FORM 2
THE PATENTS ACT 1970
(39 OF 1970)
&
The patent Rules, 2003
COMPLETE SPECIFICATION
A Process for Preparation of Sodium Phenyl butyrate
SeQuent Scientific Limited
A Company Incorporated Under The Companies Act, 1956
Having Registered Office at
116 Vardhman Industrial Complex, L.B.S Marg,
Thane (W), Mumbai - 400 601, India
The following specification particularly describes the invention and the manner in which it is to be performed:

FIELD OF INVENTION
The present invention relates to a novel and facile process for preparation of a Phenyl butyric acid of formula I.

BACKGROUND OF THE INVENTION
Sodium phenyl butyrate has been used extensively for the treatment of urea cycle disorders. Sodium phenyl butyrate is an orphan drug, marketed under the brand name Buphenyl and Ammonaps. It has also shown promising pharmaceutical properties in the treatment of sickle cell anaemia, which is under thorough investigation.
There are many processes available in prior art for the preparation of sodium phenyl butyrate. J. Chetn. Soc, 1997-99 (1938) prepare sodium phenyl butyrate by the Arndt-Einstert reaction, using diazomethane with silver oxide and sodium thiosulfate. Alternatively, thianapthene-2-acetic acid and thianapthene-3-acetic acid have been used to prepare p-phenyl butyric acid (J. Am. Chem. Soc, 70, 3768 (1948)). The Grignard reagent, benzyl magnesium chloride, has also been used in the synthesis of phenyl butyric acid, resulting in a yield of 16.1% (J. Am. Chem, Soc, 71, 2807-2808 (1949)). These processes are very moisture sensitive and need necessarily to vigorously remove the moisture from diazomethane and Grignard reagents.
J. Med. Chem., 25, pl09-l 13, 1982 [11] describes a process for the preparation of alkyl diethyl esters by condensing alkyl bromide with diethyl malonate using a solution of sodium ethoxide prepared by adding sodium in pure ethanol.

EP0361365 discloses a process for preparation of phenylethyl malonic acid by condensing phenethyl bromide with diethyl malonate in absolute ethanol in presence of sodium metal solution to form diethyl phenylethyl malonate. Diethyl phenylethyl malonate obtained was treated with 10% aqueous sodium hydroxide and heated under reflux. The resulting clear solution was made strongly acidic with 20% aqueous HCI to obtain phenylethyl malonic acid.
It would be desirable to have a process to prepare sodium phenyl butyrate that is not hindered by the synthetic restrictions, like the necessity to vigorously exclude moisture from diazomethane and Grignard reagents, doesn't involve aqueous workup containing distillation and that would give higher yields of product than the reactions described above.
SUMMARY OF THE INVENTION
The principal aspect of the present invention is to provide a single pot process for the preparation of phenyl butyric acid of formula I comprising:
a) condensing phenyl ethyl bromide of formula IV with diethyl malonate of formula V in presence of base and catalyst to form diethyl (2-phenylethyl) malonate of formula III;
b) hydrolyzing diethyl (2-phenylethyl) malonate of formula III using a base to form diacid of formula II; and
c) decarboxylating diacid of formula II obtained insitu to form phenyl butyric acid of formula I.
The present invention is illustrated by the below reaction scheme:


DETAIL DESCRIPTION OF THE INVENTION
Accordingly in an embodiment of the invention, condensation of phenyl ethyl bromide of formula IV with diethyl malonate of formula V in step (a) is carried out in presence of a base preferably an inorganic base selected from ammonia, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and the like, more preferably potassium carbonate and a catalyst preferably phase transfer catalyst selected from tetra butylammonium bromide, methyltrioctylammonium chloride and the like, more preferably tetra butylammonium bromide. The condensation reaction in step (a) is carried out at a temperature in the range of 25-120° C, preferably 25-30° C.
In another embodiment of the invention, the condensation in step (a) is carried out preferably in the absence of solvent.
In yet another embodiment of the invention, hydrolysis in step (b) is carried out in presence of a base preferably an inorganic base selected from ammonia, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and the like, more preferably sodium hydroxide. The hydrolysis reaction in step (b) is carried out at a temperature in the range of 70-120° C, preferably 90-95° C. The pH is adjusted by hydrochloric acid to a range 1.5 to 3 preferably to a range 2 to 2.5 to obtain a diacid.
In another embodiment of the invention, diacid of formula II is extracted with a suitable organic solvent selected from the group consisting of toluene, methyl

isobutyl ketone (MIBK) and monochlorobenzene, preferably monochlorobenzene to obtain a corresponding solvent layer preferably monochlorobenzene layer containing diacid.
In yet another embodiment of the invention, the decarboxylation in step (c) of the diacid obtained as a solvent layer, is carried out by heating it to a temperature range 100-130°C. In still another embodiment of the invention, the pH of the obtained mass after reflux is adjusted to 12.5 to 13 and the layers were separated. The aqueous layer is subjected to pH adjustment in the range of 2 to 2.5.
In yet another embodiment of the invention, phenyl butyric acid obtained by the present invention is further reacted with a sodium source to obtain sodium phenyl butyrate. The sodium source may selected from the group sodium hydroxide, sodium bicarbonate, sodium carbonate sodium methoxide, sodium ethoxide, sodium-2-ethylhexanoate etc.
In still another embodiment, the process of present invention has below advantages over the state of art:
a) The present invention provides a neat process for condensation of phenyl ethyl bromide with diethyl malonate, which is carried out in absence of solvent.
b) The reaction is very fast compared to prior art.
c) The present invention provides a one pot synthesis of phenyl butyric acid, which reduces the effluent load drastically.
The present invention can be illustrated by the following examples, which are not to limit the scope of invention.
Example 1: Preparation of phenyl butyric acid
Phenyl ethyl bromide is treated with 2.0 equivalent of potassium carbonate and 1.0 equivalent of diethyl malonate in presence of 1.5% of Tetra butyl ammonium bromide. The reaction mass is heated to 25-30°C for 2-2.5 hours. After completion of

reaction, reaction mass is cooled to 25-30°C, 6 volume of water, 0.3 volume of methanol, 3.0 equivalent of sodium hydroxide was added and heated to 90-95°C for 3 hours. The reaction mass cooled to 25-30°C, pH was adjusted to 2-2.5 using concentrated HC1, diacid is extracted using monochlorobenzene (MCB). The MCB layer is heated to 120°C, maintained for 4 hrs, cooled to 25-30°C and basified to pH to 12-5-13.0. Aqueous layer is separated, acidified to pH 2-2.5 and filtered to form phenyl butyric acid of purity not less than 99.99%.
Yield: 70%

We claim:
1. A single pot process for the preparation of phenyl butyric acid of formula I comprising:

a) condensing phenyl ethyl bromide of formula IV with diethyl malonate of formula V in presence of base and catalyst to form diethyl (2-phenylethyl) malonate of formula III;

b) hydrolyzing diethyl (2-phenylethyl) malonate of formula III using a base to form diacid of formula II; and

c) decarboxylating diacid of formula II obtained insitu to form phenyl butyric acid of formula 1.
2. A process according to claim 1, wherein condensation in step (a) is carried out in absence of solvent.

3. A process according to claim 1, wherein the base used in step (a) is an inorganic base selected from ammonia, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and the like.
4. A process according to claim 1, wherein the base used in step (a) is potassium carbonate.
5. A process according to claim 1, wherein the catalyst used in step (a) is a phase transfer catalyst selected from tetra butylammonium bromide, rnethyltrioctylammonium chloride and the like.
6. A process according to claim I, wherein the catalyst used in step (a) is tetra butylammonium bromide.
7. A process according to claim 1, wherein the base used in step (b) is an inorganic base selected from ammonia, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and the like.
8. A process according to claim 1, wherein the base used in step (b) is sodium hydroxide.
9. A process according to claim 1, wherein the decarboxylation in step (c) is carried out at a temperature in the range of 100-130°C.
10. A process according to claim I, wherein the obtained phenylbutyric acid is further reacted with a sodium source selected from the group consisting of sodium hydroxide, sodium bicarbonate, sodium carbonate sodium methoxide, sodium ethoxide, sodium-2-ethylhexanoate to obtain sodium phenyl butyrate.