FUNCTIONALISED POLYSULPHIDE SYNTHESIS METHOD

Abstract

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

Claims

1. A process for the synthesis of at least one functionalized organic polysulfide of formula (I):
R.sub.2X(NR.sub.1R.sub.7)C*H(CH.sub.2).sub.nS.sub.a(CH.sub.2).sub.nC*H(NR.sub.1R.sub.7)XR.sub.2(I) in which: R.sub.1 and R.sub.7, which are or are not different, are a hydrogen or an aromatic or nonaromatic, linear or cyclic, saturated or unsaturated, branched or unbranched, hydrocarbon chain of 1 to 20 carbon atoms, which can comprise heteroatoms; X is C(O) or CH.sub.2 or CN; R.sub.2 is (i) either nonexistent (when X represents CN), (ii) or a hydrogen, (iii) or OR.sub.3, R.sub.3 being a hydrogen or an aromatic or nonaromatic, linear or cyclic, saturated or unsaturated, branched or unbranched, hydrocarbon chain of 1 to 20 carbon atoms, which can comprise heteroatoms, (iv) or NR.sub.4R.sub.5, R.sub.4 and R.sub.5, which are or are not different, being a hydrogen or an aromatic or nonaromatic, linear or cyclic, saturated or unsaturated, branched or unbranched, hydrocarbon chain of 1 to 20 carbon atoms, which can comprise heteroatoms; n is equal to 1 or 2; a is an integer or decimal number between 2 and 10; and * represents an asymmetric carbon; said process comprising: a/ providing at least one compound of formula (II):
G-(CH.sub.2).sub.nC*H(NR.sub.1R.sub.7)XR.sub.2(II) in which: n, R.sub.1, R.sub.2, R.sub.7, X and * are as defined above, G represents either (i) R.sub.6C(O)O, or (ii) (R.sub.8O)(R.sub.9O)P(O)O, or (iii) R.sub.8OSO.sub.2O; R.sub.6 is a hydrogen or an aromatic or nonaromatic, 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, which are identical or different, being a proton H, an alkali metal, an alkaline earth metal or an ammonium; b/ providing at least one inorganic polysulfide; c/ reaction between said at least compound of formula (II) and said at least inorganic polysulfide in the presence of at least one enzyme chosen from sulfhydrylases; d/ obtaining at least one functionalized organic polysulfide of formula (I); e/ separation and isolation of said at least functionalized organic polysulfide of formula (I) and; f/ optionally, additional functionalization of the functionalized organic polysulfide of formula (I) obtained in stage d/ or e/; stages a/ and b/ being or not being carried out simultaneously.

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

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

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

5. The process as claimed in claim 4, in which the l-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, in which the l-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 1, in which the sulfhydrylase is chosen from the sulfhydrylases associated with the 1-serine derivatives and the sulfhydrylases associated with the 1-homoserine derivatives.

8. The process as claimed in claim 7, in which 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, in which 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, in which the inorganic polysulfide is chosen from alkali metal, alkaline earth metal and ammonium polysulfides.

11. The process as claimed in claim 1, comprising an optional stage f/ of additional functionalization of the functionalized organic polysulfide of formula (I) obtained in stage d/ or in stage e/.

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

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

14. The use of the functionalized organic polysulfide of formula (I) prepared according to the process as claimed in claim 1, in lubrication, vulcanization, the sulfidation of catalysts or the preparation of medicaments.

Description

EXAMPLES

[0079] 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

[0080] Stage 1:

[0081] O-Acetyl-L-homoserine was synthesized from L-homoserine and acetic anhydride according to Sadamu Nagai, Synthesis of O-acetyl-L-homoserine, Academic Press (1971), vol. 17, pp. 423-424.

[0082] 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.

[0084] Stage 3:

[0085] 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).

[0086] A solution of 10 ml of distilled water containing 400 l of a solution of pyridoxal 5-phosphate (10 mmol/l) and of 0.6 g of enzyme (O-acetyl-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##

[0087] 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:

[0088] 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%.

[0089] 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)

[0090] 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 l of a solution of pyridoxal 5-phosphate (10 mmol/l) 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:

[0091] O-Acetyl-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:

[0092] 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:

[0093] 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-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-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##

[0094] The only other products observed after the complete disappearance of O-acetyl-L-serine are traces of serine (hydrolysis of O-acetyl-L-serine). It can thus be concluded therefrom that the synthesis of cystine from O-acetyl-L-serine has been virtually total.

Stage 4: Separation and Isolation of the Cystine:

[0095] 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).