Cesium carbonate → GDC-0834 Racemate

HRID 1363491Notes

Reaction equation

HRID 1363491 reaction equation
[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:13]([CH3:14])[CH2:12][CH2:11][N:10]([CH3:15])[C:9]2=[O:16])=[CH:4][CH:3]=1.Br[C:18]1[C:19](=[O:44])[N:20]([CH3:43])[CH:21]=[C:22]([C:24]2[C:25]([CH3:42])=[C:26]([NH:30][C:31]([C:33]3[S:37][C:36]4[CH2:38][CH2:39][CH2:40][CH2:41][C:35]=4[CH:34]=3)=[O:32])[CH:27]=[CH:28][CH:29]=2)[N:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>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].O1CCOCC1>[CH3:14][N:13]1[CH2:12][CH2:11][N:10]([CH3:15])[C:9](=[O:16])[CH:8]1[C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:18]2[C:19](=[O:44])[N:20]([CH3:43])[CH:21]=[C:22]([C:24]3[C:25]([CH3:42])=[C:26]([NH:30][C:31]([C:33]4[S:37][C:36]5[CH2:38][CH2:39][CH2:40][CH2:41][C:35]=5[CH:34]=4)=[O:32])[CH:27]=[CH:28][CH:29]=3)[N:23]=2)=[CH:7][CH:6]=1

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 576251203-(4-Aminophenyl)-1,4-dimethylpiperazin-2-oneHCID 57625151N-(3-(6-Bromo-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide

Product 1

HCID 25235170GDC-0834 RacemateYield 36.3%

Reagents, catalysts & solvents 2

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

Procedure

A 25-mL single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with 4 (160 mg, 0.73 mmol), 11 (304 mg, 0.66 mmol), cesium carbonate (475 mg, 1.46 mmol) and 1,4-dioxane (10 mL). After bubbling nitrogen through the resulting solution for 30 minutes, Xantphos (32 mg, 0.056 mmol) and tris(dibenzylideneacetone)dipalladium(0) (30 mg, 0.033 mmol) were added and the reaction mixture was heated at reflux for 16 h. After this time the reaction was cooled to room temperature and concentrated under reduced pressure. The resulting residue was absorbed onto silica gel and purified by flash chromatography to give a residue, which was further purified by preparative reverse phase HPLC to afford a 30% yield (143 mg) of 12 as a yellow solid: mp 155-156° C.; 1H NMR (500 MHz, DMSO-d6) δ 9.82 (s, 1H), 9.43 (s, 1H), 8.08 (d, 2H, J=7.5 Hz), 7.68 (s, 1H), 7.32 (d, 2H, J=7.5 Hz), 7.27-7.32 (m, 3H), 7.24 (s, 1H), 4.88 (bs, 1H), 3.42-3.75 (m, 4H), 3.59 (s, 3H), 2.95 (s, 3H), 2.76 (m, 2H), 2.61 (m, 5H), 2.28 (s, 3H), 1.78 (m, 4H); MS (ESI+) m/z 597 (M+H).

Workup

  1. customA 25-mL single-neck round-bottomed flask equipped with a magnetic stirrer
  2. temperaturereflux condenser
  3. customAfter bubbling nitrogen through the resulting solution for 30 minutes
  4. temperaturethe reaction mixture was heated
  5. temperatureat reflux for 16 h
  6. concentrationconcentrated under reduced pressure
  7. customThe resulting residue was absorbed onto silica gel
  8. custompurified by flash chromatography
  9. customto give a residue, which
  10. customwas further purified by preparative reverse phase HPLC

Sources & evidence

ORD record
ord-8d64a23a8c574037a6bb6870902db16d
Source dataset
uspto-grants-2011_02
Patent number
US07884108B2

Reaction notes

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