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Methods of making bempedoic acid and compositions of the same

A kind of compound, technology of ethyl isobutyrate, applied in the field of preparing beipedic acid and composition thereof

Pending Publication Date: 2021-03-02
ЕСПЕРІОН ТЕРАПЕУТІКС ІНК
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] The development of reliable, cost-effective and efficient manufacturing methods to prepare pharmaceutically active compounds in desirable yields and purity remains a significant challenge

Method used

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  • Methods of making bempedoic acid and compositions of the same
  • Methods of making bempedoic acid and compositions of the same
  • Methods of making bempedoic acid and compositions of the same

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0560] Embodiment 1: the preparation process of the pharmaceutical material comprising the compound of formula (V) in a purified amount

[0561] In this example, the synthesis of purified bempedelic acid refers to figure 1 .

[0562] Step 1 - Preparation of compound of formula (I)

[0563] Lithium diisopropylamide (LDA) preparation

[0564] 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.

[0565] Alkylation reaction

[0566] 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

[0668] Example 2: Alternative Preparation Process for the Preparation of Pharmaceutical Materials Comprising Purified Amounts of Compounds of Formula (V)

[0669] Step 1 - Preparation of compound of formula (I)

[0670] Lithium diisopropylamide (LDA) preparation

[0671] 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.

[0672] Alkylation reaction

[0673] 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

[0734] Embodiment 3: the analytical method of the purity of measuring formula (V) compound

[0735] Determination of impurities

[0736] 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).

[0737] The impurity content of the compound of formula (V) in purified form was determined to be 0.05-0.50% w / w.

[0738] Column: Waters XBridge BEH C18 (4.6mm inner diameter x 150mm, 2.5μm)

[0739] Mobile phase: A: 0.05% formic acid (HCOOH) / water (H 2 O)

[0740] Mobile phase: B: 0.05% HCOOH / acetonitrile (ACN)

[0741] Sample temperature: ambient

[0742] Column temperature: 40°C

[0743] Gradient (time: A:B): (0min:90:10; 8.5min., 56:44; 20min., 45:55; 32min., 5:95; 36min., 5:95).

[0744] Flow rate: 1.2mL / min

[0745] Retention time: ~15.2min (bempedic acid in purified form)

[0746] ...

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Abstract

The invention provides methods of preparing 8-hydroxyl-2,2,14,14-tetramethyl pentadecanedioic acid and methods of making a pharmaceutical material comprising a purified amount of 8-hydroxyl-2,2,14,14-tetramethyl pentadecanedioic acid. Also provided are compositions and pharmaceutical materials including a purified amount of 8-hydroxyl-2,2,14,14-tetramethyl pentadecanedioic acid as well as methodsof treating various diseases and conditions using the compositions and pharmaceutical materials.

Description

[0001] cross reference [0002] This application claims the benefit of and priority to U.S. Patent Application No. 62 / 864,873, filed June 21, 2019, the entire contents of which are incorporated herein by reference. Background technique [0003] The development of reliable, cost-effective and efficient manufacturing methods to prepare pharmaceutically active compounds in desirable yield and purity remains a significant challenge. Bempedoic acid (8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid) is a drug developed for the treatment of various diseases including liver disease and cardiovascular disease. compound. Therefore, there is a need for a method of synthesizing bempedic acid (8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid) such that the product has the purity and impurities required by regulatory agencies to produce a commercially viable drug product characteristic. Contents of the invention [0004] The inventors have discovered an efficient process for th...

Claims

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Application Information

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IPC IPC(8): C07C59/245C07C27/02C07C51/43C07C51/42C07C51/47C07C67/307C07C69/63C07C67/313C07C69/716C07C67/31C07C69/675C07C315/04C07C317/48A61P3/06A61K31/194
CPCA61P3/06A61K31/20C07C315/00C07C51/09C07C67/307C07C67/313C07C67/31C07C317/36C07C59/245C07C69/62C07C69/738C07C69/732C07B2200/13C07C315/04C07C51/04C07C51/42C07C59/285C07C51/47C07C51/43A61K31/194A61K31/191
Inventor R.科普M.阿布德尔纳瑟C.M.西马鲁斯蒂J.莱恩M.巴克曼R.阿明A.J.库珀D.戈帕尔P.塞利格
Owner ЕСПЕРІОН ТЕРАПЕУТІКС ІНК
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