Cesium carbonate → (S)-(+)-N-(3-(6-(4-(2-(Dimethylamino)-1-(isopropyl(methyl)amino)-2-oxoethyl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide

HRID 888440Notes

Reaction equation

HRID 888440 reaction equation
[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([N:14]([CH:16]([CH3:18])[CH3:17])[CH3:15])[C:9]([N:11]([CH3:13])[CH3:12])=[O:10])=[CH:4][CH:3]=1.Br[C:20]1[C:21](=[O:46])[N:22]([CH3:45])[CH:23]=[C:24]([C:26]2[C:27]([CH3:44])=[C:28]([NH:32][C:33]([C:35]3[S:39][C:38]4[CH2:40][CH2:41][CH2:42][CH2:43][C:37]=4[CH:36]=3)=[O:34])[CH:29]=[CH:30][CH:31]=2)[N:25]=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>[CH3:13][N:11]([CH3:12])[C:9](=[O:10])[C@H:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:20]2[C:21](=[O:46])[N:22]([CH3:45])[CH:23]=[C:24]([C:26]3[C:27]([CH3:44])=[C:28]([NH:32][C:33]([C:35]4[S:39][C:38]5[CH2:40][CH2:41][CH2:42][CH2:43][C:37]=5[CH:36]=4)=[O:34])[CH:29]=[CH:30][CH:31]=3)[N:25]=2)=[CH:3][CH:4]=1)[N:14]([CH:16]([CH3:18])[CH3:17])[CH3:15]

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 57625151N-(3-(6-Bromo-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamideHCID 66941034(S)-2-(4-Aminophenyl)-2-(isopropyl(methyl)amino)-N,N-dimethylacetamide

Product 1

HCID 25234977(S)-(+)-N-(3-(6-(4-(2-(Dimethylamino)-1-(isopropyl(methyl)amino)-2-oxoethyl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamideYield 52%

Reagents, catalysts & solvents 2

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

Procedure

A 15-mL three-neck round-bottomed flask equipped with a magnetic stirrer, nitrogen inlet and reflux condenser was charged with 23 (53 mg, 0.212 mmol), 11 (98 mg, 0.212 mmol), cesium carbonate (152 mg, 0.468 mmol) and 1,4-dioxane (3 mL). After bubbling nitrogen through the resulting solution for 30 minutes, Xantphos (10.4 mg, 0.018 mmol) and tris(dibenzylideneacetone)dipalladium(0) (9.70 mg, 0.010 mmol) were added and the reaction mixture was heated at reflux for 3 h. After this time the reaction was cooled to room temperature, filtered and the filter cake washed with methylene chloride (2×25 mL). The filtrate was then concentrated under reduced pressure and the residue was purified by column chromatography to afford 24 (68 mg, 52%) as a yellow solid: mp 133-134° C.; 1H NMR (500 MHz, DMSO-d6) δ 9.79 (br s, 1H), 9.19 (br s, 1H), 7.93 (d, 2H, J=8.5 Hz), 7.68 (s, 1H), 7.30 (m, 5H), 7.20 (s, 1H), 4.56 (s, 1H), 3.55 (s, 3H), 3.01 (s, 3H), 2.84 (m, 1H), 2.76 (m, 5H), 2.63 (t, 2H, J=5.5 Hz), 2.28 (s, 3H), 2.02 (s, 3H), 1.79 (m, 4H), 0.91 (m, 6H); MS (ESI+) m/z 627.5 (M+H); [α]25D+24.0° (c 0.25, chloroform).

Workup

  1. customA 15-mL three-neck round-bottomed flask equipped with a magnetic stirrer, nitrogen inlet
  2. temperaturereflux condenser
  3. customAfter bubbling nitrogen through the resulting solution for 30 minutes
  4. temperaturethe reaction mixture was heated
  5. temperatureat reflux for 3 h
  6. filtrationfiltered
  7. washthe filter cake washed with methylene chloride (2×25 mL)
  8. concentrationThe filtrate was then concentrated under reduced pressure
  9. customthe residue was purified by column chromatography

Sources & evidence

ORD record
ord-6fcd3348d8c04bae82072b8f89a715b5
Source dataset
uspto-grants-2012_08
Patent number
US08247550B2

Reaction notes

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