HCID 719836, compound → HCID 58958171, compound

HRID 2252091Notes

Reaction equation

HRID 2252091 reaction equation
[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][C:12]([NH:14][NH2:15])=[O:13].C[Al](C)C.[CH3:20][C:21]1[CH:30]=[C:29]([NH:31][C:32]2[CH:33]=[C:34]([CH:39]=[CH:40][CH:41]=2)[C:35](OC)=[O:36])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=1>C1(C)C(C)=CC=CC=1>[CH3:20][C:21]1[CH:30]=[C:29]([NH:31][C:32]2[CH:33]=[C:34]([CH:39]=[CH:40][CH:41]=2)[C:35]([NH:15][NH:14][C:12](=[O:13])[CH2:11][N:2]2[CH2:3][CH2:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:1]2)=[O:36])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=1

Participants

5

Reactant 3

HCID 719836HCID 719836, compoundHCID 16682925TrimethylaluminumHCID 27055575HCID 27055575, compound

Product 1

HCID 58958171HCID 58958171, compoundYield 63.2%

Reagents, catalysts & solvents 1

HCID 7237O-XyleneSolvent

Procedure

Ethyl(3,4-dihydro-1H-isoquinolin-2-yl)acetate (90). To a solution of 40 (1.33 g, 10.0 mmol) in acetonitrile (50 mL) were sequentially added potassium carbonate (5.53 g, 40.0 mmol) and ethyl bromoacetate (1.67 g, 10.0 mmol). The reaction mixture was stirred at room temperature overnight, then partitioned between EtOAc (200 mL) and water (150 mL). The organic layer was dried (MgSO4) and concentrated under reduced pressure to give 90 (2.1 g, 99%). Step 2. (3,4-Dihydro-1H-isoquinolin-2-yl)acetic hydrazide (91). A solution of 90 (2.0 g, 9.12 mmol) and hydrazine (5.1 g, 91 mmol) in ethanol (30 mL) was heated at reflux overnight. The mixture was concentrated under reduced pressure to give 91 (1.87 g ˜100%) which was used without further purification. Step 3. 3-(2-Methylquinolin-4-ylamino)-N′-(2-3,4-dihydro-1H-isoquinolin-2-yl-acetyl)benzoic hydrazide (92). To a solution of 91 (205 mg, 1.0 mmol) in xylene (5 mL) was added trimethyl aluminum (2 M solution in hexanes, 0.75 mL, 1.5 mmol). The mixture was stirred under nitrogen for 10 minutes before the addition of methyl 3-(2-methylquinolin-4-ylamino)benzoate (49) (150 mg, 0.5 mmol). The reaction was heated at reflux overnight, quenched with water (2 mL), basified to pH 9 (2 N NaOH), and extracted with 7:3 CH2Cl2/MeOH. The organic layer was dried (K2CO3) and concentrated under reduced pressure, and the residue was purified by flash chromatography (SiO2, gradient elution) to give 92 as a pale yellow oil (147 mg, 63%). Step 4. {3-[5-(3,4-Dihydro-1H-isoquinolin-2-ylmethyl)-[1,3,4]oxadiazol-2-yl]phenyl}-(2-methylquinolin-4-yl)amine. A mixture of 92 (195 mg, 0.42 mmol) in phosphorous oxychloride (0.5 mL) was heated overnight before mixing cautiously with ice water (2 mL). The mixture was extracted with 7:3 CH2Cl2/MeOH, and the organic layer was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, gradient elution) to give the desired product as a pale yellow solid (69 mg, 37%).

Workup

  1. customwas used without further purification
  2. temperatureThe reaction was heated
  3. temperatureat reflux overnight
  4. customquenched with water (2 mL)
  5. extractionextracted with 7:3 CH2Cl2/MeOH
  6. dry with materialThe organic layer was dried (K2CO3)
  7. concentrationconcentrated under reduced pressure
  8. customthe residue was purified by flash chromatography (SiO2, gradient elution)

Sources & evidence

ORD record
ord-07aca8eeb9a0420482169cba527e3600
Source dataset
uspto-grants-2008_01
Patent number
US07320989B2

Reaction notes

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