JP4984717B2 - Process for producing 4- (methylthio) butane-1,2-diol - Google Patents

Description

  The present invention provides a process for producing 4- (methylthio) butane-1,2-diol.

  4- (Methylthio) butane-1,2-diol is an important compound as a pharmaceutical intermediate (for example, see Patent Document 1) and a methionine analog (for example, see Non-Patent Document 1). As a method for producing 4- (methylthio) butane-1,2-diol, a method of adding methanethiol to 3-butene-1,2-diol is known. For example, an organic peroxide is used as a catalyst. Examples thereof include a method (for example, see Non-Patent Document 1) and a method (for example, see Patent Document 2) performed in the presence of a boron compound. However, the former has problems in terms of disaster prevention, and the latter requires the use of expensive reagents. None of these are industrially satisfactory, and the development of a more efficient production method has been desired.

Japanese Patent Publication No. 6-37459 European Published Patent No. 1260500 J. of Agricultural and Food Chemistry, 23, 1137 (1975)

  Under such circumstances, the present inventors diligently studied a method for producing 4- (methylthio) butane-1,2-diol by methanethiol addition reaction to 3-butene-1,2-diol. It was found that if the reaction was carried out in the presence of a nitrogen-containing organic compound and a carboxylic acid compound that were readily available, the reaction proceeded efficiently without causing problems in terms of disaster prevention, leading to the present invention.

That is, the present invention provides a process for producing 4- (methylthio) butane-1,2-diol, in which 3-butene-1,2-diol and methanethiol are reacted in the presence of pyridine or collidine and acetic acid or formic acid. It is to provide.

According to the present invention, 3- (butene-1,2-diol) and methanethiol are reacted in the presence of pyridine or collidine , which is inexpensive and readily available , and acetic acid or formic acid, under mild conditions. Since methylthio) butane-1,2-diol can be obtained, it is industrially advantageous.

  Hereinafter, the present invention will be described in detail.

  Commercially available 3-butene-1,2-diol may be used as the raw material, for example, addition ring-opening reaction of 1,2-epoxy-3-butene with water in the presence of a sulfuric acid catalyst. A method (for example, see US Pat. No. 5,250,743), a method for isomerizing 2-butene-1,4-diol in the presence of a dirhenium heptoxide catalyst (for example, see JP-A-6-327551). It can manufacture according to well-known methods, such as.

  The raw material methanethiol is generally synthesized from methanol and hydrogen sulfide, but commercially available products can be used. As the methanethiol, a gaseous one or a liquid one may be used. Liquid methanethiol can be prepared by, for example, a method in which gaseous methanethiol is introduced into a container cooled to a boiling point (6 ° C.) or lower and condensed.

  The amount of methanethiol used is usually 1 mol times or more with respect to 3-butene-1,2-diol, and there is no particular upper limit. It is 10 mol times or less with respect to butene-1,2-diol.

  The nitrogen-containing aromatic compound is a heteroaromatic compound having 3 to 20 carbon atoms which is a monocyclic or condensed ring and at least one of the constituent atoms of the aromatic ring is a nitrogen atom, such as pyridine, pyrazine, imidazole, Examples thereof include benzimidazole, phenanthroline, oxazole, thiazole, quinoline, isoquinoline and the like. Further, on these compounds, for example, halogen atoms such as fluorine atom, chlorine atom and bromine atom; carbon such as methyl group, ethyl group, propyl group, isopropyl group, butyl group, sec-butyl group and tert-butyl group An alkyl group having 1 to 4 carbon atoms; an alkoxy group having 1 to 4 carbon atoms such as a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, and a tert-butoxy group; a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, and an isopropoxy group The substituent may have a substituent such as a C1-C4 alkoxycarbonyl group such as a carbonyl group or a tert-butoxycarbonyl group; a dialkylamino group such as a dimethylamino group or a diethylamino group; a carbamoyl group; Specific examples of the compound in which 2-methylpyridine are bonded include 2-methylpyridine, Gin, 4-methylpyridine, 2-chloropyridine, 3-chloropyridine, 4-chloropyridine, 2,3,5-collidine, 2,4,6-collidine, nicotinamide, methyl nicotinate, N-methylimidazole , 2-chloroquinoline and the like.

  The tertiary amine compound is a linear, branched or cyclic tertiary amine compound having at least one nitrogen atom, such as trimethylamine, triethylamine, tri (n-propyl). Amine, tri (n-butyl) amine, tri (n-pentyl) amine, tri (n-hexyl) amine, dimethyl (n-octyl) amine, dimethyl (n-decyl) amine, dimethyl (n-dodecyl) amine, Dimethyl (n-tetradecyl) amine, dimethyl (n-hexadecyl) amine, dimethyl (n-octadecyl) amine, di (n-hexyl) methylamine, di (n-octyl) methylamine, dimethylbenzylamine, di (n- Butyl) benzylamine, N, N-dimethylaniline, N, N-di (n-butyl) aniline, N, N Di (n-hexyl) aniline, N-methylmorpholine, N- (n-butyl) morpholine, N- (n-octyl) morpholine, N- (n-decyl) morpholine, N- (n-dodecyl) morpholine, N -Methylpyrrolidine, N- (n-butyl) pyrrolidine, N- (n-hexyl) pyrrolidine, N- (n-octyl) pyrrolidine, N- (n-decyl) pyrrolidine, N- (n-dodecyl) pyrrolidine, N -Methylpiperidine, N- (n-butyl) piperidine, N- (n-hexyl) piperidine, N- (n-octyl) piperidine, N- (n-decyl) piperidine, N- (n-dodecyl) piperidine and the like Can be mentioned.

  As these nitrogen-containing organic compounds, various compounds are commercially available and are usually readily available. Of these nitrogen-containing organic compounds, nitrogen-containing aromatic compounds are preferably used. Among them, for example, pyridine, 2-methylpyridine, 3-methylpyridine, 4-methylpyridine, 2-chloropyridine, 3-chloropyridine, 4-chloropyridine, 2,3,5-collidine, 2,4,6 -Pyridine which may have a substituent such as collidine, nicotinamide and methyl nicotinate is more preferable.

  Examples of the carboxylic acid compound include aliphatic carboxylic acid compounds and aromatic carboxylic acid compounds.

  The aliphatic carboxylic acid compound is a linear, branched or cyclic aliphatic compound having 1 to 20 carbon atoms having at least one carboxy group. For example, formic acid, acetic acid, propionic acid, butanoic acid, pentanoic acid , Hexanoic acid, oxalic acid, lactic acid, succinic acid, adipic acid, maleic acid, fumaric acid and the like.

  The aromatic carboxylic acid compound is a monocyclic or condensed cyclic C7-20 aromatic compound having at least one carboxy group, and examples thereof include benzoic acid, salicylic acid, acetylsalicylic acid, and terephthalic acid.

  As these carboxylic acid compounds, various compounds are commercially available and can be easily obtained. Of these carboxylic acid compounds, aliphatic carboxylic acid compounds are preferably used.

  If the usage-amount of a nitrogen-containing organic compound is 0.001 mol times or more normally with respect to 3-butene- 1, 2-diol, the objective of this invention can be achieved. The upper limit is not particularly limited, but considering the economical aspect, it is 1 mole or less with respect to 3-butene-1,2-diol. Moreover, the usage-amount of a carboxylic acid compound is 0.3-10 mol times normally with respect to a nitrogen-containing organic compound, Preferably it is the range of 1-5 mol times.

  The reaction of 3-butene-1,2-diol and methanethiol is usually carried out without a solvent, but a solvent may be used. As the solvent, any solvent that does not inhibit the addition reaction can be used without particular limitation. Examples thereof include water; hydrocarbon solvents such as hexane, heptane, and toluene; halogenated hydrocarbon solvents such as chlorobenzene and chloroform; diethyl ether, Examples thereof include ether solvents such as methyl tert-butyl ether and tetrahydrofuran; ester solvents such as ethyl acetate; tertiary alcohol solvents such as tert-butanol; nitrile solvents such as acetonitrile and propionitrile; The amount of the solvent used is not particularly limited, but is practically 100 weight times or less with respect to 3-butene-1,2-diol in consideration of volumetric efficiency and the like.

  The reaction temperature varies depending on the type and amount of the nitrogen-containing organic compound and the carboxylic acid compound to be used. If the reaction temperature is too low, the addition reaction hardly proceeds. If the reaction temperature is too high, the raw material 3-butene-1,2-diol Since there is a possibility that side reactions such as polymerization of the product or the product proceed, the normal reaction temperature is in the range of -10 to 100 ° C, preferably about 0 to 50 ° C.

  The reaction can be carried out under reduced pressure, normal pressure, or increased pressure. However, since the boiling point of methanethiol is 6 ° C. and it is a gas at room temperature, it is usually carried out under normal pressure or increased pressure.

  The reaction of 3-butene-1,2-diol and methanethiol is performed by contacting and mixing 3-butene-1,2-diol and methanethiol in the presence of a nitrogen-containing organic compound and a carboxylic acid compound. The mixing method is not particularly limited. When carried out under normal pressure conditions, a mixture of a nitrogen-containing organic compound, a carboxylic acid compound and 3-butene-1,2-diol is usually adjusted to a predetermined temperature, and gaseous methanethiol is blown into the mixture. The reaction is carried out. When carried out under pressure conditions, for example, a nitrogen-containing organic compound, a carboxylic acid compound, and 3-butene-1,2-diol are added to a sealable container such as an autoclave, and the container is sealed, A method of press-fitting gaseous methanethiol at a temperature, after adding a nitrogen-containing organic compound, a carboxylic acid compound, 3-butene-1,2-diol, and liquid methanethiol to the sealed container, and sealing the container The reaction is carried out by adjusting the temperature to a predetermined temperature. Nitrogen-containing organic compound, carboxylic acid compound, 3-butene-1,2-diol and methanethiol are mixed and then reacted at a predetermined temperature, or 3-butene-1,2-diol and methanethiol are reacted. In the case of mixing and adding a nitrogen-containing organic compound and a carboxylic acid compound to the reaction, in order to smoothly start the reaction, in a mixture containing 3-butene-1,2-diol and methanethiol It is preferable to keep the methanethiol at 4 mol times or less with respect to 3-butene-1,2-diol.

  The progress of the reaction can be confirmed by ordinary analysis means such as gas chromatography, high performance liquid chromatography, thin layer chromatography, nuclear magnetic resonance spectrum analysis, infrared absorption spectrum analysis and the like.

  After completion of the reaction, for example, after removing the remaining methanethiol from the reaction mixture, water or an organic solvent insoluble in water is added as necessary, followed by extraction treatment, and 4- (methylthio) butane-1,2 obtained. -By concentrating the organic layer containing diol, 4- (methylthio) butane-1,2-diol can be isolated.

  Examples of the method for removing remaining methanethiol from the reaction mixture include a method of concentrating the reaction mixture, a method of blowing an inert gas such as nitrogen gas into the reaction mixture, and the like.

  Examples of the organic solvent insoluble in water include ester solvents such as ethyl acetate; ether solvents such as diethyl ether, dibutyl ether and methyl tert-butyl ether; halogenated hydrocarbon solvents such as chloroform, methylene chloride and dichloroethane; The amount used is not particularly limited.

  If neutral water washing is performed as the extraction treatment, the nitrogen-containing organic compound and the carboxylic acid compound are usually removed to the water layer side as salts. Further, for example, the nitrogen-containing organic compound can be separated and removed by performing acidic water washing, and the carboxylic acid compound can be separated and removed by carrying out basic water washing.

  As the acid used for the acidic water washing, for example, a mineral acid such as hydrochloric acid or sulfuric acid is usually used, and its concentration and amount used are not particularly limited. Examples of the base used for basic water washing include metal hydroxides such as sodium hydroxide and potassium hydroxide; metal carbonates such as sodium carbonate and potassium carbonate; metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate. Etc. are usually used, and the concentration and amount used are not particularly limited.

  EXAMPLES Hereinafter, although an Example demonstrates this invention further in detail, this invention is not limited by these Examples.

Example 1
To a 50 mL autoclave equipped with a magnetic rotor, 2000 mg of 3-butene-1,2-diol, 9 mg of pyridine and 14 mg of acetic acid were added and cooled to 0 ° C., and 1500 mg of methanethiol was added. After sealing the autoclave, it was kept at 40 ° C. and stirred for 4 hours. The internal pressure (gauge pressure) of the autoclave was initially 2.5 kg / cm ² (equivalent to 0.25 MPa), and was 0.5 kg / cm ² (equivalent to 0.05 MPa) at the end of the reaction. After the reaction, the pressure was returned to normal pressure, and nitrogen gas was blown into the solution to remove the remaining methanethiol and diluted with 10 g of ethyl acetate. When this solution was analyzed by gas chromatography internal standard method, the yield of 4- (methylthio) butane-1,2-diol was 94%. 5% of 3-butene-1,2-diol as a raw material remained.

Example 2
In Example 1, it replaced with 9 mg of pyridines, and 14 mg of acetic acid, and carried out similarly to Example 1 except having used 28 mg of 2,4,6- collidine and 26 mg of 80% formic acid.
The yield of 4- (methylthio) butane-1,2-diol was 95%. 4% of 3-butene-1,2-diol as a raw material remained.

Reference example 1
In Example 1, it replaced with 9 mg of pyridines, and 14 mg of acetic acid, and implemented similarly to Example 1 except having used 29 mg of quinoline, and 34 mg of propionic acid.
The yield of 4- (methylthio) butane-1,2-diol was 58%. 40% of 3-butene-1,2-diol as a raw material remained.

Reference example 2
In Example 1, it replaced with 9 mg of pyridines, and 14 mg of acetic acid, and implemented similarly to Example 1 except having used 18 mg of pyridines, and 55 mg of benzoic acid.
The yield of 4- (methylthio) butane-1,2-diol was 39%. 58% of 3-butene-1,2-diol as a raw material remained.

Reference example 3
In Example 1, it replaced with 9 mg of pyridines, and 14 mg of acetic acid, and implemented similarly to Example 1 except having used 22 mg of triethylamine and 30 mg of acetic acid.
The yield of 4- (methylthio) butane-1,2-diol was 40%. 58% of 3-butene-1,2-diol as a raw material remained.

Claims (2)

A process for producing 4- (methylthio) butane-1,2-diol, comprising reacting 3-butene-1,2-diol and methanethiol in the presence of pyridine or collidine and acetic acid or formic acid . A process for producing 4- (methylthio) butane-1,2-diol, comprising reacting 3-butene-1,2-diol and methanethiol in the presence of pyridine and acetic acid or formic acid .