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

HRID 73291

반응식

HRID 73291 반응식
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

참가 물질

9

반응물 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

생성물 1

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

시약·촉매·용매 4

HCID 83717Copper iodide촉매HCID 962Water용매HCID 1140Toluene용매HCID 3776Isopropanol용매

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온도
110 °C

실험 절차

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)+.

후처리

  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

출처 및 근거

ORD 기록
ord-3285dc2904e94f4595151fcbb05b077d
출처 데이터셋
uspto-grants-2014_09
특허 번호
US08829041B2

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