Preparation method of bempedoic acid
The technology of a kind of ground acid and eleven, which is applied in the field of preparation of the lipid-lowering drug bepedelic acid, can solve the problems of restricting the industrialization process of the product, being difficult to obtain, and not suitable for large-scale production, so as to achieve the safety and environmental protection of the preparation process conditions and the preparation process. The effect of mild conditions
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Embodiment 1
[0033] Under the protection of nitrogen, add ethyl isobutyrate (5.8g, 50mmol) and solvent tetrahydrofuran 60mL into the dry reaction flask, cool down to -40°C, add base accelerator lithium diisopropylamide (1M, 55mL, 55mmol) dropwise , after the dropwise addition was completed, the temperature was maintained and the reaction was stirred for 1 hour. Add dropwise 1,11-dibromo-undecan-6-ol (II) (8.2g, 25mmol) in 50mL tetrahydrofuran solution. After the dropwise addition, slowly raise the temperature to 20°C, continue stirring for 4-6 hours, TLC Monitor the reaction for completion. The reaction was quenched with water, the pH of the reaction system was adjusted to 5-6 with dilute hydrochloric acid, and the stirring reaction was continued for 1 hour. Concentrate under reduced pressure, and add ethyl acetate to extract the residue 3 times. The organic phases were combined, washed successively with pure water and brine, dried, and concentrated to obtain 7.1 g of oily matter 8-hydro...
Embodiment 2
[0035] Add 8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid diethyl ester (III) (4.0g, 10mmol) and solvent tetrahydrofuran 40mL into the three-necked flask, stir to dissolve, and add Potassium hydroxide solution (1M, 40mL, 40mmol) was raised to room temperature, stirred for 4-6 hours, and the reaction was monitored by TLC. Adjust to neutral with dilute hydrochloric acid. Extracted 3 times with ethyl acetate. The organic phase was separated, dried, and the solvent was recovered by distillation under reduced pressure. The resulting residue was recrystallized from ethanol to obtain 3.0 g of white solid bempedelic acid (I), with a yield of 87.2%, EI-MS m / z: 345 [M+ H] + ; 1 H NMR (CDCl 3 )δ3.57(s,1H), 1.55(m,4H), 1.44(m,8H), 1.29(m,8H), 1.18(s,12H).
Embodiment 3
[0037] Add 1,11-dibromo-6-undecanone (IV) (8.2g, 25mmol) and solvent tetrahydrofuran 100mL into the three-necked flask, add sodium borohydride (1.9g, 50mmol) in batches at room temperature, and stir the reaction 4 ~6 hours. The reaction was quenched with water and adjusted to neutral with dilute hydrochloric acid. Extracted 3 times with ethyl acetate. The organic phase was separated, dried, and distilled under reduced pressure to obtain 7.1 g of a colorless oily substance, 1,11-dibromo-undecan-6-ol (II), with a yield of 86.6%, EI-MS m / z: 329[ M+H] + .
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