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• • C—CHEMISTRY; METALLURGY
  • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
  • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
  • C12P11/00—Preparation of sulfur-containing organic compounds
• • C—CHEMISTRY; METALLURGY
  • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
  • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
  • C12P13/00—Preparation of nitrogen-containing organic compounds
  • C12P13/04—Alpha- or beta- amino acids
  • C12P13/12—Methionine; Cysteine; Cystine
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
  • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
  • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
  • C07C323/57—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
  • C07C323/58—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton
• • C—CHEMISTRY; METALLURGY
  • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
  • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
  • C12P13/00—Preparation of nitrogen-containing organic compounds

Definitions

• the invention relates to the field of organic polysulfides and more particularly to a process for synthesizing functionalized organic polysulfides.
• Organic polysulfides are used in many applications. Indeed, depending on the functions they carry, they can be used as additives for lubrication, as anti-wear agent, extreme pressure agent or antioxidant. They are also used during the presulphuration of hydrotreating catalysts of petroleum cuts or vulcanization. They can also be used in the formulation of lubricating formulations, for example for gearboxes or for machining materials. In addition, they can be used in the manufacture of cement, concrete or bitumen. Finally, they may be used in the composition of certain anti-radiation drugs or for other therapeutic purposes.
• organic polysulfides are commonly synthesized by a reaction process between a mercaptan, sulfur and a basic catalyst. They can also be prepared by a reaction process between an olefin of petroleum or renewable origin with sulfur and hydrogen sulphide.
• these processes for obtaining organic polysulfides require high temperature and / or pressure conditions in order to be efficient.
• the present invention relates to a process for the synthesis of at least one functionalized organic polysulfide of formula (I):
• Ri and R 7 are a hydrogen or a branched or unsaturated branched or unsaturated hydrocarbon chain, linear or cyclic, aromatic or not, from 1 to 20 carbon atoms, which may comprise heteroatoms;
• R2 is (i) either zero (when X represents -CN), (ii) a hydrogen, (iii) or -OR3, R3 being a linear or cyclic hydrogen or a branched or unsaturated, saturated or unsaturated hydrocarbon-based chain, aromatic or not, of 1 to 20 carbon atoms, which may contain heteroatoms, (iv) or -NR4R5, R 4 and R 5 , different or different, being a hydrogen or a branched or unsaturated hydrocarbon chain, saturated or unsaturated, linear or cyclic, aromatic or not, of 1 to 20 carbon atoms, which may comprise heteroatoms;
• n 1 or 2;
• - a is an integer or decimal between 2 and 10, preferably between 2 and 6;
• said method comprising the steps of:
• R 1, R 2 , R 7, X and * are as defined above,
• R 6 is a hydrogen or a branched or unsaturated branched or unsaturated hydrocarbon chain, linear or cyclic, aromatic or otherwise, of 1 to 20 carbon atoms, which may comprise heteroatoms;
• Rg identical or different, being a proton H, an alkaline, an alkaline earth or an ammonium, preferably a proton H or an alkali, and more particularly an H or Na proton;
• the functionalized organic polysulfide of formula (I) obtained according to the process according to the invention is an enantiomerically pure organic polysulfide.
• “functionalized organic polysulfide” is meant any type of organic polysulfide of formula (I) whose nitrogen atom carries a functional group (except when R 1 represents the hydrogen atom) and / or the carbon atom alpha to the nitrogen atom carries a functional group (except when -X- represents -CH2- and R2 the hydrogen atom).
• R 1 and R 7 represent the hydrogen atom.
• R2 represents -OR3, R3 being a hydrogen.
• n is equal to 1.
• n is equal to 2.
• R 1 represents the hydrogen atom
• R 2 represents -OR 3 with R 3 being a hydrogen
• n is 1
• the compound of formula (I) is polysulfide dicysteine.
• R 1 represents the hydrogen atom
• R 2 represents -OR 3 with R 3 being a hydrogen
• n is 2
• the compound of formula (I) is dihomocysteine polysulfide.
• R 1 represents the hydrogen atom
• R2 represents -OR 3 with R 3 being a hydrogen
• n is 1 and the compound of formula (II) is a derivative of L-serine.
• the L-serine derivative used in the process according to the invention may, for example and without limitation, be chosen from ⁇ -phospho-L-serine, O-succinyl-L-serine, O-acetyl-L-serine, ⁇ -acetoacetyl-L-serine, ⁇ -propio-L-serine, O-coumaroyl-L-serine, ⁇ -malonyl-L-serine, ⁇ -hydroxymethylglutaryl-L-serine, ⁇ -pimelyl-L-serine and ⁇ -sulfato- L-serine.
• the L-serine derivative is chosen from ⁇ -phospho-L-serine, ⁇ -succinyl-L-serine, ⁇ -acetyl-L-serine and ⁇ -sulfato-L-serine.
• the L-serine derivative is O-acetyl-L-serine.
• R 1 represents the hydrogen atom
• F3 ⁇ 4 represents -OR 3 with R 3 being a hydrogen atom
• n is 2 and the compound of formula (II) is a derivative of L-homoserine.
• L-homoserine used in the process according to the invention may, for example and without limitation, be chosen from O-phospho-L-homoserine, O-succinyl-L-homoserine , ⁇ -acetyl-L-homoserine, O-acetoacetyl-L-homoserine, O-propio-L-homoserine, O-coumaroyl-L-homoserine, O-malonyl-L-homoserine, l O-hydroxymethylglutaryl-L-homoserine, ⁇ -pimelyl-L-homoserine, and O-sulfato- L-homoserine.
• the derivative of L-homoserine is chosen from O-succinyl-L-homoserine, O-acetyl-L-homoserine, O-phospho-homoserine and O-sulfato. - L-homoserine.
• the derivative of L-homoserine is O-acetyl-L-homoserine (OAHS).
• the derivative of L-serine and the derivative of L-homoserine are either commercially available or obtained by any technique known to those skilled in the art.
• the renewable raw material may be selected from glucose, sucrose, starch, molasses, glycerol, bioethanol, preferably glucose.
• the derivative of L-serine can also be produced from the acetylation of L-serine, L-serine, which can itself be obtained by fermentation of a renewable raw material.
• the renewable raw material may be selected from glucose, sucrose, starch, molasses, glycerol, bioethanol, preferably glucose.
• the derivative of L-homoserine can also be produced from the acetylation of L-homoserine, L-homoserine, which can itself be obtained by fermentation of a renewable raw material.
• the renewable raw material may be selected from glucose, sucrose, starch, molasses, glycerol, bioethanol, preferably glucose.
• the inorganic polysulfide used in the process according to the invention has an average sulfur or decimal rank of between 2 and 10, preferably between 2 and 6.
• the inorganic polysulfide is chosen from polysulfides of alkali, alkaline earth and ammonium.
• the inorganic polysulfide is selected from sodium polysulfide, potassium polysulfide, calcium polysulfide and ammonium polysulfide.
• the inorganic polysulfide is sodium polysulfide.
• the inorganic polysulfide is prepared from sulfide or sulfide according to any technique known to those skilled in the art.
• the sulfhydrate or sulphide used may be an alkali, alkaline earth or ammonium sulphide or sulphide
• the inorganic polysulfide may also be prepared from hydroxides, oxides, hydrogen sulfide or sulfur.
• the amount of sulfur added is adjusted according to the desired average sulfur rank for the inorganic polysulfide.
• the reaction between said at least one compound of formula (II) and said at least one inorganic polysulfide is carried out in the presence of at least one enzyme, said enzyme preferably being an associated sulfhydrylase. said compound of formula (II).
• the enzyme that can be used is selected from ⁇ -phospho-L-serine sulfhydrylase, O-succinyl-L-serine sulfhydrylase, ⁇ -acetyl-L-serine sulfhydrylase, ⁇ -acetoacetyl-L-serine sulfhydrylase, O-propio-L-serine sulfhydrylase, ⁇ -coumaroyl-L-serine sulfhydrylase, O-malonyl-L-serine sulfhydrylase , O-hydroxymethylglutaryl-L-serine sulfhydrylase, O-pimelyl-L-serine sulfhydrylase and ⁇ -sulfato-serine sulfhydrylase.
• the enzyme associated with the L-serine derivative is chosen from O-phospho-L-serine sulfhydrylase, O-succinyl-L-serine sulfhydrylase and O-acetyl-L. -serine sulfhydrylase and ⁇ -sulfato-serine sulfhydrylase.
• the enzyme associated with the L-serine derivative is O-acetyl-L-serine sulfhydrylase.
• the enzyme that can be used is selected from O-phospho-L-homoserine, 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, ⁇ -malonyl-L -homoserine sulfhydrylase, O-hydroxymethylglutaryl- L-homoserine sulfhydrylase, ⁇ -pimélyl-L-homoserine sulfhydrylase and ⁇ -sulfato- L-homoserine sulfhydrylase.
• the enzyme associated with the L-homoserine derivative is chosen from ⁇ -phospho-L-homoserine sulfhydrylase, ⁇ -succinyl-L-homoserine sulfhydrylase, rO-acetyl-L-homoserine sulfhydrylase and ⁇ - sulfato-L-homoserine sulfhydrylase.
• the enzyme associated with the derivative of L-homoserine is O-acetyl-L-homoserine sulfhydrylase.
• the enzyme and its associated cofactor are generally dissolved in water before being added to the reaction medium.
• the amount of enzyme relative to the weight of the compound of formula (II) is between 0.1 and 10% by weight, preferably between 1 and 5% by weight, and 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.
• the derivative of L-serine is O-acetyl-L-serine
• the inorganic polysulfide is sodium polysulfide
• the enzyme used is O-acetyl-L-serine sulfhydrylase.
• the organic polysulfide obtained by the process is polysulfide dicysteine.
• the derivative of L-homoserine is ⁇ -acetyl-L-homoserine
• the inorganic polysulfide is sodium polysulfide
• the enzyme used is ⁇ -acetyl-L homoserine sulfhydrylase.
• the organic polysulfide obtained by the process is dihomocysteine polysulfide.
• the reaction pH is between 5 and 8, preferably between 6 and 7.5, and more particularly between 6.2 and 7.2.
• the pH must be regulated according to the optimum functioning of the enzyme.
• the pH can be regulated by adding basic inorganic polysulfide, dilute sulfuric acid or dilute ammonia.
• the temperature during the reaction is between 10 and 45 ° C, preferably between 20 and 40 ° C, and more particularly between 25 and 37 ° C.
• the reaction takes place in an aqueous medium or in the presence of organic solvents if the latter are compatible with the enzymes used.
• the reaction takes place in an aqueous medium.
• the reaction can be carried out batchwise, semi-continuously or continuously. Any type of reactor, known to those skilled in the art, may be suitable for this type of reaction.
• the separation and isolation of the organic polysulfide obtained can be carried out according to any technique known to those skilled in the art, in particular by precipitation and filtration.
• the f / optional step of the method according to the invention provides additional functions and different from those obtained after step d / or step e /.
• the functionalized organic polysulfide of formula (I) obtained at the end of step d / may again be functionalized during this step f /.
• X-R2 represents a carboxylic function
• the latter can be esterified, reduced to aldehyde, reduced to alcohol and then etherified, amidated, nitrilated or others. All functions can be obtained by those skilled in the art depending on the end use intended for the organic polysulfide.
• the functionalized organic polysulfide of formula (I) obtained at the end of step d / may be subjected to one or more additional chemical reactions to obtain one or more organic polysulfides with different functions, the said reactions.
• chemical being any reactions known to those skilled in the art.
• the functionalized organic polysulfides of formula (I) obtained according to the process according to the invention can be used in many applications such as lubrication, vulcanization, sulphidation of catalysts, in the therapeutic field, and others.
• the functionalized polysulfides of formula (I) may be used as an antiwear agent, extreme pressure agent or antioxidant. They can also be used in the composition of lubricating formulations or certain drugs such as anti-radiation drugs. Finally, they can be used in the manufacture of cement, concrete or bitumen.
• Step 1 O-acetyl-L-homoserine was synthesized from L-homoserine and acetic anhydride according to Sadamu Nagai, "Synthesis of O-acetyl-L-homoserine", Academy Press, (1971), vol .17, pp. 423-424.
• OAHS O-acetyl-L-homoserine
• a solution of 10 ml of distilled water containing 400 ⁇ l of a solution of pyridoxal-5'-phosphate (10 mmol / L) and 0.6 g of enzyme (O-acetyl-L-) is prepared. homoserine sulfhydrylase) and this solution is added to the reactor. The reaction begins. The pH decreases and in order to maintain the reaction medium at a pH equal to 6.5, the sodium tetrasulfide solution is slowly added via the dropping funnel (a total of 36.2 g (ie 5.4 g of Na2S 4 expressed in 100% - 31 mmol) of the solution obtained in step 2). Samples (1 mL) are taken during the reaction.
• Step 4 Separation and isolation of dihomocysteine polysulfide:
• the reaction medium of step 3 is filtered a first time to recover, after drying, 4.4 g of dihomocysteine polysulfide.
• the residual solution is concentrated by partial evaporation of the water (so as to avoid the precipitation of the sodium acetate present in the reaction medium) under reduced pressure at 30 ° C, a new precipitate is formed.
• 3.8 g of dihomocysteine polysulfide are again obtained.
• the overall isolated yield of homoserine polysulfide is 8.2 g over 10.30 g theoretical or 79.6%. Further analyzes on this dry product have showed that this solid contained 41% (elemental analysis) of sulfur (therefore an average rank of 4.3) and that it did not contain elemental sulfur in the free state (HPLC analysis).
• Example 1 was repeated with the only difference that the solution of pyridoxal-5'-phosphate and enzyme (10 ml of distilled water containing 400 ⁇ l of a solution of pyridoxal-5'-phosphate ( 10 mmol / L) and 0.6 g of enzyme (O-acetyl-L-homoserine sulfhydrylase) were not added to the reactor, but the reaction does not start and it is impossible to to continuously add the sodium polysulfide solution while trying to maintain a pH of 6.5 By increasing to a pH of 8 by adding sodium polysulfide solution, the only reaction observed is a start of hydrolysis of This example shows that this synthesis must be catalyzed by an enzyme in order to be efficient.
• enzyme O-acetyl-L-homoserine sulfhydrylase
• Step 1
• O-acetyl-L-serine is marketed by Sigma-Aldrich. It can also be synthesized by any means known to those skilled in the art from L-serine.
• 250 g of sodium hydrosulphide (200 mmol) are added to a 250 ml glass reactor in 100 ml of distilled water which is allowed to solubilize while stirring at room temperature using a dye bath. thermostatic oil.
• 3.2 g of sulfur flower (100 mmol) are gradually added during 2 hours, the solution becomes bright yellow and the S starts degassing from the reaction medium.
• This reactor is connected to a trap containing 200 ml of a solution containing 10% by weight of sodium hydroxide (500 mmol 100% NaOH).
• This sodium hydroxide solution makes it possible to trap the h S from the reactor and to follow the progress of the reaction by means of samples analyzed by argentimetric potentiometry.
• a solution of pyridoxal-5'-phosphate (10 mmol, 0.4 mL) and the enzyme O-acetyl-L-serine sulfhydrylase (0.6 mL) are dissolved in 10 mL of water and added in the reactor.
• the reaction begins.
• the pH decreases and in order to maintain the reaction medium at a pH equal to 6.5, the sodium disulfide solution is added slowly via the dropping funnel (a total of 32 g of the solution obtained during the stage is added). 2 or 3.2 g of Na2S2 expressed in 100%, 31 mmol).
• Samples (1 mL) are taken during the reaction.
• the potentiometric, TLC, HPLC and UPLC / UV-mass analyzes show a gradual disappearance of the reagents (O-acetyl-L-serine and Na2S2) and the progressive appearance of cystine. The appearance of a precipitate resulting from the formation of cystine is also observed:
• the reaction medium of step 3 is filtered a first time to recover, after drying, 4.7 g of cystine.
• the residual solution is concentrated by partial evaporation of the water (so as to avoid the precipitation of the sodium acetate present in the reaction medium) under reduced pressure at 30 ° C., and a new precipitate is formed.
• 1.2 g of cystine are again obtained.
• the overall isolated yield of cystine is 5.74 g over 7.44 g theoretical or 77.2%. Further analyzes on this dry product showed that this solid contained 26.82% (elemental analysis) of sulfur (and therefore an average rank of 2.01) and that it did not contain elemental sulfur in the free state (analysis HPLC).

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