Methyl acetopyruvate → 1H-Pyrazole-3-carboxylic acid, 5-methyl-1-[(4-methylphenyl)methyl]-, methyl ester

HRID 2400526

Reaction equation

Cl.Cl.[CH3:3][C:4]1[CH:12]=[CH:11][C:7]([CH2:8][NH:9][NH2:10])=[CH:6][CH:5]=1.[CH3:13][C:14]([CH2:16][C:17]([C:19]([O:21][CH3:22])=[O:20])=O)=O>C(O)(=O)C>[CH3:13][C:14]1[N:9]([CH2:8][C:7]2[CH:11]=[CH:12][C:4]([CH3:3])=[CH:5][CH:6]=2)[N:10]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[CH:16]=1

Participants

Conditions

Temperature: 90 °C

Procedure

A mechanically stirred suspension of 4-(methylbenzyl)hydrazine dihydrochloride (Step 3, 81.8 g, 391 mmol) and methyl acetopyruvate (51.2 g, 356 mmol) in acetic acid (825 mL) was warmed to 90° C. and stirred for 4 h. The solid gradually dissolved, leaving an orange solution. After being cooled to rt, the reaction mixture was concentrated to an orange oil. The organic residue was diluted with EtOAc, washed with water (1×250 mL), NaHCO3 (1×250 mL), and brine (1×250 mL), was dried (Na2SO4), filtered and concentrated to an orange oil. Purification with an ISCO CombiFlash Companion, using a gradient from 0% to 30% EtOAc in hexanes afforded the title compound as a yellow-orange oil (39 g, 45%): 1H NMR (300 MHz, d6-DMSO) δ 2.20 (s, 3H), 2.24 (s, 3H), 3.75 (s, 3H), 5.31 (s, 2H), 6.56 (s, 1H), 7.01 (d, 2H), 7.12 (d, 2H). ES-MS m/z 245.0 (MH)+, HPLC RT (Method A) 3.13 min.

Workup

dissolutionThe solid gradually dissolved
customleaving an orange solution
temperatureAfter being cooled to rt
concentrationthe reaction mixture was concentrated to an orange oil
additionThe organic residue was diluted with EtOAc
washwashed with water (1×250 mL), NaHCO3 (1×250 mL), and brine (1×250 mL)
dry with materialwas dried (Na2SO4)
filtrationfiltered
concentrationconcentrated to an orange oil
customPurification with an ISCO CombiFlash Companion

Sources & evidence

ORD record: ord-7964a4cacec94f8dabeb778be8f8a92b
Source dataset: uspto-grants-2014_08
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08796253B2

Linked notes

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