DESC:FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of Bempedoic acid of Formula I using a novel intermediate of Formula VIII.

BACKGROUND OF THE INVENTION
Bempedoic acid developed by Esperion Therapeutics, is an Adenosine triphosphate-Citrate Lyase (ACL) inhibitor that lowers low-density lipoprotein cholesterol (LDL-C) by inhibition of cholesterol synthesis in the liver. ACL is an enzyme upstream of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase in the cholesterol biosynthesis pathway.

Bempedoic acid is chemically known as 8-hydroxy-2,2,14,14-tetramethyl-pentadecanedioic acid and its structure is as shown below.

US7335799B2 discloses first synthetic route for preparing Bempedoic acid. The reaction scheme disclosed therein is given below (Scheme A)

Scheme A

CN109721486A discloses similar synthetic route for the preparation of Bempedoic acid but uses water as a solvent instead of methanol for the reduction step.

Further EP3666750A1, follows similar route but differs in the last step where first reduction is carried out and then ester hydrolysis.

WO2020257571A1, further modifies EP3666750A1 route where it converts ethyl 7-halo-2,2-dimethylheptanoate intermediate into its corresponding iodo intermediate.

The prior art processes have lot of disadvantages like multi stage purification, tedious work up and more specifically a low overall yield of the final product i.e. Bempedoic acid. Thus, to overcome the drawbacks and disadvantages of the prior arts, the inventors of the present application have worked extensively to get an improved process for the preparation of Bempedoic acid in good yield and purity.

OBJECTIVE OF THE INVENTION
The main objective of the present invention is to provide a simple, efficient and industrially viable novel process for the preparation of Bempedoic acid or a pharmaceutically acceptable salt thereof wherein the formation of undesired impurities is avoided or minimized.

SUMMARY OF THE INVENTION
In first aspect of the present invention is provided a novel, industrially feasible and economical process for preparing Bempedoic acid, comprising the steps of-
a) reacting a compound of Formula II with a compound of Formula III in presence of a base to provide a compound of Formula IV,

wherein, LG is a Leaving Group;
b) optionally converting the compound of Formula IV to a compound of Formula V in the presence of an alkali metal iodide,

c) reacting the compound of Formula IV or Formula V with a compound Formula VI in presence of a base to provide a compound of Formula VII,

wherein R1 is optionally substituted C1-C6 alkyl, aryl or aryl alkyl;
d) hydrolysing the compound of Formula VII in presence of a base to provide compound of Formula VIII or pharmaceutically acceptable salts thereof,

e) treating the compound of formula VIII in presence of an acid to provide compound of formula IX or pharmaceutically acceptable salts thereof, and

f) reducing the compound of formula IX to provide Bempedoic acid or its pharmaceutically acceptable salts thereof.

In another aspect of the present invention is provided a novel intermediate of formula VIII or its pharmaceutically acceptable salts thereof.

wherein, R1 is optionally substituted C1-C6 alkyl, aryl group or aryl alkyl.
In a further aspect of the present invention, Bempedoic acid obtained is having compound of Formula A in amount less than about 0.15% (w/w).

Formula A
BRIEF DESCRIPTION OF THE DRAWINGS
Figure l depicts the X-Ray Powder Diffractogram (XRPD) of crystalline Bempedoic acid obtained as per present invention.

DETAILED DESCRIPTION OF THE INVENTION
The present invention provides an improved process for the preparation of Bempedoic acid using a novel intermediate.
Accordingly, the present invention provides an improved process for preparing Bempedoic acid comprising the steps of:
a) reacting a compound of Formula II with a compound of Formula III in presence of a base to provide a compound of Formula IV,

wherein LG is a Leaving Group;
b) optionally converting the compound of Formula IV to a compound of Formula V in the presence of an alkali metal iodide,

c) reacting the compound of Formula IV or Formula V with a compound Formula VI in presence of a base to provide a compound of Formula VII,

wherein R1 is optionally substituted C1-C6 alkyl, aryl or aryl alkyl;
d) hydrolysing the compound of Formula VII in presence of a base to provide compound of Formula VIII or pharmaceutically acceptable salts thereof,

e) treating the compound of formula VIII in presence of an acid to provide compound of formula IX or pharmaceutically acceptable salts thereof, and

f) reducing the compound of formula IX to provide Bempedoic acid or its pharmaceutically acceptable salts thereof.

In an embodiment, the present invention provides pure Bempedoic acid by further purification of the Bempedoic acid or its pharmaceutically acceptable salts thereof as obtained by the above process.

In another embodiment, the present invention provides the compound of formula VIII or its pharmaceutically acceptable salts thereof.

wherein, R1 is optionally substituted C1-C6 alkyl, aryl or aryl alkyl.

In a further embodiment, the present invention provides the compound of formula VIII or its pharmaceutically acceptable salts thereof.

wherein, R1 is methyl, tolyl, or benzyl.

In accordance to present invention, the compound of formula IV, V, VII, VIII, and IX can be either isolated or further reacted in next step without isolation.

In an embodiment of present invention “alkali metal iodide” refers to but is not limited to sodium iodide, potassium iodide and like.

In an embodiment of present invention “Organic solvent” refers to but is not limited to "ester solvents" such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, tert-butyl acetate and like; "polar-aprotic solvents" such as 1,3-dimethyl-2-imidazolidinone, dimethylacetamide, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone (NMP) and like; "chloro solvent" such as dichloromethane and like; "ketone solvents" such as acetone, methyl ethyl ketone, methyl isobutyl ketone and like; "nitrile solvents" such as acetonitrile, propionitrile, isobutyronitrile and like; "alcohol solvents" such as methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, tert-butanol, ethane-1,2-diol, propane-1,2-diol and like; "hydrocarbon solvents" such as n-hexane, n-heptane, cyclohexane, petroleum ether, benzene, toluene, xylene and like; "ether solvents" such as dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether, 1,2-dimethoxy ethane, tetrahydrofuran, 1,4-dioxane and like; "polar solvents" such as water; and mixtures thereof.

In an embodiment of present invention “Acid” refers to but is not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; acetic acid, propionic acid, maleic acid, citric acid, fumaric acid, tartaric acid, succinic acid, oxalic acid, salicylic acid, benzoic acid, methansulfonic acid, isethionic acid, benzenesulfonic acids and like.

In an embodiment of present invention “Base” refers to but is not limited to organic bases or inorganic bases.

In an embodiment of present invention “Organic base” refers to but is not limited to pyridine, DMAP (4-dimethylaminopyridine), n-butyllithium, triethylamine, DIPEA (N,N-diisopropylethylamine), N-methylpiperidine, DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), DABCO (1,4-diazabicyclo[2.2.2]octane), DBN (1,5-diazabicyclo[4.3.0]non-5-ene), N-methylmorpholine and the like.

In an embodiment of present invention “Inorganic base” refers to but is not limited to alkali and alkaline earth metal hydrides such as sodium hydride, potassium hydride, lithium hydride; alkali and alkaline earth metal carbonates such as potassium carbonate, sodium carbonate, caesium carbonate, calcium carbonate; alkali and alkaline earth metal hydrogen carbonates such as potassium hydrogen carbonate, sodium hydrogen carbonate; alkali metal alkoxides such as potassium ethoxide, sodium ethoxide, potassium tertiary butoxide, sodium tertiary butoxide; and alkali and alkaline earth metal hydroxides such as, sodium hydroxide, potassium hydroxide, calcium hydroxide and lithium hydroxide; and the like.

In an embodiment of present invention “Reducing agent” refers to but is not limited to reagents that are well known to those skilled in the art. the suitable reducing agent is selected from the group consisting of sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, diisobuyl aluminum hydride, sodium bis (2-methoxyethoxy)aluminum hydride, triisobutyl aluminum, potassium diisobutyl-tert-butoxyaluminium hydride, lithium borohydride, lithium diisobutyl-tert-butoxyaluminium hydride, sodium diisobutyl-tert-butoxyaluminium hydride, diisobuyl aluminum butylated oxytoluene, sodium aluminum hydride, lithium aluminum hydride, bis(4- methyl-1 -piperazinyl) aluminum hydride and the like.

In an embodiment of present invention “Leaving group” (LG) refers to but is not limited to any group that is eliminated from the main moiety during the reaction. Examples of leaving groups include, but are not limited to halogens such as Cl, Br, I and like; sulfonic acid derivatives i.e., mesylate, tosylate and the like.

In an embodiment of present invention “Pharmaceutically acceptable salts” refers to but is not limited to the salts of organic and inorganic acids which is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; acetic acid, citric acid, propionic acid, maleic acid, fumaric acid, tartaric acid, succinic acid, oxalic acid, salicylic acid, formic acid, ascorbic acid, mandelic acid, dibenzoyl tartaric acid, benzoic acid, p-toluenesulfonic acid, methansulfonic acid, isethionic acid, benzenesulfonic acids and the like.
Major advantage of the present invention is isolation of novel compound of Formula VIII as stable solid. In the prior art process, all the involved reaction intermediates are oily masses and are very difficult to isolate or purify. However, since novel intermediate compound of Formula VIII of Bempedoic acid is solid, it can be successfully isolated by simple filtration and purified. Moreover, the inventors of the present application also overcame the prior art process drawback of multiple hydrolysis step by instigating direct hydrolysis of diester compound of formula VII to diacid compound of formula VIII without liberation of keto group.
The bempedoic acid obtained from the prior art process has very low HPLC purity (~80%). This low purity and sticky oily nature of Bempedoic acid is not suitable as active ingredient for use in pharmaceutical product.
The inventors of the present application overcame the drawback of prior art process by isolation of novel compound of Formula VIII as stable solid wherein Bempedoic acid is obtained in high yield as crystalline solid having a high purity of more than 99.6% or above (w/w by HPLC).
In a further embodiment, the present invention includes substantially pure Bempedoic acid, wherein the amount of Bempedoic acid impurity Formula A listed in Table 1 is less than about 0.15%, or less than about 0.1%, by weight.

Table 1
Impurity Name IUPAC Name Structure
Impurity-Formula A
8-acetyloxy-2,2,14,14-tetramethylpentadecane dioicacid

Certain specific aspects and embodiments of the present invention will be better understood in connection with the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner.
The invention illustratively described herein suitably may be practiced in the absence of any element or elements, limitation or limitations which is not specifically disclosed herein. Thus, for example, in each instance herein any of the terms “comprising” and “consisting of” may be replaced with either of the terms. In addition, the solvents, temperatures, reaction durations, etc. delineated herein are for purposes of illustration only and one of ordinary skill in the art will recognize that variation of the reaction conditions can produce the desired products accordingly.
Examples:
Example 1: Preparation of ethyl 7-chloro-2,2-dimethylheptanoate (Formula IV, LG = Cl)
Tetrahydrofuran (60 ml), diisopropylamine (9.8 g) and n-BuLi solution (41.4 g) were charged into a RBF, stirred at RT under nitrogen atmosphere and the reaction mixture was cooled below -10°C. To the reaction mass 1,3-dimethyl-2-imidazolidinone (4.5 ml), ethyl isobutyrate (10.3 g) and 1-bromo-5-chloropentane (15.0 g) was charged and stirred. The reaction mass was heated and stirred at ambient temperature for 2-3 hours. After the reaction completion, reaction mass was cooled and quenched with saturated NH4Cl solution and stirred at RT. Organic layers were separated and washed with 10% HCl solution. Organic layer containing title compound is used directly in next step.
Example 2: Preparation of ethyl 7-iodo-2,2-dimethylheptanoate (Formula V)
To the organic layer containing Formula IV obtained in previous step was charged methyl ethyl ketone (75 ml) and sodium iodide (13.3 g) at RT. The reaction mass was heated and stirred at 75-80 °C. The reaction mass was distilled and cooled, followed by addition of cyclohexane and sodium bisulphite solution. Organic layers were separated and washed with water. Organic layer was evaporated to get title compound (24 g) as oily mass.
Example 3: Preparation of diethyl 8-isocyano-2,2,14,14-tetramethyl-8-tosylpentadecanedioate (Formula VII; R1=tolyl)
Ethyl 7-iodo-2,2-dimethylheptanoate (24 g), dimethyl sulfoxide (125 ml), p-toluene sulfonyl methyl isocyanide (7.4 g) and sodium t-butoxide (8.1 g) were mixed at RT under nitrogen atmosphere and stirred for 1 to 2 hours to obtain organic layer containing titled compound.
Example 4: Preparation of 8-isocyano-2,2,14,14-tetramethyl-8-tosylpentadecanedioic acid (Formula VIII; R1=tolyl)
To the organic layer containing Formula VII obtained in previous step, sodium hydroxide solution (23 g of NaOH in 72 ml of water) at ambient temperature was charged and stirred. The reaction mass was charged with water (75 ml) and toluene (75 ml) at ambient temperature and stirred. Layers were separated and aqueous layer was charged with citric acid (72 g) at 0-10 °C. Water (150 ml) was added to reaction mass and stirred for 2-3 hours. Filter the obtained mass and washed with water (37.5 ml) and dried. Further wet solid was charged with methanol (72 ml) and followed by addition of water (96 ml) and stirred for 1-2 hours. The obtained solid was filtered, washed with water and dried to get the title compound (16.5 g).
Example 5: Preparation of 8-oxo-2,2,14,14-tetramethylpentadecanedioic acid (Formula IX)
To the compound of Formula VIII (16.5 g), dichloromethane (75 ml), water (18.5 ml) and concentrated hydrochloric acid (18.5 ml) were added at ambient temperature and stirred for 1-2 hours. Layers were separated and organic layer was charged with water and sodium carbonate, followed by 50% HCl solution and water. The obtained solid was filtered, washed with water and dried to get the title compound. Yield: 10.4 g; 75.2 %
Example 6: Preparation of bempedoic acid (Formula I):
Compound of Formula IX (9.0 g) was charged in sodium carbonate (6.4 g), water (72 ml) and sodium borohydride (1.0 g) at ambient temperature and stirred for 1-2 hours. After the completion of the reaction, reaction mass was treated in dichloromethane, followed by 50% hydrochloric acid solution and methyl tert-butyl ether. The obtained solid were filtered, washed with dichloromethane and dried to get the title compound of formula I.
Yield: 6.8 g; 76 %
Example 7: Purification of Bempedoic acid (Formula I):
Bempedoic acid (6.5 g) was charged in ethyl acetate (13 ml) and water (0.3 ml) was heated to 50-55°C and raised the reaction mass temperature to 70 °C and stirred for 1 hour. Later reaction mass was cooled to ambient temperature and stirred for 3-4 hours. The obtained solid were filtered, washed with acetonitrile and dried to get the title compound in crystalline form.
Yield: 5.3 g, 81.5 %;
Purity by HPLC: 99.6 %
PXRD pattern of the crystalline compound as obtained here is depicted in Figure-1.
X-ray powder diffraction (XRPD) was performed on X-Ray powder diffractometer: (PanAlytical X'pert Pro powder diffractometer, CuKa radiation, ? = 1.5405980 A. X’Celerator detector active length (2 theta) = 3.3473mm, laboratory temperature 22-25 °C.) ,CLAIMS:1. An improved process for the preparation of Bempedoic acid, comprising the steps of:
a) reacting a compound of Formula II with a compound of Formula III in presence of a base to provide a compound of Formula IV,

wherein, LG is a Leaving Group;
b) optionally converting the compound of Formula IV to a compound of Formula V in the presence of an alkali metal iodide,

c) reacting the compound of Formula IV or Formula V with a compound Formula VI in presence of a base to provide a compound of Formula VII,

wherein R1 is optionally substituted C1-C6 alkyl, aryl or aryl alkyl;
d) hydrolysing the compound of Formula VII in presence of a base to provide compound of Formula VIII or pharmaceutically acceptable salts thereof,

e) treating the compound of formula VIII in presence of an acid to provide compound of formula IX or pharmaceutically acceptable salts thereof, and

f) reducing the compound of formula IX to provide Bempedoic acid or its pharmaceutically acceptable salts thereof.

2. The process as claimed in claim 1, wherein R1 is methyl, tolyl or benzyl.
3. The process as claimed in claim 1, wherein the compound of formula IV, V, VII, VIII and IX can be either isolated or further reacted in next step without isolation.
4. The process as claimed in claim 1, wherein the alkali metal iodide used in step b) is selected from sodium iodide or potassium iodide or any combination thereof; and/or the leaving group used in step a) and step b) is selected from halogen selected from Cl, Br or I or sulfonate selected from mesylate, tosylate or any combination thereof.
5. The process as claimed in claim 1, wherein the solvent used in step a) to step f) is independently selected from methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, tert-butyl acetate, dimethylacetamide, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone (NMP), dichloromethane, 1,3-dimethyl-2-imidazolidinone, acetone, methyl ethyl ketone, methyl isobutyl ketone, acetonitrile, propionitrile, isobutyronitrile, methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, tert-butanol, ethane-1,2-diol, propane-1,2-diol, n-hexane, n-heptane, cyclohexane, petroleum ether, benzene, toluene, xylene, dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether, 1,2-dimethoxy ethane, tetrahydrofuran, 1,4-dioxane, water; or any combination thereof.
6. The process as claimed in claim 1, wherein the base used in step a), step c) and step d) is independently selected from organic base and inorganic base, wherein the organic base is selected from pyridine, DMAP (4-dimethylaminopyridine), triethylamine, diisopropylamine, DIPEA (N,N-diisopropylethylamine), N-methylpiperidine, DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), DABCO (1,4-diazabicyclo[2.2.2]octane), DBN (1,5-diazabicyclo[4.3.0]non-5-ene), n-butyllithium, N-methylmorpholine or mixtures thereof and inorganic base is selected from sodium hydride, potassium hydride, lithium hydride, potassium carbonate, sodium carbonate, caesium carbonate, calcium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, potassium ethoxide, sodium ethoxide, potassium tertiary butoxide, sodium tertiary butoxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, lithium hydroxide or any combination thereof.
7. The process as claimed in claim 1, wherein the acid used in step e) is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; acetic acid, propionic acid, maleic acid, citric acid, fumaric acid, tartaric acid, succinic acid, oxalic acid, salicylic acid, benzoic acid, methansulfonic acid, isethionic acid, benzenesulfonic acids or any combination thereof.
8. The process as claimed in claim 1, wherein the reduction in step f) is carried out in presence of a reducing agent selected from sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, diisobuyl aluminum hydride, sodium bis (2-methoxyethoxy)aluminum hydride, triisobutyl aluminum, potassium diisobutyl-tert-butoxyaluminium hydride, lithium borohydride, lithium diisobutyl-tert-butoxyaluminium hydride, sodium diisobutyl-tert-butoxyaluminium hydride, diisobuyl aluminum butylated oxytoluene, sodium aluminum hydride, lithium aluminum hydride, bis(4-methyl-1 -piperazinyl) aluminum hydride or any combination thereof.
9. The process as claimed in claim 1, wherein the Bempedoic acid isolated is characterized by the presence of compound of Formula A in amount less than about 0.15% (w/w).

Formula A
10. A compound of formula VIII or its pharmaceutically acceptable salts thereof.

wherein, R1 is as defined in claim 1 and 2.