FI90656B - Process for purification of 2- (4-isobutylphenyl) propionic acid - Google Patents

Description

1 90656

Process for the purification of 2- (4-isobutylphenyl) propionic acid

The present invention relates to a process for the purification of 2- (4-iso-5-butylphenyl) -propionic acid (hereinafter referred to as 2,4-acid). Said compound has many uses, e.g. as an analgesic, antipyretic or antirheumatic drug and as an intermediate for many other substances. In the form of amine salts, aqueous solutions of 2,4-acid show a good corrosion protection effect during metal push cutting.

There are numerous possibilities to synthesize 2,4-acid. One possibility (Method A) for preparing the compound is the carbonylation of 1- (4-isobutylphenyl) ethanol with carbon monoxide in the presence of triphenylphosphine and optionally in the presence of a transition metal halide, as described, for example, in U.S. Patent Application Serial No. 28,514. In connection with an optimized performance of the process, the reaction mixture to be purified obtained contains about 85-93% of 2,4-acid. In addition to 2,4-acid, the reaction mixture still contains about 40 organic substances as impurities, such as triphenylphosphine and triphenylphosphine oxide. In order to purify from this reaction mixture, melting between 65-70 ° C, the 2,4-acid available as a drug, it is necessary to separate the organic impurities on the one hand and triphenylphosphine and triphenylphosphine oxide on the other hand or to reduce them to acceptable amounts so that the purified product should triphenylphosphine and triphenylphosphine oxide at a concentration of less than 10 ppm.

Separation of organic by-products alone from a 2,4-acid reaction mixture without triphenylphosphine and N-triphenylphosphine oxide is already a rather expensive operation ... and requires, as is apparent from Romanian Patent Publication 35,795,345, several process steps. Thus, for example, 2,4-acid must first be converted to a water-soluble salt, e.g. sodium salt by sodium hydroxide solution, this liberates from oeutrals by extraction with methylene chloride, decolorization of the aqueous solution of carbon-purified material, then liberation of the carboxylic acid with a suitable acid, hydrochloric acid, and finally recrystallized from water / methanol and dried.

Another patent publication (GB 971 700) discloses that the 2,4-acid obtained from the reaction mixture is in pure form only after triple recrystallization. Also in a newer, rather expensive process, such as that disclosed in EP-A 170 147, recrystallization is chosen as the purification method for 2,4-acid.

The separation task becomes particularly problematic if - as in, for example, method A described above - triphenylphosphine is present in the reaction mixture. Triphenylphosphine bases a reaction mixture of 2,4-acid and other acids at room temperature with a stable adduct of the following formula.

·· idi o i

p OdD

I H *, 0 CO 2j [which - as our own studies have shown - cannot be separated by extraction or recrystallization several times from solvents (see comparative example). Also, 35 other separation methods, such as adsorption on resins or 3,90656 ion exchangers, do not lead to the goal of removing all impurities in sufficient quantity.

In the search for a suitable separation method for purifying the reaction mixtures to give 2,4-acid, it was found that this task can be solved by rectification in vacuo. This is extremely surprising, since until the solution of the present invention was considered to be clearly impossible to carry out, the purification of 2,4-acid melting at 74.8 ° C by distillation or rectification was considered to be clearly impossible. No vapor pressure values or boiling point are known in the literature for oily viscous liquid acid above the melting point of 74.8 ° C. The relatively high melting point of the acid makes it understandable that purification possibilities were sought primarily from crystallization in the presence of various solvents and in the absence of triphenylphosphine - also found, as disclosed, e.g., in the aforementioned patents. In addition, purification involving rectification, due to the instability of 2,4-acid at high temperatures, proved to be promising little success in advance, especially as the crude acid mixture may also contain other reactive components such as triphenylphosphine, triphenylphosphine oxide, styrene oxide, ketones, which cause the mixture to discolor to a deep black or to tar or resin. In addition, it had to be considered, although not as a last resort, that 2,4-acid forms azeotropic mixtures with one or more organic impurities.

The invention then relates to a process for the purification of 2- (4-isobutylphenyl) -propionic acid from mixtures obtained in the preparation of 2- (4-isobutylphenyl) -propionic acids, and the process is characterized in that the mixture is subjected to rectification in vacuo.

4 90656

The process according to the invention has the advantage over the processes known from the prior art that 2,4-acid can be liberated from a number of concomitant impurities, in particular also triphenylphosphine 5 and triphenylphosphine oxide, in a single basic process operation, with virtually no .

Various types of columns can be used to perform the method 10 of the invention. Columns with tissue packings and columns with the same pressure drop as those with tissue packings are particularly suitable for the process of the invention because they have a lower pressure drop compared to other columns. Pressure drop in this context means the pressure difference between the column piston (Sumpf) and the peak areas. A small pressure difference requires a small temperature difference between the column flask and the peak and is necessary because the temperature of the column flask in the rectification of 2,4-acid should not exceed a certain upper limit, as 2,4-acid decomposes at a higher temperature. The susceptibility of 2,4-acid to decomposition is clarified by means of Figure 1, which shows, in relation to the duration of heating of 2,4-acid, the melting point in each case, the decrease of which is one measure of the impurity. It is noted that already at 250 ° C the melting point of the respective sample decreases even after a short heating time, due to the decomposition of 2,4-acid. The susceptibility of 2,4-acid to further decomposition may be increased due to impurities. For this reason, the maximum temperature at which the process according to the invention can still be meaningfully used depends on the composition of the mixture. To purify the reaction mixture obtained according to Method A using a prior art rectification apparatus (redistillation apparatus) as shown, e.g., in Figure 2, the temperature of the column flask should therefore preferably not exceed about 250 ° C, particularly preferably not more than about 230 ° C, in particular not more than 210 ° C.

The use of modern rectifiers, such as those equipped with liquid-film evaporators or drop-film evaporators, achieves very short residence times of the material to be rectified, and thus higher air temperatures are possible in such rectifiers. - losses. When using the latter rectification apparatus, the temperature of the column flask should preferably not be higher than about 280 ° C.

The boiling temperature in the column flask and the temperature of the steam in the region of the top of the column correspond to the vapor pressure. For example, at a vapor pressure of 10 jPa at the top of the column and 13 kPa at the bottom of the column, pure 2,4-acid is distilled at 178 ° C over a temperature range of 0.1 ° C, while in the column flask - due to the higher pressure and impurity concentration - Boiling point ranges from 190 to 220 ° C. It is preferred to keep the vapor pressure in the region of the column flask lower than about 60 hPa so that the boiling temperature of 250 ° C in the column flask is not exceeded.

. : - 25 The number of theoretical bases for rectification. lonn can vary over a wide range. A number between about 10 and 150, particularly preferably between about 25 and 70, is recommended as the number of theoretical midsoles.

• Rectification equipment suitable for the cleaning method according to the invention can be constructed in various ways.

A laboratory-scale rectifier, for example, is shown in Figure 2. A mixture containing 2,4-acid is heated in a flask (1) of a distillation column. Instead of a flask, the device may also comprise e.g.

6 90656 Liquid film evaporator or falling film evaporator. At the top of the column (2), low-boiling impurities can distill off. Below the condenser, which can be e.g. a cooling coil (3), the condensate is collected in a liquid distributor (4), by means of which the reflux ratio can also be adjusted. The pre-vessel (5), in which the various distillate fractions and the pure product are collected, should preferably be tempered to about 80 ° C, so that the product does not solidify. The sub-10 pressure required for rectification is provided by a suitable vacuum pump (6). The rectification column (7) is packed with tissue packings and develops a separation capacity corresponding to a maximum of 25 theoretical separation positions,

It is expedient to carry out the rectification under an inert gas which can be introduced into the column flask in a preferred distillation apparatus, e.g. via a boiling capillary (8). Many inert gases are suitable for this purpose. Nitrogen, argon and carbon dioxide are preferred, particularly preferably nitrogen.

It may also be appropriate to extract the crude 2,4-acid prior to rectification first with water to remove water-soluble impurities such as chlorides, phosphates, metal salts and the like.

The rectification according to the invention can in principle also be carried out by means of one or more columns and periodically, i. removing private fractions that also constantly. If continuous 1-column distillation is performed, then the column can be used advantageously so that the pure product is removed from the approximately middle steps of the column in the form of steam to the side, while the column is preferably used at full recovery. In the case of continuous rectification, before the 2,4-acid is separated, both low-boiling and high-boiling substances can be removed first, provided that this is not exceeded. 35 critical temperature stability limits for each reaction mixture.

7 90656

The process according to the invention is in itself suitable for the further treatment of any 2,4-acid-containing mixture. It is undoubtedly of particular importance in the further processing of the mixtures obtained in connection with the synthesis of 2,4-acid, in particular in the case of the reaction mixtures obtained in process A described above.

The process according to the invention is suitable for liberating the crude acid obtained from the production process according to process A from all impurities without pre-purification.

10 However, it may also make sense to rectifiably separate only some of the impurities and to separate the remaining impurities by one or more cleaning methods. Crystallization from solvents and crystallization of the melt without the use of auxiliaries are particularly suitable for this purpose. In particular, it may make sense to carry out at least one crystallization from the melt before rectification. In this case, the crude acid melt is converted into a block crystallization by cooling, from which the residual melt heavily loaded with impurities is separated and, after melting, the crystallization is subjected to rectification according to the invention. By means of said method combination, the rectification according to the invention can be carried out on a rectification column with a lower theoretical base number. The following embodiments are intended to further illustrate the invention.

· ’25 Example 1

An apparatus such as that shown in Figure 2 was charged with 500 g of a mixture of about 90% of 2,4-acid having the following composition: Table 1 Compound by weight 2- (4-isobutylphenyl) propionic acid 88.77 triphenylphosphine 0.18 isobutylphenylethane 1.90 4-isobutylbenzene 0.02. 35 4-Isobutylstyrene 0.15 8 90 656 4-Isobutylacetophenone 0.78 1- (4-Isobutylphenyl) ethanol 0.08 1- (4-Isobutylphenyl) chloroethane 0.59 2- (4-Isobutylphenyl) propionic acid ethyl 5 esters 0.05 2- (3-isobutylphenyl) propionic acid 1.10 3- (4-isobutylphenyl) propionic acid 1.90 low boiling point average molecular weight 178 1.80 10 high boiling point average molecular weight is 320 1.20 methyl ethyl ketone 0.48 other unidentified impurities about 1.0

Figure 3 shows a gas chromatogram of all impurities in mixture 15.

The mixture containing said impurities was fractionally distilled in the presence of nitrogen at a pressure of 10 hPa and a base temperature of initially 150 and finally 230 ° C with varying reflux ratios. The following 20 distillate fractions were taken: 1) 20 g of pre-distillate as a yellow liquid 2) 158 g of intermediate distillate with a 1,4-acid content of 94-98% 3) 300 g of main distillate.

25 22 g of residue remained in the flask. The composition of the main distillate 011 is as follows:

Compound wt% 2- (4-isobutylphenyl) propionic acid 99.5 triphenylphosphine 0.00005 30 other non-organophosphorus impurities 0.5

Figure 4 shows a gas chromatogram of the main fraction. Example 2

Using the rectification apparatus shown in Example 1, the 35-acid mixture of about 90% shown in said Example was subjected to a 2-stage rectification. In the first distillation step, after separation of the pre-distillate, the focus was only on separating the contents of the flask in which the critical triphenylphosphine impurity is enriched. In the second rectification step, the recti-5 was then subjected once more to the main distillation of the first rectification containing about 97% 2,4-acid at a flask temperature of about 200 ° C. The following fractions were obtained from a batch product of 942 g: 1) 245 g of an intermediate distillate with a 2,4-acid content of up to 98.8% 2) 640 g of the main distillate 3) 57 g of the distillation residue.

The composition of the main fraction was as follows: Compounds wt% 2- (4-isobutylphenyl) propionic acid 99.5 triphenylphosphine 0.00005 other non-organophosphorus impurities 0.5

Example 3

A tube crystallizer having a cooling / heating jacket connected to a thermostat was charged with about 90% of a 2,4-acid mixture having the composition of Example 1 as a melt. The melt, which had a solidification point of 58 ° C, was cooled to 40 ° C over 10 hours, whereupon a dense crystallization separated in the apparatus. The dark brown liquid portion remaining in the crystallizer was then discarded, and the resulting light crystals were melted and melted; rectification according to the invention was performed. 500 g '; 440 g of crystalline mass with an acid purity of 98.5% were obtained from a 90% batch product.

The 2,4-acid pre-purified in this way was then subjected to rectification according to the invention up to a flask temperature of 220 ° C. This gave about 370 g of a main fraction having the following composition: .0 90656

Compounds wt% 2- (4-isobutylphenyl) propionic acid 99.6 triphenylphosphine 0.00005 other non-organophosphorus impurities 0.4 Comparative Example In a refluxing glass flask equipped with a reflux condenser, 20 g of 2,4-acid was dissolved. containing 4.0 triphenylphosphine in 50 ml of n-hexane at the reflux temperature of the solvent. The solution was then cooled to room temperature, the precipitated acid was filtered off, washed with 20 ml of cold n-hexane and dried in a desiccator. Analysis of the recrystallized acid showed that the triphenylphosphine content remained unchanged. The 2,4-acid 15 thus obtained was then recrystallized from n-hexane a second, third and fourth time without being able to change the triphenylphosphine content.

Claims (8)

A process for the purification of 2- (4-isobutylphenyl) propionic acid from mixtures obtained in the preparation of 2- (4-isobutylphenyl) propionic acid, characterized in that the mixture is vacuum rectified, the piston temperature using a rectifier which is provided with a distillation boiler is below about 250 ° C and when using a rectifier 10 provided with a thin layer evaporator or a drop film evaporator is below about 280 ° C. 2. A method according to claim 1, characterized in that the rectification is carried out with columns filled with tissue fillings or columns with a comparatively small pressure loss. 3. A process according to claim 1 or 2, characterized in that the rectification is carried out by using a rectifier equipped with a distillation boiler at a piston temperature below about 250 20 ° C. 4. A method according to claim 1 or 2, characterized in that the rectification is carried out by using a rectifier equipped with a thin layer evaporator or a drop film evaporator at a piston temperature below about 280 ° C. Process according to any of claims 1-4, characterized in that the number of theoretical bottoms in the rectification column is about 10 - 150. Process according to any of claims 1-5, characterized in that the rectification is carried out in the presence of an inert gas. Process according to any one of claims 1-6, characterized in that 2- (4-isobutylphenyl) propionic acid is isolated from a mixture obtained by carbonylation of 1- (4-isobutylphenyl) ethanol with carbon monoxide 14 90 656 in the presence of triphenylphosphine and optionally a transition metal halide. Process according to any one of claims 1-7, characterized in that in the rectification 5 a mixture previously released from some of the impurities is used by means of at least one melt crystallization. 10