DESC:FIELD OF THE INVENTION
The present invention relates to an efficient process for the purification of bempedoic acid. More particularly, the invention relates to a process for the purification of bempedoic acid, substantially free from impurities.

BACKGROUD OF INVENTION
Bempedoic acid is an ATP Citrate lyase inhibitor that lowers low-density lipoprotein cholesterol (LDL-C) by inhibition of cholesterol synthesis in the liver by up-regulating the LDL receptor. The chemical name of bempedoic acid is 8-hydroxy-2,2,14,14-tetramethyl-pentadecanedioic acid having the following chemical structure (Formula-I).

Formula – I
The solubility of bempedoic acid is pH-dependent as the solubility increases with increase in pH values. It is insoluble at low pH values, and solubility increases rapidly above pH 6. Based on its low solubility and high permeability, bempedoic acid is a BCS Class II compound.
Bempedoic acid and its pharmaceutically acceptable salts have been disclosed first time in US patent US 7,335,799. The process involves reaction of 1,5 dibromopentane (1) with ethyl isobutyrate (2) in the presence of lithium diisopropylamide (LDA)/THF to obtain ethyl 7-bromo-2,2-dimethylheptanoate (3). The compound of formula (3) is treated with p-toluenesulfonyl methyl isocyanide in the presence of tetra-n-butylammonium iodide (TBAI)/sodium hydride (NaH)/ dimethyl sulfoxide (DMSO) to give diethyl 8-isocyano-2,2,14,14-tetramethyl-8-tosylpentadecanedioate (4), which is further treated with hydrochloric acid/dichloromethane to obtain diester compound (5). Upon hydrolysis of the diester compound with potassium hydroxide (KOH)/ethanol gives keto-acid (6). Finally, reducing the compound (6) with sodium borohydride in methanol to give bempedoic acid. The said process is represented by the following scheme:

The final compound i.e., bempedoic acid obtained by above said process is in low yield (60%), as very viscous oil, with low HPLC purity 83.8%. This low purity and viscous oily nature of bempedoic acid is not suitable as an active ingredient for use in pharmaceutical formulations. In pharmaceutical preparations, it is difficult to transfer viscous oils as compared to solids. Further, removal of residual solvents from viscous oil are more difficult than from the solids as longer time is required to separate them.
An Indian patent publication, IN201941027561 discloses a process for the preparation of bempedoic acid. In said patent application bempedoic acid is purified by dissolving bempedoic acid in an organic solvent, wherein the organic solvent comprises of ethers, esters, hydrocarbons, or mixture thereof. Thereafter, the reaction mass is maintained for 12-15 hours at a temperature less than 50° C and bempedoic acid is isolated as crystalline form. However, in specified examples of said application only ester solvents (ethyl acetate, isopropyl acetate) are used for the purification of bempedoic acid.
Another Indian patent publication, IN202021050188 discloses a process for the preparation of bempedoic acid and its intermediates. The application also covers a process for the purification of bempedoic acid in which bempedoic acid is dissolved in a mixture of organic solvents, wherein the solvent is selected from the group of alcohols, ketone, esters, chlorinated hydrocarbons, ethers, polar aprotic solvents water or a mixture thereof. Thereafter, the reaction mixture is heated to a specific temperature followed by cooling. Finally, pure bempedoic acid is isolated. However, in specified examples, purification of bempedoic acid is carried out in a mixture of solvent i.e., dichloromethane and methyl tert butyl ether.
Another Indian patent publication, IN202041056804 unveils a purification process for preparing crystalline form P of bempedoic acid. The process comprises of dissolving crude bempedoic acid in an ester solvent followed by heating the suspension at a suitable temperature. Afterwards, the solution is cooled and pure bempedoic acid is isolated.
Another Indian patent publication, IN202121018598 provides a process for the purification of bempedoic acid. The process comprises providing a solution of bempedoic acid in a first solvent followed by heating the reaction mixture along with optional cooling. Thereafter, a second solvent is added to the mixture and pure bempedoic acid is isolated. The first and second solvents used in purification of bempedoic acid is selected from the group of amide, ether, halogenated hydrocarbon, alcohol solvents or mixture thereof. Although in specified example, only the mixture of methyl tert butyl ether and n-heptane is used for the purification of bempedoic acid, and the application is silent about the purity of bempedoic acid after purification.
A PCT publication WO 2020/257571 discloses a process for the preparation of bempedoic acid and its pharmaceutically acceptable salts. In said publication crude bempedoic acid is purified by crystallizing the bempedoic acid in a mixture of solvent comprising ethyl acetate and water. Thereafter the crystalline form is isolated by centrifugation and then washed with ethyl acetate. Finally, the wet cake is dried under vacuum and recrystallized with the same solvent system. However, the purification process herein involves tedious and cumbersome procedures such as multiple crystallizations or isolation steps, column chromatographic purifications.
In most of the above-mentioned prior arts, when repeated, the purity of bempedoic acid obtained after purification is not up to the mark. This may be attributed due to the presence of impurities which originates mainly during the synthetic process from the raw materials, solvents, intermediate and by-products. The purity of an API depends on several factors such as starting material, reaction kinetics and the crystallization process. The presence of these impurities even in small amounts may affect the efficacy and safety of the pharmaceutical products. Therefore, the identification, quantitation, qualification, and control of impurities are a critical part of the drug development process.
According to regulatory authorities and in guidelines issued by ICH (The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use), a drug manufacturer must submit data demonstrating that the product intended for marketing complies with regulations with regard to the content of impurities. The content of an unidentified impurity cannot exceed 0.1% (1000 ppm) by weight, while the amount of a known impurity cannot exceed 0.15% (1500 ppm). The drug manufacturer usually submits analytical data to the regulatory authority demonstrating that content of each impurity is in accordance with regulations. The regulatory authority checks the submitted data in order to ensure that the drug is having acceptable amount of impurities and is suitable for marketing. But this level of 0.1% (1000 ppm) or 0.15% (1500 ppm) may be even unacceptably high for an impurity if it is genotoxic.
Nevertheless, besides the existing routes of purification of bempedoic acid there is a continuing need in the art to optimize the purification condition of bempedoic acid which will purge the impurities down to the desired level as per ICH guidelines.

OBJECT OF THE INVENTION
The principal object of the present invention is to provide an efficient process for the purification of bempedoic acid wherein the individual impurities identified by their retention time are controlled as per the prescribed guidelines of ICH.
Another object of the present invention is to provide crystalline bempedoic acid in a consistent manner by controlling the level of impurities at different RRT (relative retention time).
One another object of the present invention is to provide an effective method of purifying the bempedoic acid by using a suitable solvent system.

SUMMARY OF INVENTION
The present invention relates to a purification process of bempedoic acid wherein the individual impurities are controlled in the final product to obtain pure bempedoic acid.
According to one embodiment, the present invention provides a process for the purification of bempedoic acid of Formula-I,

Formula – I

which comprises steps of:
i. providing a solution of bempedoic acid in a suitable solvent,
ii. optionally, filtering the solution obtained in step (i),
iii. distilling the solvent to get a solid mass,
iv. dissolving the solid mass in a mixture of solvents,
v. cooling the reaction mixture obtained in step (iv),
vi. isolating pure bempedoic acid.

According to one embodiment, the present invention provides a process for the purification of bempedoic acid of Formula-I, which comprises steps of:
i. dissolving crude bempedoic acid in a mixture of solvents,
ii. cooling the reaction mixture,
iii. isolating the pure bempedoic acid.

BRIEF DESCRIPTION OF THE DRAWINGS
1. Figure-1 represents the PXRD pattern of crystalline bempedoic acid.

DETAILED DESCRIPTION OF THE INVENTION
The present invention provides an improved and industrially advantageous process for the purification of bempedoic acid of Formula-I wherein bempedoic acid obtained after purification is substantially free form impurities as per prescribed limit of ICH guidelines.
The term “substantially free” herein means bempedoic acid having each known impurity less than about 0.15% by area percentage of HPLC or each unknown impurity less than about 0.10% by area percentage of HPLC. In particular, less than about 0.10% by area percentage of HPLC. More particular, less than about 0.05% by area percentage of HPLC. Most particularly, in the range of about 0.0% to about 0.05% by area percentage of HPLC.
The term “pure” herein refers to purity of bempedoic acid, which is substantially free from, one or more impurities and having purity of greater than 99% or more of about 99.5% or more, particularly of about 99.9% or more by area percentage of HPLC.
In one general aspect there is provided bempedoic acid having a purity of about 99.5% or more by area percentage of HPLC.
In another general aspect, there is provided bempedoic acid having total impurities less than or equal to 0.5% relative to bempedoic acid as measured by area percentage of HPLC.
Generally, impurities are identified spectroscopically and/or with another physical method, and then are associated with a peak position, such as that in a chromatogram, or with a spot on a TLC plate. Thereafter, the impurity can be identified, e.g., by its relative position in the chromatogram, where the position in a chromatogram is measured in minutes between injection of the sample on the column and elution of the particular component through the detector. The relative position in the chromatogram is known as the “retention time” (RT).
Retention time can vary about a mean value based upon the condition of the instrumentation as well as many other factors. To mitigate the effects such variations, have upon accurate identification of an impurity, those skilled in the art use the “relative retention time” (RRT) to identify impurities. The RRT of an impurity is its retention time divided by the retention time of a reference marker.
Impurities in bempedoic acid are undesirable, and may be harmful to a patient being treated with a dosage form of the API in which a sufficient amount of impurities are present. Furthermore, the undesired impurities reduce the level of the API available in pharmaceutical composition.
The ICH Q7A guidance for drug manufacturers requires that process impurities be maintained below set limits by specifying the quality of raw materials, controlling process parameters, such as temperature, pressure, time, and stoichiometric ratios, and including purification steps, such as crystallization, distillation, and liquid-liquid extraction, in the manufacturing process.
The process comprises the step of preparing a suspension of bempedoic acid in a suitable solvent. The dissolution of bempedoic acid in the solvent can be achieved by heating the suspension from greater than 40? to reflux temperature of solvent used. The solvent mentioned herein may be selected from a group of organic solvents which may include but not limited to chlorinated solvents such as dichloromethane, chloroform, carbon tetrachloride; alcohols, such as methanol, ethanol, ethylene glycol, 1-propanol, 2-propanol, 2-methoxyethanol, 1-butanol, 2-butanol, iso-butyl alcohol, t- butyl alcohol, glycerol and more thereof. Preferably the solvent is methanol or dichloromethane. Thereafter, the solution can optionally be filtered. Filtration can be carried out to remove any particle if present. Subsequently, the solvent can be distilled out under vacuum to get a solid mass.
The solid mass obtained in the above process is having a low purity of 96.72%, wherein impurities present are observed 2.10% at RRT 1.49; 0.56% at RRT 0.54 and 0.17% at RRT 0.29. These impurities were observed to be present at levels which are unacceptable as per the recommended ICH guidelines. Consequently, in order to obtain the bempedoic acid of desired purity it can be further subjected for purification.
Furthermore, the solid mass can be dissolved in a mixture of solvent at a temperature greater than 40? to reflux temperature of solvent used. The solvent used herein can be selected from any suitable organic solvent which is selected from the group consisting of hydrocarbons such as n-hexane, n-heptane, cyclohexane, petroleum ether, toluene, pentane, methylcyclohexane, ethyl benzene; C1-C8 alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol and mixture thereof. Preferably, the mixture of solvent can be preferably a hydrocarbon and alcohol, more preferably the mixture of solvent can be cyclohexane and methanol.
According to another embodiment of the present invention it was also unexpectedly found that a good reproducibility of the crystalline form of bempedoic acid can be obtained by using a mixture of solvent in a specific ratio. The ratio of solvent mixture may vary from 1: 60-80, preferably 1:65-75.
Thereafter, the reaction mixture can be cooled at a temperature of 0-20? and stirred at this temperature for few minutes to few hours for complete crystallization. After complete crystallization, pure bempedoic acid can be isolated by using techniques known in the art such as filtration centrifugation etc. The resulting solid can be then washed with the solvent selected form a mixture of solvent or any of the solvent used in mixture. Afterwards, the solid obtained can be dried at a temperature range of 45-65? to obtain pure bempedoic acid. The pure bempedoic acid obtained herein is devoid of impurity at RRT 0.54 whereas the impurities at RRT 1.48 and RRT 0.29 were found to be reduced considerably and present in acceptable amount i.e., less than 0.1% w/w by HPLC.
In another embodiment, the present invention provides a process for the purification of bempedoic acid of Formula-I, wherein bempedoic acid can be dissolved in a mixture of solvent at a temperature greater than 40? to reflux temperature of the solvent used. Thereafter the solution can be cooled to a temperature of 0-20? with continuous stirring for few minutes to few hours for complete crystallization. Preferably, the reaction mixture can be stirred for 2-5 hours. After complete crystallization, pure bempedoic acid can be isolated by using techniques known in the art such as filtration centrifugation etc. The resulting solid can be then washed with the solvent selected from a mixture of solvent or any of the solvent used in mixture. Finally, the solid can be dried at a temperature of 45-65? to obtain pure bempedoic acid.
The resulting pure bempedoic acid of present invention have purity of greater than 99.5 %, preferably 99.7 % and more preferably 99.90% and all impurities have been reduced to less than 0.1% w/w by HPLC. Bempedoic acid is crystalline in nature, and have XRD pattern as depicted in the figure-1.
The crude bempedoic acid can be prepared by the methods reported in literature or by the process as given in the present specification. The process involves reaction of 1,5 dibromopentane with ethyl isobutyrate in the presence of lithium diisopropylamide (LDA)/THF to obtain ethyl 7-bromo-2,2-dimethylheptanoate. The compound ethyl 7-bromo-2,2-dimethylheptanoate is treated with p-toluenesulfonyl methyl isocyanide in the presence of tetra-n-butylammonium iodide (TBAI)/ sodium hydride (NaH)/ dimethyl sulfoxide (DMSO) to give diethyl 8-isocyano-2,2,14,14-tetramethyl-8-tosylpentadecanedioate, which is further treated with hydrochloric acid/dichloromethane to obtain diester compound. Upon hydrolysis of the diester compound with potassium hydroxide (KOH)/ethanol gives 8- Oxo-2,2,14,14-tetramethylpentadecanedoic acid compound (6). Finally, reducing the compound (6) with sodium borohydride in methanol to give crude bempedoic acid.
Although the following examples illustrate the practice of the present invention in some of its embodiments, the examples should not be construed as limiting the scope of invention. Other embodiments will be apparent to one skilled in the art from consideration of the specification and examples.

EXAMPLES:
Example 1: Preparation of pure bempedoic acid
Step -1: Preparation of bempedoic acid
8- Oxo-2,2,14,14-tetramethylpentadecanedoic acid (50g) was dissolved in 500mL of methanol. An aqueous solution of sodium hydroxide (15g in 60mL) was added to the above solution at ambient temperature. After dissolution, 6.0 g of sodium borohydride was added to the reaction mixture and stirred at a temperature of 20-30?. Thereafter, the mixture was neutralized with hydrochloric acid and extracted with methylene dichloride. The methylene dichloride layer was distilled off under vacuum to get a solid mass having HPLC purity [w/w] = 96.72%; and impurities present are: 2.10% at RRT 1.49; 0.56% at RRT 0.54 and 0.17% at RRT 0.29.
Step -2: Purification of bempedoic acid
The resulting solid mass is then dissolved in a mixture of cyclohexane- methanol (350 ml: 5 ml). The reaction mixture was allowed to cool to 5-15? and then filtered. The solid obtained after filtration was washed with cyclohexane and dried at a temperature of 50- 60? to obtain 39g of pure bempedoic acid having HPLC purity [w/w] = 99.77% and impurities present are: 0.08% at RRT 1.48; not detected at RRT 0.54 and 0.03% at RRT 0.29.
Example 2: Preparation of pure bempedoic acid
Bempedoic acid was dissolved in 50 g of methanol at reflux temperature. The solution was filtered and then the solvent was recovered under vacuum to get a solid mass. Afterwards, the resulting solid mass was crystallized from cyclohexane- methanol mixture (350 ml: 5 ml). The reaction was allowed to cool to 5-15 ? and then filtered. The solid obtained after filtration was washed with cyclohexane and dried at a temperature of 50- 60? 40g of pure bempedoic acid was obtained with a HPLC purity of 99.90%.
COMPARATIVE EXAMPLES:
Example 1: Preparation of crystalline bempedoic acid
Bempedoic acid (50g) was added in 750mL of N,N- diisopropylether to obtain a suspension. The suspension was heated to reflux to get a clear solution. The solution was cooled to a temperature of 0-10 ? followed by stirring and filtration. The solid obtained after filtration was washed with N,N- diisopropylether and dried at a temperature of 50-60? to obtain 46 g of crystalline bempedoic acid having HPLC Purity [w/w] = 98.16%; and impurities present are: 0.80% at RRT 0.77; 0.50% at RRT 1.20 and 0.29% at RRT 0.82.
Example 2: Preparation of crystalline bempedoic acid
Bempedoic acid (50g) was added in 350mL of ethyl acetate to obtain a suspension. The suspension was heated to a temperature of 40-50 ? to get a clear solution. Thereafter, 10 mL water was added to the clear solution and cooled to a temperature of 0-10 ? followed by stirring and filtration. The solid obtained after filtration was washed with ethyl acetate and dried at a temperature of 50- 60 ? to obtain 46 g of crystalline bempedoic acid having HPLC purity [w/w] = 98.53% and impurities present are 0.74% at RRT 0.77; 0.48% at RRT 1.20 and 0.25% at RRT 0.82.
Example 3: Preparation of crystalline bempedoic acid
Bempedoic acid (50g) was dissolved in 40mL of ethyl acetate to obtain a suspension. The suspension was heated to a temperature of 40-50?, resulting in a clear solution. Thereafter, 500 mL hexane was added to the clear solution and cooled to a temperature of 0-10 ?. The resulting solution was filtered and washed with hexane to obtain 46 g of crystalline bempedoic acid having HPLC purity [w/w] = 98.48 % and impurities are present 0.73% at RRT 0.76; 0.52% at RRT 1.20 and 0.27% at RRT 0.82.
It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention and specific examples provided herein without departing from the spirit and scope of the invention. Thus, it is intended that the present invention covers the modifications and variations of this invention that come within the scope of any claims and their equivalents.
,CLAIMS:We claim:
1. A process for the purification of bempedoic acid of Formula-I,

Formula – I
which comprises steps of:
i. providing a solution of bempedoic acid in a suitable solvent,
ii. optionally, filtering the solution obtained in step (i),
iii. distilling the solvent to get a solid mass,
iv. dissolving the solid mass in a mixture of solvents,
v. cooling the reaction mixture obtained in step (iv),
vi. isolating pure bempedoic acid.

2. The process as claimed in claim 1, wherein in step (i), suitable solvent is selected from chlorinated solvents such as dichloromethane, chloroform, carbon tetrachloride; alcohols, such as methanol, ethanol, ethylene glycol, 1-propanol, 2-propanol, 2-methoxyethanol, 1-butanol, 2-butanol, iso-butyl alcohol, t- butyl alcohol, glycerol and more thereof.

3. The process as claimed in claim 1, wherein mixture of solvents used in step (iv) is selected from group consisting of C1-C8 alcohol and hydrocarbon thereof.

4. The process as claimed in claim 3, wherein C1-C8 alcohol is selected from a group consisting of methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol; hydrocarbon is selected from a group consisting of n-hexane, n-heptane, cyclohexane, petroleum ether, toluene, pentane, methylcyclohexane, ethyl benzene thereof.

5. The process as claimed in claim 1, wherein mixture of C1-C8 alcohol and hydrocarbon in step (iv) are in the ratio of 1: 60-80.

6. The process as claimed in claim 1, wherein cooling of reaction mass in step (v) is carried out at 0-20?.

7. A process for the purification of bempedoic acid of Formula-I, which comprises steps of:
i. dissolving crude bempedoic acid in a mixture of solvents,
ii. cooling the reaction mixture,
iii. isolating the pure bempedoic acid.
8. The process as claimed in claim 7, wherein mixture of solvents used in step (i) is selected from group consisting of C1-C8 alcohol and hydrocarbon thereof.

9. The process as claimed in claim 8, wherein C1-C8 alcohol is selected from a group consisting of methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol; hydrocarbon is selected from group consisting of n-hexane, n-heptane, cyclohexane, petroleum ether, toluene, pentane, methylcyclohexane, ethyl benzene thereof.

10. The process as claimed in claim 7, wherein cooling of reaction mass in step (ii) is carried out at 0-20?.