JPH058691B2 - - Google Patents

Description

[Detailed description of the invention]

INDUSTRIAL APPLICATION FIELD The present invention relates to novel 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 purpose of the present invention is 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 ³ represents a hydrogen atom or a -CHR ⁴ -COOR ⁵ group (R ⁴ and R ⁵ are a hydrogen atom or a lower alkyl group, respectively), and when R ³ is a hydrogen atom, R ¹ and
One of R ² is an alkyl group having a hydroxyl group or a carboxyl group, and the other is an A-S(O)n- group (A is a lower alkyl group that may have a hydroxyl group, and n is 0, 1, or 2). show. Also R ³
is −CHR ⁴ −COOR ⁵ group, R ¹ is a lower alkyl group or

[Formula] represents a group, and R ² represents a hydrogen atom or a B-S- group (B is a phenyl group or a lower alkyl group that may have a lower alkyl group), or R ¹ and R ² both represent a Combine-
A (CH ₂ ) ₄ - group may be formed. ] In this specification, the term lower alkyl group refers to a straight chain or branched alkyl group having 1 to 6 carbon atoms, and specific examples thereof include methyl, ethyl, propyl, isopropyl. , butyl,
Included are isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, and the like. The term alkyl group refers to a linear or branched alkyl group having 1 to 20 carbon atoms, and specific examples thereof include heptyl, octyl, nonyl, decyl, undecyl, in addition to the lower alkyl groups listed above. , dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, nonadecyl, eicosyl groups, and the like. Among the naphthoquinone derivatives represented by the above general formula (1) of the present invention, those having a free carboxyl group can be, for example, salts of alkali metals such as sodium and potassium, and alkaline earth metals such as calcium and magnesium. , the present invention also includes such salts. The above-mentioned compounds of the present invention and their salts have an effect of blocking or regulating prostaglandin biosynthesis, and have anti-inflammatory, anti-rheumatic, anti-allergic, analgesic, diuretic, and platelet aggregation effects on animals, especially mammals. It exhibits various pharmacological effects such as inhibition and lowering of blood pressure. Therefore, they can be used as medicines such as anti-inflammatory agents, anti-rheumatic agents, anti-allergic agents, analgesics, diuretics, antithrombotic agents, and antihypertensive agents. The method for producing the compound of the present invention will be described in detail below. The compound of the present invention can be produced, for example, by the method shown in Reaction Scheme-1 below. [In each formula, R ¹ a, R ⁴ a and R ⁵ a each represent a lower alkyl group, and R ⁴ and R ⁵ are the same as above. ] Compound (2a) used as a starting material in the above reaction scheme-1 can be obtained, for example, as follows. That is, a method for free radical alkylation of quinone [Organic Synthesis]
Silver nitrate and ammonium persulfate [(NH ₄ ) ₂ S _2
Carbon-
2-lower alkyl-1,4-naphthoquinone obtained by forming a carbon bond, or commercially available 2-methyl-1,4-naphthoquinone, is mixed with an equimolar amount of 2-methyl-1,4-naphthoquinone in a suitable reducing agent such as hydrochloric acid and an acidic hydroalcohol. 3 times the molar amount of stannous chloride (SnCl ₂ 2H ₂ O) or 5% palladium on carbon, platinum oxide (PtO ₂ )
Catalytic reduction using hydrogen in an inert solvent in the presence of a catalytic hydrogenation catalyst such as
For example, it can be produced by methylation using dimethyl sulfate and an aqueous alkali hydroxide solution. The Friedel-Crafts reaction of compound (2a) obtained as above is performed by Rama Rao (AV
(Tetrahedron Letters, Vol. 23, 4373)
(1982)]. That is, the reaction is carried out using acetic anhydride in an amount of about 1.0 to 5.0 times the molar amount of compound (2a) and anhydrous aluminum chloride in a molar amount of about 1.0 to 5.0 times the amount of compound (2a), and an inert solvent, preferably 1,2- It is carried out in a solvent such as dichloroethane, carbon disulfide, nitromethane, dichloromethane, chloroform, etc. at about 20 to 80 °C, thereby:
The target compound (3a) can be produced in high yield. The reaction for obtaining compound (4a) from compound (3a) can follow the Willgerodt-Kindler reaction. That is, the reaction is 1.0 for compound (3a).
It is carried out by heating to about 100 to 130° C. using sulfur in a molar amount of ~5.0 times and morpholine in a molar amount of 1.0 to 10.0 times, followed by hydrolysis using an excess aqueous alkali hydroxide solution. The esterification reaction of compound (4a) obtained above can be carried out according to a conventional esterification reaction. That is, in the presence of an acid catalyst such as sulfuric acid or p-toluenesulfonic acid, in a lower alcohol, from about 50°C to
This can be easily carried out by heating to a temperature within the boiling point range of the solvent. The alkylation reaction of the compound (5a) thus obtained can also be carried out by a conventional method. For example, the alkylation reaction is carried out using an equimolar amount of a base such as sodium hydride or lithium diisopropylamide in a solvent such as dimethylformamide (DMF) or tetrahydrofuran (THF) at a temperature of -78 to 0°C. The reaction is carried out by deprotonating the active methylene of compound (5a), and then adding an equimolar amount of alkyl halide to cause the reaction. When introducing a methyl or ethyl group in the above alkylation reaction, the Tamura method [Journal of Medicinal Chemistry (J.
Med. (5a)
By adding 5.0 to 15.0 times the molar amount of alkyl halide and reacting at a temperature of 0 to 30°C, the desired alkylation reaction proceeds selectively. From compound (6a) obtained above, compound (7a) can be obtained by a usual hydrolysis reaction, preferably alkaline hydrolysis using an aqueous alkali hydroxide solution. Compound (4a) obtained by each of the above reactions
~Compound (7a) can be converted into a desired compound (1a) by subjecting them to an oxidation reaction. This oxidation reaction can be carried out, for example, with seric ammonium nitrate [(NH ₄ ) ₂ Ce(NO ₃ )
₆ ] (hereinafter referred to as “CAN”),
Alternatively, Johns oxidation reaction method can be followed. In more detail, the above method using CAN is carried out in an equimolar amount to 5 times the amount of each raw material compound (4a) to (7a) in a suitable solvent such as dioxane, acetonitrile, THF, dichloromethane, chloroform, or ether. About a molar amount, preferably about 2 to
It can be carried out using 2.5 molar amounts of CAN under temperature conditions of about -20 to 60°C, preferably about 0 to 30°C. In addition, the Johns oxidation reaction is typically described in the book by Fieser et al.
Four Organic Synthesis (Reagents)
for Organic Synthesis), Vol.142, Wiley,
New York (1967)]. As the Johns reagent, one prepared from, for example, 70 g of CrO ₃ , 500 ml of water, and 61 ml of concentrated H ₂ SO ₄ can be preferably used. The amount of Johns reagent to be used can be determined as appropriate, but it is usually an equivalent molar amount to 20 times the molar amount of the raw material compounds (4a) to (7a) as the amount of chromic acid, preferably an equivalent molar amount to 8 times the molar amount of the raw material compounds (4a) to (7a). Good. The reaction using the reagent is carried out using acetone, dioxane, ether, etc., preferably acetone, as a solvent at a temperature of about 0 to 50°C, preferably 0 to 25°C, and thus compound (1a) can be produced. . The compounds of the present invention can also be used in the following reaction schemes -2 to -3.
It can also be produced by the method shown below. [In each formula, R ⁶ represents a phenyl group. Also R ⁴ , R ⁴
a, R ⁵ and R ⁵ a are the same as above. ] According to Reaction Scheme-2, the compound (1b) of the present invention is produced as follows. That is, first, using 1,4-naphthoquinone (8) as a starting material, it is subjected to an addition reaction with a thiol (R ⁶ SH), and the resulting hydroquinone (9) is subjected to the above-mentioned methylation reaction to form a compound ( 2b).
The compound (2b) has an electron-donating group (R ⁶ S-) at the 2-position of its naphthalene ring, and therefore it is similar to the compound (2a) shown in the reaction scheme-1 above. can be subjected to a Friedel-Crafts reaction, resulting in the compound (3b)
were subsequently subjected to the same Bilgerott-Kindler reaction, esterification reaction, alkylation reaction and hydrolysis reaction to obtain compounds (4b) and 4b, respectively.
(5b), (6b) and (7b), and by subjecting these compounds to an oxidation reaction, the desired compound (1b) can be produced. The reaction of the above-mentioned 1,4-naphthoquinone (8) with thiols can be carried out by a conventional method, such as Patai et al. (S.
The Chemistry of the Patai)
Kinoid Campounds (The Chemistry of
the Quinoid Compounds, Parts 1, 2, Wiley,
New York, 1974)]. Each reaction after the methylation reaction following this reaction can be carried out in the same manner as shown in the reaction scheme-1 above. Especially compound (6b)
The oxidation reaction of compound (7b) is preferably carried out by the method using CAN. [In each formula, R ⁴ , R ⁴ a, R ⁵ and R ⁵ a are the same as above. ] According to Reaction Scheme-3, the compound (1c) of the present invention can be produced as follows using 1,4-naphthoquinone (8) as a starting material. That is, first, the 1,4-naphthoquinone (8) and butadiene are subjected to a Diels-Alder reaction in acetic acid, and then a small amount of alkali acetate is added to the reaction mixture to carry out an enolization reaction to obtain hydroquinone (10). This product is subjected to a methylation reaction in the same manner as shown in the reaction scheme-2 above, and then the unsaturated double bonds of the resulting compound (11) are hydrogenated under normal reducing conditions, for example in the presence of a PtO ₂ catalyst. and reduction to obtain compound (2c). Thereafter, compounds (3c) to (7c) were obtained by carrying out Friedel-Crafts reaction, Bilgerott-Kindler reaction, esterification reaction, alkylation reaction, and hydrolysis reaction shown in the reaction scheme-2, respectively. The desired compound (2c) can be produced by oxidation reaction of the compound. Furthermore, the compound of the present invention can also be produced by the methods shown in the following reaction schemes -4 and -5. [In the formula, R ¹ , R ⁴ and R ⁵ are the same as above. R ⁶ ' represents a lower alkyl group or a phenyl group that may have a lower alkyl group. ] In Reaction Scheme-4, the reaction between compound (1a) and thiols (R ⁶ 'SH) can be carried out in the same manner as the method for producing compound (2b) shown in Reaction Scheme-2 above. Examples of the inert solvent used in this case include lower alcohols such as methanol and ethanol, DMF, TGF, water, acetone, and mixed solvents thereof. The reaction is preferably carried out in an inert gas stream such as nitrogen or argon, using thiols in a molar amount usually 0.5 to 2 times, preferably about 1 to 1.1 times the amount of compound (1a), and about 0.
°C to about the boiling point temperature of the solvent, preferably about 20 to 80 °C
The process takes about 1 hour to 100 hours depending on the degree. In addition, according to the above reaction, a condensate represented by the following general formula (12) is produced as a by-product, but this condensate can be obtained by adding an excessive amount of ferric chloride aqueous solution into the reaction system, or Alternatively, it can be converted to the target compound (1d) by blowing oxygen (air) into it for oxidation. [In the formula, R ¹ , R ⁴ , R ⁵ and R ⁶ ' are the same as above] [In the formula, R ² a represents an alkyl group having a hydroxyl group or a carboxyl group, and R ⁷ represents a lower alkyl group that may have a hydroxyl group. ] In Reaction Scheme-5, 1,4-naphthoquinone (8) is treated with an alkyl dicarboxylic acid that provides an R ² a group by utilizing the free radical alkylation reaction of quinone already shown in Reaction Scheme-1 above. to produce a 1,4-naphquinone derivative (13) in which R ² a is an alkyl group having a carboxyl group.
Manufacture. Further, the compound (13) in which R ² a is an alkyl group having a hydroxyl group is the R ² a obtained above.
It can be produced by reducing a compound in which a is an alkyl group having a carboxyl group according to a conventional method, for example, with LiAlH ₄ and then performing air oxidation. The target compound (1e) can be obtained by subjecting the thus obtained compound (13) to an addition reaction with a thiol and a subsequent oxidation reaction shown in Reaction Scheme-4. Furthermore, the thiol compounds (1b), (1d), and (1e) of the present invention obtained by the methods shown in the above reaction schemes -2, -4, and -5 can be prepared by adding hydrogen peroxide, for example, by a conventional method. By carrying out an oxidation reaction using water, m-chloroperbenzoic acid, etc., the corresponding sulfoxide form (compound of n=1 in general formula (1))
and a sulfone compound (a compound where n=2 in general formula (1)). The above oxidation reaction can be carried out by a conventional method.
For example, in a suitable solvent such as acetic acid, chloroform, methylene chloride, etc., equimolar to about
This can be carried out by heating to a temperature ranging from about -20°C to the boiling point of the solvent in the presence of an oxidizing agent in a 3.0-fold molar amount. Further, the compound (1) of the present invention can be subjected to a reduction reaction using a conventional reducing agent such as stannous chloride, sodium borohydride, sodium hydrosulfide (Na ₂ S ₂ O ₄ ), etc. as shown in the following formula. By this, the corresponding hydroquinone form (1') can be obtained, and such hydroquinone form can be easily converted into the quinone form (1) by subjecting it to an oxidation reaction using, for example, air oxidation or ferric chloride. can be converted. The present invention provides such a quinone body (1)
It also includes hydromequinone (1'), which is a reduced form of . The target compounds and the compounds of the present invention obtained by the methods shown in the above reaction schemes can be easily separated in the reaction system by conventional separation means, and can be further purified if necessary. As this separation means and purification means, ordinary methods,
For example, a solvent extraction method, a recrystallization method, a column chromatography, etc. can be appropriately employed. Further, the salt formation reaction of the compound (1) of the present invention may be carried out according to a conventional method. Further, the compounds of the present invention have optical isomers, and the present invention naturally includes such isomers. EXAMPLES Hereinafter, in order to explain the present invention in more detail, production examples of compounds of the present invention will be given as examples, and production examples of raw material compounds will be given as reference examples. Reference Example 1 Production of 2-alkyl-1,4-dimethoxynaphthalene [compound (2a)] a From 2-methyl-1,4-naphthoquinone to the report by H.Rapoport et al. [Journal of American Chemical Society (J) .Am.Chem.Soc.), 96 , 8046
(1974)] to obtain 2-methyl-1,4-naphthohydroquinone. That is, 2-methyl-1,4-naphthoquinone
Suspend 1.72g in 100ml of ether, 10%
It was shaken with an aqueous Na ₂ S ₂ O ₄ solution until the color completely disappeared. The organic layer was washed with saturated brine, separated, dried and concentrated to obtain 1.57 g of the target compound. Melting point: 166°C (decomposed) In addition, as other alkyl-quinones, the following compounds were obtained by the following operations. b Production of 2-methyl-1,4-dimethoxynaphthalene Under an argon atmosphere, 25 g of 2-methyl-1,4-naphthoquinone was dissolved in a mixture of 500 ml of ethanol and 150 ml of methylene chloride, and SnCl ₂ 2H ₂
A solution of 4.5 g of O in 350 ml of water was added, and 35 ml of concentrated hydrochloric acid was further added, followed by stirring overnight at room temperature. The reaction mixture was concentrated, and the precipitated crystals were collected to obtain 2-methyl-1,4-naphthohydroquinone. Next, the above crystals were dissolved in a solution of 55 g of potassium hydroxide in 100 ml of water, and 73 ml of dimethyl sulfuric acid was gradually added under ice cooling, followed by further stirring at room temperature for 1 hour. The reaction mixture was transferred to water, extracted with ethyl acetate, and the organic layer was washed with water, dried, and concentrated.
Distilled under reduced pressure, boiling point 130-135℃/0.5mm
20g of Hg target was obtained. ¹ H-NMR (CDCl ₃ ): δppm 7.96-8.24 (2H, m) 7.30-7.61 (2H, m) 6.58 (1H, s) 3.94 (3H, s) 3.85 (3H, s) 2.43 (3H, s) c Production of 2-pentyl-1,4-naphthoquinone 50 g of 1,4-naphthoquinone, 55 g of hexanoic acid and 15.8 g of AgNO ₃ were added to 1.2 g of water.
and suspended in 400 ml of acetonitrile, and a solution of 79 g of (NH ₄ ) ₂ S ₂ O ₈ in 320 ml of water was added to this at 60°C.
It took 30 minutes to add. After that, under the same conditions, 1
After stirring for an hour, it was transferred to water, extracted with benzene, and the organic layer was washed with 5% NaHCO ₃ aqueous solution, dried, concentrated, and purified by column chromatography (ether:hexane = 1:30). Thus, 45 g of the target compound was obtained as an oil. ¹ H-NMR (CDCl ₃ ): δppm 8.00-8.23 (2H, m) 7.63-7.91 (2H, m) 6.77 (1H, t, J = 1.3) 2.56 (2H, bt, J = 6.8) 1.21-1.91 ( 6H, m) 0.91 (3H, t, J = 6.6) d Production of 2-pentyl-1,4-dimethoxynaphthalene Using 2-pentyl-1,4-naphthoquinone, reduce in the same manner as method b) above, Methylation gave an oil. This was subjected to column chromatography (ether: hexane = 1:70).
The target compound was obtained as an oil. ¹ H-NMR (CDCl ₃ ): δppm 7.97-8.31 (2H, m) 7.38-7.65 (2H, m) 6.60 (1H, s) 3.95 (3H, s) 3.86 (3H, s) 2.78 (2H, t, J=7.5) 1.25−1.95 (6H, m) 0.91 (3H, t, J=6.8) 2-R ⁶ S-Production of 1,4-dimethoxynaphthalene [compound (2b)] 20 g of 1,4-naphthoquinone and thio phenol
14 g was dissolved in 300 ml of acetone and stirred at room temperature for 20 hours under a stream of Algol. Then in the reaction mixture
_{40g Na2S2O4 , 90g K2CO3} and 72ml dimethyl sulfate
was added and refluxed for 20 hours. After separating the insoluble matter and washing with acetone, the mother liquor was concentrated and subjected to column chromatography (hexane → hexane: ethyl acetate =
1:10) to obtain 15 g of the target compound, 2-phenylthio-1,4-dimethoxynaphthalene.
was obtained as an oil. ¹ H-NMR (CDCl ₃ ): δppm 8.00-8.25 (2H, m) 7.20-7.70 (7H, m) 6.55 (1H, s) 3.97 (3H, s) 3.79 (3H, s) 5, 6, 7, Production of 8-tetrahydro-9,10-dimethoxyanthracene (compound (2c)) 1,4-naphthoquinone 40g and butadiene 20g
was dissolved in 150 ml of acetic acid and heated at 60°C for 20 hours.
3 g of sodium acetate was added to the reaction mixture, and the mixture was refluxed for 30 minutes. After cooling, the precipitated crystals were collected and further washed with ether/n-hexane (1:1) to obtain 30 g of 5,8-dihydro-9,10-dihydroxyanthracene. The compound obtained above was methylated in the same manner as shown in -b) above to obtain 20 g of 5,8-dihydro-9,10-dimethoxyanthracene (11).
I got it. ¹ H-NMR (DMSO-d ₆ ): δppm 7.95-8.05 (2H, m) 7.50-7.60 (2H, m) 6.03 (2H, bs) 3.93 (6H, s) 3.38 (4H, bs) Then, the above compound Dissolve in 280ml of DMF,
Add 400 mg of PtO ₂ and perform catalytic reduction under normal pressure and hydrogen flow to give 5,6,7,8-tetrahydro-9,10-
17 g of dimethoxyanthracene [compound (2c)] was obtained. Melting point: 113-116℃ ¹ H-NMR (CDCl ₃ ): δppm 7.97-8.08 (2H, m) 7.36-7.47 (2H, m) 3.86 (6H, s) 2.90-3.10 (4H, m) 1.70-2.00 ( 4H, m) 2-carboxyalkyl-1,4-naphthoquinone and 2-hydroxyalkyl-1,4-
Production of naphthoquinone [compound (13)] a 1,4-naphthoquinone 15.8g, adipic acid
34.5g and 5g of _AgNO3 in 375ml of water and _CH3
Dissolve in 125ml of CN mixture and add (NH ₄ ) ₂ S ₂ to this.
A solution of 30 g of O ₈ in 100 ml of water was added over 30 minutes at 60° C. and stirring was continued for a further 10 minutes. The reaction mixture was extracted with benzene, the organic layer was dried and concentrated, the obtained crystals were collected, and 2-
9.5 g of (4-carboxybutyl)-1,4-naphthoquinone was obtained. ^1H -NMR ( _CD3OD - _CDCl3 ): δppm 7.97-8.23 (2H, m) 7.65-7.90 (2H, m) 6.80 (1H, t, J = 1.3) 2.60 (2H, bt, J = 6.0) 2.37 (2H, t, J = 6.6) 1.50-2.00 (4H, m) b Dissolve 21g of the above compound in 25ml of THF, cool this on ice, and add 910mg of LiAlH ₄ to 70ml of THF.
ml and then refluxed for 3.5 hours. After acidification with dilute hydrochloric acid, extraction with ethyl acetate, drying and concentration of the organic layer, and column chromatography (chloroform: n-hexane = 10:1 ~
25:1) to obtain 1 g of 2-(5-hydroxypentyl)-1,4-naphthoquinone. Melting point 65-67℃ c In the above a), instead of adipic acid,
Using 1,10-decanedicarboxylic acid, 2-(10-carboxydecyl)-1,4
- Naphthoquinone was obtained. ¹ H-NMR (CDCl ₃ ): δppm 8.01-8.21 (2H, m) 7.65-7.91 (2H, m) 6.80 (1H, t, J = 1.3) 2.57 (2H, bt, J = 6.0) 2.33 (2H, t, J = 7.3) 1.15-1.93 (16H, m) Compounds (3a), (3b) and (3c) by FC reaction
Production of compounds (2a), (2b) and (2c) each at 18.3
1,2 mmol, 23 g of acetic anhydride and 54 g of AlCl ₃
-Dissolved in dichloroethylene 1 to 1 at 60℃
It was heated for 3 hours. The mixture was then transferred into ice-cooled dilute hydrochloric acid, extracted with methylene chloride, the organic layer was dried and concentrated, and the resulting crystals were recrystallized to obtain the target compound. Their physical properties are shown in Table 1 below.

【table】

[Table] Production of compounds (4a), (4b) and (4c) 10% each of compounds (3a), (3b) and (3c)
mmol was mixed with 1.8 g of morpholine and 640 mg of sulfur and heated at 130-135° C. for 1.5-5 hours.
The reaction mixture was transferred to water, extracted with methylene chloride,
To the compound obtained by concentrating the organic layer, add 3 to 15 g of potassium hydroxide to 20 to 50 ml of ethanol and 1 ml of water.
A solution of ~5 ml was added and refluxed for 20-48 hours. After cooling, the mixture was transferred to water, and the aqueous layer was washed with benzene, acidified with concentrated hydrochloric acid, and extracted with methylene chloride. The organic layer was dried and concentrated, and the resulting crystals were recrystallized from methylene chloride:hexane to obtain the target compound. The physical properties of each compound obtained are shown in Table 2. Production of compounds (5a), (5b), (5c) Each compound obtained above was dissolved in lower alcohol, a catalytic amount of concentrated sulfuric acid was added, and the mixture was refluxed for 3 to 20 hours to obtain the desired ester. . The reaction mixture was extracted with an organic solvent, the organic layer was washed with 5% _NaHCO3 and water, dried, concentrated,
It was further purified by column chromatography (ether:hexane system). The physical properties of each compound obtained are shown in Table 2. Production of compounds (6a), (6b), (6c) 18 mmol of each compound obtained above was dissolved in 60 ml of methylene chloride, and this was added with sodium hydroxide.
45 ml (23 g of NaOH dissolved in 290 ml of water), 12 g of tetra-n-butylammonium sulfate and 72 mmol of alkyl halide were added, and the mixture was stirred at 25° C. for 6 to 8 hours. The organic layer was then separated, and the mother liquor was concentrated and purified by column chromatography (ether:hexane system) to obtain the target compound. The physical properties of each compound obtained are shown in Table 2. Moreover, each of the compounds obtained above was dissolved in ethanol, and sodium hydroxide was added thereto for hydrolysis to obtain each of compounds (7a) to (7c). The physical properties of each compound are shown in Table 2 below.

[Table] No. Melting point or ¹ H-NMR (℃) (CDCl ₃ ) 1 85-86.5 2 127.5-128.5 3 65.5-66.5 4 143-143.5 5 98.5-100 6 132-133 7 8.09 (1H, d, J = 2.0), 7.98 (1H, d, J
= 8.8), 7.47 (1H, dd, J = 8.8, 2.0), 6.58
(1H, s), 4.12 (2H, q, J=7.0), 3.95 (3H,
s), 3.84 (3H, s), 3.85 (1H, q, J = 7.2),
2.42 (3H, s), 1.57 (3H, d, J=7.2), 1.19
(3H, t, J = 7.0) 8 7.98 (1H, d, J = 9.0), 7.93 (1H, d, J
= 1.7), 7.39 (1H, dd, J = 9.0, 1.7), 4.13
(2H, q, J=7.0), 3.86 (1H, q, J=7.2),
3.87 (3H, s), 3.86 (3H, s), 2.94 (2H, bs),
1.83 (2H, m), 1.58 (3H, d, J=7.2), 1.20
(3H, t, J=7.0) 9 8.08 (1H, d, J=1.8), (1H, d, J=
8.6), 7.44 (1H, dd, J=8.6, 1.8), 6.60 (1H,
s), 4.15 (2H, q, J = 7.0), 3.96 (3H, s),
3.86 (3H, s), 3.76 (2H, s), 2.78 (2H, bt),
1.25 (3H, t, J = 7.0), 0.80-2.00 (9H, m) 10 Not isolated 11 Not isolated 12 Not isolated 13 8.10 (1H, d, J = 1.8), 7.97 (1H, d, J
= 8.8), 7.46 (1H, dd, J = 8.8, 1.8), 6.60
(1H, s), 4.16 (2H, q, J=7.0), 3.96 (3H,
s), 3.85 (3H, s), 3.86 (1H, q, J = 7.2),
2.84 (2H, bt), 1.57 (3H, d, J=7.2), 1.27
(3H, t, J=7.0), 0.80-2.00 (9H, m) Example 1 Production of compounds (1a) to (1c) Oxidation reaction by CAN Compounds (4a) to (7c) obtained in the above reference example Dissolve 15.6 mmol of each in 200 ml of methylene chloride,
A solution of 21 g of CAN in 200 ml of water was added, and the mixture was shaken vigorously at room temperature. Thereafter, the organic layer was separated, dried, concentrated, and purified by column chromatography (ethyl acetate:methanol) to obtain the target compound in a yield of 60 to 80%. The physical properties of the obtained compound are shown in Table 3. Oxidation reaction using Johns reagent Compounds (4a) to (6c) obtained in the above reference example (excluding compounds (4b), (5b) and (6b)) were dissolved in 100 ml of acetone, and under ice cooling, the compounds (4a) to (6c) were dissolved in Johns reagent.
Added 18ml and continued stirring for 20-40 minutes. after that,
The reaction mixture was transferred to water, extracted with methylene chloride, the organic layer was dried, concentrated, and purified by column chromatography (ethyl acetate-methanol).
The target compound was obtained with a yield of 40-70%. The physical properties of the obtained compound are shown in Table 3. Example 2 Production of compounds (1d) and (1e) 3.3% each of compound (1a) and compound (13)
mmol was dissolved in a mixture of 20 ml of ethanol and 10 ml of DMF, and the thiol compound (HS-R ⁶ ') was added to this.
3.5 to 6.6 mmol was added, and stirring was continued at 25° C. for 20 to 72 hours (until disappearance of the starting compound was observed by thin layer chromatography). then 10%
50 ml of FeCl ₃ aqueous solution was added, and the mixture was further stirred for 2 hours.
The reaction mixture was transferred to water, extracted with ethyl acetate, the organic layer was dried and concentrated, and the crude product was purified by column chromatography (ethyl acetate:methanol) to obtain the target compound in a yield of 50-70%. I got it from The physical properties of the obtained compound are shown in Table 3. Example 3 Production of sulfoxide compound and sulfone compound 10 each of compounds (1b), (1d) and (1e)
mmol was dissolved in 200 ml of methylene chloride, 2.5 g of m-chloroperbenzoic acid (70%) was slowly added thereto under ice cooling, and stirring was continued for an additional 10 minutes. The reaction mixture was concentrated at below 30°C, and the crude product was purified by column chromatography (ethyl acetate-methanol) to obtain the target compound. The physical properties of the obtained compound are shown in Table 3 below.

【table】

【table】

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【table】

Claims (1)

[Claims] 1. General formula [In the formula, R ³ represents a hydrogen atom or a -CHR ⁴ -COOR ⁵ group (R ⁴ and R ⁵ are a hydrogen atom or a lower alkyl group, respectively), and when R ³ is a hydrogen atom, R ¹ and
One of R ² is an alkyl group having a hydroxyl group or a carboxyl group, and the other is an A-S(O) _o - group (A
represents a lower alkyl group which may have a hydroxyl group and n is 0, 1 or 2). Also, R ³ is −
When CHR ⁴ -COOR ⁵ groups, R ¹ represents a lower alkyl group or a [Formula] group, and R ² represents a hydrogen atom or a B-S- group (B is a phenyl group or a lower alkyl group that may have a lower alkyl group). ), or R ¹ and R ² are both bonded to -(CH ₂ ) ₄ -
It may also form a group. ] A naphthoquinone derivative and a salt thereof, characterized by the following: