DESC:FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of Bempedoic acid of formula (I).

Formula (I)

BACKGROUND OF THE INVENTION

Bempedoic acid is chemically described as 8-Hydroxy-2,2,14,14-tetramethylpentadecanedioic acid having structure of formula (I).

Formula (I)

Bempedoic acid (NEXLETOLTM) is an adenosine triphosphate-citrate lyase (ACL) inhibitor indicated as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia or established atherosclerotic cardiovascular disease who require additional lowering of LDL-C.
US 7335799 discloses a process for the preparation of Bempedoic acid using 1,5-dibromopentane and ethyl isobutyrate. The final product is obtained as viscous oil having low yield of 60% and HPLC purity of 83.8% only.
WO 2020257571 & IN 201941027561 also uses ethyl isobutyrate and 1-bromo-5-chloro pentane or 1,5-dibromopentane as a starting material for the preparation of Bempedoic acid.

However above prior art process requires use of high vacuum distillation for removal of unreacted bromo compound i.e. starting material and hence creates operational complexity at large scale synthesis.

Present inventors have identified an improved process for the preparation of Bempedoic acid and hence tried to overcome difficulties with the process in prior arts at large scale i.e. by avoiding high vacuum distillation which helps to obtain intermediate compounds with high purity (> 98%). The process as disclosed herein is highly reproducible and is suitable for scale up production.

SUMMARY OF THE INVENTION

In one aspect, the present application provides a process for the preparation of Bempedoic acid, comprising of following steps:
(a) reacting compound of formula (II) with compound of formula (III) in presence of base and solvent(s) to obtain compound of formula (IV);
(b) hydrolyzing compound of formula (IV) to provide compound of formula (V);
(c) reacting compound of formula (V) with TosMIC (p-toluenesulfonylmethyl isocyanide) in presence of base and solvent(s) to provide compound of formula (VI);
(d) reacting compound of formula (VI) under acidic condition to provide compound of formula (VII); and
(e) reducing compound of formula (VII) using reducing agent and solvent(s) to provide compound of formula (I).

In another aspect, the present application provides novel intermediate compounds of formula (IV):

wherein R1 represents tert-butyl group and R2 represents halogen selected from Br, Cl, F and I.

In another aspect, the present application provides novel intermediate compound of formula (VI):

In further aspect, the present invention process is schematically disclosed as below:

DETAILED DESCRIPTION OF THE INVENTION

In one of the embodiment, the present invention process for the preparation of Bempedoic acid, comprising of following steps:
(a) reacting compound of formula (II) with compound of formula (III) in presence of base and solvent(s) to obtain compound of formula (IV);
(b) hydrolyzing compound of formula (IV) to provide compound of formula (V);
(c) reacting compound of formula (V) with TosMIC (p-toluenesulfonylmethyl isocyanide) in presence of base and solvent(s) to provide compound of formula (VI);
(d) reacting compound of formula (VI) under acidic conditions to provide compound of formula (VII); and
(e) reducing compound of formula (VII) using reducing agent and solvent(s) to provide Bempedoic acid compound of formula (I).

In another embodiment, the present invention provides process for purification of Bempedoic acid of formula I comprising of following steps.
(a) providing the reaction mixture containing Bempedoic acid and first solvent;
(b) heating the reaction mixture and optionally cooling it;
(c) adding second solvent to reaction mixture; and
(d) isolating the pure Bempedoic acid.

In another embodiment, the present invention particularly provides process comprising of reacting compound of formula (II) with compound of formula (III) in presence of base and solvent(s) to provide compound of formula (IV) and hydrolyzing compound of formula (IV) in presence of acid or base to provide compound of formula (V).

wherein R1 is selected from tert-butyl and R2 at either position can be same or different and represents halogen selected from F, Br, Cl and I.

In yet another embodiment, the present invention particularly provides process comprising of reacting compound of formula (V) with TosMIC (p-toluenesulfonyl methyl isocyanide) in presence of base and solvent(s) to provide compound of formula (VI) and reacting compound of formula (VI) under acidic condition to provide compound of formula (VII).

wherein R2 is as defined above.

Base as used herein is selected from the group comprising but not limited to NaOH (sodium hydroxide), KOH (potassium hydroxide), LiOH (lithium hydroxide), NaH (sodium hydride), triethyl amine, DBU, trimethyl amine, triethylamine, triisopropyl amine, DIPEA, KHCO3, K2CO3, NaHCO3, Na2CO3, LiHMDS, KHMDS and like.

Hydrolyzing reagent as used herein involves use of acid selected from hydrochloric acid, sulfuric acid, nitric acid, acetic acid, formic acid, methane sulfonic acid, trifluoroacetic acid and p-toluene sulfonic acid and like or use of base selected from the group comprising but not limited to NaOH, KOH, LiOH, NaH, triethyl amine, DBU, trimetyl amine, triisopropyl amine, NaHCO3, Na2CO3 and like.

The catalyst optionally used herein is selected from tetraalkylammonium halide such as tetrabutylammonium iodide, benzyltrialkylammonium halide, dibenzyl dialkyl ammonium halide and the like.
Acidic condition as used herein above, for which acid is selected from the group comprising but not limited to hydrochloric acid, sulfuric acid, nitric acid, acetic acid, formic acid, methane sulfonic acid, trifluoroacetic acid and p-toluene sulfonic acid and like.

Reducing reagents as used herein is selected from the group comprising but not limited to alkali metal borohydride such as sodium triacetoxy borohydride, sodium borohydride, sodium cyano borohydride, lithium borohydride, nickel borohydride and potassium borohydride, and like.

Solvent(s) as used herein is selected from the group comprising but not limited to amide solvent are selected from dimethylformamide, dimethylacetamide, N-methylpyrrolidone, tetramethylurea and like; DMSO; sulfolane; acetonitrile; water; ether selected from tetrahydrofuran, 2-methyl tetrahydrofuran, cyclopentylmethyl ether, diisopropylether, methyl tert-butyl ether and like; halogenated solvents selected from dichloromethane, chlorobenzene, ethylenedichloride, chloroform, benzotrifluoride carbon tetrachloride and like; hydrocarbon selected from toluene, xylene, n-heptane, hexane, cyclohexane and like; ethers selected from tetrahydrofuran, 2-methyl tetrahydrofuran, cyclopentylmethyl ether, diisopropylether, methyl tert-butyl ether; alcohol solvent selected from methanol, ethanol, propanol, butanol or isopropanol and like or mixture thereof.

In another embodiment, the present invention intermediate compounds obtained in any of the above process steps can be used in subsequent steps with or without isolation.

In another embodiment, the present application provides intermediate compounds of formula (IV):

wherein R1 represents tert-butyl group and R2 at either position can be same or different and represents halogen selected from F, Br, Cl and I.

In yet another embodiment, the present application provides intermediate compound of formula (VI):

In yet another aspect, the present invention also provides following general process for preparation of Bempedoic acid as schematically disclosed below:

In another embodiment, present invention process provides preparation of Bempedoic acid in any of polymorphic form including crystalline or amorphous, more preferably crystalline form.

In further embodiment, present invention process provides Bempedoic acid and its intermediate compounds having purity of greater than 95%, preferably greater than 98% and more preferably greater than 99%.

Wherever applicable in the example of the present invention, the reaction solution may optionally be treated with carbon, flux-calcined diatomaceous earth (Hyflow) or any other suitable material to remove color, insoluble materials, improve clarity of the solution, and/or remove impurities adsorbable on such material. Optionally, the solution obtained above may be filtered to remove any insoluble particles. The insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques under pressure or under reduced pressure. The solution may be filtered by passing through paper, glass fiber, cloth or other membrane material, or a bed of a clarifying agent such as Celite® or Hyflow. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.

The present invention adopts following general method for the isolation such as methods including cooling, crash cooling, concentrating the mass, adding an anti-solvent, adding seed crystals to induce crystallization or evaporation or the like or combinations thereof. Stirring or other alternate methods such as shaking, agitation, or the like, may also be employed for the isolation.

The isolated compound according to the present invention may be recovered by methods including decantation, centrifugation, evaporation, gravity filtration, suction filtration, or any other technique for the recovery of solids under pressure or under reduced pressure. The recovered solid may optionally be dried. Drying may be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at temperatures less than about 100° C., less than about 80° C., less than about 60° C., less than about 50° C., less than about 30° C., or any other suitable temperatures, at atmospheric pressure or under a reduced pressure, as long as the compound is not degraded in quality. The drying may be carried out for any desired times until the required product quality is achieved. The dried product may optionally be subjected to a size reduction procedure to produce desired particle sizes. Milling or micronization may be performed before drying, or after the completion of drying of the product. Techniques that may be used for particle size reduction include, without limitation, ball, roller and hammer milling, and jet milling.

The main advantage of present invention is using tert-butyl isobutyrate as starting material to obtain intermediate compound i.e. tert-butyl-7-bromo-2,2-dimethyl heptanoate which further provide easy hydrolysis to obtain compound 7-bromo-2,2-dimethylheptanoic acid and also removal of unwanted bromo impurity i.e. 1,5-dibromo pentane. It avoids high vacuum distillation to get the intermediate compound with high purity (> 98%).

In the foregoing section, embodiments are described by way of an example to illustrate the process of the invention. However, this is not intended in any way to limit the scope of the present invention. Several variants of the example would be evident to persons ordinarily skilled in the art which are within the scope of the present invention.

Examples:

Example 1: Preparation of tert-butyl isobutyrate
To the mixture of tert-butanol (73.6 g), triethyl amine (195.4 g), 4-DMAP (0.5 g) in methylene chloride (500 ml), isobutyryl chloride (100 g) was added at 25-35°C followed by stirring for about 2 hours at same temperature. After completion of reaction, aq. HCl (440 ml) was added to reaction mixture followed by addition of methylene chloride. The organic layer was separated and washed with aq. sodium bicarbonate and water. The organic layer was concentrated to obtain crude product which was further distilled out under vacuum to obtain the product as oil (91 g).
Example 2: Preparation of 7-bromo-2,2-dimethylheptanoic acid
To the stirring solution of tert-butyl isobutyrate (100 g), 1,5-dibromo pentane (186 g) in toluene (400 ml), LiHMDS (1387 ml) solution was added at 25-35°C and stirred till completion. After completion of reaction, aq. HCl (550 ml) was added to reaction mixture followed by addition of toluene. The organic layer was separated and washed with aqueous sodium bicarbonate followed by water and distilled out under vacuum to obtain tert-butyl 7-bromo-2,2-dimethylheptanoate as oil.
To the above obtained product (i.e. tert-butyl 7-bromo-2,2-dimethylheptanoate), trifluoroacetic acid (400 ml) was added and stirred till completion. After completion of reaction, trifluoro acetic acid was distilled out and aq. sodium hydroxide or aq. sodium carbonate solution was added to reaction mixture. The reaction mixture was washed with toluene. The aqueous layer was further acidified using aq. HCl (140 ml) followed by addition of toluene. The organic layer was separated and washed with water and distilled out to obtain the product as solid (83 g).

Example 3: Preparation of 2,2,14,14-tetramethyl-8-oxo-pentadecanedioic acid
To the solution of DMF (1600 ml), 7-bromo-2,2-dimethylheptanoic acid (100 g) and p-toluenesulfonylmethyl isocyanide (TosMIC) (41 g) were added followed by sodium hydroxide powder (100 g) at 0-5°C and stirring at 0-5°C. After completion of reaction, water was added to the reaction mixture. The product (8-isocyano-2,2,14,14-tetramethyl-8-[(4-methylphenyl)sulfonyl]-penta decanedioic acid) formed in reaction mixture is used in subsequent step.
Toluene (1000 ml) is added to the above reaction mixture followed by addition of con. HCl (300 ml) and stirred till completion. The organic layer was separated, washed with water and distilled out to obtain crude solid product.
To the above crude product was added ethanol (200 ml) followed by addition of aq. KOH solution and reaction mixture was heated along with stirring. The solvent was distilled out partially and water was added followed by addition of conc. HCl and MDC (500 ml). The organic layer was separated and distilled out under vacuum and stripped out using acetonitrile followed by isolated from acetonitrile to obtain the product to obtain the solid product (5 g).
Example 4: Preparation of Bempedoic acid
To the mixture of 2,2,14,14-tetramethyl-8-oxo-pentadecanedioic acid (100 g) and aq. sodium hydroxide (23 g in 400 ml water) was added aq. solution of sodium borohydride (11 g) in aq. sodium hydroxide (200 ml) at about 30°C with stirring. After completion of reaction, methyl tert-butyl ether (MTBE) was added to the reaction mixture and followed by addition of aqueous HCl solution. The organic layer was separated and distilled out partly under vacuum. To the residue was added methyl tert-butyl ether and n-heptane along with stirring. The solid obtained was filtered and washed with mixture of MTBE: n-heptane and dried it under vacuum to obtain Bempedoic acid (80 g) (purity > 99.5%).
Example 5: Purification of Bempedoic acid
To solution of MTBE (400 ml) was added crude Bempedoic acid (100 g) along with stirring and the reaction mixture was heated and stirred for about 30 min. The reaction mixture was cooled to room temperature and n-heptane (300 ml) was added to it along with stirring. The solid obtained was filtered and washed with mixture of MTBE and n-heptane and dried it under vacuum to obtain solid product (95 g).

Dated this 21th day of April 2022

Alembic Pharmaceutical Ltd.
,CLAIMS:We claim:
1. A process for preparing Bempedoic acid of formula (I) comprising the steps of:
(a) reacting compound of formula (II) with compound of formula (III) in presence of base and solvent(s) to obtain compound of formula (IV);

wherein R2 represents F, Br, Cl or I
(b) hydrolyzing compound of formula (IV) in presence of acid or base to provide compound of formula (V);

(c) reacting compound of formula (V) with TosMIC (p-toluenesulfonylmethyl isocyanide) in presence of base and solvent(s) to provide compound of formula (VI);

(d) reacting compound of formula (VI) in presence of acid to provide compound of formula (VII); and

(e) reducing compound of formula (VII) using reducing agent and solvent(s) to provide compound of formula (I).

2. The process as claimed in claim 1, wherein base used in step (a) is selected from NaOH, KOH, LiOH, NaH, triethyl amine, DBU, trimetyl amine, triisopropyl amine, NaHCO3, Na2CO3, LiHMDS or KHMDS.

3. The process as claimed in claim 1, wherein acid used in step (b) is selected from hydrochloric acid, sulfuric acid, nitric acid, acetic acid, formic acid, methane sulfonic acid or trifluoroacetic acid or wherein base is selected from NaOH, KOH, LiOH, NaHCO3 or Na2CO3.

4. The process as claimed in claim 1, wherein base used in step (c) is selected from NaOH, KOH, LiOH, NaH, triethyl amine, DBU, trimetyl amine, triisopropyl amine, NaHCO3, Na2CO3, LiHMDS or KHMDS.

5. The process as claimed in claim 1, wherein acid used in step (d) is selected from hydrochloric acid, sulfuric acid, nitric acid, acetic acid, formic acid, methane sulfonic acid or trifluoroacetic acid.

6. The process as claimed in claim 1, wherein reducing reagent used in step (e) is selected from sodium triacetoxy borohydride, sodium borohydride, sodium cyano borohydride, lithium borohydride, nickel borohydride or potassium borohydride.

7. The process as claimed in claim 1 wherein solvent(s) are selected from amide solvent selected from dimethylformamide (DMF), dimethylacetamide, N-methylpyrrolidone or tetramethylurea; DMSO; sulfolane; acetonitrile; water; ether solvent selected from tetrahydrofuran, 2-methyl tetrahydrofuran, cyclopentylmethyl ether, diisopropylether or methyl tert-butyl ether; halogenated solvent selected from dichloromethane, chlorobenzene, ethylenedichloride, chloroform or benzotrifluoride carbon tetrachloride; hydrocarbon solvent selected from toluene, xylene, n-heptane, hexane or cyclohexane; alcohol solvent selected from methanol, ethanol, propanol, butanol or isopropanol or mixture thereof.

Dated this 21th day of April 2022 Dr. S. Ganesan
Alembic Pharmaceutical Ltd.