JPH05202053A - Pyrimidopteridine derivative and its production - Google Patents

Abstract

PURPOSE:To obtain a new compound useful as an intermediate raw material for agricultural chemicals, medicines, dye, perfume, oxidizing agent, etc., a monomer for polymers, a fluorescent coloring matter, etc. CONSTITUTION:A compound of formula I (R<1> is alkyl, alkenyl, alkynyl, aryl or heterocyclic; R<2> is H, alkyl, alkenyl or alkynyl; X is NH or O). The compound is obtained by reacting 3,6-diamino-2,5-pyrazinecarbonitrile of formula II with an isothiocyanate compound of the formula R<1>NCS in the presence of a base (e.g. sodium hydride) in a solvent (e.g. DMF) at -5 to 40 deg.C. The amount of the isothiocyanate compound used is >=2mols based on 1mol of the compound of formula II.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel pyrimidopteridine derivative and a method for producing the same.

[0002]

2. Description of the Related Art Pyrimidopteridine derivatives have been known for a long time and there are many reports. Among them, for example, introduction of a hydroxyl group or a carbonyl group by oxidation with electron transfer such as pyrimido [5,4-g] pteridine N-oxide [(chemical formula 8)] [Chem. Pharm. B
all. 1991 , 39 (1), 195-198] and induction of aldehydes with decarboxylation of substituted acetic acid [J. Chem. Soc. Chem. Commu
n. 1989 , (22) 1780-2, Chem. Ph
arm. Bull. 1989 , 37 (12) 3239-.
42] A compound having a function has been found.

[0003]

[Chemical 8] However, most of these are pyrimido [5,4-g] pteridine-type derivatives, and as the pyrimido [4,5-g] pteridine-type derivatives of the present invention, compounds in which all the substituents are methyl groups [( 9)] is only known (J. Am. Chem. Soc., 1955 ,
77 (8), 2243-2248, J. Chem. So
c. D 1969 , (23), 1426, Chem. P
harm. Bull. 1971 , 19 (5), 1060
-2, J. Hetrocycl. Chem. 1973 ,
10 (6), 993-6).

[0004]

[Chemical 9]

[0005]

SUMMARY OF THE INVENTION An object of the present invention is to provide a novel pyrimidopteridine derivative which can be easily synthesized.

[0006]

The present inventors have previously found 3,6-diamino-2,5-pyrazinedicarbonitrile [II]. (Japanese Patent Application No. 2-59935) As a result of extensive studies using this compound [II] as a starting material, it was found that the compound of the present invention can be easily synthesized.

That is, the present invention has the general formula [I]

[Chemical 10] (In the formula, R ¹ is an alkyl group which may have a substituent, an alkenyl group which may have a substituent, an alkynyl group which may have a substituent, and an aryl group which may have a substituent. Or a heterocyclic group which may have a substituent, R ² represents a hydrogen atom, an alkyl group which may have a substituent, an alkenyl group which may have a substituent, or an alkynyl which may have a substituent. Group, and further, X represents NH or an oxygen atom) and a method for producing the same.

A method for producing the compound of the present invention will be described. (1) conversion 11

[Chemical 11] R ¹ has the same meaning as described above. The reaction is carried out by using a suitable isothiocyanate compound in an amount of 2 times or more the molar amount of the compound [II], and adding a 2 times or more moles of a base in an appropriate solvent at -50 ° C to 40 ° C, preferably -20 ° C to room temperature. Can be obtained. As the solvent, DMF, DM
Examples of the polar solvent include SO, THF and dimethoethane (DME), which may be used alone or as a mixed solvent. Examples of the base include carbonates such as sodium carbonate and potassium carbonate, hydroxides such as sodium hydroxide and potassium hydroxide, inorganic bases such as hydrides such as sodium hydride and potassium hydride, sodium methoxide and potassium t-. Alkoxides such as butoxide, or organic bases such as amines such as DBU and triethylamine can be used.

(2) Conversion 12

[Chemical 12] R ¹ has the same meaning as described above. r ² represents an alkyl group which may have a substituent, an alkenyl group which may have a substituent or an alkynyl group which may have a substituent, and Y represents a halogen atom. The reaction is carried out by using a suitable isothiocyanate compound in an amount of 2 times by mole or more with respect to the compound [II], and adding a 2 times by mole or more of a base in an appropriate solvent at −50 ° C. to 40 ° C., preferably −20 ° C. at room temperature. It can be obtained by further reacting with an appropriate amount of 2 times or more of a suitable r ² Y [IV] (however, r ² Y may be added before adding the base). As the solvent and the base, those listed in (1) can be used.

(3) Conversion 13

[Chemical 13] R ¹ and r ² have the same meanings as described above. In the general formula [V] (Japanese Patent Application No. 2-234342), a general formula [VI] in a molar amount of at least 2 times
Can also be obtained by reacting with from −20 ° C. to room temperature. As the solvent and the base, those listed in (1) can be used.

(4) Conversion 14

[Chemical 14] R ¹ and r ² have the same meanings as described above. In a suitable solvent
50 ° C to 40 ° C, preferably -20 ° C to 2 at room temperature
It can also be obtained by adding a 2-fold mole or more of a base and further reacting with a 2-fold mole or more of a suitable r ² Y [IV] (provided that r ² Y is added before the addition of the base. Good). As the solvent and the base, those listed in (1) can be used.

(5) Conversion 15

[Chemical 15] R ¹ and R ² have the same meanings as described above. General formula [I-3]
Is heated to reflux from room temperature using an acid (such as dilute hydrochloric acid or dilute sulfuric acid) or a mixed solvent of an acid and an alcohol (such as methanol, ethanol, 1-propanol, 2-propanol and 1-butanol). It can be obtained by carrying out a reaction under a short time. After the completion of the reaction, the target product can be obtained by performing a usual post-treatment. The synthesized compounds are NMR, IR, M
It was identified by ASS and the like.

Some of the compounds of the present invention have the following tautomers.

[Chemical 16]

[0014]

EXAMPLES The present invention will be described in more detail by way of examples, but the scope of the present invention is not limited by these examples. Example 1 (Compound No. 1)

[Chemical 17] Under a nitrogen atmosphere, 3,6-diamino-2,5-pyrazinedicarbonitrile (hereinafter referred to as compound [II]) (1.2).
8 g, 8.0 mmol) and methyl isothiocyanate (1.
A suspension of 5 ml, 22 mmol) of anhydrous DMF (15 ml) was ice-cooled and oily sodium hydride (containing 60%) (1.41
g, 35 mmol) was added. After 20 minutes, iodomethane (3.0 ml, 48 mmol) was further added, and after 15 minutes, ice water (30 m) was added.
l) opened. The precipitated crystals were filtered off and water (10 ml x
2), ethyl acetate (10 ml x 1) and then acetone (5 ml)
It was washed with × 1). After drying under reduced pressure, the target product is a yellow powder.2.
01 g was obtained. Yield 75%, 320 ° C (endothermic peak) ^*
* Measured by DSC (The same applies to the following examples and tables.)

Example 2 (Compound No. 2)

[Chemical 18] Compound [II] (0.96 g, 6.0 mmo under nitrogen atmosphere)
l), ethyl isothiocyanate (1.3 ml, 15 mmo
l) and iodoethane (1.4 ml, 18 mmol) anhydrous D
The MF (20 ml) suspension solution was ice-cooled, and oily sodium hydride (containing 60%) (0.58 g, 15 mmol) was added.
After 10 minutes, the mixture was poured into ice water (50 ml), water (50 ml) was further added, and the mixture was extracted with chloroform (100 ml × 4 times). Combine the organic layers, wash with water (100 ml x 2), and then wash with ethyl acetate 5
0 ml was added and the solution was passed through a silica gel column. After concentration under reduced pressure,
Hexane (40 ml) and benzene (10 ml) were added and filtered, and the obtained crystals were washed with a mixed solvent of benzene and hexane (1: 5). After drying under reduced pressure, 1.87 g of the desired product as yellow crystals was obtained. Yield 80%, mp 277 ° C (endothermic peak)

Example 3 (Compound No. 6)

[Chemical 19] Compound [II] (3.20 g, 20.0 mm) under nitrogen atmosphere
ol) and n-butyl isothiocyanate (6.4 ml, 53
Anhydrous DMF (80 ml) suspension solution of (mmol) was cooled with ice, and oily sodium hydride (containing 60%) (2.11 g, 53 mm
ol) was added. After 10 minutes, iodoethane (6.4m
1, 80 mmol) was added, and after 10 minutes, the mixture was poured into ice water (100 ml), and water (200 ml) was further added. Chloroform (50
It was extracted with 0 ml x 4 times, the organic layers were combined, and water (500 m
It was washed once with l). After concentration under reduced pressure, hexane (100 m
l) was added and filtered, and the obtained crystals were mixed with hexane (10 ml ×
4), benzene (10ml x 2), acetone (10ml x 2)
2) It was then washed with hexane (10 ml x 1). After drying under reduced pressure, 6.09 g of the desired product of yellow flocculent crystals was obtained. Yield 6
8%, mp 270 ℃ (endothermic peak)

Example 4 (Compound No. 5)

[Chemical 20] Compound [II] (0.48g, 3.0mmo under nitrogen atmosphere)
l) and n-butyl isothiocyanate (1.1 ml, 9 mmo
A solution of l) in anhydrous DMF (8 ml) was ice-cooled and oily sodium hydride (containing 60%) (0.36 g, 9 mmol) was added. After 30 minutes, water (2 ml) was added, and after 10 minutes, water (60 ml) was added. After washing with dichloromethane (60 ml × 2), the aqueous layer was neutralized with hydrochloric acid. The precipitated crystals were separated by filtration, washed thoroughly with water, and further washed with acetone (10 ml × 3). After drying under reduced pressure, 0.95 g of black-purple crystals were obtained.
80% yield, mp350 ° C (endothermic peak)

Example 5 (Compound No. 6)

[Chemical 21] Under a nitrogen atmosphere, compound (Compound No. 5) (0.39 g, 1.0 mmol) in the formula [I] where X is NH, R ¹ is n-butyl group and R ² is hydrogen, and anhydrous DMF (5 m
l) The suspension solution is ice-cooled and oily sodium hydride (60%
) (0.12 g, 3 mmol) was added and after 10 minutes iodoethane (0.32 ml, 4 mmol) was added. After 10 minutes, pour into ice water (30 ml) and dichlo romethane (50 ml x 2).
It was extracted with. The organic layers were combined, washed with water (80 ml × 2), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, hexane (20 ml) was added to the obtained crystals and the crystals were filtered and washed with hexane (5 ml × 3) and then acetone (3 ml × 2). After drying under reduced pressure, 0.27 g of the desired product of yellow crystals was obtained.
60% yield

Example 6 (Compound No. 10)

[Chemical formula 22] Compound [II] (0.96 g, 6.0 mmo under nitrogen atmosphere)
l), cyclohexyl isothiocyanate (2.0 ml,
14 mmol) and a suspension of iodoethane (1.4 ml, 18 mmol) in anhydrous DMF (20 ml) were ice-cooled, and oily sodium hydride (containing 60%) (0.58 g, 15 mmol) was added. After 30 minutes, pour in ice water (50 ml) and then add water (50 m
l) was added and extracted with dichloromethane (100 ml × 4). The organic layers were combined, washed with water (100 ml × 2), and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure until some solvent remained, hexane (50 ml) was added, and the precipitate was filtered off. It was washed with a mixed solvent of benzene and hexane (20 ml) and dried under reduced pressure to obtain 2.01 g of the desired product as a yellow powder.
Yield 67%, mp 297 ° C (endothermic peak)

Example 7 (Compound No. 6)

[Chemical formula 23] Anhydrous D of compound [II] (0.64 g, 4.0 mmol) and n-butyl isothiocyanate (1.2 ml, 9.9 mmol)
The MF (10 ml) suspension solution was ice-cooled, and potassium t-butoxide (1.08 g, 9.6 mmol) was added. After 10 minutes, iodoethane (2.3 ml, 28.8 mmol) was added, and after 30 minutes, the mixture was poured into ice water (40 ml). Add more water (40 ml),
It was extracted with dichloromethane (60 ml x 4). The organic layers were combined, washed with water (100 ml × 4), and dried over anhydrous magnesium sulfate. After concentrating under reduced pressure, hexane (40 ml) and benzene (5 ml) were added to the precipitate and filtered. Hexane (5 ml x
3), acetone (2 ml x 1) and then hexane (5 ml x 1
After washing in 1) and drying under reduced pressure, the desired product as a yellow powder, 1.29.
g was obtained. 73% yield

Example 8 (Compound No. 6)

[Chemical formula 24] Anhydrous D of compound [II] (0.64 g, 4.0 mmol) and n-butyl isothiocyanate (1.2 ml, 9.9 mmol)
The MF (10 ml) suspension was ice-cooled and sodium methoxide (97%, 0.68 g, 12.2 mmol) was added. 1
After 5 minutes, iodoethane (1.3 ml, 16.0 mmol) was added, and after 5 minutes, the mixture was poured into ice water (40 ml). Further water (40 ml)
Was added and extracted with dichloromethane (60 ml × 3). The organic layers were combined, washed with water (100 ml × 3), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, hexane (4
0 ml) and benzene (5 ml) were added and the mixture was filtered off, and hexane (5 ml) was added.
ml × 3), acetone (2 ml × 1), then hexane (5 ml
It was washed with × 1). After drying under reduced pressure, the target product was a yellow powder.
34 g were obtained. Yield 75%

Example 9 (Compound No. 6)

[Chemical 25] Anhydrous D of compound [II] (0.48 g, 3.0 mmol) and n-butyl isothiocyanate (0.9 ml, 7.5 mmol)
The MF (8 ml) suspension was ice-cooled and powdered sodium hydroxide (96%, 0.38 g, 9.0 mmol) was added. 10
After a minute, iodoethane (1.7 ml, 21.3 mmol) was added,
After 10 minutes, pour into water (30 ml). Dichloromethane (20
(0 ml), washed with water (80 ml × 2), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, hexane (3
0 ml) was added and the mixture was filtered and washed with hexane (10 ml × 2), acetone (3 ml × 2) and hexane (10 ml × 1). After drying under reduced pressure, 0.58 g of the desired product was obtained as a yellow powder.
Yield 43%

Example 10 (Compound No. 6)

[Chemical formula 26] Anhydrous D of compound [II] (0.48 g, 3.0 mmol) and n-butyl isothiocyanate (0.9 ml, 7.5 mmol)
DBU (1.4 ml, 9.4 mmo) in MF (8 ml) suspension
l) was added. After 2 hours iodoethane (1.7 ml, 2
1.3 mmol) was added, and after 10 minutes, the mixture was poured into water (30 ml).
Extract with dichloromethane (80 ml x 2) and wash with water (100
(ml x 3), dried over anhydrous magnesium sulfate, passed through a silica gel column, and then concentrated under reduced pressure.
0 ml) was added and filtered. The crystals obtained were mixed with hexane (10
ml × 2), acetone (5 ml × 1), and then hexane (10
(ml × 2), dried under reduced pressure, and then dried as a yellow powder.
79 g were obtained. Further, the product was purified by column chromatography using silica gel as a carrier (eluent: dichloromethane-ethyl acetate 10: 1) to obtain 0.58 g of the desired product. Yield 43%

Example 11 (Compound No. 23)

[Chemical 27] A compound of the general formula [I] wherein X is NH and R ¹ and R ² are both ethyl groups (Compound No. 2) (0.39 g, 1.0 mm
A mixed solution of ol) in methanol (20 ml) and 6% sulfuric acid (20 ml) was heated under reflux for 1 hour. After allowing to cool, it was neutralized with a dilute aqueous sodium hydroxide solution while cooling. The precipitate is filtered off,
Wash with water, acetone then ethyl acetate. After drying under reduced pressure, 0.23 g of the desired product as yellow crystals was obtained. Yield 60%,
322 ° C (endothermic peak)

Example 12 (Compound No. 27)

[Chemical 28] A compound of the general formula [I] in which X is NH, R ¹ is a 4-chlorophenyl group, and R ² is an n-pentyl group (Compound No. 1
8) (1.35 g, 2.1 mmol) of dichloromethane (3
0 ml), ethanol (50 ml) and 11% sulfuric acid (20 m)
The mixed solution of l) was heated under reflux for 3 hours. After standing to cool, extract with dichloromethane (100 ml x 2) and wash with water (100 ml x
2) I did. After drying over anhydrous magnesium sulfate, concentration under reduced pressure,
50 ml of ether was added to the precipitated crystals and the crystals were separated by filtration. After drying under reduced pressure, 1.21 g of the desired product as yellow crystals was obtained. Yield 90
%, 276 ° C (endothermic peak)

Example 13 (Compound No. 9)

[Chemical 29] 6 ml of DMF of the general formula [V] (r ² = CH ₃ ) 0.62 g
0.48 g of n-octylamine was added to the solution of above at room temperature, and the mixture was reacted at the same temperature for 8 hours. After completion of the reaction, the reaction mixture was poured into water and extracted with chloroform. After washing the chloroform layer with water, chloroform was distilled off under reduced pressure, and the residue was purified by column chromatography to obtain 0.67 g of the desired product. Yield 75%, mp 204.5-205.5 ° C

Representative examples of the compounds of the present invention, including the above-mentioned examples, are shown in Tables 1 and 2.

[0028]

[Table 101]

[0029]

[Table 102]

[0030]

[Table 2]

[0031]

The compounds of the present invention are agricultural chemicals, dyes, fragrances,
It is useful as an intermediate raw material such as an oxidizing agent, a polymer monomer, or a fluorescent dye.

Claims (5)

[Claims] 1. A compound represented by the general formula [I]: [In the formula, R ¹ is an alkyl group which may have a substituent, an alkenyl group which may have a substituent, an alkynyl group which may have a substituent, and an aryl group which may have a substituent. Or a heterocyclic group which may have a substituent, R ² represents a hydrogen atom, an alkyl group which may have a substituent, an alkenyl group which may have a substituent, or an alkynyl which may have a substituent. Further, X represents NH or an oxygen atom. ] The compound represented by. 2. 3,6-Diamino-2,5-pyrazinedicarbonitrile [II] and a compound of the general formula [III] R ¹ NCS.
(In the formula, R ¹ has the same meaning as described above.) The compound of the general formula [I-1] wherein the compound is reacted in the presence of a base. (Wherein R ¹ has the same meaning as described above). 3. 3,6-Diamino-2,5-pyrazinedicarbonitrile [II], represented by the general formula [III] R ¹ NCS (wherein R ¹ has the same meaning as described above). Compound and general formula [IV] r ² Y (wherein, r ² represents an alkyl group which may have a substituent, an alkenyl group which may have a substituent or an alkynyl group which may have a substituent). And Y represents a halogen atom) in the presence of a base, the compound of the general formula [I-2] (Wherein R ¹ and r ² have the same meanings as described above). 4. A compound represented by the general formula [V]: (Wherein r ² has the same meaning as described above) and a compound represented by the general formula R ¹ NH ₂ (wherein R ¹ has the same meaning as described above). A compound of the general formula [I-2] (Wherein R ¹ and r ² have the same meanings as described above). 5. A compound represented by the general formula [I-2]: (In the formula, R ¹ and r ² have the same meanings as described above.) The compound of the general formula [I
-3] compound (Wherein R ¹ and R ² have the same meanings as described above).