Claims:We Claim:
1. A process for preparation of Ibuprofen substantially free of Impurity J comprising the steps of:
(i) adding alpha-(p-isobutylphenyl)-propionaldehyde and Jones reagent simultaneously; and
(ii). maintaining the reaction mixture at a temperature till the formation of Ibuprofen.

2. The process as claimed in Claim-1, wherein the step of simultaneously adding alpha-(p-isobutylphenyl)-propionaldehyde and Jones reagent is carried out after the preparation of Jones reagent.

3. The process as claimed in claim 1, wherein the step of simultaneously adding alpha-(p-isobutylphenyl)-propionaldehyde and Jones reagent is carried out after mixing the prepared Jones reagent with acetone.

4. The process as claimed in Claim-1, wherein the step (i) is carried out at a temperature between 20°C to 60°C.

5. The process as claimed in Claim-1, wherein the step (ii) is carried out at a temperature between 20°C to 60°C.

6. The process as claimed in claim 1, wherein the alpha-(p-isobutylphenyl)-propionaldehyde is obtained by (i) reacting isobutylacetophenone with isopropyl chloroacetate in presence of sodium isopropoxide to obtain an intermediate; and
(ii) treating the intermediate with sodium hydroxide to obtain the compound alpha-(p-isobutylphenyl)-propionaldehyde.

7. The process as claimed in claim 6, wherein sodium isopropoxide is obtained by treating sodium metal and Ferric chloride with isopropyl alcohol at a temperature between 55 to 60°C.

8. The process as claimed in Claim-1, wherein the final Ibuprofen obtained from the process comprises impurity J less than 0.05%.
9. The process as claimed in Claim-1, wherein the final Ibuprofen obtained from the process comprises impurity J less than 0.03%.

10. An Ibuprofen having impurity J less than 0.05%.

Dated this 11th day of November 2016

Afzal Hasan
IN/PA-1328
of HASAN AND SINGH

, Description:FIELD OF INVENTION

The invention relates to an improved process for preparation of Ibuprofen. More particularly, the invention relates to an improved process for preparation of Ibuprofen which is substantially free of J Impurity reported in European pharmacopeia. Impurity J is chemically known as 2-(4-isobutyryl-phenyl)propionic acid and represented as below-

BACKGROUND OF THE INVENTION

Ibuprofen is chemically known as (±) - 2 - (p - isobutylphenyl) propionic acid and is widely used nonsteroidal anti-inflammatory drug having the below mentioned formula.

Ibuprofen is nonsteroidal anti-inflammatory drug and widely used in treatment of pain, fever and headaches. Ibuprofen is marketed under the brand name ‘Nuprin®’. Ibuprofen was first disclosed in US patent no. 3,385,886. There are many process known for the production of Ibuprofen starting from 4-isobutylacetophenone. One of method for preparing Ibuprofen involves the steps of preparing of alpha-(p-isobutylphenyl)-propionaldehyde corresponding aldehyde; oxidizing the corresponding aldehyde with various oxidizing agents as mentioned below:

The Patents GB1160725 and US 3965161 discloses the preparation of 2-(4-isobutylphenyl)-propionaldehyde which is prepared by the treatment of isobutyl acetophenone with isopropyl chloroacetate in the presence of sodium isopropoxide in isopropanol.

The Patent GB 2004543 discloses the preparation of Ibuprofen by the treatment of 2-(4-isobutylphenyl)-propionaldehyde with different oxidizing agents including chromium trioxide in dilute sulfuric acid; silver oxide; hydrogen peroxide; and selenium containing catalyst.

The reaction of chromium trioxide with water results in the formation of chromic acid. The chromic acid is normally used in conjunction with sulfuric acid and this acts as a powerful oxidant. The combination of chromic oxide, sulfuric acid and acetone solvent is known as Jones reagent. Jones reagent is capable of oxidizing at benzylic positions as well.

The oxidation of 2-(4-isobutylphenyl)-propionaldehyde with Jones reagent to prepare Ibuprofen results in an undesirable impurity 2-(4-isobutyryl-phenyl)propionic acid due to the oxidation at the benzylic position. This impurity 2-(4-isobutyryl-phenyl)propionic acid is designated as Impurity J in the European pharmacopeia. The preparation of the Impurity J is disclosed in the Patent JP 52-108943.

The publication Journal of Molecular catalysis A: Chemical 196 (2003) pages 3-11 discloses the preparation of ibuprofen from 2-(4-isobutylphenyl)-1-propanol using Jones reagent.

The Patent GB 2004543 assigned to Ajinomoto discloses the oxidation of 2-(4-isobutylphenyl)-propionaldehyde in the presence of chromium trioxide and hydrogen peroxide in acetone yielding 9.5% of Ibuprofen. The present inventors understand that this reduction in the Ibuprofen yield is due to the formation of undesired Impurity J.

According to the prior art, the oxidation of 2-(4-isobutylphenyl)-propionaldehyde to ibuprofen by using Jones reagent give rise to a high level of undesired Impurity J.
Therefore, there is need for an efficient process for the preparing Ibuprofen in commercial scale at low cost employing Jones reagent.

OBJECTS OF THE INVENTION

The primary object of the present invention is to provide an improved process for preparation of Ibuprofen which is substantially free of Impurity J.

Another object of the present invention is to provide a process for preparation of Ibuprofen with improved yield.

SUMMARY OF THE INVENTION

Accordingly an improved process for preparation of Ibuprofen which is substantially free of J Impurity is disclosed. Impurity J is chemically known as 2-(4-isobutyryl-phenyl)propionic acid) and is represented as below-

The process comprises the steps of:

(i) adding alpha-(p-isobutylphenyl)-propionaldehyde and Jones reagent simultaneously; and
(ii) maintaining the reaction mixture at a temperature till the formation of Ibuprofen.

In one embodiment, the step of simultaneously adding alpha-(p-isobutylphenyl)-propionaldehyde and Jones reagent is carried out after the preparation of Jones reagent.
In another embodiment, the step of simultaneously adding alpha-(p-isobutylphenyl)-propionaldehyde and Jones reagent is carried out after mixing the prepared Jones reagent with acetone.

In an exemplary embodiment, the step (i) is carried out at a temperature between 20°C to 60°C and step (ii) is also carried out at a temperature between 20°C to 60°C.

The alpha-(p-isobutylphenyl)-propionaldehyde used in step (i) is obtained by-

(i) reacting isobutylacetophenone with isopropyl chloroacetate in presence of sodium isopropoxide to obtain an intermediate; and

(ii) treating the intermediate with sodium hydroxide to obtain the compound alpha-(p-isobutylphenyl)-propionaldehyde.

Wherein the sodium isopropoxide is obtained by treating sodium metal and Ferric chloride with isopropyl alcohol at a temperature between 55 to 60°C.

The final Ibuprofen obtained from the process comprises impurity J less than 0.05%. In one preferred embodiment, less than 0.03%

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a process for preparation of Ibuprofen substantially free of Impurity J comprising the steps of:

(i) adding alpha-(p-isobutylphenyl)-propionaldehyde and Jones reagent simultaneously; and

(ii) maintaining the reaction mixture at a temperature till the formation of Ibuprofen.

The Ibuprofen is substantially free of Impurity J obtained by process has Impurity J less than 0.05%, preferably less than 0.03%.
The Jones reagent as described in the present invention is a combination of chromic acid and sulfuric acid. Preferably the Jones reagent is a combination of chromic acid and sulfuric acid in acetone. The process of preparing chromic acid comprising the step of reacting water with Chromium oxide or reacting sodium dichloromate or potassium dichromate or potassium chromate with dilute sulfuric acid in-situ is known in the state of art.

The step of simultaneous addition of alpha-(p-isobutylphenyl)-propionaldehyde and the Jones reagent of the present invention is carried out after the preparation of Jones reagent or after mixing the prepared Jones reagent with acetone.

The simultaneous addition of alpha-(p-isobutylphenyl)-propionaldehyde and the Jones reagent is performed by addition of aldehyde and prepared Jones reagent or a mixture of prepared Jones reagent with a mixture of acetone.

Surprisingly the Inventors of the present invention found out that simultaneous addition of alpha-(p-isobutylphenyl)-propionaldehyde and the Jones reagent decreases the formation of Impurity J in the final Ibuprofen, thereby increases the yield of Ibuprofen.

The Inventors of the present invention found the root cause for the formation of Impurity J is due to the addition of aldehyde to a large excess of Jones reagent.

The reaction of step (i) may be performed at a temperature range of about 20°C to 60°C. The reaction mixture in step (ii) is maintained at the same temperature as that of step (i).

Preferably the reaction mixture may be maintained at a temperature 20°C to 60°C. The reaction mixture may be maintained at a temperature 30°C to 60°C for one or more hours till the formation of Ibuprofen.

In one preferred embodiment the reaction in step (i) is carried out at 30°C.

Another embodiment of the Invention provides a process for the preparation for Ibuprofen substantially free of Impurity J comprising the steps of:
(i) adding alpha-(p-isobutylphenyl)-propionaldehyde and the Jones reagent simultaneously;
(ii) maintaining the reaction mixture at a temperature till the formation of Ibuprofen; and

(iii) optionally isolating the formed Ibuprofen by conventional methods.

Ibuprofen having impurity J less than 0.05%, preferably less than 0.03%.

Another embodiment of the Invention provides a process for the preparation of alpha-(p-isobutylphenyl)-propionaldehyde from isobutylacetophenone comprising the steps of:

(i) reacting the isobutylacetophenone with isopropyl chloroacetate in the presence of sodium isopropoxide in polar solvent to form an intermediate;

(ii) treating the formed intermediate with sodium hydroxide to form alpha-(p-isobutylphenyl)-propionaldehyde.

The starting material alpha-(p-isobutylphenyl)-propionaldehyde may be prepared by processes from isobutyl-acetophenone as known in the state of art. The alpha-(p-isobutylphenyl)-propionaldehyde may be prepared by involving the steps of: (i) reacting isobutylacetophenone with isopropyl chloroacetate in the presence of sodium isopropoxide to obtain an intermediate; and (ii) the obtained intermediate is treated with alkali to obtain the compound alpha-(p-isobutylphenyl)-propionaldehyde.

The present invention is described by the following examples, which are for illustrative purpose only and should not be construed as to limit the scope of the invention in any manner.
EXAMPLES

EXAMPLE-1:

(i) Preparation of Sodium isopropoxide: Sodium metal (200 kg) and Ferric chloride (141 gm) were added to isopropyl alcohol (3260 ml) in a nitrogen atmosphere and heated to 55 to 60°C till the sodium metal dissolves completely to obtain sodium isopropoxide. Isopropyl alcohol (700 ml) was added to the obtained sodium isopropoxide.
(ii) Preparation of alpha-(p-isobutylphenyl)-propionaldehyde: To a mixture of Isobutyl acetophenone (1025 Kg) and isopropyl chloroacetate (1100 Kg), the freshly prepared sodium isopropoxide in step (i) was added slowly at a temperature of 25°C and then maintained the same for 2 hours. The resultant reaction mixture was distilled to obtain a residue. The residue was mixed with sodium hydroxide solution (690 L) at a temperature of 70°C. The pH of the reaction mass was then adjusted 3.8 to 4.2 by the addition of hydrochloric acid. The top organic layer was separated and sent for distillation under high vaccum. Yield: 920 Kg

EXAMPLE-2:
(i) Preparation of Jones reagent: A mixture of dilute sulphuric acid (2980 L) and sodium dichromate (975 Kg) was cooled and added to acetone (2500 L) at 25°C.

(ii) Preparation of Ibuprofen: The Prepared Jones reagent in step (i) and the aldehyde prepared in example-1 (1600 Kg) were added simultaneously at 30°C and maintained for one hour at the same temperature. After completion of the reaction, the water (300 ml) was added and then the reaction mass was heated for distillation of acetone at a temperature not more than 85°C.

The reaction mass was cooled to 55°C and allowed to settle. The settled reaction mass was mixed with hexane and stirred for 20 minutes followed by the addition of water (1600 L). The organic layer was separated from the biphasic phase was then mixed with hexane and cooled till formation crystals. The crystalline Ibuprofen was filtered, washed with hexane and dried. Yield: 1275 Kg