JPH09124616A - Production of 3,6-diamino-2,5-pyrazinecarbonitrile - Google Patents

Abstract

PROBLEM TO BE SOLVED: To simply and inexpensively produce 3,6-diamino-2,5- pyrazinecarbonitrile (SDPK for short) useful as an intermediate for a nitrogen- containing compound such as a medicine and an agrochemical and a synthetic intermediate for a (fluorescent) coloring matter, a phototransformation material and pteridine derivative. SOLUTION: Hydrogen cyanide is reacted with a disulfide of the general formula RSSR (R is an aryl group, an alkyl group or an alkenyl group) in the presence of a base. The formed 2,3-diaminoacrylonitrile derivative of the formula, without isolation, is reacted under an acidic condition to give SDPK.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to 3,6-diamino-2,5-pyrazinedicarbonitrile (hereinafter referred to as SDPK).
(Refer to)). SDPK is not only useful as an intermediate for nitrogen-containing compounds such as pharmaceuticals and agricultural chemicals, but also as a (fluorescent) dye itself, and also as a synthetic intermediate for fluorescent dyes, photoconversion materials and pteridine derivatives. It is a useful compound.

[0002]

2. Description of the Related Art Conventional general formula [1]

Embedded image (Wherein R has the same meaning as described above) 2,
3-diaminoacrylonitrile derivative (hereinafter, DAAN
Was produced according to the method shown in the following reaction formula (WO88 / 01264).

[0003]

Embedded image

[0004]

Embedded image That is, it is produced by reacting hydrogen cyanide with disulfides or by reacting expensive 2-aminomalononitrile with disulfides, thiols or thioacetic acid esters.

Further, SDPK was produced by treating free DAAN with an acid (WO91 /
03469, JP-A-7-258225).

[0006]

Although DAAN can be obtained as a free form, it is unstable with respect to heat and air. Therefore, in the conventional production method, DAAN is used when the solvent and the base are distilled off in the aftertreatment. Since a part or a considerable part is decomposed during drying or storage for removing water and solvent contained in the obtained DAAN, there is a problem that yield and quality are deteriorated. Therefore, in order to obtain DAAN stably and in a high yield, or to improve storage stability, it has been isolated and stored as a salt with an acid such as p-toluenesulfonic acid. On the other hand, in order to convert DAAN into SDPK, it is necessary to use a free form and react in the presence of an acid such as trichloroacetic acid. Therefore, it is necessary to perform an operation of treating the salt with an alkali to form a free body, and there is a problem that the operation becomes complicated. In order to solve the above problems, there has been a demand for a method capable of producing DAAN and SDPK from disulfides by a simple operation.

[0007]

DISCLOSURE OF THE INVENTION In the present invention, hydrogen cyanide and a disulfide represented by the general formula RSSR (R has the same meaning as described above) are reacted in the presence of a base to produce D.
A method for producing SDPK, which comprises reacting AAN under acidic conditions without isolation.

[0008]

BEST MODE FOR CARRYING OUT THE INVENTION In the reaction of the present invention, hydrogen cyanide and disulfides are reacted in the presence of a base in an organic solvent to give DA.
The first step of producing AN, the second step of producing SDPK by continuously adding an acid after removing the base and carrying out a reaction in an air atmosphere, are continuously performed.

As the reaction solvent in the first step, esters such as ethyl acetate and butyl acetate, nitriles such as acetonitrile, ethers such as dimethoxyethane (DME) and tetrahydrofuran (THF), benzene, toluene and xylene are used. Hydrocarbons, halogenated hydrocarbons such as dichloromethane and chloroform, alcohols such as methanol and ethanol, dimethylformamide (DM
F), dimethylacetamide (DMAC), N-methylpyrrolidinone (NMP) or dimethylsulfoxide (DMSO) can be used, and these may be used as a mixture. As the base, trimethylamine, dimethylethylamine, triethylamine, pyridine or 1,8-diazabicyclo [5.4.0] -7-undecene (DB
U) and other organic bases, sodium or potassium cyanide, and inorganic bases such as hydroxides and carbonates can be used.

The amount of base in the reaction is appropriately in the range of 0.1 to 3 molar equivalents, preferably 0.5 to 2 molar equivalents, based on the disulfides. The reaction temperature is suitably in the range of 0 to 50 ° C, preferably 10 to 40 ° C, and the reaction is carried out under atmospheric pressure.

During the production of DAAN, thiocyanate is formed along with the reaction. Complete consumption of disulfide DAA
To obtain N, hydrogen cyanide should be 4 for the minimum disulfide.
A molar equivalent is required. However, in order to proceed the reaction smoothly, 4 molar equivalents or more are required, and a range of 4 to 8 molar equivalents, preferably 5 to 7 molar equivalents is suitable.

The base is removed by washing with water or pickling. If the base remains, it causes a decrease in yield in the next production of SDPK, and therefore needs to be sufficiently removed.
The washing with water is carried out once or several times, and the washing with an acid is carried out using an amount of acid necessary for neutralizing the used base.
As the acid used for the acid washing, for example, hydrochloric acid can be used, and either concentrated hydrochloric acid or appropriately diluted dilute hydrochloric acid can be used. In the case of acid cleaning, the heat of neutralization is generated, so in order to suppress the decomposition of DAAN, 4
It is performed at 0 ° C. or lower, preferably 20 ° C. or lower. When the reaction solvent is water-soluble, it is necessary to add a water-insoluble organic solvent.

As the solvent used in the production of SDPK from DAAN, the organic solvent used in the previous reaction and, if water-soluble, the non-water-soluble organic solvent added when washing with water or acid is the basic solvent. The following solvents can be used. Esters such as ethyl acetate and butyl acetate, nitriles such as acetonitrile, ethers such as DME and THF, hydrocarbons such as benzene, toluene and xylene, halogenated hydrocarbons such as chloroform and dichloromethane, methanol and ethanol, etc. Alcohols, DMF
And amides such as DMAC and NMP, DMSO or water can be used, and these may be mixed and used. As the acid, most acids such as inorganic acid and organic acid can be used, but picric acid, trichloroacetic acid and the like are preferably used. The amount of the acid is suitably in the range of 0.1 to 1 molar equivalent, preferably 0.2 to 0.6 molar equivalent to DAAN in the organic solvent, and in water, the acidity (pH) is 2 to 5 molar equivalent. , Preferably in the range of 3 to 4 is suitable. The reaction temperature is preferably 10 to 40 ° C, which is around room temperature. Further, this reaction is considered to be a condensation reaction of oxidative dimerization. Therefore, it is necessary to make the system an oxidizing atmosphere. It is only necessary to bring it into contact with air, but it is preferable to actively blow air or oxygen.

The structure of this compound is NMR, IR, Mass.
The above data and derivatives of this compound were synthesized and determined by single crystal X-ray structural analysis and the like. Next, the conventional method that has been performed so far will be shown as a comparative example for reference.

Comparative Example 1 Synthesis of DAAN.p-toluenesulfonate 21 g of acetonitrile, 3 g of triethyleneamine, 1 g of phenyl disulfide and 7 g of hydrogen cyanide were placed in a flask and stirred at room temperature for about 1 hour. Then, the reaction solution was kept under reduced pressure to remove triethylamine and acetonitrile, and then 1.5 g of p-toluenesulfonic acid was added. The precipitated pale yellow crystals were collected by filtration, washed with n-hexane and then vacuum dried to obtain 2.3 g of crude crystals.
The obtained crude crystals were dissolved in acetonitrile and recrystallized to obtain white crystals of 2,3-diamino-3- (phenylthio) acrylonitrile p-toluenesulfonate.

Comparative Example 2 Synthesis of DAAN · p-toluenesulfonate 20g of triethylamine was stirred in 300 ml of an acetonitrile suspension of 10.5 g of thiophenol and 20 g of 2-aminomalononitrile · p-toluenesulfonate at room temperature. While dripping. After stirring for 1 hour, the solvent was distilled off under reduced pressure, 200 ml of acetonitrile was added to the residue again to make a uniform solution, and then 20 g of p-toluenesulfonic acid was added.
Was added. The precipitated crystals were filtered and washed thoroughly with acetonitrile and n-hexane to give white crystals of 2,3-
P of diamino-3- (phenylthio) acrylonitrile
-Toluene sulfonate 7g was obtained.

Comparative Example 3 Synthesis of Free DAAN 2,3-Diamino-3- (phenylthio) acrylonitrile.p-toluenesulfonate 10 g was added to ethyl acetate 1
The mixture was suspended in 00 ml, and 80 ml of a saturated aqueous sodium carbonate solution was gradually added with stirring at room temperature. After separating the organic layer,
The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained yellow crystals were recrystallized from chloroform-n-hexane to give pale yellow crystals of 2,3-diamino-.
3- (Phenylthio) acrylonitrile was obtained.

Comparative Example 4 Synthesis of SDPK 2,3-Diamino-3- (phenylthio) acrylonitrile 954 g (4.99 mol) of acetonitrile (9
Liter) solution with 0.3 molar equivalent of trichloroacetic acid 24
5 g (1.50 mol) was added, and the mixture was vigorously stirred at room temperature for 4 hours. The precipitated red crystals were collected by filtration and washed with acetone and then hexane. After drying under reduced pressure, 3,6-diamino-
283 g of 2,5-pyrazinedicarbonitrile (1.77)
mol) was obtained. The yield is 71% because one molecule of 3,6-diamino-2,5-pyrazinedicarbonitrile is produced from two molecules of 2,3-diamino-3- (phenylthio) acrylonitrile. Hereinafter, the present invention will be described more specifically with reference to examples.

[0019]

【Example】

Example 1 21.83 g (100 mmol) of phenyl disulfide
In ethyl acetate (75 ml) with stirring, with stirring, 15.2 g (150 mmo) of triethylamine with 1.5 molar equivalents.
1) was added and cooled to 5 ° C. 24 ml (612 mmol) of hydrogen cyanide of 6 molar equivalent was added all at once, and the temperature was raised to 31 ° C.
The temperature was raised to and the reaction was carried out at the same temperature for 3 hours. It was cooled to 10 ° C. and washed 3 times with 50 ml of cold water. Subsequently, with vigorous stirring at room temperature, 3.9 g of trichloroacetic acid (24 mmo
1) was added and the reaction was carried out for 3 hours. The precipitated crystals were collected by filtration and washed 3 times with 10 ml of ethyl acetate. SD after drying under reduced pressure
3.13 g (19.6 mmol) of PK was obtained. Considering that one molecule of SDDK is produced from two molecules of DAAN, the through yield from phenyl disulfide is 39%.
The yield of DAAN at the end of the first step is 63% (HPL
It was determined by the internal standard method using C. Hereinafter, the yield of DAAN was similarly obtained. )Met.

Example 2 To a solution of 10.92 g (50 mmol) of phenyl disulfide in ethyl acetate (38 ml) was added 1 g of triethylamine (5.1 g, 50 mmol) with stirring.
Cooled to 6 ° C. 12 ml of hydrogen cyanide of 6 molar equivalents
(306 mmol) was added all at once, the temperature was raised to 30 ° C., and the reaction was carried out at the same temperature for 3 hours. After cooling to 10 ° C, 17 ml of 3N hydrochloric acid was added little by little so as not to exceed 20 ° C.
After stirring for 15 minutes, the aqueous layer was removed. Subsequently, 2.0 g of trichloroacetic acid (12 mm
ol) was added and the reaction was carried out for 2.5 hours. The precipitated crystals were collected by filtration and washed twice with 10 ml of ethyl acetate. After drying under reduced pressure, 1.91 g (11.9 mmol) of SDPK was obtained. The overall yield from phenyl disulfide is 48%.
The yield of DAAN at the end of the first step was 65%.

Example 3 DAAN was synthesized in the same manner as in Example 2, and then 10 ml of acetonitrile and 2.0 g (12 mmol) of trichloroacetic acid were added with vigorous stirring at room temperature and the reaction was carried out for 2 hours. The precipitated crystals were collected by filtration, and ethyl acetate 1
Washed twice with 0 ml. After drying under reduced pressure SDPK 1.85
g (11.6 mmol) was obtained. The overall yield from phenyl disulfide is 46%. The DA at the end of the first step
The yield of AN was 65%.

Example 4 In the same manner as in Example 2 above, the reaction was carried out by changing only ethyl acetate as a solvent to butyl acetate, and 1.52 g of SDPK (9.
5 mmol) was obtained. The overall yield from phenyl disulfide is 38%. The yield of DAAN at the end of the first step was 62%.

Example 5 To a solution of 6.55 g (30 mmol) of phenyl disulfide in acetonitrile (23 ml) was added 3.04 g (30 mmol) of triethylamine in an amount of 1 molar equivalent while stirring, and the mixture was cooled to 10 ° C. 6 molar equivalents of hydrogen cyanide 7.
1 ml (181 mmol) was added all at once, the temperature was raised to 31 ° C., and the reaction was carried out at the same temperature for 1.5 hours. After cooling to 10 ° C and adding 30 ml of ethyl acetate, 1N hydrochloric acid 30 m was added.
1 was gradually added so that the temperature did not exceed 20 ° C. After stirring for 15 minutes, the aqueous layer was removed. Then, 1.2 g (7 mmol) of trichloroacetic acid was added with vigorous stirring at room temperature, and the reaction was carried out for 2 hours. The precipitated crystals were collected by filtration and washed twice with 6 ml of ethyl acetate. After drying under reduced pressure SDPK
0.92 g (5.7 mmol) was obtained. The yield is 38% from phenyl disulfide. The yield of DAAN at the end of the first step was 58%.

Example 6 To a solution of 6.55 g (30 mmol) of phenyl disulfide in toluene (23 ml), 3.04 g (30 mmol) of 1 molar equivalent of triethylamine was added with stirring, and the temperature was 5 ° C.
And cooled. 7.1 ml of hydrogen cyanide (6 molar equivalents) (1
81 mmol) and the temperature is raised to 20 ° C.
The reaction was carried out at 22 ° C. for 1 hour and 45 minutes. Cool to 10 ° C, add 15 ml of ethyl acetate, and add 10 ml of 3N hydrochloric acid.
Was gradually added so as not to exceed 20 ° C. After stirring for 5 minutes, the aqueous layer was removed. Subsequently, 1.2 g (7 mmol) of trichloroacetic acid was added with vigorous stirring at room temperature,
The reaction was carried out for 70 minutes. The precipitated crystals were collected by filtration and washed twice with 5 ml of ethyl acetate. After drying under reduced pressure, SDPK0.
93 g (5.8 mmol) was obtained. The overall yield from phenyl disulfide is 39%. In addition, D at the end of the first step
The yield of AAN was 65%.

[0025]

INDUSTRIAL APPLICABILITY The present invention is a simple and inexpensive method for producing SDPK from disulfides without isolating DAAN and is an industrially excellent production method.

Claims (1)

[Claims] 1. Hydrogen cyanide and the general formula RSSR (wherein
R represents an aryl group, an alkyl group, an aralkyl group or an alkenyl group. ) Is formed by reacting with a disulfide represented by the formula (1) in the presence of a base. (Wherein R has the same meaning as described above) 2,
A method for producing 3,6-diamino-2,5-pyrazinedicarbonitrile, which comprises reacting a 3-diaminoacrylonitrile derivative under acidic conditions without isolation.