METHOD FOR PREPARING METHIONINE

Abstract

The present invention relates to a method for preparing methionine or methionine salts. In particular, the invention describes the step of preparing 2-hydroxy-4-(methylthio)butyronitrile (MMP-CN) from 3-methylthiopropanal (MMP) and hydrogen cyanide (HCN) in the presence of ammonia by bringing a gaseous mixture comprising HCN and ammonia into contact with MMP.

Claims

1. A method for preparing 2-hydroxy-4-(methylthio)butyronitrile, the method comprising: bringing a gas mixture comprising hydrogen cyanide and ammonia into contact with 3-methylmercaptopropionaldehyde, thereby producing a product mixture comprising 2-hydroxy-4-(methylthio)butyronitrile.

2. A method for preparing methionine or a salt of methionine, the method comprising: bringing a gas mixture comprising hydrogen cyanide and ammonia into contact with 3-methylmercaptopropionaldehyde, thereby producing a product mixture comprising 2-hydroxy-4-(methylthio)butyronitrile.

3. The method according to claim 1, in which a molar ratio of ammonia to hydrogen cyanide in the gas mixture is from 0.06 to 0.99.

4. The method according to claim 1, further comprising, prior to the bringing: preparing the gas mixture essentially comprising hydrogen cyanide, ammonia and water according to an Andrussow process from methane, ammonia and oxygen.

5. Method The method according to claim 1, further comprising, prior to the bringing: preparing the gas mixture essentially comprising hydrogen cyanide, ammonia and hydrogen according to a BMA process from methane and ammonia.

6. The method according to claim 1, further comprising: separating the product mixture obtained after the bringing in and/or after the bringing into an offgas comprising nitrogen, hydrogen and/or methane, and a liquid mixture comprising hydroxy-4-(methylthio)butyronitrile, and optionally purifying the offgas.

7. The method according to claim 1, wherein the product mixture obtained in the bringing further comprises 2-amino-4-(methylthio)butyronitrile and/or 2,2-bis(2-(methylmercaptoethyl)iminodiacetonitrile.

8. The method according to claim 2 further comprising: storing the product mixture obtained in the bringing at temperatures no higher than 60 C. and a pH of 2 to 8, before the product mixture is further reacted.

9. The method according to claim 2, further comprising: first reacting the product mixture obtained in the bringing with ammonia and/or ammonium salts and carbon dioxide and/or carbonic acid salts to give 5-(2-methylmercaptoethyl)hydantoin.

10. The method according to claim 9, further comprising: second reacting the 5-(2-methylmercaptoethyl)hydantoin under basic conditions with formation of carbon dioxide and ammonia to give at least one methionine salt.

11. The method according to claim 10, further comprising: at least partially recycling the ammonia and the carbon dioxide from the second reacting to the first reacting.

12. The method according to claim 10, further comprising: at least partially recycling the ammonia obtained in the second reacting to the preparing.

13. The method according to claim 10, further comprising: at least partially disposing of the ammonia obtained in the second reacting.

14. The method according to claim 2, further comprising: purifying the product mixture from the bringing by distillation by removing at least a part of water.

15. The method according to claim 12, further comprising: freeing the ammonia obtained after the second reacting from sulfur-containing compounds and optionally from CO.sub.2 before it is recycled to the preparing.

16. The method according to claim 10, further comprising: reacting the at least one methionine salt with an acid to give methionine.

17. A method for preparing a dipeptide of methionine, methionyl methionine, the method comprising: reacting 2-hydroxy-4-(methylthio)butyronitrile prepared in the method according to claim 1.

18. A method for preparing 3,6-bis(2-methylmercaptoethyl)-2,5-diketopiperazine, the method comprising: reacting 2-hydroxy-4-(methylthio)butyronitrile prepared in the method according to claim 1.

Description

EXAMPLES

Methods Used

[0061] Determination of Free Ammonia by Neutralization Titration

[0062] The content of physically dissolved ammonia in MMP-CN was determined by means of neutralization titration with hydrochloric acid with potentiometric indication of the equivalence point. For this purpose, ca. 800 mg of the sample as a solution in distilled water (5-10 mL) was initially charged (plastic disposable syringe) and titrated with 0.1 molar hydrochloric acid. The equivalence point was determined by means of pH electrode. The performance of the neutralization titration is known to those skilled in the art.

Determination of Free Hydrocyanic Acid by Means of Titration

[0063] The content of free hydrocyanic acid in MMP-CN was determined by means of argentometric back-titration with ammonium thiocyanate using potentiometric indication of the end point (Volhard titration).

[0064] For this purpose, 70 mL of 2-propanol/glacial acetic acid mixture (5.715 mL of glacial acetic acid in 2.5 L of 2-propanol), 10 mL of 0.1 molar silver nitrate solution and ca. 4 g of sample were initially charged in a titration vessel, 1 mL of glacial acetic acid was added and the mixture titrated to the end point with 0.1 molar ammonium thiocyanate standard solution. The precise sample weight was determined by differential weighing. The performance of the Volhard titration is known to those skilled in the art.

Determination of Water Content by Karl Fischer Titration

[0065] The H.sub.2O content in MMP-CN was determined by the titration method using biamperometric indication of the end point (Karl-Fischer titration).

[0066] For this purpose, 20-30 ml of titration medium (e.g. Hydranal Solvent 5 from Fluke), were initially charged in the titration vessel and titrated to dryness with titrant, (e.g. Hydranal Titrant 5 from Fluke). An amount of sample of ca. 500 mg was added to the titrated reservoir (plastic disposable syringe) and titrated with the titrant to the end point. The precise sample weight was determined by differential weighing.

[0067] The procedure of this standard method is known to those skilled in the art (see e.g. P. A. Bruttel, R. Schlink: Wasserbestimmung durch Karl-Fischer-Titration [Water determination by Karl-Fischer titration] Metrohm AG).

High Performance Liquid Chromatography (HPLC)

[0068] The majority of the chromatographic investigations (MMP-cyanohydrin, MMP, MMP-aminonitrile, methionine, methionine amide, hydantoin, hydantoin amide, Met-Met, methionine diketopiperazine) were carried out by HPLC from JASCO on an RP-18 column (2504.6 mm; 5 pm) with subsequent UV detection at 210 nm. A phosphoric acid-acetonitrile-water mixture (3.3 g H.sub.3PO.sub.4, 6.8 g acetonitrile, 89.9 g H.sub.2O) served as eluent. At a flow rate of 1 mL/min, 10 L 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 evaluated by peak area comparison by means of the external standard method. The procedure of the standard method is known to those skilled in the art.

[0069] The iminodinitrile was determined on the HPLC system specified above with identical column, flow rate and detection. In this case, a mixture of methanol and water (each 50% by weight) served as eluent. 10 L of the respective sample solution (250 mg of sample in 25 mL of eluent) were injected.

Example 1

[0070] Preparation of MMP-Cyanohydrin from Ammonia-Containing Hydrocyanic Acid

[0071] 188 g of 3-methylthiopropionaldehyde (methylmercaptopropionaldehyde, MMP) (94.0% by weight, 1.00 equiv.) from industrial production were metered in at a rate of 6 g/min at the top of a bubble-cap tray column temperature-controlled at 55 C. (5 trays, double jacketed) equipped with reflux condenser. At the bottom of the column by the countercurrent principle, a gas mixture was introduced consisting of hydrocyanic acid (47.0 g, 1.02 equiv. based on MMP, 90 g/h), ammonia (7.99 g, 0.28 equiv. based on MMP, 15.3 g/h), steam (80 g, 156 g/h) and nitrogen (230 NL, 450 NL/h) (NH.sub.3:HCN=0.27 mol/mol). The product was collected in a flask fixed to the bottom of the column and analyzed after completion of the MMP addition (ca. 30 min). A clear, colourless biphasic product was obtained. HPLC analysis revealed a total content of 145 g of MMP-cyanohydrin (MMP-CN, 65.1% based on MMP used), 33.8 g of MMP-aminonitrile (MMP-AN, 15.3% based on MMP used) and 30.6 g of iminodinitrile (14.8% based on MMP used). MMP-CN, MMP-AN and iminodinitrile are further referred to as MMP-CN equivalents.

Comparative Example 1

[0072] 188 g of 3-methylthiopropionaldehyde (methylmercaptopropionaldehyde, MMP) (94.0% by weight, 1.00 equiv.) from industrial production were metered in at a rate of 6 g/min at the top of a bubble-cap tray column temperature-controlled at 55 C. (5 trays, double jacketed) equipped with reflux condenser. At the bottom of the column by the countercurrent principle, hydrocyanic acid (47.0 g, 1.02 equiv. based on MMP, 90 g/h) and nitrogen (230 NL, 450 NL/h) were introduced. The product was collected in a flask fixed to the bottom of the column and analyzed after completion of the MMP addition (ca. 30 min). HPLC analysis of the clear, colourless reaction product (224.0 g) revealed an MMP-cyanohydrin content of 95.4% by weight (96.1% based on MMP used).

Example 2

[0073] Stability Studies of MMP-Cyanohydrin from Ammonia-Containing Hydrocyanic Acid

[0074] In a three-necked flask cooled in an ice bath, equipped with jacketed coil condenser and thermometer, 79.0 g of 3-methylthiopropionaldehyde (96.3% by weight, 1.0 equiv.) from industrial production were stirred magnetically. A gas mixture consisting of 20.8 g of hydrocyanic acid (1.05 equiv.) and 2.12 g of ammonia (0.17 equiv.) was introduced (NH.sub.3:HCN=0.16 mol/mol), the addition rate being regulated in this case such that the temperature in the reaction vessel never exceeded 40 C. On completion of addition, the mixture was stirred at room temperature for 15 min. The colourless substance obtained was divided among three Schott flasks and stored at 10 C., room temperature or 60 C. for 10 weeks. The results of the analysis after 1 day, 1 week and 10 weeks are summarized in Table 4 below.

TABLE-US-00004 TABLE 4 Storage HPLC [% by weight] Titration [% by weight] temperature Storage period MMP-CN MMP-AN Dinitrile H.sub.2O NH.sub.3 HCN 10 C. 1 day 67.3 7.6 13.3 5.61 0.01 0.82 1 week 59.7 2.0 23.6 6.21 0.01 0.77 10 weeks 60.3 0.8 25.9 6.66 0.06 1.21 RT 1 day 59.5 2.2 23.0 6.18 0.02 0.75 1 week 58.0 1.1 25.6 6.17 0.01 1.12 10 weeks 52.9 0.9 28.7 6.36 0.08 1.42 60 C. 1 day 58.6 1.0 26.4 5.48 0.03 0.72 1 week 53.8 0.7 27.3 4.97 0.01 1.22 10 weeks 52.1 0.0 28.5 4.99 0.08 1.56

[0075] The results of Example 2 summarized in Table 4 show that the MMP-CN-containing product mixture obtained according to the invention may be kept over a long period (at least up to 10 weeks) at temperatures up to 60 C. and therefore can be used for the subsequent methionine preparation steps.

Example 3

[0076] Preparation of Hydantoin from MMP-Cyanohydrin Prepared with Ammoniacal Hydrocyanic Acid

[0077] In a 300 mL autoclave beaker equipped with a stirrer bar, distilled water (52.0 g), ammonium carbonate (11.9 g) and ammonium hydrogen carbonate (30.2 g) were added to 35.0 g of MMP-cyanohydrin prepared with ammoniacal hydrocyanic acid (NH.sub.3:HCN=0.17 mol/mol), consisting of 60.1% by weight MMP-CN, 3.7% by weight MMP-AN and 20.9% by weight iminodinitrile. The reaction vessel was transferred to a high-pressure laboratory autoclave from ROTH, equipped with manometer, heater, temperature sensor and pressure release. The autoclave was tightly sealed, heated with stirring at 105 C. over a period of 15 min 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 resulting pressure (ca. 17 bar) was vented. HPLC analysis of the reaction product (121.3 g) revealed a content of 24.8% by weight hydantoin (74.9% yield based on MMP-CN equivalents used) and 6.5% by weight hydantoin amide (17.9% yield based on MMP-CN equivalents used).

Comparative Example 3

[0078] A comparative experiment for preparing hydantoin analogous to Example 3 but using MMP-cyanohydrin prepared from ammonia-free hydrocyanic acid (35.0 g, 88% by weight) gave 104.7 g of reaction product with a composition of 27.9% by weight hydantoin (71.4% yield based on MMP-CN used) and 8.2% by weight hydantoin amide (19.1% yield based on MMP-CN used).

Example 4

[0079] Preparation of Methionine from MMP-Cyanohydrin Prepared with Ammoniacal Hydrocyanic Acid

[0080] In a 300 mL autoclave beaker equipped with a stirrer bar, distilled water (39.0 g), ammonium carbonate (13.9 g) and ammonium hydrogen carbonate (23.4 g) were added to 35.0 g of MMP-cyanohydrin prepared with ammoniacal hydrocyanic acid (NH.sub.3:HCN=0.17 mol/mol), consisting of 64.5% by weight MMP-CN, 4.6% by weight MMP-AN and 19.7% by weight iminodinitrile. The reaction vessel was transferred to a high-pressure laboratory autoclave from ROTH, equipped with manometer, heater, temperature sensor, inlet tube and pressure release. The autoclave was tightly sealed, heated with stirring at 105 C. over a period of 15 min and then maintained at this temperature for a further 20 min. At the end of the reaction period, the autoclave was cooled to 70 C. in a water bath and the resulting pressure (ca. 15 bar) was vented. 40 g of aqueous KOH solution (15 g of KOH in 25 g of H.sub.2O) was then metered in via the inlet tube over a period of 10 min. After the addition was complete, the autoclave was heated with stirring at 180 C. over a period of 25 min and then maintained at this temperature for a further 30 min. During the reaction course, the pressure was vented to 5 bar around every 5 min, but at least in the case of 10 bar being 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 (118.8 g) revealed a content of 16.6% by weight methionine (54.8% yield based on MMP equivalents used), 0.7% by weight methionine amide (2.3% yield based on MMP equivalents used), 7.1% by weight methionylmethionine (24.9% yield based on MMP-CN equivalents used) and 0.4% by weight methionine diketopiperazine (1.6% yield based on MMP-CN equivalents used).

Comparative Example 4

[0081] A comparative experiment with MMP-cyanohydrin (35.0 g, 95.4% by weight) prepared from ammonia-free hydrocyanic acid gave 142.2 g of reaction product with a composition of 15.1% by weight methionine (56.5% yield based on MMP equivalents used), 1.1% by weight methionine amide (4.1% yield based on MMP-CN equivalents used), 6.2% by weight methionylmethionine (24.7% yield based on MMP-CN equivalents used) and 0.6% by weight methionine diketopiperazine (2.6% yield based on MMP-CN equivalents used).

TABLE-US-00005 TABLE 5 Comparison of the preparation of MMP-CN, hydantoin and methionine from ammonia-free vs. ammonia-containing hydrocyanic acid: Yield, % Hydantoin Methionine MMP-CN (MMP- (Hydantoin (Met-amide; Met-Met; AN; iminodinitrile) amide) Diketopiperazine) Example 1 65.1 (15.3; 14.8) Comparative 96.1 Example 1 Example 3 74.9 (17.9) Comparative 71.4 (19.1) Example 3 Example 4 54.8 (2.3; 24.9; 1.6) Comparative 56.5 (4.1; 24.7; 2.6) Example 4

[0082] The results summarized in Table 5 show that the preparation of the intermediate hydantoin and also of the end product methionine from MMP-cyanohydrin from ammonia-containing (Examples 3, 4) and ammonia-free hydrocyanic acid (Comparative Examples 3, 4) afford comparable yields and spectra of by-products.