FIELD OF INVENTION

The present invention relates to a novel and facile process for preparation of a Sodium phenyl butyrate 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. Chem. 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.

US 6,372,938 discloses a process for preparation of sodium phenyl butyrate in which benzene is reacted with butyrolactone in presence of a catalyst and the obtained product is reacted with sodium hydroxide to obtain a sodium salt and further treated with hydrochloric acid to get phenyl butyric acid. This phenyl butyric acid is purified by vacuum distillation and reacted with 5% sodium hydroxide and dried by lyophilization. The drawback in this process is that during workup after the reaction of benzene and butyrolactone, sodium hydroxide is added to get sodium salt and again acidified to obtain acid. Moreover, in most of the prior art process sodium hydroxide is used as a source of sodium to make sodium phenyl butyrate. This necessitates the use of water, which in turn necessitates its distillation.

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 process for the preparation of sodium phenyl butyrate of formula I by treating a solution of a sodium salt of weak acid with phenyl butyric acid in an organic solvent in presence of a base under inert atmosphere.

The other aspect of the present invention is to provide a process for the preparation of phenyl butyric acid, which comprises reacting benzene with butyrolactone in presence of a catalyst and in absence of a base.

DETAIL DESCRIPTION OF THE INVENTION

Accordingly in an embodiment of the invention, the sodium salt of weak acid is selected from sodium lactate, sodium acetate, sodium-2-ethylhexanoate, preferably sodium-2-ethylhexanoate. The sodium salt of weak acid is dissolved in an organic solvent is a ketonic solvent, preferably acetone. The reaction is carried out under nitrogen and the base is preferably triethylamine (TEA). Preferably the reaction is carried out at room temperature i.e 25-30° C.

In another embodiment of the invention, benzene is reacted with butyrolactone in presence of a solvent where benzene itself is a solvent for reaction. The preferred catalyst for the reaction is Lewis acids selected from the group consisting of aluminium chloride, zinc chloride, iron chloride, stannous chloride, boron tribromide, boron trifluoride, and sulphuric acid. The most preferred catalyst is aluminium chloride. Preferably the reaction is carried out at 50° C to the boiling temperature of the solvent.

The process of present invention has the below advantages over the state of art:

a) A sodium salt of week acid e.g. sodium-2-ethylhexanoate is used as source of sodium, this avoids the use of water, which in turn avoids the distillation and generation of lot of effluent.

b) In the present process ethyl hexanoic acid, a by-product and the excess sodium-2-ethylhexanoate is getting removed along with acetone during filtration whereas in the prior art process the removal of excess reagent used to make salt while using NaOH as a sodium source is difficult.

c) Since the reagent used to make salt is organic and it is washed out by acetone, there is no question of ash content.

d) Drying of the product is easier because there is no water.

e) Filtration is fast since the material is free flowing as compared to the prior art process where the material is thick due to the presence of water.

f) The present invention gives free flowing powder product of highly desired particle size distribution d10 = 10 μm, d50 =50μm and d90=150 μm; whereas the prior art process gives a hard mass after drying and which needs to be milled to get powder.

The present invention can be illustrated by the following examples, which are not to limit the scope of invention.

Example 1: Preparation of phenylbutyric acid

Anhydrous aluminium chloride (1.94 vol.) was added in lots to benzene (4 vol.) kept at the temperature range of 15-20° C and stirred for 15 minutes. The mixture was heated to 50±2° C and stirred for one hour. γ-Butyrolactone was slowly added to it and the reaction mass was maintained for some time at 50±2° C. The reaction mass was cooled and added into a cooled water and stirred for half an hour. Concentrated hydrochloric acid was added slowly and the temperature was raised to 25±5° C. Toluene (3 vol.) was added and heated. The layers were separated and the toluene layer was washed with 10% brine solution. The toluene was distilled out under vacuum to obtain phenyl butyric acid.

Example 2: Preparation of Sodium phenylbutyrate

Phenyl butyric acid (1.0 mol) was stirred for an hour in acetone (13.3 vol.) and triethylamine (o.85 vol.) at 25-30° C. A solution of sodium-2-ethylhexanoate (1 mol.) in 10 volume of acetone was added to the above reaction mass slowly. Stirred for 5hr. Filtered and washed the solid with acetone under nitrogen. Dried the product under vacuum at 55 to 60° C for 8-10 hours.

We claim:

1. A process for the preparation of sodium phenyl butyrate of formula I by treating a solution of sodium salt of weak acid with phenyl butyric acid in an organic solvent in presence of a base under inert atmosphere.

2. A process according to claim 1, wherein sodium salt of weak acid is selected from sodium lactate, sodium acetate, sodium-2-ethylhexanoate.

3. A process according to claim 1, wherein sodium salt of weak acid is sodium-2- ethylhexanoate.

4. A process according to claim 1, wherein the organic solvent is selected from a ketonic solvent.

5. A process according to claim 1, wherein the organic solvent is acetone.

6. A process according to claim 1, wherein the base is triethylamine (TEA).

7. The other aspect of the present invention is to provide a process for the preparation of phenyl butyric acid, which comprises reacting benzene with butyrolactone in presence of a catalyst and in absence of a base.

8. A process according to claim 7, wherein the catalyst is Lewis acids selected from the group consisting of aluminium chloride, zinc chloride, iron chloride, stannous chloride, boron tribromide, boron trifluoride, and sulphuric acid.