DESC:TITLE: AN IMPROVED PROCESS FOR PREPARATION OF BEMPEDOIC ACID

FIELD OF THE INVENTION:
The present invention relates to an improved process for the preparation of Bempedoic acid compound of formula I and its intermediates which is industrially advantageous and economically significant.

BACKGROUND OF THE INVENTION:
Bempedoic acid is chemically known as 8-hydroxy-2, 2, 14, 14-
tetramethylpentadecanedioic acid and its chemical structure is depicted below in
Formula (I).

Bempedoic acid is an ATP Citrate Lyase inhibitor that reduces cholesterol biosynthesis and lowers LDL-C by up-regulating the LDL receptor. 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.

The U.S. patent no.7, 335,799 (hereafter US ‘799) first describes preparation of Bempedoic acid. The process as disclosed in US ‘799 comprises reacting 7-bromo-2,2-dimethylheptanoic acid ethyl ester with p-toluenesulfonyl methyl isocyanide in presence of anhydrous DMSO solvent, sodium hydride and phase transfer catalyst to obtain crude 8-isocyano-2.2.1.4,14-tetramethyl-8- (toluene-4-Sulfonyl)-pentadecanedioic acid diethyl ester as oil, further addition of concentrated HCl followed by column chromatography purification to obtain 2.2.1.4,14-tetramethyl-8-oxo-pentadecanedioic acid diethyl ester as a colorless oil, further hydrolysis by addition of potassium hydroxide, followed by crystallization using mixture of hexane and MTBE solvents to obtain 8-oxo-2,2,14,14 tetramethylpentadecanedioic acid, further reduction using sodium borohydride to obtain Bempedoic acid as viscous oil.
The following scheme-1 describes the process of Bempedoic acid in example 6.19 and 6.20 as given in US ‘799.

The Indian patent application IN201821049982 (hereafter IN ‘982) discloses preparation of Bempedoic acid in many ways. One such process for preparation of Bempedoic acid is depicted in Scheme-2.

The European patent application EP 3,666,750 (hereafter EP ‘750) discloses the process for preparation of Bempedoic acid comprising reacting 7-Bromo-2,2-dimethylheptanoic acid ethylester with Tosylmethylisocyanide in presence of tetrabutylammonium iodide, sodium hydride and DMO solvent to obtain 8-isocyano-2,2,14,14-tetramethyl-8-(toluene-4-Sulfonyl)-pentadecanedioic acid diethyl ester, further addition of concentrated HCl followed by purification by column chromatography to obtain 2,2,14,14-tetramethyl-8-oxopentadecanedioic acid diethyl ester as yellow oil, Further reduction by NaBH4 to obtain crude 8-Hydroxy-2,2,14,14-Tetramethylpentadecanedioic acid diethyl ester, further hydrolysis by potassium hydroxide to obtain Bempedoic acid.

The following scheme-3 describes the process for preparation of Bempedoic acid in EP ‘750.

The Prior art process for the preparation of Bempedoic acid suffer from disadvantages since the processes involve tedious and cumbersome procedures such as multiple crystallizations or isolation steps, column chromatographic purifications and thus resulting in low overall yields of the product. Bempedoic acid obtained by the processes described in the prior art does not have satisfactory purity and unacceptable amounts of impurities are formed along with Bempedoic acid at various stages of the processes that are difficult to purify and affecting the purity of final compound.

Therefore, there is a need to provide a cost effective and commercially viable process for the improved process preparation of Bempedoic acid and its intermediates which is industrially advantageous and economically significant.

OBJECT OF THE INVENTION:
The primary object of the present invention is to provide a simple, economic safe industrially viable process for preparation of Bempedoic acid compound of formula I.

Yet another object of the present invention is to provide improved process for preparation of Bempedoic acid compound of formula I having high purity and high yield.
Another one object of the present invention is to provide improved process for preparation of compound of formula III.

One more object of the present invention is to provide improved process for preparation of compound of formula IV by avoiding purification by column chromatography.

Another one object of the present invention is to provide improved process for preparation of compound of formula V.

One more object of the present invention is to provide purification process of Bempedoic acid compound of formula I.

Another one object of the present invention provides preparation of crystalline polymorphic form of Bempedoic acid compound of formula I.

SUMMARY OF THE INVENTION:
ASPECT-I:
The first aspect of the present invention is to provide process for preparation of compound of formula III

comprising the step of:
a) reacting compound formula II

with Tosylmethylisocyanide in aromatic hydrocarbon or ether solvent in presence of suitable base and suitable phase transfer catalyst to obtain compound of formula III.

ASPECT-II:
Second aspect of the present invention is to provide a process for preparation of compound of formula IV

comprising the steps of:
b) reacting compound of formula III with suitable acid at suitable temperature;
c) isolating compound of formula IV from the reaction mixture of step b); and
d) purifying the compound of formula IV using an organic solvent.
ASPECT-III:
Third aspect of the present invention is to provide a process for preparation of compound of formula V

comprising the steps of:
e) reacting compound of formula IV with base at suitable temperature; and
f) isolating compound of formula V from a nitrile or an ether solvent or mixture thereof.

Another aspect of the present invention provides a novel polymorphic form of formula V, which is isolated by the process of aspect-III.

ASPECT-IV:
Fourth aspect of the present invention is to provide a process for the preparation of Bempedoic acid compound of formula I

comprising the steps of:
a) reacting compound formula II

with Tosylmethylisocyanide in hydrocarbon or ether solvent in presence of base and phase transfer catalyst at suitable temperature to obtain compound of formula III;

b) reacting compound of formula III with acid at suitable temperature;
c) isolating compound of formula IV from the reaction mixture of step b);
d) purifying compound of formula IV using an organic solvent.

e) reacting compound of formula IV with base at suitable temperature;
f) isolating compound of formula V in suitable nitrile or ether solvent or mixture thereof.

g) reacting compound of formula V with reducing agent in presence of base; and
h) isolating Bempedoic acid compound of formula I in suitable solvent.

ASPECT-V:
The fifth aspect of the present invention is to provide a process for preparation of Bempedoic acid compound of formula I,

comprising the steps of:
g) reacting compound of formula V

with reducing agent in presence of base; and
h) isolating Bempedoic acid from dichloromethane solvent.

ASPECT-VI:
The sixth aspect of the present invention is to provide a process for purification of Bempedoic acid compound of formula I,

comprising the steps of:
i) treating Bempedoic acid compound of formula I in a mixture of organic solvents;
j) heating reaction mixture of step i) at suitable temperature; and
k) cooling the reaction mixture of step j) and isolating Bempedoic acid compound of formula I.

Another aspect of the present invention provides preparation of crystalline polymorphic form of Bempedoic acid compound of formula I.

DEFINITION
All percentages and ratios used herein are by weight of the total composition and all measurements made are at 25ºC and normal pressure unless otherwise designated.
All temperatures used herein are in degrees Celsius unless specified otherwise.
All ranges recited herein include the endpoints, including those that recite a range "between" two values.
As used herein, "comprising" means the elements recited, or their equivalents in structure or function, plus any other element or elements that may or may not be recited.
The terms "having" and "including" are also to be construed as open ended unless the context suggests otherwise.

BRIEF DESCRIPTION OF DRAWINGS:
1. Fig 01 represents PXRD diffractogram of Bempedoic acid obtained as per example 05;
2. Fig 02 represents PXRD diffractogram of Bempedoic acid obtained as per example 07;
3. Fig 03 represents PXRD diffractogram of Bempedoic acid obtained as per example 08;

DETAILED DESCRIPTION:
The inventors of the present invention have found that by employing the improved conditions of the present invention helped them in achieving the Bempedoic acid compound of formula I in high yield and purity.
Further the inventors have developed a process which avoids the use of column chromatography in the entire process to prepare Bempedoic acid. In particular, the compound of formula IV is purified using an organic solvent rather than purifying it by column chromatography.
Further, the improved process conditions of the present invention resulted in high purity of the intermediate compounds of Bempedoic acid such as compounds of formulae III, IV & V. These high purity of Intermediate compounds in turn enabled the isolation of Bempedoic acid in its solid form when isolated from Dichloromethane solvent.
The improved process for preparation of Bempedoic acid compound of formula I as per the present invention is summarized in the following schematic representation scheme-4.

The starting material of formula II of the present invention is commercially available or can be prepared by the prior art process such as the process as described in, but not limited to, US 8,629,271B2 which is incorporated herein for reference purpose only.
In one embodiment, present invention provides a process for preparation of compound of formula III

comprising the step of:
a) reacting compound formula II

with Tosylmethylisocyanide in aromatic hydrocarbon or ether solvent in presence of suitable base and suitable phase transfer catalyst at suitable temperature to obtain compound of formula III.
In the preferred embodiments of step a), the aromatic hydrocarbon solvent is selected from, but not limited to, toluene, xylene and chlorobenzene and mixtures thereof. More preferably, the aromatic hydrocarbon solvent is Toluene.
In the embodiments of step a), the ether solvent is selected from but not limited to tetrahydrofurane (THF), dioxane, dimethyl ether, diethyl ether, methyl t-butyl ether, diethylene glycol dimethyl ether, diisopropyl ether. More preferably, ether solvent is tetrahydrofurane.
In the embodiments of step a), the suitable base is selected from, but not limited to, NaH, n-butyllithium, lithium diisopropylamide, LiHMDS, LiTMP, potassium tert-butoxide and mixtures thereof. More preferably, the base is potassium tert-butoxide.
In the embodiments of step a), the suitable phase transfer catalyst is selected from, but not limited to, tetra-n-butyl ammonium bromide (TBAB), tetra-n-butyl ammonium fluoride (TBAF), tetra-n-butyl ammonium chloride (TBAC), tetra-n-butyl ammonium iodide (TBAI), tetra-n-butyl ammonium hydrogen bromide (TBAHB) and), tetra-n-butyl ammonium nitrite. More preferably, the phase transfer catalyst is tetra-n-butyl ammonium iodide (TBAI)).
In the embodiments of step a) the reaction may be suitably carried out at a temperature of about 10°C to about 40°C, preferably at about 25°C to about 35°C for sufficient period of time to complete the reaction, preferably for 0.5 to 6 hrs, more preferably for 2 to 3 hrs.
In an embodiment of step a), the product of compound of formula III obtained can optionally be used without isolating before proceeding to further steps.
Second embodiment of the present invention provides a process for preparation of compound of formula IV

comprising the steps of:
b) reacting compound of formula III with suitable acid at suitable temperature;
c) isolating compound of formula IV from the reaction mixture of step b); and
d) purifying the compound of formula IV using an organic solvent.

In the embodiments of step b), the suitable acid may be conc. HCl and reaction be suitably carried out at a temperature of about 10°C to about 40°C, preferably at about 25°C to about 35°C for sufficient period of time to complete the reaction, preferably for 0.5 to 7 hrs, more preferably for 1 to 4 hrs.

In the embodiments of step c), the product compound of formula IV formed can be isolated by the techniques known in the art such as cooling the reaction mass followed by filtration etc. or extracting the product into organic layer followed by distillation to get residue etc.

In the embodiments of step d), the suitable solvent is selected from, but 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 dichloromethane, chloroform, carbon tetrachloride, and chlorobenzene; C5-C7 alkanes such as pentane, isopentane, n-hexane, n-heptane and more thereof. More preferably C5-C7 alkanes, preferably n-heptane.

In the embodiment of step d) the product of compound of formula IV obtained can optionally be used without isolating in further steps.

Third embodiment of the present invention is to provide process for preparation of compound of formula V

comprising the steps of:
e) reacting compound of formula IV with base at suitable temperature; and
f) isolating compound of formula V from a nitrile or an ether solvent or mixture thereof.

In the embodiments of step e) the base may be selected from, but not limited to, inorganic bases or organic amino bases, such as guanidine or pyridine. Preferably, the base is selected from inorganic bases, in particular metal hydroxides and ammonium hydroxide. Among the metal hydroxides, metal hydroxides of alkali or earth alkali metals are preferred. More preferred are alkali earth metal hydroxides LiOH, NaOH, KOH, RbOH and CsOH, even more preferred is KOH.

In the embodiments of step e), the reaction may be suitably carried out at a temperature of about 20°C to about 90°C, preferably at about 75°C to about 85°C for sufficient period of time to complete the reaction, preferably for 1 to 10 hrs, more preferably for 2 to 4 hrs.

In the embodiments of step f), the nitrile solvent may be selected from, but not limited to, acetonitrile, butyronitrile, isobutyronitrile or mixture thereof, more preferably acetonitrile; ether solvent is selected from but not to tetrahydrofuran (THF), 2-methyl tetrahydrofuran, dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether (MTBE) or mixture thereof, more preferably methyl tert-butyl ether

In the embodiment of step f) the product of compound of formula V obtained can optionally be used in further steps without isolating.

In some embodments, the compound of formula V is optionally purified using a nitrile or an ether solvent or a mixture thereof; preferably using the mixture of nitrile and ether solvents.

Another embodiment of the present invention is to provide a novel crystalline polymorphic form of formula V which is obtained as per the process of the present invention.

Fourth embodiment of the present invention is to provide a process for preparation of Bempedoic acid compound of formula I

comprising the steps of:
a) reacting compound formula II

with Tosylmethylisocyanide in hydrocarbon or ether solvent in presence of base and phase transfer catalyst at suitable temperature to obtain compound of formula III;

b) reacting compound of formula III with acid at suitable temperature;
c) isolating compound of formula IV from the reaction mixture of step b);
d) purifying the compound of formula IV using an organic solvent.

e) reacting compound of formula IV with base at suitable temperature;
f) isolating compound of formula V from a nitrile or an ether solvent or mixture thereof.

g) reacting compound of formula V with reducing agent in presence of base; and
h) isolating Bempedoic acid compound of formula I in suitable solvent.

In the preferred embodiments of steps a) to h) of the above fourth embodiment, the reaction conditions such as reaction solvent, temperature, isolation techniques etc are preferably same as the preferable conditions as described for embodiments 1, 2 & 3 for the respective stages.

Fifth embodiment of the present invention is to provide a process for preparation of Bempedoic acid compound of formula I,

comprising the steps of:
g) reacting compound of formula V

with reducing agent in presence of base; and
h) isolating Bempedoic acid from dichloromethane solvent.

In the embodiments of step g), the reducing agent is selected from triacetoxy sodium boron hydride, triacetoxy tetramethylammonium borohydride, sodium cyanoborohydride, sodium borohydride, lithium borohydride, trimethoxy sodium boron hydride, tris ethyl lithium borohydride, borohydride reagents, lithium aluminum hydride, diisopropyl aluminum hydride, bis (2-methoxyethoxy) aluminum hydride, sodium aluminum hydride reagent, using a metal catalyst and a hydrogen source in the catalytic reduction or mixtures thereof, More preferably sodium borohydride.

In the embodiments of step g), the base is selected from, but not limited to, inorganic bases or organic amino bases, such as guanidine or pyridine. Preferably, the base is selected from inorganic bases, in particular metal hydroxides and ammonium hydroxide. Among the metal hydroxides, metal hydroxides of alkali or earth alkali metals are preferred. More preferred are alkali earth metal hydroxides LiOH, NaOH, KOH, RbOH and CsOH, even more preferred is NaOH.

Sixth embodiment of the present invention is to provide process for purification of Bempedoic acid compound of formula I,

comprising the steps of:
i) treating Bempedoic acid compound of formula I in a mixture of organic solvents;
j) heating the reaction mixture of step i) at suitable temperature; and
k) cooling the reaction mixture of step j) and isolating Bempedoic acid compound of formula I.

In the embodiments of step i), the suitable solvent may be selected from, but not limited to, alcohols such as methanol, ethanol, isopropanol, n-propanol, tertiary-butyl alcohol; ketone solvents such as acetone, methyl isobutyl ketone, ethyl methyl ketone; chlorinated solvents such as dichloromethane, chloroform, carbon tetrachloride; esters such as methyl acetate, ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate; ether solvents such as tetrahydrofuran, 2-methyl tetrahydrofuran, dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether; nitriles such as acetonitrile, butyronitrile, isobutyronitrile, polar aprotic solvents such as dimethyl acetamide, dimethylsulfoxide, dimethylformamide, N-methyl-2-pyrrolidone, water or a mixture thereof. Preferably mixture of solvent is chlorinated solvent and ether, more preferably mixture solvent is dichloromethane and methyl tert-butyl ether.

In the embodiments of step j) the reaction mass can be heated to a temperature of about 20°C to about 50°C, preferably at about 35°C to about 45°C.

In the embodiments of step k), the isolated Bempedoic acid is in its crystalline form.

EXAMPLES:
The following examples are illustrative of some of the embodiments of the present invention described herein. These examples should not be considered to limit the spirit or scope of the invention in any way.

Example 01:
Preparation of ethyl 7-bromo-2,2-dimethylheptanoate [Compound of formula II]
Under Nitrogen atmosphere charged tetrahydrofuran (2000 ml) and Diisopropyl amine (350 g) to the round bottomed flask. Cooled the reaction mass to -5 to +5°C. Slowly charged n-butyl lithium (1500 ml) to the reaction mass. Cooled the reaction mass to -70°C to -80°C. Charged slowly Ethyl Isobutyrate (400 gm) to the reaction mass followed by 1,5-Dibromobutane (800 gm). Maintained the reaction mass for 1 hr at -70°C to -80°C. Raised the temperature up to room temperature, maintained for 3 hrs and charged slowly ammonium chloride solution (3000 ml) followed by ethyl acetate. Separated the layers followed by sodium chloride washing of the organic layer and the organic layer was distilled out under vacuum. The obtained residue was further purified by High vacuum distillation to get pure ethyl 7-bromo-2,2-dimethylheptanoate.
Yield: 516 gm.

Example 02:
Preparation of diethyl 2,2,14,14-tetramethyl-8-oxopentadecanedioate [Compound of formula IV]
Under nitrogen atmosphere charged THF 750 ml to the round bottom flask. Charged ethyl 7-bromo-2,2-dimethylheptanoate [Compound of formula II] (150 gms) to the reaction mass, TBAI (20.8 gms) and p-Toluenesulfonyl methyl isocyanide (55.2 g). Charged lot-wise potassium tert-butoxide (76.1 gm) to the reaction mass at temperature 0-10°C. After completion of the reaction, added ice water (2250 ml). The product was extracted with Methylene Dichloride (750 ml) to obtain compound of formula III.
Charged organic layer in to RBF, charged conc. hydrochloric acid (500 ml) and stirred the reaction mass. After completion of reaction, added water to the reaction mass followed by washing with sodium bicarbonate solution. The final organic layer was distilled out under vacuum to get residue oil. The residue oil was purified by adding n-Heptane to the residue followed by addition of Hyflo powder and subsequent removal of the hyflo powder by filtration and finally distilling the organic layer under vacuum at not less than 700mm Hg at a temperature less than 60°C. The title compound diethyl 2,2,14,14-tetramethyl-8-oxopentadecanedioate [Compound of formula IV] was obtained as an oily residue.
Yield: 97.8 gm.

Example 03:
Preparation of diethyl 8-isocyano-2,2,14,14-tetramethyl-8-tosylpentadecanedioate [Compound of formula III]
Under nitrogen atmosphere charged toluene 20 ml to the round bottom flask. Charged ethyl 7-bromo-2,2-dimethylheptanoate 2.0 gm to the reaction mass followed by Tetra butyl ammonium Iodide (0.27 gms) and p-Toluenesulfonyl methyl isocyanide (0.73 gms). Charged lot wise potassium tert butoxide 1.0 gm to the reaction mass at temperature 0-10°C. After completion of the reaction, added ice water (10 ml). The product was extracted with toluene (3X 20 ml). The combine organic layers were washed with water (20 ml) and saturated NaCl solution (20 ml) and organic layer was used in the next step without purification.

Example 04:
Preparation of 2,2,14,14-tetramethyl-8-oxopentadecanedioic acid [Compound of formula V]
To the clean and dry round bottom flask charged ethanol (165 ml), potassium hydroxide solution (24.72 gm in 44 ml water). Charged diethyl 2,2,14,14-tetramethyl-8-oxopentadecanedioate [Compound of formula IV] (11.0 gm) to the reaction mass and heated the mass up to 75-85°C for 3-4 hrs. After completion of the reaction ethanol was distilled out under vacuum. Charged process water and MDC. Stirred the reaction mass and separated the layers. Aqueous layer was acidified with con HCl and product was extracted in MDC. The organic layer was again washed with NaCl solution and distilled out under vacuum. To the residue added acetonitrile, heated to get clear solution and cooled to room temperature. The product was isolated by filtration to get 2,2,14,14-tetramethyl-8-oxopentadecanedioic acid [Compound of formula IV]
Yield: 4.5 gms.
Purity: 98.16%.

Example 05:
Preparation of 8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid [Compound of formula I]
In 4-Neck round bottomed flask, charged water 495 ml and 2,2,14,14-tetramethyl-8-oxopentadecanedioic acid [Compound of formula V] [55 gms] and cooled the reaction mass up to 0-10°C. Slowly charged a solution of sodium hydroxide 67.84 gm to the reaction mass. Added lot wise sodium borohydride to the reaction mass. Maintained the mass for 5 hrs. After completion of the reaction added MDC to the reaction, separated the layers. Aq. Layer was acidified with con HCl and extracted in Methyl tertiary butyl ether. The organic layer was further washed with sodium chloride solution. The organic layer was distilled out and the title compound was isolated from Dichloromethane by dissolving the residue in Methylene Dichloride at 40-45°C followed by cooling and filtration to get the solid material.
Yield: 46.3 gms.

Example 06:
Purification of 8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid [Compound of formula I]
Charged MDC (20 ml) in to RBF. Charged 8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid [Compound of formula I] (2 gm) in to RBF, charged slowly THF (2 ml) to the reaction mass and heated to get clear solution. Cooled to 25-35°C, filtered the mass, washed with acetonitrile and dried.
Yield: 1.6 gms
Purity: 99.60%.

Example 07:
Purification of 8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid [Compound of formula I]
Charged MDC (450 ml) in to RBF, charged 8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid [Compound of formula I] (45 g) in to RBF and heated to get clear solution, charged slowly MTBE (67.5 ml) to the reaction, cooled to 25-35°C, Filtered the mass, washed with MDC and dried weight of the solid 37.2 gm.
Yield: 37.2 gm
Purity: 99.89%

Example 08:
Purification of 8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid [Compound of formula I]
Charged Methyl Tertiary Butyl Ether (50 ml) in to RBF. Charged 8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid [Compound of formula I] (10 g) in to RBF and heated to get clear solution. Charged slowly water (50 ml) to the reaction. Distiled out the solventmixture under vacuum at 40 – 50°C. Added water (50 ml) to the residue followed by cooling to 20 – 30°C. Filtered the product and dried.
Yield: 9.0 gm
Purity: 99.89%

Dated this 08th day of November, 2021.

Dr. Mayur Khunt,
Sr. Vice-President R&D,
ZCL Chemicals Ltd. ,CLAIMS:We claim:
1. A process for preparation of compound of formula III

comprising the step of:
a) reacting compound formula II

with Tosylmethylisocyanide in aromatic hydrocarbon or ether solvent in presence of suitable base and suitable phase transfer catalyst to obtain compound of formula III.

2. A process for preparation of compound of formula IV

comprising the steps of:
b) reacting compound of formula III with suitable acid at suitable temperature;
c) isolating compound of formula IV from the reaction mixture of step b); and
d) purifying the compound of formula IV using an organic solvent.

3. The process according to claim 2 wherein the organic solvent is a C3-C7 alkane solvent.

4. A process for preparation of compound of formula V

comprising the steps of:
e) reacting compound of formula IV with base at suitable temperature; and
f) isolating compound of formula V from a nitrile or an ether solvent or mixture thereof.

5. The process according to claim 4 wherein the compound of formula V is isolated from the mixture of nitrile and ether solvent.

6. A process for preparation of Bempedoic acid of formula I,

comprising the steps of:
g) reacting compound of formula V

with reducing agent in presence of base; and
h) isolating Bempedoic acid from dichloromethane solvent.

7. The process according to claim 6 wherein the Bempedoic acid isolated from dichloromethane is in solid form.

8. A process for purification of Bempedoic acid of formula I:

comprising the steps of:
i) treating Bempedoic acid compound of formula I in a mixture of organic solvents;
j) heating reaction mixture of step i) at suitable temperature; and
k) cooling the reaction mixture of step j) and isolating Bempedoic acid compound of formula I.

9. The process according to claim 8 wherein the mixture of organic solvents is selected from the mixture of two or more of chlorinated solvents, ether solvents and water.

Dated this 8th day of November, 2021

Dr. Mayur Khunt,
Sr. Vice-President – R&D,
ZCL Chemicals Ltd.