Process for preparing 3-methylselenopropan

Abstract

Process for the preparation of 3-methylselenopropanal. The invention relates to a process for the preparation of 3-methylselenopropanal (MSeP), characterized in that it comprises the following steps: a) a solution of CH3SeLi and a solution of acrolein are made available; b) the CH3SeLi solution and the acrolein solution are mixed to obtain a reaction medium in which the acrolein is converted to MSeP; c) optionally, the MSeP thus obtained is isolated and / or purified in the reaction medium. The invention also relates to the manufacture of 2-hydroxy-4-methylselenobutyric acid and selenomethionine from the MSeP thus prepared.

Description

Title of the invention: Process for preparing 3-methylselenopropan

[0001] The present invention relates to a process for preparing 3-methylselenopropanal (hereinafter abbreviated "MSeP").

[0002] Selenium is an essential micronutrient for mammals.

[0003] By way of example, 2-hydroxy-4-methylselenobutyric acid (hereinafter abbreviated as "HMSeBA"), i.e., the hydroxy analogue of selenomethionine, is of major interest in animal nutrition. Therefore, it is essential that its synthesis process be easily industrialized, that is to say, that it can be produced on a large scale, in the simplest possible way, with implementation that does not present major difficulties and with the lowest associated costs.

[0004] Given the importance of the HMSeBA market, particularly in animal nutrition as mentioned above, the optimization of its synthesis process is still the subject of numerous developments.

[0005] Application WO 2022 / 185018 A1 describes: - the preparation of HMSeBA by converting 2-hydroxy-4-methylselenobutyronitrile (hereinafter abbreviated as "HMSeBN") in the presence of at least water, a weak acid and a catalyst comprising at least one of alumina, titanium dioxide and zirconia, as well as - the preparation of selenomethionine (namely the selenium equivalent of methionine) also from HMSeBN.

[0006] This application WO 2022 / 185018 Al also describes a process for obtaining HMSeBN from MSeP and hydrocyanic acid (hereinafter abbreviated as "HCN").

[0007] Thus, application WO 2022 / 185018 Al describes a synthetic route of HMSeBA, as well as the preparation of selenomethionine which is also essential for animal nutrition.

[0008] Furthermore, application WO 2008 / 049927 A1 describes another method for preparing HMSeBA which includes the following steps: - the reaction of MSeP with an alkali cyanide (e.g., sodium cyanide, potassium cyanide, or lithium cyanide) to obtain HMSeBN; followed by - hydrolysis in a strongly concentrated acidic medium, at high temperature, in a polar protic solvent in order to obtain HMSeBA.

[0009] The synthesis route of HMSeBA described in application WO 2008 / 049927 A1 differs from that described in application WO 2022 / 185018 A1 with regard to the step of obtaining HMSeBN from MSeP: in application WO 2008 / 049927 Al an alkali cyanide is used while in application WO 2022 / 185018 Al HCN is used.

[0010] Furthermore, application WO 2008 / 049927 Al specifies that MSeP is a known compound whose preparation is described in particular in the publication by Dieden et al., entitled Synthesis of l,l-bis(seleno)-2-alkenes, Synthesis, 1988, pages 616-619.

[0011] According to this publication, MSeP can be obtained by reacting acrolein at 25°C with 2 molar equivalents of methylselenol (namely CH3SeH) and 0.1 molar equivalents of ZnCl2 in chloroform.

[0012] This method for synthesizing MSeP has the following drawbacks: - the CH3SeH compound does not exist in a commercial form. It needs to be generated in situ. In addition, it is a colorless, volatile, and flammable liquid with a foul odor and is highly toxic; - it requires the use of H2Se and CH3SeH which are not currently produced on an industrial scale and are highly toxic compounds.

[0013] In view of these drawbacks regarding the synthesis of MSeP from methylselenol and acrolein, the inventors sought to develop another route for the synthesis of MSeP which has the following advantages: - the use of starting compounds that are as non-toxic as possible and readily available on the market (i.e., which do not require in situ generation during MSeP synthesis).

[0014] Finally, as mentioned above with regard to the detailed technical content in WO 2022 / 185018 A1 and WO 2008 / 049927 A1, MSeP is used in the synthesis of HMSeBA. Therefore, in order to optimize the HMSeBA preparation process, the inventors also aimed for this new MSeP synthesis route, coupled with the transformation of MSeP into HMSeBA, to provide a new HMSeBA synthesis route from acrolein with the fewest possible steps.

[0015] The inventors have succeeded in developing a new route for the synthesis of MSeP which perfectly fulfills all these objectives and which, in addition to its use in the synthesis of HMSeBA, can, as will be detailed below, also be perfectly used in the preparation of selenomethionine.

[0016] The invention thus relates to a method for preparing MSeP which is characterized in that it comprises at least the following steps: a) We have a solution of CH3SeLi and a solution of acrolein, b) we mix the CH3SeLi solution and the acrolein solution to obtain a reaction medium in which the acrolein is converted to MSeP, c) Optionally, the MSeP thus obtained is isolated and / or purified in the reaction medium.

[0017] Throughout the description of the present invention, "reaction medium" means a medium in which at least 2 reactants have been mixed for the purpose of carrying out a chemical reaction (for example, a chemical conversion reaction).

[0018] The CH3SeLi solution may have been obtained by reaction of selenium and methyllithium (hereinafter abbreviated CH3Li).

[0019] To do this, selenium can be dissolved in an aprotic nonpolar organic solvent.

[0020] For example, the solvent can be chosen from simple cyclic ethers such as tetrahydrofuran (hereinafter abbreviated THF), 2-methyltetrahydrofuran (hereinafter abbreviated MeTHF), or simple symmetric and mixed linear ethers such as dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether, double cyclic or linear ethers such as dioxanes and dimethoxyethane.

[0021] The selenium solution thus obtained can be cooled to a cooling temperature which can be between -25°C and 25°C.

[0022] Next, a CH3Li solution can be added, preferably drop by drop, to the selenium solution, maintaining the mixture thus obtained (or in other words the reaction medium) at said cooling temperature, so as to obtain the CH3SeLi solution.

[0023] During this addition, and therefore during the conversion of CH3Li to CH3SeLi, an exothermic reaction of the medium can be observed. Furthermore, during this conversion of CH3Li to CH3SeLi, the color of the reaction medium can change from cloudy dark gray to orange-brown, then to orange, and finally to white.

[0024] Advantageously, the excess CH3Li is destroyed by adding a mineral or organic acid to the reaction medium.

[0025] The acid can be chosen from acetic acid, sulfuric acid, hydrochloric acid.

[0026] Preferably, during this addition of the acid, the reaction medium is maintained at a cooling temperature that can be between -25°C and 25°C. During this addition, exothermic reaction may occur. A momentary increase in the temperature of the reaction medium and effervescence due to the release of methane may be observed.

[0027] All these steps for preparing the CH3SeLi solution and, where applicable, for destroying excess CH3Li, are advantageously carried out in a double-jacketed reactor equipped with traps (for example, an empty trap, a trap containing NaOH, and a trap containing bleach). Preferably, during these steps, the reaction medium is placed under an inert atmosphere, for example under an atmosphere of argon or nitrogen.

[0028] Advantageously, the amount of CH3SeLi used for the conversion of acrolein to MSeP can be between 0.9 molar equivalents and 2 molar equivalents per molar equivalent of acrolein.

[0029] The acrolein solution can be an organic acrolein solution or an aqueous acrolein solution.

[0030] When the acrolein solution is an organic acrolein solution, it may have been obtained by mixing, preferably at room temperature, advantageously under an inert atmosphere (for example under an argon atmosphere), a polar aprotic organic solvent, a mineral or organic acid and acrolein.

[0031] The polar aprotic organic solvent can be chosen from simple cyclic ethers such as THF, MeTHF, simple symmetric and mixed linear ethers such as dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether, double cyclic or linear ethers such as dioxanes and dimethoxyethane.

[0032] The acid can, for example, be acetic acid.

[0033] Advantageously, the amount of acid (preferably acetic acid) used for the conversion of acrolein to MSeP can be between 0.01 molar equivalents and 2 molar equivalents per molar equivalent of acrolein.

[0034] When the acrolein solution is an aqueous acrolein solution, it may have been obtained by mixing, preferably at room temperature, water and acrolein.

[0035] During step b) in which the CH3SeLi solution and the acrolein solution are mixed, a reaction medium is obtained in which the acrolein is converted into MSeP.

[0036] In step b), the temperature of the reaction medium is advantageously fixed at a temperature between -20°C and 50°C.

[0037] Advantageously, at the end of step b), the MSeP thus obtained is isolated and / or purified.

[0038] The isolation of the MSeP is perfectly within the capabilities of a person skilled in the art.

[0039] The isolation of MSeP can, for example, be carried out in the following manner: - NaHCO3 is added to the reaction mixture obtained at the end of step b) in order to obtain a two-phase mixture; - we separate the 2 phases of the two-phase mixture; - the aqueous phase is extracted twice with methyl tert-butyl ether (hereinafter abbreviated MTBE); - the organic phases are combined, then dried, for example on Na2SO4.

[0040] MSeP can also be purified by distillation.

[0041] The purification of MSeP by distillation is perfectly within the capabilities of a person skilled in the art.

[0042] The MSeP thus obtained according to the preparation process according to the invention can then be transformed into HMSeBA.

[0043] Therefore, the invention also relates to a method for manufacturing HMSeBA which is characterized in that it comprises at least the following steps: a) the MSeP is prepared by the preparation method according to the invention as described above; bl) we convert the MSeP to HMSeBN; cl) we convert the HMSeBN to HMSeBA.

[0044] In a first embodiment of the invention, the step bl) of converting MSeP into HMSeBN can be carried out, as described for example in the aforementioned WO 2008 / 049927 Al application, namely by reacting MSeP with an alkali cyanide of formula M+CN in a polar protic solvent, and preferably in the presence of an alkali salt of bisulfite of formula M+HSO3, M representing an alkali metal atom.

[0045] The alkali cyanide is preferably chosen from sodium cyanide, potassium cyanide and lithium cyanide. Most preferably, it is sodium cyanide.

[0046] The polar protic solvent is preferably water.

[0047] Advantageously, MSeP is first mixed at room temperature with a sodium bisulfite (NaHSO3) solution. Then, alkali cyanide is added, at room temperature, to the mixture thus obtained so as to form HMSeBN in the reaction medium.

[0048] Following the conversion of MSeP to HMSeBN, the aqueous phase can advantageously be extracted once or several times (for example, twice) with a solvent, which may be dichloromethane. After extraction of the aqueous phase, the organic phases are combined. They are then dried, for example, with Na2SO4. Optionally, the combined and dried organic phases can be filtered, and the solvents evaporated to obtain HMSeBN, which is in the form of a colorless oil.

[0049] In a second embodiment of the invention, step bl) of converting MSeP into HMSeBN can be carried out, as described for example in the aforementioned WO 2022 / 185018 Al application, namely by reacting MSeP with HCN.

[0050] Advantageously, in this embodiment of the invention, this step bl) of converting MSeP to HMSeBN is carried out in the following manner: - the molar ratio of HCN to MSeP is adjusted to a value greater than or equal to 1, preferably greater than or equal to 1.02 (and advantageously not exceeding 1.5) and The pH is adjusted and maintained at a value greater than or equal to 3.5 (preferably greater than or equal to 4, more preferably greater than or equal to 5) to obtain a reaction medium in which HMSeBN is formed. - the pH of the reaction medium is lowered to a value less than or equal to 2.5 (preferably less than or equal to 2, more preferably less than or equal to 1.5) and the HCN is extracted from the reaction medium, - we retrieve the HMSeBN.

[0051] Advantageously, this conversion of MSeP to HMSeBN is carried out at a temperature between 50°C and 110°C. Depending on the temperature, the HCN is in a liquid or gaseous state. In one embodiment of the invention, the HCN is fed into the reaction medium in gaseous form, and the temperature of said reaction medium is maintained above 30°C, preferably above 50°C, and even more preferably above 60°C.

[0052] The pressure conditions in the reaction medium are on the order of 1 to 1.5 bara (i.e. absolute bar).

[0053] Advantageously, the pH is adjusted and maintained with a buffer solution. This buffer solution can be chosen from among all suitable and well-known pairs. These may include citric acid / sodium citrate, citric acid / caustic soda, or sodium citrate / phosphoric acid.

[0054] When HMSeBN is formed in the reaction medium, the pH of said reaction medium is lowered to a value less than or equal to 2.5 by an acid that a person skilled in the art can choose based on their knowledge. Advantageously, the pH of the reaction medium is lowered with an acid chosen from sulfuric acid, nitric acid, and hydrochloric acid, taken alone or in a mixture thereof.

[0055] HCN can be extracted from the reaction medium by any appropriate technique and perfectly within the reach of a person skilled in the art.

[0056] Advantageously, HCN is extracted from the reaction medium by a technique selected from evaporation, stripping (using a carrier gas such as steam, nitrogen, air, carbon dioxide, or any mixture thereof), distillation, or a membrane process. Most preferably, the HCN extraction technique is evaporation.

[0057] Extracting HCN allows it to be recycled in the reaction step with MSeP. Thus, advantageously, HCN is recycled in the process of converting MSeP to HMSeBN. HCN can be recycled directly or treated by one or more steps before being reintroduced into the reaction medium.

[0058] Advantageously, according to this 2nd embodiment of the invention, the step bl) of converting MSeP into HMSeBN is carried out continuously.

[0059] In a first embodiment of the invention, step cl) of converting HMSeBN to HMSeBA can be carried out as described in the aforementioned WO 2008 / 049927 A1. HMSeBN can be hydrolyzed in a hot, concentrated, strong acidic medium in a polar protic solvent so as to form HMSeBA in the reaction medium.

[0060] The strong acid can be chosen from hydrochloric acid, sulfuric acid, phosphoric acid, or any other mineral or organic acid taken alone or in a mixture of these.

[0061] The polar protic solvent is advantageously water.

[0062] Advantageously, the reaction medium is heated to a temperature between 25°C and 150°C. For example, the heating temperature of the reaction medium is 120°C.

[0063] Advantageously, the reaction medium is heated under reflux for a period of between 1 hour and 10 hours, for example 6 hours.

[0064] Next, the aqueous phase can be extracted once or several times (for example, 3 times) with a solvent that can be chosen from tert-butyl ether or any other linear or cyclic ether. After extraction of the aqueous phase, the organic phases are combined. Then, they are dried, for example, with Na₂SO₄. Optionally, the combined and dried organic phases can be filtered, and the solvents evaporated to obtain HMSeBA, which is in the form of a cold-crystallizing oil.

[0065] In a second embodiment of the invention, step cl) of converting HMSeBN to HMSeBA can be carried out, as described in the aforementioned WO 2022 / 185018 A1, in the presence of at least water, a weak acid, and a catalyst comprising at least one compound selected from alumina, titanium dioxide, and zirconia (in other words, zirconium dioxide). The weak acid can be selected from acetic acid, formic acid, and propionic acid, taken alone or in mixtures thereof.

[0066] Following step cl), the HMSeBA thus obtained can be transformed into one of its salts after addition with a suitable base. The transformation of HMSeBA into one of its salts is perfectly within the capabilities of a person skilled in the art.

[0067] The manufacturing process of the HMSeBA according to the invention thus comprises 3 steps.

[0068] Furthermore, the manufacturing process for HMSeBA according to the invention is simple to implement. Indeed, steps bl) and cl) as detailed above are easy to implement on an industrial scale and are well understood by those skilled in the art. In fact, they require readily available and inexpensive reagents.

[0069] As explained above, MSeP can also be used in the preparation of selenomethionine.

[0070] Therefore, the invention also relates to a process for manufacturing selenomethionine which is characterized in that it comprises at least the following steps: a2) MSeP is prepared by the preparation process according to the invention as described above; b2) we convert the MSeP to HMSeBN; c2) HMSeBN is converted into selenomethionine.

[0071] Step b2) can be carried out in the same manner as step bl) described above for the manufacture of the HMSeBA. In other words, step b2) can be carried out according to a first embodiment as described in the aforementioned WO 2008 / 049927 A1 or according to a second embodiment as described in the aforementioned WO 2022 / 185018 A1.

[0072] According to one embodiment of the invention, step c2) can be carried out as follows: - we convert HMSeBN into 2-amino-4-methylselenobutyronitrile (hereafter abbreviated AMSeBN); - the AMSeBN thus obtained is converted into 2-amino-4-methylselenobutyramide (hereinafter abbreviated AMSeBM) - the AMSeBM thus obtained is hydrolyzed into selenomethionine.

[0073] According to a second embodiment of the invention, step c2) can be carried out as follows: - we convert the HMSeBN to AMSeBN; - the AMSeBN thus obtained is converted into selenomethionine.

[0074] The conversion of AMSeBN to selenomethionine can be carried out in the presence of at least water and a catalyst comprising at least one compound selected from alumina, titanium dioxide and zirconia, and optionally in the presence of ammonia.

[0075] According to a 3rd embodiment of the invention, step c2) can be carried out as follows: HMSeBN is converted directly into selenomethionine, in the presence of at least water and a catalyst comprising at least one compound selected from alumina, titanium dioxide and zirconia, and optionally, or even preferably, in the presence of ammonia.

[0076] According to a fourth embodiment of the invention, step c2) can be carried out as follows: HMSeBN is reacted with NH3 and CO2 to produce the selenium equivalent of methionine hydantoin (namely 5-(2-methylselenoethylhydantoin)), which is then saponified with a base such as NaOH, K2CO3, to produce the selenium equivalent of Na methionine or of K; this selenium equivalent of methionate is then acidified to form selenomethionine.

[0077] The invention and its advantages are illustrated in the examples below.

[0078] Examples:

[0079] Example 1: Conversion of acrolein to MSeP in an organic medium:

[0080] a) Preparation of the CH3SeLi solution:

[0081] In a 250 mL double-jacketed reactor equipped with a temperature probe and traps (specifically, an empty trap, a trap containing NaOH at a concentration of 2 mol / L, and a trap containing bleach), 80 mL of MeTHF (67.77 g) and then 7.86 g of selenium (99% purity, or 98.55 mmol) were introduced into an argon-filled atmosphere. The resulting suspension was cooled to -20°C using the double jacket.

[0082] 34.2 mL of a CH3Li solution, namely CH3Li in solution in Diethoxymethane at a concentration of 3.1 mol / L (equivalent to 106.02 mmol of CH3Li) was then added to the double-jacketed reactor dropwise using a syringe pump over a period of one hour. Exothermic changes in the reaction medium were observed during this addition: the temperature of the reaction medium rose from -20°C to -15°C. Furthermore, as the addition continued, the reaction medium changed color, transitioning from a cloudy dark gray to an orange-brown, then orange, and finally white.

[0083] After this exothermic reaction, the reaction medium was allowed to return to -20°C, and then 1 mL of acetic acid (99% purity) was added to the reaction medium to destroy the excess CH3Li. Exothermic reaction and effervescence (release of CH4) were observed upon this addition. The reaction medium temperature dropped from -20°C to -16°C. A solution of CH3SeLi was thus obtained.

[0084] b) Preparation of the acrolein solution

[0085] In a 60 mL bottle, 50 mL of anhydrous MeTHF, 7.05 g of acetic acid (99% purity, i.e. 116.23 mmol) and 5.0 g of acrolein (85% purity, i.e. 75.81 mmol) were added successively for a period of 5 minutes under argon and under agitation at 500 revolutions per minute to obtain an acrolein solution.

[0086] c) _ _ Conversion of acrolein into MSeP

[0087] The acrolein solution thus obtained was then added, over a period of one hour, to the double-jacketed reactor containing the CH3SeLi solution thus obtained and maintained at a temperature of -20°C. No exothermic reaction was observed during this addition. The reaction mixture was stirred at 500 rpm while being maintained at a temperature of -20°C until complete conversion of the acrolein to MSeP.

[0088] The monitoring of this acrolein conversion reaction to MSeP was carried out by gas chromatography coupled with a flame ionization detector (hereinafter abbreviated as "GC-FID", namely the English acronym for Gas Chromatography-Flame ionization Detection), with a calibration curve made on the MSeP, by taking 50 mg samples of the reaction medium which were diluted in 1.5 g of acetonitrile.

[0089] Complete conversion of acrolein was obtained after 10 minutes of stirring and the reaction medium thus obtained contained MSeP with a yield of 70%.

[0090] Given the quantities of reagents used and detailed above and the fact that CH3Li was in excess, 1.3 molar equivalents of CH3SeLi and 1.55 molar equivalents of acetic acid per molar equivalent of acrolein were used for the conversion of acrolein to MSeP.

[0091] d) Isolation of the MSeP;

[0092] The reaction medium thus obtained, containing MSeP, was then stirred at 0°C, and 60 mL of an aqueous NaHCO3 solution was added. A two-phase mixture (namely, a pale yellow, clear organic phase and a light brown, clear aqueous phase at pH 8) formed spontaneously. The two-phase mixture was stirred vigorously for 10 minutes at 5°C, and then the two phases were separated. The aqueous phase was extracted twice with 50 mL of MTBE. The organic phases were combined, dried over Na2SO4, and stored in a freezer at -20°C. MSeP was thus isolated with a yield of 67%.

[0093] e) Purification by distillation:

[0094] The solvents still present with the isolated MSeP were eliminated by topping (at atmospheric pressure and at a temperature ranging from 50°C to 105°C).

[0095] Next, the MSeP was distilled at 120°C under a pressure of 10 mbar. 3.25 g of MSeP (yellow liquid) were obtained with a 1H NMR titration of 90%.

[0096] Example 2: Conversion of acrolein to MSeP in aqueous medium:

[0097] a) Preparation of the CH3SeLi solution:

[0098] The preparation of the CH3SeLi solution was identical to that detailed in the 1st example above.

[0099] b) Preparation of the acrolein solution j.

[0100] In a 40 mL bottle, 18 mL of water and then 1512 mg of NaHCO3 (17.8 mmol) were added successively while stirring at 500 rpm. After complete solubilization of the NaHCO3, 496 mg of acrolein (85% purity, 7.52 mmol) were added to obtain an acrolein solution.

[0101] c) Conversion of acrolein to MSeP

[0102] Next, in a double-jacketed reactor containing the acrolein solution thus obtained and maintained at a temperature of 0°C, the CH3SeLi solution was added over a period of 20 minutes. A slight exothermic reaction (of approximately +3.5°C) was observed during this addition. The reaction mixture was vigorously stirred (1000 rpm) while being maintained at a temperature of 0°C until complete conversion of the acrolein to MSeP.

[0103] During this step, the excess CH3Li was destroyed.

[0104] The monitoring of this acrolein to MSeP conversion reaction was carried out by GC-FID, with a calibration curve made on the MSeP, by taking 20 mg samples of the reaction medium which were diluted in 1.2 g of acetonitrile.

[0105] Complete conversion of acrolein was obtained after 10 minutes of stirring and the reaction medium thus obtained contained MSeP with a yield of 60%.

[0106] Given the quantities of reagents used and detailed above and the fact that CH3Li was in excess, 1.1 molar equivalents of CH3SeLi and 2.4 molar equivalents of NaHCO3 per molar equivalent of acrolein were used for the conversion of acrolein to MSeP.

[0107] The conversion of acrolein to MSeP in organic medium gives a higher yield than the conversion of acrolein to MSeP in aqueous medium (70% versus 60%).

[0108] Comparative examples:

[0109] In order to determine the essential nature of CH3SeLi in the MSeP preparation process according to the invention, experiments were carried out by replacing CH3SeLi with a similar compound, namely CH3SeNa. In other words, lithium was replaced by sodium in order to verify the essential nature of the lithium salt in this conversion of acrolein to MSeP.

[0110] In comparative examples 1 to 3 detailed below, CH3SeNa was generated in situ and then used in the conversion of acrolein to MSeP. [YES] Comparative example 1: Conversion of acrolein to MSeP in organic medium:

[0112] a) Preparation of a CH3SeNa solution:

[0113] In a reactor equipped with a temperature probe, 122 mg (5.36 mmol) of defatted pentane-based sodium metal were introduced under argon into 6 mL of MeTHF. A solution of 0.55 g (2.79 mmol) of dimethyldiselenium diluted in 1 mL of MeTHF was added to this suspension. The suspension was heated at 60 °C for 15 hours. As the sodium was consumed, a brown solid formed (namely CH3SeNa). The suspension was cooled to room temperature and then to -15 °C. 0.27 g (0.87 mmol) of acetic acid was added at -15 °C without any observed exothermic reaction.

[0114] b) Preparation of the acrolein solution j.

[0115] In a 20 mL vial, acrolein (0.31g, 4.79 mmol), acetic acid (0.053g, 0.87 mmol) and 2.5 mL of MeTHF were successively introduced under argon.

[0116] c) Conversion of acrolein into MSeP j.

[0117] The acrolein solution thus obtained was then added, over a period of 5 minutes, to the double-jacketed reactor containing the CH3SeNa solution thus obtained and maintained at a temperature of -15°C. The reaction mixture was stirred for 4 hours while being maintained at a temperature of -15°C until complete conversion of the acrolein to MSeP.

[0118] The monitoring of this acrolein to MSeP conversion reaction was carried out by GC-FID, with a calibration curve made on the MSeP, by taking 100 mg samples of the reaction medium which were diluted in 1.5 g of acetonitrile.

[0119] Complete conversion of acrolein was obtained after 4 hours of stirring and the reaction medium thus obtained contained MSeP with a yield of 14%.

[0120] This yield of 14% is much lower than that obtained with CH3SeLi to convert acrolein to MSeP in organic medium, which was 70%.

[0121] Comparative example 2: Conversion of acrolein to MSeP in organic medium with the addition of 15-crown-5 ether:

[0122] a) Preparation of a CH3SeNa solution

[0123] The preparation of the CH3SeNa solution was identical to that detailed in comparative example 1 above.

[0124] b) Preparation of the acrolein solution j.

[0125] The preparation of the acrolein solution was identical to that detailed in Example 1 above.

[0126] c) Conversion of acrolein to MSeP

[0127] The conversion reaction of acrolein with CH3SeNa was identical to that detailed in Comparative Example 1 above, with the sole difference that 1.4 molar equivalents of 15-crown-5 ether per molar equivalent of acrolein were added to the reaction medium. The 15-crown-5 ether was used to enhance the nucleophilicity of CH3SeNa.

[0128] The reaction medium thus obtained contained MSeP with a yield of 4%.

[0129] This yield of 4% is much lower than that obtained with CH3SeLi to convert acrolein to MSeP in organic medium, which was 70%.

[0130] Comparative example 3: Conversion of acrolein to MSeP in organic medium with the addition of LiCl:

[0131] a) Preparation of a CH3SeNa solution:

[0132] The preparation of CH3SeNa solution was identical to that detailed in comparative example 1 above.

[0133] b) Preparation of the acrolein solution j.

[0134] The preparation of the acrolein solution was identical to that detailed in Example 1 above.

[0135] c) Conversion of acrolein to MSeP

[0136] The conversion reaction of acrolein with CH3SeNa was identical to that detailed in Example 1 above, with the sole difference that 1.2 molar equivalents of LiCl per molar equivalent of acrolein were added to the reaction medium.

[0137] The reaction medium thus obtained contained MSeP with a yield of 14%.

[0138] This yield of 14% is much lower than that obtained with CH3SeLi for converting acrolein to MSeP in an organic medium, which was 70%.

Claims

Demands

1. A process for preparing 3-methylselenopropanal (hereinafter abbreviated as "MSeP"), characterized in that it comprises at least the following steps: a) a solution of CH3SeLi and a solution of acrolein are made available, b) the CH3SeLi solution and the acrolein solution are mixed to obtain a reaction medium in which the acrolein is converted to MSeP, c) optionally the MSeP thus obtained is isolated and / or purified in the reaction medium.

2. A process for preparing MSeP according to claim 1, characterized in that prior to step a), the CH3SeLi solution was obtained by reaction of selenium and methyllithium (hereinafter abbreviated CH3Li).

3. A process for preparing MSeP according to claim 1 or 2, characterized in that the amount of CH3SeLi used for the conversion of acrolein to MSeP is between 0.9 molar equivalents and 2 molar equivalents per molar equivalent of acrolein.

4. A process for preparing MSeP according to any one of claims 1 to 3, characterized in that the acrolein solution is an organic acrolein solution which has been obtained, prior to step a), by mixing a polar aprotic organic solvent, a mineral or organic acid and acrolein.

5. A process for preparing MSeP according to claim 4, characterized in that the acid is acetic acid.

6. A process for preparing MSeP according to claim 4 or 5, characterized in that the amount of acid used for the conversion of acrolein to MSeP is between 0.01 molar equivalents and 2 molar equivalents per molar equivalent of acrolein.

7. A process for preparing MSeP according to any one of claims 1 to 6, characterized in that the MSeP is purified by distillation.

8. A process for manufacturing 2-hydroxy-4-methylselenobutyric acid (hereinafter abbreviated as "HMSeBA"), characterized in that it comprises at least the following steps:

9. a) the MSeP is prepared by the preparation process according to any one of claims 1 to 7; bl) MSeP is converted into 2-hydroxy-4-methylselenobutyronitrile (hereafter abbreviated as "HMSeBN"); cl) we convert the HMSeBN to HMSeBA. A process for manufacturing selenomethionine, characterized in that it comprises at least the following steps: a2) the MSeP is prepared by the preparation process according to any one of claims 1 to 7; b2) we convert the MSeP to HMSeBN; c2) HMSeBN is converted into selenomethionine.