FI92317B - Process for purifying 2,6-diisopropylphenol - Google Patents

Description

9231 7

The present invention relates to a process for the purification of 2,6-diisopropylphenol.

2,6-Diisopropylphenol, or propofol, is a pharmaceutically important compound used in anesthesia. The substance is particularly suitable for use in short-term surgical procedures due to its short half-life. When administered intravenously, the purity requirements of the substance are very high, and the goal is a purity of at least 99.9%.

Propofol is a commercially available product. It is prepared from 15 phenols and propylene by Friedel-Crafts alkylation,

whereby the desired propofol I is formed in the reaction

20 J

in addition small amounts of other isomers and phenol derivatives, the main impurities being (II) 2,4- and (III) 2,5-diisopropylphenol, (IV) 2,4,6-25 triisopropylphenol, and (V) 1-isopropoxy-2,4-diisopropylbenzene.

The compounds formed in the reaction have previously been separated by fractional distillation, but this is very difficult due to the small boiling point differences of the compounds to be separated. After fractional distillation of the product, it still contains up to about 0.5% by weight, but normally not less than 0.3% by weight of said impurities, as determined by mass spectrometry. Of the 35 impurities mentioned above, compound (II) 2,4-diisopropylphenol makes up the majority, such as up to 3/4, e.g. about 1/4 -3/4 of the total impurities.

9231 7 2

According to the invention, a purification method has now been developed based on the differences in the physical properties of the above-mentioned reaction products, in particular the different solubility and crystallization properties of the reaction products in a certain temperature range.

Thus, the process of the invention is characterized in that the purification takes place by crystallization of the crude product containing 2,6-diisopropylphenol from the alkylation reaction of propylene and phenol at a temperature of about -25 ° C to about + 18 ° C.

The process according to the invention is based on the surprising finding that a very high degree of purity is obtained by crystallization of the crude product, which is preferably a product with reduced impurity content, e.g. by fractional distillation, as described above, at a temperature where propofol crystallizes This temperature range is below about + 18 ° C. In this temperature range, propofol crystallizes, while impurities with slightly different boiling points than propofol crystallize at temperatures well below the conditions used. The usable temperature range is up to about -25 ° C. According to a preferred embodiment, the propofol is crystallized at a temperature of -20 to -10 ° C.

The crystallization can be performed either as such without a solvent, in which case the crystallization of Propofol takes place by cooling, suitably to about -20 to -10 ° C to obtain optimal yields. At temperatures above -10 ° C, the yield is not optimal, although the quality of the product remains the same. The same applies to the use of temperatures below -20 ° C. The crystallized product is then filtered and washed, preferably with a non-polar aliphatic hydrocarbon such as hexane or petroleum ether. Residual solvents in the product can be removed by distillation and

II

3 9 231 7 The product itself is distilled in a very pure single fraction.

According to an alternative variant, the crude product 5 can be dissolved in about 0.2 to 0.5 times the amount of a non-polar aliphatic solvent such as hexane or petroleum ether. The propofol is allowed to crystallize at a suitable temperature, filtered and washed as above. Residual solvent residues are removed by evaporation. 10 Repeat the crystallization if necessary. The further processing of propofol is preferably carried out as described above for the crystallization without solvent.

The invention makes it possible to produce a product which has a very high degree of purity 15 and which can thus be safely used intravenously.

The following examples illustrate the invention but do not limit it in any way.

20

Example 1 100 g of crude propofol (commercial alkylation reaction product, purity 99.7%, main impurity compound (II) 0.2%) are taken up in a flask and cooled to -20 ° C with vigorous stirring. Once crystallization has begun, the vessel is kept at said temperature for one hour. The crystals formed are filtered off and washed with cold petroleum ether. The solvent is distilled off from the product, after which the remainder is distilled off as a single fraction. The yield is 60 to 30 g of product with a purity of> 99.9% as determined by gas chromatography.

Example 2 100 g of crude propofol (same as in Example 1) and 30 g of petroleum ether are taken up in a flask and cooled to -20 ° C with stirring. Once crystallization has begun, the flask is kept at said temperature for one hour. The crystals formed 9231 7 4 are filtered and washed with cold petroleum ether. The product is further treated as in Example 1, yield 60 g of product, purity> 99.9%

II

Claims (5)

9231 7 1. A process for the purification of 2,6-diisopropylphenol from a crude product obtained from the alkylation reaction of propylene and phenol containing, as the major impurities, not more than about 0.5% of 2,4-, 2,5-diisopropyl, 2,4,6-tri -isopropylphenol and 1-isopropoxy-2,4-diisopropylbenzene, characterized in that the purification is carried out by crystallization at a temperature in the range from about -25 to + 18 ° C, optionally using a non-polar solvent. 15 Process according to Claim 1, characterized in that the crystallization is carried out at a temperature of -20 to -10 ° C. Process according to Claim 1 or 2, characterized in that the crystallization is carried out without solvent. Process according to Claim 1 or 2, characterized in that the crystallization is carried out using hexane or petroleum ether. Process according to one of the preceding claims, characterized in that, after crystallization, the product separated by filtration is distilled as a single fraction. 30 92.5 and 7