DESC:Field of the invention:
The present invention relates to a process for the preparation of 8-hydroxy-2,2,14,14-tetramethyl-pentadecanedioic acid compound of formula-1 which is represented by the following structural formula:

Formula-1

Background of the Invention:
8-hydroxy-2,2,14,14-tetramethyl-pentadecanedioic acid is known to be Bempedoic acid. Bempedoic acid is a novel therapeutic approach for low-density lipoprotein cholesterol (LDL-C) lowering, inhibits ATP citrate lyase (ACL), an enzyme involved in fatty acid and cholesterol synthesis. Bempedoic acid as a monotherapy or in combination with Ezetimibe was approved for the treatment of hypercholesterolemia and sold under the brand name Nexletol and Nexlizet respectively.
US7335799 discloses Bempedoic acid, its process of preparation or its pharmaceutically acceptable salt, hydrate, or solvate and pharmaceutical composition.
The process for the preparation of Bempedoic acid disclosed in US7335799 and Drugs of the Future 2017, 42(4), 201-208 has been schematically represented in Scheme-I as below:

Scheme-I:

Bempedoic acid is prepared by condensation of ethyl isobutyrate (II) with 1,5-dibromopentane (III) in the presence of lithium diisopropylamide solution (2.0M in THF) in tetrahydrofuran and/or DMPU as chelating agent to give ethyl 7-bromo-2,2-dimethylheptanoate (IV). Condensation of compound (IV) with tosylmethyl isocyanide (V) in the presence of sodium hydride and tetrabutylammonium iodide in anhydrous DMSO to yield diethyl 8-isocyano-2,2,14,14-tetramethyl-8-(tosyl)-pentadecanedioate (VI), which is further treated with conc. HCl in dichloromethane to give 2,2,14,14-tetramethyl-8-oxo-pentadecanedioic acid diethyl ester (VII). Hydrolysis of compound (VII) with aqueous potassium hydroxide in ethanol at reflux temperature to yield 2,2,14,14-tetramethyl-8-oxo-pentadecanedioic acid (VIII). Reduction of compound (VIII) with sodium borohydride in methanol affords Bempedoic acid (I).

Drawbacks/Disadvantages of the above process:
• Involves higher volumes of hydrochloric acid for the hydrolysis of compound (VI) which leads to higher amount of impurities and results in low yield.
• Compound (VII) is purified by silica gel column chromatography to remove by-product p-toluene sulfinic acid which is commercially unattractive.
• Excess amount of sodium borohydride (4.3 equiv.) is required for the reduction of compound (VIII).
• Intermediate and final compounds are obtained with low yields and purity (83.8%).
• Bempedoic acid was isolated as viscous oil instead of a solid (60%).

The said process involves high amount of reagents and column chromatography making it tedious, expensive and commercially not viable. Therefore, there is a need to provide a cost effective and commercially viable process for the preparation of solid and pure Bempedoic acid which is suitable for use in pharmaceutical composition.

The process for the preparation of Bempedoic acid of the present invention has been schematically represented in Scheme-II as below:

Scheme-II:

Bempedoic acid is prepared by condensation of ethyl isobutyrate (II) with 1,5-dibromopentane (III) in the presence of lithium hexamethyldisilazne solution (1.4M in THF) in tetrahydrofuran to give ethyl 7-bromo-2,2-dimethylheptanoate (IV). Thereafter, compound (IV) was treated with tosylmethyl isocyanide (V) in the presence of sodium hydride and tetrabutylammonium iodide in DMSO (or) toluene-dimethylformamide solvent mixture to yield diethyl 8-isocyano-2,2,14,14-tetramethyl-8-(tosyl)-pentadecanedioate (VI), which was treated with conc. HCl in toluene to give 2,2,14,14-tetramethyl-8-oxo-pentadecanedioic acid diethyl ester (VII), which was further hydrolysed with aqueous potassium hydroxide in methanol at reflux temperature to yield 2,2,14,14-tetramethyl-8-oxo-pentadecanedioic acid (VIII). Reduction of compound (VIII) with sodium borohydride in methanol to give Bempedoic acid (IX), which is further recrystallized in isopropyl acetate and water solvent mixture to yield highly pure Bempedoic acid (I).

Advantages of the present process:

• Hydrochloric acid volumes were reduced to 1.57 (4.0 equiv.) from 4.15 (10.5 equiv.) for the hydrolysis of compound (VI).
• A telescoped process was developed for compound (VIII) from compound (IV) without isolating compound (VII) and avoiding column chromatography.
• Potassium hydroxide mole equivalents were reduced to 5.0 from 16.62.
• Sodium borohydride mole equivalents were reduced to 1.0 from 4.3 in the presence of aq. sodium hydroxide solution.
• Compounds (VIII) & (IX) were directly isolated from aq. solution avoiding organic solvents.
• Intermediates obtained with good purity.
• Crude Bempedoic acid was recrystallized from isopropyl acetate and water solvent mixture to yield highly pure Bempedoic acid.
• Bempedoic acid was isolated as pure crystalline powder with > 99.95% purity.
• Product is free of genotoxic impurities. Present process is capable of reducing > 0.5% of GTIs to less than 8 ppm.
• PXRD data shown consistency in polymorphic form.

Thus the present invention avoids the usage of column chromatography techniques which are commercially not viable. The present invention provides efficient, economically viable, easily scalable process for the preparation of Bempedoic acid.

Brief description of the Invention:
The first aspect of the present invention is to provide an improved process for the preparation of Bempedoic acid compound of formula-1.
The second aspect of the present invention is to provide a process for the preparation of crystalline form of Bempedoic acid compound of formula-1.

Brief description of the Drawings:
FIG.1: Illustrates the characteristic PXRD pattern of crystalline form of Bempedoic acid.

Detailed description of the Invention:
The term "suitable solvent" used in the present invention refers to "hydrocarbon solvents" selected from aliphatic hydrocarbon solvents such as n-hexane, n-heptane, cyclohexane, petroleum ether and aromatic hydrocarbon solvents such as benzene, toluene, xylene and the like; "ether solvents" such as dimethyl ether, diisopropyl ether, diethyl ether, methyl tert-butyl ether, 1 ,2-dimethoxy ethane, tetrahydrofuran, 1,4-dioxane, monoxime, dioxime 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, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone (NMP) and the like; "chloro solvents" such as dichloromethane/methylene chloride, 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; "alcoholic solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol and the like; "polar solvents" such as water or mixtures thereof.
As used herein the present invention, the term "anti-solvent" refers to a solvent which is used to precipitate the solid from a solution.
As used herein the present invention the term “suitable acid” refers to organic acids or inorganic acids. The “inorganic acid” is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid; and “organic acid” is selected from formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, oxalic acid, malonic acid, maleic acid, fumaric acid, malic acid, succinic acid, citric acid, aspartic acid, tartaric acid, mandelic acid, benzoic acid, salicylic acid, substituted/unsubstituted alkyl/aryl sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, propanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid and the like or mixtures thereof.
As used herein the present invention the term “suitable base” refers to “alkali metal carbonates” such as sodium carbonate, potassium carbonate, lithium carbonate and the like; “alkali metal bicarbonates” such as sodium bicarbonate, potassium bicarbonate and the like; “alkali metal hydroxides” such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; “alkali metal alkoxides” such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert.butoxide, potassium tert.butoxide, lithium tert.butoxide and the like; alkali metal hydrides such as sodium hydride, potassium hydride, lithium hydride and the like; alkali metal amides such as sodium amide, potassium amide, lithium amide and the like; Ammonia; and organic bases like dimethylamine, diethylamine, diisopropylamine, diisopropylethylamine, diisobutylamine, triethylamine, pyridine, 4-dimethylaminopyridine (DMAP), N-methyl morpholine (NMM), 2,6-lutidine, lithium diisopropylamide; organosilicon bases such as lithium hexamethyldisilazide (LiHMDS), sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS) or mixtures thereof.

The first aspect of the present invention is to provide an improved process for the preparation of Bempedoic acid compound of formula-1, comprising of:
a) Reacting ethyl isobutyrate of formula-(II) with 1,5-dibromopentane of formula-(III) in the presence of lithium hexamethyldisilazne solution in tetrahydrofuran to provide ethyl 7-bromo-2,2-dimethylheptanoate of formula-(IV),
b) treating the compound of formula-(IV) with tosylmethyl isocyanide of formula-(V) in the presence of sodium hydride and tetrabutylammonium iodide in DMSO (or) toluene-dimethylformamide solvent mixture to provide diethyl 8-isocyano-2,2,14,14-tetramethyl-8-(tosyl)-pentadecanedioate (VI),
c) treating the compound of formula-(VI) in-situ with conc. HCl in toluene to provide 2,2,14,14-tetramethyl-8-oxo-pentadecanedioic acid diethyl ester (VII),
d) hydrolyzing the compound of formula-(VII) with aqueous potassium hydroxide in methanol at reflux temperature to provide 2,2,14,14-tetramethyl-8-oxo-pentadecanedioic acid (VIII) and purifying the obtained compound with acetonitrile to provide pure compound of formula-(VIII),
e) reducing the compound of formula-(VIII) with sodium borohydride in methanol to provide Bempedoic acid of formula-(IX),
f) purifying the Bempedoic acid of formula-(IX) with a mixture of isopropyl acetate and water to provide pure Bempedoic acid of formula-(I).

The second aspect of the present invention is to provide a process for the preparation of crystalline form of Bempedoic acid compound of formula-1, comprising of:
a) Dissolving Bempedoic acid in a mixture of isopropyl acetate and water,
b) stirring and heating the reaction mixture,
c) treating the solution obtained in step-(b) with charcoal,
d) cooling and stirring the reaction mixture,
e) filtering, washing the solid with isopropyl acetate and drying the compound to get the crystalline Bempedoic acid of formula-1.

PXRD method of analysis:

PXRD analysis of the crystalline form of Bempedoic acid was carried out using Panlytical Expert Pro DY3248 X-ray powder diffractometer using Cu-Ka radiation of 10 wavelength 1.5406 A° and at continuous scan speed of 0.03°/min.

The best mode of carrying out the present invention was illustrated by the below mentioned examples. These examples provide as illustration only and hence should not be construed as limitation of the scope of the invention.
Examples:

Exampe-1: Process for the preparation of Ethyl 7-bromo-2,2-dimethylheptanoate (IV).
To a stirred solution of ethyl isobutyrate (II) (50.0 g, 1.0 equiv.) and 1,5-dibromopentane (III) (118.7 g, 1.2 equiv.) in tetrahydrofuran (150.0 mL), LiHMDS 1.4M in THF (1.1 equiv.) was added at -20 to -10 °C and stirred the reaction mass for 20.0 h at 25-30 °C. After completion of the reaction, 2N aq. hydrochloric acid (250.0 mL) was added at 10-15 °C and extracted with toluene (2x200.0 mL). Combined organic layer was washed with 7% aq. sodium bicarbonate solution (250.0 mL), dried over anhydrous sodium sulphate (5.0 g) and filtered. Solvent was distilled off completely under vacuum at 50-55 °C to get crude mass (135.5 g) as brown colour liquid. Crude was purified by high vacuum distillation at 120-160 °C under reduced pressure to get ethyl 7-bromo-2,2-dimethylheptanoate (IV) as colourless liquid [60.0 g (52.6%); Purity: > 98.0%].

Exampe-2: Process for the preparation of 2,2,14,14-Tetramethyl-8-oxo-pentadecanedioic acid (VIII).
To a stirred solution of ethyl 7-bromo-2,2-dimethylheptanoate (IV) (150.0 g, 1.0 equiv.) in dimethyl sulfoxide (1.5 L), tosylmethyl isocyanide (V) (55.21 g, 0.5 equiv.), tetrabutylammonium iodide (20.89 g, 0.1 equiv.) were added and stirred for 5-10 min at 25-30 °C. Reaction mass was cooled to 15-20 °C, added sodium hydride (60%, 27.15 g, 1.2 equiv.) lot wise and stirred the reaction mass for 1.5-2.5 h at 25-30 °C. After completion of the reaction, reaction mass was cooled and quenched with cold DM water (1.5 L) at 10-15 °C. Reaction mass temperature was raised to 25-30 °C, extracted with toluene (2x0.75 L) and combined org. layer (compound VI) was washed with DM water (0.75 L). Conc. HCl (235.7 mL) was added to the org. layer (compound VI) at 10-15 °C and stirred for 1.0-1.5 h. After completion of the reaction, diluted the reaction mass with DM water (1.05 L) and stirred for 10-15 min. Both layers were separated, and org. layer was washed with aq. sodium bicarbonate solution (0.75 L) and distilled off solvent completely under vacuum at 40-45 °C to get 2,2,14,14-tetramethyl-8-oxo-pentadecanedioic acid diethyl ester (VII) as residue (~ 142.0 g).

To a stirred solution of compound (VII) in methanol (0.9 L), aq. potassium hydroxide solution (158.68 g, 5.0 equiv.) was added and stirred for 4.0-5.0 h at reflux temperature. After completion of the reaction, reaction mass was cooled and distilled off solvent under vacuum at 40-45 °C. Reaction mass was further cooled to 25-30 °C, diluted with DM water (0.9 L) and washed with dichloromethane (2x0.3 L). Conc. HCl (0.15 L) was added to the aq. layer at 10-15 °C and raised the reaction mass temperature to 25-30 °C. Reaction mass pH was adjusted to 3.0-4.0 with dil. HCl and stirred for 1.0-2.0 h at 25-30 °C. The precipitated solid was filtered and washed with DM water (0.45 L). The wet solid was leached with DM water (0.45 L) for 45-60 min at 25-30 °C, filtered, washed with DM water (0.3 L) and dried under vacuum for 3.0-4.0 h at 40-45 °C to get crude compound. Crude compound was further leached with acetonitrile (273.0 mL) for 45-60 min at 25-30 °C, filtered, washed with acetonitrile (91.0 mL) and dried under vacuum for 5.0-6.0 h at 40-45 °C to get pure 2,2,14,14-tetramethyl-8-oxo-pentadecanedioic acid (VIII) as an off-white to cream coloured powder [77.3 g (40%); Purity: > 98.0%].

Exampe-3: Alternate process for the preparation of 2,2,14,14-Tetramethyl-8-oxo-pentadecanedioic acid (VIII).
Tetrabutylammonium iodide (20.89 g, 0.1 equiv.) was added to toluene (0.75 L) and dimethylformamide (0.3 L) solvent mixture and stirred the reaction mass for 5-10 min at 25-30 °C. Added sodium hydride (60%, 27.15 g, 1.2 equiv.) to the reaction mass and cooled to 0-5 °C. To this reaction mixture, a solution of tosylmethyl isocyanide (V) (55.21 g, 0.5 equiv.) and ethyl 7-bromo-2,2-dimethylheptanoate (IV) (150.0 g, 1.0 equiv.) in toluene (0.3 L) and dimethylformamide (0.15 L) was added and stirred for 5-10 min at 0-5 °C. Raised the reaction mass temperature to 10-15 °C and stirred for 2.0 h. Tosylmethyl isocyanide (V) (3.31 g, 0.03 equiv.) was added to the reaction mass and stirred for 2.0 h at cooled to 10-15 °C. After completion of the reaction, reaction mass was cooled and quenched with cold DM water (1.5 L) at 10-15 °C. Reaction mass temperature was raised to 25-30 °C, extracted with toluene (0.45 L) and combined org. layer (compound VI) was washed with DM water (0.75 L). Conc. HCl (235.7 mL) was added to the org. layer (compound VI) at 10-15 °C and stirred for 1.0-1.5 h. After completion of the reaction, diluted the reaction mass with DM water (1.05 L) and stirred for 10-15 min. Both layers were separated and org. layer was washed with aq. sodium bicarbonate solution (0.75 L) and distilled off solvent completely under vacuum at 40-45 °C to get 2,2,14,14-tetramethyl-8-oxo-pentadecanedioic acid diethyl ester (VII) as residue (~ 129.0 g).

To a stirred solution of compound (VII) and methanol (0.9 L), aq. potassium hydroxide solution (158.68 g, 5.0 equiv.) was added and stirred for 4.0-5.0 h at reflux temperature. After completion of the reaction, reaction mass was cooled and distilled off solvent under vacuum at 40-45 °C. Reaction mass was further cooled to 25-30 °C, diluted with DM water (0.9 L) and washed with dichloromethane (2x0.3 L). Conc. HCl (0.15 L) was added to the aq. layer at 10-15 °C and raised the reaction mass temperature to 25-30 °C. Reaction mass pH was adjusted to 3.0-4.0 with dil. HCl and stirred for 1.0-2.0 h at 25-30 °C. The precipitated solid was filtered and washed with DM water (0.45 L). The wet solid was leached with DM water (0.45 L) for 45-60 min at 25-30 °C, filtered, washed with DM water (0.3 L) and dried under vacuum for 3.0-4.0 h at 40-45 °C to get crude compound. Crude compound was further leached with acetonitrile (273.0 mL) for 45-60 min at 25-30 °C, filtered, washed with acetonitrile (91.0 mL) and dried under vacuum for 5.0-6.0 h at 40-45 °C to get pure 2,2,14,14-tetramethyl-8-oxo-pentadecanedioic acid (VIII) as an off-white to cream coloured powder [75.0 g (38.7%); Purity: > 98.0%].

Exampe-4: Process for the preparation of Bempedoic acid (IX).
To a stirred solution of 2,2,14,14-tetramethyl-8-oxo-pentadecanedioic acid (VIII) (65.0 g, 1.0 equiv.) in methanol (0.325 L), added aq. sodium hydroxide solution (22.78 g, 3.0 equiv.) at 10-20 °C and stirred for 15-30 min. Sodium borohydride (7.18 g, 1.0 equiv.) was added lot wise to the reaction mass at 10-20 °C and stirred for 1.0-2.0 h at 25-30 °C. After completion of the reaction, diluted the reaction mass with DM water (0.325 L), stirred for 10-15 min and distilled off solvent under vacuum at 40-45 °C. Reaction mass was cooled to 25-30 °C and washed with dichloromethane (2x0.13 L). Conc. HCl (39.0 mL) was added to the aq. layer at 15-20 °C and raised the reaction mass temperature to 25-30 °C. Reaction mass pH was adjusted to 3.0-4.0 with dil. HCl and stirred for 1.0-2.0 h at 25-30 °C. The precipitated solid was filtered, washed with DM water (0.13 L) and dried for 30-45 min under suction. A mixture of wet solid, isopropyl acetate (162.5 mL) and DM water (6.5 mL) were heated and stirred for 30-45 min at 45-50 °C. Then the reaction mass was cooled to 15-20 °C, stirred for 1.5-2.0 h, filtered, washed with chilled isopropyl acetate (48.75 mL) and dried under vacuum for 4.0-5.0 h at 40-45 °C to get Bempedoic acid (IX) as white to off-white coloured powder (53.24 g (81.43%); Purity: 99.8%].

Exampe-5: Purification of Bempedoic acid (I).
A mixture of Bempedoic acid (45.0 g), isopropyl acetate (112.5 mL) and DM water (4.5 mL) were heated to 45-50 °C. Activated carbon (0.45 g) was added to the above clear solution and stirred for 30-45 min at 45-50 °C. Filtered the reaction mass through hyflo (9.0 g) and washed with hot isopropyl acetate (22.5 mL). Filtrate was cooled and maintained for 1.5-2.0 h to 15-20 °C and the precipitated solid was filtered, washed with chilled isopropyl acetate (33.75 mL) and dried under vacuum for 4.0-5.0 h at 40-45 °C to get high pure Bempedoic acid (BMP) as an off-white to white powder [37.83 g (84.06%); Purity: > 99.95%].
The PXRD of crystalline form of Bempedoic acid compound of formula-1 is illustrated in figure-1.
,CLAIMS:We Claim:

1. A process for the preparation of Bempedoic acid compound of formula-1 which is substantially free of genotoxic impurities, comprising the steps of:
a) Reacting ethyl isobutyrate of formula-(II) with 1,5-dibromopentane of formula-(III) in the presence of lithium hexamethyldisilazne solution in tetrahydrofuran to provide ethyl 7-bromo-2,2-dimethylheptanoate of formula-(IV),
b) treating the compound of formula-(IV) with tosylmethyl isocyanide of formula-(V) in the presence of sodium hydride and tetrabutylammonium iodide in DMSO (or) toluene-dimethylformamide solvent mixture to provide diethyl 8-isocyano-2,2,14,14-tetramethyl-8-(tosyl)-pentadecanedioate (VI),
c) treating the compound of formula-(VI) in-situ with conc. HCl in toluene to provide 2,2,14,14-tetramethyl-8-oxo-pentadecanedioic acid diethyl ester (VII), wherein the molar equivalents of conc. HCl is less than or equal to 4.0 with respect to compound of formula-(IV),
d) hydrolyzing the compound of formula-(VII) with aqueous potassium hydroxide in methanol at reflux temperature to provide 2,2,14,14-tetramethyl-8-oxo-pentadecanedioic acid (VIII) and purifying the obtained compound with acetonitrile to provide pure compound of formula-(VIII), wherein the molar equivalents of aqueous KOH is less than or equal to 5.0 with respect to compound of formula-(IV),
e) reducing the compound of formula-(VIII) with sodium borohydride in methanol to provide Bempedoic acid of formula-(IX), wherein the molar equivalents of sodium borohydride is less than or equal to 1.0 with respect to compound of formula-(VIII),
f) purifying the Bempedoic acid of formula-(IX) with a mixture of isopropyl acetate and water to provide pure Bempedoic acid of formula-(I).

2. A process for the preparation of crystalline form of Bempedoic acid compound of formula-1, comprising of:
a) Dissolving Bempedoic acid in a mixture of isopropyl acetate and water,
b) stirring and heating the reaction mixture,
c) treating the solution obtained in step-(b) with charcoal,
d) cooling and stirring the reaction mixture,
e) filtering, washing the solid with isopropyl acetate and drying the compound to get the crystalline Bempedoic acid of formula-1.