JPS61268650A - Naphthoquinone derivative - Google Patents

Abstract

NEW MATERIAL:The 1,4-naphthoquinone derivative of formula I [R<3> is H or CHR<4>COOR<5> (R<4> and R<5> are H or lower alkyl); when R<3> is H, R<1> and R<2> are alkyl having OH or COOH, or AS(O)n (A is lower alkyl which may have OH group; n is 0, 1 or 2), when R<3> is CHR<4>COOR<5>, R<1> is lower alkyl or group of formula II and R<2> is H or BS (B is phenyl which may have lower alkyl, or lower alkyl), or R<1> and R<2>. together form (CH2)4] and its salt. USE:A medicinal drug having the action to block or control the biosynthesis of prostaglandin, and useful as an anti-inflammatory agent, antirheumatic agent, anti-allergic agent, analgesic agent, diuretic agent, antithrombotic agent, hypotensive agent, etc. PREPARATION:The compound of formula IV which is one of the compounds of formula I can be produced by oxidizing the compound of formula III (R<1a> is lower alkyl; R<4a> and R<5a> are R<4> and R<5>) with ceric ammonium nitrate or John's oxidization reagent.

Description

[Detailed description of the invention] Industrial applications The present invention relates to novel naphthoquinone derivatives.

Background of the Invention The naphthoquinone derivative of the present invention is a novel compound that has not been described in any literature.

p-problem that the invention seeks to solve.

An object 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.

O (in the formula, R3 represents a hydrogen atom or a -CHR'-GOOR5 group (R' and R5 are each a hydrogen atom or a lower alkyl group), and when R3 is a hydrogen atom, R1 and R2 are each a hydroxyl group or a carboxyl group. an alkyl group having a group or an A-8(0)n-group (A
It's water! ! A lower alkyl group that may have a group and n
is 0, 1 or 2). Further, when R3 is -CHRA-COOR51, R1 represents a lower elementary atom or a B-8- group (B is a phenyl group or a lower alkyl group that may have a lower alkyl group), or R
1 and R2 may be bonded together to form a -(CH2)z- group. [In this specification, the term lower alkyl group refers to a linear or branched alkyl group having 1 to 6 carbon atoms, and specific examples thereof include methyl, ethyl, propyl, isopropyl. , butyl, inbutyl, 5
eC-butyl, tert-butyl, pentyl, hexyl groups, etc. are included. Also, the word alkyl group has 1 carbon number
~20 linear or branched alkyl groups, specific examples of which include heptyl, in addition to the lower alkyl groups exemplified above.
Included are octyl, nonyl, decyl, undecyl, 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 include, for example, alkali metals such as sodium and potassium, calcium,
It can be a salt of an alkaline earth metal such as magnesium, and the present invention also includes such salts.

The above-mentioned compounds of the present invention and their salts all have blocking and regulating effects on prostaglandin biosynthesis, and have anti-inflammatory, anti-rheumatic, anti-allergic, analgesic, diuretic, and platelet effects on animals, especially mammals. It exhibits various pharmacological effects such as inhibiting aggregation and lowering blood pressure. Therefore, these include anti-inflammatory agents, anti-rheumatic agents, anti-allergic agents, analgesics, diuretics, antithrombotic agents,
It can be used as a medicine such as an antihypertensive agent.

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.

Reaction scheme-1> (2a) (3a) (1a)
(7a) [RI a, R in each formula
43 and R5a each represent a lower alkyl group, and R4 and R5 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,
Free radical alkylation method of quinone [Organic Syntheses]
), Vat. 56, p.68), known 1,4-naphthoquinone and lower alkylcarboxylic acid were mixed with silver nitrate and ammonium persulfate ((NHL)).
2-lower alkyl-1,4-naphthoquinone obtained by radically reacting with 2S208) to generate a carbon-carbon bond, or commercially available 2-methyl-1,4-naphthoquinone, A suitable reducing agent, for example, equimolar to 3 times the molar amount of stannous chloride (SnC20.2H20) or a catalyst for catalytic hydrogenation such as 5% palladium on carbon, platinum oxide (PI02), etc. in hydrochloric acid acidic aqueous alcohol. Catalytic reduction using hydrogen in an inert solvent in the presence of hydrogen, and then the resulting hydroquinones are methylated according to a conventional method (methylation reaction of phenols) using, for example, dimethyl sulfate and an aqueous alkali hydroxide solution. It can be manufactured by

The Friedel-Crafts reaction of compound (2a) obtained as described above was carried out by Rama Rao (A.V.).

[Tetrahedron letters],
Vol. 23.

4373 (1982)). That is, the reaction is about 1.0% for compound (2a).
An inert solvent,
Preferably, the reaction is carried out in a solvent such as 1,2-dichloroethane, carbon disulfide, nitromethane, dichloromethane, or chloroform at about 20 to 80°C, thereby producing the target compound (3a) in high yield. can do.

The reaction to obtain compound (4a) from compound (3a) is performed according to Willgerott-Kindler (Willgerod-Kindler).
t-Kindler) reaction.

That is, the reaction is 1.0 to 5.0% with respect to compound (3a).
It is carried out by heating to about 100 to 130° C. using 0 times the molar amount of sulfur and 1.0 to 1060 times the molar amount of morpholine, 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, it can be easily carried out by heating in a lower alcohol in the presence of an acid catalyst such as sulfuric acid or p-toluenesulfonic acid to a humidity in the range of about 0° C. to the boiling point of the solvent.

The alkylation reaction of the compound (5a) thus obtained can also be carried out according to a conventional method. For example, the alkylation reaction is carried out using an equimolar amount of a base such as sodium hydride or lithium diimbu Oviramide in a solvent such as dimethylformamide (DMF) or tetrahydrofuran (THF) at a temperature of -78 to 0°C. The active methylene of compound (5a) is then deprotonated, and then an equimolar amount of alkyl halide is added and the reaction is carried out.

When introducing a methyl or ethyl group in the above alkylation reaction, Yamamura's method (Journal Op.
Medicinal Chemistry (J.

Med. CheIIl. ), Vol. 24.
43 (1981)), compound (5a) and its 5.0'- 1 5
．． Add 0 times molar amount of alkyl halide and heat to 0 to 30℃
By carrying out the reaction under the temperature conditions, the desired alkylation reaction proceeds selectively.

Compound (7a) can be obtained from compound (6a) obtained above by a conventional hydrolysis reaction, preferably alkaline hydrolysis using an aqueous alkali hydroxide solution.

Compounds (4a) to (7a) obtained by each of the above reactions can each be converted into a desired compound (1a) by subjecting them to an oxidation reaction. This oxidation reaction can be carried out by, for example, a method using seric ammonium nidrade ((NH4)2Ce(NO3)s) (hereinafter referred to as rcANJ) or a Jones oxidation reaction method.

In more detail, the above method using CAN is carried out in an equivalent molar 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. It can be carried out using a molar amount of CAN, preferably about 2 to 2.5 molar amounts, under temperature conditions of about -20 to 60°C, preferably about 0 to 30°C. In addition, the Jones oxidation reaction is
For example, a typical book by Fieser et al.
ts for Organic 5 synthesis
), Vol.

142, Wiley, New York (1967)
) using the Jones reagent described in . As the Jones reagent, one prepared from, for example, 370 g of Cr, 500 g of water, and 46 liters of concentrated H2H2SO can be preferably used. The amount of Jones reagent to be used can be determined as appropriate, but usually the amount of raw material compound (4a) to
It is preferable to use an equimolar amount to 20 times the molar amount of (7a), preferably an equimolar amount to 8 times the molar amount. The reaction using the reagent is carried out using, for example, acetone, dioxane, ether, etc., preferably acetone, as a solvent at a temperature of about 0 to 50°C, preferably 0.
It was carried out under temperature conditions of ~25°C, thus compound (1
a) can be produced.

The compound of the present invention can also be produced by the methods shown in reaction schemes -2 to -3 below.

<Reaction scheme-2><8) (9) (2b
) (3b) (1b)
(7b) (In each formula, R6 represents a phenyl group or a lower alkyl group. Also, R', R'
a s R5 and R5a are the same as above. ] According to reaction scheme-2, the compound (1b) of the present invention is:
It is manufactured as follows. That is, first, 1,4-naphthoquinone (8) is used as a starting material, and this and thiols (R
'SH), and the resulting hydroquinones (9) are subjected to the above-mentioned methylation reaction to form compound (2).
b) obtain.

The compound (2b) has an electron-donating group (Re S-) at the 2-position of its naphthalene ring, and therefore, like the compound (2a) shown in the reaction scheme-1 above, The Friedel-Crafts reaction can be carried out, and the resulting compound (3b) can be similarly obtained by Bilgelot-Crafts reaction.
Compound (4b) can be obtained by Kindler reaction, esterification reaction, fullkylation reaction and hydrolysis reaction.
, (5b), (6b) and (7b),
By subjecting each of these compounds to an oxidation reaction, the desired compound (1b) can be produced.

The reaction of the above 1,4-naphthoquinone (8) with thiols can be carried out by a conventional method, for example, as described by Batai et al. (S.

The Chemistry of Zakinoid Cumbounds
of the Quinoid Coa+poun
ds, Partsl, 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. In particular, compound (6b) and compound (7b)
The oxidation reaction of ) is preferably carried out by the method using CAN.

<Reaction scheme-3> (11) (2c) (3c)
(4c) (lc)
(7c) [R', R' a % in each formula
R5 and R5a are the same as above. ] According to reaction scheme-3, the compound (1C) of the present invention is:
It 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 cause 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 the resulting compound (
11) under normal reducing conditions, e.g. Pt
Water* is added in the presence of an O2 catalyst to reduce the compound (2C
). Thereafter, the Friedel-Crafts reaction, Bilgerott-Kindler reaction, esterification reaction, alkylation reaction, and hydrolysis reaction shown in the reaction scheme-2 are performed to obtain compounds (3C) to (7C), respectively. The target compound (2C) is obtained by oxidation reaction of each compound.
can be manufactured.

Furthermore, the compound of the present invention can also be produced by the methods shown in the following reaction schemes -4 and -5.

<Reaction Scheme-4> (1a) (1d) [In the formula, R1, R4 and R5 are the same as above. R6 represents a lower alkyl group or a phenyl group that may have a lower alkyl group. ] Reaction scheme-4 can be carried out using compound (1a). Examples of inert solvents used in this case include lower alcohols such as methanol and ethanol, and DMF.
, T) (F, water, acetone, etc.).The reaction is preferably carried out in an inert gas stream of nitrogen, argon, etc., and the thiols are added to the compound (1a), usually at 0%.
．． Use 5 to 2 times the molar amount, preferably about 1 to 1.1 times the molar amount, and use the temperature of about 10°C to about the boiling point of the solvent, preferably about 20°C to about the boiling point temperature of the solvent.
This is carried out at about 80° C. for about 1 hour to 100 hours. According to the above reaction, the following general formula (
A condensate represented by 12) is produced as a by-product, and this condensate is
The desired compound (1d) can be converted by adding an excess amount of ferric chloride aqueous solution into the reaction system or by blowing oxygen (air) into the reaction system for oxidation.

(In the formula, R1, R4, R5 and R8 are the same as above.) Reaction scheme-5 (1e) (In the formula, R2a represents an alkyl group having a hydroxyl group or a carboxyl group, and R7 represents an alkyl group having a hydroxyl group. Indicates a certain lower alkyl group.] In reaction scheme-5, 1
, 4-naphthoquinone (8) has already been subjected to the reaction scheme-1.
Utilizing the 7-radical alkylation reaction of quinone shown in Figure 1, a 1,4-naphquinone derivative (13) in which R2a is an alkyl group having a carboxyl group is obtained by reacting an alkyldicarboxylic acid that provides an R2B group. Manufacture. In addition, compounds in which R2B is an alkyl group having a hydroxyl group (1
3), the above-obtained compound in which R2a is an alkyl group having a carboxyl group is prepared by a conventional method, for example, fA
It can be produced by reduction with IHi followed by air oxidation.

The compound (13) thus obtained is then subjected to the reaction scheme -
The desired compound (1e) can be obtained by subjecting it to the addition reaction with thiols and subsequent oxidation reaction shown in 4.

Furthermore, the thiol compound (Ib) of the present invention obtained by each method shown in the above reaction schemes -2, -4 and -5, (
1d) and (1e) can be obtained by subjecting them to an oxidation reaction using a hydrogen peroxide solution, m-chloroperbenzoic acid, etc. according to a conventional method to obtain the corresponding sulfoxide form (general formula (
1) Compounds with n=1) and sulfone compounds (general formula (1)
n -2 compounds).

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., in the presence of an oxidizing agent in an equimolar amount to approximately 3.0 times the molar amount of the raw material compound, heat to a temperature ranging from approximately -20°C to the boiling point temperature of the solvent. This can be done by doing.

In addition, the compound (1) of the present invention can be used with common reducing agents such as stannous chloride, sodium borohydride, sodium hydrosulfide (Na 23204 ) as shown in the following formula.
The corresponding hydroquinone compound (1') can be obtained by a reduction reaction using, for example, air oxidation, oxidation reaction using ferric chloride, etc. quinone body (1
) can be converted to The present invention also includes hydroquinone (1') which is a reduced form of quinone (1).

(1) (1') Each target compound and the compound of the present invention obtained by the method shown in each reaction scheme above can be easily separated from the reaction system by conventional separation means, and can be further purified if necessary. can do. As the separation means and purification means, conventional methods such as solvent extraction, recrystallization, 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.

EXAMPLE 1 Hereinafter, in order to explain the present invention in more detail, production examples of the 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 Report by Rapoport et al. [Journal of American Chemical Society] L.J., A.
n+, Chew, Soc, ), 96°8
046 (1974)) 2-methyl-1,4-
Naphthohydroquinone was obtained.

That is, 1.72 (l) of 2-methyl-1,4-naphthoquinone
was suspended in 100 ether, and 10% Na2S2O
4. Shake with aqueous solution until the color completely disappears. The organic layer was washed with saturated brine, separated, dried and concentrated to obtain the target compound 1.579.

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 argon atmosphere, 2-methyl-1,4-naphthoquinone 2
5a with 500 ethanol and 150 WII methylene chloride
3nCQ2・2H2034,5(+
A solution of 35011Q in water was added, concentrated hydrochloric acid 35111Q was further added, and the mixture was stirred 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 mg of water, and 73 mg of dimethyl sulfate was gradually added under water cooling, followed by further stirring at room temperature for 1 hour. The reaction mixture was transferred to water, extracted with ethyl acetate, the organic layer was washed with water, dried,
After concentration, distillation is performed under reduced pressure to reduce the boiling point to 130-135℃10
．． 5snH (+ target substance 201) was obtained.

'H-NMR (COCO2): δl)I) 17.96
-8.24 (2H, m) 7.30-7.61 (2H, ra) 6.58 (
IH,s) 3.94 (3H,s) 3.85 (3H,S) 2.43 (3H,s) C) Production of 2-pentyl-1,4-naphthoquinone 1.4
- Naphthoquinone 50g, hexanoic acid 55g
and AQ NO315,8! J tr, suspended in 1.2Q water and 4ooI12 acetonitrile, and added 60'
Or, (NH4)2 S201179a water 3201i
The two solutions were added over 30 minutes. After that, under the same conditions, 1
After stirring for an hour, it was transferred to water, extracted with benzene, the organic layer was washed with a 5% aqueous solution of NaHCOs, dried, concentrated, and then subjected to column chromatography (ether:hexane-1
:30) to obtain the target compound 450 as an oil.

'HNMRCCDCQG): 6pl)
18.00-8.23 (2H,l) 7.63-7.91 (2f-1,m)6.77
(IH,t, J-1,3)2.56 (2H,bt,
J-6,8) 1.21-1.91 (6H, IS)
0.91 (3H,t, J=6.6) d) Production of 2-pentyl-1,4-dimethoxynaphthalene Using 2-pentyl-1,4-naphthoquinone, the above b)
Reduction and methylation were performed in the same manner as in the method described above to obtain an oily substance.

This was purified by column chromatography (ether:hexane-1 nia 0) to obtain the target compound as an oil.

'HNMR (CDC12a): 6pD17.97
-8.31 (2H,wr)7.38-7.65 (
2H,I) 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
e S-1,4-dimethoxynaphthalene [Compound (2b
)) Production of 1.4-naphthoquinone 20a and thiophenol 14G
was dissolved in acetone 300III2 and stirred at room temperature under an argon stream for 20 hours. The reaction mixture was then charged with Na
2820 x 40 (J, K2 CO3900 and 72% dimethyl sulfate were added and centrifuged for 20 hours. Insoluble materials were separated by furnace, washed with acetone, the mother liquor was concentrated, and column chromatography (hexane→hexane:ethyl acetate) 1
:10) to obtain 15 g of the target compound, 2-phenylthio-1,4-dimethoxynaphthalene, as an oil.

' HNMR (CDCQa): δ1)I) 18.00
-8.25 (2H, m) 7, 20-7. 70 (7H, w,
)6.55 (IH,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 20a were dissolved in acetic acid 150III12 and heated at 60°C for 20 hours. 3 g of sodium acetate was added to the reaction mixture and centrifuged 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 1-b) above to obtain 20 g of 5,8-dihydro-9,10-dimethoxyanthracene (11).

'H-NMR (DMSO-ds): δpl)1
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 was dissolved in 280 mQ of DMF, and P
t 02400111 (l) was added and catalytically reduced under a hydrogen stream at normal pressure to give 5.6.7.8-tetrahydro-9゜1.
0-dimethoxyanthracene (compound (2c)) 17a
I got it.

Melting point = 113-116°C' H-NMR (CDC123): δDI)
Liu 17.97-8.08 (2H, w+) 7.36-
7.47 (2H,@) 3.86 (6H,s) 2.90-3.10 (4H,m) 1.70-2.00 (4H,m) ■ 2-Carboxyalkyl-non and 2- Preparation of hydroxyalkyl-1,4-naphthoquinone [compound (13)) a) 1,4-naphthoquinone 15.8a, adipic acid 34.50 and A! ;lNO
35 (+ water 375IIIQ and CH3CN1 25m
Dissolve in the Q mixture and add (NH4)2 820s to it.
30! A 10011i1 solution of II in water was added at 60° C. over 30 minutes, and stirring was continued for an additional 10 minutes. The reaction mixture was extracted with benzene, the organic layer was dried and concentrated, and the resulting crystals were collected to obtain 2-(4-carboxybutyl).
9.5 g of -1,4-naphthoquinone was obtained.

'H-NMR (CD300-CDC(+3):
δl)l) 1 7, 97-8.23 <28. m) 7,65-7.90 (2H.m) 6,80 (IH,t, J=1.3)2,60 (2
H,bt. J=6.0) 2, 37 (2H.t, J=
6.6) 1,50-2.00 (4H.ra) b) Dissolve 21 g of the above compound in 5 ml of THF2,
Cool this on ice, Li AI Ha 9101Q
was added to a suspension in THF70-, followed by rapid flow for 3 to 5 hours. After acidifying with dilute hydrochloric acid, extraction with ethyl acetate, the organic layer was dried and concentrated, and the resulting crude product was purified by column chromatography (RioO form di-hexane = 10:1 to 25:1). As a result, 1 g of 2-(5-hydroxypentyl)-1,4-naphthoquinone was obtained.

Melting point 65-67℃ C) In the above a>, instead of adipic acid, 1.

Using 10-decanedicarboxylic acid, 2-(
10-carboxydecyl)-1,4-naphthoquinone was obtained.

'H-NMR (CDC(+3): δppm8,01
-8.21 (2H,m > 7,65-7.91 (2H,m) 6,80 (1H.t, J=1.3)2,57 (2
H. bt, J-6.0) 2, 33 (2H, t, J-
7.3) 1, 15-1.93 (16H.m) ■ F
Production of compounds (3a), (3b) and (3C) by C reaction 18 of each of compounds (2a), (2b) and (2C)
．． 3 mmol, acetic anhydride 23o and AICI3541J
was dissolved in 1,2-dichloroethylene 1Q and heated at 60°C for 1 to 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 1 CH3 CH3 No, R'R" - fusion i ('CI C
H3 8 117.5~118.52 (CH2
) A - 70.5 to 71.5 ± - Jyu f ■ --- 1 Rainbow and double ■ Production of compounds (4a), (4b) and (4C) Compounds (3a), (3b) and ( 10 each of 3C)
mmol was mixed with 1.89 ma of morpholine and 640 ma of sulfur and heated at 130-135<0>C for 1.5-5 hours. The reaction mixture is transferred to water, extracted with methylene chloride, and the organic layer is concentrated. To the compound obtained is further added a solution of 3 to 15 g of potassium hydroxide dissolved in 20 to 50 g of ethanol and 1 to 5 g of water, 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) above ■
Each compound obtained in step 1 was dissolved in a lower alcohol, and a catalytic amount of concentrated sulfuric acid was added to obtain the desired ester compound for 3 to 20 hours.

The reaction mixture was extracted with an organic solvent, and the organic layer was diluted with 5% N.
a Washed with HCO3 and water, dried, concentrated, and 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), and (6C) 18 mmol of each compound obtained above was dissolved in 60 m of methylene chloride, and 45 molar of sodium hydroxide (NaO8
(23 g dissolved in 290 g of water), tetra-n sulfate
-butylammonium 12 (+ and alkyl halide 7
2 mmol was added and stirred at 25°C for 6-8 hours. The organic layer was then filtered, 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.

In addition, each compound obtained above was dissolved in ethanol, and sodium hydroxide was added thereto to hydrolyze it, resulting in compound (7a
)-.(7C) were obtained.

The physical properties of each compound are shown in Table 2 below.

Table 2 1CH3HHC2H5 2CH3HCH3H 3-(CH2)mu-HC2H5 4-(CH2)-CH3H 5n-C5Ht+ HCH3H 6CH3HHH 7CH3HCH3C2H5 8-(CH2) -CH3C2H5 9n-C5H++ HHC2H5 1 3n-C5H++ HC83C2H5No,
Melting point or l H-NMR-11111C)-
-Ll 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 (IH, d, J-2, 0), 7.9
8 (IH.

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 (IH.

d, J -1,7), 7.39 (1H, dd,
J = 9.0゜1.7), 4.13 (21-
1,0,J = 7.0), 3.86(I H,Q
, J= 7.2) , 3.87 (3H,s)
.

3.86 (3H, s), 2.94 (2H,
bs).

1.83 (2H, ff1), 1.58 (3
H, d, J=7.2), 1.20 (31-1,
t, J= 7.0)9 8.0 & (IH, d,
J = 1.8), (11-1゜d, J
= 8.6), 7.44 (1H, dd, J
= 8.6°1.8), 6.60 (1)-1
, S), 4.15 (2H, Q.

J=7.0), 3.96 (3H,S)
, 3.86 (3H.

s), 3.76 (2H,s), 2.7
8 (2H, bt).

1.25 (3H, t, J= 7.0),
0080-2.00 (9H, a) 10 Not isolated 11 Not isolated 12 Not isolated 13 8.10 (1H, d, J = 1.8),
7.97 (IH.

d, J = 8.8), 7.46 (1H, dd,
J -8,8゜1.8), 6.60 (I H,s
), 4.16 (2H,Q.

J -7,0), 3.96 (3H,s), 3.
85 (3H.

s > , 3.86 (I H, q, J ”-7,
2>, 2.84(2)-1,bt), 1.57
(3H, d, J= 7.2).

1.27 (3H, t, J-7,0), 0.8
0-2.00 (9H, III) Example 1 Production of compounds (1a> to (1C)) Oxidation reaction by CAN Each of compounds (4a) to (7C) obtained in the above reference example 15
．． 6 mmol was dissolved in 200 methylene chloride and CAN
A 200 mg aqueous solution of 21 (l) of water was added and shaken vigorously at room temperature.Then, the organic layer was separated, dried, concentrated, and purified by column chromatography (ethyl acetate:methanol) to obtain the target compound with a concentration of 60 to 80 The physical properties of the obtained compound are shown in Table 3.

■ Oxidation reaction using Jones reagent Compounds (4a) to (6G) obtained in the above reference examples (excluding compounds (4b), (5b) and (6b)) were dissolved in acetone 100III2, and the mixture was added with Jones reagent under water cooling. 1
BIQ was added and stirring continued 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) to obtain the target compound (40-7
Obtained with a yield of 0%. The physical properties of the obtained compound are shown in Table 3.

Example 2 Preparation of compounds (1d) and (1e) 3.3 mmol of each of compound (1a) and compound (13) were added to 20 ethanol or DMF10Ilt12.
Dissolve in the mixed solution and add thiol compound (H8-Re) to it.
Add 3.5-6.6 mmol of
Stirring was continued for an hour (until disappearance of the starting compound was observed by thin layer chromatography). Then 10% FeC
Fifty amounts of Q3 aqueous solution were added, and the mixture was further stirred for 2 hours. The reaction mixture was transferred to water, extracted with ethyl acetate, and the organic layer was dried 1
After concentration, the crude product was purified by column chromatography (ethyl acetate:methanol) to obtain the target compound from 50 to
Obtained with a yield of 70%. The physical properties of the obtained compound are shown in Table 3.

Example 3 Production of sulfoxide and sulfone compounds 10 each of compounds (1b), (1d) and (1e)
mmol was dissolved in 200 mmol of methylene chloride, 2.5 g of monochloroperbenzoic acid (70%) was slowly added thereto under water cooling, and stirring was continued for an additional 10 minutes. The reaction mixture was
It was concentrated at 0° C. or below, 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 3 1 CH3HHH 2CH38CH3)( 3CHa ○zu-CH3H 4(CH2)A-CH38 CH3 5'CH3(CH2)3 CH3HCH3 7-(CH2)4 8 CH3H1 12 CH3HHC2H5

Claims (1)

[Claims] (1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ), and the R^
When 3 is a hydrogen atom, R^1 and R^2 are an alkyl group having a hydroxyl group or a carboxyl group, respectively, or A-S (
O) n-group (A is a lower alkyl group that may have a hydroxyl group and n
is 0, 1 or 2). Also, when R^3 is -CHR^4-COOR^5 group, R
^1 indicates a lower alkyl group or a ▲group that has a mathematical formula, chemical formula, table, etc., and R^2 is 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 both R^1 and R^2 may be combined to form a -(CH_2)_4- group. ] A naphthoquinone derivative and a salt thereof, characterized by the following: