DESC:“IMPROVED PROCESS FOR PREPARATION OF BEMPEDOIC ACID”

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 using dicyclohexylammonium 2,2,14,14-tetramethyl-8-oxo pentadecanedioate (5a).

The present invention also related to a novel compound of dicyclohexylammonium 2,2,14,14-tetramethyl-8-oxo pentadecanedioate (5a).

The present invention also provides to a crystalline form of dicyclohexylammonium 2,2,14,14-tetramethyl-8-oxo pentadecanedioate (5a).

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), which is treated with hydrochloric acid/ dichloromethane to obtain compound of formula (4). The compound of formula (4) is treated with KOH (potassium hydroxide)/EtOH (ethanol) to obtain compound of formula (5). The compound of formula (5) convert into Bempedoic acid (I) in presence of NaBH4 (Sodium borohydride)/MeOH (methanol).

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:

CN 111285760 B of Nanjing Baimai Biotechnology Co., Ltd., reported a process for the preparation of Bempedoic acid (I), which comprises the compound of formula (10) is reacted with the compound of formula (9) to obtain the compound of formula (8). The compound of formula (8) is reacted with the compound of formula (7) to obtain the compound of formula (5). The compound of formula (5) is reduced with NaBH4 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
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 using dicyclohexylammonium 2,2,14,14-tetramethyl-8-oxo pentadecanedioate (5a). The present invention also related to a novel compound of dicyclohexylammonium 2,2,14,14-tetramethyl-8-oxo pentadecanedioate (5a). The present invention also provides to a crystalline form of dicyclohexylammonium 2,2,14,14-tetramethyl-8-oxo pentadecanedioate (5a).

SUMMARY OF THE INVENTION

The present disclosure provides an improved, commercially viable and industrially advantageous process for the preparation of Bempedoic acid (I) with good yield and high purity using dicyclohexylammonium 2,2,14,14-tetramethyl-8-oxo pentadecanedioate (5a). A compound of dicyclohexylammonium 2,2,14,14-tetramethyl-8-oxo pentadecanedioate (5a) and a crystalline form of dicyclohexylammonium 2,2,14,14-tetramethyl-8-oxo pentadecanedioate (5a).

The one embodiment of the present invention provides an improved process for the preparation of Bempedoic acid (I) comprising:

a) The compound of formula (1) is reacted with ethyl isobutyrate in presence of organic base and solvent to obtain compound of formula (2),

b) The compound of formula (2) is reacted with p-toluenesulfonyl methyl isocyanide in presence of alkali metal hydride base, quaternary ammonium salt and solvent to obtain compound of formula (3), followed by treated with acid to obtain compound of formula (4),

c) The compound of formula (4) is hydrolysed with inorganic base in presence of solvent and followed by reacted with Dicyclohexyl amine (DCHA) to obtain compound of formula (5a), and

d) The compound of formula (5a) is treated with inorganic base, followed by reduced with reducing agent in presence of solvent to obtain Bempedoic acid (I).

The second embodiment of the present provides a novel compound of t2,2,14,14-tetramethyl-8-oxo pentadecanedioate (5a).

The third embodiment of the present invention a crystalline form of dicyclohexylammonium 2,2,14,14-tetramethyl-8-oxo pentadecanedioate (5a).

The fourth embodiment of the present invention provides, process for the preparation of Bempedoic acid (I) with good yield and high purity having = 99.7%.

In fifth embodiment of the present invention provides the following characterization data of dicyclohexylammonium 2,2,14,14-tetramethyl-8-oxo pentadecanedioate (5a):

1H-NMR: 2.783-2.774, 2.371-2.335, 1.970-1.951, 1.778-1.765, 1.652-1.575, 1.485-1.448, 1.277-1.156 and 1.124 (ppm) as depicted in Figure 1
13H-NMR: 211.315, 183.082, 52.314, 42.681, 42.339, 41.360, 29.957, 26.093, 25.387, 25.099, 24.848 and 23.854 (ppm) as depicted in Figure 2
IR: 3417.41, 2936.2, 1718.03 (CM-1) as depicted in Figure 3

In sixth embodiment of the present invention provides, particle size distribution of the Bempedoic acid may have from D10 = 10 µm, D50 = 200 µm and D90 = 300µm, the particle size of the Bempedoic acid may have confirmed very fine. The Bempedoic aid can proceed directly to the formulation without further processing, such as milling.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1: 1H-NMR of dicyclohexylammonium 2,2,14,14-tetramethyl-8-oxo pentadecanedioate (5a)

Figure 2: 13H-NMR of dicyclohexylammonium 2,2,14,14-tetramethyl-8-oxo pentadecanedioate (5a)

Figure 3: IR of dicyclohexylammonium 2,2,14,14-tetramethyl-8-oxo pentadecanedioate (5a)

Figure 4: PXRD of dicyclohexylammonium 2,2,14,14-tetramethyl-8-oxo pentadecanedioate (5a)

Figure 5: DSC of dicyclohexylammonium 2,2,14,14-tetramethyl-8-oxo pentadecanedioate (5a)

DETAILED DESCRIPTION OF THE INVENTION

The present disclosure provides an improved, commercially viable and industrially advantageous process for the preparation of Bempedoic acid (I) with good yield and high purity using dicyclohexylammonium 2,2,14,14-tetramethyl-8-oxo pentadecanedioate (5a). A compound of dicyclohexylammonium 2,2,14,14-tetramethyl-8-oxo pentadecanedioate (5a) and a crystalline form of dicyclohexylammonium 2,2,14,14-tetramethyl-8-oxo pentadecanedioate (5a).

The one embodiment of the present invention provides an improved process for the preparation of Bempedoic acid (I) comprising:

a) The compound of formula (1) is reacted with ethyl isobutyrate in presence of organic base and solvent to obtain compound of formula (2),

b) The compound of formula (2) is reacted with p-toluenesulfonyl methyl isocyanide in presence of alkali metal hydride base, quaternary ammonium salt and solvent to obtain compound of formula (3), followed by treated with acid to obtain compound of formula (4),

c) The compound of formula (4) is hydrolysed with inorganic base in presence of solvent and followed by reacted with Dicyclohexyl amine (DCHA) to obtain compound of formula (5a), and

d) The compound of formula (5a) is treated with inorganic base, followed by reduced with reducing agent in presence of solvent 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 organic 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 -5°C to about 30°C or from about 25°C to about 30°C for 10-14 hours. In a particular embodiment, the compound of the formula (I) 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 p-toluenesulfonyl methyl isocyanide in presence of alkali metal hydride base, quaternary ammonium salt and solvent to obtain compound of formula (3). The reaction may be carried out at temperatures ranging from about 20°C to about 55°C., or from about 25°C to about 35°C for 3-6 hours. In a particular embodiment, the compound of the formula (2) is reacted with p-toluenesulfonyl methyl isocyanide in presence of DMSO, TBAI, Sodium hydride to give a compound of formula (3), which is next step without purification. The resulted compound of formula (3) was treated with acid and maintained for 1-2 hours at 25-30°C to obtain compound of formula (4).

The process according to the embodiment of the present invention, Step c) involves hydrolyzed compound of formula (4) with inorganic base in presence of solvent and followed by treated with dicyclohexyl amine (DCHA) in to obtain compound of formula (5a). The reaction may be carried out at temperatures ranging from about 20°C to about 90°C., or from about 50°C to about 90°C for 3-6 hours. In a particular embodiment, the compound of the formula (4) is hydrolysed with potassium hydroxide in the presence of ethanol and water and followed by treated with dicyclohexyl amine in presence of ethyl acetate and the obtained solid was filtered and recrystallized from ethyl acetate to give a compound of formula (5a).

The process according to the embodiment of the present invention, Step d) involves compound of formula (5a) is treated with inorganic base and followed by reduced with reducing agent in presence of solvent to obtain Bempedoic acid (I). The reaction may be carried out at temperatures ranging from about 30°C to about 80°C., or from about 25°C to about 40°C for 3 to 5 hours. In a particular embodiment, the compound of the formula (5a) is treated with sodium hydroxide solution (sodium hydroxide dissolved in water) and the reaction mas washed with toluene. sodium borohydride was added to reaction mass, then reaction mass pH was adjusted with con hydrochloric acid. The obtained crude material was recrystallized from ethyl acetate to give a pure compound of formula (I) [Bempedoic acid].

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

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 quaternary ammonium salt is selected from tetrabutylammonium iodide (TBAI), tetrabutylammonium bromide (TBAB), tetrabutylammonium chloride (TBAC), tetraethylammonium iodide (TEAI), tetraethylammonium bromide (TEAB), tetraethylammonium chloride (TEAC), triethylbenzylammonium iodide (TEBAI) triethylbenzylammonium bromide (TEBAB) and triethylbenzylammonium chloride (TEBAC), tetra-n-butylammonium fluoride, tetrabutylammonium hydroxide, tetrabutylammonium tribromide, tetraethylammonium chloride, tetraethylammonium iodide, tetramethylammonium chloride, tetramethylammonium hydroxide, tetramethylammonium pentafluoroxenate .

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.

The second embodiment of the present provides a novel compound of t2,2,14,14-tetramethyl-8-oxo pentadecanedioate (5a).

The third embodiment of the present invention a crystalline form of dicyclohexylammonium 2,2,14,14-tetramethyl-8-oxo pentadecanedioate (5a).

According to the embodiment of the present invention, the crystalline form of dicyclohexylammonium 2,2,14,14-tetramethyl-8-oxo pentadecanedioate (5a) has an X-ray powder diffraction (XRPD) pattern including diffraction peaks at 7.68, 9.07, 17.70, 17.96 18.38 and 20.02 (2?±0.2°). The Cu Ka radiation is expressed in degrees 2?.

According to the embodiment of the present invention, the crystalline form of dicyclohexylammonium 2,2,14,14-tetramethyl-8-oxo pentadecanedioate (5a) may have an XRPD pattern including diffraction peaks at 7.68, 9.07, 11.90, 14.85, 15.26, 16.72, 17.70, 17.96, 18.38, 18.69, 19.34, 20.02, 20.28, 21,26 and 21.72, (2?±0.2°).

According to the embodiment of the present invention, the crystalline form of dicyclohexylammonium 2,2,14,14-tetramethyl-8-oxo pentadecanedioate (5a) may have an XRPD pattern of FIG. 4.
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, the graph of differential scanning calorimetry (DSC) of the crystalline form of dicyclohexylammonium 2,2,14,14-tetramethyl-8-oxo pentadecanedioate (5a) may have an endothermic peak at approximately 118-128°C at heating rate of 10.00°C/min.
According to the embodiment of the present invention, the graph of differential scanning calorimetry (DSC) of the crystalline form of dicyclohexylammonium 2,2,14,14-tetramethyl-8-oxo pentadecanedioate (5a) may be the same as FIG. 5.
The fourth embodiment of the present invention provides, process for the preparation of Bempedoic acid (I) with good yield and high purity having = 99.7%.

In fifth embodiment of the present invention provides the following characterization data of dicyclohexylammonium 2,2,14,14-tetramethyl-8-oxo pentadecanedioate (5a):

1H-NMR: 2.783-2.774, 2.371-2.335, 1.970-1.951, 1.778-1.765, 1.652-1.575, 1.485-1.448, 1.277-1.156 and 1.124 (ppm) as depicted in Figure 1
13H-NMR: 211.315, 183.082, 52.314, 42.681, 42.339, 41.360, 29.957, 26.093, 25.387, 25.099, 24.848 and 23.854 (ppm) as depicted in Figure 2
IR: 3417.41, 2936.2, 1718.03 (CM-1) as depicted in Figure 3

In sixth embodiment of the present invention provides, particle size distribution of the Bempedoic acid may have from D10 = 10 µm, D50 = 200 µm and D90 = 300µm, the particle size of the Bempedoic acid may have confirmed very fine. The Bempedoic aid can proceed directly to the formulation without further processing, such as milling.
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 following examples illustrate the present invention, but should not be construed as limiting the scope of the invention.

EXAMPLES
Example 1: Preparation of ethyl 7-bromo-2,2-dimethylheptanoate (2)
Tetrahydrofuran (THF) (1000 ml) and diisopropylamine (86.0g) taken in to flask under nitrogen atmosphere and cooled to -10 to 0°C. n-butyllithium (NBL) (2.5 M) in hexanes at lower temperature, ethyl isobutyrate (100 g, 0.86 mol) in diluted THF added into reaction mixture and stir for 2 hrs at -10°C. 1,5-dibromopentane (1) (250 g, 1.26 eq) was added into reaction solution at temperature control -10°C. After completion of the conversion, the GC showed a conversion rate of 60.05%. The reaction was quenched with water (100 ml), adjusted pH to 6-7 by 3 N HCl (980 ml), liquid separation. The obtained organic phase was washed with saturated sodium chloride (1200 ml), concentrated, rectified, collected vacuum degree 180 Pa, 82~87°C fractions to obtain title compound (130g).
1HNMR: 4.14(m),3.420(m),1.891(m),1.542(m),1.453(m),1.285(m),1.15(m).
Purity: 97.0%
Yield: 56%.

Example 2: Preparation of ethyl 7-bromo-2,2-dimethylheptanoate (2)
Diisopropylamine (87.2g, 0.86 mole) was taken in Tetrahydrofuran (400ml) under nitrogen atmosphere, the reaction mass was cooled to -20 to -30°C. Then add 2.5M n-butyl lithium in hexanes (343ml) at -20 to -30°C and stir for 30-60 min. ethyl isobutyrate (100g, 0.86 mole) in THF(100ml) was added dropwise into reaction mixture at -20 to -30°C and maintained the reaction mass at -20 to -25°C for 50-60 min. Further 1,5-dibromopentane (238g, 1.030 mole) was added to reaction mass at -10 to -25°C. Then reaction mass was allowed to RT and maintained for 12hr at 25-30°C. After completion of the reaction, the reaction mass was quenched with water (50 ml) and the reaction mass pH was adjusted to 6 to 7 by using 3 N hydrochloric acid (300 ml), layers are separated. The organic phase was washed with saturated sodium chloride solution (400 ml) and the organic layer was concentrated under reduced pressure to get crude material. Pure compound was isolated by fractional distillation at 90 to 105°C at 1torr vacuum to obtain ethyl 7-bromo-2,2-dimethylheptanoate (2) (90g)
1HNMR: 4.14(m),3.420(m),1.891(m),1.542(m),1.453(m),1.285(m),1.15(m).
Purity: 97.0% by GC.
Yield: 40%.

Example 3: Preparation of 2,2,14,14-tetramethyl-8-oxo-pentadecandioic acid diethyl ester (4)
Ethyl 7-bromo-2,2-dimethylheptanoate (2) (60 g) was added to DMSO (300 ml) and tetrabutylammonium iodide (TBAI) (8.4g, 0.1eq). p-toluenesulfonylmethyl isocyanide (TOSMIC) (22 g, 0.5 eq) was added into reaction mass and then was cooled to 10-15?. Sodium hydride 10.8 g (2 eq) was added slowly into cooled solution after holding for 1 hr. The reaction mixture was raised to room temperature and maintained for 2 hrs at 25-30°C and then add purified water (300 ml) and MTBE (300 ml), then layer separation. The organic layer was washed with brine solution and then organic layer was treated with using 36% concentrated hydrochloric acid adjust the pH of the water phase to 1-2, control the temperature of the reaction mixture at 0-10°C and stir for 15 minutes, separate the layers and wash with sodium bisulphite solutions, washed with purified water (200 ml), after separation. The upper organic phase is concentrated and dried to obtained titled compound (52g).
1HNMR: 4.09(m),2.39(t),1.552(m),1.2402(t),1.127(s).
Purity: 90.0%
Yield: 57.2%

Example 4: Preparation of 2,2,14,14-tetramethyl-8-oxo-pentadecandioic acid diethyl ester (4)
Ethyl 7-bromo-2,2-dimethylheptanoate (2) (100g, 0.377 mole), tetrabutylammonium iodide (TBAI) (14g, 0.0377 mole) and p-toluenesulfonylmethyl isocyanide (TOSMIC) (36.8g, 0.188 mole) were taken in DMSO (800 ml) and the resulting reaction mixture was cooled to 15-20°C, Sodium hydride (18.1g, 0.754 mole) was added slowly, the reaction mass temperature was raised to 25-30°C and maintained for 4-5 hrs at 25-30°C. After completion of the reaction, water (800 ml) and MTBE (400ml) were added, then layer separation, the organic layer was treated with con hydrochloric acid (400 ml) at 15-20°C and maintained for 60-90 min at 25-30°C. After completion of the reaction, separate the layers and MTBE layer washed with 8% sodium bicarbonate solution (600ml), 70% sodium bisulphite solutions (500ml), 15% NaOH solution (400 ml) and finally, 15% NaCl solution (400 ml), 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) (53g).
1HNMR: 4.09(m),2.39(t),1.552(m),1.2402(t),1.127(s).
Purity: 90.0%
Yield: 35%
Example 5: Preparation of Dicyclohexylammonium 2,2,14,14-tetramethyl-8-oxo pentadecanedioate (5a)
A solution of KOH (112.4 g, 8 eq) in water (100 ml) was added to a solution of 2,2,14,14-tetramethyl-8-oxo-pentadecandioic acid diethyl ester (4) (100 g) in ethanol (200 mL). The reaction mass is heated at reflux temperature for 4 hrs. After completion of the reaction, the solution was evaporated to a volume and diluted with water (300 mL). The organic impurities were removed by extracting with dichloromethane (400 ml). The aqueous layer was acidified to pH 2 with concentrated hydrochloric acid (50 mL) and extracted with methyl tert-butyl ether (MTBE) (600 ml) and ethyl acetate (100 ml). The combined organic layers were dried over sodium sulphate and concentrated in vacuum to give the crude. The obtained crude is dissolved in ethyl acetate (900ml), crystallised with DCHA (104.6, 0.576 mole) and isolated to obtained titled compound as off white solid (140.5g).
1HNMR: 2.783(s),2.371(t),1.970(d),1.778(d),1.652(m),1.485(t),1.277(m),1.124(s).
Yield: 80%.
Purity: 90.0%

Example 6: Preparation of Dicyclohexylammonium 2,2,14,14-tetramethyl-8-oxo pentadecanedioate (5a)
A solution of KOH (112.4 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 4 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 acidified to pH 3-4 by using con hydrochloric acid (~170ml) at below 20°C and extracted with ethyl acetate (900 ml). The combined organic layer was washed with saturated NaCl solution (200 ml), 104.6g (0.576 mole) of DCHA was added to organic layer to form DCHA salt. The precipitated solid was filtered and recrystallized from ethyl acetae (800 ml) to get dicyclohexylammonium 2,2,14,14-tetramethyl-8-oxo pentadecanedioate (5a) (130g).
1HNMR: 2.783(s),2.371(t),1.970(d),1.778(d),1.652(m),1.485(t),1.277(m),1.124(s).
Purity: 90.0%
Yield: 73%.

Example 7: Preparation of Bempedoic acid (I)
Dicyclohexylammonium 2,2,14,14-tetramethyl-8-oxo pentadecanedioate (5a) (50g) was charged into purified water (100 ml) and sodium hydroxide (5g) and stir at 20°C for 30 minutes until dissolving. The base layer washed with toluene (250ml), sodium borohydride (0.6g, 0.2 eq) was added to the reaction solution and the reaction was stir for 4 hrs at 25-30°C. After completion of the reaction, concentrated hydrochloric acid (65ml) was added to the reaction solution and the mixture was adjusted to pH 1 and stir for 10 minutes, methyl tert-butyl ether (120 ml) was added. The organic layer was combined and the organic layer was separated by washing with purified water (60 ml), it was washed with saturated brine (60 ml) and dried over anhydrous sodium sulphate for 2 hrs. The obtained product filtered and evaporated to dryness to get a white solid as 8-hydroxy-2,2,14,14-tetramethyl-pentadecandioic acid (Bempedoic acid). The obtained residue was crystallized from MTBE (150ml) / Ethyl acetate (155ml) to obtain pure titled compound (34g).
1HNMR: 3.605(s),1.574(m),1.476(m),1.380(m),1.211(s).
Purity: 99.7%
Yield: 70%
Melting range (MR): 92.0°C.

Example 8: Preparation of Bempedoic acid (I)
Dicyclohexylammonium 2,2,14,14-tetramethyl-8-oxo pentadecanedioate (5a) (100g, 0.141 mole) was charged into sodium hydroxide solution (17.4 g, 0.435 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 toluene (200ml). sodium borohydride (2.2 g, 0.059 moles) was added to the reaction mass, and the reaction was continued for 4 hrs. After completion of the reaction, reaction mass was washed with ethyl acetate (200ml). Then, reaction mass pH was adjusted to pH 4-5 by using con hydrochloric acid (~60ml). After stirring for 10 min, product was extracted with methyl tert-butyl ether (500ml) 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) (27g).
1HNMR: 3.605(s),1.574(m),1.476(m),1.380(m),1.211(s).
Purity: 99.7%
Yield: 55%
MR: 92.0°C
,CLAIMS:WE CLAIM:
1. An improved process for the preparation of Bempedoic acid (I) comprising:
a) The compound of formula (1) is reacted with ethyl isobutyrate in presence of organic base and solvent to obtain compound of formula (2),

b) The compound of formula (2) is reacted with p-toluenesulfonyl methyl isocyanide in presence of alkali metal hydride base, quaternary ammonium salt and solvent to obtain compound of formula (3), followed by treated with acid to obtain compound of formula (4),

c) The compound of formula (4) is hydrolysed with inorganic base in presence of solvent and followed by reacted with Dicyclohexyl amine (DCHA) to obtain compound of formula (5a), and

d) The compound of formula (5a) is treated with inorganic base, followed by reduced with reducing agent in presence of solvent to obtain Bempedoic acid (I).

2. The process as claimed in claim 1, wherein the organic 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 alkali metal hydride base is selected from sodium hydride, potassium hydride and lithium hydride; the inorganic base is selected from sodium hydroxide, sodium hydroxide solution, potassium hydroxide (KOH), ammonium hydroxide and potassium tert-butoxide.

3. The process as claimed in claim 1, 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.

4. The process as claimed in claim 1, wherein the quaternary ammonium salt is selected from tetrabutylammonium iodide (TBAI), tetrabutylammonium bromide (TBAB), tetrabutylammonium chloride (TBAC), tetraethylammonium iodide (TEAI), tetraethylammonium bromide (TEAB), tetraethylammonium chloride (TEAC), triethylbenzylammonium iodide (TEBAI) triethylbenzylammonium bromide (TEBAB) and triethylbenzylammonium chloride (TEBAC), tetra-n-butylammonium fluoride, tetrabutylammonium hydroxide, tetrabutylammonium tribromide, tetraethylammonium chloride, tetraethylammonium iodide, tetramethylammonium chloride, tetramethylammonium hydroxide, tetramethylammonium pentafluoroxenate .

5. The process as 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.

6. The process as claimed in claim 1, wherein the reducing agent is sodium borohydride, potassium borohydride, lithium tetrahydridoaluminate, sodium cyanoborohydride, sodium triacetoxyborohydride and lithium cyanoborohydride.

7. A novel compound of dicyclohexylammonium 2,2,14,14-tetramethyl-8-oxo pentadecanedioate (5a).

8. A crystalline form of dicyclohexylammonium 2,2,14,14-tetramethyl-8-oxo pentadecanedioate (5a).

9. The crystalline form of dicyclohexylammonium 2,2,14,14-tetramethyl-8-oxo pentadecanedioate (5a) as claimed in claim 8, wherein the crystalline form XRPD pattern including diffraction peaks at 7.68, 9.07, 17.70, 17.96 18.38 and 20.02 (2?±0.2°); wherein crystalline form differential scanning calorimetry (DSC) of the endothermic peak at approximately 118-128°C at heating rate of 10°C/min.

10. The process of Bempedoic acid as claimed in claim 1 having a particle size distribution of D10 = 10 µm, D50 = 200 µm and D90 = 300µm.