WO2020194152A1

WO2020194152A1 - Process for preparation of bempedoic acid

Info

Publication number: WO2020194152A1
Application number: PCT/IB2020/052596
Authority: WO
Inventors: Srinivas ORUGANTI; Saikat Sen; J. Sembian RUSO; Vishnu Vardhana Vema Reddy EDA EDA; Rehani Rajeev Budhdev; Khushi Ram
Original assignee: Dr Reddys Laboratories Ltd
Current assignee: Dr Reddys Laboratories Ltd
Priority date: 2019-03-27
Filing date: 2020-03-20
Publication date: 2020-10-01
Anticipated expiration: 2021-09-27

Abstract

Aspect of the present application provides cost effective and commercially viable process for preparation of Bempedoic acid. The process involves the reduction of compound formula I to obtain compound formula II which is hydrolyzed to get Bempedoic acid. The present application also provides the process for preparation of Bempedoic acid using compound of formula II without purification.

Description

PROCESS FOR PREPARATION OF BEMPEDOIC ACID

CROSS-REFERENCE TO RELATED APPLICATION

The present application claims benefit of India provisional Patent Application No. 201941011853, filed March 27, 2019, which is hereby incorporated by reference in its entirety.

INTRODUCTION

Aspect of the present application provides process for the preparation of Bempedoic Acid or its pharmaceutically acceptable salts.

Bempedoic acid is an ATP Citrate Lyase inhibitor that, reduces cholesterol biosynthesis and lowers LDL-C by up-regulating the LDL receptor. The drug compound having the adopted name“Bempedoic Acid” has chemical name 8-Hydro xy-2, 2, 14, 14-tetramethylpentadecanedioic acid having the following structure:

Nexletol (Bempedoic acid) and Nexlizet (combination of Bempedoic acid and Ezetimibe) both are approved by USFDA on 20 February 2020 and 26 February 2020 respectively.

US7335799 discloses Bempedoic acid, its process of preparation or its pharmaceutically acceptable salt, hydrate, or solvate and pharmaceutical composition.

The following scheme- 1 describe the process of Bempedoic acid in example 6.19 and 6.20 as given in US7335799.

O Bempedoic acid O

Scheme- 1

The process described above (Scheme- 1) involves the use of excess amount (more than 4.2 equiv) of sodium borohydride (NaBfU) corresponding to the starting material and takes longer time (more than 8 h) to complete the reaction. In addition, Bempedoic acid is obtained with low yield (60%), as very viscous oil, with very low HPLC purity 83.8%. This low purity and viscous oily nature of Bempedoic acid is not suitable as active ingredient for use in pharmaceutical product. In view of these drawbacks the process described in the literature is neither cost effective nor suitable for manufacturing at commercial scale.

Therefore, there is a need to provide a cost effective and commercially viable process for the preparation of solid and pure Bempedoic acid which is suitable for use in pharmaceutical composition.

SUMMARY OF THE INVENTION

In an aspect the present application provides processes for the preparation of Bempedoic acid or its pharmaceutically acceptable salts which overcome the drawbacks of Bempedoic acid process known in literature.

In an aspect, the present application provides processes for the preparation of Bempedoic acid or its pharmaceutically acceptable salts having the following advantages over the prior art process;

1. Isolation of solid Bempedoic acid directly from the reaction mass in contrast to the oily syrup obtained in prior art process.

2. High purity of Bempedoic acid.

3. Less amount of reducing agent NaB¾ used in the reduction step.

4. Faster reduction reaction resulting in overall shortening of cycle time.

In an aspect the present application provides a process for preparation of Bempedoic acid or its pharmaceutically acceptable salts comprising;

a) Reducing the compound of Formula I to provide compound of Formula II

b) Hydrolyzing the compound of Formula II to Bempedoic acid or its pharmaceutically acceptable salts

In another aspect the present application provides a process for preparation of Bempedoic acid or its pharmaceutically acceptable salts comprising; hydrolyzing the compound of Formula II

In another aspect the present application provides one pot process for the preparation of Bempedoic acid or its pharmaceutically acceptable salts comprising;

Reducing the compound of Formula I to provide compound of Formula II

and hydrolyzing the compound of Formula II

BRIEF DESCRIPTION OF THE DRAWING

Figure 1 illustrates a characteristic PXRD pattern of Bempedoic acid obtained from example 2.

DETAILED DESCRIPTION

a) Reducing the compound of Formula I to provide compound of Formula II

In embodiments, step a) involves the preparation of compound of Formula II by reducing the compound of Formula I by using a suitable reducing agent and a suitable solvent.

In embodiments of step a), the reduction may be carried out by using a suitable reducing agent. The suitable reducing agents that may be used are but not limited to Lithium Borohydride, Sodium Borohydride (NaBPL), Lithium Aluminum hydride (LiAltL), Sodium triacetoxyborohydride, sodium Cyanoborohydride, or the like. In embodiments the amount of reducing agent required may vary depending on the nature of reducing agent, reaction conditions etc.

In embodiments, the amount of reducing agent in the reaction may be in the range of about 1 equiv to about 3.0 equiv with respect to the starting material. Preferably the amount of reducing agent may be used in the range of about 1.5 equiv to about 3.0 equiv more preferably in the range of about 2.0 equiv to about 3.0 equiv with respect to the starting material.

In embodiments of step a), the reduction reaction may be carried out in the presence of a suitable solvent. Examples of such solvents include, but are not limited to: ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, MTBE, dioxane, and dimethoxyethane; alcohols, such as methanol, ethanol, ethylene glycol, 1 -propanol, 2-propanol, 2-methoxyethanol, 1 -butanol, 2-butanol, iso-butyl alcohol, t-butyl alcohol, glycerol, and C1-C6 alcohols; halogenated hydrocarbons, such as dichloro methane, chloroform, carbon tetrachloride, and chlorobenzene; aromatic hydrocarbons, such as toluene; aliphatic hydrocarbons, nitriles, esters and polar aprotic solvents such as DMF, DMSO, Dimethylacetamide (DMAc), water; any mixtures of two or more thereof. In a preferred embodiment, the reduction reaction may be carried out in mixture of organic solvent and water. In a preferred embodiment, the reduction reaction may be carried out in presence of a mixture of tetrahydrofuran and water.

In embodiments of step a), the reaction may be carried out at a temperature ranging from about 0°C to about boiling temperature of the solvent. In embodiment, the reaction may be carried out from about 10°C to 70°C. In one embodiment, the reaction may be carried out at room temperature. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, under the conditions outlined above, the reaction is effected for a period of about 30 minutes to about 24 hours or longer.

In embodiments of step a), the compound of formula II may be isolated directly from the reaction mixture itself after the reaction is complete, by filtration or after conventional work up with techniques such as quenching with a suitable reagent, extraction, evaporation of solvent or the like.

In embodiments of step a), the compound of Formula II is optionally isolated by extracting in a solvent followed by removal of the solvent by evaporation. The compound of Formula II may be isolated or may be used directly in the next step without isolation.

In embodiments of step a), the compound of Formula II may be purified by using convention methods. In embodiments the compound of Formula II may be purified by column chromatography.

In embodiments, step b) involves the conversion of compound of Formula II to Bempedoic acid or its pharmaceutically acceptable salts. In embodiments, Bempedoic acid is prepared by hydrolyzing the compound of Formula II in a suitable solvent. In embodiments of step b), hydrolysis may be carried out in presence of water and can optionally include the presence of a base or acid.

In embodiments, the hydrolyzing agent comprises an acid. In embodiments, the acid is formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, oxalic acid, lactic acid, malic acid, citric acid, benzoic acid, carbonic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, aminomethylphosphonic acid, trifluoro acetic acid (TFA), phosphonic acid, sulfuric acid, nitric acid, phosphoric acid, hydrochloric acid, ethane sulfonic acid (ESA), or any combination thereof. In some embodiments, the acid is acetic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, trifluoro acetic acid (TFA), sulfuric acid, or hydrochloric acid. In some embodiments, the acid is trifluoro acetic acid (TFA) or hydrochloric acid. In some embodiments, the acid is hydrochloric acid.

In embodiments, the hydrolyzing agent comprises a base. In embodiments, a suitable hydrolyzing agent may be used are but not limited to alkali hydroxide like alkali metal hydroxides, such as, for example, lithium hydroxide, sodium hydroxide, potassium hydroxide, and cesium hydroxide or the like; alkaline earth metal hydroxides, such as, for example, barium hydroxide, strontium hydroxide, magnesium hydroxide, calcium hydroxide, or the like; alkali metal carbonates, such as, for example, sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, or the like; alkaline earth metal carbonates, such as, for example, magnesium carbonate, calcium carbonate, or the like; alkali metal bicarbonates, such as, for example, sodium bicarbonate, potassium bicarbonate, or the like

In embodiments of step b), the hydrolysis of compound of Formula II may be carried out in water and optionally, in presence of another suitable solvent. Examples of such solvents include, but are not limited to: ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, MTBE, dioxane, and dimethoxy ethane; alcohols, such as methanol, ethanol, ethylene glycol, 1-propanol, 2-propanol, 2- methoxyethanol, 1 -butanol, 2-butanol, iso-butyl alcohol, t-butyl alcohol, glycerol, and C1-C6 alcohols; halogenated hydrocarbons, such as dichloromethane, chloroform, carbon tetrachloride, and chlorobenzene; aromatic hydrocarbons, such as toluene; aliphatic hydrocarbons, nitriles, esters and polar aprotic solvents such as DMF, DMSO, Dimethylacetamide (DMAc), water; any mixtures of two or more thereof.

In embodiments of step b), the reaction may be carried out at a temperature ranging from about 0°C to about boiling temperature of the solvent. In embodiment, the reaction may be carried out from about 10°C to 80°C. In one embodiment, the reaction may be carried out at room temperature. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, under the conditions outlined above, the reaction is effected for a period of about 30 minutes to about 24 hours or longer.

In embodiments of step b), the Bempedoic acid may be isolated directly from the reaction mixture itself after the reaction is complete, by filtration or after conventional work up with techniques such as quenching with a suitable reagent, extraction, evaporation of solvent or the like.

In embodiments of step b), the Bempedoic acid obtained may be optionally further dried at suitable temperatures, and atmospheric or reduced pressures, for about 1-50 hours, or longer, using any types of drying equipment, such as a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer or the like.

In embodiments of step b), the Bempedoic acid obtained may be optionally further purified by recrystallization or by slurrying in a suitable solvent or by column chromatography or any other suitable technique.

In another aspect, step a) and step b) may be carried out in one pot. In embodiments, Bempedoic acid may be isolated by using various techniques (workup, Extraction, pH-adjustment, crystallization filtration etc.) as described in this patent application.

In another aspect, Bempedoic acid may be obtained by directly using crude compound of Formula II (without purifying the compound of Formula II) as obtained from step a) in the next step of hydrolysis. In another aspect, optionally the present application provides a process for obtaining Bempedoic acid without isolating compound of Formula II as obtained from step a). In embodiments, Bempedoic acid may be isolated by using various techniques (workup, Extraction, pH-adjustment, crystallization filtration etc.) as described in this patent application.

In another aspect the present application provides a process for preparation of Bempedoic acid or its pharmaceutically acceptable salts comprising;

Hydrolyzing the compound of Formula II

O Bempedoic acid O

In embodiments, Bempedoic acid is obtained by hydrolyzing compound of Formula II in a suitable solvent.

In embodiments, hydrolysis may be carried out in presence of water and can optionally include the presence of a base or acid.

In embodiments, the hydrolyzing agent comprises an acid. In embodiments, the acid is formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, oxalic acid, lactic acid, malic acid, citric acid, benzoic acid, carbonic acid, p- toluenesulfonic acid, trifluoromethanesulfonic acid, aminomethylphosphonic acid, trifluoro acetic acid (TFA), phosphonic acid, sulfuric acid, nitric acid, phosphoric acid, hydrochloric acid, ethane sulfonic acid (ESA), or any combination thereof. In some embodiments, the acid is acetic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, trifluoro acetic acid (TFA), sulfuric acid, or hydrochloric acid. In some embodiments, the acid is trifluoro acetic acid (TFA) or hydrochloric acid. In some embodiments, the acid is hydrochloric acid.

In embodiments, the hydrolyzing agent comprises a base In embodiments, a suitable hydrolyzing agent may be used are but not limited to alkali hydroxide like alkali metal hydroxides, such as, for example, lithium hydroxide, sodium hydroxide, potassium hydroxide, and cesium hydroxide or the like; alkaline earth metal hydroxides, such as, for example, barium hydroxide, strontium hydroxide, magnesium hydroxide, calcium hydroxide, or the like; alkali metal carbonates, such as, for example, sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, or the like; alkaline earth metal carbonates, such as, for example, magnesium carbonate, calcium carbonate, or the like; alkali metal bicarbonates, such as, for example, sodium bicarbonate, potassium bicarbonate, or the like

The same process may be applied for hydrolysis, isolation of Bempedoic acid as described in step b) above in this application.

In an aspect of the present application, Bempedoic acid may be obtained as a salt in the hydrolysis step which may be further treated with suitable acid or base by conventional methods known in the literature.

In embodiments, Bempedoic acid may be purified by making suitable salts of Bempedoic acid and then converting those salts to Bempedoic acid by using suitable base or acid by conventional methods known in the literature.

In another aspect the present application provides one pot process for the preparation of Bempedoic acid or its pharmaceutically acceptable salts comprising; reducing the compound of Formula I to provide compound of Formula II

and hydrolyzing the compound of Formula II

In embodiments, both the steps reduction followed by hydrolysis performed in one pot i.e., without isolation and purification of intermediate compound of formula II. In embodiments optionally the reaction solvents used in reduction (step a) may be evaporated before adding the hydrolyzing agent. In embodiments, Bempedoic acid may be isolated by using various techniques (workup, Extraction, pH-adjustment, crystallization filtration etc,) as described in this patent application.

The inventors of the present application reproduced the process reported in the literature US7335799 where product bempedoic acid obtained as syrupy oil with low purity which was very difficult to convert in solid state.

The bempedoic acid obtained from the prior art process has very low HPLC purity 83.8%. This low purity and viscous oily nature of Bempedoic acid is not suitable as active ingredient for use in pharmaceutical product.

However, Bempedoic acid is directly obtained from the process of the present application as crystalline solid with high HPLC purity at least more than about 95%. In embodiments, the Bempedoic acid is obtained from the process of the present application having HPLC purity more than 97%, preferably more than 98%, more than 99% or even more than 99.5%.

The following table provides comparative results of Bempedoic acid obtained from the prior art process (US7335799) and process of the present application;

The data provided in the above table clearly shows the advantage of the process of the present application over the process reported in literature.

In embodiments of the present application, Bempedoic acid obtained from the process of the present application characterized by a PXRD pattern having X- ray powder diffraction peaks selected from the following at about 10.24, 17.82, and 21.64 ± 0.2° 2Q. The crystalline Form of Bempedoic acid may be further characterized by X-ray powder diffraction peaks at about 15.40, 17.28, 18.56, 19.42, 20.21, 22.41 and 27.39°± 0.2° 2Q.

In embodiments of the present application, Bempedoic acid characterized by an X-ray powder diffraction pattern as illustrated in Figure 1.

In embodiments, the present application provides a pharmaceutical composition comprising the crystalline form of Bempedoic acid as described in the present application together with at least one pharmaceutically acceptable excipient.

Pharmaceutically acceptable excipients that are useful in the present application include, but are not limited to, any one or more of: diluents such as starches, pregelatinized starches, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar, or the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, hydroxypropyl celluloses, hydroxypropyl methylcelluloses, pregelatinized starches, or the like; disintegrants such as starches, sodium starch glycolate, pregelatinized starches, crospovidones, croscarmellose sodium, colloidal silicon dioxide, or the like; lubricants such as stearic acid, magnesium stearate, zinc stearate, or the like; glidants such as colloidal silicon dioxide or the like; solubility or wetting enhancers such as anionic, cationic, and neutral surfactants; complex forming agents such as various grades of cyclodextrins and resins; and release rate controlling agents such as hydroxypropyl celluloses, hydroxymethyl celluloses, hydroxypropyl methylcelluloses, ethylcelluloses, methylcelluloses, various grades of methyl methacrylates, waxes, or the like. Other pharmaceutically acceptable excipients that are useful include, but are not limited to, film-formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants, or the like.

Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner. Variations of the described procedures, as will be apparent to those skilled in the art, are intended to be within the scope of the present application.

General description of the PXRD equipment

X-ray diffraction was measured using Rigaku Desktop X-ray diffractometer, Model: MiniFlex600. System description: CuK-Alpha 1 wavelength= 1.54060, voltage 40kV, current 15 mA, divergence slit = 1.25°; Sample stage=Reflection. Scan type: Continuous; Detector - Scintillator Nal (Tl); Measurement parameters: Start Position [°2Th.]: 3; End Position [°2Th.]: 40; Step Size [°2Th.]: 0.02; Scan Speed [ min]: 1.

EXAMPLES

Example-1: Preparation of 8-Hydroxy-2,2, 14,14- tetramethylpentadecanedioic acid diethyl ester (Compound of Formula II)

2,2,14,14-tetramethyl-8-oxopentadecanedioic acid diethyl ester (20 g) and THF (200 mL) were added at room temperature into a 500 mL flask fitted with a magnetic stir bar and nitrogen inlet. Water (10 mL) was added into the reaction flask and the reaction mass was cooled below 10°C. Sodium borohydride (4.75 g) was added portion wise to the reaction mass at 10°C. The temperature was allowed to rise to 27 °C and the reaction mass was stirred for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, water (100 mL) was added to the reaction mass which was then extracted with ethyl acetate (3X75 ml). The combined organic layer was washed with brine solution (2X50 ml) and dried over sodium sulfate. The obtained organic layer was evaporated under reduced pressure below 45 °C to obtain crude product. The crude product was purified by column chromatography using silica gel (60-120 mesh) to obtain the title compound as pale yellow liquid.

Yield: 16.5 g; 82.08%

Example-2: Preparation of Bempedoic acid

8-Hydroxy-2,2,14,14-tetramethylpentadecanedioic acid diethyl ester (16 g), obtained from example- 1 and ethanol (240 mL) were added at room temperature into a 500 mL flask fitted with a magnetic stir bar. An aqueous solution of potassium hydroxide (35.85 g in 80 ml water) was added into the reaction mass at room temperature. The reaction mass was refluxed for 4 h at 75- 80°C. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mass was cooled to room temperature and the solvent was distilled out. Water (200 mL) was added to the residue. The aqueous layer was washed with dichloro methane (2 X 100 ml). The aqueous layer was cooled to 10-15°C. Concentrated hydrochloric acid was added to adjust the pH to 2 and the aqueous layer was then extracted with methyl ieri-butyl ether (3 X 100 mL). The combined organic layer was washed with brine solution (100 mL) and dried over sodium sulfate. The obtained organic layer was evaporated to get the crude product which was stirred with 10% ethyl acetate in hexane (50 ml) for 30 minutes. The solid product was obtained by filtration and washed with hexane (2 X 10 mL). The solid product was dried in a hot air oven at 45 °C for 1 h to provide Bempedoic acid as a white solid.

Yield: 11.67 g; 84.81% HPLC Purity: 98.21%

PXRD pattern of the product is represented in Figure 1.

Example-3: Preparation of Bempedoic acid without purification of compound of Formula II.

2,2,14,14-tetramethyl-8-oxopentadecanedioic acid diethyl ester (0.24 g) and THF (2.4 mL) were added at room temperature into a 50 mL flask fitted with a magnetic stir bar and nitrogen inlet. Water (0.12 mL) added to flask and the reaction mass was cooled to 10°C. Sodium borohydride (0.057 g) added to the reaction mass portion wise at 10°C. The temperature was allowed to rise to 27 °C and the reaction mass was stirred for 2-3 h. The progress of the reaction was monitored by TLC. After completion of the reaction, water (5 mL) was added and the reaction mixture extracted with ethyl acetate (3X10 ml). The combined organic layer was washed with brine solution (2X5 ml) and dried over sodium sulfate. The organic layer was evaporated under reduced pressure below 45°C to obtain the crude product. The obtained crude product was dissolved in ethanol (3.6 mL) and taken in a 50 mL flask, equipped with a reflux condenser. An aqueous solution of potassium hydroxide (0.54 g in 1.2 ml water) was added into the reaction mass at room temperature. The reaction mass was refluxed for 4 h at 75-80°C. The progress of the reaction was monitored by TLC. After completion of the reaction, the solvent was distilled out under reduced pressure at 45 °C and water (10 mL) was added to the residue. The aqueous layer was washed with dichloro methane (3 X 10 ml). Concentrated hydrochloric acid was added to adjust the pH to 2 and the aqueous layer was then extracted with methyl ieri-butyl ether (3 X 10 mL). The combined organic layer was separated, washed with brine solution (2 X 5 mL) and dried over sodium sulfate. The obtained organic layer was evaporated to obtain crude Bempedoic acid which was stirred with n-hexane (10 mL) for 10 minutes. The supernatant n-hexane layer was decanted and the solid residue stirred with a fresh lot of n- Hexane (10 mL). The supernatant n- hexane layer was decanted and the solid residue dried using rotatory evaporator to obtain Bempedoic acid as a white solid.

Yield: 0.126 g; 60.86% HPLC Purity: 96.68%

Reference Example:

Step-1: Preparation of 8-Oxo-2,2,14, 14-tetramethylpentadecanedioic acid

2,2,14,14-tetramethyl-8-oxo-pentadecanedioic acid diethyl ester (3 g) and Ethanol (120 mL) were added at room temperature into a 250 mL flask equipped with a magnetic stir bar. An aqueous solution of potassium hydroxide (7.05 g in 15 ml water) was added in to the reaction mass at room temperature and the reaction mass was refluxed for 4 h at 75-80°C. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mass was cooled to room temperature and the solvent was distilled out completely. Water (10 mL) was added to the residue. The aqueous layer was washed with dichloro methane (2 X 10 ml. Concentrated hydrochloric acid was added to adjust the pH to 2 and the aqueous layer was then extracted with methyl /_{<? /7}-butyl ether (3 X 10 mL). The combined organic layer was washed with brine solution (10 mL) and dried over sodium sulfate. The obtained organic layer was evaporated under reduced pressure at 45 °C to obtain the crude product as a pale yellow liquid. The residue was dissolved in methyl ieri-butyl ether (7 ml). n-Hexane (14 ml) was added to the solution and the mixture obtained stirred for 30 minutes at 10-15°C. The solid product was obtained by filtration and washed with n-Hexane (2X5 ml) to provide the title compound as a white solid.

Yield: 1.92 g; 74.50% Step-2: Preparation of Bempedoic acid

8-oxo-2,2,14,14-tetramethylpentadecanedioic acid (1.9 g), obtained from step- 1, and methanol (19 mL) were added at room temperature into a 100 mL flask fitted with a magnetic stir bar. The reaction mass was cooled between 0 to 5°C. Sodium borohydride (0.965 g) was added to the reaction mass portion wise at 0 to 5°C. The temperature was allowed to rise to room temperature and the reaction mixture was stirred for 8 h. The progress of the reaction was monitored by TLC. After completion of the reaction, water (20 mL) was added to the reaction mass and concentrated hydrochloric acid was added to adjust the pH to 1.0. The reaction mixture was extracted with dichloromethane (3 X15 mL). The combined organic layer was washed with brine solution (1 X 20 mL) and dried over sodium sulfate. The obtained organic layer was evaporated under reduced below 45 °C. The obtained crude product was purified by column chromatography using silica gel (60-120 mesh) and the solution, containing pure fractions, evaporated to obtain Bempedoic acid compound as pale yellow syrupy liquid.

Claims

Claims:

1. A process for preparation of Bempedoic acid or its pharmaceutically acceptable salts comprising;

a) Reducing the compound of Formula I to provide compound of Formula II

2. The process as claimed in claim 1, wherein the reduction in step a) is carried out in presence of a reducing agent selected from Lithium Borohydride, Sodium Borohydride (NaBH^), Lithium Aluminum Hydride (L1AIH4), Sodium Triacetoxyborohydride and Sodium Cyanoborohydride.

3. The process as claimed in claim 1, wherein the reduction in step a) is carried out in a mixture of organic solvent and water.

4. The process as claimed in claim 1, wherein the reduction in step a) is carried out in mixture of THF and water.

5. The process as claimed in claim 1 wherein the compound of formula II optionally be used in step b) without purification.

6. The process as claimed in claim 1, wherein in step b) the hydrolyzing agent comprises a base.

7. The process as claimed in claim 6, wherein the base is an alkali metal hydroxide selected from lithium hydroxide (LiOH), sodium hydroxide (NaOH), potassium hydroxide (KOH), cesium hydroxide (CsOH), and any combination thereof

8. A process for preparation of Bempedoic acid or its pharmaceutically acceptable salts comprising; hydrolyzing the compound of Formula II

9. The process as claimed in claim 8, wherein the hydrolyzing agent comprises a base.

10. The process as claimed in claim 9, wherein the base is an alkali metal hydroxide selected from lithium hydroxide (LiOH), sodium hydroxide (NaOH), potassium hydroxide (KOH), cesium hydroxide (CsOH), and any combination thereof.