Take salicylic acid as raw material; it undergoes chlorination through thionyl chloride to obtain salicylic acid chloride. Salicylic acid chloride and salicylic acid amide are placed under the condition of high temperature and vacuum distillation instead of ordinary reflux method to obtain intermediates, further evaporating into large amount of low-boiling and by-products through high temperature vacuum distillation, making the mass fraction of the intermediate be increased from 88.7% to 97.5%. Finally, after the removal of hydrochloric acid, the carboxyl-phenylhydrazine hydrochloride is subject to cyclization with the intermediate to prepare the product of deferasirox, reducing the steps of desalting and solvents steaming-off in the post-reaction treatment while reducing the amount of anhydrous ethanol as well so that the operation becomes simpler.
1. Preparation of salicylic acid chloride (Compound 1)
Salicylic acid (13.8 g, 0.1 mol), 10 drops of anhydrous pyridine and 10 mL of thionyl chloride were added to the reaction flask. The mixture was subject to stirred reaction at room temperature for 30 min and slowly heated to 70 °C with stirring until almost no hydrogen chloride gas was released. Further heat to 80 °C and stir for 3 h. Residual thionyl chloride was distilled off under reduced pressure to give a pale yellow liquid which was cooled to precipitate crystals and used directly in the next reaction.
2. Preparation of the 2-(2-hydroxyphenyl)-[1, 3] benzoxazinone (Compound 2)
Salicylic acid (13.7 g, 0.1 mol) and the compound 1 obtained from the last step of reaction are added to the reaction flask equipped with a distillation apparatus and heated to 180 ° C. The reaction mixture was reacted with distillation under reduced pressure at the same time for 3 h to remove water from the reaction. 50 mL of absolute ethanol was added under melting to precipitate the solid yellow product. After filtration and recrystallization from anhydrous ethanol, we can obtain 16.8 g of a yellow product with a yield 70.3% and mp 210-213 °C.
3. Preparation of p-carboxyphenylhydrazine hydrochloride (Compound 3)
4-aminobenzoic acid (6.85 g, 0.05 mol) and 10 mL of distilled water were added into a 250 mL three-necked flask. The mixture was stirred to become a paste and added of drop wise of 12.5 mL of concentrated hydrochloric acid at 5 ° C. The solution was cooled to 5 ° C in an ice-salt bath. Upon stirring, slowly add drop wise of a sodium nitrite saturated solution (3.5 g, 0.05 mol of sodium nitrite is dissolved in a small amount of water (8 g)) for diazotization reaction. The reaction temperature is kept below 5 ℃ and further stirred for 30 mins after the completion of dropping.
The diazonium salt solution was then poured into a solution with sodium sulfite (25.2 g, 0.2 mol) dissolved in water (100 mL) pre-cooled to 5 °C. Stir at this temperature for 30 min, and heat to 80 ° C for 1.5 h. The orange-red solution will be changed to yellowish. Cool it to room temperature; slowly add hydrochloric acid for acidification to pH 3 to obtain the p-carboxyphenylhydrazine hydrochloride precipitate. Further apply filtration and drying to get 8.3 g white product with a yield of 88.3%.
4. Preparation of Deferasirox
The compound 3 (3.8 g, 0.02 mol) was adjusted to pH 6 with 30% NaOH, stirred, and stand for layering so that the water layers were separated. The oil layer was p-carboxyphenylhydrazine. The oil layer was placed in a flask; add compound II (5.0 g; 0.02 mol) and reflux for 2 h in anhydrous ethanol (75 mL). Cool, precipitate the crystals; filtrate and rinse with 10 mL of ice ethanol, dry and perform ethanol-water recrystallization, to obtain 6.3 g micro-yellow product with a yield of 84.45%.
Figure 1 synthetic route of Deferasirox
