Sodium Carbonate → tert-Butyl 2-(4-(6-(3-(2-tert-Butyl-6-oxo-4H-thieno[2,3-c]pyrrol-5(6H)-yl)-2-methylphenyl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-ylamino)phenyl)-4-methyl-3-oxopiperazine-1-carboxylate

HRID 1772081Notes

Reaction equation

HRID 1772081 reaction equation
Br[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[C:20](=[O:21])[N:19]([CH3:22])[CH2:18][CH2:17][N:16]3[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:11][CH:10]=2)[C:5](=[O:30])[N:4]([CH3:31])[CH:3]=1.[C:32]([C:36]1[S:43][C:42]2[C:41](=[O:44])[N:40]([C:45]3[CH:50]=[CH:49][CH:48]=[C:47](B4OC(C)(C)C(C)(C)O4)[C:46]=3[CH3:60])[CH2:39][C:38]=2[CH:37]=1)([CH3:35])([CH3:34])[CH3:33].C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>C(OCC)(=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C>[C:32]([C:36]1[S:43][C:42]2[C:41](=[O:44])[N:40]([C:45]3[C:46]([CH3:60])=[C:47]([C:2]4[N:7]=[C:6]([NH:8][C:9]5[CH:10]=[CH:11][C:12]([CH:15]6[C:20](=[O:21])[N:19]([CH3:22])[CH2:18][CH2:17][N:16]6[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:13][CH:14]=5)[C:5](=[O:30])[N:4]([CH3:31])[CH:3]=4)[CH:48]=[CH:49][CH:50]=3)[CH2:39][C:38]=2[CH:37]=1)([CH3:35])([CH3:33])[CH3:34]

Participants

9

Reactant 4

HCID 10340Sodium CarbonateHCID 312751,4-DioxaneHCID 86699861tert-Butyl 2-(4-(6-Bromo-4-methyl-3-oxo-3,4-dihydropyrazin-2-ylamino)phenyl)-4-methyl-3-oxopiperazine-1-carboxylateHCID 898241832-tert-Butyl-5-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4H-thieno[3,2-c]pyrrol-6(5H)-one

Product 1

HCID 89870014tert-Butyl 2-(4-(6-(3-(2-tert-Butyl-6-oxo-4H-thieno[2,3-c]pyrrol-5(6H)-yl)-2-methylphenyl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-ylamino)phenyl)-4-methyl-3-oxopiperazine-1-carboxylateYield 88.3%

Reagents, catalysts & solvents 4

HCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolvent2×HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

A 25-mL three-neck round-bottomed flask equipped with a reflux condenser, magnetic stirrer and nitrogen inlet was charged with of 102k (200 mg, 0.486 mmol), 102g (217 mg, 0.442 mmol), sodium carbonate (115 mg, 1.08 mmol), water (1.5 mL), 1,4-dioxane (5 mL), and DMF (2 mL). After bubbling nitrogen through the resulting suspension for 30 min, tetrakis(triphenylphosphine)palladium(0) (83 mg, 0.07 mmol) was added and the reaction mixture was heated at reflux for 16 h. After this time, the mixture was cooled to room temperature and diluted with ethyl acetate (40 mL) and water (5 mL). The organic layer was separated, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gave an 88% yield (272 mg) of 102l as a brown foam: mp 120-123° C.; 1H NMR (300 MHz, CDCl3) δ 8.33 (s, 1H), 7.79 (d, 2H, J=6.9 Hz), 7.71-7.28 (m, 5H), 6.92 (s, 1H), 6.75 (s, 1H), 5.30 (s, 3H), 4.63 (s, 2H), 4.61 9s, 1H), 3.62 (s, 3H), 3.50 (m, 2H), 3.42-3.22 (m, 2H), 3.04 (m, 4H), 1.46 (s, 18H); MS (APCI+) m/z 697.5 (M+H).

Workup

  1. customA 25-mL three-neck round-bottomed flask equipped with a reflux condenser, magnetic stirrer and nitrogen inlet
  2. customAfter bubbling nitrogen through the resulting suspension for 30 min
  3. temperaturethe reaction mixture was heated
  4. temperatureat reflux for 16 h
  5. customThe organic layer was separated
  6. dry with materialdried over sodium sulfate
  7. concentrationconcentrated under reduced pressure
  8. customThe residue was purified by column chromatography on silica

Sources & evidence

ORD record
ord-d27b22ee19914e18b26303d69d68f875
Source dataset
uspto-grants-2016_02
Patent number
US09249123B2

Reaction notes

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