FIELD OF INVENTION

The present application relates to an improved process for preparation of arachidic acid.

BACKGROUND OF INVENTION

Arachidic acid has several other applications in addition to being used in the preparation of Aramchol. It is also used for the production of detergents, photographic materials and lubricants.

Several processes for the preparation of arachidic acid are known in the literature some of which are given below :

Chemistry - A European Journal, 19(9), 2956-2960; 2013 discloses Ni-catalyzed alkyl-alkyl cross -coupling of bromoalkanoic acids and alkyl Grignard reagents in the presence of 1,3-butadiene as an additive which is shown in the scheme given below : Oxidation of long chain primary alcohols with N0 ₂ gas is disclosed in ChemSusChem, 2(1), 83-88, 2009 wherein the process is shown below :

The above oxidation reaction should be performed as gas-solid reaction. Nitric acid is formed and NO and excess N0 ₂ equilibrate with N ₂ 0 .

Another conventional process that is reported for the preparation of an analog of Arachidic acid wherein sodium hydride is used in the reaction of alkyl bromide (n-butyl bromide) with diethyl malonate. However, no clear procedure is disclosed herein for the preparation of Arachidic acid. ( Journal of Organic Chemistry, 69(11), 3746-3752, 2004). Similar process is disclosed in WO 2008/115381 by reacting heptyl bromide with diethyl malonate in presence of sodium methoxide to obtain a diester. However, subsequent decarboxylation and hydrolysis is not reported in this patent application. WO 2017/039107 discloses a process wherein 1-bromoalkane, K ₂ C0 ₃ , THF and DMF were added to diethyl malonic acid, and a monoalkylation reaction was performed to obtain Compound A (diethyl 2-octadecylmalonate (5)). The process is carried out in the mixture of THF and DMF (1:1). Tetrahedron Letters No.3, pp. 215-217, 1967 and J. Org . Chem., 5, 138-147, 1978 discloses use of NaCN-Me ₂ SO reagent complex for effecting decarboxylation of analogous compounds. The disadvantage of this process is involvement of a cyanide reagent,

Similar reaction of Boric acid-promoted hydrodecarbalkoxylation of different malonic esters to obtain acetic esters, analogs of methyl arachidate, is known in Synthetic Communications, 9(7), 609-11; 1979.

Though several processes are reported for the preparation of Arachidic acid, each of these has some disadvantages. When sodium methoxide was used as base, the steryl bromide reacts with NaOMe and generates the ether impurity. NaH is pyrophoric reagent and difficult to handle on large scale manufacturing. The reaction with boric acid involves carrying out reactions at very high temperature of 170-190 °C, where as in NaCl/DMSO process the reaction temperature is 140-150 °C. Also sodium chloride is a cheaper reagent compared to boric acid.

Hence, there remains a need for a cost-effective, simple, safe base to handle and industrially suitable process for preparation of arachidic acid, which is devoid of disadvantages that are associated with prior-art. Further, the process of the present invention involve common reagents with easy isolation processes combined with an efficient purification process at each stage.

OBJECTIVE OF THE INVENTION

The main objective of the present invention is to provide an improved process for the preparation of arachidic acid. Yet another objective of the present invention is to provide improved process for the preparation of arachidic acid which comprises reaction of alkyl halide with dialkyl malonate, decarboxylation and hydrolysis. Still another objective of the present invention is to provide improved process for the preparation of arachidic acid which is easily scalable, industrially safe and involves use of easily available, commercially cheap raw materials.

SUMMARY OF INVENTION

Accordingly, the present invention relates to an improved process for the preparation of arachidic acid (III) Formula (III) comprising the steps of: a) reacting 1-bromooctadecane with dialkyl malonate in presence of base in a single solvent system to provide dialkyl 2-octadecylmalonate (I); Formula (I) b) decarboxylating dialkyl 2-octadecylmalonate (I) in a solvent to provide alkyl arachidate (II); Formula (II) and c) hydrolysis of alkyl arachidate (II) to provide arachidic acid (III).

Another embodiment of the present invention relates to an improved process for the preparation of arachidic acid (III) formula (III) comprising the steps of: a) reacting 1-bromooctadecane with dimethyl malonate in presence of potassium carbonate in a single solvent system to provide dimethyl 2-octadecylmalonate (la); Formula (la) b) decarboxylating dimethyl 2-octadecylmalonate (la) in a solvent to provide methyl arachidate (Ila); Formula (Ila) and c) hydrolysis of methyl arachidate to provide arachidic acid (III).

Another embodiment of the present invention specifically relates to an improved process for the preparation of arachidic acid (III) comprising the steps of: a) reacting 1-bromooctadecane with dimethyl malonate in presence of potassium carbonate in a solvent to provide dimethyl 2-octadecylmalonate (la); b) decarboxylating dimethyl 2-octadecylmalonate (la) with sodium chloride in a solvent to provide methyl arachidate (Ila); and c) hydrolysis of methyl arachidate to provide arachidic acid (III). Yet another embodiment of the present application relates to a process for preparation of methyl arachidate (Ila) comprising reacting dimethyl 2- octadecylmalonate (la) with sodium chloride to provide methyl arachidate (Ila).

DETAILED DESCRIPTION OF INVENTION The term “alk or alkyl” as used herein is but not limited to methyl, ethyl, n- propyl, isopropyl, iso-butyl.

The base used herein is but not limited to inorganic base like alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate and lithium carbonate; Alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate. Specifically, the base may be potassium carbonate. The solvent is a suitable aprotic polar solvent which includes but not limited to dimethyl formamide, dimethyl sulfoxide, dimethyl acetamide, hexamethylphosphoric triamide and the like. Specifically, the solvent may be dimethyl formamide. The reaction between 1-bromooctadecane and dimethyl malonate may be carried out for about 30 minutes to about 10 hours at about 0 °C to about boiling point of the solvent. Specifically, the reaction between 1- bromooctadecane and dimethyl malonate may be carried out for about 1 hour to about 5 hours at about 60 °C to about 100 °C. The product may be isolated from the reaction mass by any method known in the art. Specifically, the reaction may be quenched with water and the product may be isolated by filtration.

The hydrolysis of alkyl arachidate (II) in step (c) may be carried out using a base or acid. The base is as defined above. The acid as used herein is but not limited to acids inorganic acid such as hydrochloric acid, sulphuric acid, phosphoric acid, hydrobromic acid, hydrofluoric acid and perchloric acid, polyphosphoric acid.

In an embodiment of the present invention the reaction between 1- bromooctadecane and dimethyl malonate in step (a) may be performed in a suitable aprotic polar solvent in presence of potassium carbonate as base.

Optionally, dimethyl 2-octadecylmalonate (la), as obtained by step (a), may be purified by crystallization from a suitable solvent. Specifically, dimethyl 2- octadecylmalonate (la), as obtained by step (a), may be purified by crystallization from methanol.

In embodiments of step (b), dimethyl 2-octadecylmalonate (la), as obtained by step (a) may be reacted with sodium chloride in a suitable solvent to provide methyl arachidate (Ila). The suitable solvent may include but not limited to aprotic polar solvent, water and mixtures thereof. The suitable aprotic polar solvent includes but not limited to dimethyl formamide, dimethyl sulfoxide, dimethyl acetamide, hexamethylphosphoric triamide and the like. In one embodiment, the step (b) may be carried out in a mixture of aprotic polar solvent and water. Specifically, the step (b) may be carried out in a mixture of dimethyl sulfoxide and water. The reaction between dimethyl 2-octadecylmalonate (I) and sodium chloride may be carried out for about 30 minutes to about 30 hours at about 0 °C to about boiling point of the solvent. Specifically, the reaction between dimethyl 2-octadecylmalonate (I) and sodium chloride may be carried out for about 10 hours to about 20 hours at about 140 °C to about 150 °C. Methyl arachidate (Ila) may be isolated from the reaction mass by any process known in the art. Specifically, the reaction mass may be quenched with water and methyl arachidate (Ila) may be isolated by filtration.

Optionally, methyl arachidate (Ila), as obtained by step (b), may be purified by crystallization from a suitable solvent. Specifically, methyl arachidate (Ila), as obtained by step (a), may be purified by crystallization from a mixture of methanol and heptane.

In embodiments of step (c), methyl arachidate (Ila), as obtained by step (b), may be hydrolyzed to provide arachidic acid (III). Hydrolysis of methyl arachidate (Ila) may be performed in basic or in acidic condition. Specifically, hydrolysis of methyl arachidate (Ila) may be performed in basic condition. More, specifically, hydrolysis of methyl arachidate (Ila) may be performed in presence of sodium hydroxide in a mixture of solvents like tetrahydrofuran and water.

Optionally, arachidic acid (III) may be purified by crystallization from a suitable solvent or mixtures of solvents. Specifically, arachidic acid (III) may be purified by crystallization from a mixture of tetrahydrofuran and acetone.

The advantage of the present application lies in the use of cheap and readily available reagents. The step (a) of the present application is known to be carried out in presence of bases like sodium methoxide and sodium hydride, however this application teaches use of potassium carbonate as base. Potassium carbonate is cheaper and easily available than sodium methoxide and sodium hydride. Moreover, sodium hydride is a pyrophoric reagent whereas potassium carbonate is not a pyrophoric reagent. Hence, the industrial application of potassium carbonate is easier than sodium hydride. When sodium methoxide was used in step (a), an ether impurity of formula (A) is generated which can be arrested using potassium carbonate, thus making the present process commercially viable.

The step (b) of the current application is known to be carried out in presence of reagents like l,5-diazabicyclo[4.3.0]non-5-ene and boric acid. Sodium chloride is a very cheap reagent and very easily available than both the known reagents, making the present process commercially viable.

Second aspect of the present application relates to a process for preparation of methyl arachidate (Ila) comprising reacting dimethyl 2-octadecylmalonate (la) with sodium chloride to provide methyl arachidate. In embodiments, reaction of dimethyl 2-octadecylmalonate (la) with sodium chloride may be carried out in a suitable solvent or mixture of solvents at a suitable temperature for a sufficient time. Specifically, reaction of dimethyl 2-octadecylmalonate (la) with sodium chloride may be carried out in a mixture of dimethyl formamide and water at a temperature of about 140 °C to about 150 °C for a time period of about lhour to 20 hours. The product, methyl arachidate (Ila), may be isolated from the reaction mass by any suitable process known in the art.

Optionally, methyl arachidate (Ila), may be crystallized from suitable solvent. Specifically, methyl arachidate (Ila) may be crystallized from a mixture of methanol and heptane. The following definitions are used in connection with the present application unless the context indicates otherwise.

The terms "about," "general, ‘generally," and the like are to be construed as modifying a term or value such that it is not an absolute. Such terms will be defined by the circumstances and the terms that they modify as those terms are understood by those of skill in the art. This includes, at very least, the degree of expected experimental error, technique error and instrument error for a given technique used to measure a value.

All percentages and ratios used herein are by weight of the total composition and all measurements made are at about 25 °C and about atmospheric pressure, unless otherwise designated. All temperatures are in degree Celsius unless specified otherwise. As used herein, the terms “comprising” and “comprises” mean the elements recited, or their equivalents in structure or function, plus any other element or elements which are not recited. The terms “having” and “including” are also to be construed as open ended. All ranges recited herein include the endpoints, including those that recite a range between two values. Whether so indicated or not, all values recited herein are approximate as defined by the circumstances, including the degree of expected experimental error, technique error, and instrument error for a given technique used to measure a value.

The term “optional” or “optionally” is taken to mean that the event or circumstance described in the specification may or may not occur, and that the description includes instances where the event occurs and instances where it does not.

Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the disclosure in any manner.

EXAMPLES

Example 1: Preparation of dimethyl 2-octadecylmalonate (la):

A solution of dimethyl malonate (119 g) and dimethyl formamide (300 mL) was stirred at about 25 °C for 5-10 minutes. Potassium carbonate (207 g) and DMF (100 mL) was added to the reaction mass and stirred for 1 hour. To the above reaction mass, 1-bromooctadecane (100 g) was slowly added, followed by dimethyl formamide (100 mL). The reaction mass was heated to 80-90 °C and stirred at the same temperature for 2 hours and 30 minutes. The reaction mass was cooled slowly to 25-30 °C and quenched with water (1 L). The reaction mass was stirred for 1 hour at the same temperature and the precipitated compound was filtered. The product was washed with water (500 mL) and suck dried. The wet compound was taken in methanol (300 mL) and the reaction mass was heated to reflux for about 1 hour. The reaction mass was cooled slowly to 25-30 °C and stirred for 1 more hour. The reaction mass was again cooled slowly to 5-15 °C and stirred for 30 minutes at that temperature. The precipitated compound was filtered and washed with chilled methanol (100 mL). The compound was dried under vacuum for 21 hours to provide the title compound.

Yield: 112 g (97.3%)

Purity : 97.83%

Example 2: Preparation of methyl arachidate (Ila)

To a mixture of dimethyl 2-octadecylmalonate (la) (112 g) and dimethyl sulfoxide (1120 mL), sodium chloride (68.1 g) and water (10.49 g/mL) was added. The reaction mass was heated to 140-150 °C for about 15 hours. The reaction mass was cooled to 25-35 °C and water (560 mL) was added to the reaction mass. The reaction mass was stirred at the same temperature for about 4 hours and filtered. The wet compound was added to a mixture of methanol (560 mL) and heptane (56 mL). The reaction mass was heated to reflux for 30 minutes and then cooled to 30-35 °C and stirred for 90 minutes. The reaction mass was further cooled to 5-15 °C and stirred for 2 hours. The precipitated compound was filtered, washed with methanol (112 mL) and dried overnight under vacuum to provide the title compound.

Yield: 81.5 g (85.8%)

Purity : 90.32%

Example 3: Preparation of arachidic acid (III)

To a solution of methyl arachidate (Ila) (80 g) and tetrahydrofuran (400 mL), water (160 mL was added. A solution of sodium hydroxide, prepared by slowly adding sodium hydroxide (16.17 g) in water (160 mL), was added to the above solution maintaining the temperature of the reaction mass at 20-40 °C. Water (80 mL) was further added to the reaction mass and heated to 60-70 °C. The reaction mass was stirred for 2 hours at the same temperature and cooled to 45-55 °C. Water (80 mL) was added to the reaction mass and the temperature of the reaction mass was cooled to 25-35 °C. The pH of the reaction mass was adjusted to 6.5-7.5 by slowly adding dilute hydrochloric acid (IN) and stirred the reaction mass for 2 hours and 30 minutes. The precipitated compound was filtered. The wet compound was added to a mixture of tetrahydrofuran (80 mL) and acetone (400 mL). The reaction mass was heated to 50-60 °C and stirred for 40 minutes. The reaction mass was cooled to 25- 35 °C and stirred for 40 minutes. The reaction mass was further cooled to 5-10 °C and the precipitated compound was filtered, washed with acetone (80 mL) and dried at 40-50 °C under vacuum for 9 hours to afford the desired compound.

Yield: 65.1 g (84.5%)

Purity : 99.96%