Predominant form of neutral endopeptidase inhibitor salt and preparation method thereof
A technology with advantages and forms, applied in the direction of carboxylic acid amide preparation, organic chemical methods, chemical instruments and methods, etc., can solve the problems of unfavorable compound 2 preparation process, optimization, undisclosed preparation methods, etc., and achieve good fluidity and free speed Fast and good solubility effect
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Embodiment 1
[0046] Preparation of Compound 1(A-3)
[0047]
[0048] Dissolve A-1 (15g) in 150ml of absolute ethanol at room temperature; heat to 60°C, slowly add 8.5ml of thionyl chloride dropwise and then raise the temperature to 70°C for 2 hours; distill under reduced pressure to obtain a white solid, then add 150ml of normal After removing half of the volume of the heptane under reduced pressure, it was beaten in an ice bath for 20 minutes; filtered, the solid was rinsed with n-heptane, and dried at 30°C for 10 hours to obtain 13.4 g of a white solid (A-2).
[0049] Add 13.4g A-2 to a flask containing 250ml isopropyl acetate (IPAC) at room temperature; add 11.7g (16ml) triethylamine and 4.9g succinic anhydride in turn, react at room temperature until A-2 is completely consumed; filter directly , the filter cake was washed with IPAC, and 22 g (A-3) of the light yellow viscous liquid obtained by combining the filtrate was decompressed.
Embodiment 2
[0051] Preparation of Predominant Form of Compound 1 Calcium Salt (A-5)
[0052]
[0053] Dissolve 22g of A-3 prepared according to the method of Example 1 in 200ml of IPAC at room temperature; add 1.2 equivalents (relative to A-2) of sodium hydroxide aqueous solution (1N) dropwise, and stir at room temperature until fully salted; separate and combine Water layer (about 80ml);
[0054] Add the aqueous solution containing A-4 into a 250ml two-necked bottle at room temperature, slowly and uniformly add calcium chloride aqueous solution (3.6g calcium chloride dissolved in 20ml water) dropwise, after 10 minutes, stir at room temperature at a speed of 180r / min for 3 hours ; Filtration, washing the filter cake with water, and drying under reduced pressure at 30° C. for 6 hours to obtain 21 g of the dominant form of compound 1 calcium salt (A-5). After testing, its XRD spectrum is as follows figure 1 As shown, the DSC spectrum is as image 3 As shown, its TG spectrum is shown a...
Embodiment 3
[0056] Preparation of the dominant form of compound 1 calcium salt (A-5).
[0057]
[0058] Dissolve 22g of A-3 prepared according to the method of Example 1 in 200ml of IPAC; add 1.1 equivalent (relative to A-2) sodium hydroxide aqueous solution (1N) dropwise under ice bath, stir at 40°C until fully salted; separate liquids , Merge the water layer; After heating up to 70°C, slowly and uniformly add calcium chloride aqueous solution (3.1g calcium chloride dissolved in 20ml water) dropwise to the aqueous solution containing A-4, after 8 minutes, the temperature is raised to 70°C and the rotation speed is 180r / Stir for 2 hours; cool down to 50°C and filter, wash the filter cake with water and then purging with nitrogen for 1h, and bake under vacuum at 80°C for 48h to obtain 18g of the predominant form of compound 1 calcium salt (A-5) (purity 99.2%). After testing, its XRD spectrum is as follows figure 2 As shown, the DSC spectrum is as image 3 As shown, its TG spectrum i...
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