Pyridine → N-[5-[2-(3,5-Dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]-4-(dimethylaminomethyl)benzamide

HRID 1092010

Reaction equation

HRID 1092010 reaction equation
C(Cl)(=O)C(Cl)=O.[CH3:7][N:8]([CH2:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=1)[CH3:9].[NH2:20][C:21]1[N:25](C(OC(C)(C)C)=O)[N:24]=[C:23]([CH2:33][CH2:34][C:35]2[CH:40]=[C:39]([O:41][CH3:42])[CH:38]=[C:37]([O:43][CH3:44])[CH:36]=2)[CH:22]=1.N1C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.CN(C=O)C>[CH3:42][O:41][C:39]1[CH:40]=[C:35]([CH2:34][CH2:33][C:23]2[NH:24][N:25]=[C:21]([NH:20][C:15](=[O:17])[C:14]3[CH:13]=[CH:12][C:11]([CH2:10][N:8]([CH3:7])[CH3:9])=[CH:19][CH:18]=3)[CH:22]=2)[CH:36]=[C:37]([O:43][CH3:44])[CH:38]=1

Participants

8

Reactant 5

HCID 1049PyridineHCID 6422Trifluoroacetic acidHCID 65578Oxalyl chlorideHCID 8263194-[(Dimethylamino)methyl]benzoic acidHCID 57440371Tert-butyl 5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]pyrazole-1-carboxylate

Product 1

HCID 66589695N-[5-[2-(3,5-Dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]-4-(dimethylaminomethyl)benzamideYield 28.4%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideCatalystHCID 6344DichloromethaneSolvent3×

Procedure

Oxalyl chloride (61 μl, 0.69 mmol, 1.1 eq) was added dropwise to 4-(dimethylaminomethyl)benzoic acid (113 mg, 0.63 mmol, 1 eq) in DCM (2.5 ml) containing 1 drop of DMF. After stirring at ambient temperature for 1.5 h, a solution of tert-butyl 5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]pyrazole-1-carboxylate (196 mg, 0.56 mmol, 0.9 eq) and pyridine (137 μL, 1.69 mmol, 2.70 eq) in DCM (2 ml) was added to the reaction mixture and stirring was continued at ambient temperature for a further 2 h. A solution of TFA (384 μL, 5.16 mmol, 8.25 eq) in DCM (3.5 ml) was then added and stirring was continued at ambient temperature for 18 h. The reaction mixture was concentrated and the crude product was purified by reverse-phase prep. HPLC (basic) using a gradient of acetonitrile in water containing 1% ammonium hydroxide solution. The clean fractions were taken and evaporated to afford the title compound as a colourless solid (65 mg, 25% yield); 1H NMR (399.902 MHz, DMSO) δ 2.09 (6H, s), 2.81 (4H, s), 3.38 (2H, s), 3.65 (6H, s), 6.26-6.25 (1H, m), 6.35 (2H, d), 6.40 (1H, s), 7.31 (2H, d), 7.87 (2H, d), 10.51 (1H, br.s), 12.07 (1H, br.s). MS: m/z 409 (MH+)

Workup

  1. stirringstirring
  2. waitwas continued at ambient temperature for a further 2 h
  3. stirringstirring
  4. waitwas continued at ambient temperature for 18 h
  5. concentrationThe reaction mixture was concentrated
  6. customthe crude product was purified by reverse-phase prep
  7. customevaporated

Sources & evidence

ORD record
ord-90305c0048664ec79ebccf13c08c6fab
Source dataset
uspto-grants-2012_03
Patent number
US08129391B2

Linked notes

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