JPH0571590B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to cyclohexadiene derivatives. Disclosure of the Invention The cyclohexadiene derivative of the present invention is represented by the following general formula. [In the formula, R ¹ represents a lower alkyl group] R ² represents a hydrogen atom or a lower alkyl group, R ³ represents a hydrogen atom or a lower alkyl group, or R ² and R ³ are combined to form a group -(CH ₂ ) ₄ - or a group -CH=CH-CH =
Indicates CH−. α is an aromatic hetero 5- or 6-membered ring group containing 1 to 3 heteroatoms selected from nitrogen atoms, oxygen atoms, and sulfur atoms, pyrazine-N-oxide ring group, pyridazine-N-oxide ring group, or pyridazine -N-oxide ring group, and aromatic heterocyclic groups such as these have 1 to 3 substituents selected from lower alkyl groups, halogen atoms, phenyl groups, lower alkoxycarbonyl groups, amino groups, and lower alkoxy groups. may have. However, the above six-membered aromatic heterocyclic group must not be a pyridine ring group or a 1,3,5-triazine ring group. ] The compound of the present invention represented by the above general formula (1) is a novel compound that has not been described in any literature, and has the following general formula (2) which exhibits anti-inflammatory action and lipoxygenase inhibitory action [In the formula, R ¹ , R ² , R ³ and α are the same as above. ] It is a compound useful as a synthetic intermediate of the p-aminophenol derivative represented by the following. The p-aminophenol derivatives of general formula (2) above can be used to treat acute inflammation or chronic inflammatory diseases such as arthritis and rheumatism by reducing inflammation, and by inhibiting the production of lipoxygenase metabolites. Therefore, it is a known compound useful in the treatment of diseases such as asthma, bronchitis, and psoriasis (Japanese Patent Application Laid-open No. 25756/1983). In this specification, each group shown below is, respectively,
It has the following meaning. Examples of the lower alkyl group include straight or branched alkyl groups having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, and hexyl. Examples of lower alkoxy groups include methoxy,
Examples include straight chain or branched alkoxy groups having 1 to 6 carbon atoms such as ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy, pentyloxy, and hexyloxy groups. Examples of halogen atoms include fluorine, chlorine, bromine and iodine atoms. Examples of lower alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl,
The alkoxy moiety such as butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl group has 1 to 6 carbon atoms.
Examples include alkoxycarbonyl groups. The six-membered heterocyclic group containing 1 to 3 heteroatoms selected from nitrogen atoms, oxygen atoms, and sulfur atoms represented by α includes triazine ring group, pyridine ring group,
Examples include a pyrimidine ring group and a pyridazine ring group. Representative examples of the aromatic six-membered heterocyclic group containing 1 to 3 heteroatoms selected from nitrogen atoms, oxygen atoms, and sulfur atoms include pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3 Examples include -pyridazinyl and 4-pyridazinyl groups. Further, as representative examples of the pyrazine-N-oxide ring group, pyridazine-N-oxide ring group, or pyramidine-N-oxide ring group, pyrazine-1-oxide-2-yl, pyrazine-1-oxide-3-
yl, pyrimidin-1-oxide-2-yl, pyrimidin-1-oxide-4-yl, pyrimidin-1-oxide-5-yl, pyrimidin-1-oxide-6-yl, pyrimidin-1-oxide-
Examples include 3-yl, pyridazin-1-oxide-4-yl, pyridazin-1-oxide-5-yl, pyridazin-1-oxide-6-yl, and the like. The cyclohexadiene derivative of the present invention can be produced by various methods. A specific example thereof is shown in the reaction scheme below. <Reaction Scheme 1> [In the formula, R ¹ , R ² , R ³ and α are the same as above. ] According to the method shown in Reaction Scheme-1 above, the compound (1) of the present invention can be produced by a condensation reaction between the quinone derivative (3) and the aromatic heterocyclic amine derivative (4). In the above, among the quinone derivatives (3) used as raw material compounds, the alkylbenzoquinones are known or, for example, the chemical pharmaceutical bridine [Chem.Pharm.Bull., 34 ,
121 (1986). D. Liotta et al.'s method [J.Org.
Chem., 48, 2932 (1983)]. Alkylnaphthoquinones are also known or, for example, from journals.
American Chemical Society [J.Am.
Chem.Soc., 70 , 3165 (1948)]. F. It can be manufactured according to the method of LFFieser. Further, the aromatic heterocyclic amine derivative (4), which is the other raw material compound, is a known compound. For example, The Chemistry of Heterocyclic Compounds [GBBarlin, The
Chemistry of Heterocyclic Compounds, 41
Volume, Interscience, New York, 1982, No. 8
Chapter], same document [T. Nakagome: RN Castle edition 28
Volume, 1973, Chapter 6], same document [DJBrown, 16
Volume 1962, Chapter 9 and DJ Brown, Volume 16 (Supplement I), 1970, Chapter 9], etc. The condensation reaction shown in the above reaction scheme-1 is carried out by Ehreiker and H. Kessler (A. Reiker and H.
Tetrahedron by Kessler
23, 3723 (1976), the quinone derivative (3) and the aromatic heterocyclic amine derivative (4) were mixed into about
This can be carried out by heating the reaction to 100 to 200°C. The above condensation reaction is carried out in the presence of a halide Lewis acid such as aluminum chloride, ferric chloride, titanium tetrachloride, tin chloride, zinc chloride, etc.
It can also be carried out by reacting the quinone derivative (3) and the aromatic heterocyclic amine derivative (4) which also serves as a deoxidizing agent in an inert organic solvent. Examples of the inert organic solvent used in the reaction include 1,
Halogenated hydrocarbons such as 2-dichloroethane, 1,1,2-trichloroethane, chloroform,
Examples include aromatic hydrocarbons such as benzene, toluene, and xylene, and reaction temperature conditions range from room temperature to
Approximately 120℃ can be used. An inert organic base such as pyridine or triethylamine may also be added to the reaction system as a deoxidizing agent. Quinone derivatives (3) and aromatic heterocyclic amine derivatives
There is no particular limitation on the proportion of (4) to be used, but it is usually desirable to use the latter in an amount of about 1 to 10 times, preferably about 1 to 3 times, the former. The reaction using titanium tetrachloride is described, for example, in the Journal of Hoganic Chemistry [J.Org.
Chem., 32 , 3246 (1967)]. It can be carried out according to the method of H. Weingarten et al. In addition, the above reaction can be carried out by using a Lewis acid other than the above, such as boron trifluoride/ethyl ether, and reacting both raw materials in an appropriate solvent such as tetrahydrofuran or dioxane at a temperature of room temperature to about 100°C. It can be carried out even if it is difficult. This reaction is called J.
The method of J. Figueras et al. [J.Org.
Chem., 36, 3497 (1971). Furthermore, among the compounds of general formula (1) of the present invention, compounds in which α is a pyrazine-N-oxide ring group, a pyridazine-N-oxide ring group, or a pyrimidine-N-oxide ring group can be prepared by the following method. It can also be manufactured. <Reaction Scheme 2> [In the formula, R ¹ , R ² and R ³ are the same as above. α ₁ represents a pyrazine ring group, a pyridazine ring group, or a pyrimidine ring group, and α ₂ represents a pyrazine-N-oxide ring group, a pyridazine-N-oxide ring group, or a pyrimidine-N-
The heterocyclic group represented by α ₁ and α ₂ , which represents an oxide ring group, has 1 to 3 substituents selected from a lower alkyl group, a halogen atom, a phenyl group, a lower alkoxycarbonyl group, and a lower alkoxy group. It may have a group. ] According to the method shown in Reaction Scheme-2 above, the compound (1a) of the present invention can be obtained by the oxidation reaction of the compound (5). The production of compound (1a) from compound (5) (oxidation reaction) can be carried out using, for example, dichloromethane, chloroform,
In an inert organic solvent such as acetic acid, using an organic peracid such as 3-chloroperbenzoic acid or peracetic acid in an amount of about 1 to 5 times the molar amount of compound (5) at a temperature of about 0 to 50 ° C. 5
Advantageously, it takes about 30 hours. The compound (5) used as a raw material in this reaction is, for example, a quinone derivative (3) shown in the reaction scheme-1 above and an aromatic heterocyclic amine derivative (4) using an appropriate raw material compound.
It can be produced in the same manner as the condensation reaction with The p-aminophenol derivative of general formula (2) obtained from the compound (1) of the present invention can be obtained without or without isolating the compound (1) of the present invention obtained as described above from the reaction system. Then, as shown in reaction step 3 below, the compound can be synthesized by subjecting it to a reduction reaction. <Reaction Scheme 3> [In the formula, R ¹ , R ² , R ³ and α are the same as above. ] The reduction reaction of the compound of the present invention (1) can be carried out according to a conventional method, for example, by transferring the compound of the present invention (1) above into tetrahydrofuran and adding an aqueous solution of sodium hydrosulfite in an amount of 2 to 50 times the molar amount. . Further, the above reduction reaction is performed on the compound of the present invention (1).
Depending on the type of substituent α in It can also be carried out by a method using sodium borohydride in a mixture with. The compound (1) of the present invention obtained by the reactions shown in each of the above reaction schemes can be easily isolated and purified by conventional separation means. As the separation means,
Examples include a solvent extraction method, a recrystallization method, and a column chromatography method. Examples Hereinafter, in order to explain the present invention in more detail, production examples of raw material compounds for producing the compounds of the present invention are listed as reference examples, and then production examples of the compounds of the present invention are listed as examples. Reference example 1 2-tert-butyl-6-isopropyl-1,4
- Manufacture of benzoquinone 160g of sodium dichromate dihydrate, 97
% sulfuric acid and 230 ml of water, and add 2-tert-butyl-6-isopropylphenol.
The mixture was added dropwise to a solution of 45.0 g in 350 ml of diethyl ether while stirring at 5 to 10° C. over 2.5 hours. The reaction mixture was poured into water and extracted with diethyl ether.
The organic layer was washed with saturated aqueous sodium bicarbonate and then with saturated brine, dried over magnesium sulfate, and concentrated. The obtained crude product was subjected to silica gel column chromatography (diethyl ether:hexane=1:
10) to obtain 12.7 g of the target compound as a pale yellow oil. ¹ H-NMR (CDCl ₃ ): δ 1.12 (d, J = 6.8 Hz, 6H) 1.29 (s, 9H), 3.09 (d septet, J = 6.8 Hz,
1.1Hz, 1H) 6.45 (dd, J = 2.6Hz, 1.1Hz, 1H) 6.53 (d, J = 2.6Hz, 1H) Reference example 2 2-tert-butyl-5,6,7,8-tetrahydro-1 , 4-naphthoquinone production process 1 2-tert-butyl-1,4-benzoquinone 120
Suspend g in 370 ml of acetic acid and add butadiene under ice cooling.
52 g was blown into the flask, the flask was stoppered, and the mixture was left at room temperature for 48 hours. Thereafter, 9 g of sodium acetate was added to the reaction mixture, heated under reflux for 30 minutes, and concentrated. The residue was dissolved in dichloromethane, washed with water, and then dried over magnesium sulfate. The crude product obtained by concentration was washed with hexane, and 2-tert-butyl-5,8-
75 g of dihydro-1,4-naphthohydroquinone was obtained as a pale red solid. Melting point 122-124℃ ¹ H-NMR (CDCl ₃ ): δ 1.39 (s, 9H), 3.23 (d, J = 1.5Hz, 4H),
4.35 (broad, 2H) 5.90 (broad s, 2H) 6.64 (s, 1H) Step 2 2-tert-butyl-5,8-dihydro-1,4
- 50 g of naphthohydroquinone was suspended in 300 ml of ethyl acetate, 300 mg of platinum dioxide was added, and hydrogen gas was passed into the flask and the mixture was stirred at room temperature. hydrogen gas
After 5.1 was consumed, the reaction mixture was filtered through Celite and the liquid was concentrated. The obtained crude product was washed with hexane, 2-tert-butyl-5,
39 g of 6,7,8-tetrahydro-1,4-naphthohydroquinone was obtained as a pale red solid. Melting point 134-135℃ ¹ H-NMR (CDCl ₃ ): δ 1.38 (s, 9H), 1.70-1.90 (m, 4H), 2.50-
2.70 (m, 4H), 4.40 (broad s, 2H), 6.63
(s, 1H) Step 3 Add 22 g of 2-tert-butyl-5,6,7,8-tetrahydro-1,4-naphthohydroquinone to acetic acid.
Suspend in 100 ml and add 10 ml of sulfuric acid while stirring at room temperature.
g was added slowly. The reaction mixture was stirred at room temperature for 20 minutes, poured into water, and extracted with dichloromethane. The organic layer was washed with water, dried over magnesium sulfate, and concentrated to obtain 21 g of the target compound as a pale yellow solid. Melting point 50-52℃ ¹ H-NMR (CDCl ₃ ): δ 1.27 (s, 9H), 1.60-1.80 (m, 4H), 2.30-
2.50 (m, 4H), 6.51 (s, 1H) Example 1 Production of 2,6-di-tert-butyl-4-pyrazinylimino-2,5-cyclohexadien-1-one [Compound 1] (method) 2 , 47 g of 6-di-tert-butyl-1,4-benzoquinone and 20 g of aminopyrazine were added to 300 ml of tetrahydrofuran and dissolved by heating. To this, add 35 ml of pyridine and 200 ml of dichloromethane in advance.
A yellow suspension prepared by dropping 12 ml of titanium tetrachloride was added to the solution under ice-cooling and stirring, and the mixture was heated under reflux for 1 hour. Furthermore, a mixed suspension of 70 ml of pyridine, 24 ml of titanium tetrachloride, and 200 ml of dichloroethane was added to the reaction compound, and after heating under reflux for 2 hours, a mixed suspension of 17 ml of pyridine, 6 ml of titanium tetrachloride, and 100 ml of dichloroethane was added, and the mixture was heated for 30 minutes. Heating to reflux was repeated. The reaction mixture was then cooled to room temperature and passed through Celite. The insoluble matter was washed with ethyl acetate, and the liquid was concentrated. The resulting crude product was purified by silica gel column chromatography (eluent; diethyl ether:hexane = 1:10 → 1:1), and purified with cold hexane. I washed it with Thus, 2,6-di-tert
58 g of -butyl-4-pyrazinylimino-2,5-cyclohexadien-1-one [Compound 1] was obtained as a yellow solid. (Method) 97.1 ml of pyridine was dissolved in 944 ml of dichloromethane, 32.9 ml of titanium tetrachloride was added thereto, and the mixture was heated under reflux for 5 minutes. Then 2,6-di-tert-butyl-
132.2 g of 1,4-benzoquinone and 57.1 g of aminopyrazine were added, and the mixture was heated under reflux for 42 hours. After the reaction mixture was cooled to room temperature, it was filtered through Celite, and insoluble materials were washed with dichloromethane. The crude product obtained by concentrating the liquid was subjected to silica gel column chromatography (diethyl ether:hexane=
3:7) to obtain 82.8 g of Compound 1. (Method) Dissolve 1.62ml of pyridine in 60ml of dichloroethane, add 0.89g of aluminum chloride powder,
The mixture was heated to reflux for 15 minutes. Then 2,6-di-tert-
2.20 g of butyl-1,4-benzoquinone and 0.95 g of aminopyrazine were added, and the mixture was heated under reflux for 17.5 hours.
After the reaction mixture was cooled to room temperature, it was filtered through Celite, and insoluble materials were washed with dichloromethane. The crude product obtained by concentrating the liquid was purified by silica gel column chromatography (diethyl ether:hexane=3:7) to obtain 1.73 g of Compound 1. (Method) 11.02 g of 2,6-di-tert-butyl-1,4-benzoquinone and 4.76 g of aminopyrazine were heated at 150° C. for 6 hours with stirring. After cooling the reaction compound to room temperature, it was purified by silica gel column chromatography (diethyl ether:hexane=1:4) to obtain 3.95 g of Compound 1. Obtained compound 1 biological (melting point and ¹ H-NMR
values) are shown in Table 1. Examples 2 to 29 Production of Compounds 2 to 29 2,6-dimethyl-1,4-benzoquinone, 2,6-diisopropyl-,4-benzoquinone , 2-tert-butyl-6-isopropyl-1,
4-benzoquinone, 2,6-di-tert-butyl-
1,4-benzoquinone, 2,5-di-tert-butyl-1,4-benzoquinone, 2,3,6-trimethyl-1,4-benzoquinone, 2-methyl-5,
6,7,8-tetrahydro-1,4-naphthoquinone, 2-tert-butyl-5,6,7,8-tetrahydro-1,4-naphthoquinone and 2-methyl-
From each of the 1,4-naphthoquinones and the aminodiazine derivative, the desired compound (compounds 2 to 2)
Compound 29) was produced. The structure and physical properties of each compound obtained are shown in Table 1 below. [Table] [Table] [Table] [Table] [Table] [Table] Example 30 2,6-di-tert-butyl-4-[3-(1,
Preparation of 2,4-triazinyl)imino]-2,5-cyclohexadien-1-one [Compound 30] Dissolve 33.6 ml of pyridine in 210 ml of dichloroethane, add 11.5 ml of titanium tetrachloride, and then 33.7 g of -tert-butyl-1,4-benzoquinone and 19.5 g of 3-amino-1,2,4-triazine were added, and the mixture was heated under reflux for 1.5 hours. After concentrating the reaction mixture, the obtained crude product was purified by silica gel column chromatography (chloroform:diethyl ether = 50:1) to obtain 2,6-di-
tert-butyl-4-[3-(1,2,4-triazinyl)imino]-2,5-cyclohexadiene-
8.0 g of 1-one [Compound 30] was obtained. Physical properties of the obtained compound 30 (melting point and ¹ H-NMR
The values are shown in Table 2. Example 31 Production of Compound 31 Desired Compound 31 was produced in the same manner as in Example 30. The structure and physical properties of the obtained compound are shown in Section 2 below.
Shown in the table. [Table] [Table] Example 32 Production of 2-N-(3,5-di-tert-butyl-4-oxo-2,5-cyclohexadienylidene)aminopyridine-4-oxide [Compound 32] Pyridine 1.62 ml was dissolved in 60 ml of dichloroethane, 0.55 ml of titanium tetrachloride was added thereto, and the mixture was heated under reflux for 15 minutes. Then 2,6-di-tert-butyl-
2.20 g of 1,4-benzoquinone and 1.11 g of 2-aminopyrazine-4-oxide were added, and the mixture was heated under reflux for 2 hours. After the reaction mixture was cooled to room temperature, it was filtered through Celite, and insoluble materials were washed with dichloromethane. The crude product obtained by concentrating the liquid was purified by silica gel column chromatography (eluent; diethyl ether: haxane = 2:3) to obtain compound 57.
Obtained 0.65 g as a yellow solid. Melting point: 152-153℃ ¹ H-NMR (CDCl ₃ ): δ 1.23 (s, 9H), 1.32 (s, 9H) 6.82 (d, J = 2.6Hz, 1H) 6.98 (d, J = 2.6Hz, 1H ) 7.93−7.95 (m, 2H), 8.32 (dd, J=3.5Hz,
1.5Hz, 1H) Example 33 Production of 2-N-(3,5-di-tert-butyl-4-oxo-2,5-cyclohexadienylidene)aminopyridine-1-oxide [Compound 33] 2, 30.0 g of 6-di-tert-butyl-4-pyrazinylimino-2,5-cyclohexadien-1-one [Compound 1] and 25.0 g of 70% 3-chloroperbenzoic acid were dissolved in 1000 ml of dichloromethane, and the mixture was heated at room temperature for 15 hours. Stirred. The reaction mixture was poured into 5% aqueous sodium bicarbonate, the organic layer was separated, and the aqueous layer was further extracted with dichloromethane. The organic layers were combined and washed with 5% sodium bicarbonate solution and then with water. After drying with magnesium sulfate, it was concentrated. The obtained crude product was purified by silica gel column chromatography (eluent: diethyl ether: hexane = 1:1 → diethyl ether → ethyl acetate) to obtain 2-N- as a yellow solid.
(3,5-di-tert-butyl-4-oxo-2,
1.8 g of Compound 33 was obtained along with 9.0 g of 5-cyclohexadienylidene)aminopyridine-4-oxide (Compound 32). The physical properties of the compound 33 are as follows. Melting point: 165-167°C ¹ H-NMR (CDCl ₃ ): δ 1.23 (broad s, 9H), 1.33 (broad s,
9H), 6.54 (broad s, 1H), 7.16 (broad
s, 1H), 8.14 (broad s, 1H), 8.24 (dd,
J=4.1Hz, 0.7Hz, 1H), 8.29(d, J=4.1
Hz, 1H)

Claims (1)

[Claims] 1 General formula [Formula] [In the formula, R ¹ represents a lower alkyl group. R ² represents a hydrogen atom or a lower alkyl group, R ³ represents a hydrogen atom or a lower alkyl group, or R ² and R ³ are bonded together to form a group -(CH ₂ ) ₄ - or a group -CH=CH-CH =
Indicates CH−. α is a 6-membered aromatic heterocyclic group containing 1 to 3 heteroatoms selected from nitrogen atoms, oxygen atoms, and sulfur atoms, pyrazine-N-oxide ring group, pyridazine-N-oxide ring group, or pyrimidine-N- Indicates an oxide ring group, and aromatic heterocyclic groups such as these include a lower alkyl group, a halogen atom, a phenyl group, a lower alkoxycarbonyl group,
1- selected from amino group and lower alkoxy group
It may have three pieces. However, the above aromatic complex 6
The membered ring group must not be a pyridine ring group or a 1,3,5-triazine ring group. ] A cyclohexadiene derivative represented by