DESC:RELATED PATENT APPLICATION:

This application claims priority to and benefit of Indian Patent Application No. 202241064834 filed on November 12, 2022; the disclosures of which are incorporated herein by reference.

FIELD OF THE INVENTION:

The present invention relates to an improved process for the preparation of sodium phenylbutyrate of formula I and its intermediates thereof. The invention also relates to the preparation of intermediate diethyl-(2-phenylethyl) malonate of formula IV from the reaction of 2-phenylethylbromide with diethylmalonate followed by the preparation of sodium phenylbutyrate of formula I.

BACKGROUND OF THE INVENTION:

Sodium phenylbutyrate is a nitrogen binding agent and has a structural formula as mentioned below.

Sodium phenylbutyrate is an active pharmaceutical ingredient used in adjunctive therapy in the chronic care management of patients with urea cycle disorders. Recently the active pharmaceutical ingredient was approved for the treatment of amyotrophic lateral sclerosis in combination with taurursodiol in USA. Administration of sodium phenylbutyrate provides as alternative pathway for excreting nitrogen waste from the body in patients born with rare enzyme deficiencies in the urea cycle. There are many processes available in literature for the preparation of sodium phenylbutyrate.
The US Patent 6372938 discloses the preparation of phenyl butyric acid from the reaction of benzene with butyrolactone in the presence of aluminum chloride as mentioned below.

The US Patent 9914692 discloses the preparation of phenyl butyric acid by the oxidation of phenylbutan-1-ol in the presence of sodium chlorite, a nitroxyl radical catalyst and sodium hypochlorite in an organic solvent as mentioned below.

The Publication Journal of Organic Chemistry 1993, 58, pages 2320-2323, discloses the preparation of phenyl butyric acid involving the steps of: condensing the (2-bromoethyl)-benzene with diethyl malonate to form diethyl-2-phenethylmalonate in the presence of base in ethanol; followed by the hydrolysis of diethyl-2-phenethylmalonate to form 2-phenethylmalonic acid; and decarboxylating 2-phenethylmalonic acid to 4-phenylbutanoic acid by heating as mentioned below.

The Patent application EP0361365 discloses the preparation of diethyl-2-phenethylmalonate by condensing (2-bromoethyl)benzene with diethyl malonate in the presence of base in ethanol.

The Publication Journal of Labelled Compounds and Radiopharmaceuticals 2006, 49, pages 171-176 disclose the preparation of phenyl butyric acid from the decarboxylation of (2-phenylethyl)-malonic acid that resulted from the reaction of diethylmalonate with 2-bromoethylbenzene in the presence of sodium hydride in dimethylformamide.

The Indian Patent application IN1279/MUM/2012 discloses the preparation of phenyl butyric acid involving the steps of: condensing the (2-bromoethyl)-benzene with diethyl malonate to form diethyl-2-phenethylmalonate in the presence of potassium carbonate and tertiary butylammonium bromide without a solvent by heating as mentioned below.

Besides, the availability of different processes for the preparation of sodium phenylbutyrate, there is a need for an alternative and an improved process that is easy for handling operations at a large scale and is economically significant.

OBJECTS OF THE INVENTION:

The primary object of the present invention is to provide an efficient and industry feasible process for the preparation of sodium phenylbutyrate of Formula I.

Another object of the present invention is to provide an improved process for the preparation of sodium phenylbutyrate of Formula I from phenyl butyric acid of Formula II using an intermediate diethyl-(2-phenylethyl) malonate of Formula IV.

Yet another object of the present invention is to provide an improved process of preparation of sodium phenylbutyrate of Formula I with less impurities.

A further object of the present invention is to provide a novel process for the preparation of intermediate diethyl-(2-phenylethyl) malonate of Formula IV.

SUMMARY OF THE INVENTION:

Accordingly, the present invention provides an improved process for the preparation of sodium phenylbutyrate of Formula I with less impurities and improved yield. The present invention also provides a novel process for the preparation of intermediate diethyl-(2-phenylethyl) malonate of Formula IV.

The primary aspect of the present invention is to provide a process for the preparation of sodium phenylbutyrate of formula-I

comprising the steps of:
(i) reacting (2-bromoethyl)benzene of formula-V with diethyl malonate in presence of an inorganic base selected from alkali carbonate or alkali bicarbonate in dimethyl formamide to form diethyl-(2-phenylethyl)-malonate of formula-IV;

(ii) hydrolysing diethyl-(2-phenylethyl)-malonate of formula-IV to form 2-phenyl-ethylmalonic acid of formula-III;

(iii) decarboxylating 2-phenyl-ethylmalonic acid of formula-III to form phenyl butyric acid of formula-II; and

(iv) converting the phenyl butyric acid of formula-II to sodium phenylbutyrate of formula-I.

In the step (i) of said process alkali carbonate is selected from the group comprising of sodium carbonate, lithium carbonate or potassium carbonate; and the alkali bicarbonate is selected from the group comprising of sodium bicarbonate, potassium bicarbonate, or ammonium bicarbonate.
The step (i) of the said process is carried out at a temperature ranging from 50 to 95? for 1 to 20 hours.

In the said process, step (i) is carried out in presence of a catalyst selected from the group comprising of potassium iodide, tetrabutylammonium bromide or methyltrioctylammonium chloride, preferably tetrabutylammonium bromide.

The step (ii) of the said process is carried out in presence of acid or base in aqueous medium, wherein the acid is selected from the group comprising of hydrochloric acid, acetic acid, sulphuric acid, citric acid, or nitric acid; and the base is selected from the group comprising of sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, sodium carbonate or potassium carbonate.

Preferably, the acid employed in step (ii) of the said process is hydrochloric acid and the base employed in step (ii) of the said process is sodium hydroxide.

The step (ii) of the said process is carried out at temperature ranging from 70 to 120?.

The step (iii) of the said process is carried out at temperature ranging from 70 to 150? for 9 to 20 hours.

The decarboxylation of step (iii) of the present process is carried out in presence of an acid, wherein the acid is selected from the group comprising of acetic acid, hydrochloric acid, nitric acid, citric acid, or formic acid.

Alternatively, the decarboxylation of step (iii) of the present process is carried out in presence of a salt and a solvent, wherein the salt is selected from the group comprising of sodium chloride, potassium chloride, calcium chloride, or sodium bisulfate; and the solvent is selected from the group comprising of dimethyl formamide, dimethyl sulfoxide, methanol, methyl ethyl ketone, butanol, tert-butyl methyl ether, or triethylamine.

The step (iv) of the present process is carried out in presence of a sodium source selected from the group comprising of sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium alkoxide or sodium-2-ethyl-hexanoate.

The sodium phenylbutyrate of formula I obtained according to the present process is having purity greater than 99.5% and is characterized by the content of impurity A, B and C less than 0.1% w/w.

In another aspect present invention provides a process for the preparation of diethyl-(2-phenylethyl)-malonate of Formula-IV

comprising the step of:
(i) reacting (2-bromoethyl)benzene of formula-V with diethyl malonate in the presence of inorganic base selected from alkali carbonate or alkali bicarbonate in dimethyl formamide to form diethyl-(2-phenylethyl)-malonate of formula-IV

In the step (i) of said process alkali carbonate is selected from the group comprising of sodium carbonate, lithium carbonate or potassium carbonate; and the alkali bicarbonate is selected from the group comprising of sodium bicarbonate, potassium bicarbonate, or ammonium bicarbonate.

The step (i) of the said process is carried out at a temperature ranging from 50 to 95? for 1 to 20 hours.

In the said process, step (i) is carried out in presence of a catalyst selected from the group comprising of potassium iodide, tetrabutylammonium bromide or methyltrioctylammonium chloride, preferably tetrabutylammonium bromide.

DETAILED DESCRIPTION OF THE INVENTION:

Accordingly, in one aspect the present invention discloses and describes an improved process for the preparation of sodium phenylbutyrate of formula-I.

One embodiment of the present invention is to provide a process for the preparation of sodium phenylbutyrate of formula-I,

comprising the steps of:
(i) reacting (2-bromoethyl)benzene of formula-V with diethyl malonate in the presence of an inorganic base selected from alkali carbonate or alkali bicarbonate in dimethyl formamide to form diethyl-(2-phenylethyl)-malonate of formula-IV;

(ii) hydrolysing diethyl-(2-phenylethyl)-malonate of formula-IV to form 2-phenyl-ethylmalonic acid of formula-III;

(iii) decarboxylating 2-phenyl-ethylmalonic acid of formula-III to form phenyl butyric acid of formula-II; and

(iv) converting the phenyl butyric acid of formula-II to sodium phenylbutyrate of formula-I.

The alkali carbonate employed in step (i) is selected from the group comprising of sodium carbonate, lithium carbonate and potassium carbonate.

The alkali bicarbonate employed in step (i) is selected from the group comprising of sodium bicarbonate, potassium bicarbonate, and ammonium bicarbonate.

In one of the preferred embodiments, inorganic base employed in step (i) of the said process is alkali carbonate. The preferred alkali carbonate is potassium carbonate.

The step of reacting (2-bromoethyl)benzene of formula-V with diethyl malonate according to step (i) of the present invention is carried out at temperatures ranging from 25 to 120?, preferably 50 to 95?, more preferably 60 to 90?.
The step of reacting (2-bromoethyl)benzene of formula-V with diethyl malonate according to step (i) of the present invention is carried out for about 1-20 hours.

The step of reacting (2-bromoethyl)benzene of formula-V with diethyl malonate in the presence of an inorganic base in dimethylformamide to form diethyl-(2-phenylethyl)-malonate of formula-IV according to step (i) of the present invention may be carried out in the presence of catalyst selected from the group consisting of potassium iodide, tetrabutylammonium bromide and methyltrioctylammonium chloride and the likes, preferably tetrabutylammonium bromide.

The step of hydrolysing diethyl-(2-phenylethyl)-malonate of formula-IV to form 2-phenyl-ethylmalonic acid of formula-III according to step (ii) of the present invention is carried out in the presence of acid or base in aqueous medium.

The acid in the step of hydrolysing diethyl-(2-phenylethyl)-malonate of formula-IV to form 2-phenyl-ethylmalonic acid of formula-III according to step (ii) of the present invention is selected from the group consisting of hydrochloric acid, acetic acid, sulphuric acid, citric acid, nitric acid and the likes. The most preferred acid is Hydrochloric acid.

The base in the step of hydrolysing diethyl-(2-phenylethyl)-malonate of formula-IV to form 2-phenyl-ethylmalonic acid of formula-III according to step (ii) of the present invention is selected from the group consisting of sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, sodium carbonate or potassium carbonate. The most preferred base is Sodium hydroxide.

The step of hydrolysing diethyl-(2-phenylethyl)-malonate of formula-IV to form 2-phenyl-ethylmalonic acid of formula-III according to step (ii) of the present invention is carried out at temperatures ranging from 70 to 120?, preferably 90 to 100?.

The step of decarboxylating 2-phenyl-ethylmalonic acid of formula-III to form phenyl butyric acid of formula-II according to step (iii) of the present invention is carried out at temperatures ranging from 70 to 150?, preferably 118 to 120?.

In one embodiment, the step of decarboxylating 2-phenyl-ethylmalonic acid of formula-III to form phenyl butyric acid of formula-II according to step (iii) of the present invention is carried out in the presence of an acid.

The acid in the step of decarboxylating 2-phenyl-ethylmalonic acid of formula-III to form phenyl butyric acid of formula-II according to step (iii) of the present invention is selected from the group comprising of acetic acid, hydrochloric acid, nitric acid, citric acid, or formic acid.

In an alternate embodiment, the step of decarboxylating 2-phenyl-ethylmalonic acid of formula-III to form phenyl butyric acid of formula-II according to step (iii) of the present invention is carried out in presence of a salt and a solvent.

The salt employed in the step of decarboxylating 2-phenyl-ethylmalonic acid of formula-III to form phenyl butyric acid of formula-II according to step (iii) of the present invention is selected from the group comprising of sodium chloride, potassium chloride, calcium chloride, or sodium bisulfate.

The solvent employed in the step of decarboxylating 2-phenyl-ethylmalonic acid of formula-III to form phenyl butyric acid of formula-II according to step (iii) of the present invention is selected from the group comprising of dimethyl formamide, dimethyl sulfoxide, methanol, methyl ethyl ketone, butanol, tert-butyl methyl ether, or triethylamine.

The step of decarboxylating 2-phenyl-ethylmalonic acid of formula-III to form phenyl butyric acid of formula-II according to step (iii) of the present invention is carried out for about 9 to 20 hours.
The step of converting the phenyl butyric acid of formula-II to sodium phenylbutyrate of formula-I according to step (iv) of the present invention is carried out by treating phenyl butyric acid of formula-II with a source of sodium.

The sodium source according to step (iv) of the present invention is selected from the group consisting of sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium alkoxide, sodium-2-ethyl-hexanoate and the likes.

The sodium phenylbutyrate resulting from the process of the present invention have purity greater than 99.5% and contains the pharmacopeial impurities such A, B and C less than 0.1% w/w having the structures as mentioned below.

Surprisingly, the inventors of the present invention found that the use of dimethylformamide as a solvent during the reaction of (2-bromoethyl)benzene of formula-V with diethyl malonate in the presence of alkali carbonate or alkali bicarbonate increases the yield of the intermediate diethyl-(2-phenylethyl)-malonate of formula-IV, during the preparation of sodium phenylbutyrate. That is the intermediate diethyl-(2-phenylethyl)-malonate of formula-IV resulted from the reaction of (2-bromoethyl)benzene of formula-V with diethyl malonate in the presence of alkali carbonate or alkali bicarbonate in dimethylformamide contains unreacted (2-bromoethyl) benzene of formula-V in amount less than 20% as per TLC.

The inventors of the present invention observed that the use of solvents such as acetone, toluene and n-heptane other than dimethyl formamide were not effective in the reaction of (2-bromoethyl)benzene of formula-V with diethyl malonate in the presence of alkali carbonate as mentioned below.
Ex. Amount of
(2-bromoethyl) benzene of formula-V used in the reaction
(in gm) Amount of Diethyl malonate used in the reaction
(in gm) Amount of TBAB (tetrabutyl ammonium bromide)
used in the reaction
(in gm) Potassium carbonate as alkali carbonate (in gm)
Solvent Remarks
1 100 95.2 13.5 150 Toluene
(300ml) Reaction progresses very slowly even after 10 hours, wherein the formation of the product is only upto 47.82%.
2 10 8.7 0.2 15 Acetone
(250 ml) Very less product formation, the reactant (2-bromoethyl) benzene of formula-V was present in the reaction mass of about 60-70% as per TLC.
3 10 9.1 0 15 Without solvent
(Neat reaction) Very less product formation, the reactant (2-bromoethyl) benzene of formula-V was present in the reaction mass of about 40-45% as per TLC.

The inventors of the present invention further observed that the use of organic bases such as pyridine and sodium ethoxide are not effective than the inorganic base selected from the group consisting of alkali carbonate and alkali bicarbonate in the reaction of (2-bromoethyl)benzene of formula-V with diethyl malonate in dimethyl formamide. In some cases, use of organic bases such as pyridine and sodium ethoxide in the reaction of (2-bromoethyl)benzene of formula-V with diethyl malonate in dimethyl formamide did not result in the formation of the product.

The use of sodium hydride in the reaction of (2-bromoethyl)benzene of formula-V with diethyl malonate was not desirable in large scale preparations, since the chemical is pyrophoric in nature.

The inventors of the present invention found the use of catalyst selected from the group consisting of potassium iodide, tetrabutylammonium bromide and methyltrioctylammonium chloride and the likes, is preferred during the reaction of (2-bromoethyl)benzene of formula-V with diethyl malonate in the presence of alkali carbonate in dimethylformamide as a solvent. Addition of the catalyst increases the yield and purity of the intermediate diethyl-(2-phenylethyl)-malonate of formula-IV, as shown below.

Ex. Amount of
(2-bromoethyl) benzene of formula-V used in the reaction
(in gm) Amount of Diethyl malonate used in the reaction
(in gm) Potassium carbonate as alkali carbonate (in gm)
Amount of TBAB (tetrabutyl ammonium bromide)
used in the reaction
(in gm) Dimethyl formamide (in ml) Reaction time (in hours) Amount of unreacted
(2-bromoethyl) benzene of formula-V after the reaction
(in %) % Purity by HPLC of the Product obtained after the reaction
1 10
10.4 15 0 50 20 9.84%
73.93%
2 25
21.7 37.5 0
125 4 0.61% 62.83%

3 200
260 300 60 400 5 0.12% 88.20%

A preferred embodiment of the present invention is to provide a process for the preparation of sodium phenylbutyrate of formula-I comprising the steps of:
(i) reacting (2-bromoethyl)benzene of formula-V with diethyl malonate in the presence of alkali carbonate or alkali bicarbonates as inorganic base and catalyst in dimethylformamide to form diethyl-(2-phenylethyl)-malonate of formula-IV;

(ii) hydrolysing diethyl-(2-phenylethyl)-malonate of formula-IV to form 2-phenyl-ethylmalonic acid of formula-III;

(iii) decarboxylating 2-phenyl-ethylmalonic acid of formula-III to form phenyl butyric acid of formula-II; and

(iv) converting the phenyl butyric acid of formula-II to sodium phenylbutyrate of formula-I,

wherein the catalyst is selected from the group consisting of potassium iodide, tetrabutylammonium bromide and methyltrioctylammonium chloride and the likes.

In another aspect the present invention provides a novel process for the preparation of diethyl-(2-phenylethyl)-malonate of Formula-IV.

In another embodiment, present invention discloses a process for the preparation of diethyl-(2-phenylethyl)-malonate of Formula-IV comprising the step of:
(i) reacting (2-bromoethyl)benzene of formula-V with diethyl malonate in the presence of inorganic base selected from alkali carbonate or alkali bicarbonate in dimethyl formamide to form diethyl-(2-phenylethyl)-malonate of formula-IV.

The alkali carbonates employed in step (i) is selected from the group comprising of sodium carbonate, lithium carbonate and potassium carbonate.

The alkali bicarbonates employed in step (i) is selected from the group comprising of sodium bicarbonate, potassium bicarbonate, and ammonium bicarbonate.

Preferably, inorganic base employed in step (i) of the said process is alkali carbonate. The preferred alkali carbonate is potassium carbonate.

The step of reacting (2-bromoethyl)benzene of formula-V with diethyl malonate according to step (i) is carried out at temperatures ranging from 25 to 120?, preferably 50 to 95?, more preferably 60 to 90?.

The step of reacting (2-bromoethyl)benzene of formula-V with diethyl malonate according to step (i) is carried out for about 1-20 hours.

The step of reacting (2-bromoethyl)benzene of formula-V with diethyl malonate in the presence of an inorganic base in dimethylformamide to form diethyl-(2-phenylethyl)-malonate of formula-IV according to step (i) may be carried out in the presence of catalyst selected from the group consisting of potassium iodide, tetrabutylammonium bromide and methyltrioctylammonium chloride and the likes, preferably tetrabutylammonium bromide.

Certain specific aspect and embodiment of the present invention will be explained in 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 invention in any manner.

EXAMPLES

Example-1: Preparation of Phenyl butyric acid of Formula-II

Step-A: Preparation of diethyl-(2-phenylethyl)-malonate of Formula-IV:
To a mixture of dimethylformamide (50 ml), potassium carbonate (15 gm) and diethyl malonate (10.4 gm), 2-phenylethyl bromide solution (10 gm of 2-phenylethyl bromide in 20 ml of dimethyl formamide) was added and heated to 60-65?. The reaction mixture was maintained at 60-65? for 8 hours to 20 hours in a nitrogen atmosphere. The progress of the reaction was monitored by TLC. After the completion of the reaction, the reaction mass was cooled to 25-35? and filtered. To the filtrate, water (100 ml) was added at 25-35?, followed by the addition of toluene (100 ml) at 25-35? and stirred for 5-10 minutes to form a biphasic mixture. The organic layer was separated from the biphasic mixture. The separated organic layer was washed with water (100 ml), dried over sodium sulfate and concentrated under vacuum at 60? to obtain a residue. Yield: 16.2 gm

Step-B: Preparation of 2-phenyl-ethylmalonic acid of Formula-III:
To the residue obtained in the step-A, acetic acid (28 ml) was added at 25-35? and stirred for 15-20 minutes to obtain a solution. To the obtained solution, dilute hydrochloric acid (16.5 ml of Concentrated hydrochloric acid in 11.5 ml of water) was added at 25-35? and heated to 95-100?. The reaction mixture was maintained at 95-100? for 7 hours. The progress of the reaction was monitored TLC. The reaction mass was then heated to 108-110? and maintained for 6 hours at the same temperature. The progress of the reaction was monitored by TLC. After the completion of the reaction, the reaction was cooled to 90-95? and concentrated in vacuum at the same temperature to obtain a residue.

Step-C: Preparation of phenyl butyric acid of Formula-II:
To the residue obtained in the step-B, acetic acid solution (19 ml) was added at 90-95? and then heated to 118-120?. The reaction mixture was maintained at 118-120? for 10-12 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mass was cooled to 65-70? and concentrated in vacuum at 65-70?. To the concentrated reaction mass, water (40 ml) was added at 65-70?, then cooled to 5 to 10?. The pH of the cooled contents was adjusted to 13-13.5 by the addition of sodium hydroxide solution (3.25 gm of Sodium hydroxide in 13 ml of water) was added at 10-15?. The contents were then stirred and heated to 25-30?. To the heated contents, toluene (100 ml) was added at 25-35? and stirred for 30 minutes to form a biphasic mixture. The aqueous layer was separated from the biphasic mixture. To the separated aqueous layer, activated charcoal (1.3 gm) was added at 25-35? and stirred for 30 minutes at the same temperature. The contents were filtered under vacuum through a hyflo super cell (10 gm). To the filtrate, water (26 ml) was added at 25-35? and cooled to 10-15?. The cooled solution was stirred for 1 hour at 10-15?. The resultant solid was filtered, washed with chilled water (40 ml) and dried. Yield: 4.8 gm

Example-2: Preparation of diethyl-(2-phenylethyl)-malonate of Formula-IV

To a mixture of dimethylformamide (125 ml), potassium carbonate (37.5 gm) and diethyl malonate (21.7 gm), phenylethyl bromide (25 gm) was added at 25-35? and stirred for 30 minutes at 25-35?. The reaction mixture was then heated to 95? and maintained at the same temperature for 2-4 hours in a nitrogen atmosphere. The progress of the reaction was monitored by TLC. After the completion of the reaction, the reaction mass was cooled to 25-35? and filtered. To the filtrate, water (100 ml) was added at 25-35?, followed by the addition of toluene (125 ml) at 25-35? and stirred for 5-10 minutes to form a biphasic mixture. The organic layer was separated from the biphasic mixture. The separated organic layer was washed with water (125 ml), dried over sodium sulfate and concentrated under vacuum at 60-75? to obtain a residue. Yield: 32 gm

Example-3: Preparation of diethyl-(2-phenylethyl)-malonate of Formula-IV

To a mixture of dimethylformamide (30 ml), diethyl malonate (10.5 gm), potassium carbonate (15 gm) and tetra butyl ammonium bromide (1 gm), 2-phenylethyl bromide (10 gm) was added at 25-30°C and stirred for 3 hours at 25-35°C. The reaction mixture was heated to 60-65? and maintained at same temperature for 5-6 hours. The progress of the reaction was monitored by TLC. After the completion of the reaction, the reaction mass was cooled to 25-35? and filtered. To the filtrate, water (500 ml) was added at 25-35?, followed by the addition of toluene (200 ml) at 25-35? and stirred for 5-10 minutes to form a biphasic mixture. The organic layer was separated from the biphasic mixture. The separated organic layer was washed with water (50 ml), dried over sodium sulphate and concentrated under vacuum at 61? to obtain a residue. Yield: 16.2 gm

Example-4: Preparation of diethyl-(2-phenylethyl)-malonate of Formula-IV

To a mixture of dimethylformamide (12.5 ml), toluene (75 ml), potassium carbonate (37.5 gm), diethyl malonate (21.75 gm) and tetra butyl ammonium bromide (0.375 gm), 2-phenylethyl bromide (25 gm) was added at 25-30°C for 20 minutes and stirred for 15 min at 25-35°C. The reaction mixture was heated to 108-110? and maintained at 108-110? for 8 hours. The progress of the reaction was monitored by TLC. After the completion of the reaction, the reaction mass was cooled to 25-35? and filtered. To the filtrate, hydrochloric acid solution (1.5 gm of hydrochloride in 50 ml of water) was added and stirred for 10 minutes to form a biphasic mixture. The organic layer was separated from the biphasic mixture. The separated organic layer was washed with water (25 ml) and concentrated under vacuum at 70-75? to obtain a residue. Yield: 33.4 gm

Example-5: Preparation of Sodium-4-phenylbutyrate of Formula-I

To a mixture of methanol (24 ml) and sodium carbonate (1.21 gm), phenyl butyric acid (4 gm) was added at 25-35? under nitrogen atmosphere and stirred for 3-4 hours at 25-35? under nitrogen atmosphere. The reaction mass was then concentrated under vacuum at 50-55? to obtain a residue. To the residue, acetone (52 ml) was added at 25-35? under nitrogen atmosphere and heated to 45-50?. The heated contents were stirred for 30 minutes at 45-50? and cooled to 25-35?. To the cooled contents, acetone (8 ml) was then added at 25-35? under nitrogen atmosphere and cooled to 10-15?. The cooled contents were stirred at 10-15? for 1 hour under nitrogen atmosphere. The resultant solid was filtered, washed with chilled acetone (8 ml) at 10-15? and dried under vacuum. Yield: 3.2 gm

Example-6: Preparation of diethyl-(2-phenylethyl)-malonate of Formula-IV

To a mixture of dimethylformamide (200 ml), potassium carbonate (150 gm), diethyl malonate (130 gm), and tetra-butylammonium bromide (30 gm), 2-phenylethyl bromide (100 gm) was added at 25-35? and heated to 65-70?. The reaction mixture was maintained at 65? for 5 hours. The progress of the reaction was monitored by HPLC. After the completion of the reaction, the reaction mass was cooled to 25-35? and filtered. To the filtrate, toluene (200 ml) was added, followed by the addition of water (500 ml) at 25-35?, to form a biphasic mixture. The organic layer was separated from the biphasic mixture. The separated organic layer was washed with dilute hydrochloric acid (6 ml of concentrated hydrochloric acid in 200 ml of water) and washed with water (100 ml). The washed organic layer was concentrated under vacuum at 70-75? to obtain a residue. Yield: 169.3 gm; Purity by HPLC: 77.23% w/w

Example-7: Preparation of 2-phenyl ethylmalonic acid of Formula-III

To the residue containing the compound diethyl-(2-phenylethyl)-malonate of formula-IV (160 gm), sodium hydroxide solution (60 gm of sodium hydroxide in 640 ml of water) was added at 25-35? and heated to 75-85?. The reaction mixture was maintained at 75-85? for 2-4 hours. The progress of the reaction was monitored by HPLC. After the completion of the reaction, the reaction mass was cooled to 25-35? and washed with toluene (100 ml). To the washed reaction mass, solid sodium chloride (200 gm) at 25-35? and stirred for 30-40 minutes at the same temperature. The contents were then cooled to 10 to 20?. The pH of the cooled contents were adjusted to 2-3 with concentrated hydrochloric acid (70 ml) at 10 to 20? and stirred for 1 hour at 10-15?. The resultant solid was filtered, washed with acetone (50 ml) and dried. Yield: 146.0 gm; Purity by HPLC: 99.12% w/w.

Example-8: Preparation of phenyl butyric acid of Formula-II

To the compound 2-phenyl ethylmalonic acid of formula-III (141 gm), acetic acid (200 ml) was added at 25-35? and heated the reaction mass to 118 to 120?. The reaction mixture was maintained at 118-120? for 5 hours. The progress of the reaction was monitored by HPLC. After completion of the reaction, the reaction mass was cooled to 65? with stirring. The cooled reaction mass was concentrated at 65? under vacuum to obtain a residue. The residue was mixed with water (800 ml) and cooled to 10-15?. To the cooled contents, sodium hydroxide solution (32.5 gm of sodium hydroxide in 130 ml of water) was added at 10-15? and stirred for 10-15 minutes. The contents were then heated to 25 to 35?, followed by the addition of toluene (100 ml) at 25 to 35? to form a biphasic mixture. The aqueous layer was separated from the biphasic mixture and cooled to 10 to 15?. The pH of the separated cooled aqueous layer was adjusted to 2 -3 by the addition of concentrated hydrochloric acid at 10 to 15?. The temperature of the contents was raised to 25-35? and stirred for 60 minutes at the same temperature. The resultant solid was filtered under vacuum, washed with water (200 ml) and dried under vacuum at 25 to 35?. %Yield: 59.63%; Purity by HPLC: 99.69% w/w.

Example-9: Preparation of diethyl-(2-phenylethyl)-malonate of Formula-IV

To a mixture of dimethylformamide (200 ml), potassium carbonate (149.25 gm) and diethyl malonate (90.8 gm), 2-phenylethyl bromide (100 gm) was added and heated to 90-95?. The reaction mixture was maintained at 90-95? for 5 hours. The progress of the reaction was monitored by TLC. After the completion of the reaction, the reaction mass was cooled to 25-30?; then toluene (100 ml) was to the reaction mass and filtered. To the filtrate, toluene (200 ml) was added, followed by the addition of water (500 ml) at 25-35?, to form a biphasic mixture. The organic layer was separated from the biphasic mixture. The separated organic layer was washed with dilute hydrochloric acid (6 ml of concentrated hydrochloric acid in 200 ml of water). The washed organic layer was concentrated under vacuum at 70-75? to obtain a residue. % Yield: 94.95%; Purity by HPLC: 93.89% w/w.

Example-10: Preparation of 2-phenyl ethylmalonic acid of Formula-III

To the residue containing the compound diethyl-(2-phenylethyl)-malonate of formula-IV (50 gm), sodium hydroxide solution (20g of sodium hydroxide in 250 ml of water) was added at 25-35? and heated to 95-100?. The reaction mixture was maintained at 95-100? for 2 hours. The progress of the reaction was monitored by TLC. After the completion of the reaction, the reaction mass was cooled to 25-35?, followed by the addition of solid sodium chloride (50 gm) at 25-35?. The reaction mass was then filtered under vacuum at 25-35°C. The filtrate was stirred for 10 minutes after the addition of toluene (50 ml) to form a biphasic mixture. The aqueous layer was separated from the biphasic mixture. The pH of the separated aqueous layer was adjusted to 2-2.5 with concentrated hydrochloric acid (35 ml) at 25-35? and cooled to 10-15?. The cooled solution was stirred for 1 hour at 10-15?. The resultant solid was filtered, washed with chilled acetone (50 ml) and dried. % Yield: 80.29%; Purity by HPLC: 98.86% w/w.

Example-11: Preparation of phenyl butyric acid of Formula-II

To a mixture of the compound 2-phenyl ethylmalonic acid of formula-III (3 gm) and dimethyl formamide (30 ml), sodium chloride (1 g) was added at 25-35? and heated to 118-120?. The reaction mixture was maintained at 118-120? for 1 to 2 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mass was cooled to 25-35?, and then water (60 ml) was added at 25-35?. To the reaction mass solid sodium chloride (25 gm) was added at 25-30? and stirred for 15 minutes at the same temperature. To stirred contents, ethyl acetate (60 ml) was added at 25-35? to form a biphasic mixture. The organic layer was separated from the biphasic mixture. The separated organic layer concentrated under vacuum at 55° to obtain a residue. The obtained residue was mixed with acetone (30 ml) and concentrated to obtain a residue under vacuum at 60?. % Yield: 87.06%; Purity by HPLC: 98.39% w/w.

Example-12: Preparation of phenyl butyric acid of Formula-II

A mixture of compound 2-phenyl ethylmalonic acid of formula-III (3 gm), dimethyl sulfoxide (15 ml), solid sodium chloride (1 gm) and water (3 ml) was heated to 118-120? and the reaction mixture was maintained at 118-120? for 1 hour. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mass was cooled to 25-35?. To the cooled reaction mass, water (150 ml) was added at 25-35?, followed by the addition of dichloromethane (50 ml) at 25-30? to form a biphasic mixture. The organic layer was separated from the biphasic mixture. The separated organic layer concentrated under vacuum to obtain a residue. The obtained residue was mixed with ice cold water (50 ml) at 10-15°C.The resultant solid was filtered, washed with ice cold water (20 ml) and dried under vacuum at 45-50?. % Yield: 87.06%
Example-13: Preparation of Sodium phenylbutyrate of Formula-I

To a methanolic solution of sodium hydroxide (23.2 gm of sodium hydroxide in 600 ml of methanol), phenyl butyric acid (100 gm) was added at 25-35? under nitrogen atmosphere and stirred for 3 hours at the same temperature under nitrogen atmosphere. Then the reaction mass was filtered under vacuum through 0.45-micron filter under nitrogen atmosphere. The filtrate was concentrated under vacuum to obtain a dry mass. To the dry mass, acetone (1500 ml) was added at temperatures at 65? under nitrogen atmosphere and stirred for 10-15 minutes, then slowly cooled to 50?. The cooled contents were stirred for 60 minutes at 50? and further slowly cooled to 25-35?. The cooled contents were stirred for 10-15 minutes at 25-35? under nitrogen atmosphere and then cooled 10-15?. The cooled contents were stirred for 60 minutes at 10-15? under nitrogen atmosphere. The temperature of the contents was raised to 25-30? under nitrogen atmosphere and stirred at the same temperature for 10-15 minutes under nitrogen atmosphere. The resultant solid was filtered under vacuum in the presence of nitrogen; washed with acetone (200 ml); and dried under vacuum. % Yield: 81.54%; Purity by HPLC: 99.7% w/w.

Example-14: Preparation of Sodium-4-phenylbutyrate of Formula-I

To a mixture of methanol (600 ml) and sodium carbonate (30.5 gm), phenyl butyric acid (100 gm) was added at 25-35? under nitrogen atmosphere, then the reaction mixture was stirred for 4 hours at 25-35? under nitrogen atmosphere. After completion of the reaction, the reaction was concentrated under vacuum at 50-55? to obtain a residue. To the obtained residue, acetone (1500 ml) was added at 60? under nitrogen atmosphere and heated to 45-50?. The heated contents were stirred for 60 minutes at 50? and then cooled to 25-35?. The cooled contents were further cooled to 10-15?. The cooled contents were stirred at 10-15? for 1 hour under nitrogen atmosphere. The temperature of the contents was raised to 20-25? and stirred for 15 minutes. The resultant solid was filtered, washed with acetone (200 ml) at 20-25? and dried under vacuum. % Yield: 88.2%.

Example-15: Preparation of phenyl butyric acid of Formula-II

Step-A: To a mixture of dimethylformamide (500 ml), potassium carbonate (375 gm), diethyl malonate (325 gm) and tetrabutyl ammonium bromide (75 gm), 2-phenylethyl bromide (250 gm) was added and stirred for 5-10 minutes at 25-35?. The reaction was then heated to 60-70? and maintained at 60-70? for 4.5-5.5 hours in nitrogen atmosphere. The progress of the reaction was monitored by HPLC. After the completion of the reaction, the reaction mass was cooled to 25-35?. To the cooled reaction mass, toluene (250 ml) was added and stirred for 10-20 minutes at 25-35?. The stirred reaction mass filtered and the organic layer from the reaction was separated. The separated organic layer was washed with dilute hydrochloric acid solution (515 ml); and water (250 ml). The washed organic layer concentrated under vacuum to obtain a residue.

Step-B: To the residue obtained in the step-A, sodium hydroxide solution (150 gm of sodium hydroxide in 1600 ml water) was added at 20-25? and stirred for 15 to 20 minutes. The reaction mixture was heated to 75-85? and maintained for 2 hours at the same temperature. The progress of the reaction was monitored by HPLC. After completion of the reaction, the reaction mass was cooled to 25-35?. To the cooled reaction mass, toluene (250 ml) was added at 25-35? and stirred for 30 minutes to form a biphasic mixture. The aqueous layer was separated from the biphasic mixture. To the separated aqueous layer, solid sodium chloride was added at 25-35? and stirred for 60-70 minutes at the same temperature. The aqueous layer was acidified by the addition of concentrated hydrochloric acid (175 ml) at 10-20? and stirred for 60-70 minutes at the same temperature. The resultant solid was filtered; washed with acetone (125 ml).

Step-C: To the dried solid obtained in the step-B, acetic acid (750 ml) was added at 25-35? and stirred for 5-10 minutes at the same temperature. The reaction mixture was heated to 118-120? and maintained at 118-120? for 5 hours. The progress of the reaction was monitored by HPLC. After completion of the reaction, the reaction mass was cooled to 65-70? and concentrated under vacuum at 65-70?. To the concentrated reaction mass, water (2000 ml) was added at 65-70?, then cooled to 10 to 20?. The pH of the cooled contents was adjusted to 12-13 by the addition of sodium hydroxide solution (62.5 gm of Sodium hydroxide in 250 ml of water) was added at 10-20?. The contents were then treated activated carbon (12.5 gm) at 25-35? and stirred for 30-40 minutes at the same temperature. The treated contents were filtered through hyflo (50 gm) at 25-35?. To the filtrate, toluene (250 ml) was added at 25-35? and stirred for 30 minutes to form a biphasic mixture. The aqueous layer was separated from the biphasic mixture. The separated aqueous layer was concentrated under vacuum at 25-35? for 1 hour and then cooled to 10-20?. The pH of the cooled aqueous layer was adjusted 2.5-4 by the addition of concentrated hydrochloric acid at 10-20? and stirred for 60-70 minutes at 25-35?. The resultant solid was filtered; washed with water (750 ml) twice and dried. Yield: 142 gm
,CLAIMS:
1. A process for the preparation of sodium phenylbutyrate of formula-I

comprising the steps of the steps of:

(i) reacting (2-bromoethyl)benzene of formula-V with diethyl malonate in presence of an inorganic base selected from alkali carbonate or alkali bicarbonate in dimethyl formamide to form diethyl-(2-phenylethyl)-malonate of formula-IV;

(ii) hydrolysing diethyl-(2-phenylethyl)-malonate of formula-IV to form 2-phenyl-ethylmalonic acid of formula-III;

(iii) decarboxylating 2-phenyl-ethylmalonic acid of formula-III to form phenyl butyric acid of formula-II; and

(iv) converting the phenyl butyric acid of formula-II to sodium phenylbutyrate of formula-I.

2. The process as claimed in claim 1, wherein alkali carbonate is selected from the group comprising of sodium carbonate, lithium carbonate or potassium carbonate.

3. The process as claimed in claim 1, wherein alkali bicarbonate is selected from the group comprising of sodium bicarbonate, potassium bicarbonate, or ammonium bicarbonate.

4. The process as claimed in claim 1, wherein step (i) is carried out at a temperature ranging from 50 to 95? for 1 to 20 hours.

5. The process as claimed in claim 1, wherein step (i) is carried out in presence of a catalyst selected from the group comprising of potassium iodide, tetrabutylammonium bromide or methyltrioctylammonium chloride.

6. The process as claimed in claim 5, wherein the catalyst is tetrabutylammonium bromide.

7. The process as claimed in claim 1, wherein step (ii) is carried out in presence of acid or base in aqueous medium.

8. The process as claimed in claim 7, wherein the acid is selected from the group comprising of hydrochloric acid, acetic acid, sulphuric acid, citric acid, or nitric acid.

9. The process as claimed in claim 8, wherein the acid is hydrochloric acid.
10. The process as claimed in claim 7, wherein the base is selected from the group comprising of sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, sodium carbonate or potassium carbonate.

11. The process as claimed in claim 10, wherein the base is sodium hydroxide.

12. The process as claimed in claim 1, wherein step (ii) is carried out at temperature ranging from 70 to 120?.

13. The process as claimed in claim 1, wherein step (iii) is carried out at temperature ranging from 70 to 150? for 9 to 20 hours.

14. The process as claimed in claim 1, wherein the decarboxylation of step (iii) is carried out in presence of an acid.

15. The process as claimed in claim 14, wherein the acid is selected from the group comprising of acetic acid, hydrochloric acid, nitric acid, citric acid or formic acid.

16. The process as claimed in claim 1, wherein the decarboxylation of step (iii) is carried out in presence of a salt and a solvent.

17. The process as claimed in claim 16, wherein the salt is selected from the group comprising of sodium chloride, potassium chloride, calcium chloride, or sodium bisulfate.

18. The process as claimed in claim 16, wherein the solvent is selected from the group comprising of dimethyl formamide, dimethyl sulfoxide, methanol, methyl ethyl ketone, butanol, tert-butyl methyl ether, or triethylamine.

19. The process as claimed in claim 1, wherein step (iv) is carried out in presence of a sodium source selected from the group comprising of sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium alkoxide or sodium-2-ethyl-hexanoate.

20. The process as claimed in claim 1, wherein the sodium phenylbutyrate of formula I is having purity greater than 99.5% and is characterized by the content of impurity A, B and C less than 0.1% w/w.

21. A process for the preparation of diethyl-(2-phenylethyl)-malonate of Formula-IV

comprising the step of:

(i) reacting (2-bromoethyl)benzene of formula-V with diethyl malonate in the presence of inorganic base selected from alkali carbonate or alkali bicarbonate in dimethyl formamide to form diethyl-(2-phenylethyl)-malonate of formula-IV

22. The process as claimed in claim 21, wherein alkali carbonate is selected from the group comprising of sodium carbonate, lithium carbonate or potassium carbonate.

23. The process as claimed in claim 21, wherein alkali bicarbonate is selected from the group comprising of sodium bicarbonate, potassium bicarbonate, or ammonium bicarbonate.

24. The process as claimed in claim 21, wherein step (i) is carried out at a temperature ranging from 50 to 95? for 1 to 20 hours.

25. The process as claimed in claim 21, wherein step (i) is carried out in presence of a catalyst selected from the group comprising of potassium iodide, tetrabutylammonium bromide or methyltrioctylammonium chloride.

26. The process as claimed in claim 25, wherein the catalyst is tetrabutylammonium bromide.