JPH0432060B2 - - Google Patents

Description

[Detailed description of the invention]

INDUSTRIAL APPLICATION FIELD The present invention relates to naphthoquinone derivatives. Prior Art The naphthoquinone derivative of the present invention is a novel compound that has not been described in any literature. Problems to be Solved by the Invention The present invention aims to provide a compound useful as a pharmaceutical, as described later. Means for Solving the Problems According to the present invention, a naphthoquinone derivative represented by the following general formula (1) is provided. [In the formula, R ¹ represents a lower alkyl group. R ² is a lower alkyl group that may have a hydroxyl group as a substituent, a lower alkoxycarbonyl lower alkyl group,
lower alkylcarbonyloxy lower alkyl group,
Lower alkoxycarbonyloxy lower alkyl group, carboxy lower alkyl group or benzoyloxy lower alkyl group. R ³ is an alkyl group,
Hydroxy lower alkyl group, phenyl group that may have a lower alkyl group, halogen atom, lower alkoxy group, carboxy group, or carboxy lower alkyl group as a substituent, phenyl that may have a lower alkoxy group as a substituent on the phenyl ring It represents a lower alkyl group, a lower alkoxycarbonyl lower alkyl group, or a furanyl lower alkyl group. n represents 0, 1 or 2] In this specification, the term lower alkyl group is
It refers to a linear or branched alkyl group having 1 to 6 carbon atoms, and specific examples include methyl, ethyl, propyl, isopropyl, butyl,
Examples include isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl groups. In addition to the above-mentioned lower alkyl groups, the term alkyl group includes, for example, octyl, nonyl, decyl, undecyl, dodecyl,
Tetradecyl, hexadecyl, octadecyl, eicosyl groups, etc. are included. The term lower alkoxy group refers to a straight or branched alkoxy group having 1 to 6 carbon atoms, examples of which include methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butyloxy, and pentyloxy. ,
Examples include hexyloxy groups. Halogen atoms include chlorine, fluorine, iodine and bromine atoms. In general formula (1), the lower alkoxycarbonyl lower alkyl group, lower alkylcarbonyloxy lower alkyl group and lower alkoxycarbonyloxy lower alkyl group defined in R ² and R ³ are all the above-mentioned lower alkyl group or lower It contains an alkoxy group and the above lower alkyl group as constituent components. The carboxy lower alkyl group, benzoyloxy lower alkyl group and hydroxy lower alkyl group are the above-mentioned lower alkyl groups having a carboxy group, benzoyloxy group or hydroxy group as a substituent. Examples of phenyl lower alkyl groups that may have a lower alkoxy group as a substituent on the phenyl ring include benzyl, phenethyl,
Examples include unsubstituted phenyl lower alkyl groups such as phenylpropyl, phenylbutyl, phenylpentyl, and phenylhexyl groups, and lower alkoxy-substituted phenyl lower alkyl groups such as methoxybenzyl, ethoxybenzyl, methoxyphenethyl, and ethoxyphenylbutyl groups. Furthermore, a phenyl group that may have a lower alkyl group, a halogen atom, a lower alkoxy group, a carboxy group, or a carboxy lower alkyl group as a substituent may have a plurality of each of the above substituents on the phenyl ring, In this case, the substituents may be the same or different. The compound represented by the above general formula (1) of the present invention and its salt have an effect of blocking or regulating prostaglandin biosynthesis, and have anti-inflammatory, anti-rheumatic, anti-allergic, anti-inflammatory effects on animals, especially mammals. It exhibits effects such as pain, diuresis, platelet aggregation inhibition, and blood pressure lowering.
Therefore, it is useful as a medicine such as an anti-inflammatory agent, an anti-rheumatic agent, an anti-allergic agent, a pain agent, a diuretic, an antithrombotic agent, and an antihypertensive agent. The naphthoquinone derivative of the present invention can be produced, for example, by the method shown in each reaction scheme-1 below. [In the formula, R ¹ , R ² and R ³ are the same as above. R ² ′ represents a lower alkyl group, lower alkoxycarbonyl lower alkyl group, or carboxy lower alkyl group that may have a hydroxyl group as a substituent, and R ₂ ″ represents a lower alkylcarbonyloxy lower alkyl group, a lower alkoxycarbonyloxy lower alkyl group. or a benzoyloxy lower alkyl group.m is 1
shows. ] In Reaction Scheme-1, the reaction between compound (2) and the thiol compound (R ₃ SH) is carried out in an inert solvent. Examples of the solvent that can be used include lower alcohols such as methanol and ethanol, N,N-dimethylformamide (DMF), tetrahydrofuran (THF), dioxane, water, and mixed solvents thereof. The reaction is preferably carried out under an inert gas atmosphere such as nitrogen or argon, using a thiol compound in an amount of usually 0.5 to 2 times, preferably about 1 to 1.1 times the amount of compound (2), at about 0°C to a solvent temperature. This is carried out at about the boiling point of , preferably about 20 to 80°C, for about 1 to 50 hours. The above reaction produces an intermediate with the general formula A condensate represented by the formula [wherein R ¹ , R ² ' and R ³ are the same as above] is obtained. The condensate is then oxidized by adding an excess amount of an aqueous solution of ferric chloride into the reaction system or by blowing oxygen (air) into the reaction system, thereby obtaining compound (1-a). The obtained compound (1-a) can be easily converted into a sulfinyl form of compound (1-c) by oxidizing it. This oxidation reaction is carried out using an appropriate oxidizing agent, such as periodate salts such as sodium periodate and potassium periodate, organic peracids such as peracetic acid and m-chloroperbenzoic acid, and hydrogen peroxide. It can be carried out according to conventional methods. For more details,
The above oxidation reaction is carried out in lower alcohols such as methanol and ethanol, halogenated hydrocarbons such as dichloromethane and chloroform, organic solvents such as acetone, dioxane and acetic acid, or water-containing solvents thereof. The above-mentioned oxidizing agent is used in an amount of about 1 to 1.2 times the molar amount of the compound (1-a), for example, in the case of an organic peracid. The reaction is carried out at a temperature of about -20 to 30°C over a period of about 10 to 60 minutes. Further, among compounds (1-a), compounds in which R ² ' is a lower alkyl group having a hydroxyl group as a substituent,
By reacting this with an appropriate acid halide, the hydroxyl group is acylated to form compound (1-b).
It can be done. The acylation reaction is carried out in an aprotic solvent, preferably in the presence of an alkali, according to a conventional method. Examples of aprotic solvents that can be used include halogenated hydrocarbons such as dichloromethane and chloroform, ethers such as THF and dioxane, aromatic hydrocarbons such as benzene and toluene, and dimethyl sulfoxide (DMSO). Examples of acid halides used as acylating agents include halides of lower fatty acids such as acetyl chloride, acetyl bromide, and propionyl chloride; carbo-lower alkoxy chlorides such as carbomethoxy chloride, carboethoxy chloride, and carbopropoxy chloride; and benzoyl chloride. Examples include benzoyl halide. Examples of the alkali include organic amines such as pyridine and triethylamine, and inorganic compounds such as potassium carbonate and sodium carbonate. The amounts of acid halide and alkali to be used are not limited, but are usually about 1 to 5 times the molar amount, preferably about 1 to 1.5 times the molar amount of each compound (1-a). The above acylation reaction is generally carried out at a temperature of about 0 to 60°C, and is completed in about 0.5 to 5 hours, thus yielding compound (1-b). The oxidation reaction of the compound (1-b) is carried out in the same manner as the oxidation reaction of the above-mentioned compound (1-a), whereby the compound (1-c) can be obtained. The target products obtained by each of the above reactions can be easily isolated and purified by conventional separation means such as solvent extraction, recrystallization, column chromatography, etc. The compound used as a starting material in the above reaction scheme-1 can be obtained, for example, according to the following reaction scheme. [In each formula, R ¹ is the same as above. ] The compound (A) used as the starting material in the above reaction scheme-2 is known [J.Org.Chem., 44 , 2153
(1979)]. Bromination of compound (A) can be carried out, for example, by N-
This is carried out using a brominating agent such as bromosuccinimide (NBS). The brominating agent is preferably used in an equimolar amount to compound (A), and the reaction is carried out in an amount of about 0 to
It progresses well under the temperature condition of 80°C and is completed in about 2 to 16 hours. The lower alkoxylation of the compound (B) obtained above was carried out using methanol,
DMF using a sodium salt of a lower alcohol such as ethanol in an amount of 1 to 4 times the amount of compound (B).
and lower alcohols in a mixed solvent of about 80 to 120
It takes about 1 to 4 hours to carry out at ℃. At that time, copper salts such as cupric chloride, cuprous iodide, etc. are added to the compound (B).
The reaction will proceed more favorably if about 1/2 to 2 times the molar amount is used. Compound (C) is thus obtained. [In the formula, R ¹ is the same as above. R ⁴ is a lower alkyl group or benzyloxy lower alkyl group, R ⁴ ′ is a lower alkyl group that may have a hydroxyl group as a substituent, R ⁴ ″ is a lower alkyl group or carboxy lower alkyl group that may have a hydroxyl group as a substituent The Grignard reaction of the above-mentioned compound (C) can be carried out according to a conventional method, that is, using a Grignard reagent in a suitable solvent at about -20 to 60°C, preferably about 0 to 25°C. The Grignard reagent is prepared according to a conventional method by adding, for example, an alkyl halide, a phenyl lower alkyl halide, or a lower alkenyl halide and about 1.1 to 1.2 times the molar amount of magnesium per mole of these halides. It can be easily prepared from.As a solvent, ordinary ether, THF, etc. can be used.The amount of the Grignard reagent to be used is usually 1 to 5 times the molar amount of compound (C), preferably 5 times the molar amount of compound (C). It is desirable to set the amount at which the yellow color originally exhibited by the solvent solution disappears, which is usually about equimolar to 4 times the molar amount.
1) is obtained. The dehydration reaction of compound (C-1) is usually carried out in an organic solvent in the presence of an acid catalyst. Examples of solvents include benzene, ether, chloroform,
Dichloromethane etc. can be used. As the acid catalyst, for example, hydrogen chloride gas, p-toluenesulfonic acid, etc. can be used. The reaction proceeds well using a catalytic amount of the above-mentioned acid in a temperature range of about 0° C. to the boiling point of the solvent. The catalytic reduction reaction following the above dehydration reaction is carried out according to a conventional method, for example, using 5 to 10% palladium on carbon,
Alcohol, ethyl _acetate , DMF, water,
The reaction is carried out in a solvent such as ether under a hydrogen pressure of about 3 atm from normal pressure. In this way, debenzination of the raw material compound and reduction of double bonds are performed simultaneously, and compound (C-2) can be obtained. The oxidation reaction of compound (C-2) is carried out, for example, by the following two methods depending on the type of R ⁴ ″ group possessed by the target compound (C-3).
When producing a compound in which R ⁴ ″ is a lower alkyl group that may have a hydroxyl group as a substituent, the above oxidation reaction is preferably carried out using seric ammonium nitrate [(NH ₄ ) ₂ Cl(NO ₃ ) ₆ , hereinafter “ CAN] or silver oxide (AgO) in dilute nitric acid. The above method using CAN includes, for example, dioxane, acetonitrile, THF, dichloromethane,
In a solvent such as chloroform or ether, the compound (C
-2) using CAN in an equivalent molar amount to 5 times the molar amount, preferably 2 to 2.5 times the molar amount, about -20 to 60 ° C.
Preferably, the temperature is about 0 to 30°C. in dilute nitric acid
In the method using AgO, a compound (C
-2) using an equimolar to 20 times molar amount, preferably about 3 to 10 times the molar amount of AgO and about 6N nitric acid, at a temperature of 0 to the boiling point of the solvent, preferably 0 to 60°C. Implemented. In addition, when producing a compound in which the R ₄ ′ group is a carboxy lower alkyl group, the above oxidation reaction is performed using a Jones reagent to prepare the compound (C-2) in which R ⁴ ′ is a lower alkyl group having a hydroxyl group. Method [Reagents for
Organic Synthesis, Vol1, 142 , Wiley, New
York, 1967].
That is, the oxidation reaction is carried out using acetone, dioxane, ether, etc., preferably acetone, as a solvent at a temperature of about 0 to 30°C. The amount of John's reagent used is suitably an equivalent molar to 20 times the amount of croic acid, preferably 2 to 8 times the molar amount of compound (C-2). The raw material compound (C-
The hydroxyl group of 2) is converted into a carboxyl group, and at the same time, a naphthoquinone ring is formed by oxidation of the naphthalene ring, yielding the desired compound (C-3). Among the starting materials (2) in reaction scheme-1,
Those in which R ² ' is a methyl group or a hydroxymethyl group can be produced by a reduction reaction of compound (C) according to the following reaction scheme-4 and a subsequent oxidation reaction of the product compound (D). [In the formula, R ¹ is the same as above. R ² 〓 represents a methyl group or a hydroxymethy group. ] In the above, the reduction reaction of compound (C) can be carried out by a method using a hydride such as NaBH ₄ or LiAlH ₄ or by catalytic reduction according to a known method.
According to the reduction reaction using hydride, a compound (D) in which R ² is a hydroxymethyl group can be obtained. The catalytic reduction is carried out according to a conventional method, preferably using a small amount (catalytic amount) of perchloric acid, in the presence of a catalyst such as 5-10% palladium on carbon, PtO ₂ , Raney nickel, alcohol, ethyl acetate, DMF,
The reaction is carried out in a solvent such as water or ether under a hydrogen pressure of about normal pressure to about 10 atm, whereby a compound (D) in which R ² 〓 is a methyl group can be obtained. The oxidation reaction of the compound (D) thus obtained is carried out in the same manner as the oxidation reaction using CAN described above, thereby producing the compound (E). Among the compounds (C-3) shown in reaction scheme-3,
In particular, those in which R ⁴ ″ is a carboxymethyl group can also be obtained by the method shown in the following reaction scheme-5. [In each formula, R ¹ is the same as above. R ⁵ represents a lower alkyl group. ] According to the above method, compound (F) can be obtained by carrying out the carburizing reaction of compound (C) according to the Reformatsky reaction. The reaction is carried out by condensing compound (C) with α-haloacetate in a solvent such as benzene, toluene, xylene, etc. in the presence of zinc or the like. As the α-haloacetic acid ester, bromoacetic acid lower alkyl ester is preferably used. The amount used is usually equimolar to 5 times the molar amount, preferably equimolar to 3 times the molar amount of the compound (C), and zinc is usually equimolar to 5 times the molar amount of the compound (C). 5 times the molar amount, preferably equimolar to
It is preferable to use 3 times the molar amount. The reaction proceeds well at temperatures between about 50°C and the boiling point of the solvent. The dehydration reaction of the compound (F) thus obtained is usually carried out in an organic solvent in the presence of an acid catalyst. As the solvent, for example, benzene, ether, chloroform, dichloromethane, etc. can be used. As the acid catalyst, for example, hydrogen chloride gas, p-toluenesulfonic acid, etc. can be used. Using a catalytic amount of the above-mentioned acid, the reaction proceeds well in the temperature range of about 0° C. to the boiling point of the solvent, and Compound (G) can be obtained. The hydrolysis reaction of compound (G) is carried out according to a conventional method, and an alkaline hydrolysis method using an alkali hydroxide is particularly preferably employed. The alkali hydroxide is usually used in an equimolar to 20 times the molar amount of compound (G), and the reaction is carried out in alcohol, water, or a mixed solvent thereof at a temperature ranging from about 20°C to the boiling point of the solvent. It will be done. The hydrogenation reaction of the compound (H) obtained above is carried out according to the usual catalytic reduction reaction, for example, 5 to 10%
The reaction is carried out using palladium carbon, platinum oxide (PtO ₂ ), Raney nickel, etc. as a catalyst in a solvent such as alcohol, ethyl acetate, DMF, water, ether, etc. under a hydrogen pressure of from normal pressure to about 10 atmospheres. Moreover, the compound (I) obtained above is
Compound (J) can be derived by subjecting it to an oxidation reaction using CAN or an oxidation reaction using Jones's reagent. Of the raw material compounds (2) in reaction scheme-1
Those in which R ² ' is a lower alkoxycarbonyl lower alkyl group can be produced by the method shown in the following reaction scheme-6. [In the formula, R ¹ is the same as above. R ⁶ represents a carboxyalkyl group, and R ⁷ represents a lower alkoxycarbonylalkyl group. ] According to the above, compound (L) can be produced by esterification reaction of compound (K). The esterification reaction is preferably carried out using halides in the presence of an alkali. Examples of the halides include lower alkyl halides such as methyl iodide, methyl chloride, and isopropyl iodide. As the alkali, organic amines such as pyridine and triethylamine, potassium carbonate, sodium carbonate, etc. can be used. The reaction is carried out in a polar solvent such as DMF, DMSO, THF, etc. at a temperature of about 20-50°C. The amounts of alkali and halides to be used can be determined arbitrarily, but usually about 1 to 1 to 1,000 ml each per compound (K).
The amount is preferably 10 times the molar amount, preferably about 1 to 5 times the molar amount. [In the formula, R ¹ , R ² , R ³ and n are the same as above. ] The compound (1) of the present invention (quinone compound) can be converted to compound (M) (hydroquinone compound) by reducing it according to a conventional method. This reduction reaction can be carried out by a conventional method using well-known catalysts (catalytic hydrogenation catalysts) such as stannous chloride, sodium borohydride, and sodium hydrosulfide. For example, when using stannous chloride, the reaction is carried out in an aqueous alcohol under the acidity of hydrochloric acid in an amount of equimolar to 3 times the molar amount of compound (1).
It is carried out using SnCl ₂ .2H ₂ O at about -20 to 30°C.
In the case of sodium borohydride, the reaction is preferably carried out in an alcohol using about 1/2 to 3 times the molar amount of sodium borohydride as compound (1) at about 0 to 30°C. In the case of sodium hydrosulfide, it is used in the form of an aqueous solution of around 10% and the reaction proceeds in a solvent such as acetone, ether, dioxane, water, etc. at temperatures ranging from about 0°C to the boiling point. Compound (M) can also be prepared by air oxidation, ferric chloride,
It can be easily oxidized to the compound (1) of the present invention using an oxidizing agent such as silver oxide according to a conventional method. The above-mentioned ferric chloride is usually used in the form of an aqueous solution in an amount of equivalent to 20 times the mole of compound (M), and in this case, the reaction is carried out in a solvent such as THF, alcohol, water, etc.
Conducted at °C. Further, silver oxide is used in an amount of equimolar to 20 times the molar amount of compound (M), and in this case, the reaction is carried out in a solvent such as ether, acetone, dioxane, THF, etc. at about 0 to 30°C. The target products obtained by each of the above reactions can be easily isolated and purified by conventional separation means such as solvent extraction, recrystallization, column chromatography, etc. Among the compounds (1) of the present invention, those having a free carboxyl group can be alkali metal salts, such as sodium salts, potassium salts, etc., and alkaline earth metal salts, such as calcium salts, magnesium salts, etc. These salt-forming reactions can be carried out according to conventional methods. The salts thus obtained also have the same pharmacological activity as the free form of the compound of the present invention and are included within the scope of the present invention. Further, the compounds of the present invention may have optical isomers and geometric isomers, and such isomers are also included within the scope of the present invention. Examples Hereinafter, production examples of raw material compounds for producing the compounds of the present invention will be listed as reference examples, and then production examples of the compounds of the present invention will be listed as examples. Reference Example 1 Production of 4,5,8-trimethoxy-1-naphthaldehyde 4,8-dimethoxy-1-naphthaldehyde
Dissolve 195 g in 800 ml of dimethylformamide (DMF), and add 800 ml of a DMF solution of 160 g of N-bromosuccinimide (NBS) to this under ice cooling.
The reaction mixture was stirred overnight and then transferred to approx.
Take the precipitated crystals and wash them with water. The resulting crude crystals are dried under reduced pressure to obtain 240 g (90%) of 5-bromo-4,8-dimethoxy-1-naphthaldehyde. NMR analysis (CDCl ₃ , δ value) 10.78 (1H, s) 7.88 (1H, d, J=8.3) 7.72 (1H, d, J=8.3) 6.93 (1H, d, J=8.3) 6.77 (1H, d , J=8.3) 3.99 (3H, s) 3.97 (3H, s) This product can be used in the next reaction without purification. Then, 77.5 parts sodium to 1 part absolute methanol
155 g of copper (I) iodide (Cu) and 1 DMF are added to the solution in which g is dissolved, and 240 g of the bromine compound obtained above is added to the resulting mixed solution, and the mixture is refluxed for 1 hour. Impurities were separated from the reaction mixture, and about 6 g of water was added to the mother liquor to precipitate crystals, which were collected and washed with 10% hydrochloric acid, then with water, and then with isopropyl alcohol and then with ether to obtain the target compound. 140 g (70%) of crude crystals are obtained. NMR analysis (CDCl ₃ , δ value) 10.78 (1H, s) 7.91 (1H, d, J = 8.6) 6.90 (1H, d, J = 8.6) 6.87 (2H, bs) 4.01 (3H, s) 3.93 (3H , s) 3.91 (3H, s) This product can also be used in the next reaction without further purification. Reference Example 2 Production of 1-hydroxymethyl-4,5,8-trimethoxynaphthalene 4,5,8-trimethoxy-naphthalene obtained in Reference Example 1
8 g of 1-naphthaldehyde was dissolved in 200 ml of ethanol and 200 ml of THF, heated at 60°C, and stirred.
Gradually add 2g of _NaBH4 . After stirring for 1 hour, the reaction mixture was acidified with 3% HCl.
After extraction _{with CH2Cl2} , drying ( _MgSO4 ) and concentration,
The obtained crude crystals are recrystallized from a mixed solvent of chloroform and hexane to obtain 6.5 g (82%) of the desired product as white crystals. Melting point: 112.5-113.5°C Reference Example 3 Production of 1-methyl-4,5,8-trimethoxynaphthalene 4,5,8-trimethoxy-1 obtained in Reference Example 1
- 3 g of naphthaldehyde in 50 ml of acetic acid and 70%
Dissolved in 0.1 ml of HClO ₄ and added 700 mg of 10% Pd-C.
Hydrogenation is carried out at 25°C under normal pressure. Stirring was continued for 3.5 hours, the catalyst was separated, water was added to the liquid and CH ₂ Cl ₂
Extract, wash the organic layer with 5% _NaHCO3 aqueous solution,
Thereafter, the crystals obtained by washing with water, drying (MgSO ₄ ), and concentration are recrystallized from a mixed solvent of chloroform and hexane to obtain 1.95 g (70%) of the desired product as white crystals. Melting point 95-96.5℃ Reference example 4 3-[1-(4,5,8-trimethoxy)naphthyl)acrylic acid 4,5,8-trimethoxynaphthaldehyde 23
g, a mixed solution of 20 g of zinc plate and 600 ml of benzene,
Add 28 ml of methyl bromoacetate over about 1 hour while stirring at reflux. Thereafter, after continuing to heat under reflux for 30 minutes, the reaction mixture was transferred to water, the insoluble matter was separated and washed with methylene chloride, and the liquid was extracted with methylene chloride. After drying (MgSO ₄ ), concentration, and purification by column chromatography (silica gel, methylene chloride: ethyl acetate = 3:1), 3-hydroxy-3
-[1-(4,5,8-trimethoxy)naphthyl]
12 g (40%) of propionic acid methyl ester are obtained as pale yellow crystals. Melting point: 105-107°C Next, 10g of the compound obtained above was added to chloroform.
Dissolve in 500 ml, add 5 ml of ethanolic hydrochloric acid (90 g HCl gas/900 ml EtOH), and leave at room temperature for 2.5 hours. Thereafter, after drying with anhydrous K ₂ CO ₃ , the solvent is distilled off, and the obtained crystals are recrystallized from a mixed solvent of chloroform and hexane to obtain 9 g (95%) of a dehydrated product as yellow crystals. 4.3 g of 3-[1-(4,5,8-trimethoxy)naphthyl]acrylic acid methyl ester thus obtained was mixed with 150 ml of methanol and 70 ml of 2NNaOH, and the mixture was refluxed for 30 minutes. After cooling, acidify with concentrated hydrochloric acid, remove precipitated crystals, and wash with water. 4g of yellow crystals when dried
(97%) in 3-[1-(4,5,8-trimethoxy)
Obtain naphthyl acrylic acid. Reference Example 5 Production of 3-[1-(4,5,8-trimethoxy)naphthyl]propionic acid 4 g of 3-[1-(4,5,8-trimethoxy)naphthyl]acrylic acid obtained in Reference Example 4 was added to 300 ml of DMF.
The mixture was dissolved in 300 ml of ethanol, 1 g of 10% Pd-C was added, and hydrogenated at 25°C under normal pressure. After about 2 hours, the catalyst is separated, the solvent is distilled off, and the resulting crystals are recrystallized from a mixed solvent of chloroform and hexane to obtain 3.7 g (92%) of the desired product. Melting point 168-170℃ Reference example 6 5-hydroxymethyl-8-methoxy-1,4
-Production of naphthoquinone 8 g of 1-hydroxymethyl-4,5,8-trimethoxynaphthalene was dissolved in 100 ml of methylene chloride, and 44 g of CAN dissolved in 150 ml of water was added thereto, stirred for 15 minutes, and then the organic layer was separated. Wash with water,
The crystals obtained by drying (MgSO ₄ ) and concentrating are
Recrystallize with a mixed solvent of chloroform and ethyl ether to obtain 5.3 g (75%) of the desired product as yellow crystals. Melting point: 165-167°C (decomposed) Yellow crystals of 5-methyl-8-methoxy-1,4-naphthoquinone are obtained from 1-methyl-4,5,8-trimethoxynaphthalene in a similar manner. Melting point 116-117.5℃ Reference example 7 5-(2-carboxyethyl)-8-methoxy-
Production of 1,4-naphthoquinone 5 g of 3-[1-(4,5,8-trimethoxy)naphthyl]propionic acid is dissolved in 500 ml of acetone, 36 ml of Johns reagent is added under ice cooling, and the mixture is stirred for 30 minutes. The reaction mixture was transferred to water, extracted with methylene chloride, and the organic layer was dried (MgSO ₄ ) and concentrated. The crude crystals obtained were recrystallized from a mixed solvent of chloroform and ethyl ether to obtain 3 g of the target compound as yellow crystals. obtain. Melting point 167-168.5°C (decomposition) Reference example 8 Production of 5-(2-methoxycarbonylethyl)-8-methoxy-1,4-naphthoquinone 5-(2-carboxyethyl)-8-methoxy-
2.6 g of 1,4-naphthoquinone, 2.5 g of K ₂ CO ₃ and 3 ml of methyl iodide are mixed in 50 ml of DMF and stirred at 25° C. for 16 hours. The reaction mixture was transferred to water, extracted with ethyl acetate, the organic layer was washed with water, dried (MgSO ₄ ) and concentrated, and the resulting crystals were recrystallized from a mixed solvent of ethyl acetate and hexane to give 2 g (72%) of yellow Obtain the crystal object. Melting point 123.5-125°C Example 1 Production of 8-hydroxymethyl-5-methoxy-2-benzenesulfenyl-1,4-naphthoquinone 8-hydroxymethyl-5-methoxy-1,4
- A mixture of 1.0 g of naphthoquinone, 510 mg of thiophenol, 60 ml of ethanol and 20 ml of DMF is stirred for 5 hours. Thereafter, 50 ml of 10% FeCl ₃ solution was added and stirring was continued for an additional hour. The reaction mixture was transferred to water and precipitated with ethyl acetate. The organic layer was washed with water, dried (MgSO ₄ ), and concentrated. The resulting crystals were recrystallized from a mixed solvent of ethyl acetate and ether to give 900 mg of the target compound as yellow crystals. obtained as. Melting point 144-145℃ (decomposition) ¹ H-NMR (CDCl ₃ ) 7.71 (1H, d, J = 8.1Hz) 7.26 (1H, d, J = 8.1Hz) 7.50 (5H, bs) 6.00 (1H, s) 4.74 (2H, d, J = 7.2Hz) 4.02 (3H, s) 3.07 (1H, t, J = 7.2Hz) Examples 2 to 20 Each compound shown in Table 1 below is obtained in the same manner as in Example 1. . Note that Table 1 also lists the compounds obtained in Example 1.

【table】

[Table] Example 21 8-hydroxymethyl-5-methoxy-2-n
-Production of butanesulfinyl-1,4-naphthoquinone 8-hydroxymethyl-5-methoxy-2-n
-butanesulfenyl-1,4-naphthoquinone
Dissolve 1.6 g in 150 ml of methylene chloride and add m
- Gradually add 1.3 g of chlorperbenzoic acid (70%);
Then continue stirring for 15 minutes. Separate the insoluble matter,
Wash the solution with 5% NaHCO ₃ aqueous solution, then with water,
The compound obtained by drying (MgSO ₄ ) and concentration is subjected to silica gel chromatography and developed with chloroform to obtain 1 g of the target compound as yellow crystals. Melting point 139.5-141℃ (decomposition) NMR (CDCl ₃ ) 7.85 (1H, d, J = 8.5Hz) 7.31 (1H, d, J = 8.5Hz) 6.50 (1H, s) 4.83 (2H, d, J = 7.0 Hz) 4.01 (3H, s) 3.37 (1H, t, J = 7.0Hz) 2.81 (2H, t, J = 7.0Hz) 1.3-1.8 (4H, m) 0.97 (3H, t, J = 6.6Hz) Implementation Examples 22 to 25 The compounds shown in Table 2 below are obtained in the same manner as in Example 21. Note that the compound of Example 21 is also listed in Table 2.

[Table] Example 26 8-acetoxymethyl-5-methoxy-2-p
-Production of toluenesulfenyl-1,4-naphthoquinone 8-hydroxymethyl-5-methoxy-2-p
-Toluenesulfenyl-1,4-naphthoquinone
Dissolve 680 mg in 10 ml of chloroform and add 200 mg of pyridine.
A solution of 150 mg of acetyl chloride in 2 ml of chloroform was added dropwise under ice cooling. After continuing stirring for 1 hour, the reaction mixture was transferred to water, extracted with chloroform, and the organic layer was washed with water, dried (MgSO ₄ ),
The compound obtained by concentration is subjected to silica gel chromatography and developed with a mixed solvent of chloroform and n-hexane to obtain 540 mg of the target compound as yellow crystals. Melting point 148-150℃ (decomposition) NMR (CDCl ₃ ) 7.73 (1H, d, J = 8.8Hz) 7.41 (2H, d, J = 8.3Hz) 7.35 (1H, d, J = 8.9Hz) 7.26 (2H, d, J=8.3Hz) 6.00 (1H, s) 5.57 (2H, s) 3.96 (3H, s) 2.41 (3H, s) 2.18 (3H, s) Examples 27 and 28 Follow the steps below in the same manner as Example 26. Each compound shown in Table 3 is obtained. Note that the compound of Example 26 is also listed in Table 3.

【table】

Claims (1)

[Claims] 1. General formula [In the formula, R ¹ represents a lower alkyl group. R ² is a lower alkyl group that may have a hydroxyl group as a substituent, a lower alkoxycarbonyl lower alkyl group,
lower alkylcarbonyloxy lower alkyl group,
Lower alkoxycarbonyloxy lower alkyl group, carboxy lower alkyl group or benzoyloxy lower alkyl group. R ³ is an alkyl group,
Hydroxy lower alkyl group, phenyl group that may have a lower alkyl group, halogen atom, lower alkoxy group, carboxy group, or carboxy lower alkyl group as a substituent, phenyl that may have a lower alkoxy group as a substituent on the phenyl ring It represents a lower alkyl group, a lower alkoxycarbonyl lower alkyl group, or a furanyl lower alkyl group. n represents 0, 1 or 2] A naphthoquinone derivative and a salt thereof.