-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1-oneYield 39.3%

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
130 °C

Procedure

A microwave vial was charged with 121a (100 mg, 0.26 mmol), 3-(acetoxymethyl)-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)pyridin-4-ylboronic acid 114e (150 mg, 0.39 mmol), Pd2(dba)3 (23 mg, 0.025 mmol), P(Cy)3 (7 mg, 0.025 mmol), Cs2CO3 (170 mg, 0.52 mmol), dioxane (5 mL), and water (0.1 mL). After three cycles of vacuum/argon flush, the reaction mixture was stirred at 130° C. under microwave irradiation for 1 h. It was then filtered and the filtrate was evaporated under reduced pressure. The residue was purified with reverse-phase prep-HPLC to afford 121 (66 mg, 39%). MS-ESI: [M+H]+ 646.3. 1H NMR (500 MHz, DMSO-d6) δ 8.99 (s, 1H), 8.53 (d, J=5.0 Hz, 1H), 8.31 (d, J=1.5 Hz, 1H), 8.23 (d, J=1.5 Hz, 1H), 7.99 (d, J=1.0 Hz, 1H), 7.90 (d, J=3.0 Hz, 1H), 7.58 (d, J=1.5 Hz, 1H), 7.43-7.40 (m, 2H), 7.35 (d, J=9.0 Hz, 1H), 6.58 (s, 1H), 4.95 (bs, 1H), 4.56 (t, J=6.5 Hz, 2H), 4.46 (t, J=6.5 Hz, 2H), 4.42-4.40 (m, 2H), 4.28-4.09 (m, 3H), 3.94-3.87 (m, 1H), 3.45-3.42 (m, 1H), 3.10-3.08 (m, 4H), 2.66-2.56 (m, 2H), 2.50-2.47 (m, underneath solvent peak, 2H), 2.40-2.38 (m, 4H), 1.80-1.69 (m, 4H).

Workup

  1. customAfter three cycles of vacuum/argon flush
  2. filtrationIt was then filtered
  3. customthe filtrate was evaporated under reduced pressure
  4. customThe residue was purified with reverse-phase prep-HPLC

Sources & evidence

ORD record
ord-a914d840fe2b4787b12cfbec070b5479
Source dataset
uspto-grants-2014_05
Patent number
US08722676B2

Reaction notes

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