JPH1087605A - Production of isothiocyanate compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To safely produce the subject compound useful as a synthetic raw material for pharmaceuticals, agrochemicals and chemicals or an antibacterial agent or antifungal agent in high yield by reacting a specific clithiocarbamic acid or its salt with an acid anhydride. SOLUTION: The objective isothiocyanate compound of the formula R1 -NCS is produced by reacting a dithiocarbamic acid of the formula I (R1 is a chain paraffin group, olefin group, an alkyne group, a cycloolefin group, etc.; M is H, an alkali metal or ammonium) or its salt with an acid anhydride. The other objective cliisothiocyanate compound of the formula SCN-R2 -NCS is produced by reacting a compound of the formula II (R2 is a chain paraffin group, an olefin group, an alkyne group, etc.; M1 and M2 are each H, an alkali metal or ammonia). This process gives e.g. n-butyl isothiocyanate from dithiocarbamated n-butylamine or 1,6-hexamethylene diisothiocyanate from clithiocarbamated 1,6-hexamethylenediamine.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for producing an isothiocyanate compound.

[0002]

2. Description of the Related Art Various methods for producing compounds having an isothiocyanate group are known. For example, (1) Reaction of thiocyanic acid with olefin, epoxy compound, halide (Chem. Pharm. Bull. (Tokyo), 8,486 (1960), Che.
m. Pharm. Bull., 17, 2110 (1969), U.S. Pat. No. 3,111,536), (2) Reaction with dithiocarbamate and chloroformate (Org. Synth., III, 599 (1955), J. Org) .
Chem., 29, 3093 (1964)), (3) Reaction of amino compound with thiophosgene (US Pat. No. 2,824,887, GB 999,221)
Is known.

[0003]

However, in the above (1), it is not easy to control the production of the isomer thiocyanic acid, and in the above (2), chloroformate is relatively expensive. Toxic carbonyl sulfide is formed in the reaction. Furthermore, when chloroformate is used,
Since hydrochloric acid is generated as a by-product in the reaction solution and generates heat, it is necessary to control the reaction. Furthermore, the hydrochloric acid tends to react to produce additional by-products. In addition, (3) has a problem that expensive and toxic thiophosgene is used. Furthermore, (1)-
All of (3) have a problem that the yield is not satisfactory.

[0004] Therefore, an object of the present invention is to produce an isothiocyanate compound safely and with high yield.

[0005]

In order to solve the above-mentioned problems, in the present invention, a compound represented by the chemical formula [2] R ₁ -NCS [2] (where R ₁ is a linear paraffin, olefin, alkyne, cyclo Represents a paraffin, a cycloolefin, a cycloalkyne, an aromatic ring, a hetero compound, a secondary or tertiary amino compound, a substituted product thereof, or a hydroxyl group-containing group represented by HO—R ₃ —, wherein R ₃ is , A chain paraffin, olefin, alkyne, cycloparaffin, cycloolefin, cycloalkyne, aromatic ring, hetero compound, secondary or tertiary amino compound, or a substituted product thereof). The chemical formula [1]

[0006]

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(Wherein R ₁ represents R in the chemical formula [1]
_Same as ₁ , M represents a hydrogen atom, an alkali metal atom,
Represents unsubstituted or substituted ammonium. ) Is reacted with an acid anhydride.

Further, as a method for producing a diisothiocyanate compound represented by the chemical formula [4] SCN-R ₂ -NCS [4], formula [3]

[0009]

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(Wherein R ₂ is a chain paraffin, olefin, alkyne, cycloparaffin, cycloolefin, cycloalkyne, aromatic ring, hetero compound, secondary or tertiary amino compound, or a substituted product thereof, or following

[0011]

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Represents a hydroxyl group-containing group represented by R above
₄ represents a linear paraffin, olefin, alkyne, cycloparaffin, cycloolefin, cycloalkyne, aromatic ring, hetero compound, secondary or tertiary amino compound, or a substituted product thereof. M ₁ and M ₂ each represent a hydrogen atom, an alkali metal atom, or unsubstituted or substituted ammonium. ) Was found to react the didithiocarbamic acid or a salt thereof with an acid anhydride.

In the above reaction, since dithiocarbamic acid or a salt thereof is supplied to the reaction with the acid anhydride, it can be safely used without using toxic substances such as thiophosgene and generating toxic gas such as carbonyl sulfide. An isothiocyanate compound can be produced, and the yield can be improved. Further, since the reaction with an acid anhydride is milder than the case where a chloroformate is used, the reaction can be easily controlled.

These compounds can be used as raw materials for synthesizing medical and agricultural chemicals and chemicals, and have an antibacterial action and an antifungal action.

[0015]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described in more detail.

The dithiocarbamic acid or a salt thereof used in the production method according to the present invention is generally represented by the formula [1].

[0017]

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In the chemical formula [1], R ₁ is a chain paraffin, olefin, alkyne, cycloparaffin, cycloolefin, cycloalkyne, aromatic ring, hetero compound, secondary or tertiary amino compound, or a substitution thereof. body, or, HO-R ₃ - represents a a hydroxyl-containing group represented. R ₃ represents a chain paraffin, olefin, alkyne, cycloparaffin, cycloolefin, cycloalkyne, aromatic ring, hetero compound, secondary or tertiary amino compound, or a substituted product thereof. M represents a hydrogen atom, an alkali metal atom such as Na or K, or an unsubstituted or substituted ammonium.

The above dithiocarbamic acid or a salt thereof is
It can be obtained in any way. As an example, there is a method of dithiocarbamate-forming an amino compound.
As a raw material for the dithiocarbamate reaction, an amino compound represented by the chemical formula [5] is generally used.

[0020] R ₁ -NH ₂ (5) wherein R ₁ is the same as R ₁ in Formula (1). Specific examples of the amino compound represented by the above chemical formula [5] having R ₁ include n-propylamine, isopropylamine, n-butylamine, s-butylamine, t-butylamine, isobutylamine, and n-propylamine.
Amylamine, t-amylamine, 1,2-dimethylpropylamine, 1-ethylpropylamine, isoamylamine, 1-methylbutylamine, 2-methylbutylamine, diisopropylamine, 1,3-dimethylbutylamine, 3,3-dimethylbutylamine, n-hexylamine, 2-heptylamine, 3-heptylamine, n
Heptylamine, 1,5-dimethylhexylamine,
2-ethylhexylamine, 1-methylheptylamine, n-octylamine, t-octylamine, n-nonylamine, n-decylamine, allylamine, propargylamine, 1,1-dimethylpropargylamine,
(Aminomethyl) cyclopropane, cyclobutylamine, cyclopentylamine, cyclohexylamine, cycloheptylamine, cyclohexanemethylamine, 2
-Methylcyclohexylamine, 4-methylcyclohexylamine, 1-cyclohexylethylamine, cyclooctylamine, 2,3-dimethylcyclohexylamine, 2- (1-cyclohexyl) ethylamine, allylcyclohexylamine, 3-methoxypropylamine,
3-ethoxypropylamine, aniline, o-toluidine, m-toluidine, p-toluidine, ethylaniline, o-anisidine, m-anisidine, p-anisidine, o-phenetidine, m-phenetidine, p-phenetidine, 2- ( (Aminomethyl) -1-ethylpyrrolidine, 2- (aminoethyl) -1-methylpyrrolidine, 3
-(Aminomethyl) pyridine, 4- (aminomethyl) pyridine, 2- (2-aminoethyl) -1-methylpyrrole, N, N-dimethylethylenediamine, N, N-dimethyl-1,3-propanediamine, N , N-diethylethylenediamine, N, N-diethyl-1,3-propanediamine, o-chloroaniline, m-chloroaniline,
p-chloroaniline, o-bromoaniline, m-bromoaniline, p-bromoaniline and the like.

Those having a hydroxyl group as a substituent of R ₁ are not particularly limited. Specific examples of the amino compound represented by the above chemical formula [1] having R ₁ include 3-amino-1-propanol, 4-amino-1-butanol, 5-amino-1-pentanol,
-Amino-2,2-dimethylpropanol, 6-amino-1-hexanol, 6-amino-2-methyl-2-heptanol, 4-aminocyclohexanol, tran
s-2-aminocyclohexanol, 3-aminomethyl-3,5,5-trimethylcyclohexanol, 4-
(2-aminoethyl) phenol, 4-aminophenol, 4-aminocresol, 4-aminobenzyl alcohol, 4-aminophenethyl alcohol, 2- (2-aminoethoxy) ethanol, N-aminoethylethanolamine, N- ( 3-aminopropyl) diethanolamine and the like.

As an amino compound to be provided to the dithiocarbamate reaction, a primary amino group is contained in one molecule.
May be a diamino compound. This is represented by the chemical formula [6] H ₂ N—R ₂ —NH ₂ [6]. By using this, it is possible to produce a didithiocarbamic acid or a salt thereof having two dithiocarbamate groups in one molecule. Can be.

R ₂ in the above formula [6] represents a chain paraffin, olefin, alkyne, cycloparaffin, cycloolefin, cycloalkyne, aromatic ring, hetero compound,
A secondary or tertiary amino compound or a substituted product thereof, or
following

[0024]

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Represents a hydroxyl group-containing group represented by R above
₄ represents a linear paraffin, olefin, alkyne, cycloparaffin, cycloolefin, cycloalkyne, aromatic ring, hetero compound, secondary or tertiary amino compound, or a substituted product thereof.

The above R ₂ is not particularly limited. Such specific diamino compound represented by Formula (6) with R _2, trimethylene diamine, tetramethylene diamine, pentamethylene diamine, 2,2-dimethyl-1,3-propanediamine, hexa Methylene diamine, heptamethylene diamine, octamethylene diamine, nonamethylene diamine,
2,2,4-trimethyl-1,6-hexamethylenediamine, 2,4,4-trimethyl-1,6-hexamethylenediamine, decamethylenediamine, 1,3-cyclohexanebis (methylamine), 5-amino −2,2,4
-Trimethyl-1-cyclopentanemethylamine, 5-
Amino-1,3,3-trimethylcyclohexanemethylamine, 1,8-p-menthanediamine, m-xylylenediamine, p-xylylenediamine, ethylene glycol bis (3-aminopropyl) ether, p-phenylenediamine, 4,4′-diaminobiphenyl, 4,
4'-methylene dianiline, diethylene triamine and the like.

Those having a hydroxyl group as a substituent of R ₂ are not particularly limited. Specific examples of the amino compound represented by the above chemical formula [6] having R ₂ include 2,4-diaminophenol, 1,3-diamino-2-hydroxypropane, and 2,4-diamino-6.
-Hydroxypyrimidine and the like.

The dithiocarbamate represented by the above formula [1] or a salt thereof is formed by subjecting the amino compound represented by the above formula [5] to a dithiocarbamate reaction with carbon disulfide in the presence of a base. Is done.

When a dithiocarbamate reaction is carried out using a compound represented by the above chemical formula [6] as an amino compound, didithiocarbamic acid or a salt thereof represented by the following chemical formula [3] can be produced. .

[0030]

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It should be noted, in the chemical formula [3], R ₂ is the same as R ₂ in the chemical formula [6], M ₁ and M ₂ each represent a hydrogen atom, Na, an alkali metal atom of K and the like, unsubstituted or substituted Represents ammonium.

The proportion of the amino compound and carbon disulfide used in the dithiocarbamate reaction is not particularly limited. However, from the viewpoint of reaction efficiency, carbon disulfide is used per equivalent of amino group in the amino compound. Is preferably 1.0 to 10.0 equivalents, and more preferably 1.5 to 5.0 equivalents. If it is less than 1.0 equivalent, free amino groups remain because dithiocarbamic acid is not completely generated. This residual amino group reacts with an acid anhydride in the isothiocyanate-forming reaction according to the present invention to form an amide compound, which causes a decrease in the yield of the isothiocyanate compound. Although addition of carbon disulfide in an amount exceeding 10.0 equivalents does not particularly affect this reaction, it is not preferable in terms of reaction efficiency and volumetric efficiency.

The base used in the above dithiocarbamate reaction includes alkali metal hydroxides, alkali metal alkoxides, secondary, tertiary and quaternary amines, and heterocyclic amines. Sodium hydroxide, potassium hydroxide and tertiary amine as triethylamine. If no base is added,
It is not preferable because the reaction becomes extremely slow.

When the base does not dissolve in the reaction solution, a small amount of water can be used to make them compatible with each other. The amount of water used is not particularly limited, but from the viewpoint of reaction efficiency, an amount may be used in which the base can be in a homogeneous state with the reaction solution.

The amount of the base used depends on the type of the functional group of the amino compound. That is, when the amino compound does not have a functional group that easily reacts with an isothiocyanate group in an isothiocyanate compound as a reaction product to generate a by-product, the amino group 1 in the amino compound The equivalent is preferably used in an amount of 0.2 to 10 equivalents, more preferably 0.6 to 2 equivalents. If the equivalent is less than 0.2 equivalent, the progress of the reaction is slowed, and if it is added in excess of 10 equivalent, the reaction is not affected, but it is not preferable in terms of reaction efficiency and volumetric efficiency.

The isothiocyanate compound R ₁ -NCS (2) (In the formula represented by the following chemical formula produced by the process of the present invention [2], R ₁ is the same as R ₁ in Formula (1). ) Can be produced by adding an acid anhydride to the dithiocarbamic acid represented by the above chemical formula [1] or a salt thereof to prepare a mixed anhydride intermediate, and decomposing the mixture.

The acid anhydride used in this reaction is a compound condensed by losing one molecule of water from two acidic functional groups, for example, a compound obtained by condensing two carboxyl groups,
Compounds in which two sulfonyl groups are condensed, compounds in which one carboxyl group and one sulfonyl group are condensed, and the like can be given.

The reaction formula of the isothiocyanate-forming reaction for producing the isothiocyanate compound represented by the chemical formula [2] can be represented by, for example, the following reaction formula [7]. In this case, a compound in which two carboxyl groups were condensed was used as an acid anhydride, and a base was used for decomposing an intermediate.

[0039]

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[0040] Here, in reaction formula (7), R _1, M is the same as R _1, M in the chemical formula (1), Y _1, Y
₂ represents a linear paraffin, olefin, alkyne, cycloparaffin, cycloolefin, cycloalkyne, aromatic ring or a substituted product thereof, and M ₃ ⁺ represents an alkali metal ion.

In the reaction formula [7], when a compound in which two sulfonyl groups are condensed is used as the acid anhydride, any of the two carbonyl groups of the acid anhydride in the reaction formula [7] may be substituted with a sulfonyl group. Suffice, 1 as acid anhydride
When a compound in which one carboxyl group and one sulfonyl group are condensed is used, one carbonyl group of the acid anhydride in [7] may be a sulfonyl group. In addition, a base is generally used to decompose the intermediate. In this case, for example, a base represented by M ₃ OH in the reaction formula [7] can be mentioned.

When dithiocarbamic acid or a salt thereof isolated for the isothiocyanate formation reaction is used, it is preferable to add carbon disulfide in order to prevent a side reaction of amino compound formation. When the above amino compound is subjected to a dithiocarbamate reaction to obtain dithiocarbamic acid or a salt thereof, the reaction solution can be directly supplied to the isothiocyanate reaction without isolation. In this case, the loss to isolate,
Time can be saved and efficiency can be increased.

When didithiocarbamic acid represented by the chemical formula [3] or a salt thereof is used, each dithiocarbamino group is converted into a diisocarbamic acid represented by the following chemical formula [4] through the same chemical reaction formula. A thiocyanate compound can be produced.

The SCN-R ₂ -NCS [4] In the formula, R ₂ is the same as R ₂ in the chemical formula [3].

Examples of the acid anhydride used in the above isothiocyanation reaction include acetic anhydride, propionic anhydride, butyric anhydride, benzoic anhydride, succinic anhydride, and maleic anhydride, such as those obtained by condensing two carboxyl groups. Acid, glutaric anhydride, isobutyric anhydride, itaconic anhydride,
Examples thereof include citraconic anhydride, phthalic anhydride and the like. Examples of the condensation of two sulfonyl groups include benzenesulfonic anhydride and the like.
Examples of the condensed product of one carboxyl group and one sulfonyl group include o-sulfobenzoic anhydride.

The amount of the acid anhydride to be used is 1 to 1 equivalent of dithiocarbamic acid or its salt donated to the reaction.
It is 0 to 10.0 times equivalent, preferably 1.1 to 2.0 times equivalent. Addition exceeding 10.0 equivalents does not particularly affect the yield, but is not preferred in terms of reaction efficiency.

In the above isothiocyanation reaction,
When dithiocarbamic acid or a salt thereof is reacted with an acid anhydride, an intermediate represented by the above reaction formula [7] is produced. In order to generate an isothiocyanate compound by decomposing this intermediate, the intermediate is decomposed by using a base or subjected to thermal decomposition as shown in Reaction formula [7].

When a base is used in this reaction,
Examples thereof include alkali metal hydroxides, alkali metal alkoxides, secondary, tertiary and quaternary amines, and heterocyclic amines. Preferably, the alkali metal hydroxide is sodium hydroxide, potassium hydroxide, or tertiary amine. As triethylamine. In the case where dithiocarbamic acid or a salt thereof is supplied to the reaction using the reaction solution obtained in the above dithiocarbamate reaction or the like, if the reaction solution already has a base, the base is left as it is. It can be used for this reaction.

When the above base is not dissolved in the reaction solution of this reaction, a small amount of water may be added to make the two compatible. The amount of water to be added is not particularly limited. However, from the viewpoint of reaction efficiency, it is preferable to use an amount in which the base can be in a homogeneous state with the reaction solution.

The amount of the base used is based on 1 equivalent of the dithiocarbamate group in dithiocarbamic acid or a salt thereof.
0.5 to 10 equivalents are preferred, and 1 to 2 equivalents are preferred.
If the amount of the catalyst is less than 0.5 equivalent, side reactions easily occur,
Excess base is not preferred because it catalyzes the amidation reaction generated from isothiocyanate and free acid. In the case where dithiocarbamic acid or a salt thereof is supplied to the reaction using the reaction solution obtained in the above dithiocarbamate reaction or the like as it is, if the reaction solution already has a base, the above-mentioned base is added. What is necessary is just to add the amount which subtracted the already added amount from the amount.

The reaction solvent used in the above-mentioned isothiocyanate-forming reaction may be any solvent that does not solidify dithiocarbamic acid or a salt thereof, that is, a solvent that converts dithiocarbamic acid or a salt thereof into a dissolved state or a slurry state. As such a solvent, for example, water, ethers such as tetrahydrofuran and dioxane, ketones such as acetone, alcohols such as methanol and ethanol, 2-propanol, acetonitrile and dimethylformamide, and aprotic polar solvents such as dimethyl sulfoxide; Examples include a basic solvent such as pyridine or a mixed solvent of water and the above-mentioned water-soluble organic solvent. Also,
When triethylamine or the like is used as the base, a hydrophobic organic solvent such as chloroform, dichloromethane, hexane, or benzene can be used in addition to the above solvents.

Since this reaction proceeds even at a low temperature, there is no need to limit the reaction temperature.
It is preferable to carry out the reaction at -40 ° C. If the temperature deviates from this range, a heating device and a cooling device are required, which is not preferable in terms of energy efficiency.

Since the reaction itself proceeds very quickly, the reaction time is sufficient within 3 hours after the addition of the acid anhydride, and preferably 1 to 30 minutes. If the reaction is carried out for more than 3 hours, the free acid as a reactant reacts with the isothiocyanate compound, resulting in a decrease in yield.

The isothiosinate compound in the reaction solution thus produced can be recovered by a general method. For example, after the reaction solution is extracted with n-hexane or the like, it can be recovered by washing with an acid and distilling off the solvent. When purification is necessary, purification can be performed by distillation, recrystallization, and column chromatography.

At the time of the above-mentioned recovery, freeing can be achieved by washing with an alkali such as an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, or an aqueous sodium hydrogen carbonate solution after washing with an acid, or washing with the above alkali before washing with an acid. By-products such as acids can be removed.

In the case where a base is used in the above reaction formula [7], the intermediate is similarly decomposed by the above-mentioned alkali used for washing, so that the amount of the base used in the above reaction formula [7] can be reduced. it can.

[0057]

【Example】

Example 1 Synthesis of n-butyl isothiocyanate n-butylamine 20 mmol, triethylamine 20
100 mmol of carbon disulfide was added to a solution of 50 mmol of tetrahydrofuran and stirred under stirring for 1 hour to convert n-butylamine into dithiocarbamate. Next, 22 mmol of acetic anhydride and triethylamine 2 were added to the reaction solution.
0 mmol was added and the mixture was stirred for 10 minutes. The solution was extracted with n-hexane and washed with 1N-sulfuric acid and 1N-potassium hydroxide. After anhydrous magnesium sulfate was added to the n-hexane phase for dehydration, the magnesium sulfate was removed and distilled off under reduced pressure to obtain 2.07 g of n-butyl isothiocyanate (yield 90%).

Example 2 Synthesis of 3-methoxypropyl isothiocyanate 250 mmol of carbon disulfide was added to a solution of 50 mmol of 3-methoxypropylamine, 50 mmol of triethylamine and 125 ml of tetrahydrofuran, followed by stirring for 10 minutes. Carbamate. Next, 55 mmol of acetic anhydride and 50 mmol of triethylamine were added and stirred for 10 minutes. The solution was extracted with n-hexane and washed with 1N-sulfuric acid and 1N-potassium hydroxide. After anhydrous magnesium sulfate was added to the n-hexane phase for dehydration, magnesium sulfate was removed and the mixture was distilled off under reduced pressure to obtain 5.90 g (yield: 90%) of 3-methoxypropyl isothiocyanate.

Example 3 Synthesis of 3-diethylaminopropylisothiocyanate N, N-diethyl-1,3-propanediamine 20 mm
ol, triethylamine 20 mmol, tetrahydrofuran / water = 7/3 mixed solvent 50 ml
0 mmol was added and stirred for 1 hour, and N, N-diethyl-
1,3-propanediamine was dithiocarbamate. Next, 22 mmol of acetic anhydride and 20 mmol of triethylamine were added and stirred for 10 minutes. The solution is n
After extraction with -hexane, the extract was washed with 1N-potassium hydroxide. After anhydrous magnesium sulfate was added to the n-hexane phase for dehydration, magnesium sulfate was removed and distilled off under reduced pressure to obtain 3.06 g (89% yield) of 3-diethylaminopropylisothiocyanate.

Example 4 Synthesis of 1,6-hexamethylenediisothiocyanate 20 mmol of 1,6-hexamethylenediamine, 40 mmol of triethylamine, tetrahydrofuran / water = 7
120 mmol of carbon disulfide in 50 ml of a 3/3 mixed solvent
Was added and stirred for 1 hour to dithiocarbamate 1,6-hexamethylenediamine. Then, acetic anhydride 44m
mol and 40 mmol of triethylamine were added and stirred for 10 minutes. After extracting the solution with n-hexane, 1
Washed with N-sulfuric acid and 1N-potassium hydroxide. After anhydrous magnesium sulfate was added to the n-hexane phase for dehydration, magnesium sulfate was removed and distilled off under reduced pressure to give 3.76 of 1,6-hexamethylenediisothiocyanate.
g (94% yield).

Example 5 Synthesis of phenylisothiocyanate 20 mmol of aniline, 20 mmol of triethylamine
l, 100 mmol of carbon disulfide was added to 50 ml of distilled water, and the mixture was stirred for 5 hours to convert aniline into dithiocarbamate. Next, 40 mmol of acetic anhydride and 20 mmol of triethylamine were added and stirred for 10 minutes. The solution is n
After extraction with -hexane, the extract was washed with 1N-sulfuric acid and 1N-potassium hydroxide. After anhydrous magnesium sulfate was added to the n-hexane phase for dehydration, the magnesium sulfate was removed and distilled off under reduced pressure to obtain 2.48 g of phenylisothiocyanate (yield: 92%).

Example 6 Synthesis of p-methoxyphenyl isothiocyanate 20 mmol of p-anisidine, 20 m of triethylamine
mol, distilled water 50ml, carbon disulfide 100mmol
Was added and stirred for 1 hour to convert p-anisidine into dithiocarbamate. Next, 40 mmol of acetic anhydride and 20 mmol of triethylamine were added and stirred for 10 minutes. After extracting the solution with n-hexane, 1N-sulfuric acid and 1N-
Washed with potassium hydroxide. After anhydrous magnesium sulfate was added to the n-hexane phase for dehydration, magnesium sulfate was removed and distilled off under reduced pressure to obtain 3.07 g (yield: 93%) of p-methoxyphenylisothiocyanate.

Example 7 Synthesis of o-methoxyphenylisothiocyanate 20 mmol of o-anisidine, 20 m of triethylamine
mol, distilled water 50ml, carbon disulfide 100mmol
Was added and stirred for 1 hour to convert o-anisidine to dithiocarbamate. Next, 40 mmol of acetic anhydride and 20 mmol of triethylamine were added and stirred for 10 minutes. After extracting the solution with n-hexane, 1N-sulfuric acid and 1N-
Washed with potassium hydroxide. After anhydrous magnesium sulfate was added to the n-hexane phase for dehydration, the magnesium sulfate was removed and distilled off under reduced pressure to obtain 2.64 g (yield: 80%) of o-methoxyphenylisothiocyanate.

Example 8 Synthesis of m-methoxyphenyl isothiocyanate 20 mmol of m-anisidine, 20 m of triethylamine
mol, distilled water 50ml, carbon disulfide 100mmol
Was added and stirred for 1 hour to convert m-anisidine into dithiocarbamate. Next, 40 mmol of acetic anhydride and 20 mmol of triethylamine were added and stirred for 10 minutes. After extracting the solution with n-hexane, 1N-sulfuric acid and 1N-
Washed with potassium hydroxide. After anhydrous magnesium sulfate was added to the n-hexane phase for dehydration, magnesium sulfate was removed and distilled off under reduced pressure to obtain 2.44 g (yield 74%) of m-methoxyphenylisothiocyanate.

Example 9 Synthesis of p-chlorophenylisothiocyanate 20 mmol of p-chloroaniline, triethylamine 2
0 mmol, distilled water 50 ml, carbon disulfide 100 mm
ol was added and stirred for 1 hour to convert p-chloroaniline into dithiocarbamate. Next, 40 mmol of acetic anhydride and 20 mmol of triethylamine were added and stirred for 10 minutes. The solution was extracted with n-hexane and washed with 1N-sulfuric acid and 1N-potassium hydroxide. After anhydrous magnesium sulfate was added to the n-hexane phase for dehydration, magnesium sulfate was removed and distilled under reduced pressure to obtain 2.68 g of p-chlorophenylisothiocyanate (yield 79).
%).

Example 10 Synthesis of o-chlorophenylisothiocyanate 50 mmol of o-chloroaniline and 5 of triethylamine
0 mmol, distilled water 125 ml, carbon disulfide 150m
mol was added and the mixture was stirred for 65 hours to convert o-chloroaniline into dithiocarbamate. Then, acetic anhydride 55mmo
l and 50 mmol of triethylamine were added and stirred for 10 minutes. After extracting the solution with n-hexane, 1N-
Washed with sulfuric acid and 1N-potassium hydroxide. After anhydrous magnesium sulfate was added to the n-hexane phase for dehydration, the magnesium sulfate was removed and distilled off under reduced pressure.
5.59 g of chlorophenylisothiocyanate (yield 6
6%).

Example 11 Synthesis of m-chlorophenylisothiocyanate 50 mmol of m-chloroaniline, 5 ml of triethylamine
0 mmol, distilled water 125 ml, carbon disulfide 150m
mol was added and stirred for 5 hours to convert m-chloroaniline into dithiocarbamate. Then, acetic anhydride 55 mmol
And 50 mmol of triethylamine were added and stirred for 10 minutes. The solution was extracted with n-hexane and washed with 1N-sulfuric acid and 1N-potassium hydroxide. After anhydrous magnesium sulfate was added to the n-hexane phase for dehydration, magnesium sulfate was removed and distilled off under reduced pressure to obtain 5.42 g of m-chlorophenylisothiocyanate (yield 64).
%).

Example 12 Synthesis of n-butyl isothiocyanate 20 mmol of n-butylamine and 20 of triethylamine
20 mmol of carbon disulfide was added to a solution of 50 mmol of tetrahydrofuran, and the mixture was stirred for 1 hour while controlling the reaction temperature at 15 ° C., to dithiocarbamate n-butylamine. Next, 22 mmol of acetic anhydride and 20 mmol of triethylamine were added and stirred for 10 minutes. After extracting the solution with n-hexane, 1N sulfuric acid and 1N
-Washed with potassium hydroxide. After anhydrous magnesium sulfate was added to the n-hexane phase for dehydration, the magnesium sulfate was removed and distilled off under reduced pressure to obtain 2.05 g of n-butyl isothiocyanate (89% yield).

Example 13 Synthesis of n-butyl isothiocyanate 20 mmol of n-butylamine and 20 of triethylamine 20
mmol, 50 ml of distilled water, 60 m2 of carbon disulfide
mol was added and the mixture was stirred for 30 minutes to convert n-butylamine into dithiocarbamate. Then, acetic anhydride 22mmo
l and 20 mmol of triethylamine were added and stirred for 10 minutes. After extracting the solution with n-hexane, 1N-
Washed with sulfuric acid and 1N-potassium hydroxide. After dehydration by adding anhydrous magnesium sulfate to the n-hexane phase, the magnesium sulfate was removed and distilled off under reduced pressure to obtain n-hexane.
1.89 g (82% yield) of butyl isothiocyanate was obtained.

Example 14 Synthesis of n-butyl isothiocyanate 20 mmol of n-butylamine, 20 sodium hydroxide
100 mmol of carbon disulfide was added to a solution of 50 ml of a 9/1 solution of 9/1 tetrahydrofuran / distilled water, and the mixture was stirred for 1 hour to dithiocarbamate n-butylamine. Next, 40 mmol of acetic anhydride and 20 mmol of sodium hydroxide were added, and the mixture was stirred for 10 minutes. After extracting the solution with n-hexane, 1N-sulfuric acid and 1N-
Washed with potassium hydroxide. After anhydrous magnesium sulfate was added to the n-hexane phase for dehydration, magnesium sulfate was removed and distilled off under reduced pressure to obtain 1.84 g (yield: 80%) of n-butyl isothiocyanate.

Example 15 Synthesis of n-butyl isothiocyanate In 50 ml of tetrahydrofuran, 20 mmol of n-butyldithiocarbamate / triethylamine salt was added and dissolved. Next, 22 mmol of acetic anhydride and 20 mmol of triethylamine were added and stirred for 10 minutes. The solution was extracted with n-hexane and washed with 1N-sulfuric acid and 1N-potassium hydroxide. After anhydrous magnesium sulfate was added to the n-hexane phase for dehydration, magnesium sulfate was removed and distilled off under reduced pressure to obtain 1.91 g (yield: 83%) of n-butyl isothiocyanate.

Example 16 Synthesis of 2- (2-isothiocyanateethoxy) ethanol 20 mmol of 2- (2-aminoethoxy) ethanol
20 mmol of triethylamine, 5 of tetrahydrofuran
To 0 ml of the solution, 60 mmol of carbon disulfide was added and stirred for 30 minutes. Next, acetic anhydride 22 mmol was added to the reaction solution.
l and 20 mmol of triethylamine were added and stirred for 10 minutes. After extracting the solution with ethyl acetate, 0.1N
-Washing with sulfuric acid and saturated sodium bicarbonate. After anhydrous magnesium sulfate was added to the ethyl acetate phase for dehydration, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography to give 2- (2-isothiocyanate ethoxy).
2.35 g (yield 80%) of ethanol was obtained.

[0073]

According to the present invention, since a dithiocarbamic acid compound is reacted with an acid anhydride, an isothiocyanate compound can be produced safely without using toxic substances such as thiophosgene and the yield can be improved. be able to.

The isothiocyanate compound obtained according to the present invention can be used as a raw material for synthesizing medicines, agrochemicals and chemicals. Further, since it has an antibacterial action and an antifungal action, it can be used as an antibacterial agent and an antifungal agent.

Claims (2)

[Claims] [Claim 1] Chemical formula [1] (Wherein R ₁ is a chain paraffin, olefin, alkyne, cycloparaffin, cycloolefin, cycloalkyne, aromatic ring, hetero compound, secondary or tertiary amino compound, or a substituted product thereof, or HO-R ₃ -. in a hydroxyl group-containing group represented above R ₃ is a chain paraffins, olefins, alkynes, cycloparaffins, cycloolefins, cycloalkyne, aromatic, heteroaromatic compounds, secondary or tertiary amino compounds, or And M represents a hydrogen atom, an alkali metal atom,
Represents unsubstituted or substituted ammonium. According dithiocarbamate or a salt thereof to react with an acid anhydride), chemical formula (2) R ₁ -NCS (2) (wherein, R ₁ is the same as R ₁ in Formula (1) )), A method for producing an isothiocyanate compound represented by the formula: 2. Chemical formula [3] (Wherein, R ₂ is a linear paraffin, olefin, alkyne, cycloparaffin, cycloolefin, cycloalkyne, aromatic ring, hetero compound, secondary or tertiary amino compound, or a substituted product thereof, or 3] Represents a hydroxyl group-containing group represented by R ₄ is a chain paraffin, olefin, alkyne, cycloparaffin,
Represents a cycloolefin, cycloalkyne, aromatic ring, hetero compound, secondary or tertiary amino compound, or a substituted product thereof. M ₁ and M ₂ each represent a hydrogen atom, an alkali metal atom, or unsubstituted or substituted ammonium. A method for producing a diisothiocyanate compound represented by the chemical formula [4] SCN-R ₂ -NCS [4] by reacting the didithiocarbamic acid represented by the formula (1) or a salt thereof with an acid anhydride.