JPH11209340A - Production of s-substituted propionamide - Google Patents

Abstract

PROBLEM TO BE SOLVED: To efficiently obtain a S-substituted propionamide in high purity and desirable yield useful for medicines, agrochemicals and the like by carrying out the esterification and amidation as a serial processes. SOLUTION: The esterification of (A) the S-substituted propionic acid of formula I (X is H or S-CH2 CH2 COOH) with (B) excess amount of aliphatic alcohols of R<1> -OH (R<1> is an 1-8C alkyl) is carried out in the presence of a sulfonic acid type cation exchanging resin to obtain a S-substituted propionate of the formula II (Y is H or S-CH2 CH2 COOR<1> ), then without isolating the prescribed ester compound, an amine of the formula, R<2> -NH-R<3> (R<2> and R<3> are each H, an 1-8C alkyl, a cycloalkyl or the like) is added to the aliphatic alcohol solution of the prescribed ester compound to carry out the ester-amide exchange reaction, obtaining the subject amide of the formula III (Z is H or S-CH2 CH2 COHR<2> R<3> ).

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for producing an S-substituted propionamide.

[0002]

2. Description of the Related Art As a method for producing an S-substituted propionic amide, 3,3'-dithiopropionic acid is converted to dithiopropionic chloride using thionyl chloride in the presence of pyridine, and then a predetermined amine in toluene. A method of amidation with a compound is known (JP-A-2-278).
However, in this method, since the intermediate acid chloride is unstable, the water content in the solvent must be strictly controlled, and it is difficult to obtain a sufficient yield.

[0003] Also, 3-chloropropionic chloride is
A method of treating with hydrogen sulfide in the presence of a potassium hydride base to form 3-mercaptothiopropionic acid, and then reacting with alkyl isocyanates to amidate has also been reported (Nippon Dental University Bulletin; , 15
5 ('81)). However, this method is not a realistic production method because it involves an intermediate which is unstable with respect to moisture as described above.

Further, a method has been proposed in which methyl 3-mercaptopropionate or dimethyl 3,3'-dithiopropionate is amidated with amines in a lower alcohol (JP-A-59-31772, JP-A-59-31772). 3-9510
No. 3, JP-A-3-236380, JP-A-3-1283
No. 68). As a method for obtaining the S-substituted propionic acid ester as a raw material of the method, a method for producing a corresponding methyl ester by esterifying 3-mercaptopropionic acid or 3,3′-dithiopropionic acid in the presence of concentrated sulfuric acid is known. Although known (Japanese Patent Application Laid-Open No. 4-1175), in order to use the methyl ester as a raw material for each of the above amidations, it is necessary to isolate the target S-substituted propionate ester through a complicated step. is there.

[0005] In general, S-containing compounds have an unpleasant odor, and the conventionally known methods for producing S-substituted propionamides are considered in view of work hygiene environment, work efficiency, yield, production cost and the like. There is still room for improvement.

[0006]

SUMMARY OF THE INVENTION An object of the present invention is to provide a novel industrially excellent method for producing an S-substituted propionamide efficiently, with high purity and with high yield. I do.

[0007]

Means for Solving the Problems The present inventors have made efforts to solve the above problems, and as a result, have found the following facts, and have completed the present invention based on such findings. (1) Conventionally, the esterification of an S-substituted propionic acid and the amidation of an S-substituted propionic ester, which are proposed separately, are performed as a series of steps,
Specifically, first, S-substituted propionic acid is esterified with an excess amount of an aliphatic alcohol in the presence of a specific catalyst, and the obtained S-substituted propionic acid ester is isolated or purified without isolation or purification. Subsequently, a system containing an excess of an aliphatic alcohol (may contain esterified water).
, The desired S-substituted propionamide can be obtained in high purity and high yield under mild conditions. (2) In the esterification step, the sulfonic acid type cation exchange resin has excellent esterification catalyst performance and is easily separable, and thus has excellent workability.

That is, the method for producing an S-substituted propionamide according to the present invention comprises the general formula (1) X-S-CH ₂ CH ₂ COOH (1) wherein X is a hydrogen atom or a group S-CH ₂ represents CH ₂ COOH. And a general formula (2) R ¹ —OH (2) wherein R ¹ represents a linear or branched alkyl group having 1 to 8 carbon atoms. ] With an excess amount of an aliphatic alcohol represented by esterifying in the presence of a sulfonic acid type cation-exchange resin formula (3) Y-S-CH 2 CH 2 COOR 1 (3) [ in the formula, Y is hydrogen atom or a group S-CH ₂ CH ₂ COOR ¹
Represents R ¹ is as described above. ] Represented by
A substituted propionic acid ester is obtained, and without isolating the esterified product, a solution of the general formula (4) R ² —NH—R ³ (4) in a solution of the esterified product in an aliphatic alcohol, wherein R ² , R ^{2 3} is the same or different and is a hydrogen atom, a linear or branched alkyl group having 1 to 18 carbon atoms, a cycloalkyl group, a linear or branched alkenyl group or an alkynyl group having 1 to 18 carbon atoms. Is shown. The cycloalkyl group may have an alkyl group having 1 to 4 carbon atoms or a halogen substituent. And an ester-amide exchange reaction is carried out to obtain a compound represented by the following general formula (5): Z—S—CH ₂ CH ₂ CONR ² R ³ (5) wherein Z is a hydrogen atom or a group S— CH ₂ CH ₂ CONR ²
R ³ is shown. R ² and R ³ are as described above. The method is characterized by producing an S-substituted propionamide represented by the formula:

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION [Esterification Step] The esterification step according to the present invention comprises an S-substituted propionic acid represented by the general formula (1) and an excess amount of an aliphatic compound represented by the general formula (2). In the presence of a sulfonic acid type cation exchange resin with an alcohol,
This is a step of obtaining an S-substituted propionic acid ester represented by the general formula (3) by esterification under heating and stirring according to a conventional method, for example.

As the S-substituted propionic acid represented by the general formula (1), 3-mercaptopropionic acid and 3,3
3'-dithiopropionic acid.

As the aliphatic alcohol represented by the general formula (2), a linear or branched aliphatic alcohol having 1 to 8 carbon atoms, specifically, methanol, ethanol, n
-Propanol, isopropanol, n-butanol,
Examples include n-hexanol, n-octanol and the like,
In particular, aliphatic alcohols having 1 to 4 carbon atoms such as methanol, ethanol, n-propanol, isopropanol and butanol are preferred. If the carbon number exceeds 4,
Boiling point becomes high, and distillation at normal pressure becomes difficult.

The amount of the aliphatic alcohol to be added is S-
2 to 50 equivalents are recommended for 1 equivalent of the substituted propionic acid, and 10 to 30 equivalents are particularly preferable. If it is less than 2 equivalents, the reaction rate is low, and if it is used in excess of 50 equivalents, the productivity is reduced, which is not preferable in any case.

As the sulfonic acid type cation exchange resin,
Resins obtained by sulfonating a styrene-divinylbenzene copolymer are exemplified. Among them, an acid exchange capacity is 2 meq /
g or more of the resin is preferable, and a resin of 3 to 6 meq / g is particularly recommended. The diameter of the resin is not particularly limited, but 0.1 to 2 mm is recommended.

The sulfonic acid type cation exchange resin used in the present invention includes Diaion PK208, PK220, PK228 (trade names, manufactured by Mitsubishi Chemical Corporation), Amberlyst 15, 15E, 35 (trade names).
Rohm and Haas product name), Dowex 5
Cation exchange resins such as 0WX4 and 50WX8 (both trade names manufactured by Dow Chemical Company) are exemplified.

The recommended amount of the catalyst is 5 to 50% by weight based on the weight of the S-substituted propionic acid.
~ 30% by weight is preferred.

The esterification temperature is 25 to 200 ° C.
And particularly preferably 50 to 150 ° C.

The reaction time is, for example, 2 to 10 hours, preferably 3 to 6 hours.

The reaction atmosphere is preferably under an atmosphere of an inert gas such as nitrogen or argon.

After completion of the reaction, the catalyst is separated. As a separation method, a conventionally known method such as filtration and centrifugation is applied. Above all, vacuum filtration in a closed system is recommended.

The S-substituted propionic acid ester according to the present invention is produced by continuously passing an aliphatic alcohol solution of S-substituted propionic acid through a column reactor (reaction tower) filled with the above catalyst. Can also. Alternatively, it can be produced by charging the S-substituted propionic acid and the aliphatic alcohol through different routes and bringing them into contact in a reaction tower.

Among the S-substituted propionates thus obtained, in particular methyl 3-mercaptopropionate,
Ethyl 3-mercaptopropionate, n-propyl 3-mercaptopropionate, n-butyl 3-mercaptopropionate, dimethyl 3,3′-dithiopropionate,
Diethyl 3,3'-dithiopropionate, di-n-propyl 3,3'-dithiopropionate and di-n-butyl 3,3'-dithiopropionate are recommended as raw materials for the subsequent ester-amide exchange reaction. Is done.

[Ester-Amidation Exchange Reaction] In the present invention, the S-substituted propionic acid ester can be prepared without removing the esterified water and generally the excess aliphatic alcohol in the esterification reaction crude. An ester-amide exchange reaction is carried out using an amine as a raw material to produce an intended S-substituted propionamide. When the size of the apparatus to be used is limited, a part of the excess aliphatic alcohol may be distilled off under normal pressure or reduced pressure.

It is preferable to mix water generated by the ester reaction in the reaction system in order to accelerate the reaction. This water is preferably dissolved uniformly in the reaction system, and the recommended amount of water is 0.1 to 1 equivalent based on 1 equivalent of S-substituted propionic acid.

As the amine according to the present invention, a primary or secondary aliphatic amine or alicyclic amine represented by the general formula (4) is exemplified. In addition, R ² in the general formula
And R ³ as a hydrogen atom, an alkyl group having 1 to 18 carbon atoms, a cycloalkyl group having 5 to 20 carbon atoms,
A group or atom selected from the group consisting of an alkenyl group of 18 or an alkynyl group having 2 to 18 carbon atoms is preferable.
² or R ³ is a hydrogen atom, and the other is methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-
Amines which are straight-chain saturated aliphatic alkyl groups having 1 to 10 carbon atoms, such as hexyl and n-octyl, are recommended.

As the alkyl group, methyl, ethyl,
Examples include n-propyl, i-propyl, n-butyl, t-butyl, i-butyl, sec-butyl, pentyl, hexyl, 2-ethylhexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, and the like.

Examples of the cycloalkyl group include cyclopentyl, cyclohexyl, 4-methylcyclohexyl,
-Methylcyclohexyl and the like.

Examples of the alkenyl group include vinyl, allyl, isopropenyl and the like.

Examples of the alkynyl group include ethynyl, propynyl and the like.

As the primary amine, methylamine, ethylamine, n-hexylamine, n-octylamine,
Aliphatic amines such as decylamine and dodecylamine, and cyclopentylamine, cyclohexylamine, 2-
Alicyclic amines such as methylcyclohexylamine and 4-methylcyclohexylamine are exemplified.

Examples of the secondary amine include dimethylamine, diethylamine, di-n-propylamine, di-n-butylamine, di-n-hexylamine, dicyclopentylamine, dicyclohexylamine and the like.

Among these amines, aliphatic primary amines having 1 to 8 carbon atoms are particularly recommended.

In the ester-amide exchange reaction, the amount of the amine used is usually 2 to 50 equivalents, preferably 3 to 5 equivalents, per equivalent of the S-substituted propionic acid. If it is less than 2 equivalents, the reaction rate tends to be low and the reaction time tends to be long. On the other hand, if it is used in excess of 20 equivalents, the productivity is undesirably reduced.

The reaction temperature is preferably from 10 to 150 ° C., particularly preferably from 20 to 60 ° C.

The reaction time is 2 to 30 hours, preferably 5 hours.
The reaction is completed in about 10 hours.

One of the features of the present invention is that, in a preferred embodiment, an excess of the aliphatic alcohol used in the esterification and an excess of the amine used in the amidation are reacted in an ester-amide exchange reaction. It is to be used as a solvent. However, this does not prohibit the use of other solvents.

Solvents that can be applied as required are not particularly limited as long as they do not inhibit the reaction. Examples of applicable solvents include ethyl ether, ethers such as ethylene glycol dimethyl ether, dioxane, cyclic ethers such as tetrahydrofuran,
Examples thereof include alkyl halides such as methylene chloride, chloroform and carbon tetrachloride; aromatic hydrocarbons such as chlorobenzene, toluene and xylene; and polar solvents such as acetonitrile, dimethylformamide and dimethylsulfoxide.

The reaction is preferably carried out in an atmosphere of an inert gas such as nitrogen or argon.

After completion of the reaction, high purity S-substituted propionamide can be obtained by, for example, distilling off the water produced by esterification, excess aliphatic alcohol and excess amine under reduced pressure. This can be distilled if necessary.
Further purification can be achieved by using means such as recrystallization.

The S-substituted propionamide thus obtained is useful as an important intermediate for pharmaceuticals, agricultural chemicals, bactericides and the like, particularly as an intermediate for industrial bactericides.

[0040]

The present invention will be described in detail below with reference to examples. In addition, it was confirmed by MS and FT-IR that the reaction products in each example were the target amides.

Example 1 A three-necked 200 ml flask equipped with a magnetic stirrer, a reflux condenser and a nitrogen inlet adapter was charged with 10 g (0.09 mol) of 3-mercaptopropionic acid and 30 g of methanol.
(0.94 mol) and a sulfonic acid type cation exchange resin (Amberlyst 15E, acid exchange capacity of 4 meq / g or more,
1.5 g of Rohm and Haas Co.) was added, and the mixture was heated and refluxed for 3 hours in a nitrogen atmosphere. After filtration and separation of the catalyst,
As the filtrate, 3 containing esterification product water and methanol
-A methyl mercaptopropionate solution was obtained. As a result of calculating the esterification yield using the GC internal standard method, 9
9.1%. Under a nitrogen atmosphere, 28.6 g (0.28 mol) of n-hexylamine was added to the above solution, and then the mixture was stirred at room temperature for 10 hours. Water, methanol, n-
Hexylamine was distilled off under reduced pressure to obtain 17.5 g (yield 98.3%) of 3-mercaptopropionamide. The obtained amide was subjected to high performance liquid chromatography (ODS column;
(Tetrahydrofuran: water: acetic acid = 10: 10: 0.1)
As a result of the analysis, a single peak having a purity of 98.5% was observed.

Example 2 In place of n-hexylamine, n-octylamine 3
Except that 6.5 g (0.28 mol) was used, the same procedure as in Example 1 was carried out to obtain 20 g (yield 97.6%) of 3-mercaptopropionamide. As a result of high performance liquid chromatography analysis, the purity was 98.8%.

Example 3 Instead of 3-mercaptopropionamide, 3,3 ′
Except that 10 g (0.05 mol) of -dithiopropionic acid was used, the same procedure as in Example 2 was carried out to obtain 19.8 g (yield: 96%) of 3,3'-dithiopropionic acid di-n-octylamide. As a result of high performance liquid chromatography analysis, the purity was 9
It was 8.9%.

Comparative Example 1 20 g (0.19 mol) of 3-mercaptopropionic acid and 60 g of methanol (1.88) were placed in the same reactor as in Example 1.
Mol) and 0.5 g of concentrated sulfuric acid as an esterification catalyst, and the mixture was heated under reflux for 6 hours. After cooling, the mixture was neutralized with a sodium carbonate solution, and then extracted with ether. The ether was distilled off, and methyl 3-mercaptopyropionate was obtained at 17.5.
g (77.4% yield). As a result of high performance liquid chromatography analysis, the purity was 98.4%. 20 ml of isopropyl alcohol and 14.2 g of n-hexylamine were added to 17.5 g (0.14 mol) of this methyl propionate.
(0.14 mol), and the mixture was stirred at room temperature for 24 hours under a nitrogen atmosphere. After isopropyl alcohol and n-hexylamine were distilled off under reduced pressure, 15.0 g (yield: 56.6%) of 3-mercaptopropionic acid n-hexylamide was obtained. As a result of high performance liquid chromatography analysis, the purity was 97.
8%.

[0045]

According to the method of the present invention, the desired S-substituted propionic amides can be produced simply, efficiently and in good yield under industrially advantageous conditions.

Claims (5)

[Claims] 1. General formula (1) X—S—CH ₂ CH ₂ COOH (1) wherein X represents a hydrogen atom or a group S—CH ₂ CH ₂ COOH. And a general formula (2) R ¹ —OH (2) wherein R ¹ represents a linear or branched alkyl group having 1 to 8 carbon atoms. ] With an excess amount of an aliphatic alcohol represented by esterifying in the presence of a sulfonic acid type cation-exchange resin formula (3) Y-S-CH 2 CH 2 COOR 1 (3) [ in the formula, Y is hydrogen atom or a group S-CH ₂ CH ₂ COOR ¹
Represents R ¹ is as described above. ] Represented by
A substituted propionic acid ester is obtained, and without isolating the esterified product, a solution of the general formula (4) R ² —NH—R ³ (4) in a solution of the esterified product in an aliphatic alcohol, wherein R ² , R ³ is the same or different and is a hydrogen atom, a linear or branched alkyl group having 1 to 18 carbon atoms, a cycloalkyl group, a linear or branched alkenyl group having 1 to 18 carbon atoms or an alkynyl group; Is shown. The cycloalkyl group may have an alkyl group having 1 to 4 carbon atoms or a halogen group. Wherein Z is a hydrogen atom or a group represented by the following general formula (5): Z-CH ₂ CH ₂ CONR ² R ³ (5) S-CH ₂ CH ₂ CONR ²
R ³ is shown. R ² and R ³ are as described above. ] The manufacturing method of the S-substituted propionamide represented by these. 2. The method for producing an S-substituted propionamide according to claim 1, wherein the aliphatic alcohol is an aliphatic alcohol having 1 to 4 carbon atoms. 3. The method for producing an S-substituted propionamide according to claim 1, wherein the amount of the aliphatic alcohol to be added is 2 to 50 equivalents relative to 1 equivalent of the S-substituted propionic acid. 4. The S according to claim 1, wherein the amine is an aliphatic primary amine having 1 to 8 carbon atoms.
-A process for producing substituted propionamides. 5. The method for producing an S-substituted propionamide according to claim 1, wherein the amount of the amine is 2 to 50 equivalents relative to 1 equivalent of the S-substituted propionic acid. .