DESC:FIELD OF THE INVENTION
The present invention relates to an efficient process for preparing bempedoic acid of Formula 1 and its key intermediates.

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 describe the process of bempedoic acid.

The process as disclosed in US ‘799 comprises reacting 7-bromo-2,2-dimethylheptanoic acid ethyl ester (Formula 5) with p-toluenesulfonyl methyl isocyanide (TosMIC) in presence of anhydrous DMSO solvent, sodium hydride and phase transfer catalyst to obtain crude 8-isocyano-2,2,14,14-tetramethyl-8-(toluene-4-sulfonyl)-penta decanedioic acid diethyl ester (TosMIC diester adduct; Formula 4) as oil, further addition of concentrated HCl followed by column chromatography purification to obtain 2,2,14,14-tetramethyl-8-oxo-pentadecane dioic acid diethyl ester (di-alkylated keto ester; Formula 3) as a colorless oil.
Further, hydrolysing the resulting Formula 3 with potassium hydroxide in presence of ethanol solvent. After completion of the reaction solvent evaporated, diluted with water and the organic impurities removed by extracting with dichloromethane. The aqueous layer is 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 drawback such as low yield and purity of product and use of lengthy extraction process to isolate intermediates make it non industrial viable process and use of TosMIC for preparing TosMIC diester adduct of Formula 4 generates effluent comprises impure 4-methylbenzene sulfinic acid of Formula 6 as a by-product, which increases the effluent waste.

Formula 6

It is very important to control the impurities at intermediate stage or advanced intermediate stage to prepare high purity drug substance.
2,2,14,14-tetramethyl-8-oxopentadecanedioic acid (keto diacid) is represented by compound of Formula 2, an advanced intermediate of bempedoic acid.

Formula 2

Several organisations have tried to develop efficient method to prepare keto diacid of Formula 2 to overcome the prior art problems and the said references discussed herein below.
Chinese application publication no. 111170855 disclosed a process for the preparation of a novel compound of Formula A and its conversion to bempedoic acid of Formula 1 as per the below scheme.
The said process involves reaction of compound of Formula B with diethyl 1,3-acetone di-carboxylate to give compound of Formula A and adding water to dissolve the resulting compound. After dissolution, extract with methyl tert-butyl ether, adjusting the pH to 1-2 of the aqueous phase with 36% concentrated hydrochloric acid, control the temperature of the system to 0-10°C and dissolve the filter cake with methyl tert-butyl ether and wash with purified water. After separation, the upper organic phase is concentrated and dried. The resulting filter cake is dissolved in methyl tert-butyl ether, washed with purified water and concentrated the upper organic phase to dryness. The resulting material crystallised with methyl tert-butyl ether: n-heptane to obtain compound of Formula 2. The resulting compound of Formula 2 is converted to bempedoic acid of Formula 1 by reduction with sodium borohydride.
Chinese patent no. 111285760 disclosed a novel process for the preparation of compound of Formula 2 and its conversion to bempedoic acid of Formula 1 as per the below scheme.

In the above method, the compound of Formula 2 is isolated by the extraction method as per method as disclosed in US ‘799 viz. reaction mixture diluted with water after completion of the reaction and washing with dichloromethane. The aqueous layer acidified 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. Then, the compound of Formula 2 is converted to bempedoic acid of Formula 1.
Indian application no. 201821049982 disclosed a novel process for the preparation of compound of Formula 2 and its conversion to bempedoic acid of Formula 1 as per the below scheme.

In the above method the compound of Formula 2 is prepared from a novel compound of Formula B and the compound of Formula 2 is isolated by the extraction method viz. after completion of the reaction, adding water, adjusting aqueous layer pH (2-3) and extracting product with MDC followed by concentrating the organic layer. Then, the compound of Formula 2 is converted to bempedoic acid of Formula 1.
All of the above prior arts isolate compound of Formula 2 by using the extraction method, which adds on effluent to the environment, make the process lengthy and uneconomical at industrial scale.
Therefore, in view of the above prior art references, there is an urgent need to develop an industrially efficient process which overcomes the drawbacks as disclosed in the prior art related to preparation of bempedoic acid.
The inventors of present invention have developed an efficient process for synthesis of bempedoic acid of Formula 1, wherein the prior art extraction method is avoided for isolating intermediates mainly the compound of Formula 2 and upcycling the by-product to prepare TosMIC reagent, thereby making the process eco-friendly, economical and industrially efficient thereof.
OBJECTIVE OF THE INVENTION
The principal object of the present invention is to provide an efficient process for preparing bempedoic acid of Formula 1 and its key intermediates.
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 an efficient process for preparing bempedoic acid of Formula 1 wherein by-product such as 4-methylbenzene sulfinic acid of Formula 6 is not carried forward to effluent and the by-product upcycling for preparing TosMIC.

SUMMARY OF THE INVENTION
Accordingly, the present invention provides an efficient process for preparing bempedoic acid of Formula 1,

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

Formula 3a
wherein R is an alkyl group
with a suitable base in presence of suitable solvent to give a reaction mixture;
ii) adding water to the reaction mixture of step i) and washing aqueous layer with suitable solvent;
iii) adjusting pH of the aqueous layer with a suitable acid to precipitate out the compound of Formula 2; and

Formula 2

iv) reducing the compound of Formula 2 with suitable reducing agent to give the compound of Formula 1.

In one embodiment, the present invention provides an efficient process for preparing bempedoic acid of Formula 1,

Formula 1
comprising the step of:
i) treating compound of Formula 4a;

Formula 4a
wherein R is an alkyl group
with a suitable acid at a suitable temperature to give a reaction mixture comprises of compound of Formula 3a,

Formula 3a
wherein R is an alkyl group
and 4-methylbenzene sulfinic acid of Formula 6 as by-product;

Formula 6

ii) filtering out precipitated 4-methylbenzene sulfinic acid of Formula 6;
wherein the Formula 6 is upcycled for preparing TosMIC;
iii) washing the filtered organic layer with suitable base;
iv) isolating the compound of Formula 3a; and

Formula 3a
wherein R is an alkyl group
v) converting the compound of Formula 3a to bempedoic acid of Formula 1.

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

Formula 1
comprising the step of:
i) reacting compound of Formula 5a;

Formula 5a

wherein X is halogen and R is an alkyl group
with TosMIC to give compound of Formula 4a; and

Formula 4a
wherein R is an alkyl group
ii) converting the compound of Formula 4a to the bempedoic acid of Formula 1;
wherein in step i) TosMIC is prepared from upcycled 4-methylbenzene sulfinic acid of Formula 6.

In another embodiment, the present invention provides an efficient process for preparing compound of Formula 2,

Formula 2

comprising the step of:
i) adding a suitable acid to the aqueous layer containing the compound of Formula 2 and
ii) precipitating the compound of Formula 2 by adjusting the pH of aqueous layer between 4 to 7.

DETAILED DESCRIPTION OF THE INVENTION
The term "upcycling" used herein means conversion of waste material to a valuable product/intermediate/reagent or making wealth out of waste.
The term "efficient process" used herein means a chemical transformation during which the effluent load is reduced by upcycling by-product such as 4-methylbenzene sulfinic acid and avoiding extraction method of isolation for preparing compound of Formula 2.
The term "halogen" used herein means a group can be selected from but not limited to chlorine, bromine, iodine and alike.
The term "alkyl" used herein means a carbon chain either aliphatic or branch having C1 to C5 carbon atoms such as methyl, ethyl, propyl, isobutyl and alike.
The term “hydrocarbon solvent” used herein means a solvent that can be selected from but not limited to hexane, cyclohexane, toluene, heptane, benzene, xylene and alike or mixture thereof.
The term “ether solvent” used herein means solvent comprises methyl tert-butyl ether (MTBE), diethyl ether (DEE), di-tert-butyl ether (DTBE), diisopropyl ether (DIPE), tetrahydrofuran (THF), 2-methyltetrahydrofuran, cyclopentyl methyl ether and alike or mixture thereof.
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; alkoxide selected from sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium t-butoxide, potassium t-butoxide and alike or combination 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 present invention provides an efficient process for preparing bempedoic acid of Formula 1. The said process comprises the reaction of compound of Formula 5a,

Formula 5a

wherein X is halogen and R is an alkyl group
with TosMIC in presence of suitable solvent and suitable base at a suitable temperature to give a reaction mixture. After completion of the reaction, the reaction mixture is quenched with water, pH adjusted by using a suitable acid and extracting the compound of Formula 4a by using suitable solvent selected from hydrocarbon solvent or ether solvent.

Formula 4a
wherein R is an alkyl group
The suitable base is selected from but not limited to alkoxide such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium t-butoxide, potassium t-butoxide and alike or combination thereof.
The suitable solvent is selected from an aprotic solvent. The aprotic solvent can be selected from dimethylformamide (DMF), n,n-dimethylacetamide (DMAc), dimethyl-sulfoxide (DMSO), ether solvent and alike or mixture thereof.
The suitable temperature can be in the range of 0 °C to 40 °C or preferably in the range of 10 °C to 30 °C.
After completion of the reaction, the reaction mixture is quenched with water and followed by addition of water immiscible solvents. The layers are separated and the organic layer containing compound of Formula 4a is carried forward in-situ for further reaction. Optionally, the compound of Formula 4 can be isolated by concentrating the organic layer and converted to a compound of formula 3a.
The compound of Formula 4a is converted to a compound of formula 3a;

Formula 3a
wherein R is an alkyl group
by treating compound of Formula 4a with a suitable acid in presence of hydrocarbon solvent or ether solvent at a suitable temperature to give a reaction mixture comprises of compound of Formula 3a and 4-methylbenzene sulfinic acid of Formula 6 as by-product.

Formula 6

The suitable temperature for the said conversion can be in the range of 0 °C to 25 °C or preferably 5 °C to 15 °C.
After completion of the reaction, the by-product 4-methylbenzene sulfinic acid of Formula 6 is precipitated, filtered out and the filtrated organic layer carry forward for isolating the compound of Formula 3a or the filtrated reaction mixture carry forward in-situ for further reaction conversion.
The isolation of compound of Formula 3a comprises washing of the filtered organic layer with suitable base and followed by distillation of the solvent.
The resulting compound of Formula 3a can be converted to a compound of formula 2;

Formula 2

by hydrolysing compound of Formula 3a with a suitable base in presence of suitable solvent at a suitable temperature to give a reaction mixture.
The suitable solvent used in hydrolysis is selected from but not limited to alcohol solvent. The alcohol solvent is selected from methanol, ethanol, propanol, isopropanol and alike or mixture thereof.
The suitable temperature for hydrolysis is in the range of 50 °C to 90 °C.
After completion of the reaction, the solvent may optionally be evaporated partially or completely as suitable for further conversion.
Thereafter, water and suitable solvent such as hydrocarbon solvent or ether solvent are added for washing aqueous layer to the resulting reaction mixture and optionally, adjusting the pH of the resulting reaction mixture to 8-9 to wash out the traces of diketone impurity having the below structure.

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 water.
Then, pH of the aqueous layer is adjusted between 4 to 7 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 free from diketone impurity.
Finally, the resulting compound of Formula 2 is reduced with suitable reducing agent such as sodium borohydride or as per the method(s) known in the art to give bempedoic acid of Formula 1.
In one specific embodiment, the present invention provides a process for preparing bempedoic acid wherein compound of Formula 5a,

Formula 5a

wherein X is halogen and R is an alkyl group
is reacted with TosMIC in presence of suitable solvent, suitable base and optionally a phase transfer catalyst at a suitable temperature to give monoalkylated TosMIC intermediates having following structure.

wherein R is an alkyl group
The resulting monoalkylated TosMIC intermediate is in-situ converted to compound of Formula 4a.

Formula 4a
wherein R is an alkyl group
The phase transfer catalyst is selected from but not limited to tetrabutylammonium iodide tetrabutylammonium bromide, tetrabutylammonium chloride and alike.
Then, the resulting compound of Formula 4a is converted to bempedoic acid as per the process of the present invention as discussed herein above.
In a specific embodiment, reacting the compound of Formula 5a (wherein R is ethyl) with TosMIC to give compound of Formula 4a (wherein R is ethyl) along with two alkylated products as shown below.

Thereafter, the mixture of the resulting products are reacted with a suitable acid in presence of hydrocarbon solvent or ether solvent at a suitable temperature to give a compound of Formula 3a (wherein R is ethyl) along with two alkylated products as shown below.

Finally, the mixture of the resulting products are hydrolysed with a suitable base to give a compound of Formula 2 and reduced the compound of Formula 2 with a reducing agent to give crude bempedoic acid. Crude bempedoic acid is purified with ethyl acetate to give pure bempedoic acid having purity more than 99% and free from diketone impurity and diol impurity having the below structure.

In one embodiment, the present invention provides an efficient process for preparing bempedoic acid of Formula 1 comprises hydrolysing compound of Formula 3a to give compound of Formula 2 as per the method of present invention as described herein above. Finally, the resulting compound of Formula 2 is reduced with suitable reducing agent as per the method(s) known in the art to give bempedoic acid of Formula 1.
In prior art, the compound of 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.
The inventors of present invention come up with a solution for solving the prior art problems and developed an efficient process for synthesis of bempedoic acid of Formula 1, wherein the prior art extraction method is avoided for isolating the compound of Formula 2. In the present invention the compound of Formula 2 is isolated by adjusting the pH of aqueous layer between 4 to 7.
In one embodiment, the present invention provides an efficient process for preparing bempedoic acid of Formula 1 comprises reacting the compound of Formula 4a with a suitable acid to give a reaction mixture. The reaction mixture further treated to give compound of formula 3a and followed by conversion of resulting compound to the bempedoic acid of Formula 1 can be done by using the method of the present invention as discussed herein above.
In one embodiment of the present invention, bempedoic acid of Formula 1 is prepared by using the following scheme:

The one aspect of the present embodiment is to precipitate out the by-product 4-methylbenzene sulfinic acid of Formula 6, before isolating the compound of Formula 3a, from the reaction mixture by filtration. The by-product of Formula 6 is upcycled for preparing TosMIC and filtrated reaction mixture carry forward for isolating the compound of Formula 3a.
In prior art, the by-product 4-methylbenzene sulfinic acid of Formula 6 is carried forward to the effluent after isolation of the compound of Formula 3a.
The inventors of the present invention has developed a method for isolating the by-product 4-methylbenzene sulfinic acid of Formula 6 before isolation of the compound of Formula 3a and prevent for carry forwarding the Formula 6 for effluent treatment.
The isolated by-product of Formula 6 upcycling in continuous or batch mode to prepare TosMIC reagent that can be used in reaction to prepare compound of Formula 4a.
In another embodiment, the present invention provides an efficient process for preparing bempedoic acid of Formula 1 by reacting compound of Formula 5a with TosMIC to give compound of Formula 4a.
In the present embodiment, the TosMIC used in the reaction can be prepared from upcycling of 4-methylbenzene sulfinic acid of Formula 6.
Inventors of the present invention design the reaction condition in such a way that upcycling of 4-methylbenzene sulfinic acid of Formula 6 can be possible at industrial scale to prepare TosMIC.
The resulting compound of Formula 4a is converted to the bempedoic acid of Formula 1 as per the method of present invention as discussed herein before.
In another embodiment, the present invention provides an efficient process for preparing compound of Formula 2 by adding a suitable acid to the aqueous layer containing the compound of Formula 2 and precipitating the compound of Formula 2 by adjusting the pH of aqueous layer between 4 to 7.
Optionally, the compound of Formula 2 is purified by using solvent selected from hydrocarbon solvent, ether solvent comprises methyl tert-butyl ether (MTBE), diethyl ether (DEE), 2-methyltetrahydrofuran and alike or mixture thereof.
Bempedoic acid of Formula I, prepared by the present invention, having purity greater than 99.9% and free from diol and diketone impurities. 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.

EXAMPLES
Example 1a: Synthesis of compound of Formula 4 (TosMIC diester adduct, with isolation)
To the solution of compound of Formula 5 (29.88g, 0.11mmol) in dry DMF (60 ml), was added TosMIC (10g, 0.05 mmol) at 10-15 oC and stirred the reaction mass for 10 minutes. Sodium methoxide 8.57g, 0.16mmol) was added slowly at 10-15 oC and raised the reaction temperature to 25-30 oC. The reaction mixture was stirred for 3 hours. After completion of the reaction, the reaction mixture was quenched with water (300 ml) and pH of the reaction mass was adjusted ~7.0 using 5% aqueous HCl solution (~20 ml). Hexane (120 ml) was added into the reaction mixture, stirred, settled and separated the organic layer. The aqueous layer was re-extracted with hexane (60 ml) and combined hexane layer was washed with water (50 ml). Distilled off hexane completely to get 29g (100%) of the titled compound of Formula 4.
Example 1b: Synthesis of compound of Formula 4 (TosMIC diester adduct, without isolation)
To the solution of ethyl 7-bromo-2,2-dimethyl heptanoate (330g) in dry DMF (960 ml) was charged TBAI (22.8 g) and TosMIC (120g). The reaction mixture was cooled to 5-10 °C and sodium methoxide (84g) was added at 5-20°C. The reaction temperature was raised to 10-20oC and stirred for 1 hour. During the conversion of TosMIC to Formula 4, firstly, monoalkylated TosMIC intermediates (wherein R is methyl and ethyl) were in-situ obtained which further converted into Formula 4 along with other corresponding alkylated (viz. methyl ethyl and dimethyl esters) derivatives. The ethyl group of in-situ formed monoethyl ester gets replaced partially with methyl group due to transesterification in the presence of sodium methoxide. After completion of the reaction, the reaction mixture was quenched with water (2.28L) at 0-10 °C followed by addition of hexanes (1.68 L). The reaction mixture was stirred, settled and the layers were separated. The aqueous layer was extracted with hexane (600 ml) at temperature 20-30°C. The combined organic layers were washed with DM water (960 ml) and carry forward the organic layer containing compound of Formula 4 along with other alkylated (viz. methyl ethyl and dimethyl esters) products.

Example 2a: Synthesis of compound of Formula 3 (di-ethyl keto ester)
To the cooled reaction mixture of compound of Formula 4 (29 g, 0.0514 mmol) in hexane (180 ml) was added concentrated hydrochloric acid slowly at 0-10 oC. After the addition of concentrated hydrochloric acid, the temperature was raised to 10-15 oC and stirred for 2 hours. After completion of the reaction, filtered out precipitated 4-methylbenzene sulfinic acid of Formula 6 and washed with hexane (10 ml). Wet solid was dried to get 6.6 g of 4-methylbenzene sulfinic acid. Filtered organic layer was washed with aqueous sodium bicarbonate solution (50 ml) and distilled under reduced pressure to get 20.89g (100%) of the compound of Formula 3.

Example 2b: Synthesis of compound of Formula 3 (di-ethyl keto ester)
To the above organic layer (taken from example 1b) concentrated hydrochloric acid (156ml) was added slowly at 0-10°C and stirred for 1 hour. The organic layer containing compound of Formula 4 along with other alkylated (viz. methyl ethyl and dimethyl esters) derivatives were converted into compounds Formula 3 (di-ethyl keto ester) and other corresponding keto alkylated esters (viz. methyl ethyl and dimethyl di-keto esters) derivatives during this reaction. After completion of reaction by TLC, the in-situ generated by-product i.e. 4-methylbenzene sulfinic acid was filtered out and washed with hexane (300 ml). 4-Methylbenzene sulfinic acid (wet solid) was dried to get 72.2g of 4-methylbenzene sulfinic acid. The filtrate as obtained above was washed with demineralized water (960 ml) followed by aqueous sodium bicarbonate solution (7.5%, 960 ml). The organic layer was concentrated under vacuum at temperature below 55°C to obtain 230g of the compound of Formula 3 and other corresponding alkylated keto esters (viz. methyl ethyl and dimethyl keto esters) derivatives as oily mass.

Example 3a: Synthesis of compound of Formula 2 (keto diacid)
Aqueous potassium hydroxide solution (11.47g, 0.204 mmol in 20.4ml) was added slowly to a solution of compound of Formula 3 (20.89g, 0.0512 mmol) in ethanol (81.6 ml) at 15-20 oC. The temperature of the reaction mixture was raised up to 75-80 oC and refluxed for 15 hours. After completion of reaction (TLC monitored), ethanol was distilled off and water (81.6 ml) was added. The aqueous layer was washed with hexane twice (81.6 ml and 40.8 ml respectively). Activated carbon (1g) was charged to the reaction mixture and the temperature was raised up to 40-45oC. The reaction mixture was filtered and washed with water (20 ml). The pH of the reaction mixture was adjusted to 5.0 to 6.0 with concentrated hydrochloric acid at 15-20 oC to precipitate out the compound of Formula 2. The slurry was stirred for 2 hours at the same temperature and solid was filtered out. Wet solid was washed with water (20ml) and dried at 45-50 oC to give 14.0g of compound of Formula 2 (80%) as a white solid.

Example 3b: Synthesis of compound of Formula 2 (keto diacid)
To a solution of compound of Formula 3 and other corresponding alkylated keto esters (viz. methyl ethyl and dimethyl keto esters) derivatives (230g) in ethanol (960ml), potassium hydroxide (110g) in water (240ml) was added slowly at 20-30°C. The temperature of reaction mixture was raised up to 65-70 °C and stirred for 15 hours for completion of reaction by TLC followed by distillation of ethanol. To the residue, water (960 ml) was added, pH 8-9 adjusted with concentrated HCl (~50ml) followed by washing with MTBE twice (2x480 ml). The traces of MTBE were removed by distillation under vacuum and then the pH of the aqueous layer adjusted to 5-6 with dilute HCl (189 ml) to precipitate keto diacid. The slurry was stirred for 1.5 hours at 20-30°C and solid was filtered out. Wet solid was slurry washed with water (480 ml) followed by running wash with water (120 ml) and dried at 40-45°C to give 173.5g (82%) of the title compound having assay more than 98%w/w. The crude material (155g) was dissolved in MTBE (387.5 ml) at temperature 50-55°C, cooled to 40-45°C followed by slow addition of hexane (775 ml). The reaction mixture was cooled to 20-30°and stirred for 1hour and then again cooled to 0-5°C and stirred for 1 hour. The solid was filtered and washed with hexane (155 ml). The wet material dried at 45-50°C to give title compound 143.48g (93%) having assay more than 99%w/w.

Example 4a: Synthesis of bempedoic acid (Formula 1)
To a stirred solution of compound of Formula 2 (54g) in water (325ml), aqueous sodium hydroxide (16g in 215 ml water) was added slowly at 25-30°C. Reaction mixture was stirred for 30 minutes to get a clear solution and sodium borohydride (6 g) was added at 10-15°C. Temperature of the reaction mixture was raised up to 25-30°C and stirred for 3 hours. After completion of reaction, the pH of reaction mixture was adjusted up to 8.0-9.0 with concentrated hydrochloric acid (30ml) and reaction mixture was washed with MTBE twice (2 × 108 ml). The pH of the reaction mixture was adjusted to 2-3 by using concentrated hydrochloric acid (25ml) and extracted with MTBE twice (2 × 378ml). The organic layer was washed with water (270 ml) followed by 10% sodium chloride solution (270 ml). The organic layer was concentrated under vacuum to obtain the crude bempedoic acid (55 g). The obtained crude product was crystallized with ethyl acetate to give 35.2g of bempedoic acid (white solid).

Example 4b: Synthesis of bempedoic acid (Formula 1)
To a stirred solution of sodium hydroxide (30.0g) in water (600 ml), compound of Formula 2 (keto diacid, 120g) was added for complete dissolution. The reaction mixture was cooled to 0-15°C and Sodium borohydride (9.6 g) was added lot wise. The temperature of the reaction mass was raised to 20-30°C and stirred for ~3 hours for completion of reaction by TLC. The reaction mixture was acidified with dilute hydrochloric acid (50ml) to adjust the pH 8.0-9.0 and reaction mixture was washed with MTBE twice (2x240ml). To the aqueous layer, MTBE (600 ml) was added, and pH adjusted to 1-2 by using aqueous HCl solution (~139ml). The reaction mass stirred for 10-15 min., settled and layers were separated. The product was extracted from aqueous layer with MTBE twice (2x240ml). The combined organic layer was washed with water (600ml) and followed by activated carbon (12g) treatment at 20-30°C. After filtration of activated carbon, the organic layer was concentrated under vacuum and chased with ethyl acetate (120 ml) to obtain the crude product. The obtained crude product was dissolved in ethyl acetate (600ml) at temperature 50-60°C, slowly cooled to 20-30°C and stirred for 1hour. Again, cooled to 0-5°C, stirred for 1hour, filtered and washed with precooled ethyl acetate (60ml). The obtained solid was dissolved in ethyl acetate (360ml) at temperature 50-60°C and slowly cooled to 20-30°C, stirred for 1 hour, cooled to 0-5°C, stirred for 1 hour, filtered and washed with precooled ethyl acetate (60ml). The obtained wet solid was dried at 50-55°C to obtained 99.12g (83%) of pure bempedoic acid having purity 99.9% and diketone and diol impurties were not detected by HPLC (CAD).
,CLAIMS:Claim 1. An efficient process for preparing bempedoic acid of Formula 1,

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

Formula 3a
wherein R is an alkyl group
with a base in presence of solvent to give a reaction mixture;
ii) adding water to the reaction mixture of step i) followed by washing the aqueous layer with suitable solvent;
iii) adjusting pH of the aqueous layer with an acid to precipitate out the compound of Formula 2; and

Formula 2

iv) reducing the compound of Formula 2 with a reducing agent to give the compound of Formula 1.
Claim 2. The process as claimed in claim 1, wherein the reaction mixture of step i) is obtained by hydrolysing the compound of Formula 3a with a base and followed by distillation of solvent.
Claim 3. The process as claimed in claim 1, wherein in step i), the solvent is selected from methanol, ethanol, propanol, isopropanol and in step ii) the solvent is selected from hexane, cyclohexane, toluene, heptane, benzene, xylene, methyl tert-butyl ether (MTBE), diethyl ether (DEE), di-tert-butyl ether (DTBE), diisopropyl ether (DIPE), tetrahydrofuran (THF), 2-methyltetrahydrofuran and cyclopentyl methyl ether.
Claim 4. The process as claimed in claim 1, wherein in step iv), the reducing agent is sodium borohydride.
Claim 5. An efficient process for preparing bempedoic acid of Formula 1,

Formula 1
comprising the step of:
i) treating compound of Formula 4a;

Formula 4a
wherein R is an alkyl group
with an acid to give a reaction mixture comprises of compound of Formula 3a,

Formula 3a
wherein R is an alkyl group
and 4-methylbenzene sulfinic acid of Formula 6 as by-product;

Formula 6

ii) filtering out precipitated 4-methylbenzene sulfinic acid of Formula 6;
wherein the Formula 6 is upcycled for preparing TosMIC;
iii) washing the filtered organic layer with a base;
iv) isolating the compound of Formula 3a; and

Formula 3a
wherein R is an alkyl group
v) converting the compound of Formula 3a to bempedoic acid of Formula 1.
Claim 6. An efficient process for preparing bempedoic acid of Formula 1,

Formula 1
comprising the step of:
i) reacting compound of Formula 5a;

Formula 5a

wherein X is halogen and R is an alkyl group
with TosMIC in presence of a base to give compound of Formula 4a; and

Formula 4a
wherein R is an alkyl group
ii) converting the compound of Formula 4a to the bempedoic acid of Formula 1;
wherein in step i) TosMIC is prepared from upcycled 4-methylbenzene sulfinic acid of Formula 6.
Claim 7. The process as claimed in claim 6, wherein in step i), the base is selected from sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium t-butoxide and potassium t-butoxide.
Claim 8. An efficient process for preparing compound of Formula 2,

Formula 2

comprising the step of:
i) adding an acid to the aqueous layer containing the compound of Formula 2 and
ii) precipitating the compound of Formula 2 by adjusting the pH of aqueous layer between 4 to 7 at a temperature in the range of 10 °C to 25°C.
Claim 9. The process as claimed in claims 1, 5 and 8, wherein the acid is selected from hydrochloric acid, sulphuric acid and phosphoric acid.
Claim 10. The process as claimed in claimed in claims 1 and 5, wherein the base is selected from sodium hydroxide, potassium hydroxide or ammonium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate.

Dated this 30th day of January 2023.

Kapil
Manager-II, IPR
Ind-Swift Laboratories Limited