DESC:FIELD OF THE INVENTION:
The present invention relates to a process for the purification of 7-bromo-2,2-dimethylheptanoic acid alkyl ester of Formula I, which is an intermediate useful in the synthesis of Bempedoic acid.

Formula I

BACKGROUND OF THE INVENTION:
7-Bromo-2,2-dimethylheptanoic acid alkyl ester of Formula I, especially 7-Bromo-2,2-dimethylheptanoic acid ethyl ester is a key intermediate in the synthesis of Bempedoic acid, which is chemically known as 8-hydroxy-2,2,14,14­tetramethyl-pentadecanedioic acid and represented by the following structural formula A:

Formula A

Bempedoic acid marketed under a brand name of Nexletol by Esperion Therapeutics, Inc. Nexletol tablets, for oral use; contain Bempedoic acid, an adenosine triphosphate-citrate lyase (ACL) inhibitor. Each film-coated tablet of Nexletol contains 180 mg of Bempedoic acid and the following inactive ingredients: colloidal silicon dioxide, hydroxyl propyl cellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium starch glycolate. The film coating comprises of partially hydrolyzed polyvinyl alcohol, polyethylene glycol, talc, and titanium dioxide.

US 7335799 first disclosed a process for the preparation of 7-bromo-2,2-dimethylheptanoic acid ethyl ester of Formula (Ia) and its further conversion to Bempedoic acid (A), which involves batch process, wherein a solution of lithium diisopropylamide in THF was slowly dropped into a solution of 1,5-dibromopentane (III) and ethyl isobutyrate (II) in THF and quenched by slow addition of saturated ammonium chloride solution. The resulting solution was divided into three 4-L portions and each portion was diluted with saturated ammonium chloride solution and extracted with ethyl acetate and finally combined into a single portion to produce 7-bromo-2,2-dimethylheptanoic acid ethyl ester of Formula I, which is schematically represented by the following scheme:

The said compound of formula Ia is further converted into Bempedoic acid. Similar processes were also reported in different publications such as WO2019179494, WO2020141419.

The compound of formula Ia obtained by the reported process having higher amounts of residual dibromopentane starting material and corresponding dimer of formula Ia as an impurity. The presence of dibromopentane at higher levels leads to the formation of diol impurity in final bempedoic acid as described in the patent publication WO2020257571A1, which utilizes 1-chloro-5-bromopentane. Removal of diol impurity at final stages is difficult and required yield losing purification.

Hence there is a need in the art for purification of compound of formula I to reduce the dibromopentane and other impurities and thereby controlling the formation of diol impurity and other derivative impurities at final stages. There by avoiding the yield losing purification at final stages.
OBJECTIVE OF THE INVENTION:
The main object of the present invention is to provide a process for the purification of 7-bromo-2,2-dimethylheptanoic acid alkyl ester of Formula I.

SUMMARY OF THE INVENTION:
In one aspect, the present invention provides a process for the purification of 7-bromo-2,2-dimethylheptanoic acid alkyl ester of Formula I, which is substantially free of 1,5-dibromopentane and dimer impurities;

Formula I
wherein R is an alkyl group;
which comprises;
a) hydrolyzing a compound of Formula I to provide a compound of Formula II,

Formula II
b) optionally converting the compound of Formula II into its alkali metal salt or an organic amine salt followed by hydrolysis; and
c) esterification of the compound of Formula II to provide a pure 7-bromo-2,2-dimethylheptanoic acid alkyl ester of Formula I.

In another aspect, the present invention provides 7-bromo-2,2-dimethylheptanoic acid alkyl ester of Formula I substantially free of 1,5-dibromopentane and dimer impurities.

In another aspect, the present invention provides the use of 7-bromo-2,2-dimethylheptanoic acid alkyl ester of Formula I substantially free of 1,5-dibromopentane and dimer impurities in the preparation of bempedoic acid of formula A.

In another aspect, the present invention provides a process for the preparation of bempedoic acid, which is substantially free of diol impurity, which comprises preparing 7-bromo-2,2-dimethylheptanoic acid alkyl ester of Formula I substantially free of 1,5-dibromopentane and dimer impurities and converting the same into Bempedoic acid, which is substantially free of diol impurity.

DETAILED DESCRIPTION OF THE INVENTION:
Accordingly, the present invention provides a purification process of 7-bromo-2,2-dimethylheptanoic acid alkyl ester of Formula I to get pure formula I which is substantially free of 1,5-dibromopentane and dimer impurities.

The term “suitable solvent” used in the present invention until unless specified is selected from, but are not limited to “alcoholic solvents” such as methanol, ethanol, isopropyl alcohol, n-propanol, butanol, isobutanol, t-butanol and the like; “ester solvents” such as ethyl acetate, methyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, isopropyl acetate and the like; “ether solvents” such as tetrahydrofuran, diethyl ether, methyl tert-butyl ether, dioxane and the like; “hydrocarbon solvents” such as toluene, xylene, cyclohexane, hexane, heptane, n-pentane, petroleum ether and the like; “chloro solvents” such as dichloromethane, ethylene dichloride, carbon tetrachloride, chloroform and the like; “polar aprotic solvents” such as dimethylformamide, dimethylacetamide, dimethylsulfoxide and the like; “nitrile solvents” such as acetonitrile and the like; “ketone solvents” such as acetone, methyl isobutyl ketone, methyl ethylketone and the like; and water.

The term “suitable base” used herein the present invention until unless specified is selected from inorganic bases like “alkali metal hydroxides” such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; “alkali metal carbonates” such sodium carbonate, potassium carbonate, lithium carbonate and the like; “alkali metal bicarbonates” such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate and the like; “alkali metal hydrides” such as sodium hydride, potassium hydride, lithium hydride and the like; “alkali metal alkoxides” such as sodium methoxide, sodium ethoxide, sodium tert butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide and the like; ammonia.

In one aspect, the present invention provides a process for the purification of 7-bromo-2, 2-dimethylheptanoic acid alkyl ester of Formula I, which is substantially free of 1, 5-dibromopentane and dimer impurities;

Formula I
wherein R is an alkyl group;
which comprises;
a) hydrolyzing a compound of Formula I to provide a compound of Formula II,

Formula II
b) optionally converting the compound of Formula II into its alkali metal salt or organic amine salt followed by hydrolysis; and
c) esterification of the compound of Formula II to provide a pure 7-bromo-2,2-dimethylheptanoic acid alkyl ester of Formula I.

The step a) of the aforementioned process involves hydrolysis of a compound of Formula I, wherein R is alkyl group selected from methyl, ethyl, propyl, isopropyl, t-butyl, n-butyl and the like; preferably ethyl, in the presence of a base or an acid; preferably an acid; in a suitable solvent under appropriate reaction conditions to provide a compound of Formula II; wherein the acid is selected from HC1, HBr, sulfuric acid, acetic acid, methanesulfonic acid, trifluoroacetic acid and the like; preferably HBr and sulfuric acid, and the base is selected from inorganic base such as sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium methoxide, sodium ethoxide and the like; and the solvent is mentioned as above. The step a) reaction is carried out at a suitable temperature from about 10°C to about reflux temperature of the solvent used, and maintain for a sufficient period of time till completion of the reaction; preferably the step a) reaction is carried out at about 100°C to about 130°C for 20-24 hrs.

The step b) of the aforementioned process involves treating the compound of Formula II with a suitable alkali metal source selected from sodium metal, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide; or suitable organic amine such as dicyclohexylamine, tertiarybutylamine and the like; preferably alkali metal source and more preferably sodium methoxide in a suitable solvent, selected from the list mentioned above, preferably ether solvents and more preferably diisopropyl ether; under appropriate reaction conditions to provide corresponding alkali metal salt or organic amine salt of a compound of Formula II and is carried out at a suitable temperature from about 10°C to about reflux temperature of the solvent used, and maintain for a sufficient period of time till completion of the reaction, preferably carried out at about 0°C to about 40°C for 1-2 hrs. Thus obtained alkali metal salt or organic amine salt of a compound of Formula II, preferably alkali metal salt of a compound of Formula II undergoes hydrolysis in the presence of an acid in a suitable solvent under appropriate reaction conditions to provide a pure compound of Formula II; wherein the acid is selected from HC1, HBr, sulfuric acid, acetic acid, methanesulfonic acid, trifluoroacetic acid and the like; preferably HCl and the solvent is mentioned as above; preferably water and chloro solvents; more preferably water and dichloromethane and is carried out at a suitable temperature from about 10°C to about reflux temperature of the solvent used, and maintain for a sufficient period of time till completion of the reaction; preferably carried out at about 5°C to about 40°C for 2-3 hrs.

The step c) of the aforementioned process involves esterification of the compound of Formula II with a suitable alcohol selected from methanol, ethanol, isopropanol, t-butanol and the like; preferably ethanol in the presence of an acid catalyst in a suitable solvent under appropriate reaction conditions to provide a pure 7-bromo-2,2-dimethylheptanoic acid alkyl ester of Formula I; alternatively esterification carried out by forming acid chloride of the compound of Formula II by treating with a chlorinating agent such as thionyl chloride, oxalyl chloride followed by treating with a suitable alcohol to provide a corresponding pure 7-bromo-2,2-dimethylheptanoic acid alkyl ester of Formula I, which is substantially free of impurities; wherein the acid catalyst is selected from p-toluenesulfonic acid, sulfuric acid, methanesulfonic acid, trifluoroacetic acid and the like; preferably p-toluenesulfonic acid, and the solvent is mentioned as above; preferably hydrocarbon solvents, more preferably toluene. The step c) reaction is carried out at a suitable temperature from about 10°C to about reflux temperature of the solvent used, and maintain for a sufficient period of time till completion of the reaction; preferably carried out at about 100°C to about 120°C and maintained for 15-18 hrs.

In a specific aspect, the present invention provides a process for the purification of 7-bromo-2,2-dimethylheptanoic acid ethyl ester of Formula Ia, which is substantially free of 1, 5-dibromopentane and dimer impurities;

Formula Ia
which comprises;
a) hydrolyzing a compound of Formula Ia to provide a compound of Formula II,

Formula II
b) converting the compound of Formula II into its sodium salt followed by hydrolysis; and
c) esterification of the compound of Formula II with ethanol to provide a pure 7-bromo-2,2-dimethylheptanoic acid ethyl ester of Formula Ia.

The compound of formula Ia prepared as per the reported process having low purity (93% by GC method) and contaminated with higher level of unreacted 1,5-dibromopentane as impurity (350 ppm to 900 ppm) and dimer impurity (3.11%, 31100 ppm), which in-turn, results in lower yield. The presence of higher levels of 1,5-dibromopentane leads to the formation of diol impurity at final stages, which is difficult to remove and required additional yield losing purifications to get the required purity. The present inventors working on improving yield, purity and reducing the 1,5-dibromopentane impurity and dimer impurity content in the compound of formula I, surprisingly found that hydrolysis of ester group followed by re-esterification reduces 1,5-dibromopentane impurity to less than 10 ppm and dimer impurity to Not Detected level and provides the compound of formula Ia in purity greater than 96% by GC method. Further utilization of the same for the preparation of bempedoic acid results in bempedoic acid substantially free of diol impurity.

In another aspect, the present invention provides 7-bromo-2,2-dimethylheptanoic acid alkyl ester of Formula I, substantially free of 1,5-dibromopentane and dimer impurities.

In another aspect, the present invention provides use of 7-bromo-2,2-dimethylheptanoic acid alkyl ester of Formula I substantially free of 1,5-dibromopentane and dimer impurities in the preparation of bempedoic acid of formula A.

In another aspect, the present invention provides a process for the preparation of bempedoic acid, which is substantially free of diol impurity, which comprises preparing 7-bromo-2,2-dimethylheptanoic acid alkyl ester of Formula I substantially free of 1,5-dibromopentane and dimer impurities according to the present invention process and converting the same into Bempedoic acid, which is substantially free of diol impurity.

The term “substantially free of 1,5-dibromopentane and dimer impurities in formula I” and “substantially free of diol impurity in the bempedoic acid” as used herein the present invention refers to the compound of formula I containing less than 10 ppm of respective impurities; preferably less than 5 ppm and more preferably less than 1 ppm.

Examples:
The process details of the invention are provided in the examples given below, which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention.
Example-1:
Preparation of 7-bromo-2,2-dimethylheptanoic acid of Formula II:
To a clean and dry RBF, 7-bromo-2,2-dimethylheptanoic acid ethyl ester (100 g), aqueous hydrobromic acid (350 ml) and sulphuric acid (75 ml) were added at 25-35°C, heated to 110-120°C and maintained for 24 hrs. After completion of the reaction, the reaction mass was cooled to 25-35°C and quenched into ice water (100 ml). Dichloromethane (200 ml) were added to the above reaction mass at 25-35oC and stirred for 30 mins. The organic and aqueous layers were separated; the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with water, subjected to carbon treatment; filtered through hyflow and washed with dichloromethane. The filtrate was dried over sodium sulphate and distilled off completely under vacuum at below 50°C to get the title compound.

Example-2:
Preparation of 7-bromo-2,2-dimethylheptanoic acid sodium salt of Formula IIa.
To a clean and dry RBF, 7-bromo-2,2-dimethylheptanoic acid (100 g) and diisopropyl ether (800 ml) were added at 25-35oC and cooled to 0-10°C. To this sodium methoxide powder (23 g) was added at 0-10°C and maintained for 2 hrs. The obtained solid was filtered, washed with diisopropyl ether and dried in hot air oven to get the title compound.

Example-3:
Preparation of 7-bromo-2,2-dimethylheptanoic acid of Formula II:
To a clean and dry RBF, 7-bromo-2,2-dimethylheptanoic acid sodium salt (100 g), water (300 ml) were added at 25-35°C and cooled to 5-15°C. The reaction mass pH was adjusted to 1-2 with HCl (40 ml). Dichloromethane (100 ml) was added at 25-35°C and stirred for 30 mins. The organic and aqueous layers were separated; the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with water, dried over sodium sulphate and distilled off the solvent under vacuum and at below 50°C to get the title compound.

Example-4:
Preparation of 7-bromo-2,2-dimethylheptanoic acid ethyl ester of Formula Ia:
To a clean and dry RBF, 7-bromo-2,2-dimethylheptanoic acid (100 g), p-toluenesulfonic acid (20 g), toluene (500 ml) were added at 25-35°C, heated to 105-115°C and maintained for 2 hrs. The reaction mass was further cooled to 60-70°C, ethanol (200 ml) was added, and maintained for 18 hrs at 75-80°C. After the reaction completion, distilled off the solvent under vacuum at below 80°C and cooled to 25-35°C. Water and dichloromethane were added to the obtained crude at 25-35°C and stirred for 30 mins. The organic and aqueous layers were separated; the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with sodium bicarbonate solution, dried over sodium sulphate and distilled off the solvent under vacuum at below 50°C to get the title compound. 1,5-dibromopentane: 0.49 ppm; dimer impurity: Not detected.

Example-5:
Preparation of bempedoic acid:
p-Toluene sulfonyl methyl isocyanide (37 g), tetrabutylammonium iodide (14 g) followed by 7-bromo-2,2-dimethylheptanoic acid ethyl ester (100 g) was added to a mixture of dimethylformamide (800 ml) and sodium hydride (18.2 g) at below -10°C and stirred under nitrogen atmosphere. After reaction completion, the reaction mass was quenched with ammonium chloride solution at below 0°C and extracted into diisopropyl ether. Diisopropyl ether layer was washed with sodium chloride solution and then acidified with hydrochloric acid (100 ml) at 0-5°C and stirred for 1 hour. After reaction completion, the reaction mass was quenched with water and stirred for 10 mins at 25-35°C. Organic layer was separated, washed with water, sodium bicarbonate and sodium chloride solution followed by drying over sodium sulfate and distilled off under vacuum at below 40°C. Ethanol (200 ml) was added to the obtained residue followed by solution of sodium borohydride (3 g) in sodium hydroxide solution at 25-35°C and stirred for 2 hrs. After reaction completion, sodium hydroxide solution (45 grams dissolved in 45 ml water) was added, heated to 45-55°C and stirred for 6 hrs. After reaction completion, the reaction mass was cooled to 25-35°C, water (400 ml) was added and the reaction mass was distilled off under vacuum at below 45°C. Methyl tertiary butyl ether was added to the reaction mass, acidified with hydrochloric acid. Organic layer was separated and distilled off under reduced pressure at below 40°C followed by co-distilled with ethyl acetate. The obtained compound was further dissolved in ethyl acetate 50-60°C and stirred for 1.5 hrs. The reaction mass was cooled to 20-30°C and stirred for 6 hrs. The obtained solid was filtered and washed with ethyl acetate. The wet solid was further slurry washed with methylene chloride at 35-45°C. The solid was filtered off, washed with methylene chloride, dried and further recrystallized from mixture of ethyl acetate and acetone to get the title compound. Diol impurity: < 1 ppm.
,CLAIMS:1. A process for the purification of 7-bromo-2,2-dimethylheptanoic acid alkyl ester of Formula I,

Formula I
wherein R is an alkyl group,
which comprises;
a) hydrolyzing a compound of Formula I to provide a compound of Formula II,

Formula II
b) optionally converting the compound of Formula II into its alkali metal salt or an organic amine salt followed by hydrolysis; and
c) esterification of the compound of Formula II to provide a pure 7-bromo-2,2-dimethylheptanoic acid alkyl ester of Formula I, which is substantially free of 1, 5-dibromopentane and dimer impurities.

2. The process as claimed in claim 1, wherein R is an alkyl group selected from methyl, ethyl, propyl, isopropyl, t-butyl and/or n-butyl.

3. The process as claimed in claim 1, wherein the hydrolysis in step a) is carried out in the presence of an acid selected from hydrochloric acid, hydrobromic acid, sulfuric acid, acetic acid, methanesulfonic acid, trifluoroacetic acid and/or mixtures thereof or a base selected from sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium methoxide, sodium ethoxide and/or mixtures thereof.
4. The process as claimed in claim 1, wherein the alkali metal source in step b) is selected from sodium metal, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide and the organic amine source is selected from dicyclohexylamine and/or tertiarybutylamine.

5. The process as claimed in claim 1, wherein the hydrolysis in step b) is carried out in the presence of an acid selected from hydrochloric acid, hydrobromic acid, sulfuric acid, acetic acid, methanesulfonic acid, trifluoroacetic acid and/or mixtures thereof.

6. The process as claimed in claim 1, wherein the esterification of compound of Formula II in step c) is carried out using an alcohol selected from methanol, ethanol, isopropanol, butanol and/or t-butanol and in the presence of an acid catalyst comprises p-toluenesulfonic acid, sulfuric acid, methanesulfonic acid, trifluoroacetic acid and/or mixtures thereof.

7. The process as claimed in claim 1, the step a) to step c) reactions are carried out in a suitable solvent selected from water, alcohols, ketones, nitriles, chloro solvents, ethers, esters and/or mixtures thereof.

8. 7-Bromo-2,2-dimethylheptanoic acid alkyl ester of Formula I, substantially free of 1,5-dibromopentane and dimer impurities.

9. The process for the purification of compound of formula I, wherein R is ethyl as claimed in claim 1, which comprises;
a) hydrolyzing a compound of Formula I to provide a compound of Formula II,

Formula II
b) converting the compound of Formula II into its sodium salt followed by hydrolysis; and
c) esterification of the compound of Formula II with ethanol to provide a pure 7-bromo-2,2-dimethylheptanoic acid ethyl ester.

10. A process for the preparation of bempedoic acid of formula A, which is substantially free of diol impurity;

Formula A
comprises preparing 7-bromo-2,2-dimethylheptanoic acid alkyl ester of Formula I substantially free of 1,5-dibromopentane and converting it into Bempedoic acid substantially free of diol impurity.