SE523623C2 - Recycling method for hydrophobic nitroxyl radicals - Google Patents

Abstract

The present invention relates to a method for obtaining a catalytically active mixture based on stable nitroxyl radicals. The invention is characterized in that the stable nitroxyl radicals are hydrophobic and are selectively separated from a reaction mixture by means of hydrophobic interactions.

Description

25 30 a | ø. s »523 623 A problem in connection with the method described in WO 96/36621 is that it i.e. the stable nitroxyl radicals which have a sufficient vapor pressure at room temperature, such as can only be applied to volatile nitroxyl compounds, for example TEMPO. Thus, there is a need for a method for use in recovering the stable nitroxyl radicals, which method is independent of the vapor pressure of the stable nitroxyl radicals.

Another problem with the method according to WO 96/36621 is that about 20% of the reaction volume, mainly water, needs to be distilled off in order to achieve complete recovery of the stable nitroxyl radicals, which gives high energy costs.

Document WO 95/07303 describes that ditertiary alkylnitroxyl can be recovered by extraction.

In order to reduce production costs, there is thus a need for a method for recycling stable nitroxyl radicals, where the recycling can be achieved with smaller volumes and where less energy is required.

In addition, there is a need for a method that can be practiced at ambient pressure, regardless of the performance of the stable nitroxyl radicals.

DESCRIPTION OF THE INVENTION: In accordance with the present invention, there is provided a method for recovering stable nitroxyl radicals, which method eliminates the above problems.

A method of the kind indicated in the introduction, and designed according to the present invention, is characterized in that the stable nitroxyl radicals are hydrophobic and are separated from a reaction mixture by means of hydrophobic interactions. In accordance with one embodiment of the method of the present invention, the reaction mixture consists of a surface solution.

In one embodiment of the present invention, the hydrophobic hydrophobic nitroxyl radicals are selectively adsorbed on a solid adsorbent having hydrophobicity, the adsorbent consisting of a highly porous synthetic male selected from the group XAD-2, XAD-4, XAD-8, XAD-11, XAD-11, XAD-11, XAD-11 16, XAD-30, XAD-1180 and mixtures thereof. These Amberlite ® XAD resins are available from Sigma, USA and Supelco, Bellefonte, PA, USA. The interaction is an adsorption reaction in which the stable In another embodiment of the invention, silica gel (Kieselgel 60, Merck, Darmstadt, Germany) is used as a solid adsorbent on which the stable hydrophobic nitroxyl radicals are selectively adsorbed.

The contacting of the reaction mixture with an adsorbent can be carried out batchwise, or using a column. The recovery is preferably carried out in accordance with a chromatographic process by using a column. By filling the column with a very porous adsorbent mentioned kind) and then allowing (for example of the above reaction mixture to pass downwards through the column, the adsorbent selectively adsorbs the stable hydrophobic nitroxyl radical, while other mixing components are eliminated as effective.

Said stable hydrophobic nitroxyl radical is eluted and desorbed from the column by contacting the adsorbent with a solvent, which solvent contains water, an organic solvent, or a mixture thereof. Said organic solvents may include ethyl alcohol, (THF). Other organics, preferably miscible with water, can also be used 1-pentanol, acetone, or tetrahydrofuran solvent. 10 15 20 25 30 523 623 u | a. ~ ø I. -. ~ o Q Q s.

If the reaction mixture is contacted with the adsorbent batchwise, the adsorbent and the reaction mixture are mixed by shaking or stirring by hand, after which the resulting mixture is filtered. The stable hydrophobic nitroxyl radical is recovered from the filtrate by the addition of an organic solvent which may contain ethyl alcohol, 1-pentanol, acetone, or THF.

Other organic solvents, preferably miscible with water, may also be used.

The nitroxyl radical can be recovered from the organic solvent by evaporation, whereby the nitroxyl radical is found in the dry matter. It is preferred that said solvent exhibits high vapor pressure at room temperature. A solvent that exhibits high vapor pressure and low evaporation heat in comparison with water, keeps down energy consumption and thus also keeps down energy costs. Most of the above solvents exhibit these properties.

Thus, in this embodiment, 1-pentanol can be used as the solvent, but is less preferred as it has a high boiling point (130 ° C). In another embodiment of the invention, where the solution containing the stable hydrophobic nitroxyl radical and the 1-pentanol is not subjected to evaporation, but forms part of the catalytically active mixture, the 1-pentanol being oxidized to the corresponding acid and thus becoming soluble in the reaction mixture, however, 1-pentanol is a suitable solvent.

This means that 1-pentanol is not enriched using a continuous process for the recovery and recycling of stable hydrophobic nitroxyl radicals and where the process involves selective oxidation of primary alcohols.

However, a more preferred embodiment of the invention is, when using 1-pentanol as the solvent, to use 1-pentanol as the combined solvent, together with, for example, ethanol since 1-pentanol has limited solubility in water. After removal of ethanol, the residue, consisting of 1-pentanol and the stable hydrophobic, can be removed. . o a no o 523 623 o. n. Q a u n ø. . . . . . . the nitroxyl radical, is treated as indicated above, i.e. included as part of the catalytically active mixture. In accordance with one embodiment of the invention, the hydrophobic interaction takes place in a precipitation step, whereby β-cyclodextrin dissolved in water selectively forms complexes with the stable hydrophobic nitroxyl radicals. Preferably, a concentrated β-cyclodextrin solution is used to obtain near quantitative recovery of the stable hydrophobic nitroxyl radicals. It is also possible to use an immobilized form of β-cyclodextrin, which forms a special type of resin, comparable to the XAD resins.

The precipitate is dissolved in a solvent, after which the stable hydrophobic nitroxyl radical is selectively transferred to the solvent, said solvent comprising water, an organic solvent, or a mixture thereof. Said organic solvents may comprise ethyl alcohol, preferably acetone, or THF. Other organic solvents, miscible with water can also be used.

The stable hydrophobic nitroxyl radical can be recovered from the solvent by evaporation, whereby the stable hydrophobic nitroxyl radical is recovered in the residue. It is thus preferred that said solvent has a high vapor pressure and a low heat of evaporation. In accordance with another embodiment of the invention, the hydrophobic interaction takes place in a liquid-liquid extraction step, whereby an organic solvent is added to the reaction mixture, and the stable hydrophobic nitroxyl radicals are selectively extracted into the organic solvent.

Suitable solvents for use in the extraction step are higher primary alcohols, i.e. alcohols with G6, or higher, such as, for example, 1-octanol. 10 15 20 25 30 Q n -. nu 523 623 n s o. u o a - -. -. -. The organic phase, comprising the stable hydrophobic nitroxyl radicals and the solvent, is recovered by physical means, in a known manner, after which it will form part of the catalytically active mixture, where the water-immiscible solvent is oxidized to the corresponding acid and thus become alkaline conditions. the solvent is not enriched using a continuous process for soluble during This involves the recovery and recycling of stable hydrophobic nitroxyl radicals, and where the process involves selective oxidation of primary alcohols. An advantage of this embodiment is thus that the stable hydrophobic nitroxyl radicals back from that solvent, as is usual with conventional solvent extraction, do not have to be stripped, i.e. organic is extracted which is then usually followed by a product recovery step. It is also not necessary to evaporate or distill the organic phase to recover the stable hydrophobic nitroxyl radicals from the organic phase.

In one embodiment of the invention, the stable hydrophobic nitroxyl radical comprises TEMPO. TEMPO and its derivatives in themselves show a brown / red color, but dissolved in an aqueous solution, the solution turns yellow. However, at other times, such as when TEMPO, and / or its derivatives are concentrated on a column, or form complexes with cyclodextrin, the presence of TEMPO is indicated by a pink color.

In another embodiment of the invention, the reaction mixture forms an aqueous solution or an aqueous suspension.

EMBODIMENTS OF THE INVENTION: The method of the present invention is a method of obtaining a catalytically active mixture based on stable nitroxyl radicals by contacting a reaction mixture containing the stable nitroxyl radicals with a solid phase, or having a hydrophobic phase.

Hydrophobicity can be found, for example, in several organic solvents, resins and other adsorbents, as well as cyclodextrins. It has thus been found 10 15 20 25 523 623 ø ~ o ». Q - ~ -. . . . . . . that TEMPO, analogs and / or derivatives thereof having a hydrophobic character, can be extracted from the reaction mixture by hydrophobic interactions. Such hydrophobic interactions can be used in a solid phase extraction process, i.e. adsorption on a solid in a process where complex formation with cyclodextrins is used, or in a process where a liquid-liquid extraction step is used.

The invention will be illustrated in the following in and through some non-limiting examples. In Examples 5, 6, 7, 8, 10, 11 and 12, the absorbance was measured with a Pharmacia Biotech spectrometer (Ultraspec 400), using 1 cm of polyacrylate cuvettes at λ = 425 nm.

Example gel 1 1 gram of an XAD-4 resin was suspended in a few ml of water and then transferred to a column. 2 ml of a TEMPO solution with a concentration of 5 mg / ml and then pass through the column. After passing these 2 ml of the TEMPO solution, the column turned slightly pink and the effluent turned yellow. This indicates that the capacity of the XAD-4 resin is 10 mg TEMPO / g.

Example 2 1 gram of an XAD-16 hans was suspended in a few ml of water and then transferred to a column. 2 ml of a solution of 4-acetamido-TEMPO solution with a concentration of 5 mg / ml was then passed through the column.

After passing these 2 ml of the 4-acetamido-TEMPO solution, the column turned slightly pink and the effluent turned yellow. This indicates that the capacity of the XAD-16 resin is 10 mg of 4-acetamido-TEMP01g. The same result was obtained when an XAD-4 resin was used instead of the XAD-16 resin. 10 15 20 25 - Q n. nu 523 623 Q. -. . n n - Q ..

Example gel 3 A solution of TEMPO (5 mg / ml) was passed through a column of 2 grams of silica gel (Silica gel 60, Merck) suspended in water. After 6 ml passed through the column, the effluent turned yellow. TEMPO was then eluted with acetone.

An amount of 3 ml of acetone was required for the elution, after which the column was completely decolorized.

Example 4 5 g of potato starch (4.2 g in dry form) were gelatinized in 100 ml of water by heating the solution to 90 ° C. The solution was cooled to room temperature and then 200 mg of 4-acetamido-TEMPO was added. After dissolving this compound, 50 ml of 2M sodium hypochlorite was added to the mixture. To avoid an excessive pH change, the sodium hypochlorite was added in amounts of 2 ml per occasion. During the reaction, the pH was checked using a pH state and by the addition of 0.5 M sodium hydroxide (NaOH). The pH was kept in the range from 8.5 to 9.5. The consumption of NaOH was 55 ml.

The reaction mixture was concentrated to 100 ml and then applied to a column packed with 30 g of silica gel (Kieselgel 60, Merck). The adsorption of the TEMPO derivative on the silica gel was observed as a yellow zone, which moved slowly downwards. The column was eluted with water. The 6-carboxy starch was collected in the first 150 ml of water and after passing more water (160 ml), 4-acetamido-TEMPO began to elute. In this fraction no 6-carboxy starch could be detected, with colorimetric uronic acid assay according to Blumenkrantz and Abdoe-Hansen, Anal. Biochem. 54, 484-489 (1973). When the recovered 4-acetamido-TEMPOn was used to produce 6-carboxy starch as described above, essentially the same results were obtained as for the starting material. Example 5 To 1 g of XAD-1180 resin was added 2 ml of a solution of TEMPO (5 mg / ml).

The mixture was then stirred, resulting in a decolorization of the liquid phase and coloration of the solid phase (pink). The process took less than a minute. The resulting mixture gave an absorbance of 0.008 at 7h = 425 nm. The absorbance of the TEMPO solution before mixing was 0.40 at 425 nm. After standing for about 15 minutes, the mixture was filtered.

Acetone was then added to the filtrate, whereby the solution turned yellow and the solid phase turned white. TEMPO was thus transferred to the solution.

Example 6 The experiment performed in Example 5 was repeated with the same amounts of TEMPO but using an XAD-6 resin instead of the XAD-1180 resin. The resulting solution gave an absorbance of 0.008 (at k = 425 nm). The XAD-16 resin thus has approximately the same capacity as the XAD-1 180 resin.

Example 7 1.0 g of β-cyclodextrin was dissolved in 100 ml of water. To 10 ml of this solution was added 1 ml of a solution of TEMPO (5 mg / ml). The mixture was allowed to stand, forming a pink precipitate and the solution becoming colorless. The precipitation is a result of the complexation reaction between TEMPO and ß-cyclodextrin. The precipitate formed is very dense, so the liquid can be decanted from the solid phase without appreciable loss of solid phase.

Two additional experiments (Experiment 2 and Experiment 3) were performed, where larger amounts of TEMPO were added to 15 mg, respectively, corresponding to 2 ml and 3 ml of the TEMPO solution, respectively. The β-cyclodextrin solution, 10 mg The experiments were performed in the same manner as described in connection with Experiment 1. 10 15 20 ouo ø o. n- 523 623 v the complexing reaction between TEMPO and β-cyclodextrin (A0) and after the reaction is complete (A1). The absorbances were measured at k = 425 nm and the results are summarized in Table 1.

Table 1. Complex formation for TEMPO with ß-cyclodextrin.

Experiment Amount of TEMPO (mg) precipitate A0 A1 1 5 yes 0.050 0.004 2 10 yes 0.095 0.006 3 15 yes 0.140 0.028 l The experiments (1-3) started the precipitation after about 2-5 minutes and were practically complete after a few hours.

Based on the assumption that 1 mole of ß-cyclodextrin complexes 1 mole of TEMPO, it is given that 1134 mg of ß-cyclodextrin complexes 156 mg of TEMPO, and that 1 g of ß-cyclodextrin can thus complex 138 mg of TEMPO.

As can be seen from experiments 1 and 2 in Tab. 1, formed a significant amount (more than 90%) of TEMPO complex with β-cyclodextrin and precipitated. In Experiment 3, 80% of TEMPO precipitated. consistent with the above assumption that only 13.8 mg of the TEMPOn in This is however in Experiment 3 can theoretically form complexes with β-cyclodextrin. 523 623 11 Example gel 8 The experiments of Example 7 were repeated, but with a more dilute β-cyclodextrin solution with a concentration of 100 mg of β-cyclodextrin in 30 ml of water. The precipitation reactions in Example 8 did not start until hours after the solutions were mixed and were complete after standing for three days, at which time the absorbances (A1) were measured. The absorbances were measured at = 425 nm and the results can be seen in Tab. 2.

Ur Tab. 2 it can be seen that the results are similar to those obtained in Example 7.

However, it can be seen that recovery of TEMPO is less efficient for dilute ß-cyclodextrin solutions compared to the more concentrated ß-cyclodextrin solutions used in Example 7. This is because ß-cyclodextrin complexes have some solubility in water. It should also be borne in mind that relatively large errors are associated with measurements performed on diluted systems.

The reason for the high absorbance in experiment 3 is the excess of TEMPO in relation to the available amount of β-cyclodextrin in the solution (cf. experiment 3 in Example 7).

Table 2. Complex formation of TEMPO with ß-cyclodextrin.

Experiment Amount of TEMPO (mg) precipitate A0 A1 1 5 yes 0.017 0.003 2 10 yes 0.031 0.004 3 15 yes 0.050 0.020 Example gel 9 A reaction mixture was prepared from 2 grams of oxidized starch, 100 mg of sodium bromide, NaBr, and 50 mg of TEMPO, dissolved in 100 ml water. 2 ml 1- The resulting mixture of octanol was added to the reaction mixture. was then stirred for a few minutes and then left to separate into two phases: a lower layer consisting of the decolorized aqueous phase and an upper layer consisting of the organic phase, colored dark pink. The pink color of the organic phase and the decolorization of the aqueous phase indicate that TEMPO has been transferred to the organic phase. The organic phase was added to a solution consisting of 2 grams of gelatinized starch and 100 mg of NaBr. carboxy starch with sodium hypochlorite in the same manner as described in Example 4 since TEMPO is transferred to the Oxidation also results in the formation of octanoic acid. This is an advantage, the starch could thus actually be oxidized to 6 - the aqueous phase. since the 1-octanol solvent used in the extraction step is thus removed as octanate (sodium salt) in the work-up of the reaction mixture. Thus, recovery of stable hydrophobic liquid-liquid extraction does not require removal of nitroxyl radicals by the solvent by evaporation or distillation, or a stripping step followed by product recovery, as is usual in conventional solvent extraction.

Example 10 4 ml of a solution containing 40 mg of 4-acetamido-TEMPO was added to 2.0 grams of XAD-1180 resin. After stirring for a few minutes, a colorless solution and a pink solid phase were obtained. Spectroscopy determined that at least 95% of the TEMPO derivative was adsorbed on the XAD-1180 resin. However, the spectrum obtained differed significantly from the spectrum of 4-acetamido-TEMPO, an indication that an impurity was present. It can thus be assumed that the adsorption is higher than that measured. Example 5 11 2 ml of a solution containing 20 mg of 4-acetoxy-TEMPO was added to 1.0 gram of XAD-16 resin. The mixture was shaken by hand and in less than one minute the adsorbent spectroscopic measurements showed that at least 95% of the TEMPO derivative had been adsorbed on the XAD-16 resin. the solution was decolorized and turned pink.

Example Gel 12 Example 11 was repeated with the same resin, XAD-16, but with TEMPO-4-hydroxy-TEMPO 4-acetoxy-TEMPO.

Spectroscopic measurements showed that at least 95% of the TEMPO derivative 4-hydroxy-TEMPO had been adsorbed on the XAD-16 resin. the derivative instead of the description above has been referred to as TEMPO and the TEMPO derivatives 4-acetamido-TEMPO, 4-acetoxy-TEMPO and 4-hydroxy-TEMPO, but it is to be understood that other suitable stable hydrophobic nitroxyl radicals, i.e. Organic nitroxyl compounds without α-hydrogen atoms, such as 2,2,5,5-tetramethylpyrrolidine-N-oxyl (PROXYL), and derivatives thereof and those described in WO 95/07303 can replace TEMPO, 4-acelamido-TEMPO, 4-acetoxy -TEMPO and 4-hydroxy- TEMPO.

It is further understood that several other organic solvents, resins and cyclodextrins in addition to those described in this application may be used for the recovery of stable hydrophobic nitroxyl radicals.

Claims (16)

10 15 20 25 30 523 623 _. _. . ; - .n 111763 JBN 2002-05-16 / li PATENTKRAVI A method for obtaining a catalytically active mixture based on stable nitroxyl radicals, wherein the stable nitroxyl radicals are hydrophobic and selectively separated from a reaction mixture by hydrophobic interactions, characterized in that the hydrophobic interaction is an adsorption reaction, wherein the stable radicals are on a solid adsorbent exhibiting hydrophobicity. A method according to claim 1, wherein the reaction mixture consists of a liquid solution. A method according to claim 2, wherein the adsorbent consists of a hydrophobic synthetic resin. A method according to claim 3, wherein the hydrophobic synthetic resin is selected from the group of XAD-2, XAD-4, XAD-8, XAD-1 1, XAD-16, XAD-30, XAD-1180. A method according to claim 1, wherein said stable hydrophobic nitroxyl radical is eluted with a solvent, said solvent comprising water, an organic solvent, or a mixture thereof. A method according to claim 5, wherein said organic solvent comprises ethyl alcohol, acetone or THF, or a mixture of two or more of said solvents. A method according to claim 5 or 6, wherein said organic solvent is miscible with water. A method according to claim 7, wherein said organic solvent has a vapor pressure which is high in comparison with the vapor pressure of water. 10 15 20 25,,> Q nu .-. . _ '. -. -o 523 623 .n,. Q. .n IS A method according to claim 5, wherein the organic solvent comprises 1-pentanol. A method for obtaining a catalytically active mixture based on stable nitroxyl radicals, wherein the stable nitroxyl radicals are hydrophobic and selectively separated from a reaction mixture by hydrophobic interactions, characterized in that the hydrophobic interaction takes place in a precipitation step, wherein the precipitation is with the stable hydrophobic nitroxyl radicals. A method according to claim 10, wherein the reaction mixture consists of a liquid solution. A method according to claim 10 or 11, wherein the precipitate is obtained by selectively forming with the stable hydrophobic nitroxyl radicals. cyclodextrin complex A method according to any one of the preceding claims, wherein the method is used in a continuous process for recycling stable hydrophobic nitroxyl radicals. A method according to claim 13, wherein the process comprises selective oxidation of primary alcohols. A method according to any one of the preceding claims, wherein the stable hydrophobic nitroxyl radical is TEMPO. A method according to any one of the preceding claims, wherein the reaction mixture is an aqueous solution or an aqueous suspension.