Potassium Phosphate, Tribasic → 2-[4-((1R,2R)-2-{[(2S)-2-Methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]pyridazin-3(2H)-one

HRID 73291

Reaction equation

HRID 73291 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][C@@H:13]2[CH3:17])=[CH:4][CH:3]=1.[N:18]1[NH:19][C:20](=[O:24])[CH:21]=[CH:22][CH:23]=1.CN[C@@H]1CCCC[C@H]1NC.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.C(O)(C)C.[Cu](I)I.O>[CH3:17][C@H:13]1[CH2:14][CH2:15][CH2:16][N:12]1[CH2:11][C@@H:9]1[CH2:10][C@H:8]1[C:5]1[CH:6]=[CH:7][C:2]([N:19]2[C:20](=[O:24])[CH:21]=[CH:22][CH:23]=[N:18]2)=[CH:3][CH:4]=1

Participants

9

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 681533(2H)-PyridazinoneHCID 2733821trans-N,N'-dimethyl-1,2-cyclohexanediamineHCID 684254651-[2-(4-bromo-phenyl)-(1R,2R)-cyclopropylmethyl]-(2S)-2-methyl-pyrrolidine

Product 1

HCID 441973232-[4-((1R,2R)-2-{[(2S)-2-Methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]pyridazin-3(2H)-one

Reagents, catalysts & solvents 4

HCID 83717Copper iodideCatalystHCID 962WaterSolventHCID 1140TolueneSolventHCID 3776IsopropanolSolvent

Conditions

Temperature
110 °C

Procedure

A solution of the product from Example 4A (47 mg, 0.16 mmol; 1-[2-(4-bromo-phenyl)-(1R,2R)-cyclopropylmethyl]-(2S)-2-methyl-pyrrolidine), 3(2H)-pyridazinone (CAS #504-30-3, 20 mg, 0.2 mmol), copper iodide (1.5 mg, 0.008 mmol), N,N′-trans-dimethyl-cyclohexane-1,2-diamine (2.3 mg, 0.016 mmol) and potassium phosphate (75 mg, 0.35 mmol) in a mixture of toluene and isopropanol (4 ml, 1.1) was heated to 110° C. in a screw capped vial for 16 hours. The mixture was cooled to ambient temperature, treated with H2O and extracted with ethyl acetate (2×25 mL) The organic layer was separated, washed with brine and dried with magnesium sulfate. After filtration, the organic layer was concentrated under reduced pressure and the resulting oil was purified on silica gel with 1% to 3% methanol (containing 10% concentrated NH4OH) in dichloromethane to provide the title compound. 1H NMR (300 MHz, CD3OD) δ 1.07 (m, 1H), 1.14 (m, 1H), 1.26 (d, J=6 Hz, 3H), 1.40 (m, 1H), 1.58 (m, 1H), 1.90 (m, 3H), 2.13 (m, 1H), 2.58 (m, 1H), 2.70 (q, J=9 Hz, 1H), 2.89 (m, 1H), 3.14 (dd, J=12 Hz, J=6 Hz, 1H), 3.44 (m, 1H), 7.07 (d, J=9 Hz, 1H), 7.24 (d, J=9 Hz, 2H), 7.44 (d, J=9 Hz, 2H), 7.47 (m, 1H), 8.03 (m, 1H), MS (DCl—NH3) m/z 310 (M+H)+.

Workup

  1. customcapped vial for 16 hours
  2. temperatureThe mixture was cooled to ambient temperature
  3. extractionextracted with ethyl acetate (2×25 mL) The organic layer
  4. customwas separated
  5. washwashed with brine
  6. dry with materialdried with magnesium sulfate
  7. filtrationAfter filtration
  8. concentrationthe organic layer was concentrated under reduced pressure
  9. customthe resulting oil was purified on silica gel with 1% to 3% methanol (containing 10% concentrated NH4OH) in dichloromethane

Sources & evidence

ORD record
ord-3285dc2904e94f4595151fcbb05b077d
Source dataset
uspto-grants-2014_09
Patent number
US08829041B2

Linked notes

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