DESC:“A PROCESS FOR PREPARATION OF BEMPEDOIC ACID
AND ITS INTERMEDIATES”

FIELD OF THE INVENTION

The present invention relates to an improved, commercially viable and industrially advantageous process for the preparation of Bempedoic acid (I) with good yield and high purity via dicyclohexylamine salt of Bempedoic acid (5). The present invention also related to a process for the preparation of ethyl 7-Iodo-2,2-dimethylheptanoate (2a). The present invention also provides to process for the preparation of dicyclohexylamine salt of Bempedoic acid (5) & The present invention also provides to a crystalline form of dicyclohexylamine salt of Bempedoic acid (5).

BACKGROUND OF THE INVENTION

Bempedoic acid, chemical entitled 8-Hydroxy-2,2,14,14-tetramethyl-pentadecanedioic acid. Bempedoic acid is a small molecule inhibitor of adenosine triphosphate-citrate lyase (ACL), an enzyme upstream of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase in the cholesterol biosynthesis pathway. Bempedoic acid is a prodrug that requires activation in liver to bempedoic acid-coenzyme A, which mediates competitive inhibition of ACL. Inhibition of ACL by bempedoic acid-coenzyme A decreases cholesterol synthesis in the liver leading to increased low-density lipoprotein receptor (LDLR) expression and LDL particle clearance from the blood. Therefore, inhibition of ACL by bempedoic acid-coenzyme A decreases low-density lipoprotein cholesterol (LDL-C) via the same pathway as HMG-CoA reductase inhibition by statins. An important differentiating feature of bempedoic acid is that, unlike statins, it does not inhibit cholesterol synthesis in skeletal muscle. The enzyme required to convert bempedoic acid to bempedoic acid-coenzyme A is not present in skeletal muscle. Therefore, bempedoic acid is not anticipated to mediate the adverse effects associated with inhibition of biological intermediates within the cholesterol biosynthesis pathway in skeletal muscle.

Bempedoic acid is a once-daily LDL-C lowering agent in phase 3 clinical trials. In phase 1 and 2 studies, bempedoic acid was efficacious in lowering LDL-C when used as monotherapy and when added to a statin and/or ezetimibe and was well tolerated in patients with statin intolerance. Its structural formula is as follows:

Bempedoic acid is reported in US 7335799 by Esperion Therapeutics Inc. The synthetic process for Bempedoic acid is reported in US ‘799, which comprises, compound of formula (I) is treated with ethyl isobutyrate in presence of LDA (Lithium diisopropylamide)/THF (tetrahydrofuran) to obtain formula (2). The compound of formula (2) is treated with p-toluenesulfonyl methyl isocyanide in present of TBAI (tetra-n-butylammonium iodide)/NaH (sodium hydride)/ DMSO (Dimethyl sulfoxide) to obtain compound of formula (3).

The above process is schematically shown as below:

IN 201941011853 of Dr. Reddy’s reported process for the preparation of Bempedoic acid (I), which comprises the compound of formula (4) is reduced in presence of NaBH4 / THF and water to obtain the compound of formula (6). The compound of formula (6) is hydrolysed in presence of EtOH / KOH / H2O / HCl, 10% EtOAc and hexanes to obtain Bempedoic acid (I).

The above process is schematically shown as below:

US 2021/0139401 A1 of Esperion, disclosed a process for the preparation of Bempedoic acid (I), which comprises the compound of formula (I) is reacted with formula (II) in presence of base to obtain compound of formula (III). The compound of formula (III) is treated with a salt of formula [M]+[X-] to obtain compound of formula (IV). The compound of formula (IV) is treated with toluenesulfonylmethyl isocyanide in the presence of base to obtain compound of formula (V). The compound of formula (V) is treated with acid, followed by treated with reducing agent and hydrolyzing base to obtain Bempedoic acid (I).
The above process is schematically shown as below:

The processes taught by prior art have several drawbacks namely not suitable for scale up at plant level, difficult, giving lower yields and less user friendly. Considering the drawbacks of prior art for the preparation of the Bempedoic acid, the present invention is simple, economical, financially cheaper plant friendly process, environment friendly process for the preparation of Bempedoic acid with better yields and purity.
There is always need for alternative preparative routes, which for example use reagents, solvents that are less expensive and/or easier to handle, consume smaller amounts of reagents and solvents provide a higher yield of product, have smaller and/or eco-friendly waste products and/or provide a product of higher purity.

Aforesaid reasons above there is a need to produce Bempedoic acid synthetically by industrially applicable method to ensure the availability with high purity. Hence, there is consequently a need development for new methods to sort out prior art existing methods. So, our inventors have developed a novel method for the preparation of Bempedoic acid. The present invention is providing a simple, eco-friendly with high purity and good yield on industrial applicable process.

The present invention is to provide an improved process for preparation of Bempedoic acid, which is free from associated impurities and does not utilize column chromatography or other purification methods.

OBJECTIVE OF THE INVENTION
The present invention relates to an improved, commercially viable and industrially advantageous process for the preparation of Bempedoic acid (I) with good yield and high purity via dicyclohexylamine salt of Bempedoic acid (5).

An objective of the present invention is to provide a process for the preparation of ethyl 7-Iodo-2,2-dimethylheptanoate (2a).

SUMMARY OF THE INVENTION
The present invention relates to an improved, commercially viable and industrially advantageous process for the preparation of Bempedoic acid (I) with good yield and high purity via dicyclohexylamine salt of Bempedoic acid (5).

The present invention also related to a process for the preparation of ethyl 7-Iodo-2,2-dimethylheptanoate (2a).

One embodiment of the present invention relates to an improved process for the preparation of Bempedoic acid (I).

which comprises:
a) the compound of formula (1) is reacted with ethyl isobutyrate in presence of base and solvent to obtain compound of formula (2),

b) the compound of formula (2) is iodinated with iodinating agent to obtain compound of formula (2a),

c) the compound of formula (2a) is reacted with p-toluenesulfonyl methyl isocyanide in presence of alkali metal hydride to obtain compound of formula (3), followed by treated with an acid to obtain compound of formula (4),

d) the compound of formula (4) is hydrolysed with potassium hydroxide (KOH) in presence of solvent to obtain compound of formula (4a),

e) the compound of formula (4a) is reduced with reducing agent, followed by neutralization with an acid to give bempedoic acid,

f) optionally treated with Bempedoic acid dicyclohexylamine (DCHA) in presence of solvent to obtain dicyclohexylamine (DCHA) salt of bempedoic acid (5),

g) optionally compound of formula (5) is treated with an inorganic base in presence of solvent, followed by neutralisation with an acid to obtain Bempedoic acid (I).

The second embodiment of the present invention relates to process for the preparation of ethyl 7-Iodo-2,2-dimethylheptanoate (2a), comprising the steps of:
a) the compound of formula (1) is reacted with ethyl isobutyrate in presence of base and solvent to obtain compound of formula (2),

b) the compound of formula (2) is reacted with an iodinating agent to obtain compound of formula (2a),

The third embodiment of the present invention relates to a process for the preparation of dicyclohexylamine (DCHA) salt of Bempedoic acid (5), comprising the steps of:
a) Bempedoic acid is treated with dicyclohexylamine (DCHA) in presence of solvent,
to obtain dicyclohexylamine (DCHA) salt of Bempedoic acid,
b) optionally, addition of aprotic solvent and
c) isolating crystalline form dicyclohexylamine (DCHA) salt of Bempedoic acid.

The fourth embodiment of the present invention relates to crystalline form of dicyclohexylamine (DCHA) salt of Bempedoic acid (5).

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1: PXRD of dicyclohexylamine salt of Bempedoic acid (5).

The fifth embodiment of the present invention relates to a process for the preparation of Bempedoic acid comprising the steps of:
a) The compound of formula (4) is hydrolysed with KOH in presence of solvent to obtain compound of formula (4a),

b) The compound of formula (4a) is reduced with reducing agent, followed by treated with an acid to obtain Bempedoic acid,

c) Optionally Bempedoic acid purified with solvent.

DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to an improved, commercially viable and industrially advantageous process for the preparation of Bempedoic acid (I) with good yield and high purity via dicyclohexylamine salt of Bempedoic acid (5).

The present invention also related to a process for the preparation of ethyl 7-Iodo-2,2-dimethylheptanoate (2a).

One embodiment of the present invention relates to an improved process for the preparation of Bempedoic acid (I).

which comprises:
a) the compound of formula (1) is reacted with ethyl isobutyrate in presence of base and solvent to obtain compound of formula (2),

b) the compound of formula (2) is iodinated with iodinating agent to obtain compound of formula (2a),

c) the compound of formula (2a) is reacted with p-toluenesulfonyl methyl isocyanide in presence of alkali metal hydride to obtain compound of formula (3), followed by treated with an acid to obtain compound of formula (4),

d) the compound of formula (4) is hydrolysed with potassium hydroxide (KOH) in presence of solvent to obtain compound of formula (4a),

e) the compound of formula (4a) is reduced with reducing agent, followed by neutralization with an acid to give bempedoic acid,

f) optionally Bempedoic acid treating with dicyclohexylamine (DCHA) in presence of solvent to obtain dicyclohexylamine (DCHA) salt of bempedoic acid (5),

g) optionally compound of formula (5) is treated with an inorganic base in presence of solvent, followed by neutralisation with an acid to obtain Bempedoic acid (I).

The process according to the embodiment of the present invention, step a) involves the compound of formula (1) is reacted with ethyl isobutyrate in presence of base and solvent to obtain compound of formula (2). The reaction may be carried out at temperatures ranging from about -5°C to about 80°C., or from about -20°C to about -30°C for about 10 min to 2 hours. In a particular embodiment, the compound of the formula (1) is reacted with ethyl isobutyrate in the presence of THF, diisopropylamine, n-butyllithium in hexane to obtain a compound of formula (2).

The process according to the embodiment of the present invention, Step b) involves the
compound of formula (2) is reacted with Iodinating agent in presence of solvent to give compound of formula (2a). The reaction may be carried out at temperatures ranging from 25 - 30°C or 80-90°C for about for 15-20 hours. The iodinating agent wherein is selected from the group consisting of Tetrabutylammonium iodide, tri ethyl benzyl ammonium iodide and Ammonium Iodide. The solvent selected from dichloromethane, dichlorethane, 2-Butanone, THF, DMF, acetonitrile and acetone.

The process according to the embodiment of the present invention, Step c) involves the compound of formula (2a) is reacted with p-toluenesulfonyl methyl isocyanide and treated with alkali metal hydride base in presence of aprotic solvent to obtain compound of formula (3). The preferred alkali metal hydrides bases include but not limited to sodium hydride, potassium hydride and aprotic solvent selected from dichloromethane, dichlorethane, 2-Butanone, THF, DMF, acetonitrile. The reaction may be carried out at temperatures ranging from about 20°C to about 55°C., or from about -40 to -50°C for 4-5 hours. In a particular embodiment, the compound of the formula (2a) is reacted with p-toluenesulfonyl methyl isocyanide in presence of DMSO, Sodium hydride to give a compound of formula (3). The resulted compound of formula (3) was treated with Con hydrochloric acid and maintained for 60 to 100 mins at 10-40°C to obtain compound of formula (4).

The process according to the embodiment of the present invention, Step d) involves hydrolysed compound of formula (4) with potassium carbonate in presence of solvent to obtain compound of formula (4a). The reaction may be carried out at temperatures ranging from about 50°C to about 55°C for 10 to 20 mins or 6-8 hours. In a particular embodiment, the compound of the formula (4) is hydrolysed with potassium hydroxide in the presence of ethanol and water to give a compound of formula (4a).

The process according to the embodiment of the present invention, Step e) involves compound of formula (4a) is treated with reducing agent in presence of solvent followed treated with acid and further treated with dicyclohexylamine (DCHA) in presence of aprotic solvent to obtain compound of formula (5). The reaction may be carried out at temperatures ranging from about 50 to 55°C for 1-4 or 6-8 hours. The reducing agent selected from sodium borohydride, potassium borohydride, lithium tetrahydridoaluminate, sodium cyanoborohydride, sodium triacetoxyborohydride and lithium cyanoborohydride. In a particular embodiment, the compound of the formula (4a) treated with sodium borohydride then adjusting the pH with con hydrochloric acid in presence of water to obtain Bempedoic acid, which is further treated with dicyclohexylamine (DCHA) in presence of ethyl acetate. The precipitated solid was filtered at 20-40°C to obtain compound of formula (5).

The process according to the embodiment of the present invention, Step f) involves compound of formula (5) is treated with inorganic base in presence of solvent to give salt of Bempedoic acid, followed by treated with an acid in presence of solvent to obtain Bempedoic acid.
The reaction may be carried out at temperatures ranging from about at 20 to 35°C for 10 to 60 mins. The compound of the formula (5) treated with inorganic base wherein is selected from sodium hydroxide, potassium hydroxide (KOH), ammonium hydroxide and potassium tert-butoxide. In a particular embodiment, the compound of the formula (5) treated with sodium hydroxide in the presence of dichloromethane and followed by treated with hydrochloric acid in presence of methyl tert butyl ether to get Bemepedoic acid (I).

Optionally, the bempedoic solid can be isolated by the removal of solvents from the solution, suspension or dispersion obtained from step g) by techniques known in the art such as distillation, evaporation, oven drying, tray drying, rotational drying (such as the Buchi Rotavapor), spray drying, freeze-drying, fluid bed drying, flash drying, spin flash drying and Ultrafilm agitated thin film dryer-vertical (ATFD-V), hot melt extrusion (HME) and the like.

The process according to the embodiment of the present invention, Step g) involves the resulting Bempedoic acid (I) is purified by using solvent to obtain pure Bempedoic acid. The reaction may be carried out at temperatures ranging from about at 50 to 55°C or 15-20 °C or 25-30°C for 10 to 60 mins or 15-20 min. Bempedoic acid purified with solvent, wherein the solvent is selected form methanol, ethanol, acetone, methyl isobutyl ketone, ethyl methyl ketone, dichloromethane, chloroform, carbon tetrachloride, methyl acetate and ethyl acetate.
The solution of bempedoic acid can be filtered to remove any insoluble particles. The solution may be filtered by passing through paper, glass fiber, or other membrane material, or a bed of a clarifying agent such as Celite® or Hyflow. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization. In a particular embodiment, Bempedoic acid is purified by ethyl acetate to obtain pure Bemepedoic acid.

The second embodiment of the present invention relates to process for the preparation of ethyl 7-Iodo-2,2-dimethylheptanoate (2a), comprising the steps of:
a) the compound of formula (1) is reacted with ethyl isobutyrate in presence of base and solvent to obtain compound of formula (2),

b) the compound of formula (2) is iodinated with iodinating agent to give compound of formula (2a).

The process according to the embodiment of the present invention, step a) involves the compound of formula (1) is reacted with ethyl isobutyrate in presence of base and solvent to obtain compound of formula (2). The reaction may be carried out at temperatures ranging from about -5°C to about 80°C., or from about -20°C to about -30°C for about 10 min to 2 hour. In a particular embodiment, the compound of the formula (1) is reacted with ethyl isobutyrate in the presence of THF/diisopropylamine, n-butyllithium/hexane to obtain a compound of formula (2).

The process according to the embodiment of the present invention, Step b) involves the
compound of formula (2) is reacted with iodinating agent in presence of solvent to give compound of formula (2a). The reaction may be carried out at temperatures ranging from 25 - 30°C or 80-90°C for about for 15-20 hours. The iodinating agent wherein is selected from the group consisting of Tetrabutylammonium iodide, tri ethyl benzyl ammonium iodide and Ammonium Iodide. The aprotic solvent selected from dichloromethane, dichlorethane, 2-Butanone, THF, DMF, acetonitrile and acetone.

The third embodiment of the present invention relates to a process for the preparation of dicyclohexylamine salt of Bempedoic acid (5), comprising the steps of:
a) Bempedoic acid treating with dicyclohexylamine (DCHA) in solvent, and
b) isolating dicyclohexylamine (DCHA) salt of Bempedoic acid.

The process according to the embodiment of the present invention involves Bempedoic acid is treated a solvent, followed treated with dicyclohexylamine (DCHA) in presence of aprotic solvent to obtain dicyclohexylamine (DCHA) salt of Bempedoic acid. The reaction may be carried out at temperatures ranging from about 20 to 55°C for 1-2 or 2-3 hours. In a particular embodiment, Bempedoic acid treated with dicyclohexylamine (DCHA) in presence of ethyl acetate to get dicyclohexylamine (DCHA) salt of Bempedoic acid crude, which is precipitated and filtered at 20-40°C to get pure dicyclohexylamine (DCHA) salt of Bempedoic acid.

The fourth embodiment of the present invention relates to crystalline form of dicyclohexylamine salt of Bempedoic acid (5).

According to the embodiment of the present invention, the crystalline form of dicyclohexylamine 2,2,14,14-tetramethyl-8-oxo pentadecanedioate (5) has an X-ray powder diffraction (XRPD) pattern including diffraction peaks at 5.49, 7.95, 9.04, 9.31, 9.85,16.72, 17.11, 17.71, 17.91, 18.21, 18.63, 18.84, 19.73 and 20.04 (2?±0.2°). The Cu Ka radiation is expressed in degrees 2?.

According to the embodiment of the present invention, the crystalline form of dicyclohexylamine 2,2,14,14-tetramethyl-8-oxo pentadecanedioate (5) may have an XRPD pattern including diffraction peaks at 5.49, 7.95, 9.04, 9.31, 9.85,16.72, 17.11, 17.71, 17.91, 18.21, 18.63, 18.84, 19.73, 20.04, 20.33, 20.61 and 21.25 (2?±0.2°).

According to the embodiment of the present invention, the crystalline form of dicyclohexylamine 2,2,14,14-tetramethyl-8-oxo pentadecanedioate (5) may have an XRPD pattern of FIG. 1.

According to the embodiment of the present invention, the XRPD pattern might have been be measured by using Cu-Ka or Cu-Kß radiation, more particularly, Cu-Ka radiation, even more particularly, Cu-Ka1, Cu-K a2, Cu-Kß, or Cu-K a1 and Cu-K a2 radiation. For example, the XRPD pattern might have been be measured by using Cu-Ka radiation.
According to the embodiment of the present invention, process for the preparation of Bempedoic acid (I) with good yield and high purity having = 99.5%.

The fifth embodiment of the present invention relates to a process for the preparation of crystalline form of dicyclohexylamine (DCHA) salt of Bempedoic acid (5), comprising the steps:
a) Dicyclohexylamine (DCHA) salt of bempedoic acid with aprotic solvent,
b) Isolating crystalline form dicyclohexylamine (DCHA) salt of Bempedoic acid.

The process according to the embodiment of the present invention, involves the resulting compound of Dicyclohexylamine (DCHA) salt of bempedoic acid treating with aprotic solvent followed by isolating the crystalline form of dicyclohexylamine (DCHA) salt of Bempedoic acid. The aprotic solvent selected from group consisting of aprotic solvents such as dimethyl acetamide, dimethylsulfoxide, dimethylformamide and ethyl acetate. In a particular embodiment, the resulting compound of dicyclohexylamine (DCHA) salt of bempedoic acid with ethyl acetate followed by isolation to obtain crystalline dicyclohexylamine (DCHA) salt of Bempedoic acid (5).

The sixth embodiment of the present invention relates to a process for the preparation of Bempedoic acid comprising the steps of:
a) the compound of formula (4) is hydrolysed with KOH in presence of solvent to obtain compound of formula (4a),

b) the compound of formula (4a) is reduced with reducing agent, followed by treated with an acid to obtain Bempedoic acid,

c) the Bempedoic acid optionally purified with solvent.

The process according to the embodiment of the present invention, step a) involves hydrolysed compound of formula (4) with potassium carbonate in presence of solvent to obtain compound of formula (4a). The reaction may be carried out at temperatures ranging from about 50°C to about 55°C for 10 to 20 mins or 6-8 hours. In a particular embodiment, the compound of the formula (4) is hydrolysed with potassium hydroxide in the presence of one or more solvents comprising an alcohol selected from the group consisting of methanol, ethanol, isopropanol and butanol; or a mixture thereof with water to give a compound of formula (4a).

The process according to the embodiment of the present invention, step b) involves compound of formula (4a) is treated with reducing agent in presence of solvent followed by treated with acid to obtain Bempedoic acid. The reaction may be carried out at temperatures ranging from about 50 to 55°C for 1-4 or 6-8 hours. The reducing agent selected from group consisting of sodium borohydride, potassium borohydride, lithium tetrahydridoaluminate, sodium cyanoborohydride, sodium triacetoxyborohydride and lithium cyanoborohydride. In a particular embodiment, the compound of the formula (4a) treated with sodium borohydride and adjusted the pH with conc. hydrochloric acid in presence of water and purified by dichloromethane to obtain Bempedoic acid.

The process according to the embodiment of the present invention, wherein iodinating agent is selected from the group consisting of Tetrabutylammonium iodide, tri ethyl benzyl ammonium iodide and Ammonium Iodide.

The process according to the embodiment of the present invention, wherein the base is selected from diisopropylethylamine, n-butyllithium. triethylamine, pyridine, dimethyl amino pyridine (DMAP), diethyl amino pyridine (DEAP) and N-methyl morpholine or mixture thereof.

The process according to the embodiment of the present invention, wherein the alkali metal hydride base is selected from sodium hydride, potassium hydride and lithium hydride.

The process according to the embodiment of the present invention, wherein the inorganic base is sodium hydroxide (NaOH), sodium hydroxide solution, potassium hydroxide (KOH), ammonium hydroxide and potassium tert-butoxide.

The process according to the embodiment of the present invention, wherein the salt of Bempedoic acid is selected from sodium, potassium, lithium and calcium.

The process according to the embodiment of the present invention, wherein the solvent is alcohols such as methanol, ethanol, isopropyl alcohol, and the like or mixture thereof; ketones, such as methyl isobutyl ketone, methyl ethyl ketone, n-butanone, and the like; halogenated solvents, such as dichloromethane (MDC), ethylene dichloride, chloroform, and the like; esters, such as ethyl acetate, n-propyl acetate, isopropyl acetate, and the like; hydrocarbon solvents, such as toluene, xylene, cyclohexane, heptane, hexane and the like; ethers, such as methyl tert-butyl ether (MTBE), diethyl ether, di-tert-butyl ether, ethyl tert-butyl ether, diisopropyl ether, 1,4-dioxane, tetrahydrofuran (THF), and the like; amides such as N,N-dimethylformamide (DMF), ?,?-dimethylacetamide and the like or dimethylsulfoxide (DMSO), hexamethyl phosphoramide (HMPA), N,N-dimethylacetamide (DMA), N-methyl-2-pyrrolidone (NMP) or water mixture of solvents thereof.

The process according to the embodiment of the present invention, wherein the acid is hydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, trichloroacetic acid, acetic acid, hydrobromic acid and mixture (s) thereof.

The process according to the embodiment of the present invention, wherein the reducing agent is sodium borohydride, potassium borohydride, lithium tetrahydridoaluminate, sodium cyanoborohydride, sodium triacetoxyborohydride and lithium cyanoborohydride.

Bempedoic acid of the present invention may have high permeability, low solubility, may be remarkably stable at the accelerated conditions and long-term storage conditions and may be stably maintained with no change in content for long term. Accordingly, the Bempedoic acid of the present invention may be obtained as a raw material having high purity and may maintain high purity and its Bempedoic acid for long term even when stored for long periods of time.
In addition, Bempedoic acid of the present invention may be obtained in high purity and yield and may be therefore easily applicable for mass production and commercial purposes.
Bempedoic acid of the present invention may remarkably stable and therefore may have an excellent pharmacological effect, making it useful as an active ingredient for preventing or treating a disease selected from the group consisting of lifestyle changes (diet, weight-loss, exercise) and certain cholesterol-lowering medications (HMG-CoA reductase inhibitors [statins]) to further decrease low-density lipoprotein (LDL) cholesterol ('bad cholesterol') in the blood of adults.
Bempedoic acid may be formulated into a form selected from the group consisting of powder, granule, tablet, capsule, suspension, emulsion, syrup, aerosol, ointment, cream, suppository, eye drop, and injection according to conventional formulation methods recognized by those skilled in the art.
The above overall process is schematically shown as below:

The following examples illustrate the present invention, but should not be construed as limiting the scope of the invention.

Advantages of the present invention:
1. The present invention provide a simple, cost effective process for the preparation of Bempedoic acid with high purity and good yield on eco-friendly, commercially viable and industrial applicable process.
2. The present invention is to provide a process for preparation of ethyl 7-Iodo-2,2-dimethylheptanoate (2a), free from impurities by utilizing an ammonium iodide iodinating agent.
3. Isolation of crystalline dicyclohexylamine (DCHA) salt of Bempedoic acid (5), which is free from impurities and does not utilize column chromatography or other purification methods.

EXAMPLES
Example 1: Preparation of ethyl 7-chloro-2,2-dimethylheptanoate

Tetrahydrofuran (200 ml) and diisopropyl amine (87.2 gm) taken in to flask under nitrogen atmosphere, it allows to cool -20 to -30°C and slowly added with n-butyl lithium (2.5 M) in hexanes (343.0ml) at -20 to -30°C. ethyl Isobutyrate (100 g, 0.86 mol) added into reaction mixture and stir for 2 hr at -20°C, the obtained reaction solution added to 1-bromo-5-chloro pentane (151 g, 0.817 eq) and stir for 30-60 min. After completion of the reaction, the reaction mass was quenched with water (100ml) and the reaction mass pH was adjusted to 6-7 by using 3N Hydrochloric acid (980 ml), layers are separated. The organic phase was washed with saturated sodium chloride (1200 ml) and the organic layer was concentrated under reduced pressure to get crude material. Pure compound was isolated by fractional distillation, 82~95°C at 1torr vacuum to obtain title compound ethyl 7-chloro-2,2-dimethylheptanoate (2) (170 g).

Example 2: Preparation of ethyl 7-chloro-2,2-dimethylheptanoate (2)

Tetrahydrofuran (200 ml) and ethyl Isobutyrate (100 g, 0.86 mol) taken in to flask under nitrogen atmosphere, the reaction mass was cooled to -20 to -30°C. Then added 2.5M n-butyl lithium in hexanes (343ml), ethyl isobutyrate (100 g, 0.86 mol) added into reaction mixture and stir for 2 hr at -20°C, the obtained reaction solution added to 1-bromo-5-chloro pentane (151 g, 0.817 Eq) and stir for 30-60 min. After completion of the reaction, the reaction mass was quenched with water (100ml) and the reaction mass pH was adjusted to 6-7 by using 3N Hydrochloric acid (980 ml), layers are separated. The organic phase was washed with saturated sodium chloride (1200 ml) and the organic layer was concentrated under reduced pressure to get crude material. Pure compound was isolated by fractional distillation at 180 Pa, 82~95°C at 1torr vacuum to obtain title compound ethyl 7-chloro-2,2-dimethylheptanoate (2) (170 g).

Example 3: Preparation of ethyl 7-Iodo-2,2-dimethylheptanoate (2)

Acetonitrile (500 ml) and ethyl 7-chloro -2,2-dimethylheptanoate (100 g, 1.0 mol Eq) taken in to flask under nitrogen atmosphere at 25 to 30 °C. Then added ammonium Iodide (80.0 gm, 1.20 mol Eq) into reaction mass at 25 - 30°C, raise the reaction mass at temperature to 80-85°C, and stir the reaction mass for 5-20 hours at 80-90°C. After completion of the reaction, the reaction mass was cooled to 50°C. Then the solvent was distilled out under reduced pressure at below 50°C. Cool the reaction residue to 25-30°C. Charge the toluene and water, Stir the reaction mass for 10 min and settle the reaction mass for 20 min. Separate two layers, take toluene layer into the flask and wash the layer with sodium dithionate aqueous solution. separate two layers, take organic layer into the flask and washed with saturated sodium chloride solution, separate two layers, take toluene layer into the flask and distilled out toluene under reduced pressure at below 60°C. Cool the residual product to 25 -30° C to obtain ethyl 7-Iodo-2,2-dimethylheptanoate (2) (130 g).
Purity: 95.0%
Yield: 92.0%

Example 4: Preparation of ethyl 7-Iodo-2,2-dimethylheptanoate (2)

Acetonitrile (500 ml) and ethyl 7-chloro-2,2-dimethylheptanoate (100 g, 1.0 mol Eq) taken in to flask, the reaction mass was cooled to 25 to 30°C. Then add tri ethyl benzyl ammonium iodide (100.0 gm) into reaction mass at 25 - 30°C, raise the reaction mass at temperature to 80-85°C, and stir the reaction mass for 5-20 hours at 80-90°C. After completion of the reaction, the reaction mass was cooled to 50°C. Then the solvent was distilled out under reduced pressure at below 50°C. Cool the reaction residue to 25-30°C. Charge toluene and water, Stir the reaction mass for 10 min and settle the reaction mass for 20 min. Separate two layers, take toluene layer into the flask and washed with sodium dithionate aqueous solution. separate two layers, take organic layer into the flask and washed with saturated sodium chloride solution. separate two layers, take toluene layer into the flask and distilled out toluene under reduced pressure at below 60°C. Cool the residual product to 25 -30°C to obtain ethyl 7-Iodo-2,2-dimethylheptanoate (2) (130 g).
Purity: 95.0%
Yield: 92.0%

Example 5: Preparation of ethyl 7-Iodo-2,2-dimethylheptanoate (2)

Acetonitrile (500 ml) and ethyl 7-chloro-2,2-dimethylheptanoate (100 g, 1.0 mol Eq) taken in to flask, the reaction mass was cooled to 25 to 30°C. Then added Tetra butyl ammonium Iodide (100.0 gm) into reaction mass at 25-30°C, raise the reaction mass at temperature to 80-85°C, and stir the reaction mass for 15-20 hours at 80-90°C. After completion of the reaction, the reaction mass was cooled to 50°C. Then the solvent was distilled out under reduced pressure at below 50°C. Cool the reaction residue to 25-30°C. Charge the toluene and water, stir the reaction mass for 10 min and settle the reaction mass for 20 min. Separate two layers, take toluene layer into the flask and wash the layer with sodium dithionate aqueous solution. separate two layers, take organic layer into the flask and wash the layer with saturated sodium chloride solution. separate two layers, take toluene layer into the flask and distilled out toluene under reduced pressure at below 60°C. Cool the residual product to 25 -30° C to obtain ethyl 7-Iodo-2,2-dimethylheptanoate (2) (130 g).
Yield: 92.0%.
Purity: 95.0%

Example 6: Preparation of 2,2,14,14-tetramethyl-8-oxo-pentadecandioic acid diethyl ester (4)
Ethyl 7-iodo-2,2-dimethylheptanoate (2) (100g, 0.32 mole) and toluenesulfonyl methyl isocyanide (TOSMIC) of (31.3g, 0.16 mole) were taken in DMSO (400 ml) and the resulting reaction mixture was cooled to -40 to -50°C, sodium hydride (15.4 g, 0.384 mole) was added slowly, the reaction mass temperature was raised and maintained for 4-5 hrs at -40 to -50°C. After completion of the reaction, water (400 ml) and toluene (400 ml) were added, then layer separation, the organic layer was treated with con hydrochloric acid (100 ml) at 15-20°C and maintained for 60-90 min at 25-30°C. After completion of the reaction, separate the layers and toluene (600 ml) layer washed with 10% sodium hydroxide solution with 15% NaCl solution (400 ml) and finally after layer separation, the upper organic phase is concentrated under reduces pressure at below 50°C to get 2,2,14,14-tetramethyl-8-oxo-pentadecandioic acid diethyl ester (4) (64g).
Purity: 85.0%
Yield: 100%.

Example 7: Preparation of dicyclohexylamine hemi(8-hydroxy-2,2,14,14- tetramethylpentadecanedioate) (5)
A solution of KOH (116.4 g, 2.007 mole) in water (200 ml) was added to a solution of 2,2,14,14-tetramethyl-8-oxo-pentadecandioic acid diethyl ester (4) (100g, 0.250 mole) in ethanol (600 ml), then heated at reflux for 6-8 hrs. After completion of the reaction, the solution was evaporated at below 55°C, then diluted with water (500 ml). The organic impurities were removed by extracting with dichloromethane (300 ml). The aqueous layer was treated with 2.3 g (0.062 moles) of sodium borohydride and the reaction was continued for 4 hrs. After completion of the reaction, reaction mass was washed with ethylacetate (200 ml). Then, reaction mass adjusted pH to 4-5 by using conc. hydrochloric acid (~60ml). After stirring the reaction mass for 10 min, crude was extracted with methyl tert-butyl ether (250ml*2) and the organic layer was washed with 10% sodium chloride solution (500 ml). The organic layer was concentrated under reduced pressure and diluted with ethyl acetate (800 ml), then DCHA was added and stirred for 1-2 hr at 25-30°C. The precipitated solid was filtered at 25-30°C to get DCHA salt of Bempedoic acid (5) (108g).
Purity: 98.0%
Yield: 60%

Example 8: Preparation of Bempedoic acid (I)

Dicyclohexylamine (DCHA) salt of Bempedoic acid (100g, 0.141 mole) was charged into sodium hydroxide solution (16.92 g, 0.423 mole) (NaOH dissolved in 480 ml of water) at 25-30°C, then stirring was continued until all after dissolving at 25-30°C for 30 minutes and the reaction mass was washed with MDC (200ml). Then, reaction mass adjusted pH to 4-5 by using con hydrochloric acid (~60ml). After stirring the reaction mass for 10 min, crude was extracted with methyl tert-butyl ether (250ml*2) and the organic layer was washed with 10% sodium chloride solution (500 ml), then dried over sodium sulphate (10g). The organic layer was concentrated under reduced pressure and the obtained crude material was recrystallized from ethyl acetate (150ml) to get Bempedoic acid (I) (24g).
Purity: 99.5%
Yield: 50%

Example-9: Purification of Bempedoic acid
Bempedoic acid crude (100g, 0.29 moles) and ethyl acetate (300 ml) were taken at temperature of 25-30°C. The reaction mass temperature was raised to 50-55°C and the reaction mass was maintained at 50-55°C for 15-20 min to get clear solution. The reaction mass was cooled to 5-10°C and the precipitated solid was filtered at 5-10°C and unload wet material. The wet material and ethyl acetate (180 ml) were taken at 25-30°C. The reaction mass temperature was raised to 50-55°C and the reaction mass was maintained for 15-20 min at 50-55°C to get clear solution. Activated charcoal (5g) was added to reaction mass and maintained for 25-30 min at 50-55°C. The reaction mass was filtered through hyflo bed and filtrate was cooled to 15-20°C and the precipitated solid was filtered at 15-20°C and dried to get pure Bempedoic acid (60 g).
Purity: 99.8%

Example 10: Preparation of Bempedoic acid
A solution of KOH (116.4 g, 2.007 mole) in water (200 mL) was added to a solution of 2,2,14,14-tetramethyl-8-oxo-pentadecandioic acid diethyl ester (4) (100g, 0.250 mole) in ethanol (600 mL), The reaction mass heated to reflux temperature for 6-8 hrs. After completion of the reaction, the solution was evaporated at below 55°C, then diluted with water (500 mL). The organic impurities were removed by extracting with dichloromethane (300 ml). The aqueous layer was treated with sodium borohydride (2.3 g, 0.062 moles) and the reaction was continued for 4 hrs. After completion of the reaction, reaction mass was washed with ethyl acetate (200ml). Then, reaction mass adjusted pH to 4-5 by using con. hydrochloric acid (~60ml). After stirring for 10 min, crude was extracted with dichloromethane (250ml*2) and the organic layer was washed with 10% sodium chloride solution (500 ml). The organic layer was concentrated under reduced pressure. The obtained crude was taken in ethyl acetate (200 ml), then heated to 50-55°C and stirred for 10-20 min and cool the reaction mass to 25-30°C and further cool to 0-5°C, then filtered the solid material to get Bempedoic acid (43.5g).
Purity: 99.7%
Yield: 50%

,CLAIMS:We claim:
1. An improved process for the preparation of Bempedoic acid (I).

which comprises steps of:
a) the compound of formula (1) is reacted with ethyl isobutyrate in presence of base and solvent to obtain compound of formula (2),

b) the compound of formula (2) is reacted with iodinating agent to obtain compound of formula (2a),

c) the compound of formula (2a) is reacted with p-toluenesulfonyl methyl isocyanide in presence of alkali metal hydride to obtain compound of formula (3), followed by treated with an acid to obtain compound of formula (4),

d) the compound of formula (4) is hydrolyzed with potassium hydroxide (KOH) in presence of solvent to obtain compound of formula (4a),

e) the compound of formula (4a) is reduced with reducing agent, followed by neutralization with an acid to give bempedoic acid,

f) optionally treated with Bempedoic acid dicyclohexylamine (DCHA) in presence of solvent to obtain dicyclohexylamine (DCHA) salt of bempedoic acid (5),

g) optionally compound of formula (5) is treated with an inorganic base in presence of solvent, followed by neutralisation with an acid to obtain Bempedoic acid (I).

2. The process as claimed in claim 1, wherein the base is selected from the group of inorganic bases or organic bases comprising diisopropylamine, n-butyllithium, triethylamine, pyridine, dimethyl amino pyridine (DMAP), diethyl amino pyridine (DEAP) and N-methyl morpholine, sodium hydroxide (NaOH), sodium hydroxide solution, potassium hydroxide (KOH), ammonium hydroxide and potassium tert-butoxide.

3. The process as claimed in claim 1, wherein the iodinating agent is selected from Tetrabutylammonium iodide, tri ethyl benzyl ammonium iodide and Ammonium Iodide.

4. The process as claimed in claim 1, wherein the alkali metal hydrides is selected from sodium hydride or potassium hydride.

5. The process claimed in claim 1, wherein the reducing agent selected from group consisting of sodium borohydride, potassium borohydride, lithium tetrahydridoaluminate, sodium cyanoborohydride, sodium triacetoxyborohydride and lithium cyanoborohydride.
6. The process claimed in claim 1, wherein the solvent selected from methanol, ethanol, isopropyl alcohol, methyl isobutyl ketone, methyl ethyl ketone, n-butanone, dichloromethane (MDC), ethylene dichloride, chloroform, ethyl acetate, n-propyl acetate, isopropyl acetate, toluene, xylene, cyclohexane, heptane, acetonitrile, hexane, methyl tert-butyl ether (MTBE), diethyl ether, di-tert-butyl ether, ethyl tert-butyl ether, diisopropyl ether, 1,4-dioxane, tetrahydrofuran (THF), dichlorethane, 2-Butanone, DMF, acetonitrile, N,N-dimethylformamide (DMF), ?,?-dimethylacetamide, dimethylsulfoxide (DMSO), hexamethyl phosphoramide (HMPA), N,N-dimethylacetamide (DMA), N-methyl-2-pyrrolidone (NMP) or water mixture of solvents thereof.

7. The process claimed in claim 1, wherein the acid is hydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, trichloroacetic acid, acetic acid, hydrobromic acid and mixture (s) thereof.

8. A process for the preparation of ethyl 7-Iodo-2,2-dimethylheptanoate (2a), comprising the steps of:
a) the compound of formula (1) is reacted with ethyl isobutyrate in presence of base and solvent to obtain compound of formula (2),

b) the compound of formula (2) is iodinated with Ammonium iodide to give compound of formula (2a).

9. The process as claimed in claim 8, wherein the base is selected from diisopropylamine, n-butyllithium, triethylamine, pyridine, dimethyl amino pyridine (DMAP), diethyl amino pyridine (DEAP) and N-methyl morpholine.
10. The process claimed in claim 8, wherein the solvent selected from methanol, ethanol, isopropyl alcohol, methyl isobutyl ketone, methyl ethyl ketone, n-butanone, dichloromethane (MDC), ethylene dichloride, chloroform, ethyl acetate, n-propyl acetate, isopropyl acetate, toluene, xylene, cyclohexane, heptane, acetonitrile, hexane, methyl tert-butyl ether (MTBE), diethyl ether, di-tert-butyl ether, ethyl tert-butyl ether, diisopropyl ether, 1,4-dioxane, tetrahydrofuran (THF), dichlorethane, 2-Butanone, DMF, acetonitrile, acetone, N,N-dimethylformamide (DMF), ?,?-dimethylacetamide, dimethylsulfoxide (DMSO), hexamethyl phosphoramide (HMPA), N,N-dimethylacetamide (DMA), N-methyl-2-pyrrolidone (NMP) or water mixture of solvents thereof.