Application of p-hydroxybenzoic acid in drug synthesis

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In addition to the use of parabens as preservatives in pharmaceutical preparations, p-hydroxybenzoic acid can also be used as a base material for a variety of pharmaceutical products.
a. febuxostat
Febuxostat is a new generation of xanthine oxidase inhibitors, clinically used to treat hyperuricemia (gout), and Teijin was first listed in Japan in early 2004.
Synthesis of febuxostat: using methyl p-hydroxybenzoate as raw material, bromination and etherification to obtain methyl 3-bromo-4-(2-methylpropoxy)benzoate as key intermediate, and then cyanide The cuprous reaction is introduced into a cyano group, and then a thiazole ring is synthesized, followed by hydrolysis to obtain febuxostat, or a thiazole ring is first synthesized, and then a cyano group is introduced, and hydrolyzed to obtain febuxostat.
b. Finobert
Finobel is a second-generation phenoxy aryl acid drug that significantly lowers triglycerides (TG), moderately lowers total cholesterol and low-density lipoprotein cholesterol, and raises high-density lipoprotein cholesterol. It has been widely used clinically and was marketed in the United States by Abbott in 1998.
Synthesis of Finobel: Hydroxybenzoic acid is chlorinated with thionyl chloride, and then reacted with chlorobenzene to obtain 4-hydroxy-4'-chlorobenzophenone, followed by 2-bromo- 2-Methylisopropyl ester is reacted in the presence of a base to give fenofibrate.
c. Gabexyl methanesulfonate
Gabexyl methanesulfonate is an inhibitor of non-peptide proteases that inhibits the activity of proteases such as trypsin, kallikrein, plasmin, and thrombin, thereby stopping the pathology caused by these enzymes. The treatment of acute mild (edema) pancreatitis can also be used for adjuvant treatment of acute hemorrhagic necrotic pancreatitis. It was listed in Japan in 1978 by Ono Pharmaceutical Co., Ltd.
Synthesis of gabasulfame methanesulfonate: 6-aminocaproic acid is reacted with S-methylisothiourea sulfate, hydrochloric acid is converted to 6-mercaptohexanoic acid hydrochloride, and chlorinated with ethyl p-hydroxybenzoate The 4,4'-(thionyldioxy)dibenzoate obtained by condensation of sulfoxide is reacted to obtain the butyl sulphate hydrochloride, and then reacted with methanesulfonic acid to obtain the methanesulfonate.
d. Nitroiodonitrile
Nitroiodilonitrile is a veterinary drug. It is a new type of liverworm that can block the oxidative carbonation of insects, reduce the concentration of ATP, and reduce the energy required for cell division, leading to the death of the worm.
Synthesis of nitroiodoponitrile: using p-hydroxybenzoic acid as raw material, and uniformly mixing with urea, sulfamic acid and p-cresol, the temperature is raised, filtered, washed, and the filtrate is distilled under reduced pressure to obtain p-hydroxybenzonitrile. The p-hydroxybenzonitrile is reacted with nitric acid in glacial acetic acid to synthesize 3-nitro-4-hydroxybenzonitrile, and then reacted with iodine and hydrogen peroxide in an acidic ethanol solution to synthesize nitroiodopropenitrile.
e. Nifurate
Nifurate is a broad-spectrum antibacterial agent for the prevention of intestinal or urinary system diseases caused by Escherichia coli, Salmonella, Pasteurella (including R. brevis), Aerobacteria, Proteus, Necrobacterium and Staphylococcus. It can be used for the treatment of intestinal and systemic diseases caused by bacteria, vibri and fungi in aquatic animals, prevention of coccidiosis in chickens, white crown disease caused by leukocyte protozoa, and cecal hepatitis.
Synthesis of Nifuratezide: Hydroxybenzoate is esterified to form methylparaben, which is reacted with hydrazine to form p-hydroxybenzohydrazide, which is then reacted with 5-nitrofurfural to give nifurate.