Boronic acid salts and use thereof in the preparation of medicaments for treating thrombosis
A technology of boric acid and thrombin, which can be used in boron compound active ingredients, blood diseases, cardiovascular system diseases, etc., and can solve problems such as low bioavailability.
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Embodiment 1
[0447] The synthesis of embodiment 1-TRI50D
[0448] Step 1: Z-DIPINB
[0449] Program A
[0450] Add 17.8g (732.5mmole) of magnesium turnings, 0.1g (0.4mmole) of iodine and 127ml of anhydrous tetrahydrofuran and heat to reflux. 15 ml of a solution of 66 g (608 mmole) of 1-chloro-3-methoxypropane in 185 ml of anhydrous tetrahydrofuran are then added and stirred at reflux until a vigorous reaction occurs. After the initial exotherm had subsided, the 1-chloro-3-methoxypropane solution was slowly added to maintain a gentle reflux until all the magnesium was consumed. After the reaction was complete, the reaction mixture was cooled to ambient temperature, and a solution of 64.4 g (620 mmole) of trimethylborate in 95 ml of anhydrous tetrahydrofuran was slowly added; the latter solution was cooled to below 0° C. During its warming, the reaction mixture must be added very slowly to keep the temperature of this solution below 65°C. After the addition was complete, the reaction...
Embodiment 2
[0467] Synthesis of embodiment 2-TRI50D (diethanolamine adduct of TRI 50C)
[0468]The starting material used in this example was the TRI50b solution obtained in Example 1 (Z-DIPIN). This solution was directly subjected to the synthesis of TRI50d without further purification. The Z-DIPIN solution in t-BME (containing 7.0 g (11.5 mmole) (R, S, R) TRI50b, calculated based on the HPLC results of Z-DIPIN) was evaporated to dryness, and the evaporation residue was dissolved in 80 ml diethyl ether middle. 1.51 g (14.4 mmole) of diethanolamine were added and the mixture was heated at reflux for at least 10 hours, during which time the product precipitated. The suspension was cooled to 5-10°C, and the residue washed with diethyl ether was filtered.
[0469] To improve chirality and chemical purity, the wet filter residue (7 g) was dissolved in 7 ml of dichloromethane, cooled to 0-5°C, the product was precipitated by adding 42 ml of diethyl ether and filtered. The isolated wet pr...
Embodiment 3
[0472] The preparation of the sodium salt of embodiment 3-TRI50C
[0473] 1.5 kg (2.5 mole) of TRI50d obtained in Example 2 was dissolved in 10.5 L of dichloromethane. 11 L of 2% hydrochloric acid was added and the mixture was stirred at room temperature for up to 30 minutes (optionally about 20 minutes). A precipitate formed in the organic phase. After stirring, the layer was allowed to settle and separate. The aqueous layer was washed two more times with 2.2 L of dichloromethane. The combined organic layers were washed with a solution of 625 g ammonium chloride in 2.25 L water. (The pH of the ammonium chloride buffered aqueous extract is in the range of about pH 1-2 to about pH 4-5, since strongly acidic conditions can cleave peptide bonds). The organic phase was dried over magnesium sulfate, filtered and the filtrate was evaporated to dryness. Free boronic acid analysis (by the RPHPLC method of Example 28 at room temperature for up to 30 minutes (optionally about 20 ...
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