FUNCTIONALISED POLSULPHIDE SYNTHESIS METHOD

Abstract

Provided is process for the synthesis of at least one functionalized organic polysulfide.

Claims

1. A process for synthesizing at least one functionalized organic polysulfide of formula (I):
R.sub.2—X—(NR.sub.1R.sub.7)C*H—(CH.sub.2).sub.n—S.sub.a—(CH.sub.2).sub.n—C*H(NR.sub.1R.sub.7)—X—R.sub.2  (I) wherein: R.sub.1 and R.sub.7 are a hydrogen or an aromatic or nonaromatic, or a linear or cyclic, saturated or unsaturated, branched or unbranched, hydrocarbon chain of 1 to 20 carbon atoms, which can comprise heteroatoms, wherein R.sub.1 and R.sub.7 are identical or different; X is —C(═O)— or —CH.sub.2— or —CN; R.sub.2 is (i) nonexistent when X represents —CN, (ii) a hydrogen, (iii) —OR.sub.3, wherein R.sub.3 is a hydrogen or an aromatic or nonaromatic, or a linear or cyclic, saturated or unsaturated, branched or unbranched, hydrocarbon chain of 1 to 20 carbon atoms, which can comprise heteroatoms, or (iv) —NR.sub.4R.sub.5, wherein R.sub.4 and R.sub.5 are a hydrogen or an aromatic or nonaromatic, or a linear or cyclic, saturated or unsaturated, branched or unbranched, hydrocarbon chain of 1 to 20 carbon atoms, which can comprise heteroatoms, and wherein R.sub.4 and R.sub.5 are identical or different; n is 1 or 2; a is an integer or decimal number between 2 and 10; and C* represents an asymmetric carbon; the process comprising: (a) providing at least one compound of formula (II):
G−(CH.sub.2).sub.n—C*H(NR.sub.1R.sub.7)—X—R.sub.2  (II) wherein: n, R.sub.1, R.sub.2, R.sub.7, X and C* are as defined above, G is (i) R.sub.6—C(═O)—O—, (ii) (R.sub.8O)(R.sub.9O)—P(═O)—O—, or (iii) R.sub.8O—SO.sub.2—O—; R.sub.6 is a hydrogen or an aromatic or nonaromatic, or a linear or cyclic, saturated or unsaturated, branched or unbranched, hydrocarbon chain of 1 to 20 carbon atoms, which can comprise heteroatoms; R.sub.8 and R.sub.9 are H, an alkali metal, an alkaline earth metal or an ammonium, wherein R.sub.8 and R.sub.9, are identical or different; (b) providing at least one inorganic polysulfide; (c) reacting the at least one compound of formula (II) with the at least one inorganic polysulfide in the presence of at least one enzyme chosen from sulfhydrylase; (d) obtaining at least one functionalized organic polysulfide of formula (I); (e) separating and isolating the at least one functionalized organic polysulfide of formula (I) and; (f) optionally, further functionalizing the functionalized organic polysulfide of formula (I) obtained in stage (d) or (e); wherein stages (a) and (b) are carried out simultaneously or sequentially.

2. The process as claimed in claim 1, wherein the functionalized organic polysulfide of formula (I) is enantiomerically pure.

3. The process as claimed in claim 1, wherein the functionalized organic polysulfide of formula (I) is chosen from dicysteine polysulfide and dihomocysteine polysulfide.

4. The process as claimed in claim 1, wherein the compound of formula (II) is chosen from I-serine derivatives and I-homoserine derivatives.

5. The process as claimed in claim 4, wherein the I-serine derivative is chosen from 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-sulfo-L-serine.

6. The process as claimed in claim 4, wherein the I-homoserine derivative is chosen from O-phospho-L-homoserine, O-succinyl-L-homoserine, O-acetyl-L-homoserine, O-acetoacetyl-L-homoserine, propio-L-homoserine, O-coumaroyl-L-homoserine, O-malonyl-L-homoserine, O-hydroxymethylglutaryl-L-homoserine, O-pimelyl-L-homoserine and O-sulfo-L-homoserine.

7. The process as claimed in claim 4, wherein the sulfhydrylase is chosen from sulfhydrylases associated with the L-serine derivatives and sulfhydrylases associated with the L-homoserine derivatives.

8. The process as claimed in claim 7, wherein the sulfhydrylase associated with the L-serine derivative is chosen from O-phospho-L-serine sulfhydrylase, O-succinyl-L-serine sulfhydrylase, O-acetyl-L-serine sulfhydrylase, 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-sulfo-L-serine.

9. The process as claimed in claim 7, wherein the sulfhydrylase associated with the L-homoserine derivative is chosen 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-sulfo-L-homoserine sulfhydrylase.

10. The process as claimed in claim 1, wherein the inorganic polysulfide is chosen from alkali metal, alkaline earth metal and ammonium polysulfides.

11. A functionalized organic polysulfide of formula (I) prepared according to the process described in claim 1.

12. Dicysteine or dihomocysteine polysulfide prepared according to the process described in claim 1.

13. A process for lubrication, vulcanization, sulfidation of catalysts or preparation of medicaments, comprising using a functionalized organic polysulfide as claimed in claim 11.

14. The process as claimed in claim 1, wherein the sulfhydrylase is a sulfhydrylase associated with the compound of formula (II).

15. The process as claimed in claim 4, wherein the L-serine derivative is selected from the group consisting of O-phospho-L-serine, O-succinyl-L-serine, O-acetyl-L-serine and O-sulfo-L-serine.

16. The process as claimed in claim 4, wherein the L-homoserine derivative is selected from the group consisting of O-succinyl-L-homoserine, O-acetyl-L-homoserine, O-phospho-homoserine and O-sulfo-L-homoserine.

17. The process as claimed in claim 7, wherein the sulfhydrylase associated with the L-serine derivative is selected from the group consisting of O-phospho-L-serine, O-succinyl-L-serine sulfhydrylase, O-acetyl-L-serine sulfhydrylase and O-sulfo-L-serine.

18. The process as claimed in claim 7, wherein the sulfhydrylase associated with the L-homoserine derivative is selected from the group consisting of O-phospho-L-homoserine sulfhydrylase, O-succinyl-L-homoserine sulfhydrylase, O-acetyl-L-homoserine sulfhydrylase and O-sulfo-L-homoserine sulfhydrylase.

19. The process as claimed in claim 1, wherein the inorganic polysulfide is selected from the group consisting of sodium polysulfide, potassium polysulfide, calcium polysulfide and ammonium polysulfide.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0065] According to a preferred embodiment of the invention, the .sub.L-serine derivative is O-acetyl-.sub.L-serine, the inorganic polysulfide is sodium polysulfide and the enzyme used is O-acetyl-.sub.L-serine sulfhydrylase.

[0066] According to a preferred embodiment of the invention, the organic polysulfide obtained according to the process is dicysteine polysulfide.

[0067] According to another preferred embodiment of the invention, the .sub.L-homoserine derivative is O-acetyl-.sub.L-homoserine, the inorganic polysulfide is sodium polysulfide and the enzyme used is O-acetyl-.sub.L-homoserine sulfhydrylase.

[0068] According to a preferred embodiment of the invention, the organic polysulfide obtained according to the process is dihomocysteine polysulfide.

[0069] As regards the synthesis medium, temperature and pH conditions, reference may be made to those described in the applications WO2008013432 and WO2013029690.

[0070] Thus, according to the operating range of the enzyme, the reaction pH is between 5 and 8, preferably between 6 and 7.5 and more particularly between 6.2 and 7.2. In all cases, the pH has to be regulated according to the operating optimum of the enzyme. The pH can be regulated by addition of basic inorganic polysulfide, of dilute sulfuric acid or of dilute aqueous ammonia.

[0071] Thus, according to the operating range of the enzyme, 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.

[0072] The reaction takes place in an aqueous medium or in the presence of organic solvents, if the latter are compatible with the enzymes used. Preferably, the reaction takes place in an aqueous medium.

[0073] The reaction can be carried out batchwise, semi-continuously or continuously.

[0074] Reactors of any type which is known to a person skilled in the art may be suitable for reactions of this type.

[0075] According to one embodiment of the invention, the separation and the isolation of the organic polysulfide obtained can be carried out according to any technique known to a person skilled in the art, in particular by precipitation and filtration.

[0076] The optional stage f/of the process according to the invention makes it possible to obtain additional functional groups which are different from those obtained after stage d/or stage e/.

[0077] This is because the functionalized organic polysulfide of formula (I) obtained on conclusion of stage d/can again be functionalized during this stage f/. For example, if X—R.sub.2 represents a carboxyl functional group, the latter can be esterified, reduced to an aldehyde, reduced to an alcohol and then etherified, amidated, nitrilated or others. All the functional groups can be obtained by a person skilled in the art depending on the final use which is intended for the organic polysulfide.

[0078] Thus, the functionalized organic polysulfide of formula (I) obtained on conclusion of stage d/can be subjected to one or more additional chemical reactions in order to obtain one or more organic polysulfides with different functional groups, said chemical reactions being all reactions known to a person skilled in the art.

[0079] The functionalized organic polysulfides of formula (I) obtained according to the process according to the invention can be used in numerous applications, such as lubrication, vulcanization, the sulfidation of catalysts, in the therapeutic field, and others.

[0080] In particular, the functionalized polysulfides of formula (I) can be used as antiwear agent, extreme-pressure agent or antioxidant. They can also participate in the composition of lubricating formulations or of some medicaments, such as medicaments for combating radiation. Finally, they can be used in the manufacture of cement, concrete or asphalt.

Examples

[0081] The examples which follow make it possible to illustrate the present invention but are not under any circumstances limiting.

Example 1: Synthesis of Dihomocysteine Tetrasulfide

Stage 1:

[0082] O-Acetyl-.sub.L-homoserine was synthesized from .sub.L-homoserine and acetic anhydride according to Sadamu Nagai, “Synthesis of O-acetyl-.sub.L-homoserine”, Academic Press (1971), vol. 17, pp. 423-424.

Stage 2:

[0083] At the same time, 11.21 g of sodium hydrosulfide (200 mmol) are introduced into 100 ml of distilled water in a 250 ml glass reactor and are left to dissolve by stirring at ambient temperature using a thermostatically controlled oil bath. 9.62 g of flowers of sulfur (300 mmol) are gradually added over 2 h, the solution becomes red and H.sub.2S begins to degas from the reaction medium. This reactor is connected to a trap containing 200 g of 10% by weight sodium hydroxide solution (500 mmol of 100% NaOH). This sodium hydroxide solution makes it possible to trap the H.sub.2S originating from the reactor and also makes it possible to monitor the progression of the reaction by virtue of withdrawn samples analysed by argentometric potentiometric titration. A slight nitrogen flow is introduced into the reactor so as to facilitate the departure of the H.sub.2S. After 2 hours, the analysis of the trap shows that 100% of the H.sub.2S theoretically produced has been trapped in the sodium hydroxide solution to form sodium hydrosulfide. Once this trap is saturated (sodium hydroxide completely converted) after several syntheses of sodium polysulfides, the sodium hydrosulfide solution can be used as is for the synthesis of these polysulfides. In the main reactor, 117.1 g of a Na.sub.2S.sub.4 solution titrating 14.9% by weight are obtained.

Stage 3:

[0084] 10 g (62 mmol) of O-acetyl-L-homoserine (OAHS originating from stage 1) are introduced into 140 ml of distilled water in a thermostatically controlled 250 ml glass reactor. The solution is brought to 35° C. with mechanical stirring. The pH of the reaction medium is 4.8. It is desirable, before putting in the enzyme, for the pH to be equal to 6.5; for this, a few drops of the solution of sodium polysulfides obtained in stage 2 are added. A sample of 1 ml of the reaction medium is withdrawn (at t=0).

[0085] A solution of 10 ml of distilled water containing 400 μl of a solution of pyridoxal 5′-phosphate (10 mmol/1) and of 0.6 g of enzyme (O-acetyl-.sub.L-homoserine sulfhydrylase) is prepared and then this solution is added to the reactor. The reaction begins. The pH decreases and, in order to keep the reaction medium at a pH equal to 6.5, the sodium tetrasulfide solution is slowly added via the dropping funnel (in total, 36.2 g (i.e., 5.4 g de Na.sub.2S.sub.4 expressed as 100% −31 mmol) of the solution obtained during stage 2 are added). Samples (1 ml) are withdrawn during the reaction. The analyses by potentiometric titration, TLC, HPLC and UPLC/UV-mass show a gradual disappearance of the reactants (OAHS and Na.sub.2S.sub.4) and the gradual appearance, in increasingly large amounts, of the following compounds (it should be noted that a portion of these polysulfides precipitates during the reaction):

##STR00001##

[0086] The only other products observed after the complete disappearance of the OAHS are traces of dihomocysteine (hydrolysis of the OAHS) and traces of homocysteine. It can thus be concluded therefrom that the synthesis of dihomoserine polysulfides (mean sulfur rank of 4) from OAHS has been virtually total.

Stage 4: Separation and Isolation of the Dihomocysteine Polysulfide:

[0087] The reaction medium of stage 3 is filtered a first time in order to recover, after drying, 4.4 g of dihomocysteine polysulfide. The residual solution is concentrated by partial evaporation of the water (so as to prevent the precipitation of the sodium acetate present in the reaction medium) under reduced pressure at 30° C.; a fresh precipitate is formed. After filtration and drying, 3.8 g of dihomocysteine polysulfide are again obtained. The overall isolated yield of homoserine polysulfide is 8.2 g with regard to theoretical 10.30 g, i.e. 79.6%. Additional analyses on this dry product showed that this solid contained 41% (elemental analysis) of sulfur (thus a mean rank of 4.3) and that it did not contain elemental sulfur in the free state (HPLC analysis).

Example 2: Synthesis of Dihomocysteine Tetrasulfide (without Enzyme or Coenzyme)

[0088] Example 1 was repeated, with the only difference that the solution of pyridoxal 5′-phosphate and of enzyme (10 ml of distilled water containing 400 μl of a solution of pyridoxal 5′-phosphate (10 mmol/1) and of 0.6 g of enzyme (O-acetyl-L-homoserine sulfhydrylase)) was not added to the reactor. It turns out that the reaction does not start and that it is impossible to continually add the solution of sodium polysulfides while attempting to retain a pH of 6.5. On increasing to a pH equal to 8 by addition of sodium polysulfide solution, the only reaction observed is the beginning of hydrolysis of the OAHS to give homoserine. This example shows that this synthesis has to be catalyzed by an enzyme to be effective.

Example 3: Synthesis of Cysteine Disulfide (Cystine)

Stage 1:

[0089] O-Acetyl-.sub.L-serine is sold by Sigma-Aldrich. It can also be synthesized from L-serine by any means known to a person skilled in the art.

Stage 2:

[0090] 11.21 g of sodium hydrosulfide (200 mmol) are introduced into 100 ml of distilled water in a 250 ml glass reactor and are left to dissolve by stirring at ambient temperature using a thermostatically controlled oil bath. 3.2 g of flowers of sulfur (100 mmol) are gradually added over 2 hours, the solution becomes bright yellow and H.sub.2S begins to degas from the reaction medium. This reactor is connected a trap containing 200 ml of 10% by weight sodium hydroxide solution (500 mmol of 100% NaOH). This sodium hydroxide solution makes it possible to trap the H.sub.2S originating from the reactor and to monitor the progression of the reaction by virtue of withdrawn samples analysed by argentometric potentiometric titration. A slight nitrogen flow is introduced into the reactor so as to facilitate the departure of the H.sub.2S. After 2 hours, the analysis of the trap shows that 100% of the H.sub.2S theoretically produced has been trapped in the sodium hydroxide solution to form sodium hydrosulfide. Once this trap is saturated (sodium hydroxide completely converted) and after synthesis of sodium disulfide, the sodium hydrosulfide solution can be used as is for the synthesis of this disulfide. In the reactor, 111 g of a Na.sub.2S.sub.4 solution titrating 9.9% by weight are obtained.

Stage 3:

[0091] 9.12 g (62 mmol) of O-acetyl-L-serine are introduced into 140 ml of distilled water in a thermostatically controlled 250 ml glass reactor. The solution is brought to 35° C. with mechanical stirring. The pH of the reaction medium is 4.6. It is desirable, before putting in the enzyme, for the pH to be 6.5; for this, a few drops of the solution of sodium disulfide (Na.sub.2S.sub.2) obtained in stage 2 are added. A sample of 1 ml of the reaction medium is withdrawn (at t=0). A solution of pyridoxal 5-phosphate (10 mmol, 0.4 ml) and the enzyme O-acetyl-.sub.L-serine sulfhydrylase (0.6 ml) are dissolved in 10 ml of water and then added to the reactor. The reaction begins. The pH decreases and, in order to keep the reaction medium at a pH equal to 6.5, the sodium disulfide solution is slowly added via the dropping funnel (in total, 32 g of the solution obtained during stage 2, i.e. 3.2 g de Na.sub.2S.sub.2 expressed as 100%, 31 mmol, are added). Samples (1 ml) are withdrawn during the reaction. The analyses by potentiometric titration, TLC, HPLC and UPLC/UV-mass show a gradual disappearance of the reactants (O-acetyl-.sub.L-serine and Na.sub.2S.sub.2) and the gradual appearance of cystine. The appearance of a precipitate resulting from the formation of cystine is also observed:

##STR00002##

[0092] The only other products observed after the complete disappearance of O-acetyl-L-serine are traces of serine (hydrolysis of O-acetyl-.sub.L-serine). It can thus be concluded therefrom that the synthesis of cystine from O-acetyl-.sub.L-serine has been virtually total.

Stage 4: Separation and Isolation of the Cystine:

[0093] The reaction medium of stage 3 is filtered a first time in order to recover, after drying, 4.7 g of cystine. The residual solution is concentrated by partial evaporation of the water (so as to prevent the precipitation of the sodium acetate present in the reaction medium) under reduced pressure at 30° C., and a fresh precipitate is formed. After filtration and drying, 1.2 g of cystine are again obtained. The overall isolated yield of cystine is 5.74 g with regard to theoretical 7.44 g, i.e. 77.2%. Additional analyses on this dry product showed that this solid contained 26.82% (elemental analysis) of sulfur (thus a mean rank of 2.01) and that it did not contain elemental sulfur in the free state (HPLC analysis).