DESC:FIELD:
The present invention relates to a process for the synthesis of Bempedoic acid. More specifically, the present invention relates to a simplified and improved one-pot process for the synthesis of highly pure and lithium free solid Bempedoic acid using only non-pyrophoric reagents and solvents.

BACKGROUND:
8-hydroxy-2, 2, 14, 14-tetramethylpentadecanedioic acid or Bempedoic acid is known from PCT publication number WO2004067489 filed by Esperion Therapeutics Inc. and is represented by compound of structural formula I.

Formula I
Bempedoic acid is marketed in the United States of America under the proprietary name NEXLETOL® and NEXLIZET® by Esperion Therapeutics Inc. The NEXLETOL is an adenosine triphosphate-citrate lyase (ACL) inhibitor indicated as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia or established atherosclerotic cardiovascular disease that require additional lowering of LDL-Bempedoic acid is used as a non-statin cholesterol-lowering pro-drug. It is converted into its active metabolite by acyl-CoA synthetase 1, and the active metabolite antagonizes ATP citrate-lyase, a cytosolic enzyme upstream of HMGCoA reductase which is the rate-limiting step of cholesterol biosynthesis. As acyl-CoA synthetase 1 is present mostly in the liver and absent in skeletal muscles, use of Bempedoic acid as an alternative to statin reduces risk of myalgia and myopathy. Bempedoic acid is also prescribed as a complementary cholesterol lowering medication in patients who require additional LDL cholesterol lowering on top of what can be achieved with maximum tolerated statin therapy.

Various synthesis routes have been used in the pharmaceutical industry to manufacture Bempedoic acid.

Chinese patent CN111170855 discloses process for the preparation of Bempedoic acid by using 1,5-dibromopentane and ethyl isobutyrate and dibenzyl malonate.

PCT publication number WO2020141419 discloses novel pharmaceutically acceptable salts of Bempedoic acid.

U.S Patent No US7335799B2 describes a process for the preparation of Bempedoic acid by reacting 1,5-dibromopentane and ethyl isobutyrate using lithium diisopropylamide and THF in Argon atmosphere to form 7-Bromo-2,2-dimethylheptanoic acid ethyl ester. Further reacting 7-Bromo-2,2-dimethylheptanoic acid ethyl ester with TOSMIC, in presence of tetra-n-butylammonium iodide and sodium hydride as base and anhydrous DMSO as solvent, to form 2,2,14,14-Tetramethyl-8-oxo-pentadecanedioic acid diethyl ester. Further processing the resultant product in presence of KOH in water to form 8-oxo-2,2,14,14-tetramethylpentadecanedioic acid which is further processed under nitrogen atmosphere and with sodium borohydride to form 8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid. This process employs the reagent such as lithium diisopropylamide, sodium hydride which are pyrophoric and may cause an explosion if not handled with care. Further, continuous use of harmful chemicals has impacted climate throughout the globe. Thus, there is need to develop processes for synthesis of highly pure active ingredients which has minimal effect on environment.

IN202041051889 provides a multi-step synthesis process for the preparation of solid Bempedoic acid starting with reaction between ethyl isobutyrate and 1,5-dibromopentane in presence of suitable base and solvent. Examples cite the use of sodium hydride which is highly corrosive and pyrophoric. Sodium hydride also reacts violently with water.

IN202041024380 provides a multi-step synthesis process for the preparation of solid Bempedoic acid starting with reaction between 1,5-dibromopentane and alkyl isobutyrate in presence of suitable base and solvent. Examples cite use of corrosive and pyrophoric substances like lithium diisopropylamide (LDA), sodium hydride, and THF. The synthesis process provides Bempedoic acid with a low purity level of around 99.20%. Further, use of LDA is responsible for undesirable lithium impurities in the product.

IN201941027561 provides a multi-step synthesis process for the preparation of crystalline form of Bempedoic acid starting with 2,2,14,14-tetramethyl-8-oxo-pentadecanedioic acid. Examples cite an exemplary process for the preparation of crystalline form of Bempedoic acid starting with reaction between 1,5-dibromopentane and ethyl isobutyrate. Use of sodium hydride which is highly corrosive and pyrophoric is cited in the process.

IN202021050188 provides a multi-step synthesis process for the preparation of solid bempedoic acid starting with reaction between ethyl 7-bromo-2,2-dimethylheptanoate and tosylmethylisocyanide in presence of suitable base, solvent, and phase transfer catalyst. Examples cite an exemplary method for preparation of Bempedoic acid starting with reaction between 1,5-dibromopentane and ethyl isobutyrate. 2,2,14,14-tetramethyl-8-oxopentadecanedioic acid, the end-product in an intermediate step needs to be isolated and purified before reduction into 8-hydroxy-2,2,14,14-tetramethyl pentadecanedioic acid making the process complex. Examples cite use of corrosive and pyrophoric substances like lithium diisopropylamide (LDA) and THF. Further, use of LDA incorporates undesirable lithium impurities in the product.

CN112479856 provides a multi-step synthesis process for the preparation of bempedoic acid starting with reaction between ethyl isobutyrate and 1,5-dibromopentane in presence of suitable base and solvent. Examples cite use of corrosive and pyrophoric substances like lithium diisopropylamide (LDA), sodium hydride, and THF. The synthesis process provides Bempedoic acid with a low purity level of 99%. Further, use of LDA incorporates undesirable lithium impurity in the product.

While it is advantageous to obtain Bempedoic acid in solid state for solid compositions, most of the above cited prior art use corrosive and pyrophoric substances during the synthesis. Use of pyrophoric, corrosive, or hazardous materials in synthesis requires specialized manufacturing facilities and conditions adding to the manufacturing cost of the drug. Further, Bempedoic acid obtained in the cited prior art has low purity level even when end-product is isolated and purified using chromatography at the end of each step before proceeding to the next step. Also, use of lithium containing substances like lithium diisopropylamide (LDA) adds undesirable Li impurity in the Bempedoic acid.

Keeping in view the abovementioned disadvantages associated with prior art, it is highly desirable to develop an improved, simple, and non-hazardous synthesis process for the preparation of highly pure solid Bempedoic acid which can obviates the prior art problem.

Accordingly, inventors of the present invention have successfully developed an improved yet simple synthesis process for the preparation of highly pure solid Bempedoic acid in higher yields using only non-pyrophoric substances.

TECHNICAL ADVANTAGES:
The synthesis process disclosed herein produces solid Bempedoic acid having a purity level of more than 99.85% without need of purification using column chromatography. The high purity level of Bempedoic acid is achieved due to skillful selection of reagents, solvents, synthesis scheme and process conditions. Bempedoic acid synthesized by the process is also free from lithium impurities due to use of only non-lithium containing reagents.

Further, the synthesis process disclosed herein is simpler, quicker and requires less severe process conditions. Despite involvement of multiple reagents, solvents, and process conditions, the process disclosed herein enables synthesis of highly pure solid Bempedoic acid in a one-pot synthesis set-up and in minimal steps due to negation of various steps which render conventional synthesis process complex.

Furthermore, the synthesis process disclosed herein is extremely safe and requires simple manufacturing facilities due to involvement of only non-corrosive, non-pyrophoric, and environment-friendly substances.
Accordingly, the process as disclosed herein provides an improved yet simple synthesis scheme for the preparation of lithium-free highly pure solid Bempedoic acid in enhanced yield using only non-pyrophoric reagents and solvents.

SUMMARY OF THE INVENTION:
The present invention discloses a process for the synthesis of highly pure solid Bempedoic acid having a structural formula represented by Formula I:

Formula I

comprising steps of,
Step-a: reacting ethyl isobutyrate and 1,5-dibromopentane in presence of a non-pyrophoric reagent and a solvent to obtain ethyl 7-bromo-2,2-dimethylheptanoate;
Step-b: reacting ethyl 7-bromo-2,2-dimethylheptanoate and 1-(isocyanomethanesulfonyl)-4-methylbenzene in presence of a non-pyrophoric reagent and a solvent to obtain residue of an in-situ intermediate which is diethyl 8-isocyano-2,2,14,14-tetramethyl-8-tosylpentadecanedioate (Stage-A) and treating diethyl 8-isocyano-2,2,14,14-tetramethyl-8-tosylpentadecanedioate in presence of the non-pyrophoric reagent and the solvent to obtain diethyl 2,2,14,14-tetramethyl-8-oxopentadecanedioate (Stage-B);
Step-c: hydrolyzing diethyl 2,2,14,14-tetramethyl-8-oxopentadecanedioate (Stage-B) in presence of the non-pyrophoric reagent and the solvent to form 2,2,14,14-tetramethyl-8-oxopentadecanedoic acid (Stage-C);
Step-d: reducing 2,2,14,14-tetramethyl-8-oxopentadecanedioic acid (Stage-C) in presence of the non-pyrophoric reagent and the solvent, and forming a diisopropylammonium salt of Bempedoic acid (Stage-D) in presence of diisopropylamine and acetone; and
Step-e: purifying the diisopropylammonium salt of Bempedoic acid (Stage-D) in presence of the non-pyrophoric reagent and the solvent to obtain the highly pure Bempedoic acid (Stage-Final).
The synthesis process disclosed herein provides Bempedoic acid with a very high purity level without any column chromatography purification. Specifically, the process provides Bempedoic acid with purity more than 99.85%. The process is also completely non-hazardous and provides lithium-free crystalline Bempedoic acid due to use of one or more non-corrosive, non-pyrophoric and lithium-free reagents selected from sodium hydroxide, sodium borohydride, tetra butyl ammonium iodide, tetra butyl ammonium bromide, sodium tertiary butoxide, potassium tertiary butoxide, saturated ammonium chloride solution, sodium chloride solution, hydrochloric acid, and sodium bicarbonate. The non-hazardous nature of the process is further complimented by the use of one or more safe and eco-friendly solvents selected from acetone, n-heptane, methyl tert-butyl ether, anhydrous N,N-dimethyl formamide, ethanol, water, methyl isobutyl ketone, ethyl acetate, methylene dichloride, and dichloromethane.

The synthesis process disclosed herein starts with step-a wherein ethyl 7-bromo-2,2-dimethylheptanoate is synthesized. In step-a, ethyl isobutyrate is reacted with 1,5-dibromopentane in presence of sodium tert-butoxide and methyl isobutyl ketone to obtain ethyl 7-bromo-2,2-dimethylheptanoate. The step-a occurs under nitrogen atmosphere, at a temperature in range of 0? to 25? and for a time duration of 20 to 22 hours.

In step-b of the synthesis process disclosed herein, ethyl 7-bromo-2,2-dimethylheptanoate obtained in step-a is converted into diethyl 2,2,14,14-tetramethyl-8-oxopentadecanedioate via formation of an in situ intermediate diethyl 8-isocyano-2,2,14,14-tetramethyl-8-tosylpentadecanedioate (Stage-A). The reaction in step-b is carried out under nitrogen atmosphere in presence of one or more reagents selected from sodium tert-butoxide, potassium tert-butoxide, sodium methoxide, and sodium ethoxide and one or more solvents selected from acetone, ethanol, methyl isobutyl ketone, N,N-dimethyl formamide, water, methylene dichloride, and n-heptane. The reaction temperature is in range of -20? to 30? and reaction is completed within a time duration of 5.5 to 7.5 hours. The reaction in step-b starts with reaction between ethyl 7-bromo-2,2-dimethylheptanoate and 1-(isocyanomethanesulfonyl)-4-methylbenzene in presence of sodium tert-butoxide as base and anhydrous N,N-dimethyl formamide as solvent to obtain an in situ intermediate diethyl 8-isocyano-2,2,14,14-tetramethyl-8-tosylpentadecanedioate which is not isolated and purified before conversion into diethyl 2,2,14,14-tetramethyl-8-oxopentadecanedioate (Stage-B) in presence of hydrochloric acid, and one or more solvents selected from methylene dichloride and water. In step-b, sodium tert-butoxide is in an amount ranging from 0.2081 moles to 0.3121 moles.

In step-c of the synthesis process disclosed herein, diethyl 2,2,14,14-tetramethyl-8-oxopentadecanedioate (Stage-B) obtained in step-b is hydrolyzed into 2,2,14,14-tetramethyl-8-oxopentadecanedoic acid (Stage-C) in presence of one or more reagents selected from sodium hydroxide and hydrochloric acid and one or more solvents selected from ethanol and water. The reaction in step (c) is carried out at a temperature in range of 15? to 85? and for a time duration of 8 to 9 hours.

In step-d of the synthesis process disclosed herein, 2,2,14,14-tetramethyl-8-oxopentadecanedoic acid (Stage-C) obtained in step-c is converted into diisopropylammonium salt of Bempedoic acid (Stage-D). The reaction in step-d involves reduction of 2,2,14,14-tetramethyl-8-oxopentadecanedioic acid (Stage-C) followed by reaction with diisopropylamine in presence of acetone to obtain diisopropylammonium salt of Bempedoic acid (Stage-D). The reaction in step-d occurs in presence of one or more reagents selected from sodium borohydride and hydrochloric acid and one or more solvents selected from ethanol and ethyl acetate. The reaction in step-d is carried out at a temperature in range of 15? to 45? and for a time duration of 6.5 to 8.5 hours.

In step-e of the synthesis process disclosed herein, diisopropylammonium salt of Bempedoic acid (Stage-D) obtained in step-d is converted into highly pure Bempedoic acid (Stage-Final). The reaction in step-e involves treatment of diisopropylammonium salt of Bempedoic acid (Stage-D) with hydrochloric acid in presence of one or more solvents selected from water, methylene dichloride, and methyl isobutyl ketone. The reaction in step-e is carried out at a temperature in range of 20? to 50? and for a time duration of 24 to 27 hours.

The highly pure solid Bempedoic acid (Stage-Final) obtained in step-e is isolated by cooling, followed by filtration, followed by washing with saturated sodium chloride solution, and then drying over a drying agent selected from magnesium sulfate and sodium sulfate under a reduced pressure condition by maintaining vacuum for a duration of 6 hours to 12 hours.
The synthesis process disclosed herein does not involve use of any pyrophoric reagent and Bempedoic acid obtained in step (e) has purity level of more than 99.85% without any purification using column chromatography.

Further, solid Bempedoic acid obtained in the process disclosed herein may be in amorphous form or crystalline form.

OBJECTIVE:
It is the primary objective of the present disclosure to provide a process for the synthesis of solid Bempedoic acid having purity level more than 99.85% without any column chromatography purification.

It is further objective of the present disclosure to provide a process for the synthesis of solid Bempedoic acid with no lithium impurities.

It is further objective of the present disclosure to provide a process for the synthesis of solid Bempedoic acid without use of any pyrophoric reagent or solvent.

It is further objective of the present disclosure to provide a one-pot process for the synthesis of solid Bempedoic acid in higher yields.

BRIEF DESCRIPTION OF THE DRAWING:
To further clarify advantages and aspects of the disclosure, a more particular description of the present disclosed process will be rendered by reference to specific embodiments thereof, which is illustrated in the appended drawing(s) and explained hereinafter in the description section. It is appreciated that the drawing(s) as provided herein depicts only typical embodiments of the process and are therefore not to be considered limiting of its scope.
Figure 1: illustrates synthesis route of solid Bempedoic acid.

DETAILED DESCRIPTION OF THE INVENTION:
Those skilled in the art will be aware that the present disclosure is subject to variations and modifications other than those specifically described. It is to be understood that the present disclosure includes all such variations and modifications. The disclosure also includes all such steps of the process, features of the system, referred to or indicated in this specification, individually or collectively and all combinations of any or more of such steps or features.

The articles “a”, “an” and “the” are used to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article.

The terms “comprise” and “comprising” are used in the inclusive, open sense, meaning that additional elements may be included. It is not intended to be construed as “consists of only”.

Throughout this specification, unless the context requires otherwise the word “comprise”, and variations such as “comprises” and “comprising”, will be understood to imply the inclusion of a stated element or step or group of element or steps but not the exclusion of any other element or step or group of element or steps.

The term “including” is used to mean “including but not limited to”. “Including” and “including but not limited to” are used interchangeably.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the disclosure, the preferred method, and materials are now described.

The present disclosure is not to be limited in scope by the specific embodiments described herein, which are intended for the purposes of exemplification only. Functionally equivalent products and processes are clearly within the scope of the disclosure, as described herein.

The present disclosure relates to the synthesis process for the preparation of Bempedoic Acid, which can be implemented safely on commercial scale. Surprisingly, the present disclosure addresses both process engineering aspects as well as quality aspects together. The current disclosure further refers to the reaction at controlled temperature, less formation of impurities, clarification filtration to remove waste and purification of the crude Bempedoic acid to remove unwanted impurities and color.

The present disclosure as depicted in Figure 1 relates to a one-pot synthesis process for the preparation of highly pure Bempedoic Acid having purity of at least 99.85%, said process comprising steps of:
Step-a: reacting ethyl isobutyrate and 1,5-dibromopentane in presence of a non-pyrophoric reagent and a solvent to obtain ethyl 7-bromo-2,2-dimethylheptanoate;
Step-b: reacting ethyl 7-bromo-2,2-dimethylheptanoate and 1-(isocyanomethanesulfonyl)-4-methylbenzene in presence of a non-pyrophoric reagent and a solvent to obtain residue of an in-situ intermediate which is diethyl 8-isocyano-2,2,14,14-tetramethyl-8-tosylpentadecanedioate (Stage-A) and treating diethyl 8-isocyano-2,2,14,14-tetramethyl-8-tosylpentadecanedioate in presence of the non-pyrophoric reagent and the solvent to obtain diethyl 2,2,14,14-tetramethyl-8-oxopentadecanedioate (Stage-B). The diethyl 8-isocyano-2,2,14,14-tetramethyl-8-tosylpentadecanedioate is an important intermediate stage of in situ reaction that gives clean reaction and optimum yield. The intermediate, diethyl 8-isocyano-2,2,14,14-tetramethyl-8-tosylpentadecanedioate obtained is not isolated and organic layer is taken directly for Step-c;
Step c) Further hydrolyzing diethyl 2,2,14,14-tetramethyl-8-oxopentadecanedioate (Stage-B) in presence of the non-pyrophoric reagents and solvents to form 2,2,14,14-tetramethyl-8-oxopentadecanedoic acid (Stage-C);
Step d) Reducing 2,2,14,14-tetramethyl-8-oxopentadecanedioic acid (Stage-C) in presence of the non-pyrophoric reagent and the solvent and forming a diisopropylammonium salt of Bempedoic acid (Stage-D) in presence of diisopropylamine and acetone; and
Step-e: purifying the diisopropylammonium salt of Bempedoic acid (Stage-D) in presence of the non-pyrophoric reagent and the solvent to obtain the highly pure Bempedoic acid (Stage-Final).

The process disclosed herein is highly safe, simple, and cost effective due to use of non-pyrophoric reagents and solvents as such chemicals do not require sophisticated manufacturing facilities. Some of the non-pyrophoric reagents which can be used in the present process are selected from sodium hydroxide, sodium borohydride, tetra butyl ammonium iodide, tetra butyl ammonium bromide, sodium tertiary butoxide, potassium tertiary butoxide, saturated ammonium chloride solution, sodium chloride solution, hydrochloric acid, and sodium bicarbonate. Some of the solvents which can be used in the present process are selected from acetone, n-heptane, methyl tert-butyl ether, anhydrous N,N-dimethyl formamide, ethanol, water, methyl isobutyl ketone, ethyl acetate, methylene dichloride, and dichloromethane.

In the most preferred embodiment of the present invention, step-a is carried out in the presence of sodium tert-butoxide as base and methyl isobutyl ketone as solvent.

In step-b, wherein ethyl 7-bromo-2,2-dimethylheptanoate obtained in step-a is converted into diethyl 2,2,14,14-tetramethyl-8-oxopentadecanedioate (Stage-B) via formation of an in situ intermediate diethyl 8-isocyano-2,2,14,14-tetramethyl-8-tosylpentadecanedioate (Stage-A), preferred reagents are selected from sodium tert-butoxide, potassium tert-butoxide, sodium methoxide, and sodium ethoxide and one or more solvents selected from acetone, ethanol, methyl isobutyl ketone, N,N-dimethyl formamide, water, methylene dichloride, and n-heptane. In a most preferred embodiment, reaction between ethyl 7-bromo-2,2-dimethylheptanoate and 1-(isocyanomethanesulfonyl)-4-methylbenzene is carried out in presence of sodium tert-butoxide as base and anhydrous N,N-dimethyl formamide as solvent. Further, in a preferred embodiment, the in situ intermediate diethyl 8-isocyano-2,2,14,14-tetramethyl-8-tosylpentadecanedioate (Stage-A) is converted into diethyl 2,2,14,14-tetramethyl-8-oxopentadecanedioate (Stage-B) in presence of hydrochloric acid, and one or more solvents selected from methylene dichloride and water. In most preferred embodiment, the in situ intermediate diethyl 8-isocyano-2,2,14,14-tetramethyl-8-tosylpentadecanedioate (Stage-A) is not isolated and purified before conversion into diethyl 2,2,14,14-tetramethyl-8-oxopentadecanedioate (Stage-B). Further, in most preferred embodiment, sodium tert-butoxide is in an amount ranging from 0.2081 moles to 0.3121 moles and the reaction temperature is in range of -20? to 30?. In the most preferred embodiment, the reaction in step-b is completed within a time duration of 5.5 to 7.5 hours.
In step-c wherein 2,2,14,14-tetramethyl-8-oxopentadecanedoic acid (Stage-C) is obtained by hydrolysis of diethyl 2,2,14,14-tetramethyl-8-oxopentadecanedioate (Stage-B), preferred reagents are selected from sodium hydroxide and hydrochloric acid and preferred solvents are selected from ethanol and water. In the most preferred embodiment, the reaction in step-c is carried out at a temperature in range of 15? to 85? and for a time duration of 8 to 9 hours.

In step-d, wherein 2,2,14,14-tetramethyl-8-oxopentadecanedoic acid (Stage-C) obtained in step-c is converted into diisopropylammonium salt of Bempedoic acid (Stage-D), preferred reagents are selected from sodium borohydride and hydrochloric acid and preferred solvents are selected from ethanol and ethyl acetate. The reaction in step-d is carried out preferably at a temperature in range of 15? to 45? and for a time duration of 6.5 to 8.5 hours.

In step-e, wherein diisopropylammonium salt of Bempedoic acid (Stage-D) obtained in step-d is converted into highly pure Bempedoic acid (Stage-Final), the diisopropylammonium salt of Bempedoic acid (Stage-D) is preferably treated with hydrochloric acid in presence of one or more preferred solvents selected from water, methylene dichloride, and methyl isobutyl ketone. The reaction in step-e is preferably carried out at a temperature in range of 20? to 50? and for a time duration of 24 to 27 hours.

The solid Bempedoic acid obtained through the synthesis process disclosed herein has purity level of more than 99.85% due to skillful selection of reagents, solvents, synthesis scheme and process conditions. The process disclosed herein does not involve use of any conventional lithium containing reagents like n-BuLi and LDA during the synthesis due to which Bempedoic acid prepared using the process is substantially free from lithium impurities. Use of acetone and methyl isobutyl ketone during the synthesis of diisopropylamine salt (DIPA) of Bempedoic acid and its conversion into pure Bempedoic acid also increases purity level of Bempedoic acid due to property of these solvents to dissolve almost all the impurities incorporated during the synthesis.

EXAMPLES:
Having described the basic aspects of the present invention, the following non-limiting examples illustrate specific embodiments thereof. Those skilled in the art will appreciate that many modifications may be made in the invention without changing the essence of invention.
1: Synthesis of Bempedoic Acid of Formula I
Example-1.1: Synthesis of Ethyl 7-bromo-2, 2-dimethylheptanoate [Step-a]
In a clean 500 ml 4 necked round bottom flask (4NRBF) equipped with stirrer thermo pocket, under nitrogen atmosphere, 1000 ml of methyl isobutyl ketone is charged with 200 g of ethyl isobutyrate (1.72 mol) followed by addition of 475.1 g of 1,5-dibromopentane (2.06 mol). The reaction mass is cooled on an ice-bath and 290 g of potassium tertiary butoxide (2.58 mol) is added equal lot wise and the reaction temperature is maintained at 0°C - 5°C. The reaction mixture is then stirred at room temperature for 20 hours and progress of the reaction is monitored using TLC. After completion of the reaction, the reaction mass is quenched by slow addition of 1500 ml of saturated ammonium chloride solution. The resulting solution is then extracted with ethyl acetate (2x1500 ml) and the separated ethyl acetate layer is washed with a solution comprising saturated sodium chloride solution (1500 ml), 1 N hydrochloric acid (1500 ml), and saturated sodium bicarbonate solution (1500 ml). The separated ethyl acetate layer is then dried over magnesium sulfate and concentrated in vacuum to obtain 1800 ml of the crude material which is then purified by vacuum distillation. Two fractions are obtained: the first boiling at 95°C - 110°C. /1-2 torr (185 g) and the second boiling at 105°C -120°C. /1-2 torr (410 g) for a total yield of 62%.

Example 1.2: Synthesis of diethyl 2, 2, 14, 14-tetramethyl-8-oxopentadecanedioate (Stage-B) [Step-b]
Under Nitrogen atmosphere, 100g of Ethyl 7-bromo-2, 2-dimethylheptanoate is charged into 515.0 ml of N,-N-Dimethyl formamide in a 4 neck round bottom flask (4NRBF) under constant stirring. 14.0 g of Tetra butyl ammonium iodide (TBAI) is then charged into the reaction mass, stirred for 5 to 10 minutes, and flushed with 30 ml of N, N-Dimethyl formamide (DMF) Lot-2 under nitrogen atmosphere. The reaction mass is then cooled down to 0 to 5°C under constant stirring and 36.8 of p-toluene sulfonylmethyl isocyanide is charged into the reaction mass. followed by flushing with 30 ml of N, N-Dimethyl formamide under nitrogen atmosphere. The reaction mass is then stirred until a clear reaction mass is obtained. The reaction mass is the cooled down to -15°C to -20°C under constant stirring and 20.0 g of Sodium tertiary Butoxide is added slowly for 10 to 15 minutes while maintaining temperature between 0°C to -15°C Thereafter, the temperature of the reaction mass is raised to 10°C to 15°C and reaction mass is left for 50 to 60 minutes. The reaction mass is then transferred into a 3.0 liters 4NRBF charged with 600.0 ml of purified water and 400 ml of n-Heptane at 10°C to 15°C and temperature is maintained between 25°C and 30°C. The reaction mass is then filtered through hyflow and hyflow bed is washed with 50 ml of n-Heptane. The filtered reaction mass is then allowed to separate into an aqueous layer and an organic layer. The aqueous layer is further washed with n-Heptane and the organic layer obtained on settlement is combined with the previously obtained organic layer. The combined organic layers are charged into a clean & dry RBF and 50 ml of Concentrated HCl is added slowly in 20 to 30 minutes under constant stirring and maintaining temperature between 20°C and 25°C. The reaction mass is maintained at 20 to 30°C for 120 to 150 minutes and thereafter 200 ml of purified water is added under constant stirring. The reaction mass is then filtered through hyflow and hyflow bed is washed with 50 ml of n-Heptane. The filtrate is left for 15 to 20 minutes, and upper organic layer and lower aqueous layer is separated. The aqueous layer is further washed with n-Heptane and the organic layer obtained on settlement is combined with the previously obtained organic layer.

Example 1.3: Synthesis of 2,2,14,14-tetramethyl-8-oxopentadecanedoic acid (Stage-c) [Step-c]
The combined reaction mass containing organic layers obtained above is charged into a round bottom flask and 5.0% aqueous Sodium hydroxide is added slowly for 15 to 20 minutes at 15 to 25°C. The reaction mass is then left for 15 to 20 minutes for layer separation. The upper organic layer is then charged into a round bottom flask and solvent is distilled out from reaction mass under vacuums by applying 50°C to 60°C hot water of water bath. Thereafter, the reaction mass is degassed under vacuum. (NLT 720 mm/Hg) for 60 to 70 minutes at a temperature of below 45°C. The reaction mass is then cooled to 20°C to 30°C and vacuum is released under nitrogen atmosphere. 100.0 ml ethanol is then charged into the reaction mass and reaction mass is stirred until a clear solution is obtained. To this added aqueous solution of 25 g of Sodium hydroxide in 100 ml of purified water solution at 20°C to 30°C and temperature is raised to 80°C to 85°C. The reaction mass is then left for 360 to 390 minutes and thereafter cooled down to 20°C to 30°C. In the cooled reaction mass 200 ml of purified water is added followed by addition of 200 ml of methylene dichloride under constant stirring. The reaction mass is allowed to separate into layers for 15 to 20 minutes at a temperature between 20°C and 30°C.

Example 1.4: Synthesis of diisopropylammonium salt of Bempedoic acid (Stage-D) [Step-d]
The aqueous layer obtained above is cooled to 15°C to 20°C and 3.5 g of Sodium Borohydride is charged into the reaction mass. The reaction mass is then stirred for 120 to 150 minutes at 25°C to 30°C and thereafter pH of the reaction mass is adjusted between 2.0 and 3.0 by addition of HCl. The reaction mass is then charged with 300 ml of Ethyl acetate, stirred for 25 to 30 minutes at 25°C to 30°C and allowed to separate into layers for 15 to 20 minutes. The upper organic layer is then charged into a round bottom flask and solvent is distilled out under vacuums by applying 50 to 60°C hot water in water bath. The reaction mass is then degassed under vacuum (NLT 720 mm/Hg) for 60 to 70 minutes at a temperature below 45°C and reaction mass is cooled to 50°C to 60°C with release vacuum under nitrogen atmosphere to obtain an oily mass. The weight range of the oily mass obtained is maintained between 0.55 w/w and 0.65 w/w. The oily mass is then charged with 500.0 ml of acetone and reaction mass is stirred until a clear solution is obtained. Charged DIPA into the clear solution. The temperature can be raised to 25°C to 45°C to obtain a clear solution if required. The reaction mass is then cooled to 20 to 25°C and allowed to precipitate for 120 to 180 minutes. The reaction mass is then filtered, and aqueous layer obtained is washed with 100 ml of acetone followed by drying to obtain DIPA salt of Bempedoic acid as wet cake.

Example 1.5: Synthesis of pure Bempedoic acid (Stage-Final) [step-e]
100 g of DIPA salt of Bempedoic acid in form of wet cake obtained above is charged into 3 liters 4 Necked Round Bottom Flask with water condenser containing 550.0 ml of purified water. The reaction mass is stirred at 20°C to 30°C until a clear solution is obtained. 200 ml of methylene dichloride is then charged into the clear solution and reaction mass is maintained for 30 to 40 minutes. The reaction mass is then allowed to separate into layers for 15 to 20 minutes. The upper aqueous layer is treated with HCl to adjust the pH between 2.0-3.0 and 400 ml of methyl isobutyl ketone is added to the reaction mass under constant stirring for 30 to 40 minutes at 25°C to 30°C. The reaction mass is then allowed to separate into layers for 15 to 20 minutes and the upper organic layer is charged into a round bottom flask. The solvent is distilled out under vacuums by applying 50°C to 60°C hot water of water bath at a temperature below 50°C and thereafter reaction mass is cooled to 20 to 25°C. The slurry mass is then stirred for 600 to 720 minutes at 20°C to 25°C and reaction mass is filtered. The filter bed is washed with 25 ml of chilled methyl isobutyl ketone and suck dried for 50 to 60 minutes. Solid Bempedoic acid obtained is then vacuum dried for 720 to 730 minutes at 45°C to 50°C wherein the material is reshuffled after an interval of 6 hrs. Yield Range of Bempedoic acid: 0.4 – 0.6 and Theoretical Yield of Bempedoic acid: 63.0 g. ,CLAIMS:1. A process for the synthesis of a highly pure Bempedoic acid having a structural Formula I:

Formula I
the process comprising steps of,
a) reacting ethyl isobutyrate and 1,5-dibromopentane in presence of a non-pyrophoric reagent and a solvent to obtain ethyl 7-bromo-2,2-dimethylheptanoate;
b) reacting ethyl 7-bromo-2,2-dimethylheptanoate and 1-(isocyanomethanesulfonyl)-4-methylbenzene in presence of the non-pyrophoric reagent and the solvent to obtain residue of an in-situ intermediate which is diethyl 8-isocyano-2,2,14,14-tetramethyl-8-tosylpentadecanedioate and treating diethyl 8-isocyano-2,2,14,14-tetramethyl-8-tosylpentadecanedioate in presence of the non-pyrophoric reagent and the solvent to obtain diethyl 2,2,14,14-tetramethyl-8-oxopentadecanedioate;
c) hydrolyzing diethyl 2,2,14,14-tetramethyl-8-oxopentadecanedioate in presence of the non-pyrophoric reagent and the solvent to form 2,2,14,14-tetramethyl-8-oxopentadecanedoic acid;
d) reducing 2,2,14,14-tetramethyl-8-oxopentadecanedioic acid in presence of the non-pyrophoric reagent and the solvent, and forming a diisopropylammonium salt of Bempedoic acid in presence of diisopropylamine and acetone; and
e) purifying the diisopropylammonium salt of Bempedoic acid in presence of the non-pyrophoric reagent and the solvent to obtain the highly pure Bempedoic acid, wherein, the Bempedoic acid is free from lithium impurity.

2. The process as claimed in claim 1, wherein the non-pyrophoric reagent is selected from sodium hydroxide, sodium borohydride, tetra butyl ammonium iodide, tetra butyl ammonium bromide, sodium tertiary butoxide, potassium tertiary butoxide, saturated ammonium chloride solution, sodium chloride solution, hydrochloric acid, sodium bicarbonate, and a combination thereof; and the solvent is selected from acetone, n-heptane, methyl tert-butyl ether, anhydrous N,N-dimethyl formamide, ethanol, water, methyl isobutyl ketone, ethyl acetate, methylene dichloride, dichloromethane, and a combination thereof.

3. The process as claimed in claims 1-2, wherein in step (a) the non-pyrophoric reagent is sodium tert-butoxide, and the solvent is methyl isobutyl ketone.

4. The process as claimed in claims 1-2, wherein in step (b) the non-pyrophoric reagent is selected from sodium tert-butoxide, potassium tert-butoxide, sodium methoxide, sodium ethoxide, and the solvent is selected from acetone, ethanol, methyl isobutyl ketone, N,N-dimethyl formamide, water, methylene dichloride, and n-heptane.

5. The process as claimed in claims 1-2, wherein in step (b) ethyl 7-bromo-2,2-dimethylheptanoate and 1-(isocyanomethanesulfonyl)-4-methylbenzene are reacted in presence of the non-pyrophoric reagent, wherein, the non-pyrophoric reagent is sodium tert-butoxide and is in an amount ranging from 0.2081 moles to 0.3121 moles, and the solvent is anhydrous N,N-dimethyl formamide.

6. The process as claimed in claims 1-2, wherein in step (b) diethyl 8-isocyano-2,2,14,14-tetramethyl-8-tosylpentadecanedioate is treated with the non-pyrophoric reagent and the solvent, wherein the non-pyrophoric reagent is hydrochloric acid, and the solvent is selected from methylene dichloride, water, and a combination thereof.

7. The process as claimed in claims 1-2, wherein in step (c) the non-pyrophoric reagent is selected from sodium hydroxide, hydrochloric acid, and a combination thereof, and the solvent is selected from ethanol, water, and a combination thereof.

8. The process as claimed in claims 1-2, wherein in step (d) the non-pyrophoric reagent is selected from sodium borohydride, hydrochloric acid, and a combination thereof, and the solvent is selected from ethanol, ethyl acetate and a combination thereof.
9. The process as claimed in claims 1-2, wherein in step (e) the non-pyrophoric reagent is hydrochloric acid and the solvent is selected from water, methylene dichloride, methyl isobutyl ketone and a combination thereof.

10. The process as claimed in claim 1, wherein step (a) is carried out under nitrogen atmosphere, at a temperature in range of 0? to 25? and for a time duration of 20 to 22 hours.

11. The process as claimed in claim 1, wherein step (b) is carried out under nitrogen atmosphere, at a temperature in range of -20? to 30? and for a time duration of 5.5 to 7.5 hours.

12. The process as claimed in claim 1, wherein step (c) is carried out at a temperature in range of 15? to 85? and for a time duration of 8 to 9 hours.

13. The process as claimed in claim 1, wherein step (d) is carried out at a temperature in range of 15? to 45? and for a time duration of 6.5 to 8.5 hours.

14. The process as claimed in claim 1, wherein step (e) is carried out at a temperature in range of 20? to 50? and for a time duration of 24 to 27 hours.

15. The process as claimed in claim 1, wherein the process is a one-pot synthesis process, wherein in step (b) the in-situ intermediate is not isolated and an organic layer containing the in-situ intermediate is directly used in step (c) without column chromatography purification.

16. The process as claimed in claim 1, wherein the Bempedoic acid obtained in step (e) is isolated by cooling, followed by filtration, followed by washing with saturated sodium chloride solution, and then drying over a drying agent selected from magnesium sulfate and sodium sulfate under a reduced pressure condition by maintaining vacuum for a duration of 6 hours to 12 hours.
17. The process as claimed in claim 1, wherein the process is free from pyrophoric reagents and the highly pure Bempedoic acid obtained in step (e) have purity more than 99.85% and the high purity is achieved without column chromatography purification.