On October 14, 2011, the FDA approved the marketing of deferiprone (trade name Ferriprox) developed by ApoPharma of Canada in the United States. The drug is used to treat thalassemia that has not responded well to previous chelation therapy and has excessive iron load due to blood transfusion. 

Mechanism of action

Deferiprone is a chelating agent with affinity for trivalent iron ions. The neutral 3:1 (deferiprone: iron) complex formed by the combination of deferiprone and trivalent iron ions is stable in a wide pH range, can quickly pass through the cell membrane to remove iron in the cell, and can also reduce the iron in serum ferritin. The half-life of deferiprone is 2-3 hours, and it is mainly excreted in the urine. Deferiprone has a low binding affinity to other metals besides iron, such as copper, aluminum and zinc.

Adverse Reactions

The most common adverse reaction of deferiprone is light red/brown urine, which is due to the excretion of the iron-deferiprone complex. Common adverse reactions include: nausea, vomiting, abdominal pain, increased appetite, increased alanine aminotransferase, joint pain and neutropenia. The above adverse reactions often occur in the early stage of deferiprone treatment, and most patients are relieved after continuing treatment for several days or weeks.

Preparation method

Step 1: 3-Benzyloxy-2-methyl-4-pyridone (3)

2 (8.16 g, 0.059 mol) was dissolved in a mixed solution of methanol (82.7 ml) and 30% sodium hydroxide (9.19 ml), and benzyl chloride (9.37 g, 0.074 mol) was added. The mixture was refluxed for 6 hours, cooled and allowed to stand overnight. Concentrate to remove methanol, add water (18 ml), extract with ethyl acetate (15 ml x 3), combine the organic layers, wash with 30% sodium hydroxide solution (15 ml x 3), then wash with saturated brine until neutral, and dry with anhydrous sodium sulfate. Filter, concentrate the filtrate to obtain oily substance 3 (11.22 g, 85%). Use it directly in the next step.

Step 2: 1,2-dimethyl-3-benzyloxy-4-pyridone hydrochloride (4)

3 (11.22 g, 0.05 mol) and methylamine hydrochloride (3.65 g, 0.075 mol) were dissolved in anhydrous ethanol (58 ml) and water (117 ml), sodium hydroxide (4.7 g) was added, and the reaction was carried out at room temperature for 3 days. Add concentrated hydrochloric acid (9 ml) to adjust to pH 2.0, crystallize at 4 °C overnight, filter to obtain pale yellow solid 4 crude product (12.85 g), recrystallize with ethanol (120 ml) to obtain colorless crystal 4 pure product (9.58 g).

Step 3: Deferiprone (1)

4 (9.58 g, 0.036 mol) was added to concentrated hydrochloric acid (39 ml), refluxed for 1 h and cooled to room temperature, adjusted to pH 7.5 with 20% Na2CO3 solution, and placed at 4 °C overnight. After crystallization, filter to obtain light brown 1 crude product (5.9 g), recrystallize with hot water to obtain colorless crystal deferiprone 1 (4.32 g, 57.6%), mp 263~266 °C.