MXPA97010231A - Procedure for the obtaining of 2-hydroxy-4-methyltiobutirico acid (mha) stable during the storage - Google Patents

Abstract

The invention relates to a process for the preparation of 2-hydroxy-4-methylthiobutyric acid (= hydroxy analogue of methionine, MHA) stable during storage in primary free form by distillation of a solution of a product containing MHA and obtaining from a distillate of this type of mixtures of products containing MHA with improved stabilities during storage. The distillate can be obtained either directly from the raw MHA products, which eventually still contain solvent or water, by means of a MHA preparation process either from a commercial product of M

Description

Process for obtaining stable 2-hydroxy-4-methylthiobutyric acid (MHA) during storage DESCRIPTION OF THE INVENTION The invention relates to a process for the preparation of 2-hydroxy-4-methylthiobutyric acid (= hydroxy analogue of methionine) , MHA) stable during storage in primary free form by distillation of a solution of a product containing MHA and obtaining from a distillate of this type of mixtures of products containing MHA with improved stabilities during storage. The distillate can be obtained either directly from the raw MHA products, which eventually still contain solvent or water, by means of an MHA preparation process either or from a commercial product of MHA.

MHA is the hydroxy analogue of the essential amino acid methionine in racemic form and, like it, is an important addition of animal feed, especially from poultry farms but also in many other areas. Also in the last time also has pharmaceutical application in the form of its calcium salt for the treatment of renal failure as a replacement for dialysis treatment or as a complement to it, as indicated by ex. in the published German patent application document for information DE-OS 2531299.

In animal feed, MHA is generally applied in the form of an aqueous concentrate, where it contains, together with the monomers, a certain number of oligomers, first and foremost the acids of di- and trimeric linear esters. The content of these oligomers depends on the preparation conditions and also on the chosen concentration. However, due to their lower degree of nutritional action compared to the monomeric MHA and the negative influence REF: 26239 on the properties of flowability due to the increase in viscosity it is especially desirable to keep their percentage proportion low. The commercial formulations have a total concentration ranging from 88-90% by weight to 24% by weight, which is equivalent to approx. 27 mol%, in the sum of oligomers, equivalent to a monomer / oligomer ratio of approx. 3: 1 n = 0 = MHA monomer n = 1 = MHA dimer n = 2 - 10 oiigomer of MHA The synthesis route technically used exclusively belongs to methylmercaptopropionaldehyde (MMP), which is converted by adding HCN to the corresponding cyanohydrin (MMP-CH), which is then catalyzed with sulfuric acid to hydrolyze to obtain the hydroxy acid. From the MHA hydrolyzate, which also still contains corresponding parts of water or sulfate / ammonium acid sulfate, there are different isolation processes for the MHA material, which are described in summary form in the published German patent application for DE information. -OS 19524054 or in the German patent document DE-PS 4428608.

The processes are based either on a solvent extraction either in precipitation stages or in a combination of both to separate the MHA from the salt that was formed simultaneously. In each of these processes the corresponding solutions containing MHA are concentrated by evaporation. During this process it should be taken into account that a part of up to 27% in mol of the dimer and oligomer of MHA is formed.

Only with the careful method described in the published German patent application for DE-OS 19524054 evaporation of an organic extraction solution of MHA is it possible to keep the proportions of unwanted oligomers low or to prepare a highly concentrated product of practically free MHA of water with a primarily low proportion of oligomers below 10 mol%. However, it increases after storage for several months until it reaches a value of more than 50 mol%.

A decrease in oligomer contents at equilibrium to a maximum of 20 mol% is achieved there by dilution with water and additional mixture of methionine or ammonia, which transfers the corresponding proportion of MHA's to the ammonium salt of MHA. Therefore, it is still desirable to achieve a further reduction of the still present part of less active oligomers from the nutritional point of view in a technical MHA product. The products that can be prepared according to the published German patent application for DE-OS 19524054 as well as the commercial products available so far have an intensive brown color with iodine color figures of 24 to 300, which are due to the proportion of oligomers or also to impurities that are not known in detail. Therefore, until now, a colorless product could not be prepared technically, although this should be considered desirable in the sense of a stable improvement in the quality of the product.

A disadvantage of the distillation of the raw merchandise which is itself the closest purification process is the high boiling point of the MHA of approx. 170 ° C to 3 hPa and its marked tendency to the autocatalytic formation of oligomers. As expected, tests on a vacuum distillation apparatus led to a low yield of approx. 0.2% of the MHA theory distilled due to the formation of oligomeric and polymeric MHA products. The main part remained as a thick dark brown material in the residual part of the distillation (see also comparative example 3).

Taking into account the documented state of the art, it is the task of the invention to provide a process that can be carried out on a large scale for the preparation of 2-hydroxy-4-methyl-thiobutyric acid (MHA) leading to a decrease in the proportion of dimers and oligomers and an improvement in color and stability during storage.

If 2-hydroxy-4-methyl-thiobutyric acid (MHA) is characterized which possesses these improved properties by means of the general property of stability during storage, then such a product is obtained if a process is applied which is characterized in that it is distilled a highly concentrated liquid MHA with a content of > 95% by weight of monomeric and oligomeric components of MHA under reduced pressure at a temperature at which the monomeric MHA enters gaseous state, for such a short time, that the formation of essential by-products is prevented.

* For this procedure, good results have been obtained within the framework of the invention above all with short path evaporators. MHA 4 solutions highly concentrated with this composition are obtained eg. according to the method described in the published German patent application for information DE-OS 19524054. * The MHA obtained in this way or possibly also by some other route is then distilled preferably at a pressure ranging from 1 x 10"3 and 5 x 10 4 Pa, especially in a temperature range of 40 to 200 ° C. It is advantageous that the residence time of the MHA in the distillation ranges from 1 to 1 x 10 4 seconds. 1 shows an embodiment of the method according to the invention.

The distilled MHA obtained in the condenser is practically colorless, at room temperature it is partially crystalline and surprisingly it is completely free of dimers and oligomers. The dark brown residual product has almost no monomeric MHA. It is composed mainly of dimers and oligomers, the total amount of which only increases negligibly during the course of the distillation. Therefore, according to the invention, the damage of the product that can be expected according to the state of the art during the distillation is not registered.

It has also been found that commercial MHA solutions can also be distilled according to the invention. Solutions containing water with a content of 88-90% by weight of MHA are advantageously distilled in a two-stage distillation apparatus eg. composed of a thin-film evaporator and a short-path evaporator, as shown in Fig. 2. In the first stage of this process, water is essentially separated. The highly concentrated MHA obtained with the drainage of the residual material from the first evaporator can then be distilled according to what has been described above, in such a way that essentially only the part already present of dimers and oligomers remains as residual product. In contrast, the present monomer part of MHA is separated as a free distillate from oligomers of a very clear color. The iodine color figures found for the distillates are 4 and 5 much more favorable than the iodine color figures measured in commercial products that reach 315.

Together with the excellent color properties and the absence of the unwanted parts of dimers and oligomers in the primary product, the MHA prepared according to the invention and the mixed MHA products prepared therefrom surprisingly exhibit storage stability markedly improved compared to the products described in the published German patent application for information DE-OS 19524054.

This can be recognized because a highly concentrated MHA product distilled according to the invention presents after about 120 days of storage with 40 mol% of DIM + OLI a notoriously lower equilibrium ratio (Figure 3) than the highly concentrated product of undistilled MHA stored in a similar manner according to published German patent application for DE-OS 19524054 with an equilibrium ratio of about 53% in mol DIM + OLÍ. The equilibrium adjustment takes place slowly in the MHA distilled according to the invention. In this way, the delivery time of a product with a high proportion of monomer is favorably prolonged.

A similar favorable effect on the equilibrium position could also be recorded surprisingly in a dilution product from distilled MHA and water. The distilled MHA diluted to the usual commercial concentration of 88% by weight presented after about 90 days of storage a proportion of oligomers at the equilibrium of only 20% by mol DIM + OLÍ (Fig. 4) compared to the product commercial with 26% by mole of DIM + OLI according to the published German patent application for information DE-OS 19524054.

A surprisingly greater decrease in the oligomer content can be observed in the preparation of a mixture product of MHA and Met (methionine) from MHA distilled here prepared. A solution prepared in this way, composed of 78% MHA + 10% Met in water, presents with only 13% mol DIM + OLÍ at equilibrium after more than 90 days of storage (compare Figure 5), a even lower proportion of oligomers compared to commercial MHA 88 and compared to MHA 78 prepared according to the published German patent application for information DE-OS 19524054 + 10 Met with 20 mol% DIM + OLÍ.

Mixtures of MHA 78 + 10 MHANH 4 containing salt of MHANH 4 or MHA 69 + 19 MHANH 4 (compare Figure 6 or 7) present with only 12 or 11% mol DIM + OLÍ after 30 days of storage. 40 ° C even lower values in the equilibrium and a marked improvement compared to the mixture of MHA 78 + 10 MHANH with 20% in mol of highly concentrated MHA product without distillation, according to the German patent application published for information DE -OS 19524054.

Furthermore, in MHA 88 as well as in MHA / Met or MHA / MHANH 4 solutions with 88% active substance content, iodine color figures of only 2.5 to 4 are found, which are much more favorable than in the merchandise available so far. F All the products mentioned here remain clear liquids even after 230 days of storage and have almost unaltered color values.

The viscosity properties of the MHA formulations are generally favorably influenced by the previous distillation step (compare Figures 8-11). Thus, in the MHA 88 of MHA distilled with 50 mm 2 / s at 25 ° C, a viscosity value was found that was notoriously lower than the viscosity range of the commercial products of 61 to 122 mm 2 / s (Figure 9). Mixtures of MHA / Met and MHA / MHANH 4 are in the same viscosity range while the other properties are improved (Figure 10 or 11). The distillated MHA distillate has a viscosity value below 402 mm 2 / s (Figure 8) below the highly concentrated sedimented MHA product of 517 mm 2 / s according to the published German patent application for information DE-OS 19524054.

Advantage of the method according to the invention.

The lower proportion of distilled sedimented MHA grade oligomers is an extraordinary advantage, since on the one hand the viscosity continues to decrease and on the other hand it continues to improve the handling properties such as the pumping and transport capacity of the product.

But even more important is the notorious improvement in biological value due * to the significantly higher ratio in the monomeric MHA equilibrium in MHA 88 or in mixtures of MHA / MHANH 4 as well as in monomeric MHA + methionine in MHA 78 + 10 Met in comparison with the products previously available. The proportion of oligomers can be kept clearly below 10 mol% if the product is still applied directly within only a few days after its preparation., which brings with it an additional increase in biological value.

Other advantages are the greater purity and the notoriously lighter color, which leads to a greater acceptance of the product by the manufacturer of high quality animal feed.

In addition, the highly concentrated MHA product distilled according to the invention is highly suitable for the preparation of pharmaceutical merchandise of D.L-MHA or corresponding pharmaceutical formulations such as the MHA calcium salt mentioned at the beginning for the treatment of renal insufficiency. Here it is possible to dispense with the usual purification up to the moment comprising several steps such as the splitting of oligomers, extraction and purification of the calcium salt obtained by expensive crystallization. A simple neutralization of the MHA distillate according to the invention with a suitable calcium base such as eg. calcium hydroxide and the subsequent drying is sufficient in this case to achieve the required product quality.

By means of the distillation according to the invention in relation to the short residence time, as for example. In a short-path evaporator, it has been possible to prepare a MHA of high purity and simultaneously achieve improved qualities of MHA products, which are characterized by a higher purity and greater stability during storage as well as a higher biological value when applied as an additive for animal feed.

The combination of the distillation according to the invention with a process for the preparation of MHA, as described in the published German patent application for information DE-OS 19524054 is especially advantageous. In this case, the formulations of MHA stable during storage are elaborated directly in a corresponding integral procedure, as shown in Figure 12, from 3-methylmercapto-propionaldehyde (MMP) and hydrocyanic acid (HCN).

In addition, the high purification method found here can also be applied to MHA solutions of 88-90 percent. that can be purchased at the moment in the shops and in principle also to any other solution that contains MHA, to obtain from them the qualities of MHA correspondingly improved.

The residual sludges remaining in the distillation, which are predominantly composed of the unwanted MHA dimers and oligomers, should not be discarded according to the invention. Rather, it is possible to hydrolytically convert these MHA dimers and oligomers into the MHA monomer by means of a simple dilution with water at a suitable concentration of 10 to 90% by weight and optionally with the addition of appropriate amounts of acid, of sulfuric acid by simply heating to a temperature of 50 to 140 ° C and re-purifying the MHA monomer by means of distillation.

A regeneration and recycling of MHA of this type can be carried out very elegantly within a corresponding circuit process in which the residual sludge from the distillation is introduced continuously into a corresponding stage of ester hydrolysis and then re-pass the ester hydrolyzate rich in MHA monomer to the distillation step. In this case, the combination with an MHA process as described in the German patent application published for DE-OS 19524054 is also particularly advantageous, since the residual sludge from the distillation can be passed back to the hydrolysis step with sulfuric acid of the MHA amide that must be carried out in any case (compare via a) in Figure 12). The ester part of MHA that must be further hydrolyzed and which generally does not comprise more than 25 mol%, as is clearly indicated by tests 1 and 2 of Example 7, can be reduced without problems within this stage to the usual proportion of dimers and oligomers of approx. 5 to 15% mol. Here it is possible to add the residual sludge of the distillation to the hydrolyzate of MHA formed up to that moment before initiating the hydrolysis step or in. any other subsequent moment during the reaction. The step of hydrolysis of the amide is only affected negligibly and it is possible to dispense with an additional hydrolysis step. The proportion of MHA regenerated from the residual iodine from the distillation is reintroduced into the distillation stage along with the product stream via extraction and evaporation.

However, it is also possible to hydrolyse the dimeric or oligomeric MHA ester acids in a further step (compare via b) in FIG. 12). In order to accelerate the reaction which can also be carried out in autocatalytic form, it is particularly advantageous here to add small amounts of acid, in particular to mineral acids such as HCl or H3PO4. or also of H2SO as illustrated in Test 3 of Example 7. Here it is also possible to apply acidic ion exchangers as shown in Test 4 of Example 7, which has the advantage that no additional acid is drawn into the distillation step. The last mentioned variant applies above all when it is desired to start from the commercial product of MHA.

Therefore, the distillation of MHA and the recovery of monomeric MHA from the MHA residual sludge from the distillation can be a component of the general MHA procedure shown in Figure 12 for the preparation of high MHA formulations. purity and stable during storage.

Both a MHA distillation process and a regeneration of residual MHA distillation sludge and also the general process mentioned above work practically without loss of MHA, and this despite the fact that a high purity monomeric MHA is being generated as a final product . This is a special advantage first of all from the economic point of view as well as from the modern ecological point of view.

The following preparative examples continue to illustrate the purpose of the invention: Analytical determination methods and definitions The contents of MHA or methionine monomers were determined quantitatively in the process solutions by means of HPLC, comparing them with an external standard (pure substance). This can not be analytically differentiated between the monomer as the free acid and the monomeric part that eventually occurs as an MHA-NH4 salt. The part of MHA-NH4 is calculated in this case from the NH content.

The content of total MHA (MHAtot) = monomeric MHA + MHA (dimers + oligomers) + methionine (optionally) + MHA-NH 4 (optionally) was determined by titration of the thioether function with a measurement solution of KBr / KBrO3 and was expressed as the sum of the corresponding monomer equivalents of MHA in [% by weight] or [g] or [mol] or [mol%].

The DMA content of MHA + oligomers of MHA (DIM + OLI) was calculated by means of the difference between MHA-tot and monomeric MHA (+ event methionine) and was expressed as the sum of the corresponding monomer equivalents of MHA in [% by weight] or [g] or [mol] or [% in mol].

The water content was determined by titration according to Karl Fischer. The sulfate or ammonium content was determined by means of ion chromatography according to standard procedures. I The color number of iodine was determined in accordance with DIN 6162.

Example 1 : * Figure 1 shows a diagram of the apparatus used in example 1. This is composed of the following provision: 001 technically short distance evaporator with an exchange surface of 0.35 m 2, double heated mantle and tempered condensing surface 002 cooling trap. 003 technical system for the generation of high vacuum 004 collection vessel of the distillation product 005 collection vessel for the residual distillation sludge From an evaporation system for obtaining a highly concentrated MHA product of a MIBK-MHA extract solution (analogous to the German patent application published for information DE-OS 19524054), 8.9 kg / h were introduced of highly concentrated MHA product in the short path evaporator 001. 7.4 kg / h of MHA distillate were obtained in the collection vessel 005. The test parameters are indicated in the following table: introduction in the short path evaporator 001: flow rate of highly concentrated MHA product: 8, 9 kg / h Composition of the highly concentrated product of MHA: MHA tot 99.6% by weight 100% by mol monomeric MHA 84.6% by weight 84.9% by mol MHA DIM + OLÍ 15.0% by weight 15 , 1% in mol H 2 O 0.2% by weight SO 4 2"0.2% by weight Evaporation (001): Pressure: 0.1 hPa Temperatures: in the inlet current 60 ° C in the heating mantle 125 ° C in the condenser 45 ° C at the outlet of the residual distillation sludge 108 ° CProduct quantities: < 0, 1 kg / h in the cooling trap 002 1, 4 kg / h at the outlet of the residual distillation sludge with 99.8% by weight of MHA tot 7.4 kg / h of MHA distillate in the vessel collector 004 with the following composition: MHA tot 99.9% by weight 100% by mol MMA monomeric 99.9% by weight 100% by mol MHA DIM + OLÍ 0% by weight 0% by mol H 2 O < 0.1% by weight SO 2- 0% by weight Example 2: In Figure 2 a schematic of the apparatus used in example 2 is shown. This is composed of the following arrangement: 001 thin-film glass evaporator (Sambay) with an exchange surface of 0.06 m 2 002 water-cooled glass cooler 003 water-collection container for 004 condensate vacuum pump 005 glass short-run evaporator with an exchange surface of 0.05 m 2, 006 refrigeration trap 007 high vacuum pump 008 collection container of distillation product 009 collection container for residual distillation sludge In the thin film evaporator 001, commercial merchandise of MHA 88 (Alimet ™ or Rhodimet AT88 ™) was continuously introduced. The water obtained during the evaporation was collected in the collection vessel 003. The residual distillation sludge was introduced continuously into the short path evaporator 005. The MHA distillate was collected in the collection vessel 008 and the residual distillation sludge containing dimeric and oligomeric MHA were collected in collector vessel 009.

Test 1 Introduction in the thin film evaporator 001: Flow rate of Alimet TM (NOVUS): 0.196 kg / h Composition: MHA tot 88.6% by weight 100% in mol Monomeric MHA 67.7% by weight 76.4% by mol MHA DIM + OLÍ 20.9% by weight 23.6% by mol H 2 O 11.4% by weight SO 42 '0.9% by weight Iodine color number 24 Evaporation (001): Pressure: 24 hPa Temperatures: in the inlet stream 29 ° C in the heating mantle 140 ° C Brüden 50 ° C Evaporation (005): Pressure: 0.2 hPa Temperatures: in the input current approx. 120 ° C in the heating mantle 155 ° C in the condenser 40 ° C Product quantities: 0.035 kg / h of condensate in the collection container 003 0 kg / h of condensate in the cooling trap 006 0, 113 kg / h of MHA distillate in the collection vessel 008 with the following composition: MHA tot 100% by weight 100% in mol MMA monomeric 100% by weight 100% in mol MHA DIM + OLÍ 0% by weight 0% in mol H 2 O 0% by weight SO 4 2 '0% by weight Iodine 5 color number 0.038 kg / h of residual distillation sludge in the collection vessel 009 with the following composition: MHA tot 100% by weight 100% in mol MOM monomeric 14.0% by weight% 14.0% by mol MHA DIM + OLÍ 86, 0% by weight 86.0% by mol H 2 O 0% by weight SO 4 2 '4.6% by weight Test 2 Introduction in the thin film evaporator 001: Flow rate of Alimet ™ (NOVUS): 0.24 kg / h Composition: MHA tot 88.6% by weight 100% in mol monomeric MHA 67.7% by weight 76 , 4% by mol MHA DIM + OLÍ 20.9% by weight 23.6% by mol H2O 11, 4% by weight or 42- 0.9% by weight Iodine color figure 24 Evaporation (001): Pressure: 24 hPa Temperatures: in the inlet current 26 ° C in the heating mantle 140 ° C Brüden 47 ° C Evaporation (005): Pressure: 0.2 hPa Temperatures: in the input current approx. 120 ° C in the heating mantle 155 ° C in the condenser 40 ° C Product quantities: 0.042 kg / h of condensate in the collection tank 003 0 kg / h of condensate in the cooling trap 006 0.129 kg / h of distillate MHA in the collection container 008 with the following composition: MHA tot 99.9% by weight 100% in mol MMA monomeric 99.4% by weight 99.5% in mol MHA DIM + OLÍ 0.5% by weight 0.5 % in mol H 2 O < 0.1% by weight SO 4 2 '0% by weight Amount of iodine 5 0.050 kg / h of distillation residual sludge in the collection container 009 with the following composition: MHA tot 100% by weight 100% in mol Monomeric MHA 8.0% by weight 8.0% by mol MHA DIM + OLÍ 92.0% by weight 92.0% by mol H 2 O 0% by weight SO 2- 4.3% by weight Ensavo 3 Introduction in thin film evaporator 001: TM Flow rate of Rhodimet AT88 (Rhone Poulenc): 0.123 kg / h Composition: MHA tot 89.0% by weight 100% in mol Monomeric MHA 67.5% in pelb 75.8% in mol MHA DIM + OLÍ 21.5% in weight 24.2% in mol H 2 O 10.6% by weight SO 4 '1, 39% by weight Amount of color of iodine 315 Evaporation (001): Pressure: 24 hPa Temperatures: in the inlet current 28 ° C in the heating mantle 140 ° C Brüden 44 ° C Evaporation (005): Pressure: 0.4 hPa Temperatures: in the input current approx. 120 ° C in the heating mantle 155 ° C in the condenser 40 ° C * Product quantities: 0.013 kg / h of condensate in the collection tank 003 0 kg / h of condensate in the cooling trap 006 0.057 kg / h of distillate of MHA in the collection vessel 008 with the following composition: MHA tot 100% by weight 100% in mol MMA monomeric 100% by weight 100% in mol MHA DIM + OLÍ 0% by weight 0% in mol • H 2 O 0% in weight * SO 42 '0% by weight Iodine color figure 3.5 . 0.035 kg / h of residual distillation sludge in the collection vessel 009 with the following composition: MHA tot 100% by weight 100% in mol monomeric MHA 42.0% by weight 42.0% in mol MHA DIM + OLÍ 58.0 % by weight 58.0% by mol H 2 O 0% by weight SO 4 2 '4.8% by weight Example 3: Comparative example: distillation according to the state of the art MHA distillate yield: 0.2% theoretical 800 g of MHA hydrolyzate (37.4% by weight of total MHA, 10.7% by mole of DIM + OLI) were extracted, prepared analogously to the published German patent application for information DE-OS 19524054 example 3 , in the separating funnel with 480 g of methyl isobutyl ketone (MIBC) and the extraction solution was washed with 50 g of water. The extraction solution was evaporated on the rotary evaporator in a water jet vacuum. The oily evaporation residue composed of 91.2% by weight of total MHA with 81.9 mol% of monomeric MHA and 18.1 mol% of MHA DIM + OLI was fractionally distilled in a vacuum distillation bridge of oil pump: Pressure: 0.2 hPa Temperatures: in residual distillation iodine 150 ° C Brüden approx. 55 ° C in the condenser 40 ° C After 2 hours were obtained: 0.5 g of MHA distillate in the collecting flask with the following composition: MHA tot 97.9% by weight 100% in mol monomeric MHA 86.8 % by weight 88.6% by mol MHA DIM + OLÍ < 0.1% by weight < 0.1% in mol Unknown secondary product approx. 11.1% by weight 246 g of residual distillation sludge in the distillation flask with the following composition: MHA tot 100% by weight 100% in mol monomeric MHA 8.7% by weight 8.7% in mol MHA DIM + OLÍ 92.3% by weight 92.3% by mol Example 4: Preparation of MHA formulations Ensavo 1 Distilled from MHA # Analogously to Example 1, an MHA distillate with a content of 99.9% by weight of total MHA was prepared.

Test 2 MHA 88 In a glass beaker with a magnetic stirrer, 88.0 g (0.59 mol) of fresh MHA distillate from Example 1 were diluted with 12.0 g of water under stirring to obtain a total MHA concentration of 88.0. % in weigh.

Test 3 MHA 78 + 10 Met S In a glass beaker with a magnetic stirrer, 78.0 g (0.52 mol) of a fresh distillate of MHA from Example 1 were mixed with 10.0 g (0.067 mol) > 99 porc. of * D, L-methionine and 12.0 g of water under stirring and in that manner a homogeneous solution was prepared with the following composition: "88.0% by weight of total MHA = 78.0% by weight of monomeric MHA .0% by weight of methionine 12.0% by weight of water Test 4 Distilled from MHA Analogously to example 2, test 1, an MHA distillate with a content of 100% by weight of total MHA was prepared.

Test 5 MHA 88 44.0 g (0.29 mol) of 100% fresh MHA distillate, freshly prepared according to Example 2, Test 1, was diluted in a glass beaker with a magnetic stirrer at 6.0 g. of water under stirring to obtain a total MHA concentration of 88.0% by weight: color number of iodine 4.

Ensavo 6 MHA 78 + 10 Met Into a glass beaker with a magnetic stirrer, 39.0 g (0.26 mol) of 100% fresh MHA distillate, freshly prepared according to example 2, test 1, were mixed with stirring under stirring. (0.034 mol) of D, L-methionine at > 99 * porc. and 6.0 g of water and in that way a homogeneous solution was prepared with the following composition: 88.0% by weight of total MHA = 78.0% by weight of monomeric MHA 10.0% by weight of methionine 12.0% by weight of water Iodine color figure 2.5 Ensavo 7 MHA 78 + 10 Met- NH 4 In a glass vessel with a magnetic stirrer, 60.0 g (0.40 mol) of an MHA distillate, freshly prepared according to example 2, test 1, were mixed with stirring with 2.26 g (0.040 mol). of 30.5% ammonia solution and 6.71 g of water and thus a homogeneous solution was prepared with the following. composition: Total MHA 87.0% by weight NH 4 + 1, 08% by weight equivalent to monomeric MHA 78.0% by weight (cale.) + MHA-NH 4 10.0% by weight (cale.) 9 Water approx. 12.0% by weight (cale.) Iodine color figure 2.5 Ensavo 8 MHA 69 + 19 MHA- NH 4 In a glass vessel with a magnetic stirrer 60.0 g (0.40 mol) of an MHA distillate, freshly prepared according to example 2, test 1, were mixed with stirring with 4.58 g (0.082 mol). of 30.5% ammonia solution and 5.19 g of water and thus a homogeneous solution was prepared with the following composition: Total MHA 86.0% by weight NH 4 + 2.0% by weight equivalent to monomeric MHA 69.26% by weight (cale.) + MHA-NH 4 18.63% by weight (cale.) Water 'approx. 12.0% by weight (cale.) Color figure of iodine 2.0 Test 9 Distilled from MHA * An MHA distillate having a content of 100% by weight of total MHA was prepared analogously to example 2, test 3.

Example 5 Storage of MHA formulations The products mentioned under Figures 3 to 7 were stored in each case in a closed glass vessel without agitation at the temperatures indicated therein and for a time period of up to more than 230 days. At regular intervals samples were taken and the content of total MHA, monomeric MHA, MHA (dimers + oligomers) and eventually Met were determined (compare with the methods mentioned above).

Figure 3 The MHA distillate prepared according to Example 4, Testol, presents after about 120 days of storage at 25 ° C a stable equilibrium of 60% in mol of MHA monomers (1) 40% in mol of MHA (dimers and oligomers) (2).

Figure 4 The MHA 88 that was prepared according to example 4, test 2, presents after about 90 days of storage at 25 ° C a stable equilibrium of 80% mol of MHA monomers (1) % in mol of MHA (dimers and oligomers) (2).

This ratio is notoriously below the usual commercial merchandise.

Figure 5 The MHA 78 + 10 Met, which was prepared according to Example 4, Test 3, presents after about 90 days of storage at 25 ° C a stable equilibrium of 87% mol of MHA monomers (1) 13 mol% of MHA (dimers and oligomers) (2).

Figure 6 The MHA 78 + 10 MHANH 4 which was prepared according to example 4, test 7, presents after about 6 days of storage at 40 ° C a stable equilibrium of * 88% mol of MHA monomers (1) 12 mol% MHA (dimers and oligomers) (2).

Figure 7 The MHA 69 + 19 MHANH 4, which was prepared according to example 4, test 8, presents after about 6 days of storage at 40 ° C a stable equilibrium of 89 mol% of MHA monomers (1) 11 mol% of MHA (dimers and oligomers) (2).

The comparison of Figures 3 to 7 shows the decrease in the equilibrium proportions of the undesired parts of DIM + OLÍ in the formulations of. MHA in the distillate series of MHA, MHA 88, MHA 78 + 10 Met, MHA 78 + 10 MHANH 4, MHA 69 + 19 MHANH 4. All the MHA formulations mentioned herein have more favorable parts of (dimers + oligomers) than the corresponding formulations of the published German patent application for information DE-OS 19524054. All formulations at 88 porc. they present much more favorable parts of (dimers + oiigomers) than the commercial merchandise of MHA 88.

Example 6 Determination of viscosities according to Cannon Fenske We determined, as can be seen in Figures 8 to 11, the kinematic vicosities with a Cannon Fenske opaque type viscometer according to the ISO 3150-1976 method in relation to the temperature and for the following qualities of MHA: Distillate from MHA, which was prepared according to example 4, assay 1 was stored at 25 ° C for > 230 days according to example 5, according to curve with the reference signs 1 in Fig. 8, Viscosity (25 ° C): 402 mm 2 / s Distillate of MHA, freshly prepared according to example 4, test 4, according to curve with the reference signs 2 in Fig. 8, Viscosity (25 ° C): 555 mm 2 / s Distillate of MHA, freshly prepared according to example 4, test 9, according to curve with the reference signs 3 in Fig. 8, Viscosity (25 ° C): 717 mm 2 / s MHA 88, freshly prepared according to example 4, test 5, according to curve with reference signs 4 in Fig. 9, Viscosity (25 ° C): 50 mm 2 / s MHA 88, merchandise Aiimet ™ (NOVUS), according to curve with the reference signs 5 in Fig. 9, 2 * Viscosity (25 ° C): 61 mm * / s MHA 88, commercial merchandise Rhodimet AT 88 ™ (Rthone Poulenc), according to curve with the reference signs 6 in Fig. 9, Viscosity (25 ° C): 122 mm 2 / s MHA 78 + 10 MHANH 4 freshly prepared according to example 4, test 7, according to curve with the reference signs 7 in Fig. 10, Viscosity (25 ° C): 74 mm 2 / s MHA 78 + 10 MHANH 4, prepared according to example 4, test 7 and stored at 40 ° C for 30 days according to example 5, according to curve with reference signs 8 in Fig. 10, Viscosity (25 ° C): 79 mm 2 / s MHA 69 + 19 MHANH 4, freshly prepared according to example 4, test 8, according to curve with the reference signs 9 in Fig. 10, Viscosity (25 ° C): 96 mm / s MHA 69 + 19 MHANH 4, prepared according to example 4, test 8 and stored at 40 ° C for 30 days according to example 5, according to curve with the reference signs 10 in Fig. 10, Viscosity ( 25 ° C): 100 mm 2 / s 1 * MHA 78 + 10 Met, prepared according to example 4, assay 3 and stored at 25 ° C during > 230 days according to example 5, according to curve with the reference signs 11 in Fig. 11, Viscosity (25 ° C): 113 mm 2 / s • MHA 78 + 10 Met, freshly prepared according to example 4, test 6, according to curve with the reference signs 12 in Fig. 11, Viscosity (25 ° C): 122 mm 2 / s As the comparison of the viscosity values at 25 ° C shows, the viscosi¬ days of highly concentrated MHA products are notoriously higher than those of other MHA formulations, where longer storage results in a decrease in viscosities (compare Fig. 8 to 11). 2S 2 • * The viscosity value of 50 mm / s, which is clearly the most favorable, is recorded in MHA 88 from a highly concentrated freshly distilled product, which is also below the viscosity range of 61-122. mm 2 / s of commercial merchandise (compare Fig. 9).

The viscosities of the mixtures of (MHA + MHANH 4) are in the lower part until the middle part of the viscosity range (compare Fig. 10), which is comparable with the mixtures of (MHA + Met) in the upper part of the viscosity range of commercial merchandise (compare Fig. 11) and therefore it is also comparable in this regard with commercial products.

Example 7 Regeneration of MHA from the residual sludge from the distillation » Ensavo 1 In a 100 ml three-necked flask with reflux condenser, inner thermometer and magnetic stirrer, 14.33 g (0.095 mol) of 65% by weight H 2 SO 4 were placed at 25 ° C and under stirring throughout After 5 minutes, 13.43 g (0.1 mol) of 4-methyl-thio-2-hydroxybutyric acid nitrile (MMP-cyanohydrin) were added dropwise. The reaction mixture was stirred for a further 60 minutes at 50 ° C and the solution of MHA-amide acidified with sulfuric acid obtained in this way was then mixed with water., 73 g (0.025 mol) of residual sludge from the MHA distillation according to example 2, test 1, and with 17.59 g of water. The homogeneous solution with a content of 38% by weight of MHAtot was heated to boiling for 15 min at 108 ° C and stirred for another 105 minutes at this temperature. The analytical composition found was modified over time in the following way: Amide Time of MHA Monomer of MHA DIM + OLÍ [min] [% in mol] [% in mol] [% in mol] 5.2 60.0 34.8 after heating 2.0 69.7 28.3 60 0.5 81, 2 18.3 90 83.9 16.1 120 0 88.6 11, 4 Ensavo 2 In a 100 ml three neck flask with reflux condenser, indoor thermometer and magnetic stirrer, 60.0 g (0.15 mol) of 37.4% by weight MHA hydrolyzate (with 0.15 mol MHA tot, 0.15 mol of NH 4 HSO 4), prepared by means of a hydrolysis with 4-methyl-thio-2-hydroxybutyric acid nitrile sulfuric acid according to the published German patent application for DE-OS information 19524054, Example 4, 5.6 g (0.037 mol) of distillation sludge from the distillation of MHA according to Example 2, Test 1 and with 8.2 g of water. The homogeneous solution with a content of 38.0% by weight of MHAtot was heated to boiling for 20 min at 106 ° C and stirred for another 70 minutes at this temperature. The analytical composition found was modified over time in the following way: Time Monomer of MHA DIM + OLÍ [min] [% in mol] [% in mol] 79.6 20.4 before heating 86.7 13.3 88.6 11, 4 60 91.3 8.7 90 95.8 4.2 Ensavo 3 In a 250 ml laboratory autoclave with a glass aggregate, magnetic stirrer and internal thermometer, 16.74 g (0.111 mol) of residual distillation sludge was mixed from the MHA distillation according to Example 2, Test 1 with 27 , 32 g of water and 0.44 g of H 2 SO 4 (4.5 mol). . The mixture was heated in the closed autoclave for 20 min at an interior temperature of 130 ° C and for another 90 minutes at this temperature and stirred under 3.5 bar pressure. After rapid cooling to about 25 ° C, the reaction solution was analyzed. The composition of the solution had been modified as follows: m ore on e + [min] [mol%] [mol%] 0 14,0 86.0 before heating 110 92.8 7.2 Test 4 In a 250 ml laboratory autoclave with a glass aggregate, magnetic stirrer and internal thermometer, 16.74 g (0.111 mol) of residual distillation sludge was mixed from the MHA distillation according to Example 2, Test 1 with 27 , 32 g of water and 0.62 g of Amberlyst 15 ™ ion exchanger (Rohm &Haas, 1, 8 eq of SO 3 H / 1). The mixture was heated in the closed autoclave for 45 min at an interior temperature of 124 ° C and for another 120 minutes at this temperature and stirred under 2 bar pressure. After rapid cooling to about 25 ° C, the reaction solution was analyzed. The composition of the solution had been modified in the following way: Time Monomer of MHA DIM + OLÍ [min] [% in mol] [% in mol] 0 14,0 86.0 before heating 165 87.7 12.3 It is noted that c »relation to this date, the best method known by the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention. Having described the invention as above, the contents of the following are claimed as property:

Claims (21)

Claims

1. Process for the production of stable 2-hydroxy-4-methylthiobutyric acid (MHA) during storage, characterized in that a highly concentrated liquid MHA with a content of > 95% by weight of monomeric and oligomeric components of MHA under reduced pressure at a temperature, at which the monomeric MHA becomes gaseous, for such a short time that the formation of important parts of by-products is prevented.

2. Process according to claim 1, characterized in that the highly concentrated liquid MHA is distilled at a pressure ranging between 10 '3 and 5 x 10 Pa.

3. Process according to one of the preceding claims, characterized in that the highly concentrated liquid MHA is distilled at a temperature ranging between 40 and 200 ° C.

4. Process according to one of the preceding claims, in particular according to claim 3, characterized in that the average residence time of the MHA in the distillation ranges between 1 and 1 x 10. 4 seconds

5. Process according to one of the preceding claims, characterized in that the highly concentrated liquid MHA is obtained as an educt resulting from a previous evaporation of any MHA not highly concentrated.

6. Process according to one of the preceding claims, characterized in that an MHA is obtained as a product, whose stability during storage is greater by a factor of 1.3 to around 2.5 than the stability during storage of the reactant applied with a comparable water content, where the stability during storage is determined by comparing the content of MHA dimers and oligomers of the product * or of the educt, which is established in the equilibrium state, with a comparable water content.

7. Process according to one of claims 1 to 5, characterized in that an MHA is obtained as a solid and partial- or totally crystalline product.

8. Process according to one of the preceding claims, characterized in that a product with a color is obtained, whose iodine color number ranges from 0 to < 20.

9. Process according to one of the preceding claims, characterized in that, as short path distillation aggregates, devices are applied in which the average residence time of the MHA in the distillation ranges between 1 and 1 x 10 4 seconds.

10. Process according to one of the preceding claims, characterized in that the result is an MHA essentially free of oligomers.

11. Process according to claim 10, characterized in that the result is an MHA having an oligomer content that ranges between 0 and 5% by weight at the outlet of the evaporator.

12. Process according to one or more of the preceding claims, characterized in that the residual sludges obtained in the distillation of MHA which are composed of MHA monomers, MHA dimers and MHA oligomers are introduced in a regeneration step, with the which decreases the content of dimers and oligomers by hydrolysis to values less than or equal to 30 mol%, preferably less than or equal to 20 mol%, but in particular less than or equal to 10 mol% referred to total MHA.

13. Process according to claim 12, characterized in that in the hydrolysis step one or more mineral acids and / or salts of mineral acids and / or MHA and / or acidic ion exchangers are added.

14. Process according to claim 13, characterized in that the mineral acids are H 2 SO, HCl and / or H 3 PO and the corresponding salts of mineral acids are the corresponding ammonium salts.

15. Process according to claim 13 and 14, characterized in that the hydrolysis of the residual sludge from the MHA distillation is carried out simultaneously with the hydrolysis of the MHA amide.

16. Procedure for obtaining 2-hydroxy-4-methylthiobutyric acid (MHA), in which the MHA is isolated from a reaction mixture obtained by the addition of hydrocyanic acid (CHN) to methylmercaptopropionaldehyde (MMP) and hydrolysis of the cyanohydrin (MMP-CH) obtained in this manner with a mineral acid, wherein the reaction mixture is contacted in a liquid / liquid extraction system with an organic solvent essentially immiscible with water and thereby generates a extraction solution, which presents the solvent and MHA transferred from the reaction mixture, and the MHA is obtained as extract from this extraction solution by evaporation, characterized in that the extract is then distilled in such a way that a distillate containing esencialemnte MHA monomer and distillation waste sludge containing mainly MHA dimers and MHA oligomers, where this sludge distillation is added to the hydrolysis of MMP-CH and / or MHA amide to regenerate MHA monomers.

17. MHA, obtained according to the procedure described in apt_ericres r iviTrñcaacries, characterized prque presents go ce ce 95% in step > tft, calculated as sum of MHA monomers, MHA dimers and MHA oligomers as well as a kinematic viscosity of > 100 mm 2 / s at 25 ° C and a iodine color figure of < 20 and a proportion of < 10 mol% of MHA monomers, based on the sum of MHA monomers, MHA dimers and MHA oiigomers.

18. Use of the MHA according to claim 17 for the preparation of mixtures for animal feed supplements, characterized in that a mixture is prepared with water, whose iodine color figure is < 20 and whose oligomer content, comprising MHA dimers and MHA oligomers, is < 25 mol% after storage for more than 200 days at 25 ° C, based on the total active substance content of MHA, MHA dimers and MHA oligomers.

19. Use of the MHA according to claim 17 for the preparation of mixtures for animal feed supplements, characterized in that a mixture is prepared with methionine, whose iodine color number is < 20 and whose oligomer content, comprising MHA dimers and MHA oligomers, is < 25 mol% after storage for more than 200 days at 25 ° C, based on the total active substance content of MHA, MHA dimers and MHA oligomers as well as methionine.

20. Use of the MHA according to claim 17 for the preparation of mixtures for animal feed supplements, characterized in that a mixture is prepared with gaseous ammonia, aqueous ammonia and / or ammonia-MHA, whose iodine color number is < And whose oligomer content, which comprises dMAD dimers and MHA oligomers, is < 20 mol% after storage for more than 28 days at 40 ° C, based on the total active substance content of MHA, MHA dimers and oligomers of MHA.

21. Use of the MHA according to claim 17 for direct pharmaceutical use or as an intermediate for the preparation of a pharmaceutically applicable salt or a pharmaceutically applicable formulation.