Hydrochloric Acid → tert-Butyl 4-(6-(6-(4-Fluoro-3-(4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamido)phenyl)-3-oxo-2,3-dihydropyridazin-4-ylamino)pyridin-3-yl)-3-oxopiperazine-1-carboxylate

HRID 1907811Notes

Reaction equation

HRID 1907811 reaction equation
Cl[C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][C:17]3=[O:29])=[CH:12][CH:11]=2)[C:5](=[O:8])[NH:6][N:7]=1.[F:30][C:31]1[CH:36]=[CH:35][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][C:32]=1[NH:46][C:47]([C:49]1[S:53][C:52]2[CH2:54][CH2:55][CH2:56][CH2:57][C:51]=2[CH:50]=1)=[O:48].C(=O)([O-])[O-].[Na+].[Na+].Cl>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.CN(C=O)C>[F:30][C:31]1[CH:36]=[CH:35][C:34]([C:2]2[CH:3]=[C:4]([NH:9][C:10]3[N:15]=[CH:14][C:13]([N:16]4[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][C:17]4=[O:29])=[CH:12][CH:11]=3)[C:5](=[O:8])[NH:6][N:7]=2)=[CH:33][C:32]=1[NH:46][C:47]([C:49]1[S:53][C:52]2[CH2:54][CH2:55][CH2:56][CH2:57][C:51]=2[CH:50]=1)=[O:48]

Participants

8

Reactant 4

HCID 313Hydrochloric AcidHCID 10340Sodium CarbonateHCID 58540112N-(2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamideHCID 58540403tert-Butyl 4-(6-(6-Chloro-3-oxo-2,3-dihydropyridazin-4-ylamino)pyridin-3-yl)-3-oxopiperazine-1-carboxylate

Product 1

HCID 58539996tert-Butyl 4-(6-(6-(4-Fluoro-3-(4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamido)phenyl)-3-oxo-2,3-dihydropyridazin-4-ylamino)pyridin-3-yl)-3-oxopiperazine-1-carboxylateYield 27%

Reagents, catalysts & solvents 3

HCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolvent2×HCID 6228DimethylformamideSolvent

Conditions

Temperature
100 °C

Procedure

In a 50-mL round-bottomed flask equipped with a magnetic stirrer and reflux condenser, 2f (240 mg, 0.570 mmol), N-(2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide (251 mg, 0.630 mmol) and sodium carbonate (181 mg, 1.71 mmol) were mixed with DMF (16.0 mL) and water (3.0 mL). This mixture was degassed with nitrogen for 30 min. Tetrakis(triphenylphosphine)palladium (66 mg, 0.057 mmol) was added and the mixture was stirred at 100° C. (bath temperature) for 4 d. The reaction mixture was then cooled to room temperature, and water (50 mL) was added. The pH was adjusted to 6.5 with 2N hydrochloric acid and the resulting precipitate was filtered, and the filter cake was washed with ater (25 mL) and purified by column chromatography to afford a 27% yield of 2h (100 mg) as a tan foam: 1H NMR (300 MHz, DMSO-d6) δ 13.23 (s, 1H), 10.09 (s, 1H), 9.54 (s, 1H), 8.84 (s, 1H), 8.38 (4, 1H, J=2.7 Hz), 8.03 (dd, 1H, J=7.5, 2.1 Hz), 7.75 (d, 1H, J=2.7 Hz), 7.72 (s, 1H), 7.66 (m, 1H), 7.54 (d, 1H, J=9.0 Hz), 7.41 (t, 1H, 3=10.2 Hz), 4.09 (s, 2H), 3.70 (m, 4H), 2.77 (t, 2H, J=5.5 Hz), 2.62 (t, 2H, J=5.0 Hz), 1.79 (m, 4H), 1.45 (s, 9H); MS (ESI+) m/z 659.9 (M+H).

Workup

  1. customIn a 50-mL round-bottomed flask equipped with a magnetic stirrer
  2. temperaturereflux condenser
  3. customThis mixture was degassed with nitrogen for 30 min
  4. temperatureThe reaction mixture was then cooled to room temperature
  5. filtrationthe resulting precipitate was filtered
  6. washthe filter cake was washed with ater (25 mL)
  7. custompurified by column chromatography

Sources & evidence

ORD record
ord-25c563436be54eb19035064c8bc2c052
Source dataset
uspto-grants-2013_12
Patent number
US08598174B2

Reaction notes

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