WO2025052079A1 - Process for the synthesis of methionine and analogs thereof - Google Patents

Abstract

The invention relates to a continuous process for the production of methionine or any methionine derivative chosen from its esters, its amides, its hydroxy and oxo analogs, the esters of said analogs and the amides of said analogs, from hydrogen sulfide or methanethiol, said process comprising the biological reduction of oxygen-containing sulfur compounds chosen from sulfates resulting from said process, to give hydrogen sulfide and/or methanethiol, said process comprising the following steps: providing a reactor with gas-permeable membrane(s), of MBfR (Membrane Biofilm Reactor) type, said membrane consisting of hollow fibers defining an inner lumen and an outer surface of the membrane, immersing the reactor membrane(s) in an aqueous liquid medium which comprises at least the oxygen-containing sulfur compound(s) and sulfate-reducing microorganisms (SRMs), so as to bring the outer surface or the lumen of the membrane into contact with said medium, injecting an electron-donating compound, in gaseous form, into the lumen of the membrane if its outer surface is in contact with the aqueous liquid medium, or in contact with the outer surface of the membrane if its lumen is in contact with the aqueous liquid medium, after sulfate reduction of the oxygen-containing sulfur compound(s) of the aqueous liquid medium by the SRMs, recovering the hydrogen sulfide and/or methanethiol from said aqueous liquid medium, reacting the hydrogen sulfide with methanol to obtain methanethiol and/or reacting the methanethiol with a precursor of methionine or of one of its derivatives in order to obtain, in one or more steps, a methionine salt or a salt of its derivatives, neutralizing said methionine salt or salt of one of its derivatives in the presence of sulfuric acid, and recovering the methionine or one of its derivatives and recycling the sulfates resulting from this neutralization into said aqueous liquid medium.

Description

DESCRIPTION

TITLE: PROCESS FOR THE SYNTHESIS OF METHIONINE AND ANALOGUES

The invention relates to a method for the synthesis of sulfur compounds comprising biological production of sulfides.

Sulphide means S ^2- , HS- and any chemical compound consisting of one or more sulfur atoms, said sulfur having an oxidation state of -2, combined, by covalent bond(s), with one or more atoms and/or one or more groups of atoms, said atoms being chosen at least from hydrogen and carbon. Thus, this definition includes hydrogen sulfide (H2S), carbon disulfide (CS2), thiols corresponding to the formula R-SH and thioethers corresponding to the formula RS-R', formulas in which R and R' are hydrocarbon groups, identical or different, and containing or not one or more heteroatoms.

They are used in the synthesis of sulfur compounds. Thus, hydrogen sulfide (H2S), a major representative of sulfides, is widely used in the chemical industry to produce sulfuric acid, thiols, thioethers, as well as inorganic sulfides. Thiols, such as methylthiol (or methyl mercaptan, CH3SH) are mainly used as synthesis intermediates in the manufacture of jet fuels, insecticides, fungicides, fumigants, dyes, pharmaceuticals and other chemicals, or to odorize odorless toxic gases. Thioethers also have applications in very diverse fields, including pharmacy, agriculture, biology, but also as synthesis intermediates.

Hydrogen sulfide is primarily produced by the high-temperature chemical reaction of methane with mineral sulfur, or native sulfur, extracted from quarries or volcanic sites under often extremely hazardous conditions. H2S is a flammable gas that produces toxic fumes and is highly reactive with oxidizing agents, making it very dangerous to handle.

Among the industrially produced sulfur compounds is methionine, an essential amino acid for humans and animals, which is a thioether widely used, particularly as a food supplement, and in considerable volumes in animal nutrition for farm animals.

The synthesis routes for methionine and its derivative hydroxymethylthiobutyric acid (HMTBA), also used as a source of bioavailable methionine, are numerous, but they all use a sulfide, for example methylthiol (or methyl mercaptan) involving the upstream use of hydrogen sulfide and therefore mineral sulfur. Thus, as described in document EP0022697A, methylthiol can be reacted with acrolein to obtain methylthioproprionaldehyde (AMTP or MMP) in as an intermediate in the synthesis of methionine and derivatives. Document WO2008/006977 describes the production of methionine by ammoniacal hydrolysis of 2-hydroxy-4-methylthiobutyronitrile, the latter being derived from a reaction of acrolein with hydrocyanic acid, followed by the addition of methylthiol. Document WO1998/032735 describes a synthesis of methionine or its analogues by radical addition of methylthiol to a compound chosen in particular from 2-amino-3-butenoic acid, 2-hydroxy-3-butenoic acid, esters and amide of 2-hydroxy-3-butenoic acid. Document WO2017/191196 also describes a synthesis of methionine by radical addition of methylthiol to vinyl glycine (or 2-amino-3-butenoic acid).

These processes provide direct or indirect access to methionine, methionine derivatives or methionine salts or its derivatives. The transformation of the synthesis intermediates of methionine, its derivatives, its salts or the salts of its derivatives is well known to those skilled in the art. Thus, the aldehyde AMTP can be reacted with hydrocyanic acid to obtain 2-hydroxy-4-methylthiobutyronitrile. The latter can be converted into methionine hydantoin (5-(2-methylmercaptoethyl)hydantoin) by ammoniacal hydrolysis which is then saponified into methioninate, as described for example in documents US2557920A and US5990349A.

Given the volumes of hydrogen sulfide involved in the aforementioned industries, there is a real need to develop sulfide synthesis processes involving less mineral sulfur and limiting the synthesis and treatment of H2S.

The invention aims to provide an alternative for the synthesis of methionine or its derivatives, involving sulfides which are obtained from oxidized sulfur compounds which may be present in a medium, for example a reaction medium, as excess reagent or reaction by-products, and which can thus be recycled as synthesis intermediates for the manufacture of other sulfides, without resorting to mineral sulfur or exogenous H2S. More generally, any source of oxidized sulfur compounds is suitable, and in particular whether it is natural such as gypsum or industrial as indicated above. The solution provided by the invention also has the advantage of operating biologically by using microorganisms, and of being neither toxic nor polluting. The process of the invention uses MBfR reactor technology (Membrane Biofilm Reactor).

MBfR technology using hydrogen (also called H2-MBfR) as a substrate has been studied in recent years for the treatment of oxyanions such as perchlorates, selenates, chromates, etc., and more specifically nitrates in urban wastewater or groundwater. It has been studied to a much more limited extent in the treatment of sulfated water. The work of Jl Suarez et al., Chemosphere 244 (2020) 125508 describes a biological process for treating mining water loaded with sulfate ions SC ^2- and calcium ions Ca ²⁺ in MBfR reactors (Membrane Biofilm Reactor), with a view to their decontamination via the reduction of sulfates by autotrophic sulfate-reducing bacteria (SRB). The reactors consist of a multiplicity of hollow fibers which are fed by one of their ends with H2 possibly mixed with CO2 used as a carbon source. They are immersed in the water to be treated and the consumption of sulfate ions is analyzed. If, from the first days, the sulfates are efficiently consumed, the system is quickly saturated due to the accumulation of sulfides and carbonates formed and requires regular acidification of the environment.

According to the document, A. Schwarz et al., Science of the Total Environment 740 (2020) 140088, another process is known for the biological treatment of sulfate-laden mine waters with a view to converting them into elemental sulfur, said process involving a reduction of sulfates into sulfides and then an oxidation of sulfides into elemental sulfur, in two MBfR reactors, involving SRB bacteria chosen from bacteria of the genus Desulfovibrio and Desulfomicrobium for the first reactor and sulfur-oxidizing bacteria chosen from bacteria of the genus Thiofaba, Thiomonas, Acidthiobacillus and Sulfuricurvum, for the second reactor. However, this process does not achieve its promises due in particular to the excess presence of bacteria of the genus Sulfurospirillum initially present in the effluent to be treated and whose proliferation caused by soluble microbial products produced by the different microorganisms saturates the system.

According to the invention, a process has been developed using MBfR technology to produce, in a continuous process, on an industrial scale, methionine or its derivatives without using mineral sulfur or exogenous HhS, or using them in much smaller quantities than conventional processes.

Thus, the invention resides in a continuous process for the production of methionine or any of its derivatives chosen from its esters, its amides, its hydroxy and oxo analogues, the esters of said analogues and the amides of said analogues, from hydrogen sulphide or methanethiol, said process comprising the reduction, by biological means, of oxidized sulphur compounds chosen from the sulphates resulting from said process, into hydrogen sulphide and/or methanethiol, said process comprising the following steps, a gas-permeable membrane reactor of the MBfR type (for Membrane Biofilm Reactor) is provided, said membrane being made up of hollow fibres defining an internal lumen and an external surface of the membrane, the membrane(s) of the reactor are immersed in an aqueous liquid medium which comprises at least the oxidized sulphur compound(s) and sulphate-containing microorganisms reducing agents (MSR), so as to bring the external surface or the lumen of the membrane into contact with said medium, an electron donor compound is injected, in gaseous form, into the lumen of the membrane if its external surface is in contact with the aqueous liquid medium, or into contact with the external surface of the membrane if its lumen is in contact with the aqueous liquid medium, after sulfate reduction of the oxidized sulfur compound(s) of the aqueous liquid medium by the MSR, hydrogen sulfide and/or methanethiol are recovered from said aqueous liquid medium, hydrogen sulfide is reacted with methanol to obtain methanethiol and/or methanethiol is reacted with a precursor of methionine or one of its derivatives to obtain in one or more stages a methionine salt or a salt of its derivatives, said salt is neutralized to methionine or one of its derivatives in the presence of sulfuric acid, and the methionine or one of its said derivatives and the sulfates resulting from this neutralization are recycled in said aqueous liquid medium.

Sulfate-reducing microorganisms (SRMs) include sulfate-reducing bacteria (SRBs) and sulfate-reducing archaea (SRAs) that can perform anaerobic respiration using sulfate (SCk ² ) as the final electron acceptor, reducing it to hydrogen sulfide (H2S).

This is why the invention presents an interest which may prove essential in the synthesis of certain sulfides and in particular in that of methionine or any derivative, in particular its hydroxy analogues, 0x0, its esters and the esters of its analogues, its amides and the amides of its analogues. Indeed, the manufacture of methionine involves a final stage of neutralization of the methioninate into methionine by the addition of sulfuric acid, generating sulfate salts which are difficult to recycle and are really problematic in view of the quantities produced.

As will be illustrated in the examples, the yield and reproducibility of such a transformation are unexpected in view of the biological entities involved.

The methionine derivatives are chosen from its esters, its amides, its hydroxy and oxo analogues, the esters of said analogues and the amides of said analogues. The esters are advantageously chosen from alkyl esters, preferably C-i-Cs alkyl esters. The amides are advantageously primary amides in which the nitrogen atom linked to the carbonyl group is also linked to H and/or one or two alkyl groups, preferably C-i-Cs.

This process can be extended to the preparation of salts of methionine or any of its derivatives, in particular the salts of a metal chosen from Li, Na, K, Mg, Ca, Mn, Fe, Co, Ni, Cu, Zn, Pt. Thus, according to a variant of the process of the invention, the step of neutralizing the salt into methionine or one of its derivatives, in the presence of sulfuric acid, may be only partial, and in addition to methionine or one of its said derivatives, a salt of methionine or one of its said derivatives is recovered.

Salts or complexes of methionine or one of its said derivatives can also be obtained from methionine or one of its derivatives as prepared according to the process, as taught by way of example by document W02012/038660.

Of course, preferential modes of this process allow to optimize the results, their characteristics are described below, they can be considered alone or in combination.

Advantageously, the electron donor compound, in gaseous form, opposite the aqueous liquid medium comprising the MSRs, i.e. in the lumen of the membrane if its external surface is in contact with the aqueous liquid medium, or in contact with the external surface of the membrane if its lumen is in contact with the aqueous liquid medium, is chosen from H2, carbon monoxide and any organic compound capable of being used by the MSRs such as methane, as well as mixtures thereof.

All MSRs use a carbon source. It is preferably chosen from sugars, carboxylic acids such as formic acid, acetic acid, propanoic acid, butanoic acid and lactic acid, alcohols such as methanol and ethanol, carbon dioxide, carbonates, bicarbonates, carbon monoxide, as well as mixtures thereof. This carbon source may be present in the aqueous liquid medium, in particular at the time of immersion of the membrane(s). It may also be introduced into the aqueous liquid medium, during the process, directly or indirectly. According to a particular method, it is in gaseous form and is injected into the lumen of the membrane if its external surface is in contact with the aqueous liquid medium, or in contact with the external surface of the membrane if its lumen is in contact with the aqueous liquid medium.

In a variant of the process, the electron-donating compound is also the carbon source, for example, carbon monoxide.

Preferably, the pH of the aqueous liquid medium is adjusted to a value greater than or equal to 7, preferably from 7 to 10. This adjustment can be carried out by adding an acid solution or by injecting gaseous CO2 through the membranes instead of or mixed with hydrogen.

The membranes involved in a method of the invention are made of a material conventionally used in MBfR reactor technology; thus, it can be chosen from composite materials such as a urethane/polyethylene based material (marketed under reference MHF 200TL), polypropylene, polydimethylsiloxane, polyvinylidene fluoride, polyvinyl chloride.

According to a preferred implementation of the invention, the MSRs are in the form of a mixture of microorganisms. We speak of a sulfate-reducing consortium, it is a set of microorganisms whose diversity favors the transformation of oxidized sulfur compounds into sulfide. It can contain non-MSR microorganisms. It can come from a natural environment, then optionally be treated to obtain a more effective sulfate-reducing consortium; it can also be prepared by a selection of MSRs. According to a preferred variant of the invention, a sulfate-reducing bacterial consortium will be retained; even more advantageously, it consists mainly, or even entirely, of autotrophic sulfate-reducing bacteria.

The sulfides formed, namely hydrogen sulfide and/or methylthiol, are obtained in the aqueous liquid medium where they are in dissolved form. According to a variant, after optional acidification and at a pH of said aqueous liquid medium close to 7, they can be recovered in gaseous form.

They are then reacted with a precursor of methionine or one of its derivatives. Thus, according to a variant of the invention, the precursor of methionine or one of its derivatives with which the methanethiol is reacted is chosen from acrolein, 2-hydroxy-3-butenenitrile, 2-amino-3-butenenitrile, esters and amide of 2-hydroxy-3-butenoic acid.

In this process of the invention, said aqueous liquid medium is a medium resulting from the manufacturing process of methionine or its derivatives and containing methioninate or the salts of its derivatives and sulfates resulting from the neutralization of said methioninate into methionine and of said salts of its derivatives into said derivatives by sulfuric acid, under conditions well known to those skilled in the art.

The following examples illustrate the step of obtaining sulfide in the process of the invention and its advantages.

Example 1: Obtaining sulfides

MBfR reactor

The MBfR reactor used in the examples is a Liqui-Cel™ MM-1.7x8.75 Series Membrane Contactor (3M™) reactor modified to obtain the following characteristics: length 26.5 cm, diameter 4.3 cm, internal volume of hollow fibers of 70 mL (i.e. the volume of gas), external volume of the membranes (i.e. the volume of liquid) of 140 mL. The X50 type fiber membranes are made of polypropylene and the total membrane surface area of the module is 0.9 ^m2 .

For the liquid phase, the reactor is equipped with peristaltic pumps for its feed, its withdrawal and the recirculation loop, a pH sensor and a pressure sensor placed on the recirculation loop, the latter allowing the hydraulic pressure in the system to be measured. The entire MbFR reactor is maintained at a temperature of around 30°C.

The gas phase is introduced into the lumen of the membranes, a pressure regulation and flow measurement system allows to maintain the gas pressure in the system and to measure the gas flow rate at the outlet of the reactor. The gas introduced consists of pure hydrogen or pure CO2 when pH regulation is necessary. The gas leaving the system is then treated by a condensate trap and a soda trap in order to recover the gaseous form of hydrogen sulfide produced.

Aqueous liquid medium

It is a synthetic solution containing sulfates and nutrients necessary for bacterial growth.

The ionic composition of this solution is described in Table 1 below. [Table 1]

Seeding the reactor

Digestate from a mesophilic anaerobic pig manure digester was collected to serve as an inoculum. After filtration through a 100 μm sieve, the permeate was diluted by 10 in the synthetic solution described in Table 1. Seeding of the reactor was carried out by passing 2 liters of this preparation into the MBfR by bypassing the recirculation loop and at a flow rate of 30 ml/min to promote the attachment of the biomass to the MBfR membranes. Once seeded, the MBfR was put under gas pressure with H2 and under liquid pressure with the aforementioned synthetic solution. The temperature in the system remained between 30 and 35°C.

Reactor operating conditions

The sequencing batch reactor (SBR) was chosen for its operation. Cycles alternating between (i) filling with the synthetic solution, (ii) biological reaction, and (iii) emptying were applied. The hydraulic pressure in the system was maintained at an average of 0.50 bar and the gas pressure at 0.25 bar.

Physicochemical analyses

Major ion concentrations were determined by ion chromatography (Metrohm Professional IC 850) and sulfide concentrations were determined by photometric method (LCK653 cuvette tests, Hach) according to ISO 10530-1991.

Results

In just 4 days after the thermal regulation was implemented, microbial activity was detected. One day later, the formation of a biofilm on the MBfR module membranes was visible. This observation was confirmed by sulfate analyses indicating a conversion of sulfates to sulfides.

These initial results have thus made it possible to establish the feasibility of converting sulfates into sulfides with an H2-MBfR type reactor.

Analysis of sulfides in the different phases reveals the presence of 70% of sulfides in liquid form (dissolved H2S, HS- and ^S2 ) and 30% in gaseous form (gaseous H2S).

Table 2 below shows the material balance for sulphur (in mg S) over 4 days of reactor operation.

[Table 2]

These values demonstrate the performance of the method of the invention.

Example 2: Obtaining sulfides under different experimental conditions With the same reactor as described in Example 1, different experimental conditions were applied. Thus, different operating parameters, namely sulfate load of the aqueous liquid medium, residence time in the reactor (HRT for Hydraulic Retention Time, expressed in days), liquid (Piiq) and gas (PH ₂ ) pressures (expressed in bar gauge, barg) and salinity (expressed in gNaci/l) were tested. The influence of the gas flow rate (expressed in ml/minute) was also evaluated in some tests. A collection of the results obtained is presented in [Table 3].

Another membrane geometry (Liqui-Cel™ EXF-2.5x8 Series Membrane Contactor (3M™)) was also tested, presenting a larger exchange surface. The results obtained are also presented in Table 3.

On observe un taux de conversion en sulfates élevé quelles que soient les conditions.[Table 3]: Conversion rates of sulfates as a function of the experimental parameters applied

A high conversion rate to sulfates is observed regardless of the conditions.

According to Examples 1 and 2, it has been demonstrated that the first steps of a process of the invention, namely those involved in the MBfR technology, are operational and efficient, and can thus integrate a continuous process for the production of methionine or any of its methionine derivatives, in order to achieve the objectives of the invention.

Claims

1. Continuous process for the production of methionine or any of its methionine derivatives selected from its esters, its amides, its hydroxy and oxo analogues, the esters of said analogues and the amides of said analogues, from hydrogen sulphide or methanethiol, said process being characterized in that it comprises the reduction, by biological means, of oxidized sulphur compounds selected from sulphates resulting from said process, into hydrogen sulphide and/or methanethiol, said process comprising the following steps, a gas-permeable membrane reactor of the MBfR type (for Membrane Biofilm Reactor) is provided, said membrane being made up of hollow fibres defining an internal lumen and an external surface of the membrane, the membrane(s) of the reactor are immersed in an aqueous liquid medium which comprises at least the oxidized sulphur compound(s) and sulphate-reducing microorganisms (SRM), so as to bring the external surface or the lumen of the membrane into contact with said medium, an electron donor compound is injected, in gaseous form, into the lumen of the membrane if its external surface is in contact with the aqueous liquid medium, or into contact with the external surface of the membrane if its lumen is in contact with the aqueous liquid medium, after sulfate reduction of the oxidized sulfur compound(s) of the aqueous liquid medium by the MSR, hydrogen sulfide and/or methanethiol are recovered from said aqueous liquid medium, hydrogen sulfide is reacted with methanol to obtain methanethiol and/or methanethiol is reacted with a precursor of methionine or one of its derivatives to obtain in one or more stages a methionine salt or a salt of its derivatives, said salt is neutralized into methionine or one of its derivatives in the presence of sulfuric acid, and methionine or one of its said derivatives is recovered and the sulfates resulting from this neutralization are recycled into said aqueous liquid medium. 2. Method according to claim 1, characterized in that the electron donor compound in gaseous form is chosen from H2, carbon monoxide and any organic compound capable of being used by MSRs, as well as mixtures thereof. 3. Method according to claim 1 or 2, characterized in that a carbon source is present in the aqueous liquid medium or is supplied to the aqueous liquid medium. 4. Method according to claim 3, characterized in that the carbon source is chosen from sugars, carboxylic acids such as formic acid, acetic acid, propanoic acid, butanoic acid and lactic acid, alcohols such as methanol and ethanol, carbon dioxide, carbon monoxide, carbonates, bicarbonates, and mixtures thereof. 5. Method according to claim 3 or 4, characterized in that the carbon source is supplied to the aqueous liquid medium by injection, into the lumen of the membrane if its external surface is in contact with the aqueous liquid medium, or in contact with the external surface of the membrane if its lumen is in contact with the aqueous liquid medium, of a said carbon source in gaseous form. 6. Method according to any one of the preceding claims, characterized in that the pH of the aqueous liquid medium is greater than or equal to 7, preferably from 7 to 10. 7. Method according to any one of the preceding claims, characterized in that the MSRs are autotrophic bacteria. 8. Method according to any one of the preceding claims, characterized in that the electron donor compound is also the carbon source. 9. Method according to claim 9, characterized in that the electron donor and the carbon source are carbon monoxide. 10. Method according to any one of the preceding claims, characterized in that the hydrogen sulfide and/or methanethiol formed are recovered after acidification of the aqueous liquid medium. 11. Process according to any one of the preceding claims, characterized in that the precursor of methionine or one of its derivatives with which the methanethiol is reacted is chosen from acrolein, 2-hydroxy-3-butenenitrile, 2-amino-3-butenenitrile, esters and amide of 2-hydroxy-3-butenoic acid. 12. Process according to any one of the preceding claims, characterized in that said salt is only partially neutralized into methionine or one of its derivatives in the presence of sulfuric acid, and a salt of methionine or one of its said derivatives is also recovered.