PROCESS FOR THE PREPARATION OF HYDROXYCARBOXYLIC ACID COMPOUND OR SALT THEREOF

Technical Field

[0001]

The present invention relates to a process of a hydroxycarboxylic acid compound or a salt thereof. Background Art

[0002]

Hydroxycarboxylic acid compounds such as 4-methylthio- 2-hydroxybutyric acid are important compounds for biological reactions. In particular, 4 -methylthio-2 - hydroxybutyric acid is a compound used as an additive agent for forage.

[0003]

As a process of 4 -methylthio-2 -hydroxybutyric acid, the following process is disclosed in "Industrial Organic Chemistry", TOKYO KAGAKU-DOJIN, 1978, pp. 273-275.

[0004]

That is, a process of 4 -methylthio-2 -hydroxybutyric acid by reacting acrolein with methanethiol , reacting the mixture with hydrogen cyanide, and then hydrolyzing the mixture in the presence of sulfuric acid.

Summary of Invention

[0005]

The above-mentioned process uses hydrogen cyanide as a synthetic material. Hydrogen cyanide is a toxic material, and needs to be handled with, for example, adequate care and suitable equipments thereof.

[0006]

There has been a desire to provide a novel process of hydroxycarboxylic acid compounds such as 4-methylthio-2- hydroxybutyric acid which does not require the use of hydrogen cyanide as a synthetic material.

[0007]

The present inventions are as follows.

[1] A process of a hydroxycarboxylic acid compound of Formula (1) :

R ¹ -S—(CH ₂ ) _n -C—C0 ₂ H ₍₁₎

OH

wherein R ¹ is an optionally substituted C1-C12 alkyl group or an optionally substituted C3-C12 cycloalkyl group, and n is an integer of 1 to 4

or a salt thereof which comprises a step of reacting a ketocarboxylic acid compound of Formula (2)

R ¹ -S-(CH ₂ )n-C-C0 ₂ H ₍₂₎

0

wherein R ¹ and n are both as defined above

or a salt thereof and hydrogen in the presence of a transition metal catalyst.

[2] The process of [1] wherein the step of reacting a ketocarboxylic acid compound of Formula (2) or a salt thereof and hydrogen is carried out in the presence of a solvent .

[3] The process of [2] wherein the solvent is at least one solvent selected from the group consisting of methanol and water.

[4] The process of any one of [1] to [3] wherein the transition metal catalyst is a catalyst comprising at least one element compound selected from the group consisting of ruthenium, rhodium, palladium, platinum and iridium in which the element compound is supported on a carrier.

[5] The process of [4] wherein the carrier is at least one carrier selected from the group consisting of active carbon, alumina, silica and zeolite.

[6] The process of any one of [1] to [5] wherein the step of reacting a ketocarboxylic acid compound of Formula (2) or a salt thereof and hydrogen is carried out at temperature between 0°C and 100 °C. [0008]

Hereinafter, the present inventions are explained.

[0009]

In particular, the ketocarboxylic acid compound of Formula (2) :

R ¹ -S-(CH ₂ ) _n -C -C0 ₂ H ₍₂₎

o

or a salt thereof used herein and the hydroxycarboxylic acid compound of Formula (1) :

R ¹ -S— (CH ₂ ) _n -C— C0 ₂ H _{( 1} j

OH

or a salt thereof obtained herein are explained. [0010]

The salt of the ketocarboxylic acid compound of Formula (2) means a salt wherein H ⁺ dissociable from -COOH in Formula (2) is replaced with a cation. The cation includes, for example, alkali metal ions such as lithium ion, sodium ion and potassium ion; and alkaline earth metal ions such as calcium ion and magnesium ion.

[0011]

Hereinafter, the ketocarboxylic acid compound of Formula (2) and a salt thereof are optionally referred to as Compound (2) .

[0012]

The salt of the hydroxycarboxylic acid compound of

Formula (1) means that H ⁺ dissociable from -COOH in Formula (1) is replaced with a cation. The cation used herein includes, for example, alkali metal ions such as lithium ion, sodium ion and potassium ion; and alkaline earth metal ions such as calcium ion and magnesium ion.

[0013]

Hereinafter, the hydroxycarboxylic acid compound of Formula (1) and a salt thereof are optionally referred to as Compound (1) .

[0014]

The moiety of the carboxylic acid in Compound (1) corresponds to that of Compound (2) used in the present process (i.e., carboxylic acid or a salt thereof, and the type of the salt in case of a salt) .

[0015]

In Formula (2) and Formula (1) , R ¹ is an optionally substituted C1-C12 alkyl group or an optionally substituted C3-C12 cycloalkyl group, and n is an integer of 1 to 4. [0016]

In Formula (2) and Formula (1) , the C1-C12 alkyl group defined as an optionally substituted C1-C12 alkyl group in R ¹ includes, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec- butyl group, tert-butyl group, pentyl group, octyl group and decyl group; and the C3-C12 cycloalkyl group defined as an optionally substituted C3-C12 cycloalkyl group in R ¹ includes, for example, cyclopropyl group, cyclobutyl group, cyclopentyl group and cyclohexyl group.

[0017]

The C1-C12 alkyl group and the C3-C12 cycloalkyl group may be optionally substituted with at least one group selected from the group consisting of, for example, C6-C20 aryl groups such as phenyl group, 1-naphthyl group, 2- naphthyl group, and 4-methylphenyl group; C1-C12 alkoxy groups such as methoxy group, ethoxy group, propyloxy group, isopropyloxy group, butyloxy group, isobutyloxy group, sec- butyloxy group, and tert-butyloxy group; C1-C6 perfluoroalkyloxy groups such as trifluoromethoxy group and pentafluoroethoxy group; and halogen atoms such as fluorine atom and chlorine atom. The above-listed C6-C20 aryl groups, C1-C12 alkoxy groups and C1-C6 perfluoroalkyloxy groups may be further substituted with at least one group selected from the group consisting of C6-C20 aryl groups, C1-C12 alkoxy groups and C6-C20 aryloxy groups.

[0018]

Specific examples of the substituted C1-C12 alkyl group and the substituted C3-C12 cycloalkyl group in R ¹ includes naphthalen-l-ylmethyl group, naphthalen-2-ylmethyl group, methoxymethyl group, ethoxymethyl group, isopropyloxymethyl group, butyloxymethyl group, isobutyloxymethyl group, sec-butyloxymethyl group, tert- butyloxymethyl group, phenoxymethyl group, 2- methylphenoxymethyl group, 4 -methylphenoxymethyl group, 1- phenylethyl group, 2 -phenylethyl group, 1- (naphthalen-1- yl)ethyl group, 1- (naphthalen-2-yl) ethyl group, l-(4- methylphenyl) ethyl group, 1- (3 , 4-dimethylphenyl) ethyl group, 1- (4-methoxyphenyl) ethyl group, l-(3,4- dimethoxyphenyl) ethyl group, 1- (4-phenylphenyl) ethyl group, 1- (4-phenoxyphenyl) ethyl group, 2- (methoxy) ethyl group, 2- (ethoxy) ethyl group, 2- (isopropyloxy) ethyl group, 2- (butyloxy) ethyl group, 2- (isobutyloxy) ethyl group, 2-(sec- butyloxy) ethyl group, 2- (tert-butyloxy) ethyl group, 2- (phenoxy) ethyl group, 2- (2-methylphenoxy) ethyl group, 2- (4- methylphenoxy) ethyl group, 2-phenylcyclopropyl group and 4- phenylcyclohexyl group. [0019]

R ¹ is preferably an optionally substituted C1-C12 alkyl group; more preferably C1-C4 alkyl groups such as methyl group, ethyl group, propyl group, isopropyl group, butyl group, and tert-butyl group; and even more preferably methyl group .

[0020]

Specific examples of Compound (2) include 3- methylthio-2-oxopropionic acid, 3-tert-butylthio-2- oxopropionic acid, 3-ethylthio-2-oxopropionic acid, 4- methylthio-2-oxobutyric acid, 4-ethylthio-2-oxobutyric acid 2-oxo-4-propylthiobutyric acid, 5-methylthio-2-oxopentanoic acid, 5-ethylthio-2-oxopentanoic acid, 2-oxo-5-

(propylthio) pentanoic acid, 6-methylthio-2-oxohexanoic acid 6-ethylthio-2-oxohexanoic acid, 2-oxo-6- (propylthio) - hexanoic acid and salts thereof.

[0021]

Compound (2) may be commercially available or prepared by well-known processes such as those described in "Bull. Agr. Chem. Soc. Japan, Vol. 21, No. 6, pp. 333-336 (1957)" and "Journal of Labelled Compounds and Radiopharmaceuticals Vol. XXXVI, No. 5, pp. 431-437 (1995)".

[0022] Specific examples of Compound (1) includes 2 -hydroxy- 3- (methylthio) propionic acid, 3-tert-buthylthio-2- hydroxypropionic acid, 3-ethylthio-2-hydroxypropionic acid, 2 -hydroxy-4 - (methylthio) butyric acid, 4-ethylthio-2- hydroxybutyric acid, 2 -hydroxy-4 - (propylthio) butyric acid, 2 -hydroxy-5- (methylthio) pentanoic acid, 5-ethylthio-2- hydroxypentanoic acid, 2 -hydroxy-5- (propylthio) pentanoic acid, 2 -hydroxy-6- (methylthio) hexanoic acid, 6-ethylthio-2- hydroxyhexanoic acid, 2 -hydroxy-6- (propylthio) hexanoic acid and salts thereof.

[0023]

The present invention comprises a step of reacting Compound (2) and hydrogen in the presence of a transition metal catalyst (hereinafter, optionally referred to as the present reaction) .

[0024]

The transition metal catalyst used herein includes, for example, iron group element compounds such as nickel and cobalt; and noble metal element compounds such as ruthenium, rhodium, palladium, platinum and iridium.

[0025]

The transition metal catalyst used herein may be, for example, a catalyst comprising at least one element compound selected from transition metal elements (e.g. iron group elements and noble metal elements) which is supported on a carrier (hereinafter, optionally referred to as a carrier-supported catalyst) . The carrier used herein includes, for example, active carbon, alumina, silica and zeolite .

[0026]

The carrier-supported catalyst used herein includes, for example, ruthenium/carbon (Ru/C) , rhodium/carbon (Rh/C) , palladium/carbon (Pd/C) , platinum/carbon (Pt/C) , iridium/carbon (Ir/C) , and platinum/alumina (Pt/alumina) .

[0027]

The amount of the transition metal element compound contained in the carrier-supported catalyst is, for example, 0.1 wt¾ to 30 wt% and preferably 0.5 wt% to 20 wt% based on the total weight of the carrier and the transition metal element compound. [0028]

Furthermore, the transition metal catalyst used herein may be, for example, a non-carrier-supported catalyst comprising at least one element compound selected from transition metal elements such as iron group elements and noble metal elements. The non-carrier-supported catalyst used herein includes, for example, reduced nickel, sponge nickel (Raney® nickel) , reduced cobalt, sponge cobalt (Raney® cobalt) , ruthenium black, rhodium black, palladium black, platinum black, iridium black, ruthenium oxide, rhodium oxide, palladium oxide, platinum oxide, and iridium oxide .

[0029]

The transition metal catalyst used herein is preferably a catalyst of the noble metal element compound supported on a carrier, or sponge nickel or sponge cobalt; more preferably a catalyst of at least one element compound selected from the group consisting of ruthenium, rhodium, palladium, platinum and iridium which is supported on a carrier; and even more preferably, a catalyst of at least one element compound selected from the group consisting of platinum and rhodium which is supported on a carrier.

[0030]

The transition metal catalyst used herein may be commercially available or prepared by well-known processes.

[0031]

The amount of the transition metal catalyst used herein may vary depending on, for example, the below- described factors (e.g. the reaction temperature, the amount of the reaction reagent or solvent, and the hydrogen partial pressure) ,· and it is typically in the range of 0.0001 part to 10 parts, and preferably 0.001 part to 5 parts by weight of the transition metal element per 1 part by weight of Compound (2) . When a carrier-supported catalyst comprising at least one element compound selected from the group consisting of ruthenium, rhodium, palladium, platinum and iridium is used as a transition metal catalyst, the amount of the transition metal catalyst is preferably in the range of 0.01 part to 0.1 part by weight of the transition metal element per 1 part by weight of Compound (2) .

[0032]

When the hydrogen used in the present reaction is hydrogen gas, the partial pressure thereof is typically 10 MPa or less, preferably 0.01 MPa to 5 MPa, more preferably 0.02 MPa to 2 MPa, and even more preferably 0.05 MPa to 1.5 MPa. The hydrogen used herein may be generated from formic acid or a salt thereof by a well-known method.

[0033]

The present reaction is preferably carried out in the presence of a solvent. The solvent used herein includes, for example, aliphatic hydrocarbon solvents such as pentane, hexane, isohexane, heptane, isoheptane, octane, isooctane, nonane, isononane, decane, isodecane, undecane, dodecane, cyclopentane, cyclohexane, methylcyclohexane, tert- butylcyclohexane, and petroleum ether; ether solvents such as tetrahydrofuran, methyltetrahydrofuran, diethyl ether, dipropyl ether, diisopropyl ether, dibutyl ether, dipentyl ether, dihexyl ether, diheptyl ether, dioctyl ether, tert- butyl methyl ether, cyclopentyl methyl ether, 1,2- dimethoxyethane , and diethylene glycol dimethyl ether; alcohol solvents such as methanol, ethanol , 1-propanol, 2- propanol, 1-butanol, isobutyl alcohol, tert-butyl alcohol, 1-pentanol, 2-pentanol, isopentyl alcohol, 1-hexanol, 2- hexanol, isohexyl alcohol, 1-heptanol, 2-heptanol, 3- heptanol, isoheptyl alcohol, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monopropyl ether, ethylene glycol monoisopropyl ether, ethylene glycol monobutyl ether, ethylene glycol monoisobutyl ether, ethylene glycol monotert-butyl ether, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, diethylene glycol monopropyl ether, diethylene glycol monoisopropyl ether, diethylene glycol monobutyl ether, diethylene glycol monoisobutyl ether, and diethylene glycol monotert-butyl ether; ester solvents such as ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, tert-butyl acetate, amyl acetate, and isoamyl acetate; water; and mixtures thereof. The solvent used herein is preferably at least one type selected from the group consisting of alcohol solvents and water, and more preferably at least one type selected from the group consisting of methanol and water.

[0034]

The amount of the solvent used herein is preferably 1 mL to 200 mL, and more preferably 10 mL to 150 mL per 1 g of Compound (2) .

[0035]

Methods for carrying out the present reaction include, for example, the followings.

A method which comprises mixing Compound (2) and a transition metal catalyst, and then stirring the resultant mixture under hydrogen gas atmosphere .

A method which comprises mixing Compound (2) and formic acid, optionally adding a base such as sodium hydroxide and potassium hydroxide to the mixture to adjust the pH thereof, and then adding a transition metal catalyst to the resultant mixture .

[0036]

The reaction temperature of the present reaction is in the range of typically 0°C to 100°C, preferably 20°C to 90 °C, and more preferably 30 °C to 70 °C. The reaction time of the present reaction may vary depending on, for example, the reaction temperature, the amount of the reaction reagent or solvent, and the hydrogen partial pressure, but it is typically 1 hour to 24 hours.

[0037]

The progression of the reaction can be monitored by analytical methods such as thin- layer chromatography, gas chromatography, and high performance liquid chromatography.

[0038]

After the reaction is completed, Compound (1) can be obtained by treating the resultant mixture with post- treatments such as filtration, neutralization, extraction, and water-washing, and then isolating it by treatments such as distillation. When hydrogen is contained in the reaction mixture, the hydrogen can be removed from the reaction mixture, for example, by injecting nitrogen gas into the reaction mixture.

[0039]

The obtained Compound (1) may be purified by treatments such as extractive purification; distillation; and adsorption on, for example, active carbon, silica, and alumina . Examples

[0040]

Hereinafter, the present inventions are illustrated in more detail with some examples, but the present inventions are not limited thereto.

[0041]

In each of the following examples, the reaction mixtures were analyzed with high performance liquid chromatograph (manufactured by Shimadzu Corporation) under the analysis conditions shown below, and the conversion rates and selectivity rates were calculated based on the formulae shown below.

[0042]

Analysis Conditions

LC column: Lichrosorb-RP-8

Column temperature: 40 °C

Mobile phase: acetonitrile/water = 5/95

Additive agent: sodium 1-pentanesulfonate Concentration of additive agent: 2.5 mmol/L pH of mobile phase: pH 3 (adjusted by

adding 40 % phosphoric acid)

Flow rate: 1.5 mL/min

Detection wavelength: 210 nm

Measurement time: 60 min [0043]

Calculation of conversion rate

Conversion rate (%) =

100 (%) - [Peak area of Compound (2) (%)]

[0044]

Calculation of Selectivity rate

Selectivity rate (%) =

[Peak area of Compound (1)] /

(Peak area of all products) x 100

[0045]

Example 1

To a 50 mL autoclave were added 50 mg of sodium 4- methylthio-2-oxobutyrate, 5 g of distilled water and 61 mg of Raney® nickel (wet weight) , and the mixture was stirred. After the autoclave was pressurized to 1 MPaG (gauge pressure) with hydrogen, the mixture was heated to 50 °C and stirred for 6 hours. A portion of the reaction mixture was analyzed by high performance liquid chromatography to find that the conversion rate of sodium 4-methylthio-2- oxobutyrate was 56.6 % and the selectivity rate of 2- hydroxy-4- (methylthio) butyric acid was 67.1 ¾.

[0046]

Example 2 To a 50 mL autoclave were added 50 mg of sodium 4- methylthio-2-oxobutyrate, 5 g of distilled water and 61 mg of Raney® cobalt (wet weight) , and the mixture was stirred. After the autoclave was pressurized to 1 MPaG (gauge pressure) with hydrogen, the mixture was heated to 50 °C and stirred for 6 hours. A portion of the reaction mixture was analyzed by high performance liquid chromatography to find that the conversion rate of sodium 4 -methylthio-2- oxobutyrate was 14.6 % and the selectivity rate of 2- hydroxy-4- (methylthio) butyric acid was 21.2 %.

[0047]

Example 3

To a 50 mL autoclave were added 50 mg of sodium 4- methylthio-2-oxobutyrate, 5 g of distilled water and 126 mg of 5 % Pd/C (manufactured by N.E. Chemcat Corporation, 50 % wet) , and the mixture was stirred. After the autoclave was pressurized to 1 MPaG (gauge pressure) with hydrogen, the mixture was heated to 50 °C and stirred for 6 hours. A portion of the reaction mixture was analyzed by high performance liquid chromatography to find that the conversion rate of sodium 4-methylthio-2-oxobutyrate was 29.7 % and the selectivity rate of 2 -hydroxy-4 - (methylthio) butyric acid was 83.9 %. [0048]

Example 4

To a 50 mL autoclave were added 50 mg of sodium 4- methylthio-2 -oxobutyrate, 5 g of distilled water and 229 mg of 5 % Pt/C (manufactured by N.E. Chemcat Corporation, 50 % wet) , and the mixture was stirred. After the autoclave was pressurized to 1 MPaG (gauge pressure) with hydrogen, the mixture was heated to 50 °C and stirred for 6 hours. A portion of the reaction mixture was analyzed by high performance liquid chromatography to find that the conversion rate of sodium 4 -methylthio-2 -oxobutyrate was 68.4 % and the selectivity rate of 2-hydroxy-4- (methylthio) butyric acid was 85.4 %. [0049]

Example 5

To a 50 mL autoclave were added 50 mg of sodium 4- methylthio-2 -oxobutyrate, 5 g of distilled water and 59 mg of 5 % Ru/C (Wako Pure Chemical Industries, Ltd.), and the mixture was stirred. After the autoclave was pressurized to 1 MPaG (gauge pressure) with hydrogen, the mixture was heated to 50 °C and stirred for 6 hours. A portion of the reaction mixture was analyzed by high performance liquid chromatography to find that the conversion rate of sodium 4 -methylthio-2 -oxobutyrate was 29.6 % and the selectivity rate of 2 -hydroxy-4- (methylthio) butyric acid was 86.2 %.

[0050]

Example 6

To a 50 mL autoclave were added 50 mg of sodium 4- methylthio-2-oxobutyrate, 5 g of distilled water and 61 mg of 5 % Rh/C (Wako Pure Chemical Industries, Ltd.), and the mixture was stirred. After the autoclave was pressurized to 1 MPaG (gauge pressure) with hydrogen, the mixture was heated to 50 °C and stirred for 6 hours. A portion of the reaction mixture was analyzed by high performance liquid chromatography to find that the conversion rate of sodium 4-methylthio-2-oxobutyrate was 95.6 % and the selectivity rate of 2 -hydroxy-4- (methylthio) butyric acid was 93.9 %.

Industrial Applicability

[0051]

The present invention is useful as a process of hydroxycarboxylic acid compound or salt thereof such as 4- methylthio-2-hydroxybutyric acid.