JP2009132639A - Method for producing 3-aminothioacrylamide derivative, and method for producing 5-aminoisothiazole derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To produce a 3-aminothioacrylamide derivative by a simple, safe and industrially advantageous method at a high yield with a low environmental load. <P>SOLUTION: The 3-aminothioacrylamide derivative represented by formula (2) is produced by causing a compound represented by formula (1) to react with sodium hydrosulfide in the presence of magnesium chloride (in the formula, R represents a hydrogen atom, an alkyl group, a cycloalkyl group, an aryl group, or a heterocyclic group; and W represents an electron-attractive group). <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to a method for producing 3-aminothioacrylamide derivatives and 5-aminoisothiazole derivatives useful as synthetic intermediates for photographic additives, sensitizing dyes, dyes, electronic materials and pharmaceuticals.

3-aminothioacrylamide derivatives and 5-aminoisothiazole derivatives are useful compounds as various functional materials and pharmaceutical synthesis intermediates.
As a method for synthesizing 3-amino-2-cyano-3-phenylthioacrylamides, a reaction between α-aminobenzylidenemalononitrile and hydrogen sulfide is known (for example, Non-Patent Document 1). However, when this method is used, an excessive amount of highly toxic hydrogen sulfide is required to complete the reaction. Therefore, a method that does not use hydrogen sulfide has been desired.
As a method for synthesizing 5-amino-3-phenylisothiazole-4-carbonitriles, a reaction between 3-amino-2-cyano-3-phenylthioacrylamide synthesized by the above synthesis method and hydrogen peroxide is used. It is known (for example, Non-Patent Document 1). However, in this synthesis method, an excessive amount of hydrogen sulfide remains in the 3-amino-2-cyano-3-phenylthioacrylamide synthesis system, and severe exothermic heat is generated due to the contact between the remaining hydrogen sulfide and hydrogen peroxide. Since there is a risk, it is necessary to isolate it once, and a simple method has been demanded.
On the other hand, a method for synthesizing benzothioamide using benzonitrile using sodium hydrogen sulfide and magnesium chloride has been reported (see Non-Patent Document 2). However, the substrates shown here are only benzonitriles, and the yield was low in protic solvents.

HETEROCYCLES, Vol. 37, no. 3, p. 1615-1622 (1994) Synthetic Communications, Vol. 35, p. 761-764 (2005)

  The present invention has been made in view of such circumstances, and 3-aminothioacrylamide derivatives and 5-aminoisothiazole useful as synthetic intermediates for photographic additives, sensitizing dyes, dyes, electronic materials, pharmaceuticals and the like. It is an object of the present invention to produce a compound simply and in high yield by a safe and industrially advantageous method with low environmental impact.

  In order to solve the above-mentioned problems, the present inventors have studied variously and in detail the synthesis route, reaction conditions, and the like. As a result, they have found that the above-described problems can be achieved by the following means.

(1) A 3-aminothioacrylamide derivative represented by the following general formula (2), wherein an acrylonitrile derivative represented by the following general formula (1) is reacted with sodium hydrogen sulfide in the presence of magnesium chloride Production method.

(In the general formulas (1) and (2), R represents a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heterocyclic group. And W represents an electron withdrawing group, wherein the general formulas (1) and (2) include geometric isomers of W at the position of the carbon atom substituted by R and —NH ₂ ; R may be W and trans or cis.)
(2) An acrylonitrile derivative represented by the following general formula (1) is reacted with sodium hydrogen sulfide in the presence of magnesium chloride to synthesize a compound represented by the following general formula (2), and then the compound is isolated. Without manufacturing, the manufacturing method of 5-aminoisothiazole represented by following General formula (3) characterized by adding hydrogen peroxide and making it react.

(In the general formulas (1) to (3), R represents a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heterocyclic group. And W represents an electron withdrawing group, wherein the general formulas (1) and (2) include geometric isomers of W at the position of the carbon atom substituted by R and —NH ₂ ; R may be W and trans or cis.)
(3) The production method of (1) or (2), wherein the solvent for the reaction for obtaining the 3-aminothioacrylamide derivative represented by the general formula (2) is an alcohol solvent.
(4) The production method according to (3), wherein the alcohol solvent is methanol, ethanol or isopropanol.
(5) W in said general formula (1)-(3) is a cyano group, The manufacturing method of any one of (1)-(4) characterized by the above-mentioned.

  According to the present invention, 3-aminothioacrylamide derivatives and 5-aminoisothiazole compounds useful as synthetic intermediates for photographic additives, sensitizing dyes, dyes, electronic materials, pharmaceuticals, etc. In a simple and high yield by a particularly advantageous method.

Best Mode for Practicing the Invention

  In the specification of the present invention, the description of the constituent elements described below may be made based on typical embodiments of the present invention, but the present invention is not limited to such embodiments. Absent. In the present specification, a numerical range expressed using “to” means a range including numerical values described before and after “to” as a lower limit value and an upper limit value.

Below, the manufacturing method of this invention is demonstrated in detail.
In the production method of the present invention, the 3-aminothioacrylamide derivative represented by the general formula (2) can be produced industrially without using hydrogen sulfide. In addition, the ability to use an alcoholic solvent is advantageous in the step of taking out the compound obtained or the step of taking out the compound in the subsequent reaction step. In addition, since hydrogen sulfide is not used, oxidation reaction with hydrogen peroxide can be performed consistently, and 5-aminoisothiazole derivatives from acrylonitrile derivatives can be industrially produced in a safe, simple and high yield with little environmental impact. It can be advantageously produced.

First, each compound represented by the general formula (1), (2) or (3) in the present invention will be described in detail.
R represents a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heterocyclic group.
The alkyl group may be a linear alkyl group or a branched alkyl group, and may further have a substituent, preferably an alkyl group having 1 to 30 carbon atoms, and more preferably an alkyl group having 1 to 20 carbon atoms. preferable.
Specifically, methyl group, ethyl group, normal propyl group, isopropyl group, normal butyl group, isobutyl group, sec-butyl group, tert-butyl group, normal pentyl group, normal hexyl group, normal octyl group, 2-ethylhexyl Group, 3,5,5-trimethylhexyl group, dodecyl group, octadecyl group, benzyl group, phenethyl group, 4-chlorobenzyl group, 2,4-dichlorobenzyl group, (4-ethoxyphenyl) methyl group, N, N -A diethylcarbamoylmethyl group, an N, N-dibutylcarbamoylmethyl group, a 1- (N, N-dibutylcarbamoyl) ethyl group, or a 2-methoxyethyloxy group is preferred, and a methyl group, an ethyl group, a normalpropyl group, an isopropyl group Normal butyl group, isobutyl group, sec-butyl group, t rt-Butyl group, normal hexyl group, benzyl group, 4-chlorobenzyl group, 2,4-dichlorobenzyl group, or N, N-dibutylcarbamoylmethyl group are more preferable, methyl group, ethyl group, normal propyl group, isopropyl A group, normal butyl group, isobutyl group, sec-butyl group, tert-butyl group, benzyl group, 4-chlorobenzyl group, or 2,4-dichlorobenzyl group is particularly preferred.

The cycloalkyl group may have a substituent, is preferably a cycloalkyl group having 3 to 30 carbon atoms, and more preferably a cycloalkyl group having 5 to 20 carbon atoms.
Specifically, a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, a cyclopentyl group, and a 2,6-di-tert-butyl-4-methylcyclohexyl group are preferable, and a cyclopentyl group or a cyclohexyl group is more preferable.

The aryl group may be unsubstituted or substituted, and is preferably an aryl group having 6 to 30 carbon atoms, and more preferably an aryl group having 6 to 20 carbon atoms.
Specifically, phenyl group, 2-methylphenyl group, 3-methylphenyl group, 4-methylphenyl group, 4-phenylphenoxy group, 4-chlorophenyl group, 2-methoxyphenyl group, 3-ethoxyphenyl group, 4 -Butoxyphenyl group, 2,4-diethoxyphenyl group, 2,5-dibutoxyphenyl group, 4-phenoxyphenyl group, naphthyl group, 4- (N, N-dibutylcarbamoyl) phenyl group, or 4- (N , N-dibutylsulfamoyl) phenyl group, phenyl group, 2-methylphenyl group, 3-methylphenyl group, 4-methylphenyl group, 4-chlorophenyl group, 2-methoxyphenyl group, 3-ethoxyphenyl group 4-butoxyphenyl group, 4-phenoxyphenyl group, 4- (N, N-dibutylcarbamoyl) phenyl group Or 4- (N, N-dibutylsulfamoyl) phenyl group is more preferable, phenyl group, 2-methylphenyl group, 3-methylphenyl group, 4-methylphenyl group, 4-chlorophenyl group, 2-methoxyphenyl group. , 3-ethoxyphenyl group, or 4-butoxyphenyl group is particularly preferable.

As the heterocyclic group, a heterocyclic ring in the heterocyclic group may be a saturated heterocyclic ring or an unsaturated heterocyclic ring, preferably a 3- to 10-membered heterocyclic ring, and a 4- to 8-membered heterocyclic ring. More preferably, a 5-membered to 7-membered heterocycle is more preferable, and a 5-membered or 6-membered heterocycle is particularly preferable. As the hetero atom constituting the hetero ring itself, an oxygen atom, a nitrogen atom, and a sulfur atom are preferable, and even if they have one kind, they may be the same kind, or may be plural kinds of different kinds. Good.
The heterocyclic ring in the heterocyclic group specifically includes an oxazole ring, thiazole ring, imidazole ring, pyrazole ring, triazole ring, isoxazole ring, furan ring, thiophene ring, pyrrole ring, pyridine ring, pyrimidine ring, or triazine ring. Are preferred, more preferably oxazole ring, thiazole ring, imidazole ring, pyrazole ring, triazole ring, isoxazole ring, furan ring, thiophene ring, pyrimidine ring, or triazine ring, oxazole ring, thiazole ring, imidazole ring, pyrazole ring, triazole A ring, a furan ring, or a thiophene ring is particularly preferable.

  Examples of the substituent that the alkyl group, cycloalkyl group, aryl group and heterocyclic group may have include an alkyl group, a cycloalkyl group, a heterocyclic group, a halogen atom, an alkoxy group, an aryloxy group, and a heterocyclic oxy group. , An alkylthio group, an arylthio group, an amide group, a sulfonamide group, a carbamoyl group, or a sulfamoyl group, and a plurality of these groups may be included.

  R is preferably a hydrogen atom, methyl group, ethyl group, normal propyl group, isopropyl group, normal butyl group, isobutyl group, sec-butyl group, tert-butyl group, benzyl group, 4-chlorobenzyl group, 2, 4-dichlorobenzyl group, phenyl group, 2-methylphenyl group, 3-methylphenyl group, 4-methylphenyl group, 4-chlorophenyl group, 2-methoxyphenyl group, 3-ethoxyphenyl group, 4-butoxyphenyl group, An oxazole ring group, a thiazole ring group, an imidazole ring group, a pyrazole ring group, a triazole ring group, an isoxazole ring group, a furan ring group, or a thiophene ring group, more preferably a methyl group, an ethyl group, an isopropyl group, a tert- Butyl group, phenyl group, 4-methylphenyl group, 4-chlorophenyl group 4-butoxyphenyl group, thiazole ring group, imidazole ring group, pyrazole ring group, triazole ring group, furan ring group, or thiophene ring group, most preferably methyl group, ethyl group, tert-butyl group, phenyl group, 4-chlorophenyl group or 4-butoxyphenyl group.

W represents an electron withdrawing group. An electron-withdrawing group is a substituent having an electron-withdrawing property due to an electronic effect. If the substituent constant σ _p of the Hammett rule, which is a measure of the electron-withdrawing property and electron-donating property of a substituent, is used. , Σ _p value is a substituent of 0 or more. Hammett's rule was established in 1935 by L.L. in order to quantitatively discuss the effect of substituents on the reaction or equilibrium of benzene derivatives. P. A rule of thumb proposed by Hammett, which is widely accepted today. Substituent constants determined by Hammett's rule include σ _p value and σ _m value, and these values can be found in many general books. A. Dean, “Lange's Handbook of Chemistry”, 12th edition, 1979 (Mc Graw-Hill) and “Chemicals” special edition, 122, 96-103, 1979 (Nankodo). In the present embodiment, each substituent is limited or explained by Hammett's substituent constant σ _p, but this is limited only to a substituent having a known value that can be found in the above-mentioned book. Needless to say, it also includes a substituent that would be included in the range when the value was unknown based on the Hammett rule even if the value was unknown.

The substituent constant σ _p value is preferably 0.1 to 1.0, more preferably 0.2 to 1.0, and most preferably 0.3 to 1.0. Examples thereof include a cyano group, a nitro group, a substituted and unsubstituted sulfo group, a sulfamoyl group, a carboxy group, an alkoxycarbonyl group, a carbamoyl group, and a trifluoromethyl group. Preferred substituents for W are a cyano group, a carboxy group, an alkoxycarbonyl group, and a carbamoyl group, more preferably a cyano group, a carboxy group, and an alkoxycarbonyl group, and particularly preferably a cyano group.

  As a combination of R and W, R is preferably a methyl group, W is a cyano group, R is a methyl group, W is a carboxy group, R is a methyl group, W is an alkoxycarboxy group, R is a tert-butyl group, and W is a cyano group R, tert-butyl group, W is carboxy group, R is tert-butyl group, W is alkoxycarboxy group, R is phenyl group, W is cyano group, R is phenyl group, W is carboxy group, R is phenyl W is an alkoxycarboxy group, R is a 4-chlorophenyl group, W is a cyano group, R is a 4-chlorophenyl group, W is a carboxy group, R is a 4-chlorophenyl group, W is an alkoxycarboxy group, and R is a furan ring group W is a cyano group, R is a furan ring group, W is a carboxy group, R is a furan ring group, W is an alkoxycarboxy group, R is a thiophene ring group, W is a cyano group, and R is a thio group A cyclic group, W is a carboxy group, or R is a thiophene ring group and W is an alkoxycarboxy group, more preferably R is a methyl group, W is a cyano group, R is a methyl group, W is a carboxy group, and R is tert-butyl group, W is cyano group, R is tert-butyl group, W is carboxy group, R is phenyl group, W is cyano group, R is phenyl group, W is carboxy group, R is 4-chlorophenyl group, W Is a cyano group, or R is a 4-chlorophenyl group and W is a carboxy group, most preferably R is a methyl group, W is a cyano group, R is a tert-butyl group, W is a cyano group, or R is a phenyl group. W is a cyano group.

In the general formula (1), the bond of R and —NH ₂ is indicated by a wavy line to indicate that the general formula (1) includes a geometric isomer. That is, it is shown that the general formula (1) includes a geometric isomer with W at the position of the carbon atom substituted by R and —NH _2. Specifically, R is a cis position with respect to W. And a compound in which NH ₂ is bonded to the trans position with respect to W (ie, a compound represented by the following general formula (4)), and R is bonded to the trans position with respect to W. In other words, NH ₂ includes a compound bonded to a cis position with respect to W (that is, a compound represented by the following general formula (5)).
In addition, in the said General formula (2), the coupling | bonding represented by a wavy line is the same.

Specific examples of the compound represented by the general formula (1), (2) or (3) are shown below, but the compounds to which the present invention can be applied are not limited thereto.
The phenyl group is represented as C ₆ H ₅ .

  The present invention synthesizes the 3-aminothioacrylamide derivative represented by the general formula (2) without using hydrogen sulfide from the compound represented by the general formula (1). This is a technique for producing a 5-aminoisothiazole derivative represented by the above general formula (3) by consistently oxidizing with hydrogen peroxide without isolating the compound represented by the general formula (2).

The compound represented by the general formula (1) is described in HETEROCYCLES, Vol. 37, no. 3, p. 1615-1622 (1994) and a method analogous thereto.
As an example, α-aminobenzylidene malononitrile can be synthesized by reacting trimethylorthobenzoate with malononitrile and then reacting with ammonia. Those having other substituents can also be synthesized by a similar synthesis method with reference to such a method.

As a solvent for the reaction of the present invention, any solvent may be used as long as the compound represented by the general formula (1) is dissolved and does not affect the reaction. Examples of such solvents include aromatic hydrocarbon solvents such as toluene and xylene, ester solvents such as ethyl acetate and butyl acetate, ketone solvents such as acetone and methyl ethyl ketone, alcohol solvents such as methanol, ethanol, and isopropanol, Ether solvents such as diethyl ether, tetrahydrofuran, methyl-t-butyl ether, dioxane, amide solvents such as dimethylformamide, dimethylacetamide, halogenated hydrocarbon solvents such as chloroform, methylene chloride, dichloroethane, chlorobenzene, sulfolane, dimethyl Sulphoxide, 1-methyl-2-pyrrolidone or water is preferred. Two or more of these solvents can be used in combination. More preferably, ketone solvents such as acetone and methyl ethyl ketone, alcohol solvents such as methanol, ethanol and isopropanol, amide solvents such as dimethylformamide and dimethylacetamide, halogenated hydrocarbon solvents such as chloroform, methylene chloride, dichloroethane and chlorobenzene In addition, sulfolane, dimethyl sulfoxide, 1-methyl-2-pyrrolidone, water and the like.
In particular, alcohol-based solvents such as methanol are most preferable from the viewpoints of handleability, versatility, cost, yield, and low environmental burden, and methanol, ethanol, and isopropanol are particularly preferable. In addition, the ability to use an alcoholic solvent is advantageous in the step of taking out the compound obtained or the step of taking out the compound in the subsequent reaction step.

  The amount of the solvent is preferably 0.1 to 100 times (mass), more preferably 1 to 50 times (mass), and more preferably 3 to 8 times (mass) with respect to the compound represented by the general formula (1). Particularly preferred.

The ratio of reacting the compound represented by the general formula (1) and sodium hydrogen sulfide is 0.8 to 3 (number of moles of sodium hydrogen sulfide / number of moles of the compound represented by the general formula (1)). 0.0 is preferable, 0.9 to 2.0 is more preferable, and 1.0 to 1.3 is most preferable. Further, it may be dividedly added so that the above ratio is finally obtained even if the whole amount is not mixed from the beginning of the reaction.
In the production method of the present invention, an SH anion is used which is completely dissociated and has a very high nucleophilicity compared to hydrogen sulfide in the presence of triethylamine or ammonia. The SH anion having extremely high nucleophilicity selectively attacks the cyano group even in the compound represented by the general formula (1) having many reaction sites. As a result, the compound represented by the general formula (2) Presumed to have been obtained.

  The ratio of the compound represented by the general formula (1) and magnesium chloride is such that (number of moles of magnesium chloride / number of moles of the compound represented by the general formula (1)) is 0.8 to 3.0. Is more preferable, 0.9 to 2.0 is more preferable, and 1.0 to 1.3 is most preferable. Further, it may be dividedly added so that the above ratio is finally obtained even if the whole amount is not mixed from the beginning of the reaction.

  Although any temperature may be sufficient as reaction temperature, 0 to 125 degreeC is preferable. More preferably, it is 10 degreeC-70 degreeC, More preferably, it is 20 degreeC-50 degreeC.

  While the reaction time depends on the reaction temperature, it is preferably 5 minutes to 24 hours, more preferably 30 minutes to 12 hours, and most preferably 1 hour to 7 hours.

  Subsequently, the compound represented by the general formula (1) is reacted with sodium hydrogen sulfide and magnesium chloride to synthesize the compound represented by the general formula (2), and then the compound is isolated. The reaction conditions for synthesizing the 5-aminoisothiazole compound represented by the general formula (3), characterized in that hydrogen peroxide is added and reacted, will be described in detail.

The compound represented by the general formula (1) is reacted with sodium hydrogen sulfide and magnesium chloride to synthesize the compound represented by the general formula (2). The ratio of sodium hydrogen sulfide to the compound represented by the general formula (1), the ratio of magnesium chloride to the compound represented by the general formula (1), the solvent type, the amount of solvent, the reaction time, and the reaction temperature are the above general formula. This is the same as the formation of the compound represented by (2). Furthermore, the 5-aminoisothiazole compound represented by the general formula (3) is synthesized by adding hydrogen peroxide and reacting without isolating the compound.
At this time, even if the 3-aminothioacrylamide derivative represented by the general formula (2) is a trans isomer, the cyclization reaction proceeds by adding hydrogen peroxide to the reaction. Without being bound by any theory, the olefin moiety in the general formula (2) can be rotated by resonance in the solution even in the trans form in which the distance between the —NH ₂ group and the S atom is long. The reaction proceeds because there is.

  The ratio of the compound represented by the general formula (1) and hydrogen peroxide is such that (number of moles of hydrogen peroxide / number of moles of the compound represented by the general formula (1)) is 0.8-3. Is preferably 0.0, more preferably 1.0 to 2.3, and most preferably 1.2 to 1.8. Further, it may be dividedly added so that the above ratio is finally obtained even if the whole amount is not mixed from the beginning of the reaction.

  Although any temperature may be sufficient as reaction temperature, 0 to 125 degreeC is preferable. More preferably, it is 20 degreeC-70 degreeC, Most preferably, it is 30 degreeC-60 degreeC.

  Although the reaction time depends on the reaction temperature, it is preferably 1 minute to 10 hours, more preferably 10 minutes to 5 hours, and most preferably 10 minutes to 2 hours.

  In the production method of the present invention, an additive having an effect of promoting the reaction and an effect of improving the stability of raw materials and products may be used in the reaction system.

  The term “without isolation” means that the obtained compound is not taken out, and the reaction solution after the reaction may be transferred to another reaction kettle, but preferably manufactured in the same reaction kettle. Is preferred. In addition, separation extraction may be performed in a reaction kettle in which the reaction solution has been reacted, but it is preferable to carry out the next step reaction without separation extraction.

  The 5-aminoisothiazole derivative represented by the general formula (3) of the present invention is useful as a synthetic intermediate for photographic additives, sensitizing dyes, dyes, electronic materials, pharmaceuticals, and the like. Synthetic intermediates of azo dyes described in JP-A No. 1081, JP-A-9-292684, JP-A-7-2604, JP 2000-502046, JP 2000-503307, JP 2000-515135. No. 2001, Japanese Patent Publication No. 2001-508051 and Japanese Patent Publication No. 2001-514175.

  The features of the present invention will be described more specifically with reference to examples and comparative examples. The materials, amounts used, ratios, processing details, processing procedures, and the like shown in the following examples can be changed as appropriate without departing from the spirit of the present invention. Therefore, the scope of the present invention should not be construed as being limited by the specific examples shown below.

Example 1
280 g (2.61 mol) of aminoethylidenemalononitrile and 560 g (2.75 mol) of magnesium chloride hexahydrate were dispersed in 1680 mL of methanol, and the internal temperature was raised to 45 ° C. A solution prepared by dissolving 252 g (3.14 mol) of 70% sodium hydrogen sulfide in 500 mL of water was added dropwise over 15 minutes, and then stirred at an internal temperature of 45 ° C. for 5 hours to obtain a reaction mixture A. Thereafter, the reaction mixture A was extracted with ethyl acetate, concentrated and isolated to obtain 358 g (2.54 mol) of white crystals of 3-amino-2-cyano-3-methylthioacrylamide in a yield of 97%. .

¹ H-NMR (DMSO-d ₆ ) δ: 8.98 (s, 1H), 8.51 (s, 1H), 7.68 (s, 1H), 6.80 (s, 1H), 2. 21 (s, 3H)

(Example 2)
The reaction mixture A was obtained by the same procedure as in Example 1. Next, without isolating 3-amino-2-cyano-3-methylthioacrylamide, 448 mL of 30% hydrogen peroxide solution is carefully added to the reaction mixture A so that the internal temperature is within the range of 45 ° C to 55 ° C. The solution was added dropwise over about 1 hour, and then stirred at 45 ° C. for 1 hour. The reaction solution was cooled to 10 ° C., 280 mL of concentrated hydrochloric acid was added dropwise at an internal temperature of 20 ° C. or less, and the mixture was stirred at room temperature for 30 minutes, and then the reaction solution was cooled to 5 ° C. The precipitated crystals were collected by filtration, washed with cold water and dried to obtain 345 g (2.47 mol) of white crystals of 5-amino-3-methylisothiazole-4-carbonitrile in a yield of 94%. It was.

¹ H-NMR (DMSO-d ₆ ) δ: 7.98 (s, 2H), 2.23 (s, 3H)

(Example 3)
Aminobenzylidenemalononitrile 6.77 g (0.04 mol) and magnesium chloride hexahydrate 8.95 g (0.044 mol) were dispersed in 30 mL of methanol, and the internal temperature was raised to 45 ° C. A solution prepared by dissolving 3.36 g (0.06 mol) of 70% sodium hydrogen sulfide in 20 mL of water was dropped, and the mixture was stirred at an internal temperature of 45 ° C. for 6 hours to obtain a reaction mixture B. Thereafter, the reaction mixture B was extracted with ethyl acetate, concentrated and isolated to obtain 7.92 g (0.039 mol) of white crystals of 3-amino-2-cyano-3-phenylthioacrylamide as a 98% yield. I got it.

¹ H-NMR (DMSO-d ₆ ) δ: 9.13 (s, 1H), 8.84 (s, 1H), 7.93 (s, 1H), 7.55 (m, 5H), 6. 95 (s, 1H)

Example 4
The reaction mixture B was obtained by the same procedure as in Example 3. Next, without isolating 3-amino-2-cyano-3-phenylthioacrylamide, 7 mL of 30% aqueous hydrogen peroxide is carefully added to the reaction mixture B so that the internal temperature falls within the range of 45 ° C to 55 ° C. Over about 10 minutes, and then stirred at 45 ° C. for 1 hour. The reaction solution was cooled to 10 ° C., 5 mL of concentrated hydrochloric acid was added dropwise at an internal temperature of 20 ° C. or less, and the mixture was stirred at room temperature for 30 minutes, and then the reaction solution was cooled to 5 ° C. Precipitated crystals were collected by filtration, washed with cold water, and dried to obtain 8.05 g (0.037 mol) of 5-amino-3-phenylisothiazole-4-carbonitrile in a yield of 93%. .

¹ H-NMR (DMSO-d ₆ ) δ: 8.15 (s, 2H), 7.80-7.85 (m, 2H), 7.47-7.51 (m, 3H)

(Comparative Example 1)
HETEROCYCLES, Vol. 37, no. 3, p. According to the method described in 1615-1622 (1994), 5-amino-3-phenylisothiazole-4-carbonitrile was synthesized as follows.
Aminobenzylidene malononitrile (5.07 g, 0.03 mol) and triethylamine (3.03 g, 0.03 mol) were dispersed in ethanol (500 mL), and the internal temperature was raised to 60 ° C. Hydrogen sulfide gas was blown in, and the mixture was stirred for 3 hours while maintaining the internal temperature at 60 ° C. Thereafter, concentration and isolation yielded 5.80 g of 3-amino-2-cyano-3-phenylthioacrylamide in a yield of 95%.
6.10 g (0.03 mol) of 3-amino-2-cyano-3-phenylthioacrylamide obtained was dispersed in 250 mL of methanol, 6.0 mL of 30% aqueous hydrogen peroxide was slowly added dropwise, and the mixture was stirred overnight. Thereafter, the reaction solution was filtered and concentrated to obtain 5.40 g, 90% yield of 5-amino-3-phenylisothiazole-4-carbonitrile. The yield of all steps from aminobenzylidene malononitrile was 86%.

  When synthesizing 3-amino-2-cyano-3-phenylthioacrylamide in Comparative Example 1, the reaction product containing 3-amino-2-cyano-3-phenylthioacrylamide was cooled to room temperature and allowed to stand for a while. However, the reaction solution had an irritating odor of hydrogen sulfide, and hydrogen sulfide gas was mixed in the reaction solution. For this reason, nitrogen gas was introduced (bubbled) into the reaction solution to try to remove the hydrogen sulfide gas, but the hydrogen sulfide gas could not be completely removed. Since hydrogen sulfide and hydrogen peroxide undergo a violent exothermic reaction due to contact, hydrogen sulfide gas must be removed for safety reasons. Therefore, as described above, 3-amino-2-cyano-3-phenylthioacrylamide was isolated and used for the next step after removing hydrogen sulfide.

From the above, in the production method of the present invention, the 3-aminothioacrylamide derivative represented by the general formula (2) can be produced from the acrylonitrile derivative represented by the general formula (1) without using hydrogen sulfide, In addition, since hydrogen sulfide was not used, the oxidation reaction with hydrogen peroxide could be performed consistently. Therefore, according to the production method of the present invention, the 5-aminoisothiazole derivative represented by the general formula (3) is industrially produced simply and in high yield from the acrylonitrile derivative represented by the general formula (1). It can be advantageously produced. Furthermore, since no hydrogen sulfide is used, there is no concern about the residual hydrogen sulfide concentration in the subsequent reaction with hydrogen peroxide, which is preferable from the viewpoint of safety.
Further, from Examples 1 and 3, according to the production method of the present invention, even when an alcoholic solvent such as methanol, that is, a protic solvent is used, the general formula (1) to the general formula (2) are used. It was possible to produce a 3-aminothioacrylamide derivative represented by

Claims (5)

A method for producing a 3-aminothioacrylamide derivative represented by the following general formula (2), wherein an acrylonitrile derivative represented by the following general formula (1) is reacted with sodium hydrogen sulfide in the presence of magnesium chloride.

(In the general formulas (1) and (2), R represents a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heterocyclic group. And W represents an electron withdrawing group, wherein the general formulas (1) and (2) include geometric isomers of W at the position of the carbon atom substituted by R and —NH ₂ ; R may be W and trans or cis.) Without reacting an acrylonitrile derivative represented by the following general formula (1) with sodium hydrogen sulfide in the presence of magnesium chloride to synthesize a compound represented by the following general formula (2), the compound is not isolated. Then, a method for producing 5-aminoisothiazole represented by the following general formula (3), wherein hydrogen peroxide is added and reacted.

(In the general formulas (1) to (3), R represents a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heterocyclic group. And W represents an electron withdrawing group, wherein the general formulas (1) and (2) include geometric isomers of W at the position of the carbon atom substituted by R and —NH ₂ ; R may be W and trans or cis.)   The method according to claim 1 or 2, wherein the solvent for the reaction for obtaining the 3-aminothioacrylamide derivative represented by the general formula (2) is an alcohol solvent.   The production method according to claim 3, wherein the alcohol solvent is methanol, ethanol, or isopropanol.   W in the said General formula (1)-(3) is a cyano group, The manufacturing method of any one of Claims 1-4 characterized by the above-mentioned.