Pyridine → Sunitinib

Participants

Reaction Conditions

Reaction Steps

A mixture of 5-((Z)-(5-fluoro-2-oxoindolin-3-ylidene) methyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (70 g) in DMF (1050 mL) was cooled to 15-19° C. To this mixture p-toluene sulfonyl chloride (133.4 g) in DMF (350 mL) was added in 15 min. 4-dimethylamino pyridine (81.3 g) in DMF (350 mL) was added in 15 min and pyridine (36.9 g) was added in 15 min at 15-19° C. The reaction mixture was stirred at the same temperature over a period of 60-90 minutes. The reaction mass was cooled to 13-16° C. To the above reaction mixture N, N-diethyl ethylene diamine (81.3 g) in DMF (350 mL) was added in 10 min at 13-16° C. The reaction mass was maintained under stirring for a period of 30 minutes at the same temperature. The progress of the rection was monitored by HPLC with a limit of 5-((Z)-(5-fluoro-2-oxoindolin-3-ylidene)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid not more than 5.0%. After the completion of reaction 28 mL of water was charged and DMF was distilled off under vacuum. 1050 mL of 5% sodium bicarbonate solution was charged under stirring. The pH of the above solution was adjusted to 12-13 by 50% NaOH solution. Ethyl acetate was charged and it was stirred for 5 min. The organic layer were separated and treated with 1% NaOH, and brine solution followed by separation of the ethyl acetate fraction and distillation off under vacuum below 50° C. The residue was treated with 30% methanol in water to isolate the material. It was treated with methanol to obtain sunitinib base. The obtained solid was dried under vacuum at 55 -65° C. over for a period of 5 hrs. Yield: 65.6 g of Sunitinib base with ˜0.5% des ethyl sunitinib.

Provenance & Evidence