Background and overview[1]
Tosinib phosphate PVC resin salt can regulate the activity of protein kinase (“PK”) and therefore can be used to treat conditions associated with abnormal PK activity.
Preparation[1]
Tosinib phosphate is prepared as follows:
1) 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (61g), 5-fluoro-1,3-dihydro-indol-2-one (79g) , ethanol (300 mL) and pyrrolidine (32 mL) were refluxed for 4.5 hours. Acetic acid (24 mL) was added to the mixture and reflux was continued for 30 minutes. The mixture was cooled to room temperature and the solid was collected by vacuum filtration and washed twice with ethanol. The solid was stirred in 40% aqueous acetone (mL) containing 12N hydrochloric acid (6.5 mL) for 130 minutes. The solid was collected by vacuum filtration and washed twice with 40% aqueous acetone. The solid was dried under vacuum to give 5-[5-fluoro-2-oxo-1,2-dihydro-indole-(3Z)-ylidenemethyl]-2,4-dimethyl-1H as an orange solid -pyrrole-3-carboxylic acid (86 g, 79% yield).
2) 5-[5-Fluoro-2-oxo-1,2-dihydro-indole-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3 -Carboxylic acid (100g) and dimethylformamide (500mL) were stirred, and benzotriazol-1-yloxytris(dimethylamino)phosphine hexafluorophosphate (221g), 1-(2- Aminoethyl)pyrrolidine (45.6 g) and triethylamine (93 mL). The mixture was stirred at ambient temperature for 2 hours. The solid product was collected by vacuum filtration and washed with ethanol. The solid was slurry-washed by stirring in ethanol (500 mL) at 64°C for one hour and allowed to cool to room temperature. The solid was collected by vacuum filtration, washed with ethanol, and dried under vacuum to give 5-[5-fluoro-2-oxo-1,2-dihydro-indole-(3Z)-ylidenemethyl]-2, 4-Dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-ylethyl)-amide (101.5 g, 77% yield).
3) Add 2.67 mmol of 5-[5-fluoro-2-oxotonso-1,2-dihydro-indole-(3Z)-ylidenemethyl]-2,4-dimethyl -1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-ylethyl)-amide was added to the flask with 40 mL of 0.092 M phosphoric acid (approximately 40% molar excess relative to the assumed 1:1 salt) and 40 mL of isopropyl alcohol. middle. Acetonitrile was then continuously added to the aqueous solution in 30 mL aliquots, and the solution was rotary evaporated at 60°C to remove water. A total of 120 mL of acetonitrile was used to remove water from the solution. The crystals were filtered and air dried. The crystals were free flowing and orange in color; 1.09 g of tosinib phosphate was collected, yielding 83%.
Main reference materials
[1]CN200680034505.3 Solid salt form of pyrrole-substituted 2-indolone
