WO2020212955A1

WO2020212955A1 - Process for the preparation of a key intermediate of gemfibrozil

Info

Publication number: WO2020212955A1
Application number: PCT/IB2020/053691
Authority: WO
Inventors: Hitesh Trambak Kubavat; Vikrant Maruti Patil; Somnath Nandkumar Salalkar; Pravin Mahadu NAVALE; Srinivas DUDDEDA; Sandeep SURYAWANSHI; Sudhir Nambiar
Original assignee: Hikal Limited
Priority date: 2019-04-18
Filing date: 2020-04-18
Publication date: 2020-10-22

Abstract

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, by using radical initiator in an environment friendly and commercially viable manner with safer conditions in high yield and high chemical purity.

Description

PROCESS FOR THE PREPARATION OF A KEY INTERMEDIATE

OF GEMFIBROZIL

RELATED APPLICATION

This application claims the benefit to Indian Provisional Application No. 201921015587 filed on April 18, 2019, the contents of which are incorporated by reference herein.

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, by using radical initiator in an environment friendly and commercially viable manner in high yield and high chemical purity.

BACKGROUND OF THE INVENTION

Gemfibrozil, or 2,2-dimethyl-5-(2,5-xylyloxy)-valeric acid is used in the treatment of hyper lipidemias. The U.S. Patent no. 3,674,836 discloses the gemfibrozil and analogues thereof with process for preparation of the same. 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 ester of 5-halo-2,2-dimethyl-pentanoic acid such as 5-bromo- or 5-chloro-2,2- dimethylpentanoic acid methyl ester or lower alkyl ester. The special emphasis of several literature includes the synthesis of gemfibrozil by using 5-bromo-2,2- dimethylpentanoic acid methyl 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 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 process uneconomical.

The European Patent no. 0219117 discloses the preparation of 2,2-dimethyl-5- bromovaleric acid by reacting 2,2-dimethyl-4-pentenoic acid (DMP) with hydrogen bromide in solvents selected from aliphatic hydrocarbons, aromatic hydrocarbons, ethereal solvents or halogen-containing solvents, in the presence or absence of a catalyst i.e. radical initiator selected from an organic peroxide or an organic azo compound.

The Indian Patent no. 175368 discloses the preparation of 2,2-dimethyl-5-bromo pentanoic acid by reacting 2,2-dimethyl-4-pentenoic acid with hydrobromic acid (hydrogen bromide), in the presence of benzoyl peroxidein solvent petroleum ether.

The Indian Patent application 201721035354 discloses the reaction of isobutyric acid isobutyl ester with 3-chloropropene using sodium hydride and dimethoxy ethane in presence or absence of catalyst to obtain 2,2-dimethyl-4-pentenoic acid isobutyl ester which is treated with brominating agent such as HBr in acetic acid in solvent such as hexane, cyclohexane to obtain 5-bromo-2,2-dimethylpentanoic acid methyl ester. However, on higher scale, the reaction was not completed and simultaneously 15-20% 4-bromo-2,2-dimethylpentanoic acid isobutyl ester (4- bromo IBDV) impurity of formula (III) was formed compared to maximum 3% of the same in the laboratory experiments.

To get the pure 5-bromo-2,2-dimethylpentanoic acid isobutyl ester, the aforesaid impurity must be removed by any means. The removal of the said impurity from synthesis or crude IBDV by fractional distillation is difficult due to close boiling point of functional group positional isomers5-bromo-2,2-dimethylpentanoic acid isobutyl ester and 4-bromo-2,2-dimethylpentanoic acid isobutyl ester, which also resulted in the loss of yield and required additional time cycle for production at commercial quantities. Based on the observations at higher scale reaction, additional radical initiator may be required for smooth reaction, to drive the reaction for completion and to control the formation of another isomer 4-bromo

IBDV. The significance of by-products from reactions in process development work arises from the need to control or eliminate their formation which might affect product cost, process safety, product purity and environmental health. Now days, not only purity profile but also impurity profile has become mandatory according to various regulatory authorities. Since, the strict regulations of the regulatory authorities pertaining to the presence of impurities in the active ingredient, it is highly essential to align the research in line with the guidelines of the regulatory authorities in accordance to appropriate regulations and limits to register and commercialize the product in respective countries.

Appraising the importance of the key intermediates, 5 -halo-2, 2-dimethyl- pentanoic acid esters for preparation of gemfibrozil and to overcome existing problem associated with the formation of excess 4-bromo IBDV impurity, incomplete reaction and more time cycle required for higher batch production, the inventors of instant invention developed process for preparation of 5-bromo-2,2- dimethylpentanoic acid isobutyl ester with cost-saving and industrially convenient way with high purity and less time cycle at commercial quantities, which can further utilize for the preparation of gemfibrozil.

The aforesaid prior art documents singly as a whole or combinedly, (a) do not motivate to pursue the research using radical initiator which also controls the formation of another isomer 4-bromo IBDV in the preparation of 5-bromo-2,2- dimethylpentanoic acid isobutyl ester; (b) do not identify the formation of 4- bromo IBDV isomer impurity or problem associated with it having so identified this isomer. Also, the inventors of the instant invention have for the first time identified an excess formation of 4-bromo IBDV isomer impurity, lactonizing it to corresponding lactone derivative of formula (IV) by using acid as a catalyst and process for removal of same which no one has reported earlier. Additionally, the prior processes are silent about the said isomer impurity.

The advantages of 5-bromo-2,2-dimethylpentanoic acid isobutyl ester over 5- bromo-2,2-dimethylpentanoic acid methyl ester is the bulkiness of isobutyl group over methyl group, which is easily eliminated during reaction or chemical transformation. Therefore, it is easier to convert 4-bromo-2,2-dimethylpentanoic acid isobutyl ester to lactone derivative compared to 4-bromo-2,2- dimethylpentanoic acid methyl ester or lower alkyl ester.

The prior art documents do not disclose the use of radical initiator to control formation of an unwanted isomer impurity, 4-bromo-2,2-dimethylpentanoic acid isobutyl ester (4-bromo IBDV) and process for removal of said isomer in the preparation of 5-bromo-2,2-dimethylpentanoic acid isobutyl ester. 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 of formula (I) by using radical initiator, with or without acid, with high yield, high chemical purity in an economically and commercially viable manner.

OBJECTIVES OF THE INVENTION

The main object of the present invention is to provide an improved process for the preparation of 5-bromo-2,2-dimethyl-pentanoic acid isobutyl ester of formula (I) using radical initiator, which is simple, economical friendly and commercially viable.

Another objective of the present invention is to provide an improved process for the preparation of 5-bromo-2,2-dimethyl-pentanoic acid isobutyl ester of formula (I) using radical initiator to control an excess formation of impurity 4-bromo-2,2- dimethylpentanoic acid isobutyl ester of formula (III).

Another objective of the present invention is to provide a process for purification of 5-bromo-2,2-dimethyl-pentanoic acid isobutyl ester of formula (I) by using acid to lactonize unwanted isomer impurity 4-bromo-2,2-dimethylpentanoic acid isobutyl ester of formula (III) to corresponding lactone derivative of formula (IV) and subsequently removing the said lactone. Another objective of the present invention is to provide an improved process for the preparation of 5-bromo-2,2-dimethyl-pentanoic acid isobutyl ester 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 5-bromo-2,2-dimethyl-pentanoic acid isobutyl ester of formula (I) in a high yield with high chemical purity.

Yet another objective of the present invention is to provide an improved process for the preparation of Gemfibrozil using 5-bromo-2,2-dimethyl-pentanoic acid isobutyl ester of formula (I) obtained by a process of the instant invention.

SUMMARY OF THE INVENTION

In one aspect of 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:

a) reacting a compound of formula (II) with brominating reagent in presence of a radical initiator, in a suitable solvent or mixture of solvents thereof;

b) obtaining the crude compound of formula (I);

c) optionally, treating the crude compound of formula (I) with acid;

d) obtaining a pure compound of formula (I). An another aspect of the present invention provides process for purification of 5- bromo-2,2-dimethyl-pentanoic acid isobutyl ester of formula (I) by using acid to lactonize unwanted isomer impurity 4-bromo-2,2-dimethylpentanoic acid isobutyl ester of formula (III) to corresponding lactone derivative of formula (IV) and subsequently removing the said lactone to obtain pure compound of formula (I).

In another aspect of the instant 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:

a) reacting a compound of formula (II) with brominating reagent in presence of a radical initiator to control excess formation of impurity 4-bromo-2,2- dimethylpentanoic acid isobutyl ester of formula (III), in a suitable solvent or mixture of solvents thereof;

b) obtaining the crude compound of formula (I);

c) optionally, treating the crude compound of formula (I) with acid to lactonize the unwanted impurity 4-bromo-2,2-dimethylpentanoic acid isobutyl ester of formula (III) to corresponding lactone derivative of formula (IV)

d) obtaining a pure compound of formula (I). 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.

b) obtaining the crude compound of formula (I);

c) optionally, treating the crude compound of formula (I) with acid;

d) obtaining a pure compound of formula (I).

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

In another aspect of the present invention provides process for purification of 5- bromo-2,2-dimethyl-pentanoic acid isobutyl ester of formula (I) by using acid to lactonize unwanted isomer impurity, 4-bromo-2,2-dimethylpentanoic acid isobutyl ester of formula (III) to corresponding lactone derivative of formula (IV) and subsequently removing the said lactone by fractional distillation to obtain pure compound of formula (I) with high chemical purity in an economically and commercially viable manner.

An another aspect of the instant 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:

b) obtaining the crude compound of formula (I);

c) optionally, treating the crude compound of formula (I) with acid to lactonize the unwanted impurity 4-bromo-2,2-dimethylpentanoic acid isobutyl ester of formula (III) to corresponding lactone derivative of formula (IV);

(IV) d) obtaining a pure compound of formula (I).

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) by using radical initiator, with or without acid, with high yield, high chemical purity in an economically and commercially viable manner.

In an embodiment of the present invention, wherein the use of radical initiator enhances reaction speed, which reduces time cycle and makes process cost efficient.

In an embodiment of the present invention, wherein the radical initiator used in step (a) is one or more selected from the group consisting of air, oxygen, peracid, organic peroxide, an organic azo compound. The peracid is selected from the group consisting of peracetic acid, trifluoroperacetic acid, 2,4-dinitroperbenzoic acids, m-chloroperbenzoic acid(MCPBA), persulfuric acid, percarbonic acid, perboric acid and the like. The organic peroxide is selected from the group consisting of benzoyl peroxide, hydrogen peroxide, hydroperoxides, di-tert-butyl peroxide, tert-butylcumyl peroxide, dicumyl peroxide, isobutyryl peroxide, propionyl peroxide, tert-butyl hydroperoxide, cumene hydroperoxide, diisopropylbenzene hydroperoxide, para-menthane hydroperoxide and the like.

In another embodiment of the present invention, wherein the said solvent used in step (a) is selected from the organic solvent, aliphatic hydrocarbons, aromatic hydrocarbons, ethereal solvents and halogen-containing solvents or mixture of solvents thereof. Specific examples of the solvent include for example hexane, cyclohexane, n-hcptanc, pentane, ether, toluene, carbon tetrachloride, benzene, dioxane, tetrahydrofuran (THF), acetic acid and the like or mixture of solvents thereof. In another embodiment of the present invention, wherein the said brominating reagent used in step (a) is hydrogen bromide (HBr); preferably hydrogen bromide in acetic acid.

In another embodiment of the present invention, the reaction step (a) is carried out at temperature between 0°C to -10°C.

In another embodiment of the present invention, wherein the step (c) the reaction mixture comprises the crude 5-bromo-2,2-dimethyl-pentanoic acid isobutyl ester of formula (I), isomer 4-bromo-2,2-dimethylpentanoic acid isobutyl ester (4- bromo IBDV) of formula (III), is treated with acid such as concentrated sulphuric acid (cone. FhSQ which results in conversion of excess 4-bromo IBDV to corresponding lactone derivative of formula (IV) and the compound of formula (I) remain as it is. Further, the5-bromo-2,2-dimethylpentanoic acid isobutyl ester of formula (I) and lactone derivative of formula (IV) are easily separated by fractional distillation in different fraction taking advantage of a significant difference in their boiling points to obtain pure 5-bromo-2,2-dimethylpentanoic acid isobutyl ester (IBDV) of formula (I). The reaction scheme as shown below indicates the removal of unwanted isomer.

In another embodiment of the present invention, wherein the said acid used in step (c) is selected from one or more organic acid or inorganic acid such as hydrochloric acid, nitric acid, sulfuric acid, or mixture thereof.

In another embodiment of the present invention, wherein the preparation of a 5- bromo-2,2-dimethyl-pentanoic acid isobutyl ester of formula (I)is performed in an in-situ manner. In another embodiment of the present invention, wherein all the crude compound is used as such or may be purified by distillation or crystallization or by different techniques well understood by those skilled in the art.

The compound 5-bromo-2,2-dimethyl-pentanoic acid isobutyl ester of formula (I) is prepared with the process of instant invention is further 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 5-bromo-2,2-dimethyl-pentanoic acid isobutyl ester (I)

100 g of 2,2-dimethyl-pent-4-enoic acid isobutyl ester (AIBIB) and 200 mL of cyclohexane were charged in to the dry round bottom flask (RBF) at temperature between 25°C to 30°C. The reaction mixture was cooled to -5°C to 0°Cunder stirring. To the reaction mixture, 3.0 g of peracetic acid was added. To the cooled reaction mass, 333 g of HBr in acetic acid (2.5 eq.) was dropwise added at temperature -5°C to 0°Cover period of 1-2 h. The progress of reaction was monitored by GC. The HBr in acetic acid layer was separated from cyclohexane layer and cyclohexane layer washed with water. Finally, cyclohexane layer was washed with saturated NaHCCL solution. The cyclohexane was distilled off under reduced pressure to obtainel58.0 g crude 5-bromo-2,2-dimethyl-pentanoic acid isobutyl ester (IBDV) (GC purity: IBDV 91.92%; 4-Bromo IBDV 2.80).

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

100 g of 2,2-dimethyl-pent-4-enoic acid isobutyl ester (AIBIB) and 200 mL of cyclohexane were charged in to the dry RBF at temperature between 25°C to 30°C. The reaction mixture was cooled to -5°C to 0°C under stirring. To the reaction mixture, 3.0 g of peracetic acid was added. To the cooled reaction mass, 333 g of HBr in acetic acid (2.5 eq.) was dropwise added at temperature -5°C to 0°Cover period of 1-2 h. The progress of reaction was monitored by GC. The HBr in acetic acid layer was separated from cyclohexane layer and cyclohexane layer washed with water. Finally, cyclohexane layer was washed with saturated NaHCCF solution. The cyclohexane was distilled off under reduced pressure to obtained 158.33 g crude 5-bromo-2,2-dimethyl-pentanoic acid isobutyl ester (IBDVXGC purity: IBDV 92.53%; 4-bromo IBDV 0.97%).

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

In a clean and dry glass reactor (30L capacity), 5.49 kg crude 2,2-dimethyl-pent- 4-enoic acid isobutyl ester (assay: 72.76%) and cyclohexane (8 L) were charged at temperature between 25°C to 30°C. The reaction mixture was cooled to -5°C to 0°C under stirring. To the reaction mixture, 160 g (1% w.r.t AIBIB) of peracetic acid solution was added at temperature -5°C to 0°C. To the cooled reaction mass, 13.31 kg of HBr in acetic acid was dropwise added at temperature -5°C to 0°C. The progress of reaction was monitored by GC. The HBr in acetic acid layer was separated from cyclohexane layer and cyclohexane layer washed with water. Finally, cyclohexane layer was washed with saturated NaHC0₃ solution till neutral pH of aqueous layer. The cyclohexane was distilled off under reduced pressure to obtain crude 5-bromo-2,2-dimethyl-pentanoic acid isobutyl ester (IBDV) followed by fractional distillation to yield 5.10 kg pure final product IBDV (yield: 88.60%; GC purity: 98.83%).

Example 4: Purification of 5-bromo-2,2-dimethylpentanoic acid isobutyl ester

(I)

In a clean and dry round bottom flask equipped with thermometer pocket, 845.40 g of crude 5-bromo-2,2-dimethyl-pentanoic acid isobutyl ester (IBDV) (IBDV 75.67%, 4-bromo IBDV 15.87 %) was charged. 4.23 g (0.5%) of concentrated sulphuric acid was added. The reaction mass was heated to 130°C to 140°C for 4h. The conversion of 4-bromo IBDV isomer to corresponding lactone derivative was characterized by GC. The fractional distillation of reaction mass yield 398 g of pure IBDV (GC purity: 97.61%).

Abbreviations

AcOH Acetic acid

AIBIB 2,2-dimethyl-4-pentenoic acid isobutyl ester

4-bromo 4-bromo-2,2-dimethylpentanoic acid isobutyl

IBDV ester

DMP 2,2-dimethyl-4-pentenoic acid

Eq Equivalent

G Gram

GC Gas chromatography

H Hour/s

H₂O Water

HBr Hydrogen bromide

HPLC High performance liquidchromatography

5-bromo-2,2-dimethyl-pentanoic acid isobutyl

IBDV

ester

Kg Kilogram

L Fitre

MCPBA m-chloroperbenzoic acid

mL Millilitre

NaHCOs Sodium bicarbonate

RBF Round bottom flask

RM Reaction mixture

Rt Room temperature

THF T etr ahydro fur an

V Volume

w.r.t With respect to

Claims

CLAIM:

1. An improved process for the preparation of 5-bromo-2,2-dimethyl-pentanoic acid isobutyl ester of formula (I) which comprises the steps of:

a) reacting a compound of formula (II) with brominating reagent in presence of a radical initiator, in a solvent or mixture of solvents thereof;

b) obtaining the crude compound of formula (I);

c) optionally, treating the crude compound of formula (I) with acid; d) obtaining a pure compound of formula (I).

2. A process for purification of 5-bromo-2,2-dimethyl-pentanoic acid isobutyl ester of formula (I)

by using acid to lactonize unwanted isomer impurity 4-bromo-2,2- dimethylpentanoic acid isobutyl ester of formula (III) to corresponding lactone derivative of formula (IV)

and subsequently removing the said lactone.

3. An improved process for the preparation of 5-bromo-2,2-dimethyl-pentanoic acid isobutyl ester of formula (I) which comprises the steps of:

a) reacting a compound of formula (II) with brominating reagent in presence of a radical initiator to control excess formation of impurity 4-bromo-2,2-dimethylpentanoic acid isobutyl ester of formula (III), in a solvent or mixture of solvents thereof;

b) obtaining the crude compound of formula (I);

d) removing lactone derivation of formula (IV) to obtain pure compound of formula (I).

4. The process as claimed in claim 1 and 3, wherein the radical initiator is selected from air, oxygen, peracid, organic peroxide, or an organic azo compound, where peracid is selected from peracetic acid, trifluoroperacetic acid, 2,4-dinitroperbenzoic acids, m-chloroperbenzoic acid(MCPBA), persulfuric acid, percarbonic acid and perboric acid, where organic peroxide is selected from benzoyl peroxide, hydrogen peroxide, hydroperoxides, di-tert- butyl peroxide, tert-butylcumyl peroxide, dicumyl peroxide, isobutyryl peroxide, propionyl peroxide, tert-butyl hydroperoxide, cumene hydroperoxide, diisopropylbenzene hydroperoxide and para-menthane hydroperoxide.

5. The process as claimed in claim 1 and 3, wherein the solvent used in step (a)is selected from hexane, cyclohexane, n- heptane, pentane, ether, toluene, carbon tetrachloride, benzene, dioxane, tetrahydrofuran (THF), acetic acid or mixture of solvents thereof.

6. The process as claimed in claim 1 and 3, wherein the said brominating reagent used in step (a) is hydrogen bromide (HBr); preferably hydrogen bromide in acetic acid.

7. The process as claimed in claim 1 and 3, the reaction step (a) is carried out at temperature in between 0°C to -10°C.

8. The process as claimed in claim 1, 2 and 3, wherein the acid is selected from one or more organic acid or inorganic acid.

9. The process as claimed in claim 1, 2 and 3, wherein the acid is selected from hydrochloric acid, nitric acid, sulfuric acid, or mixture thereof.