Triethylamine → 5-Amino-1-(5-carboxy-2-methyl-phenyl)-1H-pyrazole-4-carboxylic acid ethyl ester

HRID 251360

Reaction equation

Cl.[NH:2]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:7]([OH:9])=[O:8])[NH2:3].[CH2:14]([O:16][C:17](=[O:26])[C:18]([C:24]#[N:25])=[C:19]=COCC)[CH3:15].C(N(CC)CC)C>C(O)C>[CH2:14]([O:16][C:17]([C:18]1[CH:19]=[N:3][N:2]([C:4]2[CH:5]=[C:6]([C:7]([OH:9])=[O:8])[CH:10]=[CH:11][C:12]=2[CH3:13])[C:24]=1[NH2:25])=[O:26])[CH3:15]

Participants

Conditions

Temperature: 65 °C

Procedure

To a stirred solution of 3-hydrazino-4-methylbenzoic acid hydrochloride (Example 3A, 478 mg, 2.36 mmol, 1.0 eq) in 20 mL of ethanol were added ethyl(ethoxymethylene)cyanoacrylate (399 mg, 2.36 mmol, 1.0 eq) and triethylamine (329 μL, 2.36 mmol, 1.0 eq) and the mixture was heated at 65° C. for 5 hrs. After standing at room temperature overnight, additional 3-hydrazino-4-methylbenzoic acid hydrochloride (159 mg, 0.78 mmol, 0.3 eq) and triethylamine (110 μL, 0.78 mmol, 0.3 eq) and heated for 2.5. The mixture was cooled to room temperature and concentrated. The crude residue was purified by flash chromatography on silica gel (gradient elution from 7/3 hexanes/EtOAc to 1/1 to elute byproducts followed by EtOAc and 9/1 EtOAc/MeOH to elute product) to provide the product as a brown solid (464 mg, 68%). HPLC (4 minute 10-95 gradient) tR 1.87 min; MS m/z 290.1 [M+H]+; 1H NMR (CD3OD), δ 8.08 (d, J=7.0 Hz, 1 H), 7.93 (s, 1 H), 7.76 (s, 1 H), 7.54 (d, J=8.0 Hz, 1 H), 4.29 (q, J=7.1 Hz, 2 H), 2.19 (s, 3 H), 1.35 (d, J=7.1 Hz, 3 H), ppm; 13C NMR (CD3OD), δ 166.5, 163.8, 150.4, 141.7, 139.9, 135.3, 130.8, 129.5, 128.6, 93.8, 58.8, 15.8, 12.9 ppm.

Workup

temperatureThe mixture was cooled to room temperature
concentrationconcentrated
customThe crude residue was purified by flash chromatography on silica gel (gradient elution from 7/3 hexanes/EtOAc to 1/1 to elute byproducts followed by EtOAc and 9/1 EtOAc/MeOH to elute product)

Sources & evidence

ORD record: ord-65718befb97e478fbdece0aa3ce7c5b2
Source dataset: uspto-grants-2011_01
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US07863314B2

Linked notes

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