FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of 5- bromo-2,2-dimethyl-pentanoic acid isobutyl ester of formula (I), a key intermediate of gemfibrozil, in an environment friendly and commercially viable manner with safer conditions in high yield and high chemical purity.

(I)

BACKGROUND OF THE INVENTION

Gemfibrozil, or 2,2-dimethyl-5-(2,5-xylyloxy)-valeric acid is used in the treatment of hyperlipidemia. The U.S. Patent no. 3,674,836 discloses the gemfibrozil and analogues thereof with process for preparation of the same. The various literature discloses the synthesis of gemfibrozil by using the ester of 5- halo-2,2-dimethyl-pentanoic acid. The esters of 5-halo-2,2-dimethyl-pentanoic acid are an important and key intermediate for the preparation of gemfibrozil and many pharmaceutical compounds.

The various literature discloses the synthesis of gemfibrozil by principally using 5-bromo- or 5-chloro-2,2-dimethylpentanoic acid methyl ester or lower alkyl ester. Some of the literature discloses the use of 5-bromo- or 5-chloro-2,2- dimethylpentanoic acid methyl ester or lower alkyl ester are summarized below.

The U.S. Patent no. 4,665,226 discloses the reaction of 2,5-dimethylphenol with 5-bromo- or 5-chloro-2,2-dimethylpentanoic acid ester, in a mixed solvent system to yield gemfibrozil. The said patent also discloses the reaction of a lower alkyl ester of 2-methylpropanoic acid (isobutyric acid), lithium diisopropylamide and either l-bromo-3-chloropropane or 1,3-dibromopropane to yield the corresponding lower alkyl ester of 5-bromo- or 5-chloro-2,2-dimethylpentanoic acid.

The U.S. Patent no. 5,654,476 discloses the reaction of 2,5-dimethylphenol with a 5-bromo- or 5-chloro-2,2-dimethylpentanoic acid esters in absence of solvents and in the presence of an ammonium or phosphonium quaternary salt to yield gemfibrozil. The said patent has referred the known, conventional methods for preparation of the 5-bromo- or 5-chloro-2,2-dimethylpentanoic acid esters, in the description.

The Asian Journal of chemistry, vol. 27, no. 3 (2015), 925-928 discloses the reaction of isobutyric acid with allyl alcohol to obtain allyl isobutyrate, which was reacted with sodium hydride in solvent toluene to obtain 2,2-dimethyl-4-pentenoic acid. Further, 2,2-dimethyl-4-pentenoic acid was treated with hydrogen bromide in presence of dibenzoyl peroxide and solvent hexane to obtain 5-bromo-2,2- dimethylpentanoic acid, followed by esterification with methanol and concentrated sulphuric acid to synthesize the 5-bromo-2,2-dimethylpentanoic acid methyl ester which was further converted to gemfibrozil. The preparation of 5- bromo-2,2-dimethylpentanoic acid methyl ester involved the multiple steps and use of more solvents, which makes the process uneconomical.

The various literature discloses the synthesis of gemfibrozil by using the ester of 5-halo-2,2-dimethyl-pentanoic acid with special emphasis on the synthesis of 5- bromo-2,2-dimethylpentanoic acid methyl ester. The other ester of 5-halo-2,2- dimethyl-pentanoic acid other than only methyl ester is remained to be the non- explored area which can be used further for synthesis of gemfibrozil. Appraising the importance of the key intermediates, 5-halo-2,2-dimethyl-pentanoic acid esters for preparation of gemfibrozil, the instant inventors are motivated to explore the research in preparation of 5-bromo-2,2-dimethyl-pentanoic acid isobutyl ester with cost-saving and industrially convenient way, which can further utilize for the preparation of gemfibrozil.

Additionally, the economical synthesis of intermediate is need of an hour as it ultimately impacts on the manufacturing cost of final drug. Hence, to overcome the cost constrains and multiple synthesis steps, the instant inventors are motivated to pursue the research to synthesize 5-bromo-2,2-dimethyl-pentanoic acid isobutyl ester from isobutyl isobutyrate and 3-chloropropene through intermediate 2,2-dimethyl-4-pentenoic acid isobutyl ester having high yield, high chemical purity in an economically and commercially viable manner. The instant invention avoids the use of hazardous material such as lithium metal or lithium diisopropylamide, instead of it the industrially suitable least expensive alkali metal hydridesuch as 55% to 60% sodium hydride is employed, which is readily available in large commercial quantities.

OBJECT OF THE INVENTION

The main object of the present invention is to provide an improved process for the preparation of a compound of formula (I), which is simple, economical, user- friendly, safer and commercially viable.

Another objective of the present invention is to provide an improved process for the preparation of a compound of formula (I), which would be easy to implement on commercial scale, and to avoid excessive use of reagent(s) and organic solvent(s), which makes the present invention environment friendly as well.

Yet another objective of the present invention is to provide an improved process for the preparation of a compound of formula (I) in a high yield with high chemical purity. SUMMARY OF THE INVENTION

Accordingly, the present invention provides an improved process for the preparation of 5-bromo-2,2-dimethyl-pentanoic acid isobutyl ester of formula (I) which comprises the steps of:

(I) a) obtaining a compound of formula (3) by reacting a compound of formula (1) with a compound of formula (2) in presence of alkali metal hydride and with or without catalyst in a suitable solvent or mixture of solvents thereof in suitable conditions; and

b) obtaining a compound of formula (I) by reacting a compound of formula (3) with hydrobrominating reagent in a suitable solvent or mixture of solvents thereof in suitable conditions.

The above process is illustrated in the following general synthetic scheme:

DETAILED DESCRIPTION OF THE INVENTION

The present invention now will be described more fully hereinafter. The invention may be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will satisfy applicable legal requirements. As used in the specification, and in the appended claims, the singular forms "a", "an", "the", include plural referents unless the context clearly indicates otherwise.

The instant invention relates to the process for preparation of 2,2-dimethyl-4- pentenoic acid isobutyl ester (3) by reacting isobutyric acid isobutyl ester (1) and 3-chloropropene (2) using alkali metal hydride, with or without use of catalytic amount of potassium iodide (KI) or sodium iodide (Nal) in a suitable solvent. The 2,2-dimethyl-4-pentenoic acid isobutyl ester is then treated with hydrobrominating reagent such as hydrogen bromide (HBr) using hydrocarbon solvent to yield the 5-bromo-2,2-dimethylpentanoic acid isobutyl ester.

In accordance with the objectives, wherein the present invention provides an improved process for the preparation of 5-bromo-2,2-dimethyl-pentanoic acid isobutyl ester of formula (I) and 2,2-dimethyl-4-pentenoic acid isobutyl ester of formula (3).

In an embodiment of the present invention,wherein the said alkali metal hydride used in step (a) may be selected from the group consisting of sodium hydride (NaH), potassium hydride (KH) and the like; more preferably NaH.

In an embodiment of the present invention,wherein the said catalyst used in step (a) may be selected from the group consisting of potassium iodide (KI), sodium iodide (Nal) and the like; more preferably KI. In another embodiment of the present invention, wherein the said solvent used in step (a) may be selected from the group consisting of 1,2-dimethoxy ethane (DME), tetrahydrofuran (THF), 2-methyl tetrahydrofuran and the like or mixture of solvents thereof; more preferably 1,2-dimethoxy ethane.

In another embodiment of the present invention, wherein the said hydrobrominating reagent used in step (b) is hydrogen bromide (HBr) and the like; preferably hydrogen bromide in acetic acid.

In another embodiment of the present invention, wherein the said hydrobrominating reagent used in step (b) is generated by using conventional methods well known in the prior art.

In another embodiment of the present invention, wherein the said solvent used in step (b) may be selected from group of non-polar hydrocarbon solvents consisting of hexane, cyclohexane, « -heptane and the like or mixture of solvents thereof; more preferably hexane or cyclohexane.

In another embodiment of the present invention, the reaction step (a) is carried out is a suitable solvent volume range, wherein said solvent volume range is selected from 1 to 6 volume; more preferably 3 volume.

In another embodiment of the present invention, the reaction step (b) is carried out is a suitable solvent volume range, wherein said solvent volume range is selected from 1 to 6 volume; more preferably 4 volume.

In another embodiment of the present invention, the reaction step (a) is carried out at temperature 40°C to 80°C; more preferably at 60°C to 65 °C and the step (b) is carried out at temperature -5°C to 10°C; more preferably at 0°C to 5°C. In another embodiment of the present invention, wherein all the crude compound may be used as such or may be purified by distillation or crystallization or by different purification techniques well understood by those skilled in the art.

In another embodiment of the present invention, wherein the preparation of a compound of formula (I) may be performed in an in-situ manner.

The compound 5-bromo-2,2-dimethyl-pentanoic acid isobutyl ester is prepared with the process of instant invention may befurther use for the preparation of gemfibrozil.

The preparation of the starting materials and reagents used in the present invention are well known in prior art.

The invention is further illustrated by the following examples, which should not be construed to limit the scope of the invention in anyway.

EXAMPLES

Example 1; Preparation of 2,2-dimethyl-pent-4-enoic acid isobutyl ester(3)

In a 2L reactor connected with heating cooling system and equipped with mechanical stirrer, thermometer pocket and inert nitrogen gas inlet, isobutyl isobutyrate (200.0g; l.Oeq), 60% sodium hydride (110.94g; 2.0eq), potassium iodide (20.0g; 10 mol%) and first lot of allyl chloride (53. Og; 0.5eq) were added in 600 mL (3.0V) of 1,2-dimethoxy ethane at 25°C. The reaction mass was heated to temperature between 60°C to 65°C and maintained for 3h. Then second lot of allyl chloride (53. Og; 0.5eq) was added and the reaction mass was maintained at 60°C to 65°C for 3h. The third lot of allyl chloride (53. Og; 0.5eq) was added to reaction mass and maintained the temperature at 60°C to 65°C for 16h to 20h. The reaction mass was cooled to 0°C to 5°C and quenched with 80mL (0.4V) saturated ammonium chloride solution. The reaction mass was diluted with 320 mL of water (1.6V) and warm to 20°C to 25°C. The organic layer and aqueous layer were separated. The aqueous layer was extracted with lOOmL (0.5V) of toluene. The organic layers werecombined,and toluene layer evaporated to yield crude 2,2-dimethyl-pent-4-enoic acid isobutyl ester (AIBIB) as a liquid with GC purity 89.46%.

Example 2: Preparation of 2,2-dimethyl-pent-4-enoic acid isobutyl ester (3)

In a 2L reactor connected with heating cooling system and equipped with mechanical stirrer, thermometer pocket and inert nitrogen gas inlet, isobutyl isobutyrate (150.0g; l.Oeq), 60% sodium hydride (83. Og; 2.0eq), potassium iodide (15.0g; 10 mol%) and first lot of allyl chloride (40. Og; 0.5eq) were added in 450mL (3.0V) of 1,2-dimethoxy ethane at temperature 25°C. The reaction mass was heated to temperature between 60°C to 65°C and maintained for 3h. Then second lot of allyl chloride (40.0g; 0.5eq) was added with stirring at 60°C to 65°C for 3h. The third lot of allyl chloride (40.0g; 0.5eq) was added to reaction mass and maintained the temperature at 60°C to 65°C for 16h to 20h. The reaction mass was cooled to 20°C to 25°C and poured into the previously cooled water (300mL) by maintaining temperature below 20°C. The reaction mass was warm to 25 °C to 30°C. The organic layer and aqueous layer were separated. The aqueous layer was extracted with 75mL (0.5V) of toluene. The organic layers were combined, and toluene layer evaporated to yield crude 2, 2-dimethyl-pent-4-enoic acid isobutyl ester as a liquid with GC purity 91.0%.

Example 3: Preparation of 5-bromo-2,2-dimethyl-pentanoic acid isobutyl ester (I)

In a clean and dry round bottom flask (RBF) equipped with liquid addition funnel, thermometer pocket, the crude 2,2-dimethyl-pent-4-enoic acid isobutyl ester (170.0g, 100% basis) and hexane (680mL, 4.0V) were charged at temperature between 25°C to 30°C. The reaction mass was stirred and cooled to 0°C to 5°C. To the reaction mass, 33% HBr in acetic acid (454.54g, 2.0eq.) was dropwise added at temperature 0°C to 5°C. After complete addition, the reaction mass was stirred at 0°C to 10°C. The progress of reaction was monitored by GC. After completion of reaction, organic layer and aqueous layer were separated. The hexane layer was washed with water (2x500mL, 5.88V) and then with saturated sodium bicarbonate (NaHC0 ₃ ) solution (lx500mL, 2.94V) until the pH of the aqueous layer become neutral. The hexane was distilled off under reduced pressure to obtain crude 5-bromo-2,2-dimethyl-pentanoic acid isobutyl ester (IBDV). Further, the crude IBDV was distilled by fractional distillation under reduced pressure to obtain pure 5-bromo-2,2-dimethyl-pentanoic acid isobutyl ester as a liquid (yield: 67%, GC purity: 95.70%)

Example 4: Preparation of 5-bromo-2,2-dimethyl-pentanoic acid isobutyl ester (I)

In a clean and dry RBF equipped with liquid addition funnel, thermometer pocket, the crude 2,2-dimethyl-pent-4-enoic acid isobutyl ester (187.0g, with GC purity: 91.0%) and cyclohexane (510mL; 3.0V w.r.t AIBIB) were charged at temperature between 25°C to 30°C. The reaction mass was stirred and cooled to 0°C to 5°C. To the reaction mass, 33% HBr in acetic acid 27.4% (546. Og; 2.0eq) was dropwise added at temperature 0°C to 5°C. After complete addition, the reaction mass was stirred at 0°C to 10°C. The progress of reaction was monitored by GC. After completion of reaction, organic layer and aqueous layer were separated. The cyclohexane layer was washed with water (2x340mL, 2.0V w.r.t AIBIB) and then with saturated NaHC0 ₃ solution (255mL, 1.5V w.r.t AIBIB) until the pH of the aqueous layer become neutral. The cyclohexane was distilled off under reduced pressure to obtain crude 5-bromo-2,2-dimethyl-pentanoic acid isobutyl ester (IBDV). Further, the crude IBDV was distilled by fractional distillation under high vacuum to obtain pure 5-bromo-2,2-dimethyl-pentanoic acid isobutyl ester as a liquid (yield: 66%, GC purity:93.89%). Example 5: Preparation of 5-bromo-2,2-dimethyl-pentanoic acid isobutyl ester (I)

In a clean and dry RBF equipped with liquid addition funnel, thermometer pocket crude 2, 2-Dimethyl-pent-4-enoic acid isobutyl ester 25.0g (33.07g with GC assay: 75.59%), cyclohexane (50 mL; 2.0 V w.r.t AIBIB) and acetic acid 20mL were charged at 25°C to 30°C. The reaction mass was stirred and cooled to 0°C to 5°C. The NaBr (55.97g 4.0eq. w.r.t AIBIB) and H ₂ SO ₄ (0.5eq. w.r.t. NaBr) were added simultaneously into the reaction mass in four equal lots at 0°C to 5°C. After complete addition of cone. H ₂ S0 _4i the reaction mass was stirred at 0°C to 5°C. The progress of reaction was monitored by GC. Organic layer and aqueous layer were separated and the cyclohexane layer was washed with water (2 x 25mL, 1.0V w.r.t AIBIB) and with sat. NaHC0 ₃ solution (25 mL, 1.0 V w.r.t AIBIB) until the pH of the aqueous layer become neutral.The cyclohexane was distilled off under reduced pressure to obtain crude 5-bromo-2,2-dimethyl-pentanoic acid isobutyl ester (IBDV). Crude IBDV: 40.30g (GC purity: 84.23%).

Example 6: Preparation of 5-bromo-2,2-dimethyl-pentanoic acid isobutyl ester (I)

In a clean and dry Glass reactor (30L capacity), crude 2, 2-Dimethyl-pent-4-enoic acid isobutyl ester 5.10 kg (Assay: 76.56%) and cyclohexane (19.44 L) at 25°C to 30°C were charged and cooled to -5°C to 0°C. To the reaction mass, 33% HBr in acetic acid (546. Og; 2.0eq) was added dropwise at temperature at -5°C to 0°C. After complete addition reaction mass was stirred at -5°Cto 0°C for 2h. The progress of reaction was monitored by GC. After completion of reaction, organic layer and aqueous layer were separated and cyclohexane layer washed with water (2 x 5.10L, 1.0V w.r.t AIBIB) and with sat. NaHC0 ₃ solution until the pH of the aqueous layer become neutral. The cyclohexane was distilled off under reduced pressure to obtained crude 5-bromo-2,2-dimethyl-pentanoic acid isobutyl ester (IBDV). Crude IBDV: 6.60 kg (GC purity: 95.02%) and further distilled by fractional distillation under reduced pressure to obtain pure 5-bromo-2,2- dimethyl-pentanoic acid isobutyl ester as a liquid: 5.15 kg (Yield : 91%; GC Purity : 98.41%).

Abbreviations

AcOH : Acetic acid

AIBIB : 2,2-dimethyl-pent-4-enoic acid isobutyl ester

DME : 1 ,2-dimethoxy ethane

eq : Equivalent

g : Gram

GC : Gas chromatography

h : Hour/s

H ₂ 0 : Water

HBr : Hydrogen bromide

HPLC : High performance liquidchromatography

IBDV : 5-bromo-2,2-dimethyl-pentanoic acid isobutyl ester

IB IB : Isobutyl isobutyrate

Kg : Kilogram

KH : Potassium hydride

KI : Potassium iodide

L : Litre

mL : Millilitre

NaH : Sodium hydride

NaHC0 ₃ : Sodium bicarbonate

Nal : Sodium iodide

RBF : Round bottom flask

RM : Reaction mixture

rt : Room temperature

THF : Tetrahydrofuran

V : Volume

w.r.t : With respect to Advantages of the present invention

1. The instant invention produces 5-bromo-2,2-dimethyl-pentanoic acid isobutyl ester in a high yield with high chemical purity.

2. The 5-bromo-2,2-dimethyl-pentanoic acid isobutyl ester intermediate is more reactive than 5-chloro-2,2-dimethyl-pentanoic acid isobutyl ester, therefore the same can be utilized simply for synthesis of gemfibrozil.

3. The handling of mineral oil coated sodium hydride in synthesis of 5-bromo- 2,2-dimethyl-pentanoic acid isobutyl ester is safer than the bare lithium metal used in the synthesis of 5-chloro-2,2-dimethyl-pentanoic acid isobutyl ester.

4. Sodium hydride is abundantly available in the market with cheaper rate, however, with inadequate source and increasing consumption of lithium metal in various industries including the process chemistry, which impacts on the price of the lithium and leads to higher cost.

5. In the instant process recovery of more than 80% of solvents is achieved which can be recycled and reused for successive synthesis process.

6. The instant robust invention leads to low effluent generation, hence makes the process more environmentally friendly, safer and thereby commercially viable.