Scaled-Up Preparation of an Intermediate of Upatinib, ACT051-3

Here, a protocol for the scaled-up synthesis of an intermediate of upatinib, ACT051-3, is presented. This method is simple to operate, low cost, and environmentally friendly. To begin, prepare ACT051-2 by dissolving 50 grams of the compound 2-bromo-5-tosyl-5H-pyrrolo[2, 3-b]pyrazine in 15 milliliters of N, N-dimethylformamide, or DMF in a round-bottom flask.

Add 65.3 grams of diisopropylethylamine to the reaction solution under nitrogen protection, and cool the temperature to 0 to 5 degrees Celsius through a cool water bath. Add 60.2 grams of para-toluene sulphonyl chloride, or TsCL, dissolved in 12 milliliters of DMF, and raise the temperature to 20 to 30 degrees Celsius through the warm water bath. Stir for about 1 hour.

Add 600 milliliters of cool water to the mixture, and stir for another 1 hour. Filter the product under a vacuum using a glass funnel with a sanding board padded with filter paper. Wash with 200 milliliters of water several times, and dry, using an electric thermostatic drying oven to obtain pale yellow solid ACT051-2 with a yield of 78%For the synthesis of ACT051-3, dissolve 176.11 grams of ACT051-2 in 366.31 grams of 1, 4-dioxane in a three-port round-bottom flask, and add 65.75 grams of tert-butyl carbamate, 138.21 grams of granular potassium carbonate, 11.57 grams of Xantphos, and 2.25 grams of palladium acetate to the solution.

Heat the mixture to 105 degrees Celsius, and stir for 7 hours under a nitrogen atmosphere. After cooling the mixture to room temperature, filter the product with a Buchner funnel. Wash the filter residue with 200 milliliters of ethyl acetate.

Use a circulating water vacuum pump to concentrate the product under reduced pressure at 50 to 60 degrees Celsius, with a pressure value of minus 0.095 megapascal. Keep the pump working to maintain the pressure and obtain a dark brown oil. Purify the crude product with column chromatography, eluting with petroleum ether and ethyl acetate to obtain the target compound as a white solid with a yield of 93.5%For the pilot scale-up synthesis of ACT051-2, add one kilogram of 5.05 molar ACT051-1 and 1.305 kilograms of 10.1 molar DIPEA to a four-port round-bottom flask.

Add 3 liters of DMF to the flask, and dissolve the solid. Heat the reaction mixture to 35 degrees Celsius. Add 1.203 kilograms of 6.31 molar TsCL to the reaction solution and stir for 1 hour.

Stir the mixture until the completion of the reaction is confirmed by thin-layer chromatography, or TLC, and HPLC. Pour in 8.4 liters of cool water, and stir for another half an hour. Filter all liquids with a Buchner funnel, and rinse the crude product with 600 milliliters of water.

Dry the resulting product at 70 degrees Celsius overnight using an electric thermostatic drawing oven, and obtain a product with a yield of 94.9%For the pilot scale-up synthesis of ACT051-3, add 3.31 liters of tert-amyl alcohol and 4.97 liters of toluene to the reaction kettle, and then add 1.66 kilograms of ACT051-2, 0.83 kilograms of tert-butyl carbamate, 1.301 kilograms of powdered potassium carbonate, 0.11 kilograms of Xantphos, and 0.31 kilograms of DIPEA to the solution. After evacuating nitrogen three times, as shown earlier, add 10 grams of palladium acetate to the reaction solution under nitrogen protection. Heat the reaction mixture to 90 degrees Celsius and stir for 4 hours.

After that, cool the mixture to 40 degrees Celsius or below. Filter the reaction solution with a Buchner funnel using diatomite as a filter aid, and wash the filter cake with toluene. Collect and concentrate the filtrate using a circulating water vacuum pump, as shown earlier.

Add 300 milliliters of heptane and stir for 20 minutes. After filtering the reaction solution again with a Buchner funnel, rinse the crude product with 50 milliliters of heptane. Dry and obtain the product with a yield of 96.3%The reaction route and conditions of the intermediate ACT051-3 before optimization and after optimization are presented in this figure.

The effect of different forms of TsCL on the synthetic compound ACT051-2 is shown here. The results show that solid TsCL is more conducive to industrial production. The effect of adding TsCL at different temperatures on the synthesis of ACT051-2 is shown here.

The product yield was increased from 97.49%to 98.44%when TsCL was added from 0 to 5 degrees Celsius to 23 to 35 degrees Celsius. The effect of different post-treatment water consumption on the synthesis of ACT051-2 is presented here. The optimal conditions were achieved at a post-treatment water volume of 6 milliliters per gram ACT051-2.

This data shows the effect of adding DIPEA to the reaction for the synthesis of ACT051-3. The introduction of DIPEA reduced the amount of palladium acetate by a factor of 2.5. The effect of different states of potassium carbonate and different reaction solvents on the reaction of the synthetic compound ACT051-3 are presented here.

The results show that by changing the state of potassium carbonate involved in the reaction, the reaction time was reduced from 7 hours to 3.5 hours. Additionally, by switching from tert-amyl alcohol/1, 4-dioxane to tert-amyl alcohol/toluene, the reaction time was shortened to 3 hours, and the product peak area increased from 84.22%to 88.52%The addition of DIPEA is critical for the pilot scale-up synthesis and industrial production of compound ACT051-3.