EP3607112A1

EP3607112A1 - Method of producing vinylglycine

Info

Publication number: EP3607112A1
Application number: EP18726329.8A
Authority: EP
Inventors: Thomas Haas; Christian Richter
Original assignee: Evonik Operations GmbH
Current assignee: Evonik Operations GmbH
Priority date: 2017-04-03
Filing date: 2018-04-03
Publication date: 2020-02-12
Also published as: WO2018185084A1

Abstract

The present invention relates to a method of producing vinylglycine and/or derivatives thereof, the method comprising, - contacting glutamic acid and/or derivatives thereof with an electrolysis medium; and - subjecting the glutamic acid and/or derivatives thereof to anodic electrooxidation in an electrolytic cell to produce the vinylglycine and/or derivatives thereof, wherein the electrolytic cell comprises at least two electrodes and an electric current between the electrodes, and wherein the electric current density is ≥ 30mA/cm2 of electrode.

Description

METHOD OF PRODUCING VINYLGLYCINE

FIELD OF THE INVENTION

The present invention relates to a method of producing vinylglycine and/or derivatives thereof. In particular, the method relates to a one step method of producing vinylglycine and/or derivatives thereof from glutamic acid and/or derivatives thereof.

BACKGROUND OF THE INVENTION

One of the more important and useful unsaturated amino acids available is vinylglycine (2- aminobut-3-enoic acid). Vinylglycine, is a natural, non-protein oamino acid and is usually isolated from fungi and is known to irreversibly inhibit many enzymes that use pyridoxal phosphate (PLP) as a cofactor. Vinylglycine and derivatives thereof have thus been utilized as enzyme inhibitors and/or antibiotics.

A three-step synthesis of vinylglycine has been developed using but-3-enenitrile as the starting material based on the Neber rearrangement of the corresponding N-chloroimidate. However, this method is complicated and the starting material difficult to access. Other more common ways of preparing L-vinylglycine include the pyrolysis of protected methionine sulfoxide (MetO) and thermolysis of aryl selonoxides obtained from either L-glutamate, L-homoserine, or L- homoserine lactone. However, due to the high vacuum (≤3 mm Hg) and temperature (>150° C) requirements, isomerization is a consistent problem for the reaction. Further, the chances of the L-vinylglycine converting to the thermally stable β-methyldehydroalanine is also very high in these methods. This reduces the yield of L-vinylglycine. It is also difficult to isolate vinylglycines from the resultant reaction mixture by chromatography using this method. Vinylglycines may also be produced by contacting butadiene with an epoxidase to produce butadiene epoxide which is then hydrolysed, where the epoxide group is converted to the diol. The diol is then oxidised to the hydroxy acid and aminated to form vinylglycine. However, this method of forming vinylglycine requires many steps and is therefore costly, and may result in loss of products along the way. Other classical ways to produce vinylglycine include starting from acrolein and exploiting the Strecker or Bucherer reactions or modifcations of them. On a lab scale, multi-step syntheses start from aminomalonates or natural aminoacids and proceed via addition and/or elimination reactions.

Hanessian and Soho (Tetrahedron Letters, 25, 1425-1428, 1984) disclosed one method of producing vinylglycine from protected glutamic acid using a complicated protocol. In this method, Scheme 1 was hypothesised to have taken place. Scheme 1 : Oxidative decarboxylation of protected glutamic acid. (Tetrahedron Letters, 25, 1425-1428, 1984)

This protocol however exhibits severe drawbacks like multi step protection/deprotection chemistry and the excessive use of the toxic oxidant lead(IV) acetate. In general, the known approaches suffer from the use of expensive or toxic reagents, the need for protection groups and the number of synthetic steps, which render all known protocols to be inefficient for large scale synthesis of vinylglycine.

Accordingly, there is still a need in the art to find a different means of producing vinylglycine that does not use a non-pyrolytic large scale approach and that uses an easily available starting material. In particular, there is a need to develop a simple production process for vinylglycine and/or derivative thereof using an easily available and reasonably priced raw material.

DESCRIPTION OF THE INVENTION

The present invention attempts to solve the problems above by providing a means of producing vinylglycine and/or derivatives thereof from abundantly available glutamic acid and/or derivatives thereof. In particular, the glutamic acid and/or derivative thereof may undergo electooxidation (also known as a non-Kolbe electrolysis) to produce vinylglycine and/or derivatives thereof. The electrooxidation may be an anodic electrooxidation. This method overcomes the drawback of using toxic chemicals in the production of vinylglycine. In particular, this method allows for the production of vinylglycine using a simple method that does not involve the excessive use of toxic chemicals.

According to one aspect of the present invention, there is provided a method of producing vinylglycine and/or derivatives thereof, the method comprising,

- contacting glutamic acid and/or derivatives thereof with an electrolysis medium; and

- subjecting the glutamic acid and/or derivatives thereof to anodic electrooxidation in an electrolytic cell to produce the vinylglycine and/or derivatives thereof,

wherein the electrolytic cell comprises at least two electrodes and an electric current between the electrodes, and wherein the electric current density is about ^ 30mA cm2 of electrode. The glutamic acid and/or derivatives thereof used as a substrate for production of

vinylglycine and/or the respective derivative may be protected or unprotected. In one example, the glutamic acid and/or derivatives according to any aspect of the present invention may be unprotected. The use of unprotected glutamic acid and/or derivatives thereof simplifies the method according to any aspect of the present invention as no extra step is required to protect the glutamic acid and/or derivatives thereof. This saves time and resources. Also, usually for protection of glutamic acid, large amounts of toxic oxidant lead(IV) acetate may be used. The use of unprotected glutamic acid and/or derivatives may thereof have less health risks. Usually when an unprotected amino acid is used as a substrate in electrooxidation, many undesired products resulting from dimerization, over- elimination, reduction, and oxidation etc. of the amino acid may be produced.

Regioselectivity may also have been an expected problem. However, surprisingly when glutamic acid is subjected to anodic electrooxidation, vinylglycine was produced

unexpectedly. The method according to any aspect of the present invention offers a new substrate, unprotected glutamic acid and/or derivatives thereof, for the production of vinylglycine and/or derivatives thereof. In another example, the glutamic acid and/or derivative thereof used as substrate according to any aspect of the present invention may be protected. Protection groups might be Boc, Fmoc, Cbz or ester moieties or a combination of them. The protected glutamic acid and/or derivative thereof however may be selected from N-Boc protected glutamic acid and N- Acetyl protected glutamic acid.

Glutamic acid and glutamate is the amino acid with one of the highest production volumes in living things. The glutamate used according to any aspect of the present invention may be an L and/or a D isomer. Instead of glutamic acid or glutamate, derivatives of glutamate may be used as substrate according to any aspect of the present invention. Derivatives of glutamic acid include esters and/or amides of glutamic acid. In particular, derivatives of glutamic acid may include alkoxy esters, N-Boc protected derivatives, N-Acetyl protected derivatives, salts of glutamic acid, such as sodium glutamate etc., and homo or hetero peptides of glutamic acid.

In one example, a mixture of glutamic acid and at least one derivative of glutamic acid may be used as a substrate according to any aspect of the present invention for producing vinylglycine and/or the respective derivative.

The glutamic acid and/or derivatives thereof may be brought into contact with an electrolysis medium prior to the glutamic acid and/or derivative thereof is subjected to electrooxidation. The electrolysis medium may comprise at least one solvent. The solvent may be selected from the group consisting of methanol, ethanol, propanol, isopropanol, butanol, water, and a mixture thereof. In particular, the solvent may be water, methanol or a mixture of both. More in particular, the solvent may be water. In one example, the mixture of both water and methanol may mean the electrolysis medium comprises between about 0.5 percent to about 50 percent water by volume. The resulting mixture of the electrolysis medium and glutamic acid and/or derivative thereof may then be subject to electrooxidation. In particular, the electrooxidation may be anodic electrooxidation. The conditions of anodic electrooxidation are known in the art and may be carried out in an electrolytic/ electrochemical cell comprising electrodes (anode and cathode). In particular, the material of the electrode may be selected from the group consisting of platinum, iridium, palladium, ruthenium, rhodium, osmium, carbon, lead and a mixture thereof. More in particular, the electrode may be platinum electrodes. In one

example, the electrodes may be coated with platinum.

In a further example, the anodic and cathodic compartments may be separated by a

diaphragm or a membrane. In particular, the anode and the cathode may be separated by a semi-permeable membrane.

In particular, the electrooxidation is an example of an organic redox reaction that takes place in an electrochemical cell. This method has several advantages which include for example the possibility to control the potential of the electrode. It may also be considered a simple reaction because no reducing or oxidizing agents are required. In electrooxidation, the oxidation does not take place chemically but electrolytically. The glutamic acid and/or derivative thereof may be oxidised electrolytically to produce vinylglycine and/or the respective derivative thereof.

The vinylglycine and/or derivative thereof formed may then be easily separated by decantation, distillation, filtration, liquid-liquid extraction, crystallization or other means known in the art.

The electrolytic/ electrochemical cell may comprise at least two electrodes and an electric current between the electrodes, and the electric current may have an density of at least 30mA cm² of electrode. An electric current density equal to or greater than 30mA cm² of electrode has been shown to result in better yield of vinylglycine and/or derivatives thereof from the substrate of glutamic acid and/or derivatives thereof compared to when the substrate the subjected to a lower electric current density.

In particular, the electric current density may be about 30 mA cm². More in particular, the electric current density may be selected from the range of 30 to 2000 mA/cm². In one example, the electric current density may be selected from the range of 35-2000, 40-2000, 50-2000, 60-2000, 70-2000, 80-2000, 90-2000, 100-2000, 150-2000, 200-2000, 250-2000, 300-2000, 350-2000, 400-2000, 450- 2000, 500-2000, 550-2000, 600-2000, 650-2000, 700-2000, 750-2000, 800-2000, 850-2000, 900- 2000, 950-2000, 1000-2000, 1 100-2000, 1 150-2000, 1200-2000, 1250-2000, 1300-2000, 1350- 2000, 1400-2000, 1450-2000, 1500-2000 mA/cm² and the like. In another example, the electric current density present according to any aspect of the present invention may be about 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1 100, 1 150, 1200, 1250, 1300, 1350, 1400, 1450, 1500, 1550, 1600, 1650, 1700, 1750, 1800, 1850, 1900, 1950 mA/cm² and the like. More in particular, the current density may be 250- 500 mA/cm², 250-400 mA/cm², 250-350 mA/cm², or 250-300 mA/cm² of electrode.

According to any aspect of the present invention, the electrooxidation step may comprise the presence of a salt, usually the alkali salt of the glutamic acid, water and two metal electrodes. The salt may be an electrolyte and the electrolyte may be present in the electrolysis medium to improve the movement of the substrate, glutamic acid and/or derivative thereof, between the electrodes. The electrolyte may be an organic or inorganic salt. In particular, the electrolyte may be selected from the group consisting of a halide salt, an oxide salt, a perchlorate salt, a borate salt, a carbonate salt, a phosphate salt and mixtures thereof. More in particular, the electrolyte may be selected from the group consisting of perchlorate salt, a p-toluenesulfonate salt, a tetrafluoroborate salt, and mixtures thereof.

In another example, the electrooxidation may be performed in methanol instead of water as solvent. Platinum electrodes may be used in this example as well. The use of methanol may be considered advantageous as it may yield excellent conversion rates and continuous electrolysis. Selectivity of the electrolysis may be improved with the use of methanol. In particular, methanol or mixtures of methanol and water may be used in combination with protected glutamic acid as substrate for solubility reasons.

Matthessen R., et al, (2014) Eur. J Org Chem. reported that the choice of solvent and redox mediator is of great importance for the reaction outcome.

The pH of the electrolysis medium may be adjusted to a value between 5 and 10. In particular the pH may be between 5 and 8. more in particular the pH may be selected from 5 to 7. The pH of the electrolysis medium according to any aspect of the present invention may be maintained by using an acid or alkali where necessary. A skilled person would understand how to modify the electrolysis medium to maintain the pH throughout the method according to any aspect of the present invention. In one example, KOH may be used to adjust the pH. In another example, hydroxides, metal oxides, carbonates, phosphates, amines, carboxylic acids, mineral acids and mixtures thereof may be used to adjust and maintain the pH. A skilled person would be capable of maintaining the pH by methods known in the art. In particular, the skilled person would regularly measure the pH of the electrolysis medium and adjust the pH by adding an acid or base to the electrolysis. In one example, a base such as KOH may be added to the electrolysis medium automatically as the pH is measured automatically. In another example, this addition may be manual.

The anodic electrooxidation may be conducted at a temperature in a range of 15 °C to 100 °C. In particular, the mixture comprising the electrolysis medium with the adjusted pH and glutamic acid and/or derivatives thereof may be introduced into the tank of an electrolysis cell comprising electrodes, particularly platinum, and the temperature may be close to ambient temperature.

particularly from 15° to 20° C. A potential difference sufficient to cause the substrate, glutamic acid and/or derivative thereof, to be traversed by an electric current is required between the electrodes. In one example, an electrolyte may be present in the electrolysis medium to aid in the movement of the substrate. The voltage may be between 5-10V, 6-9 V, 7-9V or 7-10V. In particular, the voltage may be about 7V and the current about 300A to give an optimum yield. As used herein, the terms "about" and "approximately", as applied to the conditions for electrooxidation refer to a range of values that are similar to the stated reference value for that condition. In certain examples, the term "about" refers to a range of values that fall within 25, 20, 19, 18, 17, 16, 15, 14, 13, 12, 1 1 , 10, 9, 8, 7, 6, 5, 4, 3, 2, 1 percent or less of the stated reference value for that condition. For example, a temperature employed during the method according to any aspect of the present invention when modified by "about" includes the variation and degree of care typically employed in measuring in an experimental condition in production plant or lab. For example, the temperature when modified by "about" includes the variation between batches in multiple experiments in the plant or lab and the variation inherent in the analytical method. Whether or not modified by "about," the amounts include equivalents to those amounts. Any value stated herein and modified by "about" can also be employed in the present invention as the amount not modified by "about."

In particular, the desired product according to any aspect of the present invention may be vinylglycine and/or derivatives thereof. Vinylglycine has a general chemical formula of C4H7NO2 and a structural formula of:

The derivatives of vinylglycine may be selected from the group consisting of amides of vinylglycine, esters of vinylglycine, rhizobitoxin, aminoethoxyvinylglycine, amine esters of vinylglycine, amide esters of vinylglycine, HCI-Salts of vinylglycine, a protected amino acid of vinylglycine and the like. Protection groups might be Boc, Fmoc, Cbz or ester moieties or a combination of them. In particular, the derivatives of vinylglycine may be selected from the group consisting of rhizobitoxin, aminoethoxyvinylglycine, amine esters of vinylglycine, amide esters of vinylglycine, amides of vinylglycine, esters of vinylglycine and vinylglycine peptides. More in particular, the derivative of vinylglycine that may be formed according to any aspect of the present invention may depend on the starting material- the derivative of glutamic acid used.

In one example, only vinylglycine may be produced according to any aspect of the present invention as the starting material used was glutamic acid. In another example, a mixture of vinylglycine and at least one derivative may be formed as the starting material used in the method according to any aspect of the present invention may have been glutamic acid and at least one derivative thereof. In yet another example, the starting material according to any aspect of the present invention may have been a mixture of glutamic acid derivatives and the resultant product may be the respective mixture of derivatives of vinylglycine.

According to a further aspect of the present invention, there is provided a method of producing methionine, the method comprising,

(a) producing vinylglycine and/or derivatives thereof according to any aspect of the present invention; and (b) contacting the vinylglycine and/or derivatives thereof of (a) with a free radical methyl mercaptan.

An intermediate step between steps (a) and (b) according to this aspect of the present invention involves a step of separating the vinylglycine and/or derivative thereof before bringing the vinylglycine and/or derivative thereof in contact with the free radical methyl mercaptan

The term "contacting", as used herein, means bringing about direct contact between the vinylglycine and/or derivatives thereof, used as a substrate, and the free radical methyl mercaptan. For example, the vinylglycine may be introduced into an aqueous medium comprising methyl mercaptan.

Methyl mercaptan also known as methanethiol has a chemical formula of ChUS and structure of Formula II:

Formula II

The free-radical addition of a methyl mercaptan to vinylglycine may result in the radicalized methyl mercaptan to acting on the terminal carbon-carbon double bond of vinylglycine to produce 2-amino 4- (methylthio) butanoic acid. This step has an advantage of producing L- and/or D-methionine economically through having high conversion rates and short reaction time. Further, compared to methods used in the art where acetylhomoserine is used as the substrate for methyl mercaptan activity, the use of vinylglycine has other advantages. For example, using acetylhomoserine as the substrate for methyl mercaptan activity results in the production of a side product, acetic acid. This production may be considered to be a loss in carbon, where not all the carbon from the substrate (i.e. acetylhomoserine) is converted to the target product, methionine. Also, with acetic acid release, the methionine partly absorbs the scent of acetate. The methionine produced using this method thus has a trace of acetate. These problems may be overcome by the method according to any aspect of the present invention. The method according to any aspect of the present invention thus has an advantage of producing L-methionine and/or D-methionine economically through having high conversion rates and short reaction time.

On the other hand, using vinylglycine as a substrate for the activity of radicalized methyl mercaptan does not have the same disadvantages as those mentioned when acetylhomoserine is used. Firstly, there is no loss of carbon as all the carbon in vinylglycine is converted to be part of methionine. There is also no production of acetic acid. Further, the substrate vinylglycine can be synthesized easily from readily available glutamate, the amino acid with one of the highest production volumes in living things. The glutamate may be the L and/or the D isomer. The radicalized methyl mercaptan step, also known as Thiol- ene coupling reaction, may also be considered to be relatively selective as no side product may be released when vinylglycine is used as the substrate.

The free radicalization of methyl mercaptan by any means known in the art may result in the breaking of the sulfur- hydrogen bond in methyl mercaptan to produce a methyl mercaptan free radical. The methyl mercaptan free radical may then act across the terminal carbon-carbon double bond in the vinylglycine. This action may result in the double bond being reduced to a single bond and a methylthio group added according to the Anti- arkovnikov rule at the terminal carbon atom. The unpaired electron on the adjacent, non-terminal carbon atom in the substrate binds with a hydrogen atom supplied by the methyl mercaptan, thereby creating another methyl mercaptan free radical and this continues the addition cycle.

In particular, the ratio of methyl mercaptan to vinylglycine or derivatives thereof may be 1 :1 , particularly in the reaction medium. However, a skilled person would be capable of varying this ratio depending on the initiator used to form the radical. In one example, the ratio of methyl mercaptan to vinylglycine or derivatives thereof may be selected from the range of 1 :1 to 1 :10. In particular, the ratio may be 1.2: 1. In one example, the ratio of methyl mercaptan to vinylglycine or derivatives thereof may be selected from 3:1-6: 1. This may be advantageous according to any aspect of the present invention as in Thiol-ene coupling reactions, an excess of Thiol may be necessary.

In one example, the free radicalization of methyl mercaptan may be carried out by contacting the methyl mercaptan with at least one free radical initiator. There are several initiators that may be used according to any aspect of the present invention. A skilled person may be capable of identifying these initiators. For example, the free radical initiator may be selected from the group consisting of azobisisobutyronitrile (AIBN), N-bromosuccinimide (NBS), dibenzoyl peroxide (DBPO), Vazo®-44 (2,2'-azobis[2-(2-imidazolin-2-yl)propane]dichloride) and the like. When in contact with any of these free radical initiators, the methyl mercaptan may be radicalized to produce a free radical that may then react with the vinylglycine to produce methionine. In one example, AIBN is the free radical initiator. AIBN is thermally stable at room temperature.

However, upon being heated to an activation temperature it produces a free radical which may then start the free radical addition chain reaction with vinylglycine. In another example, the Vazo®-44 may be the free radical initiator. The VAZO® series of free radical initiators are available from DuPont Chemicals of Wilmington, Delaware, U.S.A. In particular, the free radical initiator may be selected from the group consisting of azobisisobutyronitrile (AIBN) and 2,2- azobis (2-(2-imidazolin-2-yl)propane) dihydrochloride. In another example, instead of using a chemical agent like a free radical initiator to radicalize methyl mercaptan, an ultraviolet light source may be used. The UV light may be at wavelengths of 300nm or 365nm. In particular, the UV light may have a wavelength of 300nm. In a further example, free radicalization of the methyl mercaptan may be carried out by a combination of UV light and a photo initiator such as 2,2-Dimethoxy-2-phenylacetophenone (DPAP). In this example, the UV light may have a wavelength of 365nm.

In one example, free radicalization of the methyl mercaptan may be carried out without an additional initiator. In this example, no chemical initiator and/or UV rays are needed.

Radicalization of methyl mercaptan may take place autocatalytically upon heating or may assisted by ultrasonic sound or impurities (e.q. oxygen). A skilled person would be capable of carrying out the radicalization using a variety of means. Reactions without additional chemical initiator may however suffer from low reaction rates and yields. In all the above examples, the step of free radicalization of methyl mercaptan may be carried out at the same time as the conversion of vinylglycine to methionine. Therefore, both steps of free radicalization and conversion of vinylglycine to methionine may be carried out in the same pot.

For example, when a temperature activated free radical initiator such as AIBN is used, the temperature and pressure conditions of the reaction are firstly maintained such that the reactants (i.e. methyl mercaptan, vinylglycine and AIBN) are present as liquids and the temperature is below the activation temperature of the free radical initiator. The order of introduction of the reactants and free radical initiator into the pot is unimportant as the

conditions of the reaction mixture in the pot are such that essentially no reaction occurs. When the temperature is increased, the reaction kick starts and radicalized AIBN results in the formation of the free radical of methyl mercaptan which then attacks the C double bond in vinylglycine to form methionine.

In particular, the ratio of free radical initiator to methyl mercaptan may be within the range of 1 : 10000 to 1 :5. More in particular, the ratio of the free radical initiator to methyl mercaptan may be within the range of 1 : 10000 to 1 :10. Even more in particular, the ratio of the free radical initiator to methyl mercaptan may be about 1 : 1000, 1 :500, 1 : 100, 1 :50, 1 :20, 1 :30, 1 : 10, 1 :3 and the like.

In another example, the pot may have a translucent portion (e.g., a reactor window) where UV light may be shone into the pot. Alternatively, the ultraviolet light source may be disposed within a translucent envelope extending into the pot. The UV light in the reaction pot may then radicalize the methyl mercaptan in the pot. The process may take at least about 5 hours or more. The reaction mixture may then be cooled to room temperature and excess methyl mercaptan may be allowed to volatilize and is removed from the reaction pot. The excess methyl mercaptan may then be recovered for reuse. Methionine may then be left behind in the pot.

In a further example, the pot with a translucent portion may comprise vinylglycine, a photo initiator like DPAP and methyl mercaptan. Without UV light, no reaction takes place in the pot. When UV light at 365nm is introduced into the pot by any means known in the art, the photo initiator may be activated to radicalize methyl mercaptan. The free radical of methyl mercaptan may then act on vinylglycine to produce methionine. The excess vinylglycine may then be removed as described above and recycled. The resultant product in the pot may then be only methionine.

EXAMPLES

The foregoing describes preferred embodiments, which, as will be understood by those skilled in the art, may be subject to variations or modifications in design, construction or operation without departing from the scope of the claims. These variations, for instance, are intended to be covered by the scope of the claims.

Example 1

Oxidative decarboxylation of glutamic acid to vinylglycine under anodic electrooxidation

The anodic electrooxidation of glutamic acid (1 M) with KOH (1 eq.) was carried out in water (20 mL) with platinum electrodes (0.567 cm²). A row of experiments was carried out under different conditions (see table 1 ). After the indicated reaction time, the current was switched off and the water was evaporated. The residue was dried in vacuum and afterwards analyzed by H-NMR to determine the ratio of glutamic acid to vinylglycine. The signal set of vinylglycine was confirmed by measuring pure reference material.

Table 1. Oxidative decarboxylation of glutamic acid (a sample of entry 1 was analyzed by chiral LC-MS to determine the ee of vinylglycine: 97% ee) Example 2

Synthesis of methionine starting from vinylglycine via Thiol-ene-coupling (TEC) under ambient pressure.

In a flask (100 mL) equipped with a reflux condenser vinylglycine (1.01 1 g, 10.00 mmol, 1.00 eq.) is dissolved in methanol/water (1/1 , 40 mL) and AIBN (0.082 g, 0.50 mmol, 0.05 eq.) was added. Sodium thiomethoxide (6.205 g, 60.00 mmol, 6.00 eq.) was placed in a second flask and dissolved in distilled water (10 mL). The second flask (50 mL) was equipped with a dropping funnel (25 mL), which contained hydrochloric acid (6 M, 12 ml). The acid was added dropwise to the thiomethoxide solution over a period of 20 minutes to liberate gaseous methylmercaptan, which was passed into the flask with the Vinylglycine. The flask with the vinylglycine solution was kept at 60 °C for 12 h. This flask was connected to gas washing bottles, which contained a sodium hydrogen peroxide solution (dist. water (100 mL), H202 (35%, 40 mL), NaOH (5.21 g)) in order to destroy escaping methylmercaptan. After heating for 12 h, a nitrogen stream was passed through the reaction mixture for 16 h to push all remaining methylmercaptan into the hydrogen peroxide trap. The residual reaction mixture was evaporated and the off-white residue was analyzed by 1 H-NMR. The NMR measurement revealed that 1 % of the vinylglycine was converted to methionine.

Example 3

Synthesis of methionine starting from vinylglycine via Thiol-ene-coupling (TEC) under excess pressure.

Vinylglycine (1.01 1 g, 10.00 mmol, 1 .00 eq.) and AIBN (0.082 g, 0.50 mmol, 0.05 eq.) was dissolved in methanol/water (1/1 , 40 mL) in a stainless steel autoclave (300 mL). On one side the autoclave was connected to a methylmercaptan gas cylinder via a U-shaped glass tube. The glass tube acted as an intermediate reservoir for methylmercaptan. On the other side the autoclave was connected to gas washing bottles, which contained a sodium hydrogen peroxide solution (dist. water (100 mL), H2O2 (35%, 40 mL), NaOH (5.21 g)) in order to destroy escaping methylmercaptan. The whole apparatus was gently flushed with nitrogen for 20 min. The valves of the autoclave were then closed and the glass tube was cooled down below -30 °C. The gas cylinder was slowly opened to begin condensing of methylmercaptan inside the glass tube. Having condensed a sufficient amount of methylmercaptan (3 mL, 60 mmol, 6 eq.) the gas cylinder was closed again. Next, the autoclave was cooled down below -30 °C and the valve between autoclave and glass tube was opened. The cooling bath of the glass tube was replaced by a water bath to enable condensation of the methylmercaptan inside the autoclave. After complete evaporation of the methylmercaptan inside the glass tube, the autoclave was sealed and the reaction mixture was heated at 60 °C for 18 h (final pressure at 3.5 bar).

Afterwards, the autoclave was cooled down below -30 °C (no excess pressure) and the apparatus was pressurized with nitrogen (ca. 1.2 bar). The valves of the autoclave were carefully opened and a nitrogen stream was passed through the reaction mixture for 22 h to push all remaining methylmercaptan into the hydrogen peroxide trap. Then the autoclave was opened and the yellowish residue was suspended in methanol/water (1/1 , 40 mL). The precipitated methionine was filtered off, washed with methanol (2 x 20 mL) and dried in vacuum. The methionine (0.50 g, 34%, purity<NMR): 98%) was obtained as an off-white solid. The combined filtrates were evaporated and the residue (0.90 g) was analyzed by H-NMR. The NMR measurement revealed that the residue is a mixture of vinylglycine and methionine in a ratio of 27 to 73. Therefore, the overall conversion from vinylglycine to methionine can be calculated to 81 %.

Example 4 Synthesis of methionine starting from vinylglycine via Thiol-ene-coupling (TEC) under excess pressure at lower pH.

Vinylglycine (1.01 1 g, 10.00 mmol, 1.00 eq.) and AIBN (0.082 g, 0.50 mmol, 0.05 eq.) was dissolved in methanol/water (1/1 , 40 mL) in a stainless steel autoclave (300 mL). Acetic acid (1.201 g, 20.00 mmol, 2.00 eq.) was added to the solution (pH = 2.5 - 3). Afterwards, methylmercaptan (3 mL, 60 mmol, 6 eq.) was condensed into the reaction mixture and the autoclave was sealed. (For more details how to handle methylmercaptan see procedure above.) The reaction mixture was heated at 68 °C for 23 h (final pressure at 2.9 bar). The reaction was cooled down and the methylmercaptan was removed. The solvent of the obtained suspension was removed and the residue was washed with EtOH (2 x 10 mL). The off-white solid (0.77 g) was dried in vacuum and analyzed by H-NMR. The NMR measurement revealed that the residue is a mixture of vinylglycine and methionine in a ratio of 13 to 87.

Example 5

Synthesis of methionine starting from vinylglycine via Thiol-ene-coupling (TEC) under excess pressure without radical starter. Vinylglycine (1 .01 1 g, 10.00 mmol, 1.00 eq.) was dissolved in methanol/water (1/1 , 40 mL) in a stainless steel autoclave (300 mL). Afterwards, methylmercaptan (3 mL, 60 mmol, 6 eq.) was condensed into the reaction mixture and the autoclave was sealed. (For more details how to handle methylmercaptan see procedure above.) The reaction mixture was heated at 66 °C for 22 h (final pressure at 3.2 bar). The reaction was cooled down and the methylmercaptan was removed. The solvent of the obtained solution was removed and the residue was dried in vacuum. Analysis by H-NMR revealed that the residue (1 .06 g) is a mixture of vinylglycine and methionine in a ratio of 88 to 12. Example 6

Synthesis of methionine starting from vinylglycine via Thiol-ene-coupling (TEC) under excess pressure with peroxo radical starter.

Vinylglycine (1 .01 1 g, 10.00 mmol, 1.00 eq.) and ammonium peroxodisulfate (0.024 g, 0.10 mmol, 0.01 eq.) was dissolved in methanol/water (1/1 , 40 mL) in a stainless steel autoclave

(300 mL). Afterwards, methylmercaptan (3 mL, 60 mmol, 6 eq.) was condensed into the reaction mixture and the autoclave was sealed. (For more details how to handle methylmercaptan see procedure above.) The reaction mixture was heated at 66 °C for 23 h (final pressure at 3.2 bar). The reaction was cooled down and the methylmercaptan was removed. The solvent of the obtained solution was removed and the residue was dried in vacuum. Analysis by H-NMR revealed that the residue (1.12 g) is a mixture of vinylglycine and methionine in a ratio of 77 to 23.

Claims

1. A method of producing vinylglycine and/or derivatives thereof, the method comprising,

contacting glutamic acid and/or derivatives thereof with an electrolysis medium; and subjecting the glutamic acid and/or derivatives thereof to anodic electrooxidation in an electrolytic cell to produce the vinylglycine and/or derivatives thereof,

wherein the electrolytic cell comprises at least two electrodes and an electric current between the electrodes, and

wherein the electric current density is > 30mA/cm² of electrode.

2. The method according to claim 1 , wherein the electric current density is in the range of 30 to 2000 mA/cm² of electrode.

3. The method according to either claim 1 or 2, wherein the electric current density is about 300 mA cm² of electrode.

4. The method according to any one of the preceding claims, wherein the electrolysis medium comprises a solvent selected from the group consisting of methanol, ethanol, propanol, isopropanol, butanol, water, and a mixture thereof.

5. The method according to claim 4, wherein the solvent is water.

6. The method according to any one of the preceding claims, wherein the vinylglycine derivative is selected from the group consisting of rhizobitoxin, aminoethoxyvinylglycine, amine esters of vinylglycine, amide esters of vinylglycine, amides of vinylglycine, esters of vinylglycine and vinylglycine peptide.

7. The method according to any one of the preceding claims, wherein the glutamic acid and/ or derivatives thereof are unprotected.

8. The method according to any of the preceding claims, wherein the electrolysis medium

comprises at least one organic or inorganic electrolyte.

9. The method according to claim 8, wherein the electrolyte is selected from the group consisting of a halide salt, an oxide salt, a perchlorate salt, a borate salt, a carbonate salt, a phosphate salt and mixtures thereof.

10. The method according to any one of the preceding claims, wherein at least one electrode used in the anodic electrooxidation is of a material selected from the group consisting of platinum, iridium, palladium, ruthenium, rhodium, osmium, carbon, lead and a mixture thereof.

1 1. The method according to any one of the preceding claims, wherein the anode and cathode used in the anodic electrooxidation is of platinum.

12. A method of producing methionine, the method comprising,

(a) producing vinylglycine and/or derivatives thereof according to any one of claims 1 to 1 1 ;

(b) contacting the vinylglycine or derivatives thereof of (a) with a free radical methyl

mercaptan.

13. The method according to claim 12, wherein the ratio of methyl mercaptan to vinylglycine or derivatives thereof is 1 :1-1 : 10.

14. The method according to either claim 12 or 13, wherein the free radical methyl mercaptan is formed by contacting methyl mercaptan with at least one free radical initiator in the reaction medium.

15. The method according to claim 14, wherein the free radical initiator is selected from the group consisting of azobisisobutyronitrile (AIBN), N-bromosuccinimide (NBS), dibenzoyl peroxide (DBPO) and 2,2-Azobis (2-(2-imidazolin-2-yl)propane) dihydrochloride.