The present invention relates to a process for a purification of 2,6- diisopropyl phenol (propofol). More particularly, the present invention relates to a purification of 2,6-diisopropyl phenol by a chlorination reaction followed by a hydrogenation reaction.

Background of the Invention

Propofol is used as an anesthesia, which is administered intravenously. Therefore an extremely high purification degree is necessary. Propofol is a compound available on the market. Methods for the production of propofol are well-known in the art. Typically propofol is prepared by Friedel-Crafts alkylation from phenol and propene or 2-propanol. However, in this reaction small amounts of other isomers and phenol derivatives than 2,6- diisopropyl phenol are formed.

The International Patent Application WO 00/34218 {Dong Kook Pharmaceutical Co., Ltd,} discloses a purification process of propofol, wherein a raw 2,8-diisopropy! phenol is treated first with an inorganic acid and second with a base, extracted with a solvent and purified by distillation or crystallization at a temperature of -20 ~-30°C.

EP 0 862 544 B1 (Albemarle Corporation) describes a process for the purification of propofol comprising washing the impure propofol with aqueous alkali metal hydroxide solution and/or alkali earth metal hydroxide solution, in an inert atmosphere, separating the aqueous and organic phases, washing the resulting organic phase with water, and then subjecting the water-washed organic phase to distillation in an inert environment to recover purified 2,6- diisopropyl phenol. EP 0 716 645 B1 (Archimica S.P.A.) describes a process for purifying propofol by reacting the raw 2,6-diisopropyf phenol with an alkaline agent, isolating the alkaline metal salt and neutralizing the isolated pure salt,

EP 0 783 473 B1 (Zambon Group S.P.A.) discloses a process for the purification of propofol comprising transform ating the crude propofol into its ester with a carboxylic or sulphonic acid, crystallizing the ester and subsequent hydrolyzing it.

EP 0 511 947 B1 {Leiras Oy) discloses a process for the purification of propofol, wherein the raw 2,6-diisopropyl phenol product containing as major contaminants not more then 0.5 % by weight of 2,4-2,5-drisopropyl-,2,4 ₁ 6-triisopropyl phenol and 1- isopropoxy-2,4-diisopropyl benzene, is purified by crystallizing the same at a temperature range of -25°C to +18°C,

The International Patent Application WO 2010/067089 (University of Liverpool) discloses a method for producing halosubstituted propofol compounds (e.g. 4-bromopropofol, 4-chloropropofol). Said compounds are used as starting materials for synthesising aryl-substituted propofol analogues.

However, all the cited processes lack economical efficiency and practical usability. Moreover, the known purification processes use large amounts of solvents. Therefore there is still a need to improve the process of purifying 2,6-diisopropyl phenol.

Summary of the Invention

The object of the present invention is to provide an effective and ecological process for purifying 2,6-diisopropyl phenol into a highly pure product. This object is solved by the subject-matter of the independent claims. Preferred embodiments are indicated in the dependent claims. The purification process according to the present invention provides 2,6-diisopropyl phenol in high yield and with a high purity in an economical effective way. One of the benefits of the present invention is that the chlorination reaction may be carried without any solvents.

The present invention provides a process for purifying 2.6- diisopropyl phenol starting from commercially available technical grade propofol, said process comprising converting 2,6-diisopropyl phenol to a 4-chloro-2,6-diisopropyl phenol and further converting said 4-chloro-2,6-diisopropyf phenol to a purified 2,6-diisopropyl phenol.

The purification process according to the present invention is analogical applicable for purification of other 2,6-dialkyl phenols and 2,4-diatkyl phenols, in particular for purification of short-chain, preferably of C<-C ₄ 2,4-dialkyl phenols and 2,6-dialkyl phenols.

It has been surprisingly found that 2,6-diisopropyl phenol having a high degree of purity (>99.5 %) can be obtained by performing first a chlorination reaction converting the technical grade (97%) 2,6- diisopropyl phenol to a 4-chloro-2,6-diisopropyl phenol. The following hydrogenation reaction converts the 4-chloro-2.6- diisopropyl phenol into a high purity 2.6-diisopropyl phenol.

Detailed Description of the Invention

Hereinafter, the best mode for carrying out the present invention is described in detail.

The present invention provides an improved method for the purification of 2,6-diisopropyl phenol. Said process comprises converting technical grade (97 %) 2,6-diisopropyl phenol into 4- chloro-2,6-diisopropyl phenol and further converting said 4-chloro- 2,6-diisopropyl phenol into 2.6-diisopropyi phenol with a high degree of purity (>99 5 %).

The process of the present invention is based on the surprising observation that a very high degree of purity (>99.5 %) of propofoi can be achieved by using economical and ecological process comprising a chlorination and a hydrogenation steps. In particular, the chlorination step may be carried out without any solvents.

As known from the prior art, the purification of technical grade propofoi by distillation is difficult due to the photosensitivity and oxidation sensitivity of propofoi. The process according to the present invention allows the purification of 4-chloro-2,6-diisopropyl phenol by distillation, since the 4-chloropropofoi intermediate is thermal stable.

The following scheme shows the chlorination (a) and hydrogenation (b) reactions according to the present invention;

The chlorination agent may comprise any appropriate agent that permits the chlorination reaction (a). In a preferred embodiment, the chlorination agent is selected from the group of thionyl chloride, chlorine gas and sulfuryf chloride. The most preferred chlorination agent is sulfuryl chloride.

The chlorination agent is preferably present in the reaction solution in the amount of up to 2 eq in respect to the amount of propofoi. wherein eq refers to the molar equivalent. More preferably, the amount of the chforination agent is between 1.0-1.3 eq.

In general, the chlorination reaction may be carried out in any solvent known to the man skilled in the art, preferably in a polar aprotic solvent Most preferably, the chlorination reaction is carried out without any solvents,

The chlorination reaction is carried out at any temperature that permits the reaction to be performed, preferably at the temperature in the range of 20-100°C, more preferably in the range of 40-80X, even more preferably in the range of 55-75 and most preferably in the range of 60-70X.

In a preferred embodiment, propofol and the chlorination agent are charged in a flask, optionally under inert atmosphere, and heated for several hours. The most preferable inert gas is nitrogen. After the completion of the chlorination reaction, the resulting 4-chloro- 2,6-diisopropyl phenol is purified according to the methods known to the man skilled in the art. Preferably the 4-chloro-2,6-diisopropyl phenol is purified by distillation.

The purified 4-ch!oro-2,6-diisopropyl phenol is further hydrogenated (b) into high purity (>99.5 %) 2,6-diisopropyl phenol.

In a preferred embodiment, the 4-chloro-2,6-diisopropyl phenol is first dissolved in a solvent. Any appropriate solvent may be used. Preferably, the solvent is selected from the group of water, alcohols and mixtures thereof. More preferably, the solvent is selected from the group of water, methanol, ethanol, propanol, 2- propanol and mixtures thereof. Most preferably the solvent is water.

The hydrogenation reaction (b) is preferably carried out in the presence of a base. Any inorganic or organic base may be used. Preferably, the base is selected from the group of triethy!amine, diethylamine, methyiamine, ethylamine, sodium hydroxide, potassium hydroxide and mixtures thereof. Most preferably the base is sodium hydroxide.

The hydrogenation reaction (b) is preferably effected by adding a catalyst and holding the reaction mixture under hydrogen gas (H2). The hydrogen gas is applied at a pressure known to the man skilled in the art. Preferably, the pressure is up to 100 bar, more preferably in a range between 1-10 bar and most preferably in a range between 3-5 bar.

In a preferred embodiment, the catalyst is selected from a palladium or platinum catalyst. Preferably, the catalyst is a carbon supported palladium or platinum catalyst, well known in the art. The hydrogenation reaction (b) is carried out at any temperature that permits the reaction to be performed, preferably at a temperature in a range of 0-100°C, more preferably in the range of 10-60°C and most preferably in the range of 20-30°C. The hydrogenation reaction (b) is preferably carried out in an autoclave equipped with stirring means. The reaction mixture is hydrogenated until the reaction is completed.

In a preferred embodiment, the catalyst is then filtered off and the organic layers are separated The product phase (2.6-diisopropyl phenol) is preferably washed with any appropriate acid, more preferably with an inorganic acid, optionally diluted. Most preferably, the acid is diluted hydrogen chloride. The product phase is further distilled, preferably in vacuum.

The degree of the purity of the technical grade (97 %) 2,6- diisopropyl phenol, 4-chloro-2,6-diisopropyl phenol and purified {>99.5 %) 2,6-diisopropyl phenol may be measured by using GC. The purified (>99.5 %) propofoi may further be prepared into pharmaceutical dosage forms using methods known to the man skilled in the art.

Hereinafter, the present invention is illustrated in more detail by the examples, which however are not intended to limit the present invention. Example 1 : Purification of 2,6-diisopropyi phenol

Step (a): Chlorination

181.7 g of sulfur l chloride is charged in the flask under nitrogen and heated to 70 °C. 200 g of 2,6-diisopropylphenol (technical grade) is added slowly and after complete addition the mixture is stirred for additional 1-2 hours. The dark solution of 4-chloro-2,6- diisopropyl phenol is cooled and purified by fractionated distillation in vacuum. 167 g (70 %) of pure 4-chloro-2,6-diisopropylphenol is isolated.

Step (b): Hvdroqenation

100 g 4-0 Ioro ^» 2,6-diisopropyIphenol is added to a mixture of 500 g of water and 70 g 30% sodium hydroxide solution at 20-25 °C. 4 g 5% palladium on charcoal (50% w/w water wet) is added and the mixture is hydrogenated at 3-5 bar hydrogen pressure for 2-4 hours at 25 °C. The catalyst is removed by filtration and the organic layers are separated. The product phase (2,6-diisopropyl phenol) is washed with diluted hydrogen chloride once and distilled in vacuum to yield 75 g (90 %) pure 2,6-diisopropylphenol (>99 5

%).

Example 2: Purification of 2,6-diisopropyl phenol Step (a): Chlorination

300 g technical grade Propofol is charged in a flask under nitrogen and heated to 70 °C. 272.5 g sulfuryl chloride is added slowly over several hours and after complete addition the mixture is stirred for additional 1-2 hours. The dark solution of 4-chloro-2,6-diisopropyl phenol is cooled and purified by fractionated distillation in vacuum. 261 g (73 %) of pure 4-chloro-2,6-diisopropylphenol is isolated.

Step (b): Hvdrooenatton

100 g 4-chloro-2,6-diisopropylphenol is added to a mixture of 500 g of water and 70 g 30% sodium hydroxide solution at 20-25 X. 4 g 5% palladium on charcoal (50% w/w water wet) is added and the mixture is hydrogenated at 3-5 bar hydrogen pressure for 2-4 hours at 25 °C The catalyst .is removed by filtration and the organic layers are separated. The product phase (2,6-diisopropyl phenol) is washed with diluted hydrogen chloride once and distilled in vacuum to yield 75 g (90 %} pure 2,6-diisopropylphenol (>99.5

%)·