A kind of preparation method of pharmaceutical intermediate compound
A compound and mixture technology, applied in the field of preparation of pharmaceutical intermediate compounds, can solve the problems of limited application, unsuitability for large-scale industrial synthetic compounds, low yield of intermediate compounds, etc., and achieve low toxicity of raw materials, simple and efficient industrialization , low cost effect
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Embodiment 1
[0051] The preparation of embodiment 1 compound T541-B
[0052]
[0053] Table 1: Bill of Materials for Preparation of T541-B
[0054]
[0055] The preparation steps of T541-B include the following operations:
[0056] (1) Reaction
[0057] Add 50 grams of T541-RM1 and 650 grams of toluene to the kettle. The reaction mixture was cooled to -70~-60°C, and 61.5 g of 2.5M n-butyllithium was slowly added dropwise at a temperature of -70~-55°C. Stir at a temperature of -70 to -55°C for 3-5 hours, and then take a sample for in-process analysis (IPC analysis) (indicator: T541-RM1≤3.0%), showing that there is no T541-RM1 residue. 15 g of acetone was slowly added dropwise to the reaction mixture at a temperature of -70 to -50°C. The mixture was stirred at a temperature of -70 to -50°C for 0.5 to 1.5 hours.
[0058] (2) Quenching
[0059] Add about 11.5% by weight ammonium chloride aqueous solution (prepared from 50 grams of water and 6.5 grams of salt) to the reaction mixt...
Embodiment 2
[0095] Preparation of Example 2 T541-C
[0096]
[0097] Table 7: Bill of Materials for Preparation of T541-C
[0098]
[0099] The preparation steps of T541-C include the following operations:
[0100] (1) Reaction
[0101] 45.61 g of T541-B in toluene and 21.56 g of imidazole were added to the reaction kettle. Adjust the temperature of the reaction mixture to 10-20° C., control the temperature at 10-20° C., and slowly add 29.11 g of trimethylchlorosilane dropwise. After the dropwise addition, continue to stir at a temperature of 20-30° C. for 10-15 hours. Samples were taken for in-process analysis (standard: T541-B≤1.0%), which showed no T541-B residue.
[0102] (2) Quenching
[0103] Cool the reaction mixture obtained in step (2) to 10-20° C., then add 200 grams of water into the reaction mixture at a temperature of 10-30° C., and stir for 20-40 minutes at the same temperature. After standing for 30-60 minutes, the layers are separated, the water phase at the ...
Embodiment 3
[0116] Example 3 Preparation of T541-D
[0117]
[0118] Table 9: Bill of Materials for Preparation of T541-D
[0119]
[0120]
[0121] The preparation steps of T541-D include the following operations:
[0122] (1) Reaction
[0123] The reactor was inertized 3 times with nitrogen, and 60.84 grams of T541-C solution, 450 grams of 1,4-dioxane, 62.14 grams of potassium acetate, and 53.60 grams of pinacol diborate ((BPIN) 2 ) and 1.85 g of 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (PdCl 2 (dppf)) into the reactor. Heat to 80-90°C and stir at this temperature for 10-15 hours. Sampling analysis (standard: T541-C≤0.5%) showed no T541-C residue.
[0124] (2) The first filter
[0125] Cool the reaction mixture obtained in step (1) to 15-25°C. The reaction mixture was filtered and the filter cake was washed twice with 91 g of 1,4-dioxane.
[0126] (3) The first concentration
[0127] Concentrate the filtrate obtained in step (2) in vacuum at a temperat...
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