Potassium Phosphate, Tribasic → 2-(4-chlorophenyl)-6-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)thieno[2,3-d]pyridazin-7(6H)-one

HRID 1009810Notes

Reaction equation

HRID 1009810 reaction equation
Br[C:2]1[CH:13]=[CH:12][C:5]([O:6][CH2:7][C:8]([CH3:11])([OH:10])[CH3:9])=[C:4]([O:14][CH3:15])[CH:3]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[S:32][C:26]3[C:27](=[O:31])[NH:28][N:29]=[CH:30][C:25]=3[CH:24]=2)=[CH:19][CH:18]=1.CN[C@@H]1CCCC[C@H]1NC.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC1(N)CCCCC1(C)N>O1CCOCC1.C(Cl)Cl.[Cu-]=O.CO>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[S:32][C:26]3[C:27](=[O:31])[N:28]([C:2]4[CH:13]=[CH:12][C:5]([O:6][CH2:7][C:8]([OH:10])([CH3:11])[CH3:9])=[C:4]([O:14][CH3:15])[CH:3]=4)[N:29]=[CH:30][C:25]=3[CH:24]=2)=[CH:21][CH:22]=1

Participants

10

Reactant 5

HCID 62657Potassium Phosphate, TribasicHCID 2733821trans-N,N'-dimethyl-1,2-cyclohexanediamineHCID 115798042-(4-Chlorophenyl)thieno[2,3-d]pyridazin-7(6H)-oneHCID 15141090Dimethylcyclohexane-1,2-diamineHCID 595950491-(4-Bromo-2-methoxyphenoxy)-2-methylpropan-2-ol

Product 1

HCID 251172722-(4-chlorophenyl)-6-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)thieno[2,3-d]pyridazin-7(6H)-oneYield 38.7%

Reagents, catalysts & solvents 4

HCID 178419072HCID 178419072, compoundCatalystHCID 887MethanolSolventHCID 6344DichloromethaneSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
130 °C

Procedure

A mixture of 1-(4-bromo-2-methoxyphenoxy)-2-methylpropan-2-ol (157 mg, 0.571 mmol), 2-(4-chlorophenyl)thieno[2,3-d]pyridazin-7(6H)-one (150 mg, 0.571 mmol), (1R,2R)—N1,N2-dimethylcyclohexane-1,2-diamine (24.36 mg, 0.171 mmol), K3PO4 (0.142 ml, 1.713 mmol) and cupric oxide (24.51 mg, 0.171 mmol) in dioxane (4 ml) was stirred at 130° C. under N2 in a sealed tube for 24 hours. Since LC-MS analysis revealed no product, another portion of cupric oxide (24.51 mg, 0.171 mmol) was added to the mixture which was then was stirred at 130° C. under N2 in a sealed tube for another 24 hours. Since LC-MS analysis indicated only 25% conversion to product, another equivalent of copper (I) oxide and dimethylcyclohexane-1,2-diamine was added. The mixture was stirred at 150° C. under N2 in a seal tube for 8 hours. After cooling to RT, LC-MS analysis showed the conversion was 45% to product. The mixture was diluted with CH2Cl2 (40 ml) prior to removal of the inorganic solid by filtration. The CH2Cl2 filtrate was washed with a solution of saturated NaHCO3 (3×40 ml), dried over Na2SO4 and concentrated. The crude product was purified by ISCO chromatography on two silica gel column (2×4.0 g) employing a 10 min gradient ranging from hexane to 100% ethyl acetate to elute partially pure product. After titration with MeOH, 2-(4-chlorophenyl)-6-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)thieno[2,3-d]pyridazin-7(6H)-one (101 mg, 0.221 mmol, 38.7% yield) was obtained as light brown solid. LC MS at t=2.52 min. (m+H=457) PHENOMENEX® S5 C18 4.6X30 mm column/water-MeOH-TFA 90:10:0.1 to 10:90:0.1 gradient over 2 min at 5 mL/min with 1 min hold at the end of the gradient. 1H NMR (400 MHz, CDCl3) 8 ppm 1.36 (s, 6H), 3.89 (d, J=3.78 Hz, 5H), 7.00 (d, J=8.56 Hz, 1H), 7.17-7.24 (m, 2H), 7.42-7.54 (m, 3H), 7.66 (d, J=8.31 Hz, 2H), 8.31 (s, 1H).

Workup

  1. stirringwas then was stirred at 130° C. under N2 in a sealed tube for another 24 hours
  2. stirringThe mixture was stirred at 150° C. under N2 in a seal tube for 8 hours
  3. temperatureAfter cooling to RT
  4. customto removal of the inorganic solid
  5. filtrationby filtration
  6. washThe CH2Cl2 filtrate was washed with a solution of saturated NaHCO3 (3×40 ml)
  7. dry with materialdried over Na2SO4
  8. concentrationconcentrated
  9. customThe crude product was purified by ISCO chromatography on two silica gel column (2×4.0 g)
  10. waitemploying a 10 min
  11. washto elute partially pure product

Sources & evidence

ORD record
ord-1be6d0bfff264031b9378b12e16dc468
Source dataset
uspto-grants-2011_07
Patent number
US07973159B2

Reaction notes

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