FIELD OF THE INVENTION:

The invention relates to a novel diisopropylammonium salt of bempedoic acid, its polymorphic form and process of preparation thereof. The novel diisopropylammonium salt of bempedoic acid is used in an improved, commercially viable and industrially advantageous process for the preparation of bempedoic acid with good yield and high purity.

BACKGROUND OF THE INVENTION:

8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid or bempedoic acid is known from PCT publication number W02004067489 filed by Esperion Therapeutics Inc. and herein 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 prodrug. 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. The synthetic process for bempedoic acid is reported in US7335799, which comprises, reaction of 1,5 -dibromopentane with ethyl isobutyrate in presence of LDA (Lithium diisopropylamide)/THF (tetrahydrofuran) to obtain 7-Bromo-2,2-dimethylheptanoic acid ethyl ester which is further treated with p-toluenesulfonyl methyl isocyanide in presence of TBAI (tetra-n-butylammonium iodide)/NaH (sodium hydride)/ DMSO (Dimethyl sulfoxide) to obtain diethyl 8-cyano-2,2,14,14-tetramethyl-8-tosylpentadecanedioate, which is treated with hydrochloric acid/ dichloromethane to obtain diethyl 2,2,14,14-tetramethyl-8- oxopentadecanedioate. The obtained diethyl 2,2,14,14-tetramethyl-8-oxopentadecanedioate is treated with KOH (potassium hydroxide)/EtOH (ethanol) to obtain 8-oxo-2,2,14,14- tetramethylpentadecanedioic acid which is further converted into bempedoic acid (I) in presence of NaBH-i (Sodium borohydride)/MeOH (methanol).

Scheme I 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, bempedoic acid obtained by using said process is in the form of viscous oil as it contains lot of impurities.

US 11407705 discloses the process for preparation of bempedoic acid by reaction of ethyl isobutyrate with l-bromo-5 -chloropentane or l-iodo-5-chloropentane in the presence of a base to obtain ethyl 7-chloro-2,2-dimethylheptanoate. The obtained ethyl 7-chloro-2,2- dimethylheptanoate is further reacted with lithium bromide (LiBr), lithium iodide (Lil), potassium bromide (KBr), potassium iodide (KI), sodium bromide (NaBr) and sodium iodide (Nal) to obtain 7-bromo-2,2-dimethylheptanoate or 7-iodo-2,2-dimethylheptanoate which is further reacted with toluenesulfonylmethyl isocyanide to obtain diethyl 8-cyano-2,2, 14,14- tetramethyl-8-tosylpentadecanedioate, which is treated with acid to obtain diethyl 2,2,14,14- tetramethyl-8-oxopentadecanedioate. The obtained diethyl 2,2,14,14-tetramethyl-8- oxopentadecanedioate is reduced further to form diethyl 2,2,14,14-tetramethyl-8- hydroxypentadecanedioate which is further hydrolysed with base to form bempedoic acid.

Scheme II US’705 is further disclosed process impurities of bempedoic acid as listed in below table I.

Table I

The process disclosed in US’705 involves the use of very strong bases such as lithium bromide (UiBr) or lithium iodide (Lil), which is the prime reason of formation of impurities such as diol impurity, dimer impurity and acetate impurity etc. Also apart from impurities disclosed in US’705, there are formation of other impurities as listed in below table II.

Table II

Further US’705 discloses crystallisation of bempedoic acid using ethyl acetate to remove these impurities. However it is observed that all impurities of bempedoic acid are not removed by using ethyl acetate as solvent. Also US’705 fails to disclose overall yield of bempedoic acid obtained by using said process. W02020/141419 discloses laundry list of various salts of bempedoic acid like alkaline metals (such as lithium, sodium, potassium, etc.), alkaline earth metals (such as magnesium, calcium, barium, etc.), transition metals (such as zinc, iron, etc.), organic bases (such as trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, piperazine, tert-butyl amine, meglumine, ethylenediamine, pyridine, picoline, quinolin, etc.), amino acids, or mixtures thereof. However WO’419 only exemplified synthesis of sodium, potassium, calcium, piperazine, bis-piperazine, bis-tert-butyl amine salt of bempedoic acid. Further WO’419 fails to disclose synthesis of bempedoic acid from said salts.

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

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.

Bempedoic acid prepared by using sodium, potassium, calcium and piperazine salt of bempedoic acid contains monoethyl ester impurity as only one acid group remained protected. Further bempedoic acid obtained by using its bis-piperazine and bis-tert-butyl salt having very low yield.

Hence, there is a need of efficient process for the preparation of bempedoic acid which avoid the formation of impurities or effectively remove the formed impurities providing the product with high yield and known individual impurity less than 0.15% which meets the regulatory requirement.

The invention relates to a novel diisopropylammonium salt of bempedoic acid, which further converted to bempedoic acid having better yield and known individual impurity less than 0.15%. Further, invention relates to a process for preparation of novel diisopropylammonium salt of bempedoic acid.

SUMMARY OF THE INVENTION:

In one aspect, the invention provides a novel diisopropylammonium salt of bempedoic acid invention of formula II.

Formula II

In another aspect, the invention provides methods of preparing a novel diisopropylammonium salt of bempedoic acid.

In another aspect, the invention provides bempedoic acid having better yield and purity above 99.8% using its novel diisopropylammonium salts.

In another aspect, the invention provides process for preparation of novel diisopropylammonium salts of bempedoic acid and its further conversion to bempedoic acid.

In another aspect, the invention provides crystalline form of diisopropylammonium salts of bempedoic acid of formula II.

In another aspect, the invention provides industrial feasible; one pot process for preparation of bempedoic acid by using novel diisopropylammonium salts of bempedoic acid.

In another aspect, the invention relates to an improved process for the preparation of diisopropylammonium salt of bempedoic acid of formula II

Formula II and its further conversion to bempedoic acid of formula I, comprising;

(a) reacting ethyl isobutyrate and 1,5 -dibromopentane in presence of non-pyrophoric base and a solvent to obtain ethyl 7-bromo-2,2-dimethylheptanoate; (b) reacting ethyl 7-bromo-2,2-dimethylheptanoate and l-(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 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 of formula II using diisopropylamine and acetone; and

(e) purifying the diisopropylammonium salt of bempedoic acid of formula II in presence of the non-pyrophoric reagent and the solvent to obtain the highly pure bempedoic acid.

The process for preparation of pure bempedoic acid is represented in below scheme III.

Scheme III DESCRIPTION OF THE DRAWINGS:

Figure 1 : X-ray diffraction (XRD) pattern of diisopropylammonium salt of bempedoic acid, prepared according to Example 1.4.

Figure 2: IR spectra of diisopropylammonium salt of bempedoic acid, prepared according to Example 1.4.

Figure 3 : HNMR of diisopropylammonium salt of bempedoic acid, prepared according to Example 1.4.

DETAILED DESCRIPTION OF THE INVENTION:

The disclosure in this patent application 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.

Accordingly, the invention relates to a novel diisopropylammonium salt of bempedoic acid of formula II.

The invention provides an improved process for the preparation of diisopropylammonium salt of bempedoic acid of formula II and its further conversion to bempedoic acid of formula I, comprising the steps of; a. reacting ethyl isobutyrate and 1,5 -dibromopentane in presence of a non-pyrophoric base and a solvent to obtain ethyl 7-bromo-2,2- dimethylheptanoate ; b. reacting ethyl 7-bromo-2,2-dimethylheptanoate with l-(isocyanomethanesulfonyl)-4- methylbenzene in presence of a non-pyrophoric reagent and a solvent to obtain intermediate diethyl 8- isocyano-2,2, 14, 14-tetramethyl-8-tosylpentadecanedioate and treating diethyl 8-isocyano-2,2,14,14-tetramethyl-8-tosylpentadecanedioate with acid to obtain diethyl 2,2,14,14-tetramethyl-8-oxopentadecanedioate; c. hydrolyzing diethyl 2,2,14,14-tetramethyl-8-oxopentadecanedioate in presence of the base 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 of formula II using 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.

The invention relates to the process for preparation of diisopropylammonium salt of bempedoic acid and its conversion to bempedoic acid wherein preparation of diisopropylammonium salt of bempedoic acid can be carried out without isolating the intermediate of step (a), (b), (c) and (d).

The non-pyrophoric base used in the step (a) is sodium tert-butoxide and solvent is methyl isobutyl ketone.

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 via formation of an in situ intermediate diethyl 8-isocyano-2,2, 14, 14-tetramethyl-8-tosylpentadecanedioate.

The non-pyrophoric reagent used in the step (b) is selected from sodium tert-butoxide, potassium tert-butoxide, sodium methoxide and sodium ethoxide.

The solvent used in the step (b) is selected from acetone, ethanol, methyl isobutyl ketone, Nodimethyl formamide, water, methylene dichloride and n-heptane. In a most preferred embodiment, reaction between ethyl 7-bromo-2,2-dimethylheptanoate and l-(isocyanomethanesulfonyl)-4-methylbenzene is carried out in presence of sodium tert- butoxide as base and anhydrous N,N-dimethyl formamide as solvent.

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°C to 30°C.

Further, in a preferred embodiment, the in situ intermediate diethyl 8-isocyano-2,2, 14,14- tetramethyl-8-tosylpentadecanedioate is converted into diethyl 2,2,14,14-tetramethyl-8- oxopentadecanedioate 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 is not isolated and purified before conversion into diethyl 2,2, 14, 14-tetramethyl-8-oxopentadecanedioate.

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 is obtained by hydrolysis of diethyl 2,2,14,14-tetramethyl-8-oxopentadecanedioate.

The base used in step-c are selected from sodium hydroxide and potassium hydroxide.

The solvents used in step (c) selected from methanol, ethanol, isopropanol, butanol, ethyl acetate, water and the combination thereof.

The reaction in step-c is carried out at a temperature in range of 15°C to 85°C and for a time duration of 8 to 9 hours.

In step-d, wherein 2,2,14,14-tetramethyl-8-oxopentadecanedoic acid obtained in step-c is reduced and further converted into diisopropylammonium salt of bempedoic acid wherein diisopropylammonium salt of bempedoic acid is in crystalline form. The non-pyrophoric agent used in the step (d) is sodium borohydride.

The solvent used in step (d) is selected from methanol, ethanol, isopropanol, butanol, ethyl acetate, water and a combination thereof.

The reaction in step-d is carried out preferably at a temperature in range of 15°C to 45°C and for a time duration of 6.5 to 8.5 hours.

In step-e, wherein diisopropylammonium salt of bempedoic acid of formula II obtained in step- d is converted into highly pure bempedoic acid of formula I, wherein the diisopropylammonium salt of bempedoic acid of formula II is preferably treated with hydrochloric acid in presence solvent.

In the most preferred embodiment, the solvents used in step (e) is 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°C to 50°C and for a time duration of 24 to 27 hours.

Further, according to another aspect, the invention relates novel diisopropylammonium salt of bempedoic acid of formula II.

The diisopropylammonium salt of bempedoic acid according to the invention has a characteristic IR spectrum as shown in Figure-2 and IR values are one or more of 3401.22 cm" \ 3038.09 cm’ ¹ , 2981.86 cm’ ¹ , 2927.85 cm’ ¹ , 2854.20 cm’ ¹ , 2794.64 cm’ ¹ , 2410.92 cm’ ¹ , 1617.44 cm’ ¹ , 1533.83 cm’ ¹ , 1495.01 cm’ ¹ , 1469.88 cm’ ¹ , 1395.20 cm’ ¹ , 1362.80 cm’ ¹ , 1333.04 cm’ ¹ , 1306.46 cm’ ¹ , 1282.47 cm’ ¹ , 1249.75 cm’ ¹ , 1204.78 cm’ ¹ , 1168.10 cm’ ¹ , 1153.55 cm’ ¹ , 1106.92 cm’ ¹ , 1068.22 cm’ ¹ , 1015.28 cm’ ¹ , 986.63 cm’ ¹ , 941.29 cm’ ¹ , 869.23 cm’ ¹ , 824.82 cm’ \ 805.76 cm , 789.74 cm ⁴ , 755.95 cm ⁴ , 721.39 cm ⁴ , 590.93 cm ⁴ , 542.57 cm ⁴ , 522.21 cm ⁴ , 469.47 cm ⁴ .

In one embodiment, the particle size distribution Dv(50) of diisopropylammonium salt of bempedoic acid is ranging from 20 pm to 40 pm. In the preferred embodiment, the particle size distribution Dv(50) of diisopropylammonium salt of bempedoic acid is ranging from 30 pm to 35 pm.

In another embodiment, the particle size distribution Dv(90) of diisopropylammonium salt of bempedoic acid is ranging from 70 pm to 100 pm.

In the preferred embodiment, the particle size distribution Dv(90) of diisopropylammonium salt of bempedoic acid is ranging from 85 pm to 95 pm.

It is known in the art that solubility of drug substance and its impurity is differs in different solvent. Therefore, skilful selection of solvent for isolation of drug substance to get desire yield and purity is critical aspect in process chemistry.

There are several impurities known in the art for bempedoic acid which needs separation at each step of synthesis. However, it was found that impurities and intermediates of bempedoic acid are having higher solubility in common solvents like acetone, makes it difficult to prepare highly pure bempedoic acid. Specifically, the bempedoic acid salts (which is one step before the final synthesis of bempedoic acid), disclosed in the prior art showed higher solubility in various commonly used solvents like acetone. Therefore, selection of intermediates, especially the salt of bempedoic acid having low solubility in common solvent like acetone is important to achieve highly pure ingredient.

The inventor of the invention found that diisopropylammonium salt of bempedoic acid has very low solubility in acetone solvent. Therefore, yield and purity of bempedoic acid obtain by using diisopropylammonium salt better than prior art processes.

In an embodiment bempedoic acid obtained by using invention having purity more than 99.85% with any known individual impurity less than 0.15%.

In the preferred embodiment, bempedoic acid obtained by using invention having any individual known impurity less than 0.05%.

In the most preferred embodiment, any individual known impurity is not detected in the bempedoic acid which is obtained by using process of the invention. Yet another aspect of the invention provides crystalline form of diisopropylammonium salt bempedoic acid. In another aspect of the invention provides diisopropylammonium salt bempedoic acid, wherein at least 50% of the salt is in crystalline form.

A powder X-ray powder diffraction pattern as depicted in Figure 1 characterizes the crystalline form of diisopropylammonium salt bempedoic acid of the invention.

Another aspect of the invention provides a crystalline form of diisopropylammonium salt of bempedoic acid of formula II, wherein the X-ray powder diffraction (XRPD) pattern having peaks at 2 theta values 11.35±0.2, 13.40±0.2, 18.85±0.2, 19.30±0.2, 20.35±0.2, 24.65±0.2.

Another aspect of the invention crystalline form of bempedoic acid having PXRD characteristic peaks, d-spacing and relative intensity shown in below Table III.

Another aspect of the invention provides a diisopropylammonium salt of bempedoic acid of formula II used in preparation of bempedoic acid, wherein bempedoic acid is having purity more than 99.85% with individual impurity not more than 0.15% and the high purity is achieved without column chromatography purification.

Yet another aspect of the invention provides a diisopropylammonium salt of bempedoic acid of formula II is having a total impurity less than 1.0% and the amount of one or more impurities selected from the group diol impurity, ketone impurity, acetate impurity, dimer impurity, monoethyl ester impurity and diethyl ester impurity is less than about 0.15%, about 0.125%, about 0.1%, about 0.075%, about 0.05%, about 0.025%, about 0.01%, about 0.001%, or about 0.0001% by weight based on the total weight of the diisopropylammonium salt.

Another aspect of the invention provides a diisopropylammonium salt of bempedoic acid of formula II is having a total impurity less than 1.0% and the amount of the one or more unidentified impurities in the diisopropylammonium salt is less than about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, or about 0. 1% by weight based on the total weight of the diisopropylammonium salt.

Another aspect of the invention provides a diisopropylammonium salt of bempedoic acid of formula II used in preparation of bempedoic acid, wherein bempedoic acid is having a total impurity less than 1.0% and the amount of one or more impurities selected from the group diol impurity, ketone impurity, acetate impurity, dimer impurity, monoethyl ester impurity and diethyl ester impurity is less than about 0.15%, about 0. 125%, about 0.1%, about 0.075%, about 0.05%, about 0.025%, about 0.01%, about 0.001%, or about 0.0001% by weight based on the total weight of bempedoic acid.

Another aspect of the invention provides a diisopropylammonium salt of bempedoic acid of formula II used in preparation of bempedoic acid is having a total impurity less than 1.0% and the amount of the one or more unidentified impurities in the diisopropylammonium salt is less than about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07% , about 0.08%, about 0.09%, or about 0.1% by weight based on the total weight of the diisopropylammonium salt.

The solid bempedoic acid obtained through the synthesis process disclosed herein has purity level of more than 99.85% due to skilful 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 (DIP A) 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 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. 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 ml of N,-N-Dimethyl formamide in a 4 neck round bottom flask (4NRBF) under constant stirring. 14 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°C 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 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 HC1 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°C 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 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 25g 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 200ml 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 HC1. 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°C 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°C 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.

Particle size:

Dv (50) - 31.4 pm

Dv (90) - 90.1 pm

Characterisation of diisopropylammonium salt of bempedoic acid:

H ¹ NMR (400 MHz, MEOD/TMS): 5 (ppm): 1.086 [s, 12 H, (4 -CH3)], 1.29-1 ,27[d, 36 H,(8- CH3 & 6-CH2)], 1.446-1.372[m, 12 H,( 4-CH2 & 2-NH2)] 3.401-3.368 [m, 4 H, (4-CH)], 3.468-3.433 [m, 1H, (1-OH)]

Melting point: 110.6°C

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 HC1 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.