Process for preparing 2,4-dihydroxybutyric acid

Abstract

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

Description

Title of the invention: Process for preparing 2,4-dihydroxybutyric acid

[0001] The present invention relates to a process for preparing 2,4-dihydroxybutyric acid (2,4-DHB) or its salt.

[0002] 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).

[0003] 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 the increase in the carbon balance.

[0004] 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 method.

[0005] The authors of the present invention have thus developed a process for activating the sulfonium of HMTBA without using a benzyl halide. To this end, 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 the equivalent of benzyl methyl sulfide.

[0006] 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)

[0007] [Chem.l] S.... | R2 (D

[0008] in which

[0009] R1 represents H,

[0010] R2 represents a group selected from OH, NH2, OR4, OCOR4 and NHR4 where R4 represents 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 chosen 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, possibly substituted by one or more substituents chosen from alkyl groups having from 1 to 10 carbon atoms, linear or branched, or R1 and R2 together represent =0,

[0011] R3 represents COOH or a COOR5 group where R5 represents a group selected from alkyl groups having from 1 to 10 carbon atoms, linear, cyclic or branched, benzyl, and benzyl groups substituted by one or two substituents selected 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 R3 represents a cyano group,

[0012] 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)

[0013] [Chem.2] X " J ] RS (II)

[0014] in which R1 and R2 have the above definition,

[0015] R6 represents COOCH3, or a COOR5 group where R5 has the above definition, or a cyano group, or a -C(=NH)-OCH3 group,

[0016] HX is a mineral or organic acid and X is the corresponding counter-ion,

[0017] then a saponification of the sulfonium thus obtained is carried out in a basic medium to obtain 2,4-dihydroxybutyric acid or its salt.

[0018] Before describing the invention in more detail, the definition of terms used in this description and the claims is provided below.

[0019] Definitions

[0020] By salt of a compound of formula (I) is meant any compound of formula (I) in which the hydrogen of the carboxyl group is replaced by a metal, in particular an alkali metal, an alkaline earth metal, or a transition metal. This metal is preferably chosen from Na, Ca, K, Li, NH4, Mn, Zn, Mg, Cr. It may be a single or multiple salt. Thus, a calcium salt of 2-hydroxy-4-methylthiobutanoic acid may be chosen from the salts of formula (HMTBA)nCa where n varies from 2 to 10. This concept of salt naturally covers all mixtures of salts falling within the definition above.

[0021] By oligomer of a compound of formula (I) is meant any oligomer and in particular dimer such that it can coexist, including in trace amounts, with said compound when the latter is not used in a totally purified state.

[0022] Within the scope of the present invention: - 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; - An aryl group refers to a monovalent, hydrocarbon, aromatic radical. Examples include phenyl, benzyl, tolyl, naphthyl, and biphenyl groups; - An alkoxy group designates an O-alkyl radical, where the term alkyl corresponds to the definition above. - A counterion X is an entity that will ensure the electroneutrality of the sulfonium of formula (II).

[0023] 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 the 2,4-DHB or its salt.

[0024] In the first step, methanol is reacted in the presence of an acid on the compound of formula (I) in order to obtain a sulfonium of said compound.

[0025] Advantageously, 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.

[0026] Preferably, R2 is OH.

[0027] Preferably, R3 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, C7H8O3S, and mixtures thereof. Heterogeneous sulfonic resins may also be mentioned.

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

[0030] The reaction temperature during this first step can range from about 25°C to about 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(II) 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 by adding a basic compound selected from alkali metal salts, alkaline earth metal salts, ammonia (NH4OH), zinc hydroxide (Zn(OH)2), and mixtures thereof. The basic compound may advantageously be selected 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, mention may be made of 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 about 25°C to about 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. EXPERIMENTAL SECTION

[0039] In the present experimental part:

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

[0041] - TmR means temperature of the reaction medium,

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

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

[0051]

[0052]

[0053] Reagents and charge table: [Tables 1] Reagent Molecular Weight (g / mol) Titration (%) Density (g / mol) Mass (g) Volume (mL) n (mm³ ol) Eq. AT88 monomer 150.20 68 - 6.8 - 45.3 1 dimer 282.38 18.5 - 1.85 - 6.55 trimer 414.56 1.8 - 0.18 - 0.43 MeOH 32.04 99 0.792 17.82 22.5 550 10.5 H₂SO₄ 98.08 96 1.83 13.72 7.5 134 2.5 h₂O 18 distilled 1 23 23 1278 24 NaOH 40 10N - - 24.5 245 4.7 Step 1: 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) is added dropwise to the solution. The solution is then heated to 60°C. (Lauda setpoint 60°C) and the medium is stirred until the HMTBA and then the HMTBE are consumed (contact time 24h). Reaction monitoring was carried out by HPLC (calibration curves performed on the HMTBA and HMTBE) by taking 100 pL samples of the reaction medium diluted in 3 mL of a H2O / ACN mixture (1:1). 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 (ESI+) analysis with direct introduction m / z 179 (mass corresponding to sulfonium without counterion). After complete conversion of HMTBE, a distillation setup is attached to the reactor and 23 mL of distilled water is 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.

[0054] Step 2:

[0055] The pH of the aqueous solution is adjusted to 9 with a 10 N sodium hydroxide solution, and then the reaction mixture is 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 = 78% and an NMR titer of 23%.

[0056] EXAMPLE 2: comparative

[0057] For comparison purposes, an attempt was made to prepare 2,4-DHB by replacing methanol with isopropanol, by reacting the isopropanol on T AT88.

[0058] Under these conditions, the formation of the corresponding sulfonium was validated by LC-MS (ESI+) and ¹H NMR analyses. However, adjusting the pH of the reaction medium with 10N sodium hydroxide (pH range studied 6 to 12) did not allow the generation of 2,4-DHB. Only the HMBI resulting from the hydrolysis of the sulfonium was isolated; see the reaction scheme below:

[0059] [Chem.5]

[0060] Reagents and charge table

[0061] [Tables2] Reagent Molecular Weight (g / mol) Titration (%) Density (g / mol) Mass (g) Volume (mL) n (mm³ ol) Eq. AT88 monomer 150.20 68 -0.341 -2.26 1 dimer 282.38 18.5 -0.093 -0.33 trimer 414.56 1.8 -0.001 -0.002 ' PrOH 60.1 99.5 0.785 1.12 1.43 5.53 7.2 H2SO4 98.08 96 1.83 0.412 0.225 1.34 1.6 h2o 18 distilled 2 111 NaOH 40 10N - - 0.6 89 2.3

[0062] Step 1:

[0063] 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 are 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). The reaction was monitored by HPLC (calibration curve performed on the HMTBA) using 20 pL samples of the reaction medium diluted in 3 mL of a 1:1 H2O / ACN mixture. Sulfonium formation was observed by LC-MS (ESI+) analysis with direct introduction m / z 235 (mass corresponding to sulfonium without counter-ion).

[0064] Step 2:

[0065] The reaction medium is allowed to cool to 25°C, and then 2 mL of water are added. The 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 medium is heated to 90°C. The sulfonium conversion is monitored by LC-MS analysis. After complete sulfonium conversion, the medium is cooled to 25°C and analyzed by ¹H NMR. 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.

[0066] EXAMPLE 3: Comparison

[0067] For comparison purposes, an attempt was made to prepare 2,4-DHB by replacing methanol with tertiobutanol ('BuOH), by reacting tertiobutanol on 1'AT88.

[0068] Under these conditions, the formation of the corresponding sulfonium was validated by LC-MS (ESI+) and ¹H NMR analyses. However, adjusting the pH of the medium The reaction with sodium ion (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:

[0069] [Chem.6]

[0070] Reagents and charge table:

[0071] [Tables3] Reagent Molecular weight (g / mol) Titration (%) Density (g / mol) Mass (g) Volume (mL) n (mm ol) Eq. AT88 monomer 150.20 64 - 0.96 - 6.39 1 dimer 282.38 20 - 0.3 - 1.06 trimer 414.56 3 - 0.045 - 0.11 'BuOH 74.1 99.5 0.786 2.61 3.31 35.07 4.6 H2SO4 98.08 96 1.83 4.38 2.3 42.87 5.7 d2o 18 distilled 1 1.9 1.9 105.6 14 NaOH 40 10N - - 8.9 89 11.8

[0072] Step 1:

[0073] 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), 2.61 g of BuOH, and 1.89 g of D2O are introduced. The solution is cooled to 4°C, and 2.3 mL of 96% H2SO4 (exothermic ATMR = +3°C) are added dropwise. The solution is allowed to cool to 24°C and stirred at this temperature until 97% HMTBA conversion is achieved (contact time 17 h). The reaction was monitored by HPLC (using a calibration curve based on HMTBA) by taking 20 pL samples of the reaction mixture diluted in 10 mL of a 1:1 H2O / ACN mixture. Sulfonium formation is observed by LC-MS (ESI+) analysis in direct introduction m / z 207 (mass corresponding to sulfonium without counter ion).

[0074] Step 2:

[0075] The solution is heated to 70°C (pH < 0) and then the pH of the solution is adjusted using a 10 N sodium hydroxide solution. After adding 8 mL of NaOH (pH = 1.2), three The following 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 is continued. After the addition of a further 0.9 mL (pH = 10.5), only HMTBA is detected in the reaction medium (HPLC and ¹H NMR analyses). Other unidentified impurities are observed by LC-MS analysis.

Claims

1. Demands Process for preparing 2,4-dihydroxybutyric acid (2,4-DHB) from a compound, or its salt or oligomers, said compound corresponding to formula (I) [Chem.7] (I) in which R1 represents H, R2 represents a group chosen from OH, NH2, OR4, OCOR4 and NHR4 where R4 represents a group chosen from alkyl groups having from 1 to 14 carbon atoms, linear, cyclic or branched, and aryl groups having from 6 to 10 carbon atoms, possibly substituted by one or more substituents chosen from alkyl groups having from 1 to 10 carbon atoms; and OSiRR'R” where R, R' and R” are chosen 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, possibly substituted by one or more substituents chosen from alkyl groups having from 1 to 10 carbon atoms, linear or branched, where R1 and R2 together represent =0, R3 represents COOH or a COOR5 group where R5 represents 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 R3 represents a cyano group, 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] (II) in which R1 and R2 have the above definition, R6 represents COOCH3, or a COOR5 group where R5 has the above definition, 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 a saponification of the sulfonium thus obtained is carried out 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. Method according to claim 1 or 2, characterized in that R2 is OH.

4. A process according to any one of claims 1 to 3, characterized in that R3 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 about 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

8.

9. addition of a basic compound chosen from alkali metal salts, alkaline earth metal salts, ammonia (NH4OH), zinc hydroxide (Zn(OH)2) and mixtures thereof. A process according to claim 7, characterized in that the basic compound is sodium hydroxide. Process according to claim 8, characterized in that the saponification reaction temperature is approximately 100°C.