A practical procedure for the synthesis of esonarimod, (R,S)-2-acetylthiomethyl-4-(4-methylphenyl)-4-oxobutanoic acid, an antirheumatic agent (part 1).
An efficient and practical procedure for the synthesis of esonarimod, (R,S)-2-acetylthiomethyl-4-(4-methylphenyl)-4-oxobutanoic acid (1), a new antirheumatic drug, has been developed. The intermediate, 2-methylene-4-(4-methylphenyl)-4-oxobutanoic acid (2), was prepared by Friedel-Crafts acylation of toluene with itaconic anhydride (3) in the presence of aluminum trichloride and nitrobenzene in 63% yield without silica gel column purification. Compound 1 was prepared by Michael addition of 2 with thioacetic acid (4) in 74% yield. Overall, 1 was obtained in 47% yield from 3. The structures and synthetic mechanisms of by-products (five compounds) of 2 were also clarified.
Noguchi
Toshiya
T
Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd., Saitama, Japan. t.noguhi@po.rd.taisho.co.jp
Onodera
Akira
A
Tomisawa
Kazuyuki
K
Yokomori
Sadakazu
S
D018501:Antirheumatic Agents / Q000138:chemical synthesis* / Q000737:chemistry; D010666:Phenylpropionates / Q000138:chemical synthesis* / Q000737:chemistry
D018501:Antirheumatic Agents; D010666:Phenylpropionates; C078547:esonarimod