STORAGE-STABLE FORM OF 3-METHYLTHIOPROPIONALDEHYDE

Abstract

A chemical compound of formula (I),

##STR00001##

and specific compositions including 3-methylthiopropionaldehyde, 3-methylthiopropane-1,1-diol, a compound of formula I and water, and processes for producing same and also the use of same may be used for the production of 2-hydroxy-4-(methylthio)butyronitrile, methionine hydantoin, methionine. Protected forms may be used for the storage and/or transport of 3-methylthiopropionaldehyde.

Claims

1. A composition comprising: 3-methylthiopropionaldehyde, in a range of from 40 to 95 wt. %; 3-methylthiopropane-1,1-diol, in a range of from 1 to 20 wt. %; a compound of formula (I), in a range of from 2 to 25 wt. %; ##STR00004## water, in a range of from 2.5 to 25 wt. %.

2. The composition of claim 1, comprising: the 3-methylthiopropionaldehyde, in a range of from 40 to 94.5 wt. % the 3-methylthiopropionaldehyde, in a range of from 40 to 94.5 wt. %.

3. The composition of claim 1, comprising: the 3-methylthiopropionaldehyde, in a range of from 40 to 92 wt. %; and the water, in a range of from 5 to 10 wt. %.

4. A method of storing and/or transporting 3-methylthiopropionaldehyde, the method comprising: contacting the composition of claim 1, 3-methylthiopropane-1,1-diol, or the compound of formula (I), with the 3-methylthiopropionaldehyde.

5. The method of claim 4, conducted at a temperature in a range of from 0 to 60° C., for a period of time of up to 12 months.

6. The method of claim 5, conducted at a temperature in a range of from 5 to 40° C.

7. The method of claim 5, conducted for a period of time of up to 8 months.

8. The method of claim 5, conducted for a period of time of up to 4 months.

9. A method of producing 2-hydroxy-4-(methylthio)butyric acid, the method comprising: contacting the composition of claim 1, 3-methylthiopropane-1,1-diol, or the compound of formula (I), with hydrocyanic acid, ammonia carbon dioxide, ammonium carbonate, and/or ammonium bicarbonate.

10. A method for producing the composition of claim 1, the method comprising: reacting 3-methylthiopropionaldehyde, while mixing intensively, with 2.5 to 25 wt. % of water, based on a total amount of the 3-methylthiopropionaldehyde and water used, at a temperature in a range of from 0 to 100° C.

11. The method of claim 10, wherein the reaction is conducted for a duration in a range of from 0.5 to 72 h.

12. The method of claim 10, further comprising: distilling the 3-methylthiopropionaldehyde before the reacting.

13. A method for producing 2-hydroxy-4-(methylthio)butyronitrile, the method comprising: reacting the composition of claim 1, 3-methylthiopropane-1,1-diol, or the compound of formula (I), with hydrocyanic acid in the presence of an amine base.

14. A method for producing methionine hydantoin, the method comprising: reacting the composition of claim 1, 3-methylthiopropane-1,1-diol, or the compound of formula (I), in the presence of water with hydrocyanic acid, ammonia, and carbon dioxide.

15. A method for producing D,L-methionine the method comprising: reacting the composition of claim 1 with HCN, NH.sub.3, and carbon dioxide to give methionine hydantoin; and subsequently hydrolyzing the methionine hydantoin, under alkaline conditions, to give a methionine alkali metal salt; and then neutralizing the methionine alkali metal salt with acid to give methionine.

16. The composition of claim 1, produced by a method comprising: reacting 3-methylthiopropionaldehyde, while mixing intensively, with 2.5 to 25 wt. % of water, based on a total amount of the 3-methylthiopropionaldehyde and water used, at a temperature in a range of from 0 to 100° C.

Description

EXAMPLES

Methods Used:

1 Residue Determination by Means of Vacuum Distillation

[0043] The residue determination was carried out in a Kugelrohr evaporator of the GKR-50 type from Büchi. For this purpose, the empty weight of the flask used for the distillation was firstly determined. A weight of 15 g of the substance to be distilled (m (initial weight)) was then precisely weighed in and the flask introduced into the Kugelrohr evaporator. The heating of the distillation flask was set to 200° C., and a pressure of 30 mbar was set via the pressure regulator of the vacuum pump. The distillation was carried out on all samples over a period of 20 min. After cooling of the distillation apparatus, the apparatus was vented. The flask was subsequently removed and weighed to determine the weight (m (residue)). The residue was determined using the following formula:

[00001]$\mathrm{Residue}\left[\%\mathrm{by}\mathrm{weight}\right]=\frac{m\left(\mathrm{residue}\right)}{m\left(\mathrm{initial}\mathrm{weight}\right)}$

2 NMR Spectroscopic Investigations

[0044] The content of the compounds 3-methylthiopropionaldehyde, 3-methylthiopropane-1,1-diol and 1-(1′-hydroxy-3-(methylthio)propoxy)-3-(methylthio)propan-1-ol, present in equilibrium, in a sample was determined by means of NMR spectroscopy (nuclear magnetic resonance) on an Advance 600 type device from Bruker.

[0045] For the examples, .sup.13C NMR spectra of samples to which a solvent had not been added were recorded at 150 MHz. From the recorded spectra, the molar ratios of the constituents to one another were read off. The reference substance used was d.sub.6-DMSO, which was introduced in a sealed capillary into the NMR tube of the relevant sample. The ratios were formed by selecting characteristic signals of 3-methylthiopropionaldehyde, 3-methylthiopropane-1,1-diol and 1-(1′-hydroxy-3-(methylthio)propoxy)-3-(methylthio)propan-1-ol in the .sup.13C NMR spectrum. These were, for 3-methylthiopropionaldehyde, the signal —CH.sub.2—CHO at 42.3 ppm; for 3-methylthiopropane-1,1-diol, the signal —CH.sub.2—C(OH).sub.2 at 89.7 ppm; and for 1-(1′-hydroxy-3-(methylthio)propoxy)-3-(methylthio)propan-1-ol, the signal O(C(OH)—CH.sub.2—CH.sub.2—SCH.sub.3).sub.2 at 91.2 and 96.4 ppm, in this case the sum integral across both diastereomers was formed.

[0046] The mass ratios were calculated from the molar ratios taking the total water content, determined by means of Karl Fischer titration, into account.

[0047] The appended FIGS. 2 and 3 each show an exemplary .sup.13C NMR (150 MHz, without solvent, de-DMSO capillary) and 1H NMR spectrum (600 MHz, de-DMSO) of an inventive composition.

3 Determination of Water Content by Means of Karl Fischer Titration

[0048] The content of water in the inventive compositions was determined by the Karl Fischer method by titration using biamperometric indication of the end point. To this end, 20 to 30 ml of titration medium, e.g. Hydranal Solvent 5 from Fluka, were initially charged in the titration vessel and titrated to dryness with titrant, e.g. Hydranal Titrant 5 from Fluka. An amount of sample of approx. 500 mg was added to the dry-titrated flask using a plastic disposable syringe and titrated with the titrant to the end point. The precise sample weight was determined by differential weighing.

[0049] The performance of these standard methods is known to the person skilled in the art and described extensively in the relevant literature, for example, in P. A. Bruttel, R. Schlink, “Wasserbestimmung durch Karl-Fischer-Titration” [Water Determination by Karl Fischer Titration], Metrohm AG, 2006).

4 High Performance Liquid Chromatography (HPLC)

[0050] Chromatographic investigations (MMP cyanohydrin, MMP, methionine, methionine amide, hydantoin, hydantoin amide, hydantoic acid, Met-Met) were carried out by means of HPLC from JASCO on an RP-18 column (250×4.6 mm; 5 μm) with subsequent UV detection at 210 nm. A phosphoric acid-acidified acetonitrile-water mixture (3.3 g of H.sub.3PO.sub.4, 6.8 g of acetonitrile, 89.9 g of H.sub.2O) served as eluent. At a flow rate of 1 ml/min, 10 μl of the respective sample solution (50 mg of sample in 25 ml of H.sub.2O) were injected. Calibration was effected in advance by the injection of suitable calibration solutions and evaluation was effected by peak area comparison by means of the external standard method. The procedure of the standard method is known to the person skilled in the art.

Examples 1-2: Preparation of 3-methylthiopropane-1,1-diol (MMP-OH) and of 1-(1′-hydroxy-3′-(methylthio)propoxy)-3-(methylthio)propan-1-ol (MMP.SUB.2.O)

[0051] Distilled 3-methylthiopropionaldehyde from industrial production (97.4% by weight; 196.0 g (Example 1), 180.1 g (Example 2)) was initially charged in a flask and admixed with water (4.0 g (Example 1), 20.0 g (Example 2)) while stirring at room temperature. The resulting product mixture was subsequently stirred for 3 days at room temperature and analyzed by means of NMR spectroscopy and Karl Fischer Titration. In Example 1, a content of MMP.sub.2O of 2.9 mol % (corresponding to 6.0% by weight, cf. Tab.1) was ascertained. In Example 2, a content of 7.9 mol %/14.3% by weight was ascertained. The results of Examples 1 and 2 are summarized in Table 1.

TABLE-US-00001 TABLE 1 Overview of Examples 1 and 2 Product composition Reactants MMP MMP-OH MMP.sub.2O H.sub.2O MMP % by % by % by % by Example wt./wt. H.sub.2O mol %* weight ** mol %* weight ** mol %* weight ** weight ** 1 98 2 95.1 90.6 2.0 2.2 2.9 6.0 1.2 2 90 10 81.8 68.2 10.3 10.1 7.9 14.3 7.4 *relative molar ratios from the .sup.13-C NMR without taking free water into account. ** % by weight calculated taking into account the added water content.

(MMP=3-methylthiopropionaldehyde, MMP-OH=3-methylthiopropane-1,1-diol, MMP.SUB.2.O=1-(1′-hydroxy-3-(methylthio)propoxy)-3-(methylthio)propanol)

Examples 3-5: Investigation of the Equilibrium Position of Monophasic Water-Saturated Mixtures with Inventive Composition Depending on the Temperature

[0052] Distilled 3-methylthiopropionaldehyde from industrial production (96.1% by weight; 30 ml in each case) was admixed with water (30 ml in each case) in a reaction flask with temperature-control jacket. The temperature of the mixture was adjusted (Example 3: 5° C., Example 4: 25° C., Example 5: 40° C.) and the mixture was mixed at this temperature under vigorous stirring (120 rpm) for 15 min. After 15 min the stirrer was switched off, temperature control continued to be maintained. Within a few minutes (Example 5)/a few days (Example 3), two clear, colourless phases formed. The lower organic phase was removed and swiftly characterized by means of HPLC, temperature-controlled NMR spectroscopy and also Karl Fischer titration. The maximum content of MMP.sub.2O was ascertained at 25° C. with approx. 23% by weight (Example 4). The maximum content of MMP-OH within the series of experiments was exhibited by the sample at 5° C.—a content of approx. 15% by weight was ascertained (Example 3). The results of Examples 3 to 5 are summarized in Table 2.

TABLE-US-00002 TABLE 2 Overview of Examples 3 to 5 of water-saturated mixtures of the inventive composition at various temperatures Product composition* MMP MMP-OH MMP.sub.2O H.sub.2O Example Temperature (% by wt.) (% by wt.) (% by wt.) (% by wt.) 3  5° C. 45.0 15.3 17.9 21.0 4 25° C. 51.8 12.2 23.2 12.5 5 40° C. 63.1 4.9 21.0 11.0 *determined by calculation by means of HPLC (total content of MMP) and Karl Fischer analysis (total content of H.sub.2O) and also .sup.13C NMR spectroscopy (molar ratios of MMP:MMP-OH:MMP.sub.2O).

(MMP=3-methylthiopropionaldehyde, MMP-OH=3-methylthiopropane-1,1-diol, MMP.SUB.2.O=1-(1′-hydroxy-3-(methylthio)propoxy)-3-(methylthio)propanol)

Examples 6-9: Storage stability of mixtures containing 1-(1′-hydroxy-3-(methylthio)propoxy)-3-(methylthio)propanol (MMP.SUB.2.O)

[0053] Distilled 3-methylthiopropionaldehyde (MMP, 99.8% by weight; water content 0.14% by weight) was admixed with various amounts of water while stirring at room temperature (Example 6: 0.0 g of water for 182.2 g of MMP; Example 7: 4.6 g of water for 179.4 g of MMP; Example 8: 9.4 g of water for 178.6 g of MMP; Example 9: 19.6 g of water for 176.4 g of MMP). The samples were stored at room temperature for a plurality of weeks and the residue was determined at regular intervals by means of vacuum distillation. The results are summarized in Table 3 and also in appended FIG. 1. The results clearly show that a mixture having an increased proportion of MMP.sub.2O, such as in particular for Examples 8 and 9, exhibits a markedly reduced residue formation compared to a mixture without MMP.sub.2O.

TABLE-US-00003 TABLE 3 Overview of Examples 6 to 9 Example 6 7 8 9 H.sub.2O in MMP 0% by wt. 2.5% by wt. 5% by wt. 10% by wt. MMP.sub.2O content* 0% by wt. 5% by wt. 8% by wt. 15% by wt. Time in weeks Residue in % by weight 0 0.00 0.02 0.05 0.00 2 1.35 1.03 0.48 0.27 4 3.39 2.18 0.26 0.40 6 7.37 3.51 0.90 0.60 8 9.06 5.01 1.10 0.37 *estimated values from NMR spectra.

(MMP=3-methylthiopropionaldehyde, MMP.SUB.2.O=1-(1′-hydroxy-3-(methylthio)propoxy)-3-(methylthio)propan-1-ol)

Example 10: Preparation of 2-hydroxy-4-(methylthio)butyronitrile (MMP cyanohydrin) from an inventive composition containing 1-(1′-hydroxy-3-(methylthio)propoxy)-3-(methylthio)propan-1-ol (MMP.SUB.2.O), 3-methylthiopropane-1,1-diol (MMP-OH=MMP hydrate) and MMP

[0054] 180.1 g of distilled 3-methylthiopropionaldehyde from industrial production (97.4% by weight) were initially charged in a flask and admixed with 20.0 g of water while stirring at room temperature. The product mixture obtained was subsequently stirred for a further 3 days (72 h) at room temperature. Characterization by NMR spectroscopy and Karl Fischer titration yielded a content of 68.2% by weight of 3-methylmercaptopropionaldehyde, 10.1% by weight of MMP-OH and 14.3% by weight of MMP.sub.2O (referred to hereafter as MMP equivalents).

[0055] 173.6 g of the product mixture (1.50 mol of MMP equivalents) were admixed with catalytic amounts of triethanolamine (58 mg) in a three-neck flask fitted with jacketed coil condenser and dropping funnel, and cooled by means of an ice bath. Cooled hydrocyanic acid (43.48 g, 1.59 mol, 1.06 equiv.) was added over a period of 20 min via the dropping funnel. The dosing was regulated during this so that a temperature of 30° C. was not exceeded. The solution continued to be stirred at room temperature overnight. The colourless, clear product (205.28 g) was characterized by means of HPLC analysis and contained 92.82% by weight of the target compound MMP cyanohydrin (1.45 mol, 96.8% of yield based on MMP equivalents used) and also 1.15% by weight of 3-methylmercaptopropionaldehyde (0.03 mol, 2% by weight) that was in equilibrium with free hydrocyanic acid. The results above show that MMP cyanohydrin can also be produced from water-containing MMP that has been enriched with MMP.sub.2O and MMP-OH, that is to say the inventive composition.

Examples 11-12 with Comparative Examples 1-2: Preparation of methionine via the intermediates 5-[2′-(methylthio)ethyl]imidazolidine-2,4-dione (methionine hydantoin) and MMP cyanohydrin from an inventive composition containing 1-(1′-hydroxy-3-(methylthio)propoxy)-3-(methylthio)propan-1-ol (MMP.SUB.2.O) and MMP

[0056] 180.1 g of distilled 3-methylthiopropionaldehyde from industrial production (97.4% by weight) were initially charged in a flask and admixed with 20.0 g of water while stirring at room temperature. The product mixture obtained was subsequently stirred for a further 3 days (72 h) at room temperature. Characterization by NMR spectroscopy and Karl Fischer titration yielded a content of 68.2% by weight of 3-methylmercaptopropionaldehyde, 10.1% by weight of MMP-OH, 14.3% by weight of MMP.sub.2O and 7.4% by weight of water.

[0057] 173.6 g of the product mixture (1.50 mol of MMP equivalents) were admixed with catalytic amounts of triethanolamine (58 mg) in a three-neck flask fitted with jacketed coil condenser and dropping funnel, and cooled by means of an ice bath. Cooled hydrocyanic acid (43.48 g, 1.59 mol, 1.06 equiv.) was added over a period of 20 min via the dropping funnel. The dosing was regulated during this so that a temperature of 30° C. was not exceeded. The solution continued to be stirred at room temperature overnight and the excess of hydrocyanic acid was determined by means of characterization. A further 12.6 g of 3-methylmercaptopropionaldehyde (0.12 mol) were dosed and stirring was continued at room temperature for 20 h in order to adjust the excess of hydrocyanic acid to 0.0 mol %.

[0058] 37.2 g of the MMP cyanohydrin thus obtained (0.257 mol of MMP equivalents) were admixed with distilled water (35.5 g), ammonium carbonate (13.9 g, 0.15 mol) and ammonium hydrogencarbonate (23.4 g, 0.30 mol) in a 300 ml autoclave beaker equipped with a stirrer bar. The reaction vessel was transferred into a high-pressure laboratory autoclave from ROTH, equipped with manometer, heating system, temperature sensor and pressure relief. The autoclave was tightly sealed, heated within 15 min to 105° C. while stirring and then maintained at this temperature for a further 20 min. At the end of the reaction period, the autoclave was cooled to room temperature under running water and the pressure generated (approx. 15 bar) was released.

[0059] 41.3 g of aqueous KOH solution (17 g of KOH in 24.3 g of H.sub.2O) was then metered in via the inlet tube. After the addition was complete, the autoclave was heated within 25 min to 180° C. while stirring and then maintained at this temperature for a further 40 min. During the reaction period, the pressure was released to 5 bar approx. every 5 min, but at least when 10 bar was exceeded. At the end of the reaction period, the autoclave was cooled to room temperature under running water and depressurized to standard pressure. HPLC analysis of the reaction product (134.7 g) yielded, for a conversion of 97.2%, 60.1% methionine, 6.9% methionine amide and 30.2% methionylmethionine. In a repeat experiment (Example 12), 71.4% methionine, 6.6% methionine amide and 21.4% methionylmethionine were obtained with a conversion of 99.5%.

Comparative Examples 1 and 2

[0060] A Comparative Example 1 for the preparation of methionine analogously to Example 11, but using MMP cyanohydrin prepared from MMP.sub.2O-poor 3-methylmercaptopropionaldehyde (containing 1.2% by weight of water) according to Example 1, yielded, with a conversion of 95.0%, 63.0% methionine, 5.5% methionine amide and 26.5% methionylmethionine; in a repeat experiment (Comparative Example 2), 65.8% methionine, 6.5% methionine amide and 24.2% methionylmethionine were obtained with a conversion of 96.5%.

TABLE-US-00004 TABLE 4 Comparison of methionine preparation from MMP.sub.2O-rich and MMP.sub.2O-poor inventive composition containing MMP Reactant composition, % by weight Conversion, % MMP.sub.2O (MMP, MMP-OH, H.sub.2O) Methionine (Met-amide; Met-Met) Example 11 14.3 (68.2; 10.1; 7.4) 60.1 (6.9; 30.2) Example 12 71.4 (6.6; 21.4) Comparative 6.0 (90.6; 2.2; 1.2) 63.0 (5.5; 26.5) example 1 Comparative 65.8 (6.5; 24.2) example 2

(MMP=3-methylthiopropionaldehyde, MMP-OH=3-methylthiopropane-1,1-diol, MMP.SUB.2.O=1-(1′-hydroxy-3-(methylthio)propoxy)-3-(methylthio)propan-1-ol)

[0061] The results summarized in Table 4 show that MMP.sub.2O-rich inventive compositions (Examples 11, 12) and MMP.sub.2O-poor inventive compositions (Comparative Examples 1, 2) deliver comparable yields and by-product spectra in the preparation of methionine, and so MMP.sub.2O (1-(1′-hydroxy-3-(methylthio)propoxy)-3-(methylthio)propan-1-ol) and also MMP-OH (3-methylthiopropane-1,1-diol) can clearly also be converted to methionine via MMP cyanohydrin and methionine hydantoin. The relatively high proportions of Met-Met of above 20% can in this case be attributed to the execution in the laboratory, and are in the low percentage region in continuous industrial hydrolysis columns in the methionine process.