Salt forms of bempedoic acid and methods for using the same
A technology of calcium salt and potassium salt, applied in the field of pharmaceutical composition or preparation
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Embodiment 1
[0557] Embodiment 1: the preparation process of the pharmaceutical material comprising the compound of formula (V) in a purified amount
[0558] In this example, the synthesis of purified bempedelic acid refers to figure 1 .
[0559] Step 1 - Preparation of compound of formula (I)
[0560] Lithium diisopropylamide (LDA) preparation
[0561] Diisopropylamine (317±3 kg, 1.1 equiv) and tetrahydrofuran (THF, 2,102±105 L) were added to the reaction vessel, and the mixture was then cooled to ≤-10°C. n-Butyllithium (n-BuLi, 757±8 kg, 1.2 equivalents) was then added within ≥1 hour while maintaining the temperature ≤-10°C. The feed line was flushed with THF. Addition is highly exothermic. Finally, the batch was cooled back to <-10°C while stirring.
[0562] Alkylation reaction
[0563] Ethyl isobutyrate (317 ± 3 kg, 1.1 equivalents) was added to the reactor at ≤ -10 °C for ≥ 1 hour ( figure 1 ). The batch was stirred while maintaining the temperature < -10°C. 1-Bromo-5-chlo...
Embodiment 2
[0663] Example 2: Alternative Preparation Process for the Preparation of Pharmaceutical Materials Comprising Purified Amounts of Compounds of Formula (V)
[0664] Step 1 - Preparation of compound of formula (I)
[0665] Lithium diisopropylamide (LDA) preparation
[0666] About 321 kg of diisopropylamine and about 1870 L of tetrahydrofuran (THF) were added to the reaction vessel, and the mixture was then cooled to -18°C to -5°C. About 794 kg of n-butyllithium (n-BuLi, solution in heptane) was slowly added while maintaining the temperature at -18°C to -5°C. The batch was maintained at -18°C to -5°C with stirring.
[0667] Alkylation reaction
[0668] Approximately 317 kg of ethyl isobutyrate was added to the reactor containing LDA over a target time of ≥ 1 hour, and the temperature was controlled at -18°C to -5°C. The line is then flushed with about 100 L of THF. The batch was stirred while maintaining the temperature at -18°C to -5°C. Approximately 460 kg of 1-bromo-5-c...
Embodiment 3
[0729] Embodiment 3: the analytical method of the purity of measuring formula (V) compound
[0730] Determination of impurities
[0731] The impurity content of the compound of formula (V) in purified form was determined using a high performance liquid chromatograph equipped with a gradient function, a thermostatic column compartment and a detector with aerosol detection (CAD).
[0732] The impurity content of the compound of formula (V) in purified form was determined to be 0.05-0.50% w / w.
[0733] Column: Waters XBridge BEH C18 (4.6mm inner diameter x 150mm, 2.5μm)
[0734] Mobile phase: A: 0.05% formic acid (HCOOH) / water (H 2 O)
[0735] Mobile phase: B: 0.05% HCOOH / acetonitrile (ACN)
[0736] Sample temperature: ambient
[0737] Column temperature: 40°C
[0738] Gradient (time: A:B): (0min:90:10; 8.5min., 56:44; 20min., 45:55; 32min., 5:95; 36min., 5:95).
[0739] Flow rate: 1.2mL / min
[0740] Retention time: ~15.2min (bempedic acid in purified form)
[0741] ...
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