DESC:FIELD OF THE INVENTION
The present invention relates to an eco-friendly process for preparing bempedoic acid of Formula 1 and its advanced intermediate.

Formula 1

BACKGROUND OF THE INVENTION
Bempedoic acid chemically known as 8-hydroxy-2,2,14,14-tetramethylpenta decanedioic acid and represented by compound of Formula 1.

Formula 1

Bempedoic acid of Formula 1 is an ATP Citrate Lyase inhibitor that reduces cholesterol biosynthesis and lowers LDL-C by up-regulating the LDL receptor.
Both Bempedoic acid and a combination of Bempedoic acid/ Ezetimibe have been approved for the treatment of patients with elevated low-density lipoprotein cholesterol (LDLC).
US patent no. 7,335,799 (hereafter US ‘799) first time discloses bempedoic acid, its process of preparation or its pharmaceutically acceptable salt, hydrate, or solvate and pharmaceutical composition. The following scheme describes the process of bempedoic acid.

The process as disclosed in US ‘799 comprises hydrolysis of Formula 3a (keto diester) with potassium hydroxide in presence of ethanol solvent and after completion of the reaction solvent evaporated, diluted with water and the organic impurities removed by extracting with dichloromethane. The aqueous layer acidified to pH 2 with concentrated hydrochloric acid and extracted with methyl tert-butyl ether (MTBE). The combined organic layers dried, concentrated in vacuo and followed by crystallization using mixture of hexane and MTBE solvents to obtain 8-oxo-2,2,14,14-tetramethylpentadecanedioic acid (keto diacid; Formula 2), further reduction using sodium borohydride to obtain bempedoic acid as viscous oil.
Bempedoic acid is obtained in low yield (60%), as viscous oil, with low HPLC purity 83.8%. The low purity and viscous oily nature of bempedoic acid is not suitable as active ingredient for use in pharmaceutical product.
Further, US ‘799 suffered from several drawbacks such as low yield, low purity of product and use of lengthy extraction process to isolate intermediates make it non industrial viable process which increases the effluent waste.
To overcome the above drawbacks, the applicant of Chinese publication no. 112110828 tried preparation of bempedoic acid via enzymatic reduction of keto diacid (Formula 2) by using alcohol dehydrogenase and coenzyme NADP or NADPH to obtain a crude compound. Then, the crude product was crystallized with ethyl acetate and n-heptane to give bempedoic acid.
The said Chinese reference is suffered from several drawbacks such as use of additional solvents for purification, which increases the cost of process at industrial scale and makes the process uneconomical.
In prior art, it is known that the keto diacid (Formula 2) is isolated by using the extraction method, which add on effluent to the environment, make the process lengthy and uneconomical at industrial scale.
Further, there is no literature wherein the keto diacid (Formula 2) is prepared by eco-friendly method or by enzymatic method.
The enzymes are enabling various industries to guarantee the quality and stability of its products with increased production efficiency. The enzymatic processes are environment-friendly and consuming less energy, water and raw materials and generating less waste. Enzymes are readily biodegradable and usually lead to reduced or no toxicity when they reach the environment after use in industrial production. Therefore, use of enzymes in the synthesis makes the process eco-friendly.
Therefore, in view of the above prior art references, there is an urgent need to develop an eco-friendly process which overcomes the drawbacks as disclosed in the prior art related to preparation of bempedoic acid.
The inventors of present invention have developed a novel process for synthesis of bempedoic acid, whereby the process uses enzymatic transformations and/or a combination of chemical reactions at hydrolysis and reduction steps. The enzymatic or chemo-enzymatic reactions used in the process of the present invention effectively reduces the overall cost of the process for synthesis of the bempedoic acid. Further, as the use of chemicals is significantly reduced, the process is greener as compared to the processes known in the art.

OBJECTIVE OF THE INVENTION
The principal object of the present invention is to provide an eco-friendly and efficient process for preparing bempedoic acid.
Yet another object of the present invention is to provide an improved process for preparation of bempedoic acid compound of Formula 1 having high purity and high yield.
Another one object of the present invention is to provide eco-friendly and efficient process for preparing bempedoic acid; wherein the process uses enzymatic transformations and/or a combination of chemical reactions at hydrolysis and reduction steps. The enzymatic or chemo-enzymatic reactions used in the process of the present invention effectively reduces the overall cost of the process for synthesis of the bempedoic acid.
SUMMARY OF THE INVENTION
Accordingly, the present invention provides an eco-friendly and efficient process for the preparation of bempedoic acid of Formula 1,

Formula 1
comprising the step of:
i) hydrolysing compound of Formula 3,

Formula 3
wherein R is carboxylic acid protecting groups
with an esterase in presence of suitable base to give compound of Formula 2; and

Formula 2

ii) reducing the compound of Formula 2 to give bempedoic acid of Formula 1.

In one embodiment, the present invention provides an eco-friendly and efficient process for the preparation of bempedoic acid of Formula 1,

Formula 1
comprising the step of:
i) hydrolysing compound of Formula 3,

Formula 3
wherein R is carboxylic acid protecting groups
in presence of suitable base to give compound of Formula 2; and

Formula 2

ii) reducing the compound of Formula 2 in the presence of keto reductase to give bempedoic acid of Formula 1.

In another embodiment, the present invention provides an eco-friendly and efficient process for the preparation of bempedoic acid of Formula 1,

Formula 1
comprising the step of:
i) hydrolysing compound of Formula 3,

Formula 3
wherein R is carboxylic acid protecting groups
with an esterase in presence of suitable base to give compound of Formula 2; and

Formula 2

ii) reducing the compound of Formula 2 in the presence of keto reductase to give bempedoic acid of Formula 1.

DETAILED DESCRIPTION OF THE INVENTION
The term "efficient process" used herein means a chemo-enzymatic process used for preparing compounds of Formula 2 and bempedoic acid with high yield and purity and use of enzymatic or chemo-enzymatic process effectively reduces the overall cost of the process.
The term "eco-friendly process" used herein means enzymatic or chemo-enzymatic process which avoids the use of solvent during reaction, workup and purification either during ester hydrolysis or during reduction reaction or during ester hydrolysis and reduction reactions.
The term “suitable base” used herein means a base that can be selected from but not limited to sodium hydroxide, potassium hydroxide or ammonium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and alike or mixture thereof.
The term “suitable acid” used herein means an acid that can be selected from but not limited to hydrochloric acid, sulphuric acid, phosphoric acid and alike or combination thereof.
The term “suitable buffer” used herein means a buffer that can be selected from but not limited to potassium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, sodium phosphate, sodium dihydrogen phosphate, hydrogen phosphate disodium and alike or combination thereof.

The term “carboxylic acid protecting groups” used herein means carboxylic acid function protected by the group selected from but not limited to primary, secondary and tertiary alkyl such as methyl, ethyl, propyl, isopropyl, trityl, methoxymethyl, aryl, any aromatic ring and derivatives thereof.
The present invention provides an efficient process for preparing bempedoic acid of Formula 1 comprises the hydrolysis of compound of Formula 3,

Formula 3
wherein R is carboxylic acid protecting groups
with an esterase in presence of suitable base at suitable temperature to give a reaction mixture.
The esterase used in the present invention can be any enzyme which is capable of converting the protected carboxylate to carboxylic acid.
In one embodiment of the present invention lipase is used as esterase.
The said hydrolysis is carried out in the presence of buffer having pH 8 and the pH is maintained by using suitable base. The suitable temperature used for the hydrolysis is in the range of 30 °C to 90 °C and preferably 50°C to 80°C.
The hydrolysis reaction may be completed in 10 to 40 hours and preferably 20 to 30 hours.
After completion of the reaction, the compound of Formula 2 or its salts,

Formula 2

can be isolated from the reaction mixture by using the techniques known in the prior art or by the method of present invention.
In the present invention, the compound of Formula 2 can be isolated by cooling the reaction mixture at 20 °C to 35 °C followed by filtration and adding hydrochloric acid to the filtrate to precipitate out compound of Formula 2. The resulting precipitate can be washed with suitable solvent and dried to give highly pure compound of Formula 2.
In a preferred embodiment, the resulting precipitate can be slurry washed with mineralized water and dried to give highly pure compound of Formula 2.
The resulting compound of Formula 2 or its salt can be converted to bempedoic acid by using any efficient method known in the prior art or by using the method of the present invention.
In the present invention, the bempedoic acid of Formula 1 is prepared by reducing the resulting compound of Formula 2 or its salt with a suitable reducing agent at a suitable temperature in the presence of suitable solvent and suitable base to give a reaction mixture.
The suitable reducing agent used herein can be selected from sodium borohydride or source of hydrogen in presence of catalyst selected from palladium on carbon, Raney nickel and alike.
In a preferred embodiment, the suitable solvent used for reduction is demineralized water.
The suitable temperature used for reduction can be in the range of 0°C to 40°C.
Finally, bempedoic acid of Formula 1 can be isolated from the resulting reaction mixture by the techniques known in the prior art or by the method of the present invention.
In the present invention, after completion of the reaction bempedoic acid of Formula 1 can be isolated from the resulting reaction mixture with extraction method comprises pH adjustment with hydrochloric acid.
The water immiscible solvent selected from ether such as methyl tert-butyl ether, tetrahydrofuran, diethyl ether, diisopropyl ether and alike are used in the extraction method.
The extracted product is washed with suitable solvent such as ether solvent and the resulting crude product can be crystallized by using suitable solvent, preferably ester solvent selected from ethyl acetate, methyl acetate, propyl acetate and alike.

In one embodiment, the present invention provides an eco-friendly and efficient process for the preparation of bempedoic acid of Formula 1 by hydrolysing compound of Formula 3 in presence of suitable base to give compound of Formula 2 and reducing the compound of Formula 2 or its salt in the presence of keto reductase to give highly pure bempedoic acid of Formula 1.
The said process comprises hydrolysis of compound of Formula 3 with a suitable base in presence of suitable solvent at a suitable temperature to give a reaction mixture.
The suitable solvent used in hydrolysis can be selected from but not limited to alcohol solvent. The alcohol solvent can be selected from methanol, ethanol, propanol, isopropanol and alike or mixture thereof.
The suitable temperature for hydrolysis is in the range of 40 °C to 90 °C or preferably 50 °C to 80°C.
After completion of the reaction, the solvent may optionally be evaporated partially or completely as suitable for further conversion.
Thereafter, demineralized water and suitable solvent such as hydrocarbon solvent or ether solvent are added to the resulting reaction mass and optionally, adjusting the pH of the resulting reaction mixture to 8-9.
The aqueous layer is separated and optionally, treating the aqueous layer with charcoal or activated carbon at a suitable temperature in the range of 30 °C to 50°C and filtered, washed with demineralized water.
Then, pH of the aqueous layer is adjusted with a suitable acid at a suitable temperature in the range of 10 °C to 25°C to precipitate out the compound of Formula 2.
Finally, the resulting compound of Formula 2 or its salt is reduced in the presence of keto reductase (KRED) and hydrogen source to give highly pure bempedoic acid of Formula 1.
The said reduction reaction involves reaction of compound of Formula 2 with a base followed by reaction with hydrogen source in presence of keto reductase (KRED) and water as a solvent to give a reaction mixture. The pH of the reaction mixture is adjusted to 7 to maintain the activity of keto reductase.
In one embodiment, KRED used in the present invention is addzyme or other suitable enzyme(s).
The pH is maintained for a suitable time at a suitable temperature for proceeding the reduction reaction.
The suitable temperature can be in the range of 20 °C to 50 °C or preferably 25 °C to 45°C and suitable time can be 2 to 40 hours or preferably 5 to 25 hours.
The hydrogen source used in the reduction may be selected from D-glucose or alike.
After completion of the reaction, a base is added for denaturing the KRED and heating the reaction mixture at suitable temperature from 40 °C to 70°C for 20 to 60 minutes. Then, the reaction mixture is filtered, washed with water and pH of the filtrate is adjusted between 1 to 4. The resulting reaction mixture is stirred at 20 °C to 30 °C for 0.5 to 4 hours and thereafter temperature is lowered down to 0 °C to 25 °C. The precipitated material is filtered, washed and dried to get highly pure bempedoic acid of Formula 1.

In the above embodiments, the compound of Formula 2 prepared by the present invention may optionally be carried forward in-situ (without isolation) for further reaction to prepare bempedoic acid.

In another embodiment, the present invention provides an enzymatic process for the preparation of bempedoic acid of Formula 1,

Formula 1
comprises the hydrolysis of compound of Formula 3,

Formula 3
wherein R is carboxylic acid protecting groups
with an esterase in presence of suitable base at suitable temperature to give a reaction mixture.
The esterase used in the present invention can be any enzyme which is capable of converting the protected carboxylate to carboxylic acid.
In one embodiment of the present invention lipase is used as esterase.
The said hydrolysis is carried out in the presence of buffer having pH 8 and the pH is maintained by using suitable base. The suitable temperature used for the hydrolysis is in the range of 30 °C to 90 °C and preferably at 50°C to 80°C.
The hydrolysis reaction may be completed in 10 hours to 40 hours and preferably 20 to 30 hours.
After completion of the reaction, the compound of Formula 2 or its salts,

Formula 2

can be isolated or in-situ carry forward for further reaction.
In a preferred embodiment, the resulting compound of Formula 2 or its salts can be carried forward in-situ and converted to bempedoic acid of Formula 1.
The resulting compound of Formula 2 or its salt is reduced with hydrogen source in presence of keto reductase (KRED) to give highly pure bempedoic acid of Formula 1.
The said reduction reaction involves treatment of reaction mixture comprising compound of Formula 2 or its salt with a suitable acid to maintain the pH 7-8 followed by reaction with hydrogen source in presence KRED and water as solvent. The pH is maintained for a suitable time at a suitable temperature for proceeding the reduction reaction.
In one embodiment, KRED used in the present invention is addzyme or other suitable enzyme(s).
The suitable temperature can be in the range of 20 °C to 50 °C or preferably 25 °C to 45°C and suitable time can be 2 to 40 hours or preferably 10 to 30 hours.
The hydrogen source used in the reduction may be selected from D-glucose or alike.
After completion of the reaction, a suitable base is added for denaturing the KRED and heating the reaction mixture at suitable temperature from 40 °C to 70°C for 20 to 60 minutes. Then, the reaction mixture is filtered, washed with water followed by water immiscible solvent to remove the impurities.
The pH of the aqueous layer is adjusted between 1 to 4 and the resulting reaction mixture is stirred at 20 °C to 30 °C for 0.5 to 4 hours. The precipitated material is filtered, washed and dried to get highly pure bempedoic acid of Formula 1.

In another embodiment, the present invention provide a process for the preparation of bempedoic acid of Formula 1 comprises reduction of compound of Formula 3 to give compound of Formula 2a or its salt and followed by hydrolysis to give bempedoic acid.

Formula 2a
wherein R is carboxylic acid protecting groups
The said process conversion can be performed by utilizing the methodology as discussed herein any above embodiments.
The salt compound of Formula 2 or Formula 2a used in the present invention can be selected from but not limited to sodium, potassium, calcium and alike.
The compound of Formula 3 used in the present invention can be prepared by any method known in the prior art.
The compound of Formula 2 or its salts (wherein isolated) and bempedoic acid of Formula 1 prepared by the process of the present invention having high yield and high purity.

In the present invention, an optional treatment of the reaction mixture with carbon/ charcoal or with celite can be given wheras required.
The enzymes used in the present invention are commercially available and procured from the market. In the present invention the quantity of esterase or ketoreductase (viz. enzymes) can be varied to achieve the best results.
In the present invention, the purity of final product/intermediates, reaction completion and monitoring of the reaction of the present invention is checked by any analytical techniques known in the prior art such as high-performance liquid chromatography (HPLC), thin-layer chromatography (TLC), gas chromatography (GC) and alike.
Having described the invention with reference to certain preferred aspects, other aspects will become apparent to one skilled in the art from consideration of the specification. The invention is further defined by reference to the following examples describing in detail an improved cost-effective, eco-friendly process for preparing bempedoic acid of Formula 1 or its pharmaceutically acceptable salts and its key intermediates.
EXAMPLES
Example 1: Synthesis of diethyl 2,2’,14,14’-tetramethyl-8-oxopentadecane dioate (keto diester)
To the solution of ethyl 7-bromo-2,2’-dimethylheptanoate (274.36g, 1.03mmol) in dry dimethylformamide (800 ml) tetra-n-butylammonium iodide (TBAI) (18.9g, 0.05mmol) and 1-(isocyanomethanesulfonyl)4-methylbenzene (TosMIC) (100g, 0.51 mmol) were added to give a reaction mixture. The reaction mixture was cooled to 5-10 oC under nitrogen and sodium methoxide (69.2g, 1.28mmol) was added slowly at 5-20 oC in ~2 hours. Then, the reaction temperature was slowly raised to 10-20 oC and stirred for 1 hour. After complete addition of TosMIC (TLC monitored) the reaction mixture was quenched with demineralized water (1900 ml) at 0-10 oC and hexane (1400 ml) was added at 0-30 oC. The organic layer was stirred, settled, separated and re-extracted aqueous layer with hexane (500 ml). The combined organic layer (hexane) was washed with demineralized water (800 ml, 8.0Vol). The organic layer containing 1,15-diethoxy-2,2’,14,14’-tetra methyl-8-(4-methylbenzene-1-sulfonyl)-N-methylidyne-1,15-dioxopentadecan-8-aminium (TosMIC-diester adduct) was settled and separated and cooled to 0-5 oC. To the resulting layer concentrated HCl (130ml, 1.24mmol) was added at 0-10 oC and reaction mixture was stirred for 1 hour at 0-10 oC. After completion of the reaction (checked by TLC), the solid 4-methylbenzene-1-sulfinic acid crystallized out during reaction and filtered, washed and dried to get 60g of dried 4-methylbenzene-1-sulfinic acid. The collected filtrate (organic layer) washed with demineralized water (800ml, 8Vol) followed by aqueous sodium bicarbonate solution (60g in 800ml demineralized water , 0.71 mmol). The organic layer was settled, separated and distilled off under reduced pressure at 45-50 oC to get 158.5g (77.89%) of crude oily mass of diethyl 2,2’,14,14’-tetramethyl-8-oxopentadecanedioate.
Example 2: Synthesis of bempedoic acid via enzymatic hydrolysis followed by chemical reduction
Step 1. Enzymatic synthesis of 2,2’,14,14’-tetramethyl-8-oxopentadecanedioic acid (keto di-acid):
To a solution of diethyl 2,2’,14,14’-tetramethyl-8-oxopentadecanedioate (20.0 g, 0.050mmol) phosphate buffer (200.0ml, pH-8.0) and Lipase (20.0 g) were added. The resulting reaction mixture was shaken at 70-75°C for 24.0 hours and the pH of the reaction mixture was constantly maintained to 8 with Sodium hydroxide solution (5M). After completion of the reaction, the reaction mixture was cooled to room temperature and filtered the reaction mixture. The clear filtrate was collected and pH was adjusted to 3-4 with concentrated HCl to precipitate out solid material. After complete precipitation, the suspension was further stirred for 1 hour at 20-30oC. The suspension was filtered, slurry washed with demineralized water (50.0 ml) and suck dried to give the wet cake and further dried to get 15.5g (90.22%) of 2,2’,14,14’-tetramethyl-8-oxopentadecanedioic acid as white to off white solid.
Step 2. Synthesis of 8-hydroxy-2,2’,14,14’-tetramethylpentadecane dioic acid (bempedoic acid)
A solution of Sodium hydroxide (3.67g, 0.092mmol) in demineralized water (75.0 ml) was prepared and 2,2’,14,14’-tetramethyl-8-oxopentadecanedioic acid (15.0 g, 0.044mmol) was added to the solution. The resulting solution was cooled at 0-15 °C and added sodium borohydride (1.15 g,0.0306mmol) was added at 0-15°C. After complete addition of sodium borohydride, the temperature was raised to 20-30°C and the reaction mixture was stirred for 3-4 hours. After completion of the reaction (checked by TLC), the pH of the reaction mixture was adjusted with diluted HCl (concentrated HCl-5ml, DM water-5.0ml) up to pH 8-9 and the reaction mixture was washed with methyl tert-butyl ether (MTBE) (2 X 30ml).The product was extracted twice from aqueous layer with MTBE by adjusting the pH 1-2 with diluted HCl (50% ) at 20-30 °C. The organic layer was washed with demineralized water (75.0 ml) and the layers were separated. The product layer was treated with activated carbon (10%) at 20-30°C for 30 minutes; filtered through the celite bed and washed by MTBE (30.0ml). The solvent was evaporated completely and degassed for 1.0 hour at 50-55°C. to give crude bempedoic acid.
The crude bempedoic acid was crystallised with ethyl acetate to give 11.25g (74.55%) of pure bempedoic acid.
Example 3: Synthesis of bempedoic acid via chemical hydrolysis followed by enzymatic reduction
Step 1. Synthesis of 2,2’,14,14’-tetramethyl-8-oxopentadecanedioic acid (keto di-acid)
Aqueous potassium hydroxide solution (92g, 1.64 mmol in 200ml, 20Vol DM water) was added slowly in the solution of diethyl 2,2’,14,14’-tetramethyl-8-oxopentadecanedioate in ethanol (800 ml, 8Vol). Slowly charged at 20-35 oC. The temperature of the reaction mixture was raised to 65-70 oC and stirred for 15 hours. After completion of reaction (TLC monitored) ethanol was distilled off and demineralized water (800 ml, 8Vol) was added. The resulting reaction mixture was stirred at 20-30 oC and pH was adjusted to 8-9 with concentrated HCl (~ 100ml). The aqueous layer was washed with methyl tert-butyl ether (MTBE) (400x2 ml) and separated aqueous layer was degassed to remove the traces of organic solvents. The pH of the reaction mixture was adjusted to 5.0 to 6.0 with dilute HCl solution (100ml HCl in 100ml demineralized water). Solid material precipitated out and after complete precipitation further stirred the suspension for 1 hour at 20-30 oC. The solid was filtered and slurry washed with demineralized water (400ml) and dried to get 135g (77.3%) of 2,2’,14,14’-tetramethyl-8-oxopentadecanedioic acid as white to off white solid.
Step 2: Enzymatic synthesis of 8-hydroxy-2,2’,14,14’-tetramethylpentadecane dioic acid (bempedoic acid)
To a mixture of 2,2’,14,14’-tetramethyl-8-oxopentadecanedioic acid (20.0 g, 0.058mmol) and demineralized water (200.0 ml) and sodium hydroxide solution (5M, pH-8.5-9.5) was added to give a clear solution. The solution was treated with charcoal (5%) for 30 minutes and filtered through a celite bed. The pH of resulting clear solution was adjusted to 7.0±0.2 with diluted HCl solution and D-Glucose (12.63 g, 0.07mmol), addzyme (KRED, 3.0g, 15%) was added at 30±5°C. The same temperature and pH of the reaction mixture was maintained for 5-6 hours. After reaction completion (checked by TLC) the pH of the reaction mixture was raised to 8.5-9.5 and celite (5.0 g, 0.25times) was added. Then, the reaction mixture was heated at 50-60°C and stirred for 30 minutes. The reaction mixture was filtered through the celite bed and washed with demineralized water (20.0 ml). The pH of the resulting clear filtrate was adjusted to ? 2, while adjusting the pH precipitation was obtained at 25-30°C and stirred for 1 hour. Then, the reaction mixture was cooled to 10-15°C and stir for 30 minutes. Finally, the product was filtered, washed and dried to give 17g (84.5%) of bempedoic acid
Example 4: One-pot enzymatic synthesis of 8-hydroxy-2,2’,14,14’-tetramethylpentadecanedioic acid (bempedoic acid) from diethyl 2,2’,14,14’-tetramethyl-8-oxopentadecanedioate (keto diester)
To the solution of diethyl 2,2’,14,14’-tetramethyl-8-oxopentadecanedioate (20.0 g, 0.050mmol) phosphate buffer (200.0ml, pH-8.0) and Lipase (Novozyme-435, 20.0 g) were added. The reaction mixture was shaken at 70-75°C for 24.0 hours by maintaining the pH 8 constantly with Sodium hydroxide solution (5M). After completion of the reaction (checked by TLC) the reaction mixture was cooled to room temperature and filtered off the enzyme. The clear filtrate was treated with charcoal (5%) for 30 minutes and filtered through celite bed. The pH of the clear solution (filtrate) was adjusted 7.0 with diluted HCl solution and D-Glucose (12.63 g, 0.07mmol), KRED (addzyme, 3.0g, 15%) were added at 30±5°C. The temperature of the resulting reaction mixture was maintained at 30-34 °C and the pH was maintained 7.0±0.2 for 24.0 hours. After reaction completion (checked by TLC), the pH of the reaction mixture was raised to 8.5-9.5 and celite (5.0 g, 0.25 times) was added. The reaction mixture was heated to 50-60°C and stirred for 30 minutes and filtered, washed with demineralized water (20.0 ml). Ethyl acetate (100.0ml) was added to the reaction mixture under stirring for 15-20 minutes and the layers were separated. The pH of the aqueous layer was adjusted to ?1-2, while adjusting the pH precipitation was obtained at 25-30°C. Further, the reaction mixture was stirred for 1.5 hours at the same temperature and filtered, washed the product with demineralized water (20.0 ml). Finally, the wet product was suck dried to give 14g (80.99% from starting material) of bempedoic acid.
,CLAIMS:Claim 1. An eco-friendly process for the preparation of bempedoic acid of Formula 1,

Formula 1
comprising the step of:
i) hydrolyzing a compound of Formula 3,

Formula 3
wherein R is carboxylic acid protecting groups
with an esterase in presence of suitable base to give compound of Formula 2; and

Formula 2

ii) reducing the compound of Formula 2 to give bempedoic acid of Formula 1.

Claim 2. An eco-friendly process for the preparation of bempedoic acid of Formula 1,

Formula 1
comprising the step of:
i) hydrolysing compound of Formula 3,

Formula 3
wherein R is carboxylic acid protecting groups
in presence of suitable base to give compound of Formula 2; and

Formula 2

ii) reducing the compound of Formula 2 in the presence of keto reductase to give bempedoic acid of Formula 1.

Claim 3. An eco-friendly and efficient process for the preparation of bempedoic acid of Formula 1,

Formula 1
comprising the step of:
i) hydrolysing compound of Formula 3,

Formula 3
wherein R is carboxylic acid protecting groups
with an esterase in presence of suitable base to give compound of Formula 2; and

Formula 2

ii) reducing the compound of Formula 2 in the presence of keto reductase to give bempedoic acid of Formula 1.

Claim 4. The process as claimed in claim 1, wherein compound of Formula 2 is reduced with suitable reducing agent selected from sodium borohydride or source of hydrogen in presence of catalyst selected from palladium on carbon and Raney nickel.
Claim 5. The process as claimed in claims 1 and 2, wherein the suitable base is selected from sodium hydroxide, potassium hydroxide or ammonium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate.

Claim 6. The process as claimed in claims 1 and 3, wherein the esterase used in hydrolysis is Lipase (Novozyme-435).

Claim 7. The process as claimed in claims 2 and 3, wherein keto reductase used for reducing the compound of Formula 2 is addzyme.

Claim 8. The process as claimed in claims 2 and 3, wherein compound of Formula 2 is reduced with hydrogen source.

Claim 9. The process as claimed in claim 8, wherein the hydrogen source is D-glucose.

Dated this 11th day of September 2023.