5-(Methoxycarbonyl)-1-tosyl-1H-pyrrol-3-yl-3-boronic acid synthesis

Yield:869886-88-4 74.94%

Reaction Conditions:

with palladium diacetate;anhydrous sodium carbonate;tricyclohexylphosphine tetrafluorohydroborate in water monomer at 20 - 85;Inert atmosphere;Reflux;Large scale;

Steps:

2.2

In Step 2, a clean and dry 300 L glass-lined reactor was evacuated to -0.08 MPa, and then filled with nitrogen to normal pressure three times. Glycol dimethyl ether (73.10 kg) was charged into the 300 L glass-lined reactor at 20-30°C. ASYM-112060 (Asymchem) (10.46 kg) and ASYM-111938 (Asymchem) (12.34 kg, 11.64 kg after corrected) were added into the mixture in turn under the protection of nitrogen. Maintaining the temperature at 20-30°C, purified water (10.50 kg) and anhydrous sodium carbonate (5.67 kg) were added into the mixture. Palladium acetate (0.239 kg) and tricyclohexylphosphonium tetrafluoroborate (0.522 kg) were added into the mixture under the protection of nitrogen. After addition, the mixture was evacuated to -0.06 MPa, and then filled with nitrogen to normal pressure. This was repeated for ten times until residual oxygen was 300 ppm. The mixture was heated to 75-85°C for refluxing. The mixture reacted at 75-85°C. After 4 h, the mixture was sampled and analyzed by HPLC every 2-3 h for content of ASYM83 112060. The content of ASYM-112060 was 6.18%, so additional ASYM-111938 (0.72 kg) was added and continued reaction until the content of ASYM-112060 was 3%. The mixture was cooled to 25-35°C and filtered with a 30 L stainless steel vacuum filter. The filter cake was soaked and washed twice with THE (14.10kg). The filtrate and washing liquor were combined and concentrated at 50°C under reduced pressure (-0.08 MPa) until 10-15 L remained. The mixture was cooled to 15-25°C. Methanol (11.05 kg) was added into the concentrated mixture. Then the mixture was stirred for crystallization. After 2 h, the mixture was sampled and analyzed by HPLC every 2-4 h until the wt% of the mother liquor was 2%. The mixture was filtered with a 30 L stainless steel vacuum filter. The filter cake was soaked and washed twice with methanol (8.30 kg). The filter cake was transferred into a 50 L plastic drum. Then ethyl acetate (7.10 kg) and petroleum ether (46.30 kg) were added into the drum. The mixture was stirred for 1.5-2 h and then filtered with a nutsche filter. The filter cake was soaked and washed with petroleum ether (20.50 kg). The filter cake was dried in the nutsche filter under nitrogen at 30-40°C. After 8 h, the solid was sampled and Karl Eischer (KE) analysis was performed in intervals of 4-8 h to monitor the drying process. Drying was completed when the KE result was 1.0% water. During drying, the solid was turned over and mixed every 4-6 h. 12.15 kg of product was recovered as a brownish yellow solid at 98.32% purity.

References:

WO2016/123574,2016,A1 Location in patent:Paragraph 0228; 0230