FORM 2
THE PATENTS ACT 1970
(Act 39 of 1970)
&
THE PATENTS RULE, 2003
COMPLETE SPECIFICATION
(SECTION 10 and Rule 13)
TITLE OF THE INVENTION
"AN IMPROVED PROCESS FOR PREPARING 2,6-DIISOPROPYL
PHENOL"
Emcure Pharmaceuticals Limited.,
an Indian Company, registered under the Indian Company's Act
1957 and having its Registered Office at
Emcure House, T-184, M.I.D.C., Bhosari, Pune-411026, India.
THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED.

FIELD OF THE INVENTION
The present invention relates to an improved process for preparation of 2,6-diisopropyl phenol of formula (I). Specifically, this method relates to a process for isolation of 2,6-diisopropyl phenol which does not require elaborate in-built purification steps and pH adjustment for removal of associated impurities.

BACKGROUND OF THE INVENTION
Propofol, chemically known as 2,6-diisopropylphenol, is a short-acting, intravenously administered sedative hypnotic agent for induction and maintenance of anaesthesia or sedation. Intravenous injection of a therapeutic dose of propofol induces hypnosis with minimal excitation usually within 40 seconds from the start of the injection.
2,6-Diisopropyl phenol is administered intravenously, therefore, it is imperative that the administered product should be free from associated impurities. Prior art reveals that the synthesis of 2,6-diisopropyl phenol is associated with the formation of various impurities such as phenol, dialkyl phenol isomers of the desired 2,6-diaIkyl phenol etc.
US 5,696,300, US 4,275,248, US 3,029,276, WO 2005033279, CN 1197055, WO 200034218, EP169359, US 3,367,981, US 3,271,314, US 3,766,276, SU 170505, US 2,831,898, US 2,207,753, GB 1318100, US 4,391,998, US 4,774,368, US 5,589,598 and US 6,362,234 disclose various methods for preparation and purification of 2,6-

diisopropylphenol. One of the preferred methods for commercial scale preparation, utilizing 4-hydroxy benzoic acid is disclosed in SU 443019 Al and more recently in WO 2011161687 Al.
SU 443019 Al discloses a process for preparation of 2,6-diisopropylphenol which comprises preparation of 3,5-diisopropyl-4-hydroxybenzoic acid followed by decarboxylation in presence of triethylamine. However, the drawback of this process is requirement of acid neutralization during isolation of 3,5-diisopropyl-4-hydroxybenzoic acid which is quite exothermic and will be difficult to control on an industrial scale. A further drawback involves formation of a large number of associated impurities during the preparation of 3,5-diisopropyl-4-hydroxybenzoic acid, which necessitates repeated purification either at the intermediate stage or at the final stage.
WO 2011161687 Al like SU 443019 Al also discloses preparation of 2,6-diisopropylphenol by the same route. However, the isolation method disclosed in WO 2011161687 also requires quenching of the reaction mixture with caustic soda, which is quite exothermic. Further, the inbuilt purification method during isolation of 3,5-diisopropyl-4-hydroxybenzoic acid is quite lengthy and arduous for practice on an industrial scale.
Therefore, there is a need for a simple convenient and improved process for the preparation of 2,6-diisopropylphenol by utilizing 4-hydroxy benzoic acid and which avoids the extreme exothermicity during its isolation observed in prior art methods and does not require an elaborate method for removal of associated impurities at the intermediate stage.

OBJECT OF THE INVENTION
An object of the present invention is to provide an improved process for the preparation of 2,6-diisopropylphenol which avoids the exothermicity that is encountered during isolation of 3,5-diisopropyl-4-hydroxybenzoic acid.
Another object of the invention is to provide a simple, convenient process, which does not require an elaborate isolation method as in prior art for removal of associated impurities.
SUMMARY OF THE INVENTION
An aspect of the present invention is to provide an improved process for the preparation of 2,6-diisopropylphenol comprising:
(a) reaction of 4-hydroxy benzoic acid with isopropanol in presence of aqueous acid at 55-60°C;
(b) adding the reaction mass gradually to a mixture of water and toluene at 10-20°C,
(c) separating the organic layer and concentrating the mixture,
(d) dissolving the residue in alcohol and adding water to obtain 4-hydroxy-3,5-diisopropylbenzoic acid,
(e) slurrying the 44iydroxy-3,5-diisopropylbenzoic acid in a non-polar solvent and filtering to obtain pure 4-hydroxy-3,5-diisopropylbenzoic acid of desired purity
(f) heating 4-hydroxy-3,5-diisopropylbenzoic acid in 2-ethoxy ethanol and in presence of alkali metal hydroxide to obtain 2,6-diisopropylphenol conforming to regulatory specification.

DETAIL DESCRIPTION OF THE INVENTION
The present invention relates to a simple, convenient process for isolation of 2,6-diisopropylphenol, wherein prior art drawbacks relating to extreme exothermicity, lengthy isolation procedure for removal c)f impurities have been circumvented.
In an embodiment, the method involves alkylation of 4-hydroxy benzoic acid in
heated at a temperature of 55 to 60°C.
The aqueous mineral acid employed is an inorganic acid which comprises of hydrochloric acid, sulphuric acid etc but preferably sulphuric acid.
The reaction mixture is cooled to room temperature and is added to a mixture of water and toluene at 10-20°C.
The organic layer is concentrated at reduced pressure to obtain a residue, which is dissolved in alcohol and optionally treated with charcoal and filtered. The alcohol is selected from the group comprising of methanol, ethanol, propanol etc but preferably methanol.
Water is then added gradually to the mixture at 15 to 25°C to separate out 4-hydroxy-3,5-diisopropylbenzoic acid, which is then filtered.
The wet cake of 4-hydroxy-3,5-diisopropylbenzoic acid is then slurry washed in a non-polar solvent at room temperature to obtain 4-hydroxy-3,5-diisopropylbenzoic acid having purity of more than 99%.

The non-polar solvents are selected from the group comprising of n-hexane, cyclohexane, n-heptane etc, but preferably cyclohexane.
The final step involves heating 4-hydroxy-3,5-diisopropyl benzoic acid in 2-ethoxy ethanol as solvent and in the presence of an alkali metal hydroxide in an inert atmosphere to yield 2,6-diisopropylphenol (propofol).
The alkali hydroxide is selected from sodium hydroxide, potassium hydroxide, but preferably sodium hydroxide.
The mixture is heated in the temperature range of I20-160°C, till completion of the reaction as monitored by HPLC. The reaction mixture is cooled and extracted with a hydrocarbon solvent such as toluene followed by washing the organic layer with aqueous hydrochloric acid and then with aqueous sodium bicarbonate. The organic layer was separated and concentrated under reduced pressure to obtain an oily residue, which was distilled under reduced pressure to provide 2,6-diisopropylphenol (propofol) conforming to regulatory specification, having GC purity of more than 99.5% and which could then be used for pharmaceutical preparation.
The advantages of the present invention are as follows:
i) During the preparation of 4-hydroxy-3,5-diisopropylbenzoic acid, the product is isolated from die reaction mixture by quenching with a mixture of water and toluene at 10-20°C and does not involve die highly exothermic neutralization of sulphuric acid with an alkali solution. Thus me present invention completely eliminates utilization of an alkali during die work up.
ii) The associated impurities are removed from the product by a simple slurry wash with cyclohexane, hence, does not involve elaborate work up for removal of impurities, which is employed in prior art.
iii) Use of 2-ethoxyetiianol as the selective solvent for decarboxylation wherein during aqueous work-up, die desired product (propofol) gets extracted into

toluene layer (at basic pH) without the need of neutralization using acid as reported in the earlier processes which uses ethylene glycol for decarboxylation.
The examples as described for the presented invention are purely illustrative and are not limited to the particular embodiments illustrated herein but include the permutations, which are obvious as set forth in the description.

EXAMPLES
Example 1: Preparation of 3, 5-diisopropyl-4-hydroxybenzoic acid
Concentrated sulphuric acid (360 ml) was added gradually to a flask containing water (25 ml) cooled to 5°C. 4-Hydroxy benzoic acid (100 gms) was added, followed by slow addition of isopropyl alcohol (166 ml) at the same temperature. The reaction mixture was heated to 55 to 60°C (preferably 57-58°C) till completion of reaction as monitored by HPLC. The reaction mixture was cooled to room temperature and carefully poured into a pre-cooled (5°C) mixture of water (1000ml) and toluene (800ml) while maintaining the temperature below 20°C. The organic layer was separated and concentrated under reduced pressure to provide a residue, which was then dissolved in methanol (300ml) and gradually diluted with water (450ml) at 20°C, to separate out the product, which was then filtered. The wet cake was slurry washed with cyclohexane (400ml) and dried to give the desired intermediate 3,5-diisopropyl-4-bydroxybenzoic acid. Yield: 140 gms HPLC purity: >99%.
Example 2: Preparation of 2,6-diisopropylphenol (Propofol)
To a mixture of 3,5-diisopropyl-4-hydroxybenzoic acid (lOOgms) in 2-ethoxyethanol (300 ml) was added sodium hydroxide (42 gms) and the contents were heated at 125-130°C till completion of reaction as monitored by HPLC. The reaction mixture was cooled to room temperature and diluted with water (1000 ml) followed by toluene (600 ml). The organic layer was separated and concentrated under reduced pressure to provide an oily residue, which was then distilled under reduced pressure to provide propofol. Yield: 60gms GC purity: 99.5%

WE CLAIM,
1) A process for the preparation of 2, 6-diisopropylphenol comprising:
(a) reaction of 4-hydroxy benzoic acid with isopropanol in presence of aqueous acid at 55-60°C;
(b) adding the reaction mass gradually to a mixture of water and toluene at 10-20°C;
(c) separating the organic layer and concentrating the mixture;
(d) dissolving the residue in alcohol and adding water to obtain 4-hydroxy-3,5-diisopropylbenzoic acid;
(e) slurrying 4-hydroxy-3,5-diisopropylbenzoic acid in a non-polar solvent and filtering to obtain pure 4-hydroxy-3,5-diisopropylbenzoic acid of desired purity;
(f) heating 4-hydroxy-3,5-diisopropylbenzoic acid in 2-ethoxyethanol and in
presence of alkali metal hydroxide to obtain 2,6-diisopropylphenol
conforming to regulatory specification.
2) The process as claimed in claim 1, wherein aqueous acid is selected from an organic acid or inorganic acid, preferably inorganic acid such as hydrochloric acid or sulphuric acid.
3) The process as claimed in claim 1, wherein the alcohol is selected from the group of methanol, ethanol and propanol.
4) The process as claimed in claim 1, wherein the non-polar solvent is selected from the group of n-hexane, cyclohexane, pentane and heptane.
5) The process as claimed in claim 1, wherein alkali hydroxide is sodium hydroxide and potassium hydroxide.