Process for synthesizing functionalized mercaptans under h2s pressure

Abstract

To provide an improved process for synthesizing functionalized mercaptans, particularly processes with improved yields.SOLUTION: Provided is a process for synthesizing functionalized mercaptans, comprising reacting a compound of the formula R2-X-C*H(NR1R7)-(CH2)n-G(II) with H2S in the presence of at least one enzyme selected from sulfhydrylases. The reaction is carried out in a reactor, and the H2S partial pressure in a gas headspace of the reactor is 0.01 bar to 4 bar, preferably 0.1 bar to 3 bar, for example 0.1 bar to 2.5 bar, and more preferentially 0.25 bar to 2 bar, at a reaction temperature.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a process for synthesizing functionalized mercaptans and in particular to compositions that make it possible to carry out this process. [Background technology]

[0002] Mercaptans are used in many industrial fields and many methods for their synthesis are known, such as the sulfurization of alcohols, the catalytic or photochemical addition of hydrogen sulfide to unsaturated organic compounds, or the substitution of halides, epoxides, or organic carbonates with hydrogen sulfide.

[0003] However, these processes have many drawbacks and are not necessarily suitable for the synthesis of functionalized mercaptans, i.e., mercaptans containing at least one functional group other than a thiol group (-SH). This type of mercaptan constitutes a chemical family with great potential, particularly amino acids and derivatives containing a thiol function, especially homocysteine. They can be used, for example, as synthetic intermediates in the cosmetics industry. However, currently, there are no effective synthetic methods available that are industrially viable and suitable for the production of these functionalized mercaptans, especially for applications in the field of commodity chemicals.

[0004] For example, among conventional chemical processes, substitution with hydrogen sulfide often requires high temperatures and pressures, resulting in the formation of undesirable by-products of the olefin, ether, sulfide and / or polysulfide type. The catalytic or photochemical addition of hydrogen sulfide to unsaturated compounds is generally carried out under slightly milder conditions, but as above, many by-products are formed by isomerization, non-regioselective addition or double addition of the starting materials, leading to the formation of sulfides and / or polysulfides.

[0005] Therefore, these conventional synthetic methods require operating conditions that are too harsh for compounds such as functionalized mercaptans, resulting in the coproduction of large amounts of sulfides and / or polysulfides that are difficult to upgrade.

[0006] The synthesis of functionalized mercaptans via biological routes is a known alternative to chemical routes. For example, cysteine ​​is currently produced biologically via a fermentation route (Maier T., 2003. Nature Biotechnology, 21:422-427). These biological routes are milder and more suitable for multifunctional molecules. However, these biological routes often have low yields and / or are difficult or impossible to set up on an industrial scale. Furthermore, even here, the production of the desired mercaptans is accompanied by the corresponding polysulfides, such as sulfides and / or disulfides (see, for example, International Publication No. WO2012 / 053777).

[0007] Therefore, there is a need for improved processes for synthesizing functionalized mercaptans, especially by biological routes.

[0008] In particular, there is a need for a process for synthesizing functionalized mercaptans that makes it possible to obtain good yields, i.e., yields of at least 20%, preferably at least 60%, more preferably at least 80% and even more preferentially at least 90%.

[0009] There is also a need for a process for synthesizing functionalized mercaptans that is feasible on an industrial scale under mild operating conditions. Summary of the Invention [Problem to be solved by the invention]

[0010] One object of the present invention is to provide an improved process for the synthesis of functionalized mercaptans, in particular with improved yields, i.e. at least 20%, preferably at least 60%, more preferably at least 80% and even preferentially at least 90%.

[0011] Another object of the present invention is to provide an industrial process which is mild and has suitable operating conditions for the synthesis of polyfunctional mercaptans.

[0012] Another object of the present invention is to avoid the use of hydrosulfide salts and / or sulfide salts as reagents, thus providing a more environmentally friendly process.

[0013] The present invention achieves the above objectives in whole or in part. [Means for solving the problem]

[0014] According to the present invention, functionalized mercaptans of formula (I), as defined below, in particular L-homocysteine, are advantageously synthesized by reacting a compound of formula (II) with HS in the presence of the enzyme sulfhydrylase, under a specific range of HS partial pressure in the reactor in which the reaction takes place, in particular the HS partial pressure is between 0.01 bar and 4 bar, for example between 0.01 bar and 3 bar, preferably between 0.1 bar and 3 bar, for example between 0.1 bar and 2.5 bar, more preferentially between 0.25 bar and 2 bar.

[0015] Thus, the present inventors have found that the conversion of the compound of formula (II) to the functionalized mercaptan of formula (I) is strongly dependent on the HS partial pressure in the reactor. Surprisingly, the present inventors have found that within a specific range of HS partial pressure in the reactor, conversions and / or yields of at least 20%, preferably at least 60%, more preferably at least 80%, and even preferentially at least 90% can be obtained. For example, conversions and / or yields of 80% to 100%, or even 90% to 100%. In particular, conversions and / or yields of 100%.

[0016] In fact, contrary to expectations, increasing the H2S partial pressure in the reactor beyond a certain limit does not improve the conversion and / or yield of the reaction, and may even limit or inhibit the latter. The higher the H2S partial pressure in the reactor, the greater the amount of H2S in the reaction medium (especially in dissolved form in the liquid reaction medium), which would be expected to promote the reaction. However, in practice, too high a H2S partial pressure is detrimental to the reaction.

[0017] Furthermore, the specific range of H2S partial pressure in the reactor according to the present invention allows for fast reaction kinetics. For example, a 100% yield can be achieved in 1 hour. Therefore, the reaction time may be 0.15 to 10 hours, for example, 0.25 to 4 hours, and preferably 0.5 to 1 hour.

[0018] It has also been observed that the process according to the invention can obtain better yields than processes using hydrosulfide and / or sulfide salts as reagents. Thus, the use of hydrogen sulfide can limit or even simplify the waste purification and management steps required when using these salts. Therefore, the process according to the invention is more environmentally friendly.

[0019] The present invention therefore provides a method for producing a polymer comprising at least one functionalized mercaptan of the following general formula (I): Regarding the process of creating: R2-XC * H(NR1R7)-(CH2) n-SH (I) During the ceremony, - R1 and R7 are the same or different and are each a hydrogen atom or an aromatic or non-aromatic, linear, branched or cyclic, saturated or unsaturated hydrocarbon chain having 1 to 20 carbon atoms, which may contain one or more heteroatoms; - X is selected from -C(=O)-, -CH2- and -CN; - R2: (i) Does not exist when X represents -CN (ii) or a hydrogen atom (iii) or -OR3, R3 is a hydrogen atom or an aromatic or non-aromatic, linear, branched or cyclic, saturated or unsaturated hydrocarbon chain having 1 to 20 carbon atoms, which may contain one or more heteroatoms; (iv) or -NR4R5, R4 and R5 are the same or different and represent a hydrogen atom or an aromatic or non-aromatic, linear, branched or cyclic, saturated or unsaturated hydrocarbon chain having 1 to 20 carbon atoms, which may have one or more heteroatoms; n is 1 or 2; * represents an asymmetric carbon; The process includes the following stages: a) providing at least one compound of the following general formula (II): R2-XC * H(NR1R7)-(CH2) n -G (II) During the ceremony, * , R1, R2, R7, X and n are as defined for formula (I); G represents either (i) R6-C(O)-O-, or (ii) (RO)(RO)-P(O)-O-, or (iii) RO-SO2-O-; R6 may be a hydrogen atom or one or more linear, branched, or cyclic, saturated or unsaturated, aromatic groups, and -OR 10 , (=O), -C(O)OR 11 , -NR 12 R 13 is a hydrocarbon chain having 1 to 20 carbon atoms which may be substituted with one or more groups selected from the group consisting of: R 10 , R 11 , R 12 and R 13 are each independently selected from: H or a linear, branched or cyclic, saturated or unsaturated hydrocarbon chain having 1 to 20 carbon atoms; R7 and R8 are the same or different and are a proton, an alkali metal, an alkaline earth metal, or ammonium; R9 is selected from a proton, an alkali metal, an alkaline earth metal, and ammonium; b) providing H2S; c) sulfhydrylase, preferably a sulfhydrylase associated with the compound of formula (II) reaction of at least one compound of formula (II) with H2S in the presence of at least one enzyme selected from the group consisting of hydroxylase, hydroxypropyl methyl ... the reaction is carried out in a reactor, the H2S partial pressure in the gas headspace of the reactor being from 0.01 bar to 4 bar, for example from 0.01 bar to 3 bar, preferably from 0.1 bar to 3 bar, for example from 0.1 bar to 2.5 bar, more preferentially from 0.25 bar to 2 bar, at the reaction temperature; d) obtaining at least one functionalized mercaptan of formula (I); e) of at least one functionalized mercaptan of formula (I) obtained in stage d). Optional separation; and f) Optionally, the functionalized mercaptan of formula (I) obtained in stage d) or e). further functionalization and / or optional deprotection by Stages a) and b) are optionally performed simultaneously.

[0020] The expression "X to X" includes the stated limits unless otherwise specified.

[0021] An unsaturated hydrocarbon chain has at least one double or triple bond between two carbon atoms. It is understood that the hydrocarbon chain has a carbon number of 1 or 2.

[0022] Heteroatoms are understood to be atoms selected in particular from O, N, S, P and the halogens.

[0023] Inert gas is understood to be any gas that has little or no reactivity in the context of the process according to the invention, examples of which include dinitrogen, argon or methane, preferably dinitrogen.

[0024] A reaction medium (or mixture) is understood in particular to be a medium comprising at least one compound of formula (II), H2S and said at least one sulfhydrylase.

[0025] Thus, the reaction medium is at least one compound of formula (II) as defined below, - H2S, at least one sulfhydrylase as defined below, optionally its cofactor as defined below, optionally a base as defined below, and Optionally, it may contain a solvent, preferably water.

[0026] Preferably, the reaction medium is in the form of a liquid, for example an aqueous solution, especially under the temperature and pressure conditions of stage c).

[0027] The H2S is in gaseous form, especially under the temperature and pressure conditions of stage c), and it is understood in particular that part of the H2S is dissolved in the reaction medium to carry out the reaction of stage c), and another part is in gaseous form in the gas headspace of the reactor under said partial pressures.

[0028] "Gas headspace" is understood to mean the space in the reactor located above the reaction medium, preferably above the liquid reaction medium. More specifically, "gas headspace" is understood to mean the space located between the surface of the liquid reaction medium and the top of the reactor (or above the reactor containing the gas phase, if the lower part of the reactor contains a liquid phase). The gas headspace comprises in particular a gas phase containing HS at said partial pressure.

[0029] The reaction medium and H2S are introduced into the reactor in particular in amounts such that a gas headspace is located above the reaction medium contained in the reactor.

[0030] Alternatively, stage c) can be described as follows: c) reaction of at least one compound of formula (II) with H2S in the presence of at least one enzyme selected from sulfhydrylases, preferably sulfhydrylases associated with the compound of formula (II); The reaction is carried out in a reactor, the H2S partial pressure above the reaction medium being between 0.01 bar and 4 bar, for example between 0.01 bar and 3 bar, preferably between 0.1 bar and 3 bar, for example between 0.1 bar and 2.5 bar, more preferentially between 0.25 bar and 2 bar, at the reaction temperature.

[0031] According to one embodiment, the H2S partial pressure corresponds to the total pressure of the gas phase present in the gas headspace (i.e., only H2S is present in the gas headspace of the reactor).

[0032] According to one embodiment, the H2S partial pressure can be kept constant throughout the entire duration of stage c) by continuously introducing H2S into the reactor during stage c) or by adding H2S to the reactor in a regular or irregular and isolated manner. In fact, the decrease in H2S partial pressure can be compensated for since H2S is consumed during the reaction.

[0033] According to another embodiment, the H2S partial pressure can be achieved before or during stage c), after which the introduction of H2S into the reactor is stopped, and the H2S partial pressure is thus reduced during stage c), preferably until the reaction has stopped.

[0034] The H2S partial pressure can be controlled throughout stage c) by any known technique, for example by means of a pressure gauge. H2S can be added so as to reach a state of equilibrium between the liquid phase (reaction medium) and the gas phase (containing H2S at said partial pressure) in the reactor.

[0035] Preferably, the total pressure of the gas phase in the gas headspace (e.g., the pressure of HS when the latter is the only gas, or the total pressure of a mixture of HS and an inert gas) corresponds approximately to atmospheric pressure (about 1.01325 bar). It is also possible to choose to work at subatmospheric or superatmospheric pressure, depending on the desired operating conditions.

[0036] For example, the following method can be mentioned.

[0037] According to one embodiment, a vacuum is created in the reactor and then H2S is introduced at a partial pressure according to the invention, for example, a vacuum is drawn to -1 bar and then a H2S pressure of 0.25 bar is applied.

[0038] According to another embodiment, the following stages are performed: - Purging the reactor headspace with an inert gas such as N2; then - Create a partial vacuum; then - H2S is introduced at a partial pressure according to the invention. For example, after purging the reactor headspace with N2, a vacuum is pulled to -0.25 bar, and then 0.25 bar of H2S is added.

[0039] According to another embodiment, a mixture of an inert gas such as N2 and H2S at a partial pressure according to the invention can be introduced into the reactor, for example, a mixture of 0.25 bar H2S and 0.75 bar N2 can be introduced.

[0040] According to another embodiment, an inert gas such as N2 can be introduced into the reactor (purging the gas headspace) and then H2S can be added at partial pressures according to the invention. For example, N2 can be added at a pressure of 1 bar, followed by H2S at a pressure of 0.25 bar.

[0041] The temperature during stage c) can be between 10°C and 60°C, preferably between 20°C and 40°C, more particularly between 25°C and 40°C.

[0042] The reactor used in stage c) can be of any type, preferably selected from plug-flow or continuous reactors, preferably stirred and / or with gas phase recirculation and / or liquid phase recirculation. Preferably, the reactor allows for the recirculation (or recycling) of the gas phase present in the gas headspace.

[0043] Stages a) and b) can be performed simultaneously or in any order.

[0044] The reaction medium can be prepared by adding the compound of formula (II), sulfhydrylase and optionally its cofactor in any order. Preferably, H2S is then introduced. This makes it easier to manage the H2S pressure introduced into the reactor in particular.

[0045] Preferably, the compound of formula (II) and / or the sulfhydrylase are in the form of a solution, more preferentially in the form of an aqueous solution.

[0046] The H2S can be introduced into the reactor by any known method, in particular by bubbling into the reaction medium, preferably by bubbling into the reaction medium from the bottom of the reactor. Bubbling can be carried out by mixing the H2S with an inert gas, such as dinitrogen, argon or methane, preferably dinitrogen. Preferentially, the H2S is introduced purely (without mixing with other gases). The H2S can also be introduced via the headspace of the reactor and then, for example, equilibrated with the reaction medium. Preferably, the reaction medium is then stirred.

[0047] Preferably during stage c), and more preferentially throughout the entire duration of stage c), H2S is preferably in excess relative to the compound of formula (II), preferably in molar excess, and therefore preferably during stage c), and more preferentially throughout the entire duration of stage c), H2S may be in a superstoichiometric amount relative to the amount of compound of formula (II).

[0048] In particular, the molar ratio of HS / compound of formula (II) is preferably between 1.1 and 20, preferably between 1.1 and 10, preferentially between 2 and 8, for example between 3.5 and 8, even more preferentially between 3.5 and 5, during stage c), and more preferentially for the entire duration of stage c). Said ratio may be kept constant throughout the entire duration of stage c).

[0049] Stage c) can be carried out in a solution, in particular in an aqueous solution, for example comprising 50% to 99% by weight of water, preferably 75% to 97% by weight of water, relative to the total weight of the solution.

[0050] The pH of the reaction medium in stage c) may be between 4 and 9, for example between 5 and 8, preferably between 6 and 7.5, more particularly between 6.2 and 7.2, especially when the reaction medium is an aqueous solution.

[0051] The pH can be adjusted within the above ranges, in particular according to the operating optimum of the selected sulfhydrylase. The pH can be measured by conventional methods, for example using a pH probe. The pH can be adjusted, in particular by adding a base, preferably during the reaction in stage c). Any type of base can be used, but bases containing sulfur atoms are preferred. A base is understood to be in particular a compound or a mixture of compounds having a pH above 7, preferably between 8 and 14.

[0052] The base can be selected from hydrosulfide and / or sulfide salts, sodium hydroxide, potassium hydroxide or ammonia. A preferred base is ammonium hydrosulfide (NH4SH).

[0053] The hydrosulfide salt and / or sulfide salt may be selected from the group consisting of ammonium hydrosulfide, alkali metal hydrosulfides, alkaline earth metal hydrosulfides, alkali metal sulfides, and alkaline earth metal sulfides.

[0054] Alkali metals are understood to be lithium, sodium, potassium, rubidium and cesium, preferably sodium and potassium.

[0055] Alkaline earth metals are understood to be beryllium, magnesium, calcium, strontium and barium, preferably calcium.

[0056] In particular, the hydrosulfide salt and / or sulfide salt may be selected from the group consisting of: Ammonium hydrosulfide NH4SH, sodium hydrosulfide NaSH, potassium hydrosulfide KSH, calcium hydrosulfide Ca(SH)2, sodium sulfide Na2S, ammonium sulfide (NH4)2S, potassium sulfide K2S and calcium sulfide CaS. The preferred hydrosulfide is ammonium hydrosulfide NH4SH.

[0057] The base can be added at a concentration of 0.1 M to 10 M, preferably 0.5 M to 10 M, more preferably 0.5 M to 5 M. Concentrated bases are particularly used to limit the dilution of the reaction medium when adding the base.

[0058] Stage c) can be carried out batchwise, semi-continuously or continuously.

[0059] Stage c) carried out essentially in the absence of oxygen:

[0060] Oxygen is understood to mean in particular dioxygen O2.

[0061] Preferably, stage c) is carried out essentially in the absence of oxygen or in the absence of oxygen. If stage c) is carried out essentially in the absence of oxygen (or in the absence of oxygen O), it is possible, if necessary, to limit (or prevent) the co-production of undesired by-products, sulfides and / or polysulfides, in particular disulfides (see French Patent Application No. FR 2007577).

[0062] More specifically, "essentially in the absence of oxygen" is understood to mean that a certain amount of oxygen may remain in the reaction medium and / or gas phase (contained in the gas headspace of the reactor) so that the amount of sulfides and / or polysulfides formed is not more than 5% by weight relative to the total weight of compounds of formula (I) formed.

[0063] For example, "essentially in the absence of oxygen" is understood to mean that the reaction medium contains less than 0.0015% by weight (preferably strictly less than 0.0015% by weight) of oxygen relative to the total weight of the reaction medium, and / or that the gas phase (contained in the gas headspace) contains less than 21% by volume (preferably strictly less than 21% by volume) of oxygen relative to the total volume of the gas phase.

[0064] Thus, the reaction medium may contain from 0% to 0.0015% by weight (preferably strictly less than 0.0015% by weight) of oxygen relative to the total weight of the reaction medium, and / or the gas phase (contained in the gas headspace) may contain from 0% to 21% by volume (preferably strictly less than 21% by volume) of oxygen relative to the total volume of the gas phase. In particular, the amount of oxygen in the reaction medium and / or gas phase (contained in the gas headspace) is such that the amount of sulfides and / or polysulfides produced is 5% by weight or less relative to the total weight of compounds of formula (I) produced.

[0065] For example, stage c) can be carried out in a closed reactor (ie without oxygen supply from the air).

[0066] Highly preferably, the gas phase (contained in the gas headspace) is oxygen-free. Preferably, the gas phase (contained in the gas headspace) is oxygen-free and the reaction mixture contains between 0% and 0.0015% (preferably exactly 0.0015%) by weight of oxygen relative to the total weight of the reaction mixture. %) of oxygen, since O2 / H2S mixtures can present an explosion hazard and represent a clear risk to operator safety.

[0067] More specifically, when stage c) is carried out essentially in the absence (or in the absence) of oxygen, L-homocysteine ​​can be produced as needed while limiting (or preventing) the co-production of the undesired by-products L-homocystine and / or L-homocysteine ​​sulfide (also known as 4,4'-sulfanediylbis(2-aminobutanoic acid) / L-homolantionine).

[0068] L-homocysteine ​​sulfide has the formula: [ka]

[0069] L-homocystine has the following formula: [ka]

[0070] Conventional methods are available for carrying out stage c) essentially in the absence of oxygen or in the absence of oxygen.

[0071] According to one embodiment, before stage c), oxygen is removed from the reaction medium, for example by degassing.

[0072] According to another embodiment, prior to stage c), oxygen is removed from each component individually or from a mixture of at least two of the components forming the reaction medium, for example, each of the solutions comprising the compound of formula (II), the sulfhydrylase and optionally a solvent is degassed.

[0073] Oxygen can also be removed from the gas phase of the reactor headspace, preferably by degassing.

[0074] The reactor may also be inerted with an inert gas such as dinitrogen, argon or methane, preferably dinitrogen.

[0075] Various techniques may be combined.

[0076] Preferably, the substantial or complete absence of oxygen is achieved in the following manner: the reactor is inerted with an inert gas such as dinitrogen, argon or methane, preferably dinitrogen; Each of the solutions comprising the compound of formula (II), the sulfhydrylase and optionally the solvent is degassed. Commercial degassing methods are well known and include, for example: - Decompression (vacuum degassing) - Temperature control (increase the temperature of the aqueous solvent and decrease the temperature of the organic solvent) - Membrane degassing - Degassing by repeated freeze-degas-thaw cycles - Degassing by sparging with an inert gas (e.g. argon, dinitrogen or methane). According to one embodiment, in stage c), oxygen is neither present in dissolved form in a liquid (in particular in the reaction medium) nor in gaseous form (in particular in the gas phase).

[0077] The separation stage e) can be carried out according to any technique known to those skilled in the art, in particular when the final product is a solid: - by extraction and / or decantation with a solvent immiscible with the reaction medium, followed by evaporation of said solvent; by precipitation (by partial evaporation of the solvent or by adding a solvent in which the target compound is poorly soluble), which is generally followed by a stage of filtration according to any method known to those skilled in the art, after which the final product can be dried; or - By selective precipitation by adjusting the pH as a function of the respective solubility of the various compounds.

[0078] Homocysteine ​​may be recovered, particularly in solid form.

[0079] If the final product is in liquid form, separation can be achieved by distillation or by liquid / liquid extraction followed by distillation or evaporation.

[0080] The stage f) of further functionalization and / or optional deprotection makes it possible to obtain additional chemical functions and / or deprotect certain chemical functions by conventional methods. For example, if X-R2 represents a carboxyl function, the latter can be esterified, reduced to an aldehyde, reduced to an alcohol, then esterified, amidated, nitrified, etc. All functional groups can be obtained and / or deprotected by a person skilled in the art depending on the intended end use of the functionalized mercaptan of formula (I).

[0081] Thus, the functionalized mercaptan of formula (I) obtained at the end of stage d) or e) may be subjected to one or more additional chemical reactions in order to obtain one or more mercaptan derivatives with different functionality, said chemical reactions being well known reactions.

[0082] Functionalized mercaptans of general formula (I): The process according to the invention aims to obtain functionalized mercaptans of general formula (I): R2-XC * H(NR1R7)-(CH2) n -SH (I) During the ceremony, - R1 and R7 are the same or different and are each a hydrogen atom or an aromatic or non-aromatic, linear, branched or cyclic, saturated or unsaturated hydrocarbon chain having 1 to 20 carbon atoms, which may contain one or more heteroatoms; - X is selected from -C(=O)-, -CH2- and -CN; - R2: (i) Does not exist when X represents -CN (ii) or a hydrogen atom (iii) or -OR3, R3 is a hydrogen atom or an aromatic or non-aromatic, linear, branched or cyclic, saturated or unsaturated hydrocarbon chain having 1 to 20 carbon atoms, which may contain one or more heteroatoms; (iv) or -NR4R5, R4 and R5 are the same or different and represent a hydrogen atom or an aromatic or non-aromatic, linear, branched or cyclic, saturated or unsaturated hydrocarbon chain having 1 to 20 carbon atoms, which may have one or more heteroatoms; n is 1 or 2; * represents an asymmetric carbon.

[0083] These mercaptans are called functionalized mercaptans because, in addition to the chemical functionality -SH, they also contain at least one amine-type functionality -NR1R7.

[0084] Preferably, n is 2.

[0085] Preferably, X is -C(=O)-.

[0086] Preferably, R2 is -OR3, where R3 is as defined above. R3 may in particular be a hydrogen atom or a linear or branched saturated hydrocarbon chain having 1 to 10 carbon atoms, preferably 1 to 5 carbon atoms. In particular, R3 is H.

[0087] R1 and R7 are the same or different and are preferably a hydrogen atom or a linear or branched saturated hydrocarbon chain having 1 to 10 carbon atoms, preferably 1 to 5 carbon atoms. Preferably, R1 and R7 are H.

[0088] In particular, X is -C(=O)- and R2 is -OR3, where R3 is as defined above.

[0089] The functionalized mercaptan of formula (I) can be selected from the group consisting of homocysteine, cysteine, and derivatives thereof.

[0090] In particular, the functionalized mercaptans of formula (I) are L-homocysteine ​​and L-cysteine.

[0091] A preferred functionalized mercaptan of formula (I) is homocysteine, in particular L-homocysteine ​​of the formula: [ka]

[0092] In the case of L-homocysteine, n is 2, X is —C(═O)—, R2 is —OR3, R3 is H, and R1 and R7 are H.

[0093] It has been observed that the configuration of the asymmetric carbon atom is preserved throughout the reaction of stage c), and therefore the functionalized mercaptans of formula (I) obtained according to the process of the present invention may be enantiomerically pure.

[0094] The functionalized mercaptans of formula (I) are chiral compounds. In this specification, if no enantiomeric form is specified, the compound is included regardless of its enantiomeric form.

[0095] According to one embodiment, the reaction medium at the end of stage c) is free of sulfides or polysulfides, in particular free of sulfides or polysulfides corresponding to the functionalized mercaptan of formula (I) obtained, for example, the reaction medium at the end of stage c) contains less than 10 mol %, preferably less than 5 mol %, of sulfides and polysulfides relative to the total number of moles of compounds of formula (II) converted into compounds of formula (I).

[0096] Sulfides are understood to be those corresponding to the compounds of formula (I), in particular those of formula (III): R2-XC * H(NR1R7)-(CH2) n -S-(CH2) n -(NR1R7)C * HX-R2(III) * , R1, R2, R7, X and n are as defined above.

[0097] Polysulfides are understood to be those corresponding to the compounds of formula (I), in particular those of formula (IV): R2-XC * H(NR1R7)-(CH2) n -(S) m -(CH2) n -(NR1R7)C * HX-R2(IV) * , R1, R2, R7, X and n are defined above, and m is an integer of 2 to 6 inclusive, for example, m is 2 or 3. Preferably, m is 2 (corresponding to a disulfide).

[0098] In particular, when the compound of formula (I) is L-homocysteine, the reaction medium at the end of stage c) contains neither L-homocysteine ​​sulfide nor L-homocystine.

[0099] Preferably, following the reaction of the compound of formula (II) with HS during stage c), the following is obtained: a functionalized mercaptan of formula (I) as defined above and a compound of formula (V) GH, where G is defined below, i.e., a compound of type (i') R6-C(O)-OH, (II') (RO)(RO)-P(O)-OH, or (iii') RO-SO2-OH; R6, R7, R8, and R9 are defined below. In particular, when compound (II) is O-acetyl-L-homoserine, L-homocysteine ​​and acetic acid are obtained. The compound of formula (V) can participate in the acidification of the reaction medium during stage c). Thus, the pH of the reaction medium can be maintained between 4 and 9, for example between 5 and 8, preferably between 6 and 7.5, more particularly between 6.2 and 7.2, especially during stage c), as described above, and especially by the addition of a base as defined above.

[0100] Compounds of general formula (II): Regarding the compound of the following general formula (II): R2-XC * H(NR1R7)-(CH2) n -G (II) * , R1, R2, R7, X and n are as defined for compounds of formula (I); G represents either (i) R6-C(O)-O-, or (ii) (RO)(RO)-P(O)-O-, or (iii) RO-SO2-O-; R6 may contain a hydrogen atom or one or more linear, branched or cyclic, saturated or unsaturated aromatic groups, -OR 10 , (=O), -C(O)OR 11 , and -NR 12 R 13 a hydrocarbon chain having 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms, which may be substituted with one or more groups selected from the following: R10 , R 11 , R 12 and R 13 are each independently selected from: H or a linear, branched or cyclic, saturated or unsaturated hydrocarbon chain having 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms; R7 and R8 are the same or different and are a proton, an alkali metal, an alkaline earth metal or ammonium, preferably a proton or an alkali metal, more particularly H + or Na + and; R9 is selected from a proton, an alkali metal, an alkaline earth metal, and ammonium, preferably a proton or an alkali metal, more particularly a proton H + or Na + and; In particular, G represents either R6-C(O)-O- or R9O-SO2-O-; preferably, G is R6-C(O)-O-. In particular, R6 is a hydrogen atom or a linear or branched, saturated or unsaturated -OR 10 , (=O) and -C(O)OR 11 a hydrocarbon chain having 1 to 10 carbon atoms, preferably 1 to 5 carbon atoms, which may be substituted with one or more groups selected from the group consisting of 10 and R 11 are each independently selected from: H, or a linear or branched, saturated or unsaturated hydrocarbon chain having 1 to 10 carbon atoms, preferably 1 to 5 carbon atoms. More specifically, R 10 and R 11 is H. In particular, R 12 and R 13 is H. An aromatic group is understood to be preferentially a phenyl group.

[0101] The compounds of general formula (II) are in particular derivatives of serine (when n is 1) or homoserine (when n is 2), in particular L-serine or L-homoserine. They can, for example, be selected from the group consisting of: O-phospho-L-homoserine, O-succinyl-L-homoserine, O-acetyl-L-homoserine, O-acetoacetyl-L-homoserine, O-propio-L-homoserine, O-coumaroyl-L-homoserine, O-malonyl-L-homoserine, O-hydroxymethylglutaryl-L-homoserine, O-pimelyl-L-homoserine, O-sulfato-L-homoserine, O-phospho-L-serine, O-succinyl-L-serine, O-acetyl-L-serine, O-acetoacetyl-L-serine, O-propio-L-serine, O-coumaroyl-L-serine, O-malonyl-L-serine, O-hydroxymethylglutaryl-L-serine, O-pimelyl-L-serine, and O-sulfato-L-serine.

[0102] More specifically, it can be selected from the group consisting of: O-phospho-L-homoserine, O-succinyl-L-homoserine, O-acetyl-L-homoserine, O-acetoacetyl-L-homoserine, O-propio-L-homoserine, O-coumaroyl-L-homoserine, O-malonyl-L-homoserine, O-hydroxymethylglutaryl-L-homoserine, O-pimelyl-L-homoserine, and O-sulfato-L-homoserine.

[0103] The compound of general formula (II) can be selected from the group consisting of: O-phospho-L-homoserine, O-succinyl-L-homoserine, O-acetyl-L-homoserine, O-sulfato-L-homoserine and O-propio-L-homoserine.

[0104] The compound of general formula (II) can be selected from the group consisting of: O-phospho-L-homoserine, O-succinyl-L-homoserine, O-acetyl-L-homoserine.

[0105] A highly preferred compound of formula (II) is O-acetyl-L-homoserine (OAHS), where n is 2, X is -C(=O)-, R2 is -OR3, R3 is H, R1 and R7 are H, G is -OC(O)-R6, and R6 is methyl.

[0106] Compounds of formula (II) are commercially available or can be prepared by any technique known to those skilled in the art. Therefore, it is obtained.

[0107] They can be obtained through a fermentation process from hydrocarbon and nitrogen sources, as described, for example, in WO 2008 / 013432.

[0108] They can be obtained, for example, by fermenting renewable starting materials, which can be selected from glucose, sucrose, starch, molasses, glycerol and bioethanol, preferably glucose.

[0109] L-serine derivatives can also be produced by acetylation of L-serine, which itself may be obtained by fermentation of renewable starting materials, which may be selected from glucose, sucrose, starch, molasses, glycerol and bioethanol, preferably glucose.

[0110] L-homoserine derivatives can also be produced by acetylation of L-homoserine, which itself may be obtained by fermentation of renewable starting materials, which may be selected from glucose, sucrose, starch, molasses, glycerol and bioethanol, preferably glucose.

[0111] Sulfhydrylase: The reaction of at least one compound of formula (II) with HS is carried out in the presence of at least one enzyme selected from sulfhydrylases, preferably sulfhydrylases associated with compounds of formula (II). Sulfhydrylases associated with compounds of formula (II) are easily distinguishable by sharing the same name, e.g., O-acetyl-L-homoserine sulfhydrylase (OAHS sulfhydrylase) is associated with O-acetyl-L-homoserine.

[0112] Sulfhydrylase may in particular catalyze the reaction of the compound of formula (II) with HS (enzymatic reaction). A "catalyst" is generally understood to be a substance that accelerates a reaction and remains unchanged at the end of the reaction. Sulfhydrylase, and optionally its cofactor, may be used in catalytic amounts. A "catalytic amount" is understood to be an amount sufficient to specifically catalyze a reaction. More specifically, a reagent used in a catalytic amount is used in a smaller amount, for example, about 0.01% to 20% by weight, relative to the amount of the reagent used in the stoichiometric proportion.

[0113] The sulfhydrylase enzyme preferably belongs to the transferase class specifically designated in the EC 2.XXXX (or notated EC2) classification. The EC classification of Enzyme Commission numbers is widely used and can be found on the website https: / / enzyme.expasy.org / . In particular, the enzyme is selected from the sulfhydrylases of the EC 2.5.X.XX class (or notated EC2.5.) and refers to a transferase that transfers alkyl or aryl groups other than methyl groups.

[0114] Sulfhydrylases in particular are of the class EC2.5.1.XX (XX varies depending on the enzyme's substrate).

[0115] for example: - O-acetylhomoserine sulfhydrylase is of the EC2.5.1.49 type. - O-phosphoserine sulfhydrylase is of the EC 2.5.1.65 type. - O-Succinylhomoserine sulfhydrylase is of the EC 2.5.1.49 type.

[0116] for example: - O-acetyl-L-homoserine sulfhydrylase is of the EC 2.5.1.49 type. - O-phospho-L-serine sulfhydrylase is of the EC 2.5.1.65 type. - O-Succinyl-L-homoserine sulfhydrylase is of the EC 2.5.1.49 type.

[0117] Therefore, particularly when the compound of formula (II) is a derivative of L-homoserine or L-serine, the sulfhydrylase used may be O-phospho-L-homoserine sulfhydrylase, O-succinyl-L-homoserine sulfhydrylase, O-acetyl-L-homoserine sulfhydrylase, O-acetoacetyl-L-homoserine sulfhydrylase, O-propio-L-homoserine sulfhydrylase, O-coumaroyl-L-homoserine sulfhydrylase, O-malonyl-L-homoserine sulfhydrylase, O-hydroxymethylglutaryl-L-homoserine sulfhydrylase, O-pimelyl-L-homoserine sulfhydrylase, ...propio-L-homoserine sulfhydrylase, O-propio-L-homoserine sulfhydrylase, O-propio-L-homoserine sulfhydrylase, O-propio-L-homoserine sulfhydrylase, O-propio-L-homoserine sulfhydrylase, O-propio-L-homoserine sulfhydrylase, O-propio-L-homoserine sulfhydrylase, O-propio-L-homoserine sulfhydrylase, O-propio-L-homoserine sulfhydrylase, O-propio-L-homoserine sulfhydrylase, O-propio-L-homoserine sulfhydrylase, O-propio-L-homoserine sulfhydrylase, O-propio-L-homoserine sulf The enzyme may be selected from the group consisting of O-sulfato-L-homoserine sulfhydrylase, O-phospho-L-serine sulfhydrylase, O-succinyl-L-serine sulfhydrylase, O-acetyl-L-serine sulfhydrylase, O-acetoacetyl-L-serine sulfhydrylase, O-propio-L-serine sulfhydrylase, O-coumaroyl-L-serine sulfhydrylase, O-malonyl-L-serine sulfhydrylase, O-hydroxymethylglutaryl-L-serine sulfhydrylase, O-pimelyl-L-serine sulfhydrylase and O-sulfato-serine sulfhydrylase.

[0118] More specifically, the sulfhydrylase used can be selected from O-phospho-L-homoserine sulfhydrylase, O-succinyl-L-homoserine sulfhydrylase, O-acetyl-L-homoserine sulfhydrylase, O-acetoacetyl-L-homoserine sulfhydrylase, O-propio-L-homoserine sulfhydrylase, O-coumaroyl-L-homoserine sulfhydrylase, O-malonyl-L-homoserine sulfhydrylase, O-hydroxymethylglutaryl-L-homoserine sulfhydrylase, O-pimelyl-L-homoserine sulfhydrylase, and O-sulfato-L-homoserine sulfhydrylase.

[0119] In particular, the sulfhydrylase may be selected from O-phospho-L-homoserine sulfhydrylase, O-succinyl-L-homoserine sulfhydrylase, O-acetyl-L-homoserine sulfhydrylase, O-sulfato-L-homoserine sulfhydrylase and O-propio-L-homoserine sulfhydrylase.

[0120] The sulfhydrylase can be selected from O-phospho-L-homoserine sulfhydrylase, O-succinyl-L-homoserine sulfhydrylase, and O-acetyl-L-homoserine sulfhydrylase.

[0121] Most preferably, the enzyme is O-acetyl-L-homoserine sulfhydrylase (OAHS sulfhydrylase).

[0122] Sulfhydrylases, particularly O-acetyl-L-homoserine sulfhydrylases, can originate or be derived from the following bacterial strains: Pseudomonas sp., Chromobacterium sp., Leptospira sp., Hyphomonas sp.

[0123] Sulfhydrylases, as is well known to those skilled in the art, can function in the presence of a cofactor such as pyridoxal 5'-phosphate (also known as PLP) or one of its analogues, preferably pyridoxal 5'-phosphate.

[0124] As an analogue of the cofactor pyridoxal phosphate, α 5 -Pyridoxal methyl phosphate, 5'-methylpyridoxal-P, pyridoxal-5'-sulfate, α 5 -pyridoxal acetate or any other known derivatives (Groman et al., Proc. Nat. Acad. Sci. USA Vol. 69, No. 11, pp. 3297-3300, November 1972).

[0125] According to one embodiment, a cofactor for the sulfhydrylase can be added to the reaction medium. Thus, the cofactor for the sulfhydrylase, for example pyridoxal 5'-phosphate, can be provided before stage c) or added during stage c). If stage c) is carried out in an aqueous solution, the enzyme and optionally its cofactor can be pre-dissolved in water before being added to said solution.

[0126] According to another embodiment, the cell, e.g., a bacterial cell or other cell, can produce or overproduce the cofactor while simultaneously expressing or overexpressing a sulfhydrylase enzyme, so as to avoid the step of replenishing the cofactor.

[0127] According to one embodiment, the sulfhydrylase, and optionally its cofactors, is: - in isolated and / or purified form, for example in aqueous solution; The separation and / or purification of the enzyme produced can be carried out by any means known to those skilled in the art, such as techniques chosen from electrophoresis, molecular sieving, ultracentrifugation, differential precipitation, for example with ammonium sulfate, ultrafiltration, membrane filtration or gel filtration, ion exchange, separation by hydrophobic interactions or affinity chromatography, for example of the IMAC type. - or in a crude extract, i.e. in an extract of disrupted cells (lysate); the enzyme of interest may or may not be overexpressed in said cells (hereinafter referred to as host cells). The host cell may be any host cell suitable for producing the enzyme of interest from the expression of the corresponding coding gene. This gene may be located in the genome of the host or carried by an expression vector.

[0128] For the purposes of the present invention, a "host cell" is understood to be in particular a prokaryotic or eukaryotic cell. Host cells commonly used for the expression of recombinant or non-recombinant proteins include, in particular, bacterial cells such as Escherichia coli, Bacillus sp. or Pseudomonas, yeast cells such as Saccharomyces cerevisiae or Pichia pastoris, fungal cells such as Aspergillus niger, Penicillium funiculosum or Trichoderma reesei, insect cells such as Sf9 cells, or mammalian (in particular human) cells such as HEK293, PER-C6 or CHO cell lines.

[0129] Preferably, the enzyme of interest and optionally the cofactors are expressed in the bacterium Escherichia coli. Preferentially, the enzyme of interest is expressed in an E. coli strain such as E. coli BL21(DE3).

[0130] Cell lysates can be obtained according to various known techniques, such as by sonication, pressure (French press), or the use of chemicals (e.g., xylene, Triton). It corresponds to a crude extract of disrupted cells. - or present in the whole cell. For this, the same techniques as above can be used without the cell lysis step.

[0131] According to one embodiment, the amount of biomass expressing the sulfhydrylase enzyme is between 0.1% and 10% by weight, preferably between 1% and 5% by weight, relative to the mass of the compound of formula (II), and / or the amount of cofactor relative to the compound of formula (II) is between 0.1% and 10% by weight, preferably between 0.5% and 5% by weight.

[0132] The reaction medium may also contain: one or more solvents optionally selected from buffers such as water, phosphate buffer, Tris-HCl, Tris base, ammonium bicarbonate, ammonium acetate, HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid), CHES (N-cyclohexyl-2-aminoethanesulfonic acid), or salts such as sodium chloride, potassium chloride, or their media; - optional additives such as surfactants, especially to facilitate the solubility of one or more reagents or substrates.

[0133] The various components that can be used in the reaction of stage c) above are readily commercially available or can be prepared by techniques known to those skilled in the art. These various elements can be in solid, liquid or gaseous form and can be very advantageously in solution for use in the process of the invention or dissolved in water or any other solvent. The enzymes used can also be grafted onto a support (in the case of supported enzymes).

[0134] According to a preferred embodiment, the compound of formula (II) is O-acetyl-L-homoserine, the enzyme used is O-acetyl-L-homoserine sulfhydrylase, and the resulting functionalized mercaptan of formula (I) is L-homocysteine.

[0135] The present invention also relates to a composition, preferably an aqueous solution, comprising: a compound of formula (II) as defined above; - a sulfhydrylase, preferably a sulfhydrylase associated with a compound of formula (II), said sulfhydrylase being as defined above; and - Preferably excess dissolved H2S.

[0136] Preferably, the composition comprises: - O-acetyl-L-homoserine; - O-acetyl-L-homoserine sulfhydrylase; and - Preferably excess dissolved H2S.

[0137] Said composition corresponds in particular to the reaction medium defined above.

[0138] The conditions, properties and optional ingredients are as defined for the reaction medium defined above.

[0139] In particular, the composition of the present invention does not contain dissolved oxygen. Preferably, H2S is in excess relative to the compound of formula (II), preferably in molar excess. Thus, H2S can be in a superstoichiometric amount relative to the amount of the compound of formula (II).

[0140] In particular, the molar ratio of H2S / compound of formula (II) is 1.1 to 20, preferably 1.1 to 1 0, preferentially 2 to 8, for example 3.5 to 8, even more preferentially 3.5 to 5.

[0141] The composition may also include a cofactor for the sulfhydrylase as defined above.

[0142] In particular, the composition according to the invention makes it possible to carry out the process according to the invention. [Brief explanation of the drawings]

[0143] [Figure 1] FIG. 1 shows the yield (%) of the enzymatic synthesis of L-homocysteine ​​after 1 hour of reaction as a function of the H2S partial pressure (bar).

[0144] The following examples make it possible to illustrate the invention without, however, limiting it in any way. [Example]

[0145] The general definitions of conversion, selectivity, and yield are as follows: Conversion = (moles of initial reactants - moles of reactants remaining after reaction) / (moles of initial reactants) Selectivity = moles of reactant converted to desired product / (moles of initial reactant - moles of reactant remaining after reaction) Yield = Conversion rate × Selectivity

[0146] Example 1: Enzymatic preparation of L-homocysteine ​​from O-acetyl-L-homoserine under H2S partial pressure

[0147] Stage 1: Preparation of O-acetyl-L-homoserine (OAHS) O-acetyl-L-homoserine was synthesized from L-homoserine and acetic anhydride according to the protocol described in Sadamu Nagai's "Synthesis of O-acetyl-L-homoserine," Academic Press (1971), vol. 17, pp. 423-424.

[0148] Stage 2: Preparation of the reaction medium 10 g / l of O-acetyl-L-homoserine obtained in stage 1) is dissolved in 250 ml of water and placed in a thermostatically controlled 500 ml stainless steel reactor. The solution is brought to 37°C with mechanical stirring. 5 g / l OAHS sulfhydrylase and 0.4 g / l pyridoxal phosphate cofactor are added to the reaction medium to make up a total volume of 300 ml. The pH is maintained at a set value of 6.5 using aqueous ammonia (4 M). The reaction medium is then degassed by bubbling nitrogen through it for about 10 minutes.

[0149] Stage 3: H2S addition under pressure The reactor is placed under vacuum to remove any gas present in the reactor headspace in order to closely control the pressure of the hydrogen sulfide added. A constant pressure of H2S is then applied (PH2S = Ptotal). The initiation of the reaction is confirmed by the gradual acidification of the reaction medium (due to the gradual release of the acetic acid co-product), and the pH of the solution is maintained at about 6.5 by the gradual addition of ammonium hydroxide (4 M).

[0150] analysis The yield of the reaction was determined through an approach to quantify the mercaptans formed by argentometric potentiometric titration after 1 h of reaction. The results are also confirmed by NMR and HPLC analysis.

[0151] result The yield of L-homocysteine ​​after 1 hour of reaction was determined in several tests at different H2S partial pressures in the gas headspace of the reactor used. The results indicate the existence of three phases (see Figure 1). - Increased yield at H2S partial pressures from 0 bar to 0.25 bar; - Plateau phase with a yield of 90%-100% at H2S partial pressures of 0.25 bar to 2 bar; - Yield reduction at H2S partial pressures above 2 bar and below 4 bar.

[0152] Example 2: Enzymatic preparation of L-homocysteine ​​from O-acetyl-L-homoserine under H2S partial pressure and in a non-degassed reaction medium

[0153] Stage 1: Preparation of O-acetyl-L-homoserine (OAHS) O-acetyl-L-homoserine was synthesized from L-homoserine and acetic anhydride according to the protocol described in Sadamu Nagai's "Synthesis of O-acetyl-L-homoserine," Academic Press (1971), vol. 17, pp. 423-424.

[0154] Stage 2: Preparation of the reaction medium 10 g / l of O-acetyl-L-homoserine obtained in stage 1) is dissolved in 250 ml of water and placed in a thermostatically controlled 500 ml stainless steel reactor. The solution is brought to 37°C with mechanical stirring. 5 g / l OAHS sulfhydrylase and 0.4 g / l pyridoxal phosphate cofactor are added to the reaction medium to make up a total volume of 300 ml. The pH is maintained at a set value of 6.5 using aqueous ammonia (4 M).

[0155] Stage 3: H2S addition under pressure The reactor is placed under vacuum to remove any gas present in the reactor headspace in order to closely control the pressure of the hydrogen sulfide added. Then, a 0.25 bar H2S pressure is applied. The initiation of the reaction is confirmed by the gradual acidification of the reaction medium (due to the gradual release of the acetic acid co-product), and the pH of the solution is maintained at about 6.5 by the gradual addition of ammonium hydroxide (4 M).

[0156] analysis The yield of the reaction is determined by argentometric potentiometric titration after 1 hour of reaction, an approach that quantifies the mercaptans formed (results that are also confirmed by NMR and HPLC analysis).

[0157] result Final L-homocysteine ​​yield: 88.4%

Claims

1. A process for synthesizing at least one functionalized mercaptan of general formula (I): R ２ -X-C ＊ H(NR １ R ７ )-(CH ２ ) ｎ -SH (I) During the ceremony, -R １ and R ７ are the same or different and represent a hydrogen atom or an aromatic or non-aromatic, linear, branched or cyclic, saturated or unsaturated hydrocarbon chain having 1 to 20 carbon atoms, which may contain one or more heteroatoms; - X is -C(=O)-, -CH ２ - and -CN; -R ２ teeth: (i) Not present when X represents —CN (ii) or a hydrogen atom (iii) or -OR ３ , R ３ is a hydrogen atom or an aromatic or non-aromatic, linear, branched or cyclic, saturated or unsaturated hydrocarbon chain having 1 to 20 carbon atoms, which may contain one or more heteroatoms; (iv) or -NR ４ R ５ , R ４ and R ５ are the same or different and represent a hydrogen atom or an aromatic or non-aromatic, linear, branched or cyclic, saturated or unsaturated hydrocarbon chain having 1 to 20 carbon atoms, which may contain one or more heteroatoms; n is 1 or 2; ＊ represents an asymmetric carbon; The process includes the following stages: a) providing at least one compound of the following general formula (II): R ２ -X-C ＊ H(NR １ R ７ )-(CH ２ ) ｎ -G (II) During the ceremony, ＊ , R １ , R ２ , R ７ , X and n are as defined for formula (I); G is (i) R ６ —C(O)—O—, or (ii) (R ７ O) (R ８ O)—P(O)—O—, or (iii) R ９ O-SO ２ -O-; R ６ may contain a hydrogen atom or one or more linear, branched or cyclic, saturated or unsaturated aromatic groups, -OR １０ , (=O), -C(O)OR １１ , -NR １２ R １３ a hydrocarbon chain having 1 to 20 carbon atoms which may be substituted with one or more groups selected from the group consisting of: R １０ , R １１ , R １２ and R １３ are each independently selected from: H or a linear, branched or cyclic, saturated or unsaturated hydrocarbon chain having 1 to 20 carbon atoms; R ７ and R ８ are the same or different and are a proton, an alkali metal, an alkaline earth metal, or ammonium; R ９ is selected from a proton, an alkali metal, an alkaline earth metal, and ammonium; b) H ２ Provision of S; c) reacting at least one compound of formula (II) with H in the presence of at least one enzyme selected from sulfhydrylases, preferably sulfhydrylases associated with the compound of formula (II); ２ Reaction with S; The reaction is carried out in a reactor, and H in the gas headspace of the reactor ２ the S partial pressure is from 0.01 bar to 4 bar, for example from 0.01 bar to 3 bar, preferably from 0.1 bar to 3 bar, for example from 0.1 bar to 2.5 bar, at the reaction temperature; d) obtaining at least one functionalized mercaptan of formula (I); e) optional separation of said at least one functionalized mercaptan of formula (I) obtained in stage d); and f) optional further functionalization and / or optional deprotection of the functionalized mercaptan of formula (I) obtained in stage d) or e); Stages a) and b) are optionally performed simultaneously.

2. H in the gas headspace of the reactor ２ The S partial pressure is 0.25 bar to 2 bar; The synthesis process of claim 1.

3. The H ２ 3. The synthesis process according to claim 1 or claim 2, wherein S is in excess relative to the compound of formula (II).

4. The synthesis process according to any one of claims 1 to 3, wherein stage c) is carried out in an aqueous solution.

5. The H ２ 5. The synthesis process of claim 1, wherein the S partial pressure corresponds to the total pressure in the gas headspace.

6. The H ２ 6. The synthesis process according to claim 1, wherein the S partial pressure is kept constant throughout stage c).

7. 7. The synthetic process according to any one of claims 1 to 6, wherein the compound of formula (II) is selected from the group consisting of O-phospho-L-homoserine, O-succinyl-L-homoserine, O-acetyl-L-homoserine, O-acetoacetyl-L-homoserine, O-propio-L-homoserine, O-coumaroyl-L-homoserine, O-malonyl-L-homoserine, O-hydroxymethylglutaryl-L-homoserine, O-pimelyl-L-homoserine and O-sulfato-L-homoserine, preferably O-acetyl-L-homoserine.

8. The synthetic process according to any one of claims 1 to 7, wherein the functionalized mercaptan of formula (I) is L-homocysteine.

9. 9. The synthetic process according to any one of claims 1 to 8, wherein the compound of formula (II) is O-acetyl-L-homoserine, the enzyme used is O-acetyl-L-homoserine sulfhydrylase, and the functionalized mercaptan of formula (I) is L-homocysteine.

10. The process according to any one of claims 1 to 9, wherein stage c) is carried out essentially in the absence of oxygen, preferably in the absence of oxygen.

11. The process according to any one of claims 1 to 10, wherein the temperature during stage c) is between 10°C and 60°C, preferably between 20°C and 40°C, more particularly between 25°C and 40°C.

12. a compound of formula (II) as defined in claim 1; sulfhydrylase; and - Dissolved H ２ S A composition comprising:

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