CA1337553C - Process for purifying 2-(4-isobutylphenyl)-propionic acid - Google Patents
Process for purifying 2-(4-isobutylphenyl)-propionic acidInfo
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- CA1337553C CA1337553C CA000589392A CA589392A CA1337553C CA 1337553 C CA1337553 C CA 1337553C CA 000589392 A CA000589392 A CA 000589392A CA 589392 A CA589392 A CA 589392A CA 1337553 C CA1337553 C CA 1337553C
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- rectification
- acid
- isobutylphenyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
- C07C57/30—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
- C07C51/43—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation
- C07C51/44—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation by distillation
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- Organic Chemistry (AREA)
- Crystallography & Structural Chemistry (AREA)
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Process for purifying 2-(4-isobutylphenyl)-propionic acid 2-(4-Isobutylphenyl)-propionic acid is purified by sub-jecting it to a vacuum rectification, in which the tem-perature is below the decomposition temperature of the acid.
Description
1 3375~3 Description Process for purifying 2-t4-isobutylphenyl)-propionic acid The present invention relates to a process for purifying 2-(4-isobutylphenyl)-propionic acid (called 2,4-acid in the following text). The said compound is widely used, for example as an analgesic, as an anti-inflammatory agent or antirheumatic, and as an intermediate for many further substances. In the form of amine salts, aqueous solutions of 2,4-acid show good anti-corrosive behavior in metal cutting.
There are numerous possibilities for synthesi 2 ing 2,4-acid. One possibility (method A) of preparing the com-pound is the carbonylation of 1-(4-isobutylphenyl)-eth-anol with carbon monoxide in the presence of triphenyl-phosphine and, if appropriate, in the presence of a trans-ition metal halide, as is described, for example, in US
Patent Application Serial No. 28,514. With optimized process operation, the resulting reaction mixture, which has to be purified, contains about 85% to 93~ of 2,4-acid.
In addition to 2,4-acid, the reaction mixture also con-tains about 40 organic impurities as well as triphenyl-phosphine and triphenylphosphine oxide. In order to ob-tain a purified 2,4-acid, which can be used as a pharma-ceutical, from this reaction mixture which melts between65C and 70C, the organic impurities on the one hand and the triphenylphosphine and triphenylphosphine oxide on the other hand must be separated off or reduced to an acceptable quantity, and the concentration of triphenyl-phosphine and triphenylphosphine oxide in the purifiedproduct should be less than 10 ppm.
Just the separation of organic by-products from a 2,4-acid reaction mixture without triphenylphosphine and 1 3~7553 triphenylphosphine oxide is already very expensive and requires several process steps, as is evident from Romanian Patent 79,345. Thus, for example, the 2,4-acid must first be converted into a water-soluble salt, for example converted with sodium hydroxide solution into the sodium salt, the latter must be freed of neutral substances by extraction with methylene chloride, the aqueous raffinate solution must be decolorized with carbon, the carboxylic acid must then be liberated with a suitable acid, i.e. hydrochloric acid, and finally recrystallized from water/methanol and dried.
The invention will now be described in relation to the drawings, in which:
Figure 1 is a graph illustrating the susceptibility of 2,4-acid to decomposition in which the particular melting point, the depression of which is a measure of impurities, is plotted as a function of the duration of heating of 2,4-acid;
Figure 2 is a an illustration of a conventional rectification apparatus (still rectification apparatus) which may be used for the purification process according to the invention;
Figure 3 is a gas chromatogram of all the impurities in a 2,4-acid mixture employed in a process according to the invention; and Figure 4 is a gas chromatogram of the main fraction obtained after processing a 2,4-acid mixture using the process according to the invention.
' ,~ ~
In another patent specification (British Patent 971,700), it is described that the 2,4-acid from a reaction mixture is in the pure form only after having been recrystallized 3 times. Even in a more recent, very involved process, such as described in EP-A 17û,147, recrystalli~ation is chosen as the purification method for 2,4-acid.
~he separation problem becomes particularly acute if -such as, for example, in method A described above - tri-phenylphosphine is present in the reaction mixture. As a base, triphenylphosPhine forms, ~ith the 2,4-acid and other acids in the reaction mixture, an adduct, ~hich is stable at room temperature, of the type of the following formula CO
~hich - as our experiments sho~ed - cannot be separated off by extraction or by repeated recrystallization from _ 3 _ 1 337553 -solvents (see comparison example). Other separation pro-cesses, such as adsorption on resins or ion exchangers, also do not fulfil the aim of adequately separating off all the impurities.
In the search for a suitable separation process for puri-fying reaction mixtures for isolating 2,4-acid, it has now been found that this object can be achieved by a vacuum rectification. This is extremely surprising be-cause, until the said object was achieved by the presentinvention, purification of 2,4-acid, which melts at 74.8C, by distillation or rectification was evidently regarded as not feasible. Neither vapor pressure data nor the boiling point of the oily-viscous liquid acid, existing above the melting point of 74.8C, are known from the literature. The relatively high melting point of the acid makes it understandable that the chances for purification were mainly sought in crystallization from various sol-vents and - in the absence of triphenylphosphine - were indeed found as described, for example, in the abovemen-tioned patent specifications. Moreover, due to the in-stability of 2,4-acid at high temperatures, purification by rectification evidently appeared to be a priori not very promising, in particular since other reactive com-ponents such as triphenylphosphine, triphenylphosphineoxide, ketones, styrene derivatives, alcohols and bases, which cause a deep-black discoloration going as far as the formation of tar or resinification of the mixture, can also be present in the crude acid mixture. Not last, it was also to be expected in addition that 2,4-acid forms azeo-tropic mixtures with one or more organic impurities.
Accordingly, the invention relates to a process for puri-fying 2-(4-isobutylphenyl)-propionic acid from mixtures such as are obtained in the preparation of 2-(4-isobutyl-phenyl)-propionic acid, which comprises subjecting the mixtures to a vacuum rectification. The process accord-ing to the invention has the advantage over the processes according to the state of the art that numerous, _ 4 _ 1337553 ~ simultaneosly present impurities, and in particular also triphenylphosphine and triphenylphosphine oxide, can be removed from the 2,4-acid in a single process engineering - unit operation, with virtually no effluent and no waste air arising.
Various types of column can be employed for carrying out the process according to the invention. Columns with a metal gauze packing and columns having a pressure drop compar-able to that of columns with a metal gauze packing are particu-larly suitable for the process according to the invention because, in these columns, the pressure drop arising is small as compared with other columns. In this connection, pressure drop means the difference between the pressure in the bottom region and in the top region of the column.
A small pressure drop causes a small temperature differ-ence between the bottom and top of a column and is neces-sary, because the bottom temperature in the rectification of 2,4-acid should not exceed a certain upper limit, since 2,4-acid decomposes at high temperature. The suscepti-bility of 2,4-acid to decomposition is illustrated by Figure 1, in which the particular melting point - the depression of which is a measure of impurities - is plot-ted as a function of the duration of heating of 2,4-acid.
It can be seen that, even at 250C, the melting point of the particular sample falls already after a short heat-ing period, which is to be ascribed to decomposition of the 2,4-acid. The susceptibility of 2,4-acid to decompo-sition can be further increased by impurities. For this reason, the maximum temperature, at which the process according to the invention can still reasonably be used, depends on the mixture composition. For purification of the reaction mixture arising according to method A, the bottom temperature in the rectification should therefore preferably not be above about 250C, particularly prefer-ably not above about 230C and especially not above 210C, when a conventional rectification apparatus (still rectification apparatus) such as is illustrated, for example, in Figure 2, is used.
_ _ 5 _ 1337553 When modern rectification apparatus is used, such as, for example, of the type equipped with thin-layer evaporators, or falling-film evaporators, very short residence times of the material to be rectified can be achieved, and higher bottom temperatures are thus possible in the case of such rectification apparatus, without major product losses being incurred. When the last mentioned recti-fication apparatus is used, the bottom temperature should preferably not exceed about 28ûC.
The boiling temperature in the bottom and the vapor tem-perature in the region of the top of the column are given by the vapor pressure. For example at a vapor pressure of 10 hPa in the column top and 13 hPa in the bottom, the pure 2,4-acid passes over the top at 178C within a temperature span of 0.1C, whereas in the bottom - due to the higher pressure and the impurities content - the boil-ing temperature varies between 190 and 220C. It is advantageous to keep the vapor pressure in the bottom region at lower than about 60 hPa, so that a boiling tem-perature of 250C in the bottom is not exceeded.
The number of theoretical plates in the separation column can be varied within a wide range. A number of theoret-ical plates between about 10 and 150, particularly prefer-ably between about 25 and 70, is to be preferred.
The rectification devices suitable for the purification process according to the invention can be of different structures. An example of a rectification device on the laboratory scale is shown in Figure 2. The mixture con-taining the 2,4-acid is heated in the still (1) of the column. In place of the still, the device can also con-tain, for example, a thin-layer evaporator or falling-film evaporator. Low-boiling impurities can be distilled off at the top (2) of the column. Below the condenser, which can be, for example, a cooling coil (3) the conden-sate is collected in the liquid divider (4), by means of which the reflux ratio can also be adjusted. The ` - 6 - l 33755~ _ receiver (5~, in which various distillate fractions and the pure product are collected, should advantageously be controlled at a temperature of about 80C, so that the product does not solidify. The vacuum required for the rectification is generated by suitable vacuum pumps (6).
The separation column (7) is packed with a metal gauze packing and produces a separation effect of 25 theoretical separ-ation stages as a maximum.
1û It is advantageous to carry out the rectification under inert gas which, in a preferred distillation device, can be introduced, for example, via a gas leak capillary tube (8) into the bottom of the column. Various inert gases are suitable for this purpose. Nitrogen, argon and carbon dioxide are preferred, and nitrogen is particu-larly preferred. It can also be advantageous to extract the crude 2,4-acid first with water before the rectifi-cation, in order to remove water-soluble impurities such as chlorides, phosphates, metal salts and the like.
2û
In principle, the rectification according to the inven-tion can be carried out by means of one or more columns either discontinuously, that is to say by taking off in-dividual fractions, or continuously. If a continuous one-column distillation is carried out, the column can preferably be set up in such a way that the pure product is taken off as a vapor side stream approximately in the middle region of the column, while the column is prefer-ably operated under total reflux. In continuous recti-fication, both the low-boiling and the high-boiling sub-stances can first be separated off before the 2,4-acid is separated off, if for this purpose the temperature/sta-bility limit critical for the particular reaction mixture is not exceeded.
The process according to the invention is by itself suit-able for processing any possible mixtures containing 2,4-acid. It is of particular importance, however, in the processing of mixtures which are obtained in the _ 7 _ l 337 553 ~ synthesis of 2,4-acid, in particular those reaction mix-tures which are formed in method A described above.
The process according to the invention is suitable for removing all impurities from the crude acid, arising in the production methods according to method A, without prepurification. However, it may also be appropriate to separate off only a part of the impurities by rectifica-tion and to separate off the remaining impurities by one or more purification methods. Crystallization from sol-vents and melt crystallization without auxiliary materials are particularly suitable for this purpose. In particular, it can be appropriate to carry out at least one melt crys-tallization before the rectification. In this case, the crude acid melt is converted by cooling into blocks of crystals, from which the heavily contaminated residual melt is eliminated and the crystals are subjected, after melting, to the rectification according to the invention.
As a result of the said process combinations, the recti-fication according to the invention can be carried outvith a separation column having a smaller number of the-oretical plates. The invention will be explained in more detail by the illustrative examples vhich follow.
Example 1 500 9 of an approximately 90% 2,4-acid mixture of the following composition are employed in a fractional rec-tification apparatus as shown in Figure 2.
_ - 8 ~ 133755~
Table 1 Compound % by weight 2-(4-lsobutylphenyl)-propionic acid 88.77 5 Triphenylphosphine 0.18 Isobutylphenylethane 1.90 4-Isobutylbenzene 0.02 4-Isobutylstyrene 0.15 4-Isobutylacetophenone 0.78 10 1-(4-Isobutylphenyl)-ethanol 0.08 1-(4-Isobutylphenyl)-chloroethane 0.59 Ethyl 2-(4-isobutylphenyl)-propionate 0.05 2-(3-Isobutylphenyl)-propionic acid 1.10 3-(4-Isobutylphenyl)-propionic acid 1.90 15 Light ends of average molecular weight 178 1.80 Heavy ends of average molecular weight 320 1.20 Methyl ethyl ketone 0.48 Remaining unidentified impurities about 1.0 Figure 3 shows a gas chromatogram of all the impurities in the mixture.
The mixture containing the said impurities was fraction-ally distilled in the presence of nitrogen under a pres-sure of 10 hPa and at a bottom temperature from initially 150 to finally 230C with varying reflux ratios. The following distillate fractions were here taken off:
1) 20 9 of light ends as a yellow liquid 2) 158 9 of intermediate fraction with a 2,4-acid content of 94 - 98%
3) 300 9 of main fraction.
22 9 remained as residue in the flask. The main fraction had the following composition:
1 3~7 553 -Compounds % by weight 2-(4-Isobutylphenyl)-propionic acid 99.5 Triphenylphosphine O.OOOOS
Other non-phosphororganic impurities 0.5 Figure 4 shows a gas chromatogram of the main fraction.
Example 2 Using the rectification apparatus described in Example 1, the approximately 90% 2,4-acid mixture described therein was subjected to a two-stage rectification. In this case, in the first distillation pass after the light ends have been separated off, emphasis was placed only on separat-ing off the bottoms, in which the critical triphenylphos-phine impurity concentrates. In a second rectification pass, the main fraction, containing approximately 97% of 2,4-acid, from the first rectification was rectified once more, the bottom temperature being about 200C. In this case, the following fractions were obtained from 942 9 of feed product:
1) 245 9 of intermediate fraction with a 2,4-acid con-tent of up to 98.8%
2) 640 9 of main fraction 3) 57 9 of distillation residue.
The main fraction had the following compostion:
Compounds % by weight 2-(4-lsobutylphenyl)-propionic acid 99.5 Triphenylphosphine 0.00005 Other non-phosphororganic impurities 0.5 Example 3 The approximately 90% 2,4-acid mixture of a composition as in Example 1 was introduced as a melt into a tubular crystallizer, the cooling/heating jacket of which is connected to a thermostat. The melt having a solidification point of 58C was cooled to 40C within 10 hours, compact crystals depositing in the apparatus. The dark-brown liquid fraction remaining in the crystallizer was then drained off, and the light crystals thus obtained S were melted and subjected to the rectification according to the invention. 440 9 of crystals having an acid purity of 98.5% were obtained from 500 9 of 90% feed product.
The 2,4-acid prepurified in this way was then subjected to the rectification according to the invention up to a bottom temperature of 220C. About 370 9 of a main fraction of the following composition were obtained in this case:
15 Compounds % by weight 2-(4-Isobutylphenyl)-propionic acid 99.6 Triphenylphosphine 0.00005 Other non-phosphororganic impurities 0.4 Comparison example 1 20 9 of 2,4-acid, which contained 0.4% of triphenylphos-phine, were dissolved in 50 ml of n-hexane at the reflux temperature of the solvent in a 250 ml glass flask with reflux condenser. The solution was then cooled to room temperature, and the acid which had precipitated was filtered off, washed with 20 ml of cold n-hexane and dried in an exsiccator. Analysis of the recrystallized acid showed that the triphenylphosphine content had remained unchanged. The 2,4-acid thus obtained was then recrys-tallized again for a second, third and fourth time from n-hexane, without it being possible to change the tri-phenylphosphine content.
There are numerous possibilities for synthesi 2 ing 2,4-acid. One possibility (method A) of preparing the com-pound is the carbonylation of 1-(4-isobutylphenyl)-eth-anol with carbon monoxide in the presence of triphenyl-phosphine and, if appropriate, in the presence of a trans-ition metal halide, as is described, for example, in US
Patent Application Serial No. 28,514. With optimized process operation, the resulting reaction mixture, which has to be purified, contains about 85% to 93~ of 2,4-acid.
In addition to 2,4-acid, the reaction mixture also con-tains about 40 organic impurities as well as triphenyl-phosphine and triphenylphosphine oxide. In order to ob-tain a purified 2,4-acid, which can be used as a pharma-ceutical, from this reaction mixture which melts between65C and 70C, the organic impurities on the one hand and the triphenylphosphine and triphenylphosphine oxide on the other hand must be separated off or reduced to an acceptable quantity, and the concentration of triphenyl-phosphine and triphenylphosphine oxide in the purifiedproduct should be less than 10 ppm.
Just the separation of organic by-products from a 2,4-acid reaction mixture without triphenylphosphine and 1 3~7553 triphenylphosphine oxide is already very expensive and requires several process steps, as is evident from Romanian Patent 79,345. Thus, for example, the 2,4-acid must first be converted into a water-soluble salt, for example converted with sodium hydroxide solution into the sodium salt, the latter must be freed of neutral substances by extraction with methylene chloride, the aqueous raffinate solution must be decolorized with carbon, the carboxylic acid must then be liberated with a suitable acid, i.e. hydrochloric acid, and finally recrystallized from water/methanol and dried.
The invention will now be described in relation to the drawings, in which:
Figure 1 is a graph illustrating the susceptibility of 2,4-acid to decomposition in which the particular melting point, the depression of which is a measure of impurities, is plotted as a function of the duration of heating of 2,4-acid;
Figure 2 is a an illustration of a conventional rectification apparatus (still rectification apparatus) which may be used for the purification process according to the invention;
Figure 3 is a gas chromatogram of all the impurities in a 2,4-acid mixture employed in a process according to the invention; and Figure 4 is a gas chromatogram of the main fraction obtained after processing a 2,4-acid mixture using the process according to the invention.
' ,~ ~
In another patent specification (British Patent 971,700), it is described that the 2,4-acid from a reaction mixture is in the pure form only after having been recrystallized 3 times. Even in a more recent, very involved process, such as described in EP-A 17û,147, recrystalli~ation is chosen as the purification method for 2,4-acid.
~he separation problem becomes particularly acute if -such as, for example, in method A described above - tri-phenylphosphine is present in the reaction mixture. As a base, triphenylphosPhine forms, ~ith the 2,4-acid and other acids in the reaction mixture, an adduct, ~hich is stable at room temperature, of the type of the following formula CO
~hich - as our experiments sho~ed - cannot be separated off by extraction or by repeated recrystallization from _ 3 _ 1 337553 -solvents (see comparison example). Other separation pro-cesses, such as adsorption on resins or ion exchangers, also do not fulfil the aim of adequately separating off all the impurities.
In the search for a suitable separation process for puri-fying reaction mixtures for isolating 2,4-acid, it has now been found that this object can be achieved by a vacuum rectification. This is extremely surprising be-cause, until the said object was achieved by the presentinvention, purification of 2,4-acid, which melts at 74.8C, by distillation or rectification was evidently regarded as not feasible. Neither vapor pressure data nor the boiling point of the oily-viscous liquid acid, existing above the melting point of 74.8C, are known from the literature. The relatively high melting point of the acid makes it understandable that the chances for purification were mainly sought in crystallization from various sol-vents and - in the absence of triphenylphosphine - were indeed found as described, for example, in the abovemen-tioned patent specifications. Moreover, due to the in-stability of 2,4-acid at high temperatures, purification by rectification evidently appeared to be a priori not very promising, in particular since other reactive com-ponents such as triphenylphosphine, triphenylphosphineoxide, ketones, styrene derivatives, alcohols and bases, which cause a deep-black discoloration going as far as the formation of tar or resinification of the mixture, can also be present in the crude acid mixture. Not last, it was also to be expected in addition that 2,4-acid forms azeo-tropic mixtures with one or more organic impurities.
Accordingly, the invention relates to a process for puri-fying 2-(4-isobutylphenyl)-propionic acid from mixtures such as are obtained in the preparation of 2-(4-isobutyl-phenyl)-propionic acid, which comprises subjecting the mixtures to a vacuum rectification. The process accord-ing to the invention has the advantage over the processes according to the state of the art that numerous, _ 4 _ 1337553 ~ simultaneosly present impurities, and in particular also triphenylphosphine and triphenylphosphine oxide, can be removed from the 2,4-acid in a single process engineering - unit operation, with virtually no effluent and no waste air arising.
Various types of column can be employed for carrying out the process according to the invention. Columns with a metal gauze packing and columns having a pressure drop compar-able to that of columns with a metal gauze packing are particu-larly suitable for the process according to the invention because, in these columns, the pressure drop arising is small as compared with other columns. In this connection, pressure drop means the difference between the pressure in the bottom region and in the top region of the column.
A small pressure drop causes a small temperature differ-ence between the bottom and top of a column and is neces-sary, because the bottom temperature in the rectification of 2,4-acid should not exceed a certain upper limit, since 2,4-acid decomposes at high temperature. The suscepti-bility of 2,4-acid to decomposition is illustrated by Figure 1, in which the particular melting point - the depression of which is a measure of impurities - is plot-ted as a function of the duration of heating of 2,4-acid.
It can be seen that, even at 250C, the melting point of the particular sample falls already after a short heat-ing period, which is to be ascribed to decomposition of the 2,4-acid. The susceptibility of 2,4-acid to decompo-sition can be further increased by impurities. For this reason, the maximum temperature, at which the process according to the invention can still reasonably be used, depends on the mixture composition. For purification of the reaction mixture arising according to method A, the bottom temperature in the rectification should therefore preferably not be above about 250C, particularly prefer-ably not above about 230C and especially not above 210C, when a conventional rectification apparatus (still rectification apparatus) such as is illustrated, for example, in Figure 2, is used.
_ _ 5 _ 1337553 When modern rectification apparatus is used, such as, for example, of the type equipped with thin-layer evaporators, or falling-film evaporators, very short residence times of the material to be rectified can be achieved, and higher bottom temperatures are thus possible in the case of such rectification apparatus, without major product losses being incurred. When the last mentioned recti-fication apparatus is used, the bottom temperature should preferably not exceed about 28ûC.
The boiling temperature in the bottom and the vapor tem-perature in the region of the top of the column are given by the vapor pressure. For example at a vapor pressure of 10 hPa in the column top and 13 hPa in the bottom, the pure 2,4-acid passes over the top at 178C within a temperature span of 0.1C, whereas in the bottom - due to the higher pressure and the impurities content - the boil-ing temperature varies between 190 and 220C. It is advantageous to keep the vapor pressure in the bottom region at lower than about 60 hPa, so that a boiling tem-perature of 250C in the bottom is not exceeded.
The number of theoretical plates in the separation column can be varied within a wide range. A number of theoret-ical plates between about 10 and 150, particularly prefer-ably between about 25 and 70, is to be preferred.
The rectification devices suitable for the purification process according to the invention can be of different structures. An example of a rectification device on the laboratory scale is shown in Figure 2. The mixture con-taining the 2,4-acid is heated in the still (1) of the column. In place of the still, the device can also con-tain, for example, a thin-layer evaporator or falling-film evaporator. Low-boiling impurities can be distilled off at the top (2) of the column. Below the condenser, which can be, for example, a cooling coil (3) the conden-sate is collected in the liquid divider (4), by means of which the reflux ratio can also be adjusted. The ` - 6 - l 33755~ _ receiver (5~, in which various distillate fractions and the pure product are collected, should advantageously be controlled at a temperature of about 80C, so that the product does not solidify. The vacuum required for the rectification is generated by suitable vacuum pumps (6).
The separation column (7) is packed with a metal gauze packing and produces a separation effect of 25 theoretical separ-ation stages as a maximum.
1û It is advantageous to carry out the rectification under inert gas which, in a preferred distillation device, can be introduced, for example, via a gas leak capillary tube (8) into the bottom of the column. Various inert gases are suitable for this purpose. Nitrogen, argon and carbon dioxide are preferred, and nitrogen is particu-larly preferred. It can also be advantageous to extract the crude 2,4-acid first with water before the rectifi-cation, in order to remove water-soluble impurities such as chlorides, phosphates, metal salts and the like.
2û
In principle, the rectification according to the inven-tion can be carried out by means of one or more columns either discontinuously, that is to say by taking off in-dividual fractions, or continuously. If a continuous one-column distillation is carried out, the column can preferably be set up in such a way that the pure product is taken off as a vapor side stream approximately in the middle region of the column, while the column is prefer-ably operated under total reflux. In continuous recti-fication, both the low-boiling and the high-boiling sub-stances can first be separated off before the 2,4-acid is separated off, if for this purpose the temperature/sta-bility limit critical for the particular reaction mixture is not exceeded.
The process according to the invention is by itself suit-able for processing any possible mixtures containing 2,4-acid. It is of particular importance, however, in the processing of mixtures which are obtained in the _ 7 _ l 337 553 ~ synthesis of 2,4-acid, in particular those reaction mix-tures which are formed in method A described above.
The process according to the invention is suitable for removing all impurities from the crude acid, arising in the production methods according to method A, without prepurification. However, it may also be appropriate to separate off only a part of the impurities by rectifica-tion and to separate off the remaining impurities by one or more purification methods. Crystallization from sol-vents and melt crystallization without auxiliary materials are particularly suitable for this purpose. In particular, it can be appropriate to carry out at least one melt crys-tallization before the rectification. In this case, the crude acid melt is converted by cooling into blocks of crystals, from which the heavily contaminated residual melt is eliminated and the crystals are subjected, after melting, to the rectification according to the invention.
As a result of the said process combinations, the recti-fication according to the invention can be carried outvith a separation column having a smaller number of the-oretical plates. The invention will be explained in more detail by the illustrative examples vhich follow.
Example 1 500 9 of an approximately 90% 2,4-acid mixture of the following composition are employed in a fractional rec-tification apparatus as shown in Figure 2.
_ - 8 ~ 133755~
Table 1 Compound % by weight 2-(4-lsobutylphenyl)-propionic acid 88.77 5 Triphenylphosphine 0.18 Isobutylphenylethane 1.90 4-Isobutylbenzene 0.02 4-Isobutylstyrene 0.15 4-Isobutylacetophenone 0.78 10 1-(4-Isobutylphenyl)-ethanol 0.08 1-(4-Isobutylphenyl)-chloroethane 0.59 Ethyl 2-(4-isobutylphenyl)-propionate 0.05 2-(3-Isobutylphenyl)-propionic acid 1.10 3-(4-Isobutylphenyl)-propionic acid 1.90 15 Light ends of average molecular weight 178 1.80 Heavy ends of average molecular weight 320 1.20 Methyl ethyl ketone 0.48 Remaining unidentified impurities about 1.0 Figure 3 shows a gas chromatogram of all the impurities in the mixture.
The mixture containing the said impurities was fraction-ally distilled in the presence of nitrogen under a pres-sure of 10 hPa and at a bottom temperature from initially 150 to finally 230C with varying reflux ratios. The following distillate fractions were here taken off:
1) 20 9 of light ends as a yellow liquid 2) 158 9 of intermediate fraction with a 2,4-acid content of 94 - 98%
3) 300 9 of main fraction.
22 9 remained as residue in the flask. The main fraction had the following composition:
1 3~7 553 -Compounds % by weight 2-(4-Isobutylphenyl)-propionic acid 99.5 Triphenylphosphine O.OOOOS
Other non-phosphororganic impurities 0.5 Figure 4 shows a gas chromatogram of the main fraction.
Example 2 Using the rectification apparatus described in Example 1, the approximately 90% 2,4-acid mixture described therein was subjected to a two-stage rectification. In this case, in the first distillation pass after the light ends have been separated off, emphasis was placed only on separat-ing off the bottoms, in which the critical triphenylphos-phine impurity concentrates. In a second rectification pass, the main fraction, containing approximately 97% of 2,4-acid, from the first rectification was rectified once more, the bottom temperature being about 200C. In this case, the following fractions were obtained from 942 9 of feed product:
1) 245 9 of intermediate fraction with a 2,4-acid con-tent of up to 98.8%
2) 640 9 of main fraction 3) 57 9 of distillation residue.
The main fraction had the following compostion:
Compounds % by weight 2-(4-lsobutylphenyl)-propionic acid 99.5 Triphenylphosphine 0.00005 Other non-phosphororganic impurities 0.5 Example 3 The approximately 90% 2,4-acid mixture of a composition as in Example 1 was introduced as a melt into a tubular crystallizer, the cooling/heating jacket of which is connected to a thermostat. The melt having a solidification point of 58C was cooled to 40C within 10 hours, compact crystals depositing in the apparatus. The dark-brown liquid fraction remaining in the crystallizer was then drained off, and the light crystals thus obtained S were melted and subjected to the rectification according to the invention. 440 9 of crystals having an acid purity of 98.5% were obtained from 500 9 of 90% feed product.
The 2,4-acid prepurified in this way was then subjected to the rectification according to the invention up to a bottom temperature of 220C. About 370 9 of a main fraction of the following composition were obtained in this case:
15 Compounds % by weight 2-(4-Isobutylphenyl)-propionic acid 99.6 Triphenylphosphine 0.00005 Other non-phosphororganic impurities 0.4 Comparison example 1 20 9 of 2,4-acid, which contained 0.4% of triphenylphos-phine, were dissolved in 50 ml of n-hexane at the reflux temperature of the solvent in a 250 ml glass flask with reflux condenser. The solution was then cooled to room temperature, and the acid which had precipitated was filtered off, washed with 20 ml of cold n-hexane and dried in an exsiccator. Analysis of the recrystallized acid showed that the triphenylphosphine content had remained unchanged. The 2,4-acid thus obtained was then recrys-tallized again for a second, third and fourth time from n-hexane, without it being possible to change the tri-phenylphosphine content.
Claims (11)
1. A process for purifying 2-(4-isobutylphenyl)-propionic acid from a mixture obtained in the carbonylation of 1-(4-isobutylphenyl)-ethanol with carbon monoxide in the presence of triphenylphosphine, which comprises subjecting the mixtures to a vacuum rectification using a rectification apparatus fitted with a thin-layer evaporator or falling-film evaporator at bottom temperatures below about 280°C
2. The process as claimed in claim 1, wherein the rectification is carried out by means of columns provided with metal gauze packing, or columns having a comparably small pressure drop.
3. The process as claimed in claim 1, wherein the rectification is carried out using a still rectification apparatus at bottom temperatures below about 250°C.
4. The process as claimed in any one of claims 1 to 3, wherein the number of theoretical plates in the separation column is between about 10 and 150.
5. The process as claimed in any one of claims 1 to 3, wherein the rectification is carried out in the presence of an inert gas.
6. The process as claimed in any one of claims 1 to 3, wherein the rectification is carried out discontinuously, using one or more columns.
7. The process as claimed in any one of claims 1 to 3, wherein the rectification is carried out continuously, using one or more columns.
8. The process as claimed in any one of claims 1 to 3, wherein the 2-(4-isobutylphenyl)-propionic acid is isolated from a mixture obtained in the carbonylation of 1-(4-isobutylphenl)-ethanol with carbon monoxide in the presence of triphenylphosphine and in the presence of a transition metal halide.
9. A process as claimed in any one of claims 1 to 3, wherein the 2-(4-isobutylphenyl)-propionic acid is freed of all impurities by the rectification.
10. The process as claimed in any one of claims 1 to 3, wherein a mixture is used for rectification, from which a part of the impurities has been removed beforehand by at least one melt crystallization.
11. The process as claimed in any one of claims 1 to 3, wherein only a part of the impurities is separated off by rectification and, for separating off the remaining impurities, a crystallization from solvents and/or a melt crystallization are carried out.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE3802619A DE3802619C1 (en) | 1988-01-29 | 1988-01-29 | |
| DEP3802619.8 | 1988-01-29 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1337553C true CA1337553C (en) | 1995-11-14 |
Family
ID=6346221
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000589392A Expired - Fee Related CA1337553C (en) | 1988-01-29 | 1989-01-27 | Process for purifying 2-(4-isobutylphenyl)-propionic acid |
Country Status (22)
| Country | Link |
|---|---|
| EP (1) | EP0326027B1 (en) |
| JP (1) | JP2688515B2 (en) |
| KR (1) | KR0129753B1 (en) |
| CN (1) | CN1025609C (en) |
| AR (1) | AR244196A1 (en) |
| AT (1) | ATE83766T1 (en) |
| AU (1) | AU607837B2 (en) |
| CA (1) | CA1337553C (en) |
| DD (1) | DD278778A5 (en) |
| DE (2) | DE3802619C1 (en) |
| DK (1) | DK175685B1 (en) |
| ES (1) | ES2042811T3 (en) |
| FI (1) | FI90656C (en) |
| GR (1) | GR3007235T3 (en) |
| HU (1) | HU202172B (en) |
| IE (1) | IE63324B1 (en) |
| IL (1) | IL89094A (en) |
| NO (1) | NO169118C (en) |
| NZ (1) | NZ227756A (en) |
| PT (1) | PT89535B (en) |
| RU (1) | RU1819257C (en) |
| ZA (1) | ZA89619B (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3833448A1 (en) * | 1988-10-01 | 1990-04-12 | Hoechst Ag | METHOD OF OBTAINING IBUPROFEN FOR DIRECT TESTING |
| DE3833446A1 (en) * | 1988-10-01 | 1990-04-05 | Hoechst Ag | METHOD FOR THE PRODUCTION OF MEDICAMENT PARTICLES WITH IMPROVED FLUID, STORAGE AND FORMULATION PROPERTIES AND MEDICAMENTS CONTAINING SUCH MEDICAMENT PARTICLES |
| US5151551A (en) * | 1990-09-06 | 1992-09-29 | Hoechst Celanese Corporation | Method for purification of ibuprofen comprising mixtures |
| GB0519350D0 (en) | 2005-09-22 | 2005-11-02 | Boots Healthcare Int Ltd | Therapeutic agents |
| CN204505103U (en) * | 2015-04-14 | 2015-07-29 | 杭州巨星科技股份有限公司 | Worm gear clamping anti-loose structure and locking adjustable wrench |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB971700A (en) * | 1961-02-02 | 1964-09-30 | Boots Pure Drug Co Ltd | Anti-Inflammatory Agents |
| US3344045A (en) * | 1964-10-23 | 1967-09-26 | Sun Oil Co | Electrolytic preparation of carboxylic acids |
| HU173576B (en) * | 1975-06-24 | 1979-06-28 | Chinoin Gyogyszer Es Vegyeszet | Process for preparing substituted phenyl-alkyl-carboxylic acids |
| DE2557011A1 (en) * | 1975-12-18 | 1977-06-23 | Dynamit Nobel Ag | PROCESS FOR THE PRODUCTION OF ALPHA-ARYL-SUBSTITUTED PROPIONIC ACID ALKYLESTERS |
| US4694100A (en) * | 1984-07-14 | 1987-09-15 | Nippon Petrochemicals Company, Ltd. | Method for producing α-(p-isobutylphenyl)propionic acid or its alkyl esters |
-
1988
- 1988-01-29 DE DE3802619A patent/DE3802619C1/de not_active Expired
-
1989
- 1989-01-20 DE DE8989100912T patent/DE58903057D1/en not_active Expired - Fee Related
- 1989-01-20 EP EP89100912A patent/EP0326027B1/en not_active Expired - Lifetime
- 1989-01-20 AT AT89100912T patent/ATE83766T1/en not_active IP Right Cessation
- 1989-01-20 ES ES89100912T patent/ES2042811T3/en not_active Expired - Lifetime
- 1989-01-26 AR AR89313081A patent/AR244196A1/en active
- 1989-01-26 FI FI890386A patent/FI90656C/en active IP Right Grant
- 1989-01-26 ZA ZA89619A patent/ZA89619B/en unknown
- 1989-01-26 PT PT89535A patent/PT89535B/en active IP Right Grant
- 1989-01-27 IL IL89094A patent/IL89094A/en not_active IP Right Cessation
- 1989-01-27 DD DD89325298A patent/DD278778A5/en unknown
- 1989-01-27 NZ NZ227756A patent/NZ227756A/en unknown
- 1989-01-27 CA CA000589392A patent/CA1337553C/en not_active Expired - Fee Related
- 1989-01-27 IE IE26889A patent/IE63324B1/en not_active IP Right Cessation
- 1989-01-27 AU AU28857/89A patent/AU607837B2/en not_active Ceased
- 1989-01-27 JP JP1016525A patent/JP2688515B2/en not_active Expired - Fee Related
- 1989-01-27 NO NO890344A patent/NO169118C/en unknown
- 1989-01-27 HU HU89418A patent/HU202172B/en not_active IP Right Cessation
- 1989-01-27 KR KR1019890000868A patent/KR0129753B1/en not_active IP Right Cessation
- 1989-01-27 CN CN89101467A patent/CN1025609C/en not_active Expired - Fee Related
- 1989-01-27 DK DK198900376A patent/DK175685B1/en not_active IP Right Cessation
- 1989-01-28 RU SU894613357A patent/RU1819257C/en not_active IP Right Cessation
-
1993
- 1993-03-05 GR GR930400198T patent/GR3007235T3/el unknown
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