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Cesium carbonate → GDC-0834 Racemate

HRID 888431
Notes
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Reaction equation

HRID 888431 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
ParticipantsProcedureWorkupSources & evidenceReaction notes

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 25235170
GDC-0834 Racemate
Yield 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-c8e47494dc81455d85e167a3fe2dbb05
Source dataset
uspto-grants-2012_08
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08247550B2

Reaction notes

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On this pageParticipantsProcedureWorkupSources & evidenceReaction notes