JP2001328976A - Isothiocyanatoformate derivative and method for producing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a new isothiocyanatoformate derivative which is suitable as a reacting agent for the production of pyrrolotriazinone compounds, and to provide a method for producing the isothiocyanatoformate derivative in a high purity and in a high yield. SOLUTION: This isothiocyanatoformate derivative represented by the general formula (A), wherein R1 is a substituted or non-substituted alkyl or a substituted or non-substituted aryl; R2 is a substituted or non-substituted alkyl, a substituted or non-substituted aryl, or a substituted or non-substituted heterocyclic group; R3 is a substituted or non-substituted >=3C alkyl, or a substituted or non- substituted aryl. The method for producing the isothiocyanatoformate derivative represented by the general formula (A), characterized by containing either of the process [1], the process [2] and the process [3].

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an isothiocyanatoformate derivative suitably used as a reactant in the production of a pyrrolotriazinone compound and a method for producing the same.

[0002]

2. Description of the Related Art Isothiocyanato formate derivatives are used as reactants in the synthesis of pyrrolotriazineone compounds useful as precursors of color-forming components and physiologically active substances in light-sensitive materials, heat-sensitive materials and photographic materials. Isothiocyanato formate derivatives are described in J. Am. C.
S. It is known that it can be synthesized by the method described in Perkin I, page 2644 (1973). The production scheme of the isothiocyanatoformate derivative described in the literature is shown below.

[0003]

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In the conventional production method, a hydroxy derivative represented by the general formula (2 ′) is added later to ethyl isothiocyanatoformate produced by reacting potassium isothiocyanate and ethyl chloroformate. ing. However, since the reactivity between the potassium isothiocyanate and the ethyl chloroformate is high and the generated ethyl isothiocyanatoformate is unstable, a part of the ethyl isothiocyanatoformate is represented by the general formula (2 ′). Decomposes before reacting with hydroxy derivatives. As a result, there is a problem that the unreacted hydroxy derivative remains and the purity and yield of the intermediate represented by the general formula (4 ′) are reduced.

The intermediate represented by the general formula (4 ′) synthesized by the conventional production method and the isothiocyanatoformate derivative represented by the general formula (A ′) (R ′ is a methyl group or an ethyl group) Has a low melting point, and its purification requires crystallization at a low temperature of -50 ° C or lower. Therefore, the operation becomes complicated, and it is difficult to industrially obtain the intermediate and the isothiocyanatoformate derivative with high purity and high yield. In the case where the intermediate represented by the general formula (4 ′) and the isothiocyanatoformate derivative represented by the general formula (A ′) each have 3 or more carbon atoms in R ′, many of them are oily. Therefore, from this point, there is a problem that it is difficult to obtain industrially with high purity and high yield.

The purity of the isothiocyanatoformate derivative represented by the general formula (A ') produced by the conventional production method is as low as 50 to 60%, and the isothiocyanatoformate derivative can be used as a reactant without purification. When a pyrrolotriazin-4-one is used to synthesize a pyrrolotriazin-4-one, a tar component derived from a by-product at the time of production of the isothiocyanatoformate derivative represented by the general formula (A ′) is generated, so that operability and pyrrolotriazin-4-one are obtained. There are also problems such as a decrease in the yield of triazin-4-one.

[0007]

SUMMARY OF THE INVENTION An object of the present invention is to solve the above-mentioned conventional problems and achieve the following objects. That is, the present invention provides a novel isothiocyanatoformate derivative suitably used as a reactant in the synthesis of a pyrrolotriazinone compound, and provides a method for producing the isothiocyanatoformate derivative with high purity and high yield. With the goal.

[0008]

The present inventors have conducted intensive studies on the isothiocyanatoformate derivative of the present invention and the method for producing the same, and as a result, the presence of the hydroxy derivative represented by the above general formula (2) in advance. , Isothiocyanatoformate (R ¹ OOCNC)
It has been found that decomposition of S) is suppressed, and as a result, the yield of the intermediate represented by the general formula (4) is improved. Further, by reacting the compound represented by the general formula (5) on the intermediate represented by the general formula (4), the intermediate represented by the general formula (6) is converted into a crystal. Get out,
Further, since it can be purified by recrystallization, the purity and yield of the isothiocyanatoformate derivative represented by the general formula (A) are improved, and it has been found that the isothiocyanatoformate derivative is suitably used as a reactant in the synthesis of a pyrrolotriazinone compound. .

The present invention is based on the above findings by the present inventors, and the means for solving the above problems are as follows. That is, <1> an isothiocyanato formate derivative represented by the following general formula (A).

[0010]

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In the general formula (A), R ¹ represents a substituted or unsubstituted alkyl group or a substituted or unsubstituted aryl group. R ² represents a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heterocyclic group. R ³ has ³ carbon atoms
The above represents a substituted or unsubstituted alkyl group or a substituted or unsubstituted aryl group.

<2> A chloroformate represented by the following general formula (3) is added to an isothiocyanate represented by the following general formula (1) and a hydroxy derivative represented by the following general formula (2). And a step of producing an intermediate represented by the following general formula (4):
Is a method for producing an isothiocyanatoformate derivative represented by the formula:

[0013]

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In the general formula (1), Z represents a sodium atom or a potassium atom. The general formula (2),
In the general formulas (3) and (4), R ¹ and R
³ has the same meaning as that in the formula (A).

<3> A process for producing an intermediate represented by the following general formula (6) from an intermediate represented by the following general formula (4) and a compound represented by the following general formula (5): A method for producing an isothiocyanatoformate derivative represented by the following general formula (A):

[0016]

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In the general formula (5), M represents an alkali metal atom, an alkaline earth metal atom, an aluminum atom, or a magnesium atom. In the general formula (6), R ¹ and R ³ have the same meaning as in the general formula (A).

<4> An intermediate represented by the following general formula (6) is reacted with an alkylating agent represented by the following general formula (7) or (8) to obtain a compound represented by the following general formula (A) A method for producing an isothiocyanato formate derivative represented by the following general formula (A), comprising a step of producing an isothiocyanato formate derivative represented by the following formula:

[0019]

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In the general formula (7), X represents a halogen atom or SO ₃ Ar. Ar represents a substituted or unsubstituted aryl group. In the general formulas (7) and (8), R ² has the same meaning as in the general formula (A).

[0021]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the isothiocyanatoformate derivative of the present invention and a method for producing the same will be described in detail.

(Isothiocyanato formate derivative)
The isothiocyanato formate derivative of the present invention is a compound represented by the following general formula (A).

[0023]

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In the general formula (A), R ¹ represents a substituted or unsubstituted alkyl group or a substituted or unsubstituted aryl group. Among the R ¹ , when the R ¹ is a substituted or unsubstituted alkyl group, an alkyl group having 1 to 18 carbon atoms is preferable, and a methyl group, an ethyl group, an n-propyl group, an n-butyl group, an isobutyl group, n-amyl group, hexyl group, heptyl group, n-octyl group, 2-ethyl-hexyl group, nonyl group, decyl group, hexadecyl group, 2-
A methoxyethyl group, a benzyl group and the like are more preferred. On the other hand, when R ¹ is a substituted or unsubstituted aryl group, an aryl group having 6 to 30 carbon atoms is preferable, and a phenyl group, 4
-Nitrophenyl group, 2-naphthyl group and the like are more preferable.

In the general formula (A), R ² represents a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heterocyclic group. Among the R ² , when the R ² is a substituted or unsubstituted alkyl group, an alkyl group having 1 to 18 carbon atoms is preferable, and a methyl group, an ethyl group, an n-propyl group, an n-butyl group, an isobutyl group, More preferred are n-amyl, hexyl, heptyl, n-octyl, 2-ethyl-hexyl, nonyl, decyl, hexadecyl, 2-methoxyethyl, benzyl and the like. When R ² is a substituted or unsubstituted aryl group, an aryl group having 6 to 30 carbon atoms is preferable, and a phenyl group, a 4-nitro-phenyl group,
A 2-naphthyl group and the like are more preferred. When R ² is a substituted or unsubstituted hetero ring, a saturated or unsaturated hetero ring is preferable, and a 2-pyridyl group, a 4-pyridyl group, a 2-pyrimidyl group, a methyl-tetrazoyl group, an ethyl-triazole group, Thiazoyl groups, benzoxazoyl groups and the like are more preferred.

In the general formula (A), R ³ represents a substituted or unsubstituted alkyl group having 3 or more carbon atoms, or a substituted or unsubstituted aryl group. Among the R ³ , when the R ³ is a substituted or unsubstituted alkyl group having 3 or more carbon atoms, an alkyl group having 3 to 18 carbon atoms is preferable,
n-propyl, n-butyl, isobutyl, n-amyl, isoamyl, hexyl, heptyl, n-
Octyl group, 2-ethylhexyl group, nonyl group, decyl group, hexadecyl group, 2-methoxyethyl group, ethoxycarbonylmethyl group, 2-ethyl-hexylcarbonylmethyl group, aminocarbonylmethyl group, N, N-dimethylaminocarbonylmethyl Group, N-methylaminocarbonylmethyl group, isopropyloxy-ethyl group, butoxyethyl group, phenoxyethyl group, cyanomethyl group,
A 3,7-dimethyl-octyl group, a 3,5,5-trimethyl-hexyl group, a benzyl group and the like are more preferable, and a branched alkyl group and an alkoxyethyl group are particularly preferable. When R ³ is a substituted or unsubstituted aryl group, it has 6 carbon atoms.
To 30 aryl groups are preferable, and a phenyl group, a 4-nitro-phenyl group, a 2-naphthyl group and the like are more preferable.

Specific examples of the isothiocyanato formate derivative represented by the general formula (A) (exemplified compounds A-1 to A-1)
35) is shown below, but the present invention is not limited to these specific examples.

[0028]

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[0029]

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[0030]

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[0031]

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[0032]

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[0033]

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The isothiocyanatoformate derivative represented by the general formula (A) of the present invention is suitably used as a reactant in the production of a pyrrolotriazinone compound. For example, when an isothiocyanatoformate derivative represented by the general formula (A) of the present invention is added as a reactant to an aminopyrrole compound, a pyrrolotriazin-4-one is produced through an addition reaction and a cyclization reaction. it can.

(Method for Producing Isothiocyanatoformate Derivative) Here, a method for producing the isothiocyanatoformate derivative of the present invention will be described. An isothiocyanatoformate derivative can be produced through the following production scheme.

[0036]

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As shown in the above scheme, the isothiocyanato formate derivative of the present invention has the general formula (4)
A step [1] of obtaining an intermediate represented by the general formula (6)
And the step [3] of obtaining an isothiocyanatoformate derivative represented by the general formula (A). Note that these 3
It is not necessary to go through the step, and the step [1],
[2] or [3] only, or 2 of the above 3 steps
The isothiocyanatoformate derivative can also be produced by combining the selected steps with known steps. However, in order to obtain an isothiocyanatoformate derivative preferably used as a reactant for the pyrrolotriazinone compound in high yield and high purity, it is preferable to go through all of the above three steps. Next, each step will be described.

-Step [1]-In the step [1], an isothiocyanate represented by the general formula (1) and a hydroxy derivative represented by the general formula (2) are added to a reaction solvent. By adding a chloroformic acid derivative represented by the general formula (3),
This is a step of producing an intermediate represented by

In the general formula (1), Z represents a sodium atom or a potassium atom. The general formula (2),
In the general formulas (3) and (4), R ¹ and R
³ has the same meaning as that in the formula (A).

The amount (mol) of the isothiocyanate represented by the general formula (1) is based on the amount (mol) of the chloroformate derivative represented by the general formula (2).
1 to 5 times is preferable, and 1 to 3 times is more preferable. Also,
The amount (mol) of the hydroxy derivative represented by the general formula (3) is 0.5 to 3 times the amount (mol) of the chloroformate derivative represented by the general formula (2). Is preferable, and 0.5 to 1.5 times is more preferable.

In the step [1], for example, the isothiocyanate represented by the general formula (1) and the hydroxy derivative represented by the general formula (2) are dissolved in a reaction solvent. The intermediate represented by the general formula (4) can be produced by dropping and reacting the chloroformate derivative represented by the formula (3).

Suitable examples of the reaction solvent include acetonitrile, acetone, tetrahydrofuran and the like, and among them, acetonitrile and acetone are preferred. The reaction temperature in the step [1] is -25.
C. to 40 C. are preferred, and -5 C. to 25 C. are more preferred.

In the step [1], the isothiocyanate represented by the general formula (1) and the hydroxy derivative represented by the general formula (2) coexist in advance, whereby the compound represented by the general formula (1) ) And an isothiocyanatoformate (R ¹ OONCCS) formed by reacting the isothiocyanate represented by the general formula (2) with the chloroformate derivative represented by the general formula (2); By reacting immediately with the hydroxy derivative, the decomposition of the isothiocyanatoformate (R ¹ OONCCS) is suppressed, and as a result, the yield of the intermediate represented by the general formula (4) is reduced by the conventional production method. It will be higher in comparison.

-Step [2]-The step [2] is performed by converting the intermediate represented by the general formula (4) and the compound represented by the general formula (5) into the compound represented by the general formula (6). This is a step of producing the intermediate represented.

In the general formula (5), M represents an alkali metal atom, an alkaline earth metal atom, an aluminum atom, or a magnesium atom. In the general formula (6), R ¹ and R ³ have the same meaning as in the general formula (A).

As the alkali metal atom, a lithium atom, a sodium atom, a potassium atom and a cesium atom are preferable. As the alkaline earth metal atom, a calcium atom and a barium atom are preferable.

In the step [2], for example, the compound represented by the general formula (5) is dissolved in a reaction solvent, and the intermediate represented by the general formula (4) is added to the solution. ,
It can be produced by precipitating the intermediate represented by the general formula (6) as crystals. Water, as the reaction solvent,
Methanol, ethanol, acetonitrile, acetone,
Tetrahydrofuran and the like are preferably mentioned, and among them,
Methanol, ethanol and the like are preferred.

The amount (mol) of the compound represented by the general formula (5) is preferably 1 to 5 times the amount (mol) of the intermediate represented by the general formula (4). . In order to promote crystallization, a compound represented by the general formula MY (M
Has the same meaning as that in the general formula (5). Y
Represents a halogen atom. ) May be added. The amount (mol) of the compound represented by the general formula MY is 1 to the amount (mol) of the intermediate represented by the general formula (4).
10 to 10 times is preferred.

In the step [2], the compound represented by the general formula (5) is allowed to act on the intermediate represented by the general formula (4), whereby the intermediate represented by the general formula (6) is reacted. The represented intermediate can be taken out as crystals, and can be further purified by a method such as recrystallization.

-Step [3]-In the step [3], the intermediate represented by the general formula (6) and the alkylating agent represented by the general formula (7) or (8) are used. To produce the isothiocyanatoformate derivative represented by the general formula (A).

In the general formula (7), X represents a halogen atom or SO ₃ Ar. Ar represents a substituted or unsubstituted aryl group. As the halogen atom,
Chlorine, bromine and iodine are preferred.

In the general formulas (7) and (8), R ² has the same meaning as in the general formula (A).

The amount (mol) of the alkylating agent represented by the general formulas (7) and (8) is used (mol) of the intermediate represented by the general formula (6). Is preferably 1 to 3 times, more preferably 1 to 1.5 times.

In the step [3], for example, the intermediate represented by the general formula (6) is suspended in a reaction solvent, and the intermediate represented by the general formula (7) or (8) is suspended therein. By dropping the alkylating agent represented by the general formula (A)
The isothiocyanato formate derivative represented by the following formula can be produced.

Examples of the reaction solvent include acetonitrile, acetone, dimethylformamide, dimethylacetylamide, tetrahydrofuran, dimethylsulfoxide, alcohols (eg, methanol, ethanol, isopropanol, propanol, n-butanol, t-butanol) Etc.) are preferred. Among them, acetonitrile, ethyl acetate, butyl acetate, benzene, toluene,
Dimethylformamide, dimethylacetylamide, tetrahydrofuran and dimethylsulfoxide are preferred.
The reaction temperature in the step [3] is -2.
5 ° C to 40 ° C is preferred, and -5 to 25 ° C is more preferred.

[0056]

EXAMPLES The present invention will now be described specifically with reference to examples, but the present invention is not limited to these examples. (Examples)-Production Example of Exemplary Compound (A-1) of Isothiocyanatoformate Derivative-Exemplary compound (A-1) and a production example thereof are shown below.

[0057]

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1) Preparation of Intermediate (6-1) 48.5 g of potassium isothiocyanate (KNCS)
(0.5 mol) and tetrahydrogeraniol (3,7
-Dimethyl-1-octanol) (71 g, 0.45 mol) was dissolved in 250 ml of acetone. After cooling the solution to an internal temperature of 5 ° C., ethyl chloroformate (ClCOOC ₂
48.5 g (0.45 mol) of H _{5 were} added dropwise over 1 hour so that the internal temperature did not rise to 15 ° C. or higher. The reaction solution was reacted for 3 hours while cooling, then returned to room temperature, and allowed to stand overnight.

Next, barium hydroxide (Ba (OH) ₂ )
Dissolve 94 g (0.3 mol) of hydrate in 500 ml of water,
The reaction solution was added to the aqueous solution to precipitate crystals.
The obtained crystals were filtered and washed with water until the alkali was removed. After drying, 114 g (0.16 mol) of the intermediate (6-1) was obtained as white crystals. The intermediate (6-1)
Was 71% in terms of tetrahydrogeraniol. The purity of the intermediate (6-1) was 98% or more as measured by gas chromatography.

The intermediate (6-1) was neutralized, and ¹ H-NMR (solvent: CDCl ₃ ,
Structural analysis was performed according to TMS standard (300 MHz). The data is shown below. ¹ H-NMR [δ, ppm]: 8.13 (1H, N
H), 4.58 (2H, -OCH 2 CH 2), 4.21
_{(2H, -OCH 2 CH 3)} , 2.37 (3H, -SCH
₃ )

2) Preparation of Exemplified Compound (A-1) 75 g of the Intermediate (6-1) Obtained in 1)
(0.115 mol) was suspended in acetone. The reaction solution was cooled to 15 ° C., and dimethyl sulfate was used as an alkylating agent.
g (0.24 mol) was added dropwise over 15 minutes. Then one
After reacting for an hour, the reaction solution was filtered to remove inorganic components. The obtained filtrate was concentrated under reduced pressure, 100 ml of ethyl acetate and 100 ml of water were added to the concentrate for extraction, and the organic layer was concentrated under reduced pressure to give the exemplary compound (A-1) of the isothiocyanato formate derivative in pale yellow color As an oily component, 6
4 g (0.21 mol) were obtained. Exemplified compound (A-1)
Was 91%. Further, the exemplified compound (A
The purity of -1) was 98% as measured by gas chromatography.

With respect to the exemplified compound (A-1), ¹ H
-NMR (solvent: CDCl _3, 300MHz, TMS standard) and structural analysis was performed using. The data is shown below. ¹ H-NMR (δ, ppm): 4.36 (2H, -OC
_{H 2 CH 2), 4.23 (} 2H, -OCH 2 CH 3), 2.
37 (3H, -SCH ₃₎

(Comparative Example)-Preparation Example of Comparative Compound (A'-1) of Isothiocyanatoformate Derivative-Exemplary compound (A'-1) and a preparation example thereof are shown below.

[0064]

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1) Preparation of Intermediate (4'-1) 48.5 g of potassium isothiocyanate (KCNS)
(0.5 mol) was dissolved in 250 ml of acetone. After the reaction solution was cooled to an internal temperature of 5 ° C, ethyl chloroformate (ClC
OOC ₂ H ₅ ) 48.5 g (0.45 mol)
Add dropwise over 1 hour so that the temperature is 5 ° C or higher, and add 3 drops.
Stirred for hours. Then, tetrahydrogeraniol 71
g (0.45 mol) was added to the reaction and left at room temperature overnight. After adding 5 g of activated carbon to the reaction mixture, the mixture was filtered,
Activated carbon and inorganic components were removed. The obtained filtrate was concentrated under reduced pressure to obtain 95 g of an intermediate (4′-1) as a yellow oil. The purity of the intermediate (4′-1) obtained by the above method is
When measured using gas chromatography, 55
%Met.

2) Production of Comparative Compound (A'-1) 95 g of the intermediate (4'-1) obtained in 1) (0.
33 mol) and 50 g (1.36 mol) of potassium carbonate were suspended in 500 ml of acetone. The reaction solution is kept at 15 ° C.
And 46 g of dimethyl sulfuric acid as an alkylating agent
(0.36 mol) was added dropwise over 30 minutes. Thereafter, the reaction was performed for 2 hours, and the reaction solution was filtered to remove inorganic components.
The obtained filtrate was concentrated under reduced pressure.
0 ml and 500 ml of water were added for extraction, and the organic layer was concentrated under reduced pressure to obtain 90 g of a comparative compound (A'-1) of an isothiocyanatoformate derivative as a pale yellow oil component. The purity of the comparative compound (A′-1) was 40% as measured by gas chromatography.

From the above results, it was confirmed that according to the production method of the present invention, an isothiocyanatoformate derivative can be produced with higher yield and higher purity than the production method of the comparative example.

[0068]

According to the present invention, there is provided a novel isothiocyanatoformate derivative suitably used as a reactant in the synthesis of a pyrrolotriazineone compound, and a method for producing the isothiocyanatoformate derivative with high purity and high yield. Can be provided.

Claims (4)

[Claims] 1. An isothiocyanato formate derivative represented by the following general formula (A). Embedded image In the general formula (A), R ¹ represents a substituted or unsubstituted alkyl group or a substituted or unsubstituted aryl group. R ² represents a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heterocyclic group. R ³ represents a substituted or unsubstituted alkyl group having 3 or more carbon atoms, or a substituted or unsubstituted aryl group. 2. A chloroformate represented by the following general formula (3) is added to an isothiocyanate represented by the following general formula (1) and a hydroxy derivative represented by the following general formula (2), A method for producing an isothiocyanatoformate derivative represented by the following general formula (A), comprising a step of producing an intermediate represented by the following general formula (4). Embedded image In the general formula (1), Z represents a sodium atom or a potassium atom. The general formula (2) and the general formula (3)
And in the general formula (4), R ¹ and R ³ have the same meanings as in the general formula (A). 3. A process for producing an intermediate represented by the following general formula (6) from an intermediate represented by the following general formula (4) and a compound represented by the following general formula (5): A method for producing an isothiocyanatoformate derivative represented by the following general formula (A): Embedded image In the general formula (5), M is an alkali metal atom,
Represents an alkaline earth metal atom, an aluminum atom, or a magnesium atom. In the general formula (6), R ¹ and R ³ have the same meaning as in the general formula (A). 4. An intermediate represented by the following general formula (6) is reacted with an alkylating agent represented by the following general formula (7) or the following general formula (8) to give an intermediate represented by the following general formula (A) A method for producing an isothiocyanato formate derivative represented by the following general formula (A), comprising a step of producing an isothiocyanato formate derivative represented by the following formula: Embedded image In the general formula (7), X is a halogen atom or S
Represents O ₃ Ar. Ar represents a substituted or unsubstituted aryl group. In the general formulas (7) and (8), R ² has the same meaning as in the general formula (A).