Sodium Carbonate → 2-tert-Butyl-5-(2-methyl-3-(4-methyl-6-(4-(1-methyl-3-oxopiperazin-2-yl)phenylamino)-5-oxo-4,5-dihydropyrazin-2-yl)phenyl)-4H-thieno[2,3-c]pyrrol-6(5H)-one

HRID 1772093Notes

Reaction equation

HRID 1772093 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])[NH:19][CH2:18][CH2:17][N:16]3[CH3:22])=[CH:11][CH:10]=2)[C:5](=[O:23])[N:4]([CH3:24])[CH:3]=1.[C:25]([C:29]1[S:36][C:35]2[C:34](=[O:37])[N:33]([C:38]3[CH:43]=[CH:42][CH:41]=[C:40](B4OC(C)(C)C(C)(C)O4)[C:39]=3[CH3:53])[CH2:32][C:31]=2[CH:30]=1)([CH3:28])([CH3:27])[CH3:26].C(=O)([O-])[O-].[Na+].[Na+]>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.O>[C:25]([C:29]1[S:36][C:35]2[C:34](=[O:37])[N:33]([C:38]3[CH:43]=[CH:42][CH:41]=[C:40]([C:2]4[N:7]=[C:6]([NH:8][C:9]5[CH:14]=[CH:13][C:12]([CH:15]6[C:20](=[O:21])[NH:19][CH2:18][CH2:17][N:16]6[CH3:22])=[CH:11][CH:10]=5)[C:5](=[O:23])[N:4]([CH3:24])[CH:3]=4)[C:39]=3[CH3:53])[CH2:32][C:31]=2[CH:30]=1)([CH3:28])([CH3:26])[CH3:27]

Participants

6

Reactant 3

HCID 10340Sodium CarbonateHCID 666097582-(4-(6-Bromo-4-methyl-3-oxo-3,4-dihydropyrazin-2-ylamino)phenyl)-1-methyl-3-oxopiperazineHCID 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 569284422-tert-Butyl-5-(2-methyl-3-(4-methyl-6-(4-(1-methyl-3-oxopiperazin-2-yl)phenylamino)-5-oxo-4,5-dihydropyrazin-2-yl)phenyl)-4H-thieno[2,3-c]pyrrol-6(5H)-oneYield 13%

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolvent

Conditions

Temperature
110 °C

Procedure

A 5-mL reaction tube equipped with a magnetic stirrer was charged with 104d (65 mg, 0.166 mmol), 102g (68 mg, 0.166 mmol), sodium carbonate (53 mg, 0.498 mmol) dioxane (1.0 mL) and water (0.2 mL). This mixture was degassed with nitrogen for 30 min. Tetrakis(triphenylphosphine)palladium (19 mg, 0.017 mmol) was added, and the tube was sealed. After heating at 110° C. (bath temperature) for 16 h, the reaction mixture was cooled to room temperature and concentrated to a residue. The resulting residue was purified by flash chromatography on silica gel. This material was further purified using a preparative HPLC to afford a 13% yield (12.5 mg) of 104 as a yellow solid: mp 174-176° C. dec; 1H NMR (500 MHz, DMSO-d6) δ 9.19 (s, 1H), 7.91 (d, 2H, J=8.5 Hz), 7.82 (d, 1H, J=4.5 Hz), 7.43 (t, 2H, J=8.0 Hz), 7.34 (t, 1H, J=7.8 Hz), 7.22 (s, 1H), 7.19 (d, 2H, J=8.5 Hz), 7.14 (s, 1H), 4.78 (s, 2H), 3.55 (s, 3H), 3.52 (s, 1H), 3.40 (td, 1H, J=11.0, 3.5 Hz), 3.13 (m, 1H), 2.90 (dd, 1H, J=6.0, 3.0 Hz), 2.47 (m, 1H), 2.24 (s, 3H), 2.05 (s, 3H), 1.42 (s, 9H); MS (ESI+) m/z 597.7 (M+H).

Workup

  1. customA 5-mL reaction tube
  2. customequipped with a magnetic stirrer
  3. customThis mixture was degassed with nitrogen for 30 min
  4. customthe tube was sealed
  5. temperaturethe reaction mixture was cooled to room temperature
  6. concentrationconcentrated to a residue
  7. customThe resulting residue was purified by flash chromatography on silica gel
  8. customThis material was further purified

Sources & evidence

ORD record
ord-8d0aad5269094655b1f3863e83810225
Source dataset
uspto-grants-2016_02
Patent number
US09249123B2

Reaction notes

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