DESC:“PROCESS FOR BEMPEDOIC ACID USING NOVEL INTERMEDIATES”

FIELD OF THE INVENTION

The present invention relates to a process for the preparation of Bempedoic acid (I) and the present invention further relates to a novel intermediate compounds of formulae (3) and (4) are used in the preparation of Bempedoic acid (I).

And

BACKGROUND OF THE INVENTION

Bempedoic acid, chemical entitled 8-Hydroxy-2,2,14,14-tetramethyl-pentadecanedioic acid. Bempedoic acid is a small molecule inhibitor of adenosine triphosphate-citrate lyase (ACL), an enzyme upstream of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase in the cholesterol biosynthesis pathway. Bempedoic acid is a prodrug that requires activation in liver to bempedoic acid-coenzyme A, which mediates competitive inhibition of ACL. Inhibition of ACL by bempedoic acid-coenzyme A decreases cholesterol synthesis in the liver leading to increased low-density lipoprotein receptor (LDLR) expression and LDL particle clearance from the blood. Therefore, inhibition of ACL by bempedoic acid-coenzyme A decreases low-density lipoprotein cholesterol (LDL-C) via the same pathway as HMG-CoA reductase inhibition by statins. An important differentiating feature of bempedoic acid is that, unlike statins, it does not inhibit cholesterol synthesis in skeletal muscle. The enzyme required to convert bempedoic acid to bempedoic acid-coenzyme A is not present in skeletal muscle. Therefore, bempedoic acid is not anticipated to mediate the adverse effects associated with inhibition of biological intermediates within the cholesterol biosynthesis pathway in skeletal muscle.

Bempedoic acid is a once-daily LDL-C lowering agent in phase 3 clinical trials. In phase 1 and 2 studies, bempedoic acid was efficacious in lowering LDL-C when used as monotherapy and when added to a statin and/or ezetimibe and was well tolerated in patients with statin intolerance. Its structural formula is as follows:

Bempedoic acid is reported in US 7335799 by Esperion Therapeutics Inc. The synthetic process for Bempedoic acid is reported in US ‘799, which comprises, compound of formula (I) is treated with ethyl isobutyrate in presence of Lithium diisopropylamide (LDA)/ tetrahydrofuran (THF) to obtain formula (2). The compound of formula (2) is treated with p-toluenesulfonyl methyl isocyanide in presence of tetra-n-butylammonium iodide (TBAI) / sodium hydride (NaH) / Dimethyl sulfoxide (DMSO) to obtain compound of formula (3). The compound of formula (3) is treated with hydrochloric acid/dichloromethane to obtain compound of formula (4). The compound of formula (4) is treated with potassium hydroxide (KOH) / ethanol (EtOH) to obtain compound of formula (5). The compound of formula (5) convert into Bempedoic acid (I) in presence of Sodium borohydride (NaBH4) / methanol (MeOH)

The above process is schematically shown as below:

IN 201941011853 of Dr. Reddy’s reported process for the preparation of Bempedoic acid (I), which comprises the compound of formula (4) is reduced in presence of NaBH4 /THF and water to obtain the compound of formula (6). The compound of formula (6) is hydrolysed in presence of EtOH / KOH / H2O / HCl, 10% EtOAc and hexanes to obtain Bempedoic acid (I).

The above process is schematically shown as below:

Scheme-I
The processes taught by prior art have several drawbacks namely not suitable for scale up at plant level, difficult, giving lower yields and less user friendly. Considering the drawbacks prior art process of Bempedoic acid, the present invention is simple, economical, financially cheaper plant friendly process, environment friendly process for the preparation of Bempedoic acid with better yields and purity.
There is always need for alternative preparative routes, which for example use reagents, solvents that are less expensive and/or easier to handle, consume smaller amounts of reagents and solvents provide a higher yield of product, have smaller and/or eco-friendly waste products and/or provide a product of higher purity.

Aforesaid reasons above there is a need to produce Bempedoic acid synthetically by industrially applicable method to ensure the availability with high purity. Hence, there is consequently a need development for new methods to sort out prior art existing methods. So, Further, there is a clear need to develop a method for the preparation of Bempedoic acid by employing novel intermediates. The present invention is providing a simple, eco-friendly with high purity and good yield on industrial applicable process.

SUMMARY OF THE INVENTION

The present invention relates to a process for the preparation of Bempedoic acid (I) and the present invention further relates to a novel intermediate compounds of formulae (3) and (4) are used in the preparation of Bempedoic acid (I).

In one aspect of the present invention provides a process for the preparation of Bempedoic acid (I), comprising the steps of:

a) reacting the compound of formula (1) with isobutyronitrile in presence of base and solvent to obtain the compound of formula (2);

b) reacting the compound of formula (2) with p-toluenesulfonyl methyl isocyanide in presence of base to obtain compound of formula (3);

c) treating the compound of formula (3) with an acid to obtain compound of formula (4);

d) hydrolyzing the compound of formula (4) with base or acid to obtain the compound of formula (5);

e) treating the compound of formula (5) with reducing agent to obtain the compound of formula Bempedoic acid (I) and;

In another aspect of the present invention provides a novel intermediate compounds of formulae (3) and (4).

And

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a process for the preparation of Bempedoic acid (I).
In one aspect of the present invention provides a process for the preparation of Bempedoic acid (I), comprising the steps of:

a) reacting the compound of formula (1) with isobutyronitrile in presence of base and solvent to obtain the compound of formula (2);

b) reacting the compound of formula (2) with p-toluenesulfonyl methyl isocyanide in presence of base to obtain compound of formula (3);

c) treating the compound of formula (3) with an acid to obtain compound of formula (4);

d) hydrolyzing the compound of formula (4) with base or acid to obtain the compound of formula (5);

e) treating the compound of formula (5) with reducing agent to obtain the compound of formula Bempedoic acid (I) and;

The process according to the embodiment of the present invention, step a) involves the compound of formula (1) is reacted with isobutyronitrile in presence of base and solvent to obtain compound of formula (2). The reaction is carried out temperature at -60°C to -80°C for 2 to 6 hours. In a particular embodiment, the compound of the formula (I) is reacted with isobutyronitrile in the presence of diisopropylamine/THF, n-butyllithium/hexane at -70oC to -75oC to obtain a compound of formula (2).

The process according to the embodiment of the present invention, Step b) involves the compound of formula (2) is reacted with p-toluenesulfonyl methyl isocyanide in presence of base and solvent to obtain compound of formula (3). The reaction is carried out temperature at -5°C to 25°C for 2 to 6 hours. In a particular embodiment, the compound of the formula (2) is reacted with p-toluenesulfonyl methyl isocyanide in presence of sodium hydride and tetrahydrofuran at -10oC to 0oC to obtain a compound of formula (3).

The process according to the embodiment of the present invention, Step c) involves the compound of formula (3) is treated with acid in presence of solvent to obtain compound of formula (4). The reaction is carried out temperature at 20°C to 40°C for 2 to 4 hours. In a particular embodiment, the compound of the formula (3) is treated with hydrochloric acid in presence of tetrahydrofuran at room temperature to obtain a compound of formula (4).

The process according to the embodiment of the present invention, Step d) involves the compound of formula (4) is treated with base or acid in presence of solvent to obtain compound of formula (5). The reaction is carried out temperature at 80°C to 120°C for 12-18 hours. In a particular embodiment, the compound of the formula (3) is treated with potassium hydroxide in presence of ethanol at 100°C-110°C to obtain a compound of formula (4).

The process according to the embodiment of the present invention, Step e) involves the compound of formula (5) is treated with reducing agent in presence of solvent to obtain compound of formula (I). The reaction is carried out temperature at 20°C to 40 °C for 2-6 hours. In a particular embodiment, the compound of the formula (5) is treated with sodium borohydride in presence of methanol at room temperature to obtain a compound of formula (I).

According to an embodiment of the present invention, wherein the solvent selected from “hydrocarbon solvents” such as n-hexane, n-heptane, cyclohexane, pet ether, benzene, toluene, pentane, cycloheptane, methyl cyclohexane, ethylbenzene, m-, o, or p-xylene, or naphthalene and the like; “ether solvents” such as dimethoxymethane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, t-butyl methyl ether, 1,2-dimethoxy ethane and the like; “ester solvents” such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate and the like; “polar-aprotic solvents such as dimethylacetamide (DMA), dimethylformamide (DMF), dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP) and the like; “chloro solvents” such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like; “ketone solvents” such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; “nitrile solvents” such as acetonitrile, propionitrile, isobutyronitrile and the like; “alcohol solvents” such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 1,2-propanediol (propylene glycol), 2-methoxyethanol, l, 2-ethoxyethanol, diethylene glycol, 1, 2, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol and the like; “polar solvents” such as water or mixtures thereof.

According to an embodiment of the present invention, wherein the base is selected from inorganic bases like “alkali metal hydroxides” such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; “alkali metal carbonates” such as 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; ammonia; and organic bases such as “alkali metal alkoxides” such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide and the like; triethyl amine, methyl amine, ethylamine, 1,8-diaza bicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo(4.3.0)non-5-ene (DBN), lithiumdiisopropylamide (LDA), n-butyl lithium, tribenzylamine, isopropylamine, diisopropylamine, diisopropylethylamine, N-methyl morpholine, N-ethylmorpholine, piperidine, dimethylaminopyridine, morpholine, pyridine, 2,6-lutidine, 2,4,6-collidine, imidazole, 1-methyl imidazole, 1,2,4-triazole, 1,4-diazabicyclo [2.2.2]octane (DABCO) or mixtures thereof.

According to an embodiment of the present invention, wherein the reducing agent are selected from iron powder, sodium borohydride (NaBH4), nickel, raney nickel, rhodium, palladium hydroxide (Pd(OH)2), palladium acetate, lithium aluminum hydride, stannic chloride, diisobutylaluminum hydride and diborane sodium amalgam, lithium borohydride, sodium aluminium hydride, hydrazine hydrate, sodium dithionate, sodium sulfide, ammonium sulfide, palladium catalyst (e.9,, palladium carbon, palladium hydroxide carbon, palladium oxide and the like), nickel catalyst (e.9., Raney-nickel and the like), platinurn catalyst (e.9., platinum oxide, platinum carbon and the like), Rhodium catalyst (e,g., rhodium carbon and the like), cobalt catalyst (e.9,, Raney-cobalt and the like) and the like.

According to an embodiment of the present invention, wherein the acid is selected from hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, alkyl/aryl sulfonic acids such as methane sulfonic acid, ethane sulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like.
In another aspect of the present invention provides a novel intermediate compounds of formulae (3) and (4).

The above overall process is schematically shown as below:

The process details of the present 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.

EXAMPLES

Example-1:
Preparation of 7-bromo-2,2-dimethylheptanenitrile
Diisopropylamine (65g, 0.648 mol) was dissolved in Tetrahydrofuran (500 mL) and allow to cool at -20oC to -30oC, followed by dropwise addition of n-BuLi (2.5 M in n-Hexane, 256 mL, 0.640 mol) for 30 min. The reaction mixture was stir at -20oC to -30oC for 30 min and further cool to -70oC to -75oC, followed by added Isobutyronitrile (44.75 g, 0.648 mol), Tetrahydrofuran (100 mL) and stir for 30 mints. The reaction mixture was slowly added to 1,5-Dibromo pentane (100 g, 0.44 mol), tetrahydrofuran (200mL) and stir for 1h. The reaction mixture was maintained for 4h at -70oC to -75oC. After completion of the reaction, the reaction mixture was quenched with 1N hydrochloric acid (100 mL) dropwise, then the reaction mass temperature slowly raised to room temperature (25-30oC) and extracted with ethyl acetate (100 mLx2). The combined organic extracts were washed with water (100 mL) and brine solution (50 mL). The organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure to obtain a 7-bromo-2,2-dimethylheptanenitrile (97 g).
Yield: 95%
Example-2:
Preparation of 8-isocyano-2,2,14,14-tetramethyl-8-tosylpentadecanedinitrile
7-Bromo-2,2-dimethylheptanenitrile (80 g, 0.4606 mol), Tetrahydrofuran (200 mL) and TOSMIC (145 g, 0.2303 mol) were added in RB flask. The obtained reaction was allow to cool at 0 to 5oC, followed by added portion wise sodium hydride (50% in paraffin, 20 g, 0.5066 mol) and stir for 5-6 h at 0 to 5oC. After completion of the reaction, the reaction mixture was quenched with methanol (10 mL) then the reaction mass temperature slowly raised to room temperature (25-30oC). The reaction was diluted with water (500 ml) and extracted with ethyl acetate (500 mL and 250 mL). The combined extracts were washed with water (500 mL) and brine solution (25 mL). The organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure to obtain 8-Isocyano-2,2,14,14-tetramethyl-8-tosylpentadecanedinitrile (44g).
Yield: 66.66 %.
Example-3:
Preparation of 8-isocyano-2,2,14,14-tetramethyl-8-tosylpentadecanedinitrile
7-Bromo-2,2-dimethylheptanenitrile (80 g, 0.4606 mol), DMF (400 mL) and TOSMIC (145 g, 0.2303 mol) were added in RB flask. The obtained reaction was allow to cool at 0 to 5 oC, followed by added portion wise sodium hydride (50% in paraffin, 20 g, 0.5066 mol) and the reaction mixture stir for 5-6h at 0 to 5oC. After completion of the reaction, the reaction mixture was quenched with 10% Ammonium chloride solution (200 mL) and then the reaction mass temperature slowly raised to room temperature (25-30oC). The reaction was diluted with water (500 ml) and extracted with ethyl acetate (500 mL). The combined extracts were washed with water (500 mL) and brine solution (25 mL). The organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure. Charged IPA (30 mL) and cool to 0 to 50C for 60 min. Filtered and washed with IPA (45mL) to obtain 8-Isocyano-2,2,14,14-tetramethyl-8-tosylpentadecanedinitrile (45 g).
Yield: 65 %.
Example-4:
Preparation of 2,2,14,14-tetramethyl-8-oxopentadecanedinitrile
8-Isocyano-2,2,14,14-tetramethyl-8-tosylpentadecanedinitrile (40g, 0.085 mol) and Tetrahydrofuran (200 mL) was added in to RB flask. The reaction mixture was cooled to 0oC, added 5N hydrochloric acid (20 mL). The reaction mixture was allow to maintain at 0 to 5oC for 2h. After completion of the reaction, the reaction mixture was quenched with 2gr of (NaOH dissolved in water) and then separate the two layers. The combined extracts were washed with water (25 mL) and brine solution (20 mL). The organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure to give 20.5 g of 2,2,14,14-Tetramethyl-8-oxopentadecanedinitrile.
Yield: 80.2 %
Example-5:
Preparation of 2,2,14,14-tetramethyl-8-oxopentadecanedinitrile
8-Isocyano-2,2,14,14-tetramethyl-8-tosylpentadecanedinitrile (40g, 0.085 mol) and MTBE (200 mL) was added in to RB flask. The reaction mixture was cooled to 0oC and add 5N hydrochloric acid (20 mL). The reaction mixture was allow to maintain at 0 to 5oC for 2h. After completion of the reaction, the reaction mixture was quenched with 2gr of (NaOH dissolved in water) (50 mL x 2) and then separate the two layers. The combined extracts were washed with water (25 mL) and brine solution (20 mL). The organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure to give 20.8 g of 2,2,14,14-Tetramethyl-8-oxopentadecanedinitrile.
Yield: 81.2 %
Example-6:
Preparation of 2,2,14,14-tetramethyl-8-oxopentadecanedioic acid
2,2,14,14-Tetramethyl-8-oxopentadecanedinitrile (5g, 0.064 mol) was dissolved in Ethanol (100 mL) and allow to cool at 25 to 30oC and then added potassium hydroxide solution (KOH in water; 46 g, 0.822 mol, 50 mL). The reaction mixture was heated to 98oC and stir for 23-24h. After completion of the reaction, the reaction was concentrated under reduced pressure. The reaction mass was diluted with water (50 mL) and cooled to 0oC and adjusted the pH to 2-3 with conc. hydrochloric acid (100 mL). The off-white solid precipitate was filtered and concentrated to give 16.50 g of 2,2,14,14-Tetramethyl-8-oxopentadecanedioic acid.
Yield: 75%
Example-7:
Preparation of 8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid (Bempedoic acid).
2,2,14,14-Tetramethyl-8-oxopentadecanedioic acid (5.00 g, 0.0146 mol) was dissolved in Methanol (50 mL) and allow to cool at 0-5oC, followed by portion wise addition of sodium borohydride (2.2g, 0.0584 mmol). The reaction temperature maintained at 0-5oC for 4h. Charged purified water (25 mL) and adjusted pH (2-3) with 1N hydrochloric acid, extracted with ethyl acetate (260 mL). The combined organic extracts were washed with water (10 mL) and brine solution (10 mL). The organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure to obtain 8-Hydroxy-2,2,14,14-tetramethylpentadecanedioic acid as an off-white solid (3.6 g).
Yield: 72 %
Purity: 98.92 %
,CLAIMS:We Claim:
1. A process for the preparation of Bempedoic acid (I), which comprises the steps of:
a) reacting the compound of formula (1) with isobutyronitrile in presence of base and solvent to obtain the compound of formula (2);

b) reacting the compound of formula (2) with p-toluenesulfonyl methyl isocyanide in presence of base to obtain compound of formula (3);

c) treating the compound of formula (3) with an acid to obtain compound of formula (4);

d) hydrolyzing the compound of formula (4) with base or acid to obtain the compound of formula (5);

e) treating the compound of formula (5) with reducing agent to obtain the compound of formula Bempedoic acid (I) and;

2. The process as claimed in claim 1, wherein the base is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, sodium hydride, potassium hydride, lithium hydride, ammonia, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, triethyl amine, methyl amine, ethylamine, lithiumdiisopropylamide (LDA), n-butyl lithium, tribenzylamine, isopropylamine, diisopropylamine, diisopropylethylamine, N-methyl morpholine, N-ethylmorpholine, piperidine, dimethylaminopyridine, morpholine, pyridine, imidazole, 1-methyl imidazole, 1,2,4-triazole or mixtures thereof.

3. The process as claimed in claim 1, wherein the solvent is selected from n-hexane, n-heptane, cyclohexane, benzene, toluene, pentane, cycloheptane, methyl cyclohexane, ethylbenzene, tetrahydrofuran, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol, diethylene glycol, dimethyl ether, triethylene glycol, anisole, t-butyl methyl ether, 1,2-dimethoxy ethane, methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, dimethylacetamide (DMA), dimethylformamide (DMF), dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP), dichloromethane, dichloroethane, chloroform, carbon tetrachloride, acetone, methyl ethyl ketone, methyl isobutyl ketone, acetonitrile, propionitrile, isobutyronitrile, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, 2-nitroethanol, 2-fluoroethanol, 1,2-propanediol (propylene glycol), 2-methoxyethanol, cyclohexanol, benzyl alcohol, phenol, glycerol, water or mixtures thereof.

4. The process as claimed in claim 1, wherein the acid is selected from hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, methane sulfonic acid, ethane sulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid.

5. The process as claimed in claim 1, wherein the reducing agent is selected from iron powder, sodium borohydride (NaBH4), nickel, raney nickel, rhodium, palladium hydroxide (Pd(OH)2), palladium acetate, lithium aluminum hydride, stannic chloride, diisobutylaluminum hydride, diborane sodium amalgam, lithium borohydride, sodium aluminium hydride, hydrazine hydrate, sodium dithionate, sodium sulfide, ammonium sulfide, palladium carbon, palladium hydroxide carbon, palladium oxide, Raney-nickel, platinum oxide, platinum carbon, rhodium carbon, Raney-cobalt.

6. A compound of formula (3).

7. A compound of formula (4).