Triethylamine → N-(1-bromoisoquinolin-3-yl)-1-(4-methoxyphenyl)cyclopropanecarboxamide

HRID 1891284Notes

Reaction equation

HRID 1891284 reaction equation
[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:12]([OH:14])=O)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.S(Cl)(Cl)=O.[Br:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[C:22]([NH2:30])[N:21]=1.CCN(CC)CC>C(Cl)Cl.CN(C=O)C>[Br:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[C:22]([NH:30][C:12]([C:9]2([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[CH2:10][CH2:11]2)=[O:14])[N:21]=1

Participants

7

Reactant 4

HCID 8471TriethylamineHCID 24386Thionyl Chloride2×HCID 855751-(4-Methoxyphenyl)cyclopropane-1-carboxylic acidHCID 2898451-Bromoisoquinolin-3-amine

Product 1

HCID 57733030N-(1-bromoisoquinolin-3-yl)-1-(4-methoxyphenyl)cyclopropanecarboxamideYield 75%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolvent2×HCID 6344DichloromethaneSolvent2×

Conditions

Temperature
50 °C

Procedure

To 1-(4-methoxyphenyl)cyclopropanecarboxylic acid (4.07 g, 21.17 mmol), thionyl chloride (4.64 mL, 63.52 mmol) and DMF (64 μL) were stirred at 50° C. for 3 hours, after which additional thionyl chloride (4 mL) and DMF (60 μL) were added and the mixture was stirred at 50° C. for 1 additional hour. The excess thionyl chloride was evaporated under reduced pressure. The resulting acid chloride was dissolved in anhydrous DCM (20 mL) and was slowly added to a cooled suspension of (0° C.) of 1-bromoisoquinolin-3-amine in DCM (50 mL) and Et3N (14.05 mL, 100.8 mmol). The reaction mixture was stirred at room temperature for 18 hours. The resulting mixture was diluted with DCM and washed with water (1×30 mL), 1 N NaOH (2×30 mL), 1 N HCl (1×30 mL), saturated aqueous NaHCO3 (1×30 mL) and brine (1×30 mL). The organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (0-50% ethyl acetate in hexane) to yield N-(1-bromoisoquinolin-3-yl)-1-(4-methoxyphenyl)cyclopropanecarboxamide (6.0 g, 75%) as a yellow solid. ESI-MS m/z calc. 396.05. found 397.3 (M+1)+. Retention time 2.24 minutes. 1H NMR (400.0 MHz, CDCl3) d 8.55 (s, 1H), 8.15 (d, J=8.5 Hz, 1H), 7.89 (s, 1H), 7.78 (d, J=8.2 Hz, 1H), 7.69-7.65 (m, 1H), 7.56-7.52 (m, 1H), 7.46-7.42 (m, 2H), 7.01-6.98 (m, 2H), 3.90 (s, 3H), 1.75 (dd, J=3.7, 6.8 Hz, 2H) and 1.21 (dd, J=3.7, 6.9 Hz, 2H) ppm.

Workup

  1. customThe excess thionyl chloride was evaporated under reduced pressure
  2. dissolutionThe resulting acid chloride was dissolved in anhydrous DCM (20 mL)
  3. stirringThe reaction mixture was stirred at room temperature for 18 hours
  4. washwashed with water (1×30 mL), 1 N NaOH (2×30 mL), 1 N HCl (1×30 mL), saturated aqueous NaHCO3 (1×30 mL) and brine (1×30 mL)
  5. dry with materialThe organic layer was dried over anhydrous Na2SO4
  6. customevaporated under reduced pressure
  7. customThe crude product was purified by column chromatography on silica gel (0-50% ethyl acetate in hexane)

Sources & evidence

ORD record
ord-cabd52b2e2044ca5877378df5bb3f0a2
Source dataset
uspto-grants-2013_08
Patent number
US08507524B2

Reaction notes

Loading…