A PROCESS FOR 2 -OXO-4 -METHYLTHIOBUTANOIC ACID OR SALTS THEREOF

TECHNICAL FIELD

The present invention relates to a process for producing 2-oxo-4-methylthiobutanoic acid or salts thereof. BACKGROUND ART

It is known that 2-oxo-4-methylthiobutanoic acid or salts thereof is useful as starting material for methionine which is an essential amino acid (see for example, WO 2006/113085 pamphlet) . It is also known that 2-oxo-4- methylthiobutanoic acid or salts thereof is useful as a feed additive (see for example, US Patent Publicaiton No. 2008/0069920) .

As a process for producing 2 -oxo-4 -methylthiobutanoic acid or salts thereof, for example, the above US Patent Publicaiton No. 2008/0069920 suggests a process by mixing an aqueous 2-oxo-3-butenoic acid solution and gaseous or liquid methyl mercaptan (methanethiol) in the presence of a catalyst . DISCLOSURE of INVENTION (PROBLEMS TO BE SOLVED BY INVENTION)

An object of the present invention is to provide a novel process for producing 2-oxo-4-methylthiobutanoic acid or salts thereof.

(MEANS TO SOLVE PROBLEMS)

The present inventor has intensively studied to find out the process for producing 2-oxo-4-methylthiobutanoic acid or salts thereof, and as a result, has completed the present invention.

That is, the present invention provides:

[1] A process for producing 2-oxo-4-methylthiobutanoic acid or salts thereof comprises a step (1) of reacting methanethiol and organic base, and a step (2) of reacting the product obtained in the above step (1) and 2-oxo-3- butenoic acid.

[2] The process according to the above [1] , wherein the above step (2) is a step of reacting the product obtained in the step (1) and 2-oxo-3-butenoic acid in the presence of water.

[3] The process according to the above [1] or [2] , wherein the organic base used in the above step (1) is a tertiary amine or a nitrogen-containing heterocyclic aromatic compound.

[4] The process according to the above [1] or [2] , wherein the organic base used in the above step (1) is triethyl amine or pyridine .

(EFFECT OF INVENTION)

The present invention enables to provide a novel process for producing 2-oxo-4-methylthiobutanoic acid or salts thereof.

MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention is explained in detail .

The present invention comprises a step (1) of reacting methanethiol and organic base and a step (2) of reacting a product obtained in the above step (1) and 2-oxo-3-butenoic acid. The above step (1) and the above step (2) enable to produce 2-oxo-4-methylthiobutanoic acid or salts thereof.

Firstly, the step (1) is explained. The step (1) is a step of reacting methanethiol and organic base.

The methanethiol used in the step (1) is commercially available, or may be prepared according to a well known method, for example, by reacting methanol and a hydrogen sulfide .

Example of the organic base used in the step (1) includes a tertiary amine such as triethylamine, trimethylamine, diisopropylethylamine, tri-n-butylamine, N- methylmorpholine and the others, and a nitrogen-containing heterocyclic aromatic compound such as pyridine, quinoline, N-methylimidazole and the others. The organic base is preferably triethylamine or pyridine.

The amount used of the organic base is for example,

0.8 to 2 moles, preferably 0.9 to 1.5 moles, and more preferably 0.95 to 1.1 moles, as opposed to 1 mole of methanethiol .

The step (1) can be carried out in the absence of solvent or for example, in the presence of solvent. Example of the solvent includes water; a chain hydrocarbons such as pentane, hexane, heptane, octane, nonane and the others; an alicyclic hydrocarbons such as cyclohexane and the others; an aromatic hydrocarbons such as benzene, styrene, ethylbenzene , toluene, xylene, isopropylbenzene and the others; ethers such as dibutyl ether, 1- isopropoxybutane , 1 , 2 -dimethoxyethane , 1 , 2 -diethoxyethane , 1-ethoxybutane, diisopropylether, tetrahydrofuran and the others; nitriles such as butyronitrile, acetonitrile, propionitrile and the others; ketones such as cyclopentanone, dipropyl ketone, methyl isobutyl ketone, methyl isopropyl ketone, 5-methylhexane-2-one, 2-pentanone, methyl ethyl ketone and the others; and mixed solvent thereof, and is preferably water. The amount used of solvent is for example, 0.1 to 20 parts by weight or 1 to 10 parts by weight, as opposed to 1 part by weight of methanethiol .

The step (1) is preferably carried out in the absence of solvent in terms of a volumetric efficiency.

Example of a method for step (1) includes a method of adding the organic base to a methanethiol -containing solution or a liquified methanethiol, or a method of adding a methanethiol -containing solution or a liquified methanethiol to the organic base. A temperature at adding the organic base to the methanethiol-containing solution or a liquified methanethiol, and a temperature at adding the methanethiol -containing solution and a liquified methanethiol to the organic base can be selected from for example, a range of -50°C to 50°C, and preferably a range of -25°C to 25°C.

A reaction temperature in the step (1) is selected from for example, a range of -25°C to 45°C, and preferably a range of -10°C to 35°C. A reaction period of the step (1) is for example, 10 min. to 24 hours, and preferably 30 min. to 10 hours.

The above step (1) enables to produce an adduct of methanethiol and organic base. That is, the product obtained in the step (1) is an adduct of methanethiol and organic base .

A formation of the adduct of methanethiol and organic base can be confirmed for example, by color test using pH indicator paper. For example, the adduct of methanethiol and tertiary amine indicates pH 9 to pH 10 in the color test using pH indicator paper. Also for example, the adduct of methanethiol and nitrogen-containing heterocyclic aromatic compound indicates pH 5 to pH 6 in the color test using pH indicator paper.

The product obtained in the step (1) may be used in the step (2) below-mentioned after being subjected to a concentration treatment or a purification treatment and the others, or may be used directly in the step (2) without being subjected to a concentration treatment or a purification treatment and the others. Preferably, the product is used directly in the step (2) without being subjected to a concentration treatment or a purification treatment in terms of production efficiency.

Specific example of the product obtained in the step (1) includes an adduct of methanethiol and triethylamine, an adduct of methanethiol and trimethylamine, an adduct of methanethiol and diisopropylethylamine, an adduct of methanethiol and tri-n-butylamine, an adduct of methanethiol and N-methylmorpholine, an adduct of methanethiol and pyridine, an adduct of methanethiol and quinoline, or an adduct of methanethiol and N- methylimidazole, and is preferably an adduct of methanethiol and triethylamine or an adduct of methanethiol and pyridine .

Next, the step (2) is explained. The step (2) is a step of reacting the product obtained in the above step (1) with 2-OXO-3 -butenoic acid. The step (2) enables to produce 2-oxo-4-methylthiobutanoic acid or salts thereof.

The 2 -oxo-3 -butenoic acid used in the step (2) can be prepared for example, by a method of oxidizing 1,2- dihydroxy-3-butene . Example of the method of oxidizing 1, 2-dihydroxy-3-butene includes a method described in JP-A- 2008-526720, specifically a method of oxidizing 1,2- dihydroxy-3-butene in the presence of a catalyst.

Example of the catalyst used in the method of oxidizing 1, 2-dihydroxy-3-butene (heareinafter , sometimes referred to oxidation catalyst) includes a catalyst comprising a noble metal, preferably a catalyst comprising at least one kind of noble metal selected from the group consisting of palladium, platinum, ruthenium, iridium and rhodium, and more preferably a catalyst comprising at least one kind of noble metal selected from the group consisting of palladium and platinum. The catalyst may be a catalyst supported in a carrier (hearinafter, sometimes referred to a supported catalyst) . Example of the carrier includes almina, silica, activated charcoal, graphite and the others When the supported catalyst is used, the content of noble metal as opposed to the supported catalyst is for example, 0.1 to 20 % by weight, and preferably 0.5 to 10 % by weight.

The oxidation catalyst may further comprise at least one kind of a cocatalyst selected from the group consisting of bismuth, lead, antimony, tin, niobium, tellurium, indium, gallium, zinc, copper, nickel, cobalt, tungsten, molybdenum, rhenium, vanadium, chromium, manganese and iron, or at least one kind of a cocatalyst selected from the group consisiting of bismuth and lead. The amount of the cocatalyst is for example, 0.00005 to 5 parts by weight, and preferably 0.00005 to 1 part(s) by weight, as opposed to 1 part by weight of the noble metal .

More preferably, the oxidation catalyst is a supported catalyst comprsing at least one kind of noble metal selected from the group consisting of palladium and platinum and at least one kind of cocatalyst selected from the group consisting of bismuth and lead.

The oxidation catalyst can be prepared, for example by a method of reducing a catalyst precursor that is prepared by an impregnation method. Example of a reagent for reduction includes formaldehyde, sodium formate, sodium borohydride, hydrogen, hypophosphorous acid, hydrazine and reducing sugar. A reduction temperature is selected from for example, a range of 20°C to 400°C.

Oxidation of 1 , 2 -dihydroxy-3 -butene is preferably carried out in the presence of solvent .

The solvent is not particulalrly limited unless it can be one that solubilizes 1, 2-dihydroxy-3-butene, and includes for example, water; a chain hydrocarbons such as pentane, hexane, heptane, octane, nonane and the others; an alicyclic hydrocarbons such as cyclohexane and the others; an aromatic hydrocarbons such as benzene, styrene, ethylbenzene, toluene, xylene, isopropylbenzene and the others; esters such as ethyl formate, butyl formate, isobutyl formate, ethyl acetate, allyl acetate, propyl acetate, butyl acetate, hexyl acetate, ethyl propionate, vinyl propionate, ethyl acrylate, butyl acrylate, methyl isobutanoate, methyl butanoate, and the others,- ethers such as dibutyl ether, 1-isopropoxybutane, 1, 2 -dimethoxyethane, 1, 2 -diethoxyethane, 1-ethoxybutane, diisopropylether, tetrahydrofuran and the others; nitriles such as butyronitrile, acetonitrile, acrylonitrile, propionitrile and the others; ketones such as cyclopentanone, dipropyl ketone, methyl isobutyl ketone, methyl isopropyl ketone, 5- methylhexane-2-one, 2-pentanone, methyl ethyl ketone and and the others; and mixed solvent thereof, and is preferably water.

Oxygen is used in oxidation of 1, 2-dihydroxy-3-butene. Example of oxygen includes molecular oxygen, air, mixed gas of oxygen and inert gas. Oxidation of 1 , 2-dihydroxy-3 -butene is carried out for example, by mixing 1, 2-dihydroxy-3-butene, oxidation catalyst and solvent, and then by stirring the resulting mixture in the presence of oxygen under a pressured condition or atmospheric pressure condition.

Oxidation of 1, 2-dihydroxy-3-butene is preferably carried out under pH 4 to 11 condition, and more preferably under pH 5.5 to 7.5 condition. Adjustment of pH can be carried out for example, by adding alkali metal hydroxide such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the others; alkaline-earth metal hydroxide such as calcium hydroxide, magnesium hydroxide and the others; alkali metal or alkaline-earth metal carbonates such as sodium carbonate, sodium hydrogen carbonate, potassium carbonate and the others to the above mixture.

The reaction temperature is selected from for example, a range of 10°C to 95°C, and preferably a range of 25°C to 70 °C. The reaction period is for example, 20 min. to 15 hours .

The step (2) can be carried out in the presence of solvent. Example of the solvent used in the step (2) includes water; a chain hydrocarbons such as pentane, hexane, heptane, octane, nonane and the others; an alicyclic hydrocarbons such as cyclohexane and the others; an aromatic hydrocarbons such as benzene, styrene, ethylbenzene, toluene, xylene, isopropylbenzene and the others; ethers such as dibutyl ether, 1-isopropoxybutane, 1, 2-dimethoxyethane, 1, 2 -diethoxyethane, 1-ethoxybutane, diisopropylether, tetrahydrofuran and the others; nitriles such as butyronitrile, acetonitrile, propionitrile and the others; ketones such as cyclopentanone, dipropyl ketone, methyl isobutyl ketone, methyl isopropyl ketone, 5- methylhexane-2-one, 2-pentanone, methyl ethyl ketone and the others; and mixed solvent thereof, and is preferably water. The amount used of solvent is for example, 0.1 to 100 parts by weight and preferably 1 to 50 parts by weight, as opposed to 1 part by weight of 2-oxo-3-butenoic acid.

The rection temperature is selected from for example, a range of -30°C to 30°C and preferably a range of -20°C to 20°C. When the reaction temperature is below -30 °C, the reaction of the step (2) tends to slow, while when the reaction temperature is over 30°C, the 2-oxo-3-butenoic acid used in the reaction of the step (2) tends to decompose .

The reaction period of the step (2) is for example, 10 min. to 24 hours, and preferably 1 to 10 hour(s) .

The reaction of the step (2) is preferably carried out in the range of pH 5 to 10.

The step (2) can be carried out in the absence of catalyst, and preferably can be carried out by the following methods:

(A) a method of adjusting 2-oxo-3-butenoic acid or a solution containing the same to the above-mentioned reaction temperature of the step (2) and thereto adding the product obtained in the step (1) ;

(b) a method of adjusting the product obtained in the step

(1) to the above-mentioned reaction temperature of the step

(2) and thereto adding the 2-oxo-3 -butenoic acid or a solution containing the same;

(C) a method of adding the product obtained in the step (1) to the 2 -oxo-3 -butenoic acid or a solution containing the same and adjusting the resulting mixture to the above- mentioned reaction temperature of the step (2) ; or

(D) a method of adding the 2 -oxo-3 -butenoic acid or a solution containing the same to the product obtained in the step (1) and adjusting the resulting mixture to the above- mentioned reaction temperature of the step (2) ,

and more preferably can be carried out by the above method of (A) . That is, the step (2) is more preferably carried out by adding the product obtained in the above step (1) to the 2 -oxo-3 -butenoic acid or the solution containing the same that is adjusted to the temperature selected from a range of -30°C to 30°C, and is further preferably carried out by adding the product obtained in the above step (1) to the 2 -oxo-3 -butenoic acid or the solution containing the same that is adjusted to the temperature selected from the range of -20°C to 20°C.

The process degree of the reaction of the step (2) can be confirmed by analytical means such as gas chromatography, high-performance liquid chromatography, thin-layer chromatography, nuclear magnetic resonance spectrum analysis, infrared absorption spectrum analysis and the others .

After a completion of the reaction of the step (2) , for example, a mineral acid such as sulfuric acid, hydrochloric acid and the others, is added to a reaction mixture, and the resulting acidic mixture is mixed with water-immiscible organic solvent, and then an extraction treatment can be carried out to take out 2-oxo-4- methylthiobutanoic acid. Example of the water-immiscible organic solvent includes esters such as methyl acetate, ethyl acetate, butyl acetate and the others, aromatic hydrocarbons such as toluene, xylene and the others, halogenated solvents such as chlorobenzene, dichlorobenzene and the others, ketones such as methyl isobutyl ketone and the others .

2-0x0-4 -methylthiobutanoic acid taken out can be subjected to washing treatment such as water washing and the others, or purification treatment such as distillation, column chromatography, crystallizaiton and the others. The reaction mixture obtained in the step (2) contains organic base used in the step (1) . The organic base can be recovered by performing the above-mentioned extraction treatment and subsequently neutralization treatment of the resulting aqueous phase. The organic base recovered can be recycled, for example in the step (1) .

2-Oxo-4-methylthiobutanoic acid obtained in such manner may be salts thereof wherein H ⁺ that can be dissociated from its carboxy group is replaced with an optional cation. Example of the cation includes alkali metal ion such as sodium, potassium and the others, alkaline-earth metal ion such as calcium, barium and the others, and ammonium ion such as triethylammonium ion and the others .

EXAMPLES

Next, the present invention is described in more detail below with some examples, but the present invention should not be construed to be limited thereto.

<Preparation Example 1> (2-oxo-3-butenoic acid)

Aqueous 2-oxo-3-butenoic acid solution was prepared by oxidizing 1, 2-dihydroxy-3-butene according to the method described in Example 7 of JP-A 2008-526720.

The aqueous solution obtained was used in the below- mentioned Example 1 directly without concentration treatment .

<Example 1>

Step (1) (Preparation of adduct of methane thiolate and triethylamine)

To methanethiol that was cooled to -10°C and liquefied 1.2g (25mmol) was added triethylamine 2.5g (25mmol) at the same temperature with stirring, and then the resulting mixture was heated to room temperature (about 25°C) . After heating, the mixture was stirred for additional one hour to give clear and colourless oil. The clear and colourless oil obtained indicated pH 9 to 10 in color test using pH indicator paper.

Step (2) (Preparation of 2 -oxo-4 -methylthiobutanoic acid)

The aqueous 2-oxobut-3-enoic acid solution obtained in the Preparation Example 1 lmL was cooled to -10°C, and thereto was added the adduct of methane thiolate and triethylamine obtained in the step (1) 20mg. The resulting mixture was stirred at 0°C for 3.5 hours.

The resulting reaction mixture was analyzed by liquid chromatography/mass spectrometry and confirmed a formation of objective 2 -oxo-4 -methylthiobutanoic acid.

Also the resulting reaction mixture was analyzed by high-performance liquid chromatography (manufactured by Shimadzu Corp.) under the following analytical condition, to confirm a formation of 2-oxo-4-methyl butanoic acid in 23.6% (liquid chromatgraphy area normalization method).

(Anaytical condition)

LC column : Sumipax Lichrosob RP-18

(30cmx4.0mm, ΙΟμπι)

Column temperature : 40°C

Mobile phase : isocratic

Mobile phase A: 1-pentane sulfonic acid 2.64g/2850mL water Mobile phase B: acetonitrile

0 min B 5%

60 min B 5% STOP

Flow rate : 1 mL/min

Detection wavelength: 210nm

Measurement time : 60min

<Example 2>

Step (1) (Preparation of adduct of methane thiolate and pyridine)

To methanethiol that was cooled to -10°C and liquefied

1.7g (35mmol) was added pyridine 2.8g (35mmol) at the same temperature with stirring, and then the resulting mixture was heated to room temperature (about 25 °C) . After heating, the mixture was stirred for additional one hour to give clear and colourless oil. The clear and colourless oil obtained indicated pH 5 to 6 in color test using pH indicator paper. Separately, pyridine indicated pH 7 to 8 in color test using pH indicator paper.

Step (2) (Preparation of 2-oxo-4-methylthiobutanoic acid) The aqueous 2-oxobut-3-enoic acid solution obtained in the Preparation Example 1 lmL was cooled to -10°C, and thereto was added the adduct of methane thiolate and pyridine obtained in the step (1) 20mg. The resulting mixture was stirred at 0°C for 3.5 hours.

The resulting reaction mixture was analyzed by liquid chromatography/mass spectrometry and confirmed a formation of objective 2-oxo-4-methylthiobutanoic acid.

Also the resulting reaction mixture was analyzed by high-performance liquid chromatography (manufactured by Shimadzu Corp.) under the same analytical condition as described in Example 1, to confirm a formation of 2-oxo-4- methyl butanoic acid in 9.2% (liquid chromatgraphy area normalization method) . INDUSTRIAL APPLICABILITY

It is known that 2-oxo-4-methylthiobutanoic acid or salts thereof is useful as starting material for methionine which is an essential amino acid. It is also known that 2- oxo-4-methylthiobutanoic acid or salts thereof is useful as a feed additive. Accordingly, a novel process for preparing 2 -oxo-4 -methylthiobutanoic acid or salts thereof of the present invention is industrially applicable.