Ethanol → Montelukast

Participants

Reaction Conditions

Reaction Steps

143.6 g of sodium hydroxide were added to a solution of 102 g of (R,E)-2-(1-((1-(3-(2-(7-chloroquinolin-2-yl)vinyl)phenyl)-3-(2-(2-hydroxypropan-2-yl)phenyl)propylthio)methyl)cyclopropyl)acetonitrile in 407 ml of ethanol 96% (v/v). The mixture was stirred at reflux temperature for 30 hours. After this period of time, the solvent was distilled off under vacuum (Purity by HPLC: 61.5 area %; impurity i2: 1.84 area %; impurity i5: 3.70 area %; impurity i6: 1.42 area %). The mixture was partitioned with 1000 ml of toluene and 1500 ml of water at room temperature. The aqueous phase with the inorganic salts dissolved, was discarded. The organic phase was mixed with 1500 ml of water and the mixture was heated to 60° C. and stirred for 15 minutes. At this point the product was dissolved in the aqueous layer. The pH of the aqueous layer was 12.5. Some impurities from the process were dissolved in the organic layer. Therefore, the organic layer was discarded. The toluene wash at 60° C. was repeated. The outcome aqueous layer was cooled down to room temperature and 1000 ml of toluene were added. Then, the pH of the mixture was adjusted to 5.6 with a 2M solution of acetic acid. The mixture was stirred for 30 minutes and the aqueous layer was discarded. Finally, the organic layer was washed with 1000 ml of water and kept as a solution of purified Montelukast acid (Purity by HPLC: 84.4 area %; impurity i2: 0.81 area %; impurity i5: 0.70 area %; impurity i6: 0.007 area %). Yield corrected by HPLC of the title compound from the outcome solution: 86%.

Provenance & Evidence