Method for producing 2,4-dihydroxybutyric acid

Abstract

The present invention relates to a method for producing 2,4-dihydroxybutyric acid (2,4-DHB) or its salt.

Description

[0001] DESCRIPTION

[0002] TITLE: Process for the preparation of 2,4-dihydroxybutyric acid

[0003] The present invention relates to a process for preparing 2,4-dihydroxybutyric acid (2,4-DHB) or its salt.

[0004] It is known to prepare 2,4-DHB from the sulfonium of 2-hydroxy-4-methylthiobutyric acid (abbreviated interchangeably as HMTBA, HMBA, AT88, or Rhodimet AT88). The latter is an important synthetic intermediate in the synthesis of 2,4-DHB. The sulfonium of HMTBA can be prepared industrially in a known manner from HMTBA and benzyl bromide in one step (WO2012 / 049435).

[0005] The problem posed by this route lies in the production of an equivalent of benzyl methyl sulfide which must then be eliminated and which contributes to increasing the carbon balance.

[0006] The authors of the present invention sought to develop a method for synthesizing 2,4-DHB that does not present these disadvantages while remaining a simple and efficient process.

[0007] The authors of the present invention have thus developed a process for activating the sulfonium of HMTBA without using a benzyl halide. To achieve this, the process according to the invention uses methanol as a reagent, which also has the advantage of being inexpensive. Under the conditions of the process according to the invention, 2,4-DHB is isolated with a yield of 78%. 2,4-DHB can therefore be prepared by a simple, inexpensive, industrially scalable, and environmentally friendly process. Indeed, the preparation process according to the invention does not generate any by-products that contribute to an increased carbon footprint, such as benzyl methyl sulfide equivalents.

[0008] Thus, an object of the invention is a process for preparing 2,4-dihydroxybutyric acid (2,4-DHB) from a compound, or its salt or oligomers, said compound corresponding to the formula (I) in which

[0009] R 1 represents H,

[0010] R 2 represents a group chosen from OH, NH2, OR 4 OCOR 4 and NHR 4 where R 4represents a group selected from alkyl groups having from 1 to 14 carbon atoms, linear, cyclic, or branched, and aryl groups having from 6 to 10 carbon atoms, optionally substituted by one or more substituents selected from alkyl groups having from 1 to 10 carbon atoms; and OSiRR'R” where R, R', and R” are selected independently of each other from alkyl groups having from 1 to 10 carbon atoms, linear, cyclic, or branched, aryl groups having from 6 to 10 carbon atoms, optionally substituted by one or more substituents selected from alkyl groups having from 1 to 10 carbon atoms, linear or branched, or R 1 and R 2 represent together = 0.

[0011] R 3 represents COOH or a COOR group 5 where R 5represents a group chosen from among alkyl groups having from 1 to 10 carbon atoms, linear, cyclic or branched, benzyl, and benzyl groups substituted by one or two substituents chosen from alkyl groups having from 1 to 10 carbon atoms, linear or branched, halogens and hydroxyl, amino, nitro and alkoxy groups having from 1 to 10 carbon atoms, or R 3 represents a cyano group, a process in which methanol is reacted in the presence of an acid HX on the compound of formula (I) in order to obtain a sulfonium of said compound, said sulfonium corresponding to formula (II)

[0012] [Chem 2] ci) in which R 1 and R 2 have the above definition,

[0013] R 6 represents COOCH3, or a COOR grouping 5 where R 5 to the definition above, or a cyano group, or a -C(=NH)-OCH3 group,

[0014] HX is a mineral or organic acid and X- is the corresponding counter-ion, then the sulfonium thus obtained is saponified in a basic medium to obtain 2,4-dihydroxybutyric acid or its salt.

[0015] Before describing the invention in more detail, the definition of terms used in this description and the claims is provided below.

[0016] Definitions

[0017] A salt of a compound with formula (I) is defined as any compound with formula (I) in which the hydrogen atom of the carboxyl group is replaced by a metal, particularly an alkali metal, an alkaline earth metal, or a transition metal. This metal is preferably chosen from Na, Ca, K, Li, NF, Mn, Zn, Mg, and Cr. It can be a single or multiple salt. Thus, a calcium salt of 2-hydroxy-4-methylthiobutanoic acid can be chosen from among the salts with the formula (HMTBA)nCa, where n ranges from 2 to 10. This concept of a salt naturally covers all mixtures of salts that fall within the definition above.

[0018] An oligomer of a compound of formula (I) means any oligomer, and in particular a dimer, which can coexist, including in trace amounts, with the said compound when the latter is not used in a totally purified state.

[0019] Within the scope of the present invention:

[0020] An alkyl group refers to a monovalent, hydrocarbon, saturated, linear, cyclic, alicyclic, or branched radical. As indicated, it has from 1 to 14 carbon atoms, preferably from 1 to 10 carbon atoms, and even more preferably from 1 to 6 carbon atoms. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, pentyl, neopentyl, n-hexyl, cyclohexyl... groups;

[0021] An aryl group refers to a monovalent, hydrocarbon, aromatic radical. Examples include phenyl, benzyl, tolyl, naphthyl, and biphenyl groups;

[0022] An alkoxy group designates an O-alkyl radical, where the term alkyl corresponds to the definition above.

[0023] A counterion X- is an entity that will ensure the electroneutrality of the sulfonium of formula (II).

[0024] The process according to the invention comprises at most two steps, namely the step of obtaining the sulfonium of the compound of formula (I), then the step of saponification of the sulfonium thus obtained to obtain 2,4-DHB or its salt.

[0025] In the first step, methanol is reacted in the presence of an acid with the compound of formula (I) to obtain a sulfonium of said compound. Advantageously, the compound of formula (I) is chosen from 2-hydroxy-4-methylthiobutyric acid (HMTBA), 2-oxo-4-methylthiobutyric acid (KMB), the isopropyl ester of HMTB (HMBI), their salts and their oligomers.

[0026] Preferably, R 2 is OH.

[0027] Preferably, R 3 is COOH.

[0028] The HX acid used for this first step can be any organic or mineral acid. Among the organic or mineral acids suitable for carrying out the first step of the process according to the invention are H2SO4, HCl, H3PO4, HNO3, CH3SO3H, C / HsOsS, and mixtures thereof. Heterogeneous sulfonic resins may also be mentioned.

[0029] Advantageously, the acid used in the reaction of methanol on the compound of formula (I) is H2SO4.

[0030] The reaction temperature during this first step can range from approximately 25°C to approximately 150°C.

[0031] Advantageously, the reaction temperature of methanol on the compound of formula (I) is about 60°C.

[0032] In the second step, the compound of formula (ll) is saponified in a basic medium to obtain 2,4-dihydroxybutyric acid or its salt.

[0033] Advantageously, the saponification step is carried out by regulating the pH to 9 through the addition of a basic compound chosen from alkali metal salts, alkaline earth metal salts, ammonia (NH4OH), zinc hydroxide (Zn(OH)2), and mixtures thereof. The basic compound may advantageously be chosen from alkali metal hydroxides, alkali metal carbonates, alkaline earth metal hydroxides, alkaline earth metal carbonates, and mixtures thereof.

[0034] Among the alkali metal hydroxides and alkaline-earth metal hydroxides suitable for carrying out the second step of the process according to the invention, we can mention soda (NaOH), potash (KOH), lithium (LiOH), calcium hydroxide (Ca(OH)2), magnesium hydroxide (Mg(OH)2), and mixtures thereof.

[0035] Advantageously, the basic compound is sodium hydroxide.

[0036] The reaction temperature during this second step can range from approximately 25°C to approximately 200°C.

[0037] Advantageously, the saponification reaction temperature is approximately 100°C.

[0038] The present invention and its advantages are illustrated in the following examples.

[0039] EXPERIMENTAL SECTION In this experimental section:

[0040] - RR means yield of product calculated in relation to the substrate processed,

[0041] - TMR stands for temperature of the reaction medium.

[0042] - HMTBE (2-hydroxy-4-(methylthio)butanoic acid methyl ester) means methyl ester of 2-hydroxy-4-(methylthio)butanoic acid,

[0043] - HMBI (2-hydroxy-4-(methylthio)butanoic acid isopropyl ester) means isopropyl ester of 2-hydroxy-4-(methylthio)butanoic acid.

[0044] EXAMPLE 1: Preparation of 2,4-DHB from HMTBA (or AT88)

[0045] Reaction scheme

[0046] Step 1:

[0047] [Chem 3]

[0048] Step 2:

[0049] [Chem 4]

[0050] Reagents and charge table: [Table 1]

[0051] Step 1:

[0052] In a 100 mL double-jacketed reactor equipped with a temperature probe, 10 g of AT88 (whose mono-, di-, and trimer ratio, determined by HPLC, is 77:21:2) and 22.5 mL of MeOH are introduced. 7.5 mL of 96% H₂SO₄ (exothermic ATMR = +6°C) are added dropwise to the solution. The solution is heated to 60°C (Lauda setpoint 60°C) and the mixture is stirred until the HMTBA and then the HMTBE are consumed (contact time 24 h). The reaction was monitored by HPLC (calibration curves performed on HMTBA and HMTBE) by taking 100 pL samples of the reaction mixture diluted in 3 mL of a 1:1 H₂O / ACN mixture. The solution is then diluted again (25 pL taken and diluted in 1.5 mL of a 1:1 H2O / ACN mixture). Sulfonium formation is observed by LC-MS analysis (ESI +) by direct introduction m / z 179 (mass corresponding to sulfonium without counterion). After complete conversion of HMTBE, a distillation setup is fitted to the reactor and 23 mL of distilled water are added to the reaction medium. Methanol is distilled to perform solvent exchange. Distillation is stopped when a temperature of 85°C is reached at the top of the column (88°C in the reaction medium, 110°C as set by Lauda). The distillation setup is removed and a condenser is installed.

[0053] Step 2:

[0054] The pH of the aqueous solution is adjusted to 9 with 10 N sodium hydroxide solution, and the reaction mixture is then heated to 100°C. The pH is automatically maintained at 9 by adding 10 N sodium hydroxide using a syringe pump. Sulfonium consumption is monitored by LC-MS analysis. After complete conversion, the mixture is cooled to 25°C. The reaction mixture is filtered, and the filtrate is lyophilized. A white solid (m = 28.8 g) is obtained. 2,4-DHB is isolated as sodium salts with an isolated RR of 78% and an NMR titer of 23%.

[0055] EXAMPLE 2: Comparison

[0056] For comparison, an attempt was made to prepare 2,4-DHB by replacing methanol with isopropanol, by reacting the isopropanol with AT88.

[0057] Under these conditions, the formation of the corresponding sulfonium was validated by LC-MS analyses (ESI + ) and by NMR 1H. However, adjusting the pH of the reaction medium with 10 N sodium hydroxide (pH range studied 6 to 12) does not allow the generation of 2,4-DHB. Only HMBI resulting from the hydrolysis of sulfonium is isolated; see reaction scheme below:

[0058] [Chem 5]

[0059] Reagents and charge table

[0060] [Table 2]

[0061] Step 1: In a 4 mL vial equipped with a temperature probe and a magnetic stir bar, 502 mg of AT88 (whose mono-, di-, and trimer ratio, determined by HPLC, is 73:23:3) and 425 pL of 'PrOH are introduced. 75 pL of 96% H2SO4 is added dropwise to the solution (no exothermic reaction). The solution is stirred at 25°C for 22 h. The solution is then heated to 60°C, and 1 mL of 'PrOH and 150 pL of H2SO4 are added. The solution is stirred for an additional 3 h at 60°C (88% HMTBA converted). Reaction monitoring was performed by HPLC (calibration curve performed on the HMTBA) using 20 pL samples of reaction medium diluted in 3 mL of a 1:1 H2O / ACN mixture. Sulfonium formation was observed by LC-MS analysis (ESI). + ) in direct introduction m / z 235 (mass corresponding to sulfonium without counter ion).

[0062] Step 2:

[0063] The reaction mixture is allowed to cool to 25°C, and then 2 mL of water are added. Excess isopropanol is removed using a rotary evaporator (40°C, 110 mbar). The pH of the aqueous solution is adjusted to pH 12 using a 10 N sodium hydroxide solution, and then the reaction mixture is heated to 90°C. Sulfonium conversion is monitored by LC-MS analysis. After complete sulfonium conversion, the mixture is cooled to 25°C and analyzed by NMR. 1 H. Only HMBI is detected in the reaction medium. 2,4-DHB is not detected by HPLC or LC-MS (ESI). Saponification of the isopropyl ester is not observed.

[0064] EXAMPLE 3: Comparison

[0065] For comparison, an attempt was made to prepare 2,4-DHB by replacing methanol with tert-butanol ( f BuOH), by reacting tertiobutanol with AT88.

[0066] Under these conditions, the formation of the corresponding sulfonium was validated by LC-MS analyses (ESI + ) and by NMR 1 H. However, adjusting the pH of the reaction medium with 10 N sodium hydroxide (pH range studied 6 to 12) does not allow the generation of 2,4-DHB. Only HMBA resulting from the hydrolysis of sulfonium is isolated; see reaction scheme below:

[0067] [Chem 6]

[0068] Reagents and charge table: [Table 3]

[0069] Step 1:

[0070] In a 40 mL vial equipped with a temperature probe and a magnetic stir bar, 1.5 g of AT88 (whose mono-, di-, and trimer ratio, determined by HPLC, is 73:23:3) and 2.61 g of fBuOH and 1.89 g of D2O were added dropwise to the solution. The solution was cooled to 4°C, and 2.3 mL of 96% H2SO4 (exothermic ATMR = +3°C) were added dropwise. The solution was allowed to cool to 24°C and stirred at this temperature until 97% HMTBA conversion was achieved (contact time 17 h). Reaction monitoring was performed by HPLC (calibration curve established on HMTBA) using 20 pL aliquots of the reaction medium diluted in 10 mL of a 1:1 H2O / ACN mixture. Sulfonium formation was observed by LC-MS analysis (ESI). + ) in direct introduction m / z 207 (mass corresponding to sulfonium without counter ion).

[0071] Step 2:

[0072] The solution is heated to 70°C (pH < 0), and then the pH is adjusted using 10 N sodium hydroxide solution. After adding 8 mL of NaOH (pH = 1.2), three phases are observed: a clear, brown organic phase, a colorless, cloudy aqueous phase, and a solid phase (salt-like). The organic phase is withdrawn, and the addition of NaOH continues. After adding a further 0.9 mL (pH = 10.5), only HMTBA is detected in the reaction mixture (HPLC and NMR analyses). 1 H). Other unidentified impurities are observed by LC-MS analysis.

Claims

DEMANDS 1. Process for preparing 2,4-dihydroxybutyric acid (2,4-DHB) from a compound, or its salt or oligomers, said compound having the formula (I) [Chem 7] in which R 1 represents H, R 2 represents a group chosen from OH, NH2, OR 4 OCOR 4 and NHR 4 where R 4represents a group selected from alkyl groups having from 1 to 14 carbon atoms, linear, cyclic, or branched, and aryl groups having from 6 to 10 carbon atoms, optionally substituted by one or more substituents selected from alkyl groups having from 1 to 10 carbon atoms; and OSiRR'R” where R, R', and R” are selected independently of each other from alkyl groups having from 1 to 10 carbon atoms, linear, cyclic, or branched, aryl groups having from 6 to 10 carbon atoms, optionally substituted by one or more substituents selected from alkyl groups having from 1 to 10 carbon atoms, linear or branched, or R 1 and R 2 represent together = 0. R 3 represents COOH or a COOR group 5 where R 5represents a group chosen from among alkyl groups having from 1 to 10 carbon atoms, linear, cyclic or branched, benzyl, and benzyl groups substituted by one or two substituents chosen from alkyl groups having from 1 to 10 carbon atoms, linear or branched, halogens and hydroxyl, amino, nitro and alkoxy groups having from 1 to 10 carbon atoms, or R 3 represents a cyano group, a process in which methanol is reacted in the presence of an acid HX on the compound of formula (I) in order to obtain a sulfonium of said compound, said sulfonium corresponding to formula (II) [Chem 8] in which R 1 and R 2 have the above definition, R 6 represents COOCH3, or a COOR grouping 5 where R 5 to the definition above, or a cyano group, or a -C(=NH)-OCH3 group, HX is a mineral or organic acid and X- is the corresponding counter-ion, then the sulfonium thus obtained is saponified in a basic medium to obtain 2,4-dihydroxybutyric acid or its salt.

2. A process according to claim 1, characterized in that the compound of formula (I) is selected from 2-hydroxy-4-methylthiobutyric acid (HMTBA), 2-oxo-4-methylthiobutyric acid (KMB), HMTB isopropyl ester (HMBI), their salts and their oligomers.

3. A method according to claim 1 or 2, characterized in that R 2 is OH.

4. A method according to any one of claims 1 to 3, characterized in that R 3 is COOH.

5. A process according to any one of claims 1 to 4, characterized in that the acid used in the reaction of methanol on the compound of formula (I) is H2SO4.

6. A process according to any one of claims 1 to 5, characterized in that the reaction temperature of methanol on the compound of formula (I) is approximately 60°C.

7. A process according to any one of claims 1 to 6, characterized in that the saponification step is carried out by regulating the pH to 9 by adding a basic compound selected from alkali metal salts, alkaline earth metal salts, ammonia (NH4OH), zinc hydroxide (Zn(OH)2) and mixtures thereof.

8. A process according to claim 7, characterized in that the basic compound is sodium hydroxide.

9. Process according to claim 8, characterized in that the saponification reaction temperature is approximately 100°C.

Images