JPS62230745A - Production of 2-hydroxymethyl-2,5,12-trihydroxy-1,2,3,4-tetrahydronaphthacene-6,11-dione - Google Patents

Abstract

PURPOSE:To readily obtain the titled substance which is a synthetic raw material for compounds useful as a carcinostatic agent in a short process, by reducing a readily available 2-alkoxycarbonyl-2,5,12-trihydroxy-1,2,3,4- tetrahydronaphtn-acene-6,11-dione. CONSTITUTION:A 2-alkoxycarbonyl-2,5,12-trihydroxy-1,2,3,4-tetrahydronaphth- acene-6,11-dione expressed by formula I (R is alkyl) is reduced with a composite metal hydride based reducing agent, particularly preferably using tri-tert- butoxyaluminum lithium hydride to afford the aimed compound expressed by formula II. The amount of the above-mentioned composite metal hydride based reducing agent used is an excess amount of 4-50 equivalents, preferably 10-25 equivalents based on the compound expressed by formula I. The above- mentioned reducing reaction is preferably carried out at 0 deg.C - room temperature, preferably using dimethyl sulfoxide as a solvent.

Description

Detailed Description of the Invention [Industrial Application Field] The present invention relates to 2-hydroxymethyl-2,5゜12-trihydroxy-1,2,3,4-tetrahydronaphthalene represented by the following formula (I!>). It relates to a method for producing cene-6,11-dione.More specifically, the present invention relates to a method for producing cene-6,11-dione.More specifically, the present invention relates to a method for producing cene-6,11-dione.
2-hydroxymethyl-2 represented by the above formula (11), characterized in that -trihydroxy-1,2,3,4-tetrahydronaphthacene-6,11-dione is reduced with a complex metal hydride reducing agent. ,5-121lihydroxy-1,2,3゜4-tetrahydronaphthacene-6,1
The present invention relates to a method for producing 1-dione.

2-hydroxymethyl-2,5,12-)rihydroxy-1,2 represented by the above formula (ff) obtained by the present invention
, 3,4-tetrahydronaphthacene-6,11-dione is represented by the following formula (Iff) and general formula (IV) (wherein R1 is a lower alkyl group or an aryl group.

) 3-Hydroxymethyl-1,3,5,12-tetrahydroxy-1,2,3,4-tetrahydronaphthacene-
6,11-dione and 3-carbamoyloxymethyl-
pot,'! ', 5.12-tetrahydroxy-1,2,3
, 4-tetrahydronaphthacene-6,11-dione (see reference side below), the compounds represented by the above formula (m) and the above general formula (rV) have excellent anticancer activity. It is an aglycone of a 4-demethoxy anthracycline analog having a hydroxymethyl group or a carbamoyloxymethyl group at the 9-position, and is reported to have a hydroxymethyl group or a carbamoyloxymethyl group at the 9-position. 4 having a hydroxymethyl group or carbamoyloxymethyl group in
- can lead to demethoxy anthracycline analogues (JP-A-57-53497, JP-A-59-8069)
(see 2).

[Conventional technology]

Conventionally, 2-hydroxymethyl-2,5,12-trihydroxy-1°2, 3. 4
-Tetrahydronaphthacene-6,11-dione is produced by a method for deriving its optically active 2(R) monomer from D-lactose (C, MOnnllretlat al, Tat
rahedron, ↓ standing.

4669 (1984)) has only been reported, however, this synthetic method has multiple steps and is obviously very difficult to implement industrially.

(Problems to be Solved by the Invention) Under these circumstances, the present inventors have conducted extensive research and investigation and found that 2-alkoxycarbonyl-2,5
, 12-trihydroxy-1,2゜3.4-tetrahydronaphthacene-6,11-dione by selectively reducing the 2-alkoxycarbonyl group to an alcohol without damaging the anthraquinone skeleton at all. 2-hydroxymethyl-2,5,12-trihydroxy-1,2,3,
We have discovered a new method for producing 4-tetrahydronaphthacene-6,11-dione easily and in a short process, and have completed the present invention.

[Means for solving problems]

The present invention provides 2-alkoxycarbonyl-2,5゜12-trihydroxy-1,2,
A complex metal hydride reducing agent is applied to 3,4-tetrahydronaphthacene-6,11-dione to selectively reduce the alkoxycarbonyl group without creating an anthraquinone core, resulting in a compound represented by formula (If). 2-hydroxymethyl-2゜5.12-)dihydroxy-1,2,3,
4-tetrahydronaphthacene-6,11-dione is obtained.

(In the formula, R represents an alkyl group.) 2-Alkoxycarbonyl-2,5,12-1-dihydroxy-1,2 represented by the general formula (1) used as a raw material
,3,4-tetrahydronaphthacene-6,11-dione can be synthesized in large quantities from 5,12-dihydroxy-1,2,3,4-tetrahydronaphthacene-2゜6,11-trione.゜12-trihydroxy-1,2,3
,4-tetrahydronaphthacene-6,11-dione-2
-It is a compound that can be synthesized by subjecting carboxylic acid to a normal esterification reaction (Y, Kimura.

at al,, Bull, Chem, Soc.

Japan, Dan, 415 (1986).

Also, di-2,5,12-)dihydroxy-1°2.
3.4-tetrahydronaphthacene-6,11-dione-
(R)-2,5,1 obtained by optical resolution of 2-carboxylic acid
From 2-trihydroxy-1,2゜3.4-tetrahydronaphthacene-6,11-dione-2-carboxylic acid, (R)-2-alkoxycarbonyl-2,5゜12-tri Hydroxy-1,2,3,4-
Tetrahydronaphthacene-6,11-dione is obtained (Y, Kimura, et al., Bull.

Chem, Sac, Japan, 59+ 415 (1
986),).

The alkyl group in the general formula above is a substituted or unsubstituted linear or branched alkyl group, such as a methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, pentyl group, isopentyl group. , octyl group, benzyl group, p-methoxybenzyl group, 3,4-dimethoxybenzyl group, etc. Synthesis of the compound represented by the formula (II) by reduction of the compound represented by the general formula (1) is as follows: This can be carried out using a complex metal hydride reducing agent. Examples of the complex metal hydride reducing agent include lithium aluminum hydride, monohydride [-
Butoxyaluminum lithium, di(-butoxyaluminum lithium hydride, tri-t-butoxyaluminum lithium hydride, tri-t-butoxyaluminum sodium hydride, tri[-butoxyaluminum potassium hydride, monomethoxyaluminum lithium hydride, dimethoxy hydride Aluminum lithium, trimethoxyaluminum lithium hydride, monoethoxyaluminum lithium hydride, jetoxyaluminum lithium hydride, triethoxyaluminum lithium hydride,
Examples include lithium tripropoxyaluminum hydride, lithium triisopropoxyaluminum hydride, and lithium trit-butoxyaluminum hydride is preferably used from the viewpoint of selectivity of the reduction reaction. The composite metal hydride reducing agent is used in an excess amount of 4 to 50 equivalents, preferably 10 to 25 equivalents, relative to the compound represented by formula (r).

This reduction reaction is preferably carried out in a solvent, where 'ζ is an ether solvent such as diethyl ether, tetrahydrofuran, dioxane, or 1,2-dimethoxyethane, dimethyl sulfoxide, or N.

Aprotic solvents such as N-dimethylformamide are used, but dimethyl sulfoxide is preferably used from the viewpoint of reaction selectivity.
Proceeds in ~50 hours, preferably at 0°C ~ room temperature, 5~2 hours
It will be finished in 4 hours.

2- represented by the above formula (II) obtained by reduction
Hydroxymethyl-2,5,12-trihydroxy-1
, 2,3,4-tetrahydronaphthacene-6,11-dione is an extremely poorly soluble compound, and for purification, the hydroxyl group at the 13th position is replaced by 1-butyldimethylsilyl ether, or the hydroxyl groups at the 2nd and 13th positions are used. It is desirable to obtain a derivative such as acetonide, etc., which is purified by removing the protecting group by a method known to those skilled in the art to obtain 2-hydroxymethyl-2, represented by the above formula (n). 5,12-)lihydroxy-1,
2,3,4-tetrahydronaphthacene-6,11-dione can be obtained with high purity.

2-hydroxymethyl-2,5,12-trihydroxy-1,2,3,4-tetrahydronaphthacene-6,11 represented by formula (■) synthesized by the above reaction steps
-dione can be derived into 4-demethoxyanthracyclinone having a hydroxymethyl group and a carbamoyloxymethyl group at the 9-position represented by general formulas (III) and (IV) using the following reaction formula.

(In the formula, R1 is a lower alkyl group or an aryl group,
R1, R2, and R4 are alkyl groups. ) [First step] In this step, the 2-hydroxymethyl-
The 2-hydroxymethyl group of 2,5,12-1-lihydroxy-1,2゜3.4-tetrahydronaphthacene-6,11-dione is selectively silylated to form 2-hydroxymethyl group represented by general formula (V). -trialkylsilyloxymethyl-2,5
, 12-trihydroxy-1,2,3,4-tetrahydronaphthacene-6,11-dione derivatives.

This step is integrated with the reduction step of the compound of the general formula (H) to induce the compound of the formula (■), which is a reduction product, into the compound of the general formula (V), and then converts the compound of the general formula (V) into the compound of the general formula (V). It is also carried out when purifying the compound (11).Silylation is carried out when compound (11)
4-trialkylsilyloxy-3-pentene-2-
This is done by reacting with on. 4-Trimethylsilyloxy-3-penten-2-one includes 4-trimethylsilyloxy-3-penten-2-one, 4-isopropyldimethylsilyloxy-3-penten-2-one, 4-propyldimethylsilyloxy -3
-penten-2-one, 4-t-butyldimethylsilyloxy-3-penten-2-one, 4-t-butyldiphenylsilyloxy-3-penten-2-one, etc., preferably 4- 0 reactions in which t-butyldimethylsilyloxy-3-penten-2-one is used are diethyl ether, tetrahydrofuran, dioxane,
1. Ether solvents such as 2-dimethoxyethane, hydrocarbon solvents such as benzene, toluene, hexane, and cyclohexane, chloroform, dichloromethane, l, 2-
Halogenated carbon solvents such as dichloroethane, N, N-
Dimethylformamide, N,N-dimethylacetamide, N.

It is carried out in an aprotic polar solvent such as N,N-hexamethylphosphoric triamide, but preferably in an aprotic polar solvent such as N,N-hexamethylphosphoric triamide.
-dimethylformamide is used. The reaction is carried out in the presence of an acidic catalyst, and the acidic catalysts include p-)luenesulfonic acid, benzenesulfonic acid, and dl-camphor-10-
The reaction, which can use sulfonic acid, d-camphor-10-sulfonic acid, etc., proceeds at -20°C to 50°C.

[Second Step] This step consists of 2-trialkylsilyloxymethyl-2,5,12-1-lihydroxy-1 represented by the general formula (v).
, 2,3,4-tetrahydronaphthacene-6,11-dione derivative is brominated at the 4-position, and then substituted with a hydroxyl group to obtain 3-trialkylsilyloxymethyl-1°3. represented by the general formula (Vl). 5.12-tetrahydroxy-1
, 2,3°4-tetrahydronaphthacene-6,11-dione derivatives are synthesized. Since bromination involves dichloromethane, chloroform, and l,2-dichloroethane, it is desirable to carry out the reaction under white light irradiation. Bromination proceeds smoothly at -20°C to 50°C. In the reaction of substituting the 4-position bromine of the obtained brominated product with a hydroxyl group, 0.1 to 1.0% of the bromination reaction solution is added. The 0 reaction carried out by adding an aqueous solution of sodium hydroxide at 0°C to 5°C
Proceeds smoothly at 0°C.

[Third step] This step removes the silyl group of the trialkylsilyloxymethyl group at the 2-position of general formula 1) to obtain 3-hydroxymethyl-1,3゜5.12-tetra represented by general formula (III). Hydroxy-1,2,3,4-tetrahydronaphthacene-
This step, which synthesizes 6,11-dione, is carried out with reagents commonly used for the removal of trialkylsilyl groups from trialkylsilyloxy groups, such as hydrochloric acid, hydrogen fluoride, or pyridinium fluoride in acetonitrile. The 0 reaction proceeds smoothly at -20°C to 50°C.

[Fourth step] This step consists of 3-hydroxymethyl-1,3,5,12-tetrahydrokidi-1,2,3 represented by formula (III).
, 4-tetrahydronaphthacene-6゜11-dione is reacted with an isocyanate derivative to obtain 3-carbamoyloxymethyl-1,3,5,12- represented by general formula (IV).
A tetrahydroxy-1,2,3,4-tetrahydronaphthacene-6°11-dione derivative is obtained. The isocyanate used is phenyl isocyanate.
Examples include p-chlorophenylisocyanate, benzylisocyanate, and 2-ethynylisocyanate. The reaction is carried out in a solvent, and examples of the solvent include basic aromatic hydrocarbons such as pyridine, picoline, 2,6-lutidine, 2,4,6-collidine, quinoline, and isoquinoline, N, N-dimethylformamide, N, The reaction, which uses aprotic polar solvents such as N-dimethylacetamide, N,N,N-hexamethylphosphoric triamide, etc., is carried out between -20°C and 50°C.

Hereinafter, the present invention will be explained in detail with reference to Examples and Reference Examples, but the present invention is not limited thereto.

Reference example 1 di-2,5,121lihydroxy-1,2°3.4-
Tetrahydronaphthacene-6,11-dione-2-carboxylic acid (506 µ, 1.43 m-mo +) was added to a mixed solvent of methanol (50 ml) and dimethyl sulfoxide (10 ml), and concentrated sulfuric acid (7 drops) was added. The reaction mixture was then heated under reflux for 4 hours, poured into 50% saturated aqueous sodium hydrogen carbonate solution (100 ml), and extracted with ethyl acetate.

The extracts were combined and washed successively with water and saturated brine.

After drying over anhydrous magnesium sulfate, filtration and distillation under reduced pressure yielded almost pure dl-methyl 2.5゜12-trihydroxy-1,2,3,4-tetrahydronaphthacene-6,1.
1-dione-2-carboxylene) (524■, 100
%) was obtained as red powder crystals.

mp　198-200℃.

(Literature value, mp 198.5-199.5°C.

Y, Kimura, at, Bull.

Chem, Soc, Japan, 59.415 (198
6),) Reference Example 2 Optically active (R)-2,5,12-)rihydroxyl 1.
2,3.4-tetrahydronaphthacene-6,11-dione-2-carboxylic acid (500 μm).

1.41m+nol) and anhydrous dimethyl sulfoxide (1
0 ml), anhydrous methanol (50 ml), concentrated sulfuric acid (0,
A mixture of 2 ml) was heated under reflux for 10 hours. Under water cooling, saturated aqueous sodium bicarbonate solution (50 ml) and water (10
0 ml) was added sequentially, and chloroform (3 times, total of 300 ml) was added.
1).

The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by filtration column chromatography (silica gel, chloroform-ethyl acetate (
5: l)) and optically active (!?)-2-
Methoxycarbonyl-2,5゜12-trihydroxy-
1,2,3,4-tetrahydronaphthacene-6,11-
Zeon (474g.

(Yield: 91%) was obtained as red crystals. Further, it was recrystallized with benzene to obtain a pure product.

mp　213-214℃.

(α〕” 60.0” (c O, 110, ri a
oform).

(Literature value 0mp 210.5-211.5℃.

[α] is also “-60,0° (c O, 10, chloroform), y, Ktmura, at al.

But 1. Chem, Soc, Japan
n.

59, 415 (1986), ) Example 1 dl-2-methoxycarbonyl-2,5,12-trihydroxy-1,2,3,4-tetrahydronaphthacene-
6,11-dione (301■.

0.817 mmol) in anhydrous dimethyl sulfoxide (
Lithium tri-t-butoxyaluminum hydride (5.22 g, 20.5 m-mol) dissolved in
was added dropwise to a suspension of anhydrous dimethyl sulfoxide (10 ml). After stirring for 5 hours at room temperature under an argon atmosphere,
A water-cooled aqueous oxalic acid solution (200 ml) was added, and the mixture was stirred at room temperature overnight. Tetrahydrofuran and ethyl acetate (6
The organic phase was extracted with dilute hydrochloric acid and water (
After washing sequentially with water (4 times), the solution was concentrated under reduced pressure. residue and 4-t-
Butyldimethylsilyloxy-3-penten-2-one (525N, 2.45 mmol 1) in anhydrous N.

The mixture was dissolved in N-dimethylformamide (10 ml), a solution of anhydrous p-)luenesulfonic acid in anhydrous tetrahydrofuran (0.05 M/j!, 0.5 ml) was added, and the mixture was stirred at room temperature under an argon atmosphere for 5 hours. Water-cooled sewage (20rn
1) was added and extracted with chloroform (3 times). The organic phase was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.

The residue was purified by column chromatography (silica gel, chloroform-ethyl acetate (30:1)), and dl
-2-t-butyldimethylsilyloxymethyl-2,5
゜12-trihydroxy-1,2,3,4-tetrahydronaphthacene-6,11-dione 190 ■ (yield 51%)
) was obtained as a red-orange solid. The NMR spectrum of this product matched that of Example 8.

Example 2 di-2-methoxycarbonyl-2,5,12-dolihydroxy-1,2,3,4-tetrahydronaphthacene-
6,11-dione (68,2■.

0.185 mmol) in anhydrous dimethyl sulfoxide (
5 ml), tri-t-butoxyaluminum lithium hydride (708 ml, 2.78 m-m01) was added thereto, and the mixture was stirred at room temperature under an argon atmosphere for 5 hours. A water-cooled supersaturated oxalic acid aqueous solution (10 ml) was added, and the mixture was extracted with tetrahydrofuran and ethyl acetate (twice in total). The crude product obtained by washing the organic phase with water and concentrating under reduced pressure was dissolved in anhydrous tetrahydrofuran (5 ml) and anhydrous acetone (2 ml).
-dimethoxypropane (0,2 ml) and dl-camphor-10-sulfonic acid 14 m (0,06 mmol)
was added thereto, and the mixture was stirred at room temperature under an argon atmosphere for 3 hours.

Add powdered sodium bicarbonate aqueous solution, methylene chloride (3
extraction). The organic phase was washed with water, dried over anhydrous magnesium sulfate, and then vacuumed to $I. The residue was purified by column chromatography (silica gel, chloroform) to give di-2-hydroxymethyl-2,13-0-isopropylidene-2, 5゜12-trihydroxy-1,2,
3,4-tetrahydronaphthacene-6,11-dione (
38.6*, yield 55%) was obtained as a reddish-orange solid. The NMR spectrum of this product matched that of Example 9.

mp 263-265.5°C (benzene).

Di-2-methoxycarbonyl- by changing reducing agent and solvent
2,5,12-)dihydroxy-1,2゜3.4-tetrahydronaphthacene-6,11-dione was subjected to a reduction reaction, and di-2-hydroxymethyl-2 was subjected to the same post-treatment as in Example 2. ,13-O-isopropylidene-2,5
, 12-) dihydroxy-1,2,3,4-tetrahydronaphthacene-6,11-dione was obtained. The results are summarized in Table 1.

Example 8 Optically active (R)-2-methoxycarbonyl-2°5.1
2-trihydroxy-1,2,3,4-tetrahydronaphthacene-6,11-dione (253*, 0.687m
Mo 1) was dissolved in anhydrous dimethyl sulfoxide (20 ml), and this was added dropwise into a suspension of tri-L-butoxyaluminum lithium hydride (4.31 g, 17.0 mmol) in anhydrous dimethyl sulfoxide (15 ml).

After stirring the reaction solution at 25°C for 5 hours under an argon atmosphere, the same post-treatment and silylation as in Example 1 were carried out using 3,4-tetrahydronaphthacene-6,11-dione (171at,
Yield 55%) was obtained as a reddish-orange solid. Further, a pure product was obtained by recrystallization from carbon tetrachloride.

mp　15'8.5~159.5℃.

[α] -40,7° (c O, 059, chloroform).

NMR (CDCI: δ 0.13 (6H.

s, SiMex), 0.96 (9H, s.

S i+), 1.5-2.2 (2H, m, 3-Hz)
, 2.57 (IH,s, 2-0H).

2.7-3.1 (4H, m, I Ht, 4-Hz)
, 3.64 (2H,s, 13-Hz).

7.7"7.9 (2H, m, A roma t
i cHz), 8.2-8.4 (2H, m.

Aromatic Hs), 13.27 (2H, S,
phenol Hz).

rR (KBr): 3600. 3450°1620
, 1590. 1410. 1250°840cm-
'.

Mass spectrum (m/e): 454 (3,M”)
.

455 (1, M”+1).

Elemental analysis: C! Calculated value as SH3゜O, S +:
C, 66,05; H, 6,65%.

Measured values: C, 66,09, H, 6,94%.

Example 9 Optically active (R)-2-methoxycarbonyl-2°5.1
2-) Lyhydroxy-1.2.3.4-tetrahydronaphthacene-6,11-dione (54,5w, 0.148
mmo+) in anhydrous dimethyl sulfoxide (5 ml) and hydrogenated tri-t-butoxyaluminum lithium (563 ml).

(R)-2-hydroxymethyl-
2,13-0-isopropylidene-2゜5.12-trihydroxy-1,2,3,4-tetrahydronaphthacene-6,11-dione (29.9cm, yield 53%) as a reddish-orange solid obtained as. Further, it was recrystallized from benzene to obtain a pure product.

mp　221.5-222.5℃.

(α) ”・-52,0° (c O,050,')
octyhlum).

(Literature value, mp 232-234℃ (α)!, @-
52° (CO, 03, chloroform).

C, Monn5ret, et al.

Tetrahedron, 40. 4669 (19
84)).

NMR (CDCIs): δ 1.44 (
6H.

Hz), 2.9-3.2 (4H, m, 1-
Hz, 4 Hz), 3.95 (21L
s.

1 3-H-), 7.8-8.0 (2H, m.

Aromatic H2), 8.3~
8.5 (2H, m, Aromatic Hri.

1 3.49 (IH,s, phsno I
H＞.

13.50 (LH,s, phenol H
).

IR (KBr): 1625. 1590°14
10, 1260. 1240cm-'.

Mass spectrum (m/e): 380 (100°M"), 381 (27, M"+1).

Elemental analysis: CzzHz. 0. as Calculated values: C, 69,46; H, 5,30%.

Measured values: C, 69,43; H, 5,50%.

Example 10 (R)-2-t-butyldimethylsilyloxymethyl-
2,5,12-1-lihydroxy-1,2゜3.4-tetrahydronaphthacene-6,11-dione (71,Ow
, 0.156 mmo I) in tetrahydrofuran (2 m
1), add concentrated hydrochloric acid (0.5ml) and stir at room temperature for 30 minutes.
Stirred for 0 minutes. Add water, extract with tetrahydrofuran and ethyl acetate (3 times), wash the organic phase with water (2 times), filter, concentrate under reduced pressure, and (R)-2-hydroxymethyl-
2,5°12-trihydroxy-1,2,3,4-tetrahydronaphthacene-6,11-dione (55,3■.

Quantitative yield) was obtained as an orange solid. A pure product was obtained by recrystallization from tetrahydrofuran-benzene.

mp　264.5-266.5℃.

[α)7)'-52,0° (cO,050, dioxane).

(Literature value, mp 235-238℃ [α]20-3
2° (cO,062, dioxane).

C, Monnere L, et al.

Tetrahedron, 40.4669 (1984)
,).

NMR (400MHz, d et al.-DMS 0.65°C): 6
1.64-1.80 (2H, m, 3Hz), 2.
68 (2H, s, l H2).

2.70-2.85 (2H, m, 4-Hz).

3.36~3.45 (2H, m, 13H
.

4.24 (IH, s, 2-0H), 4.6
0 (IH, t, J=5Hz, 13-0H).

7.88~7.94 (2H, m, A rom
aticHz), 8.17~8.23 (2H,
m.

Aromatic Hz), 13.29 (2H
,sX2. phenol HX2).

TR(KBr) = 3425. 1620°159
0, 1420. 1405. 1280°1 250
clI-'.

? 71. Spectrum (m/e): 340 (100゜M
'), 341 (23, M'+1).

Elemental analysis: C+*H+i0i ・1/10H! Calculated values as O: C, 66,70%, H, 4,77%.

Measured values: C, 66,70, H, 4,88%.

Example 11 dl-2-hydroxymethyl-2,13-0-isopropylidene-2,5,12-trihydroxy-1,2,3
, 4-tetrahydronaphthacene-6, ■ 1-dione (1
07w, 0.281 mmol) was suspended in tetrahydrofuran (3 ml), 1 ml of concentrated hydrochloric acid was added, and the mixture was stirred at 60°C for 1 hour. Water was added, extracted with tetrahydrofuran and ethyl acetate (twice), and the organic phase was washed with water (twice), concentrated under reduced pressure and dl-2-hydroxymethyl-2,5,12
-Trihydroxy-1,2,3,4-tetrahydronaphthacene-6,11-dione (94 µm, 98%) was obtained as a red-orange solid.

Reference Example 3 (R)-2-t-butyldimethylsilyloxymethyl-
2,5,12-)lihydroxy-1,2゜3,4-tetrahydronaphthacene-6,11-dione (163,3w
, 0.359 mmo 1) was dissolved in 35 ml of anhydrous carbon tetrachloride under an argon atmosphere, and while cooling with water and irradiating white light, bromine was dissolved in carbon tetrachloride Wi, (0,0894 M/1,4
．． 0 ml) was added dropwise over 15 minutes. After 1 hour, 0.5 ml of a bromine solution in carbon tetrachloride was added, and after another 30 minutes, 0.5 ml was added, and the mixture was stirred for a total of 2 hours. Add 0.3N sodium hydroxide water ifi (15ml) under water cooling and leave it for 15 minutes.
The mixture was further stirred at room temperature for 15 minutes. The mixture was neutralized by adding water and 3N hydrochloric acid under water cooling, and immediately extracted with chloroform (3 times). The organic phase was washed with water (twice), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel).

Chloroform-chloroform-ethyl acetate (30:1)
) to give 3(R)-t-butyldimethylsilyloxymethyl-1(S),3(R),5゜12-tetrahydroxy-1,2,3,4-tetrahydronaphthacene-6, 11-dione (72.5μ, 43% yield) was obtained as a reddish-orange solid. In addition, raw material (12.3 cm, 8%) was recovered.

ml) 138-147°C.

'+135° to [α] (c O, 055, chloroform).

NMR (90MHz, CDCIs): δ0.13 (
6H,s,S iMez), 0.95(9H,s,S
i+-), 1.92 (I H.

dd, J=15.0and5.4Hz, 2-Hax),
2.29 (LH, ddd, J=15.0, 1.8a
nd 1.7Hz, 2-Heq).

2.68 (LH, d, J-18, 9Hz, 4-Ha
x), 3.13 (II(, dd, J-18
, 9and 1.7Hz, 4-Hsq).

3.32 (4H,s, 3-0H), 3.6
2 (IH, d, J-9, 6Hz, 13-H).

3.64 (IH, d, J=9.6Hz, 1
3-H), 3.90 (IH, d, J=7'
, OHz.

1-0H), 5.28 (IH, ddd, J
-1,0,5,4and 1.8Hz, 1-H)
.

7,'? ” ~7.9 (2H, m, Ar o
maticHg), 8.2-8.4 (2H, m
.

Aromatic Hz), 13.35 (IH
, s, phenol H), 13.61 (
IH,s, phenol H).

IR (KBr): 3480. 1625°1590
, 1430. 1415. 1375°1255,
10?0. 840. 780cm-'.

Mass spectrum (m/e): 470 (7, M'').

471 (2, M”+1).

Reference example 4 3 (R)-t-butyldimethylsilyloxymethyl-
1(S), 3(R), 5.12-tetrahydroxy-
1,2,3,4-tetrahydronaphthacene-6,11-
Dione (66.1 rw, 0.140 mmol) was dissolved in acetonitrile (5 ml), hydrogen fluoride acetonitrile solution (0.68 M/L 1 ml) was added, and the mixture was stirred at room temperature for 3 mL.
Stirred for 0 minutes. Add water, extract 3 times with tetrahydrofuran and ethyl acetate (total 200ml), wash the organic phase with water (2 times), filter and concentrate under reduced pressure. (R), 5.12-tetrahydroxy-1,2,3,4-tetrahydronaphthacene-6,11-dione (52.2 μm, quantitative yield) was obtained as a red-orange solid. A pure product was obtained by further recrystallization from benzene.

mp　201.5-204.5℃.

(α)”+167° (CO, 024, dioxane).

(&) ”+ l 11° (c O, 052, tetrahydrofuran).

(Literature value, mp 230°C, [α]. +95° (C
O, 05, Tetrahydrofuran) C, Monneret, et al.

Tetrahsdron, 40.4669 (1984)
; mp 212-214°C.

To [α]'+131.3° (CO, 1, dioxane)
.

Japanese Patent Publication No. 59-80692).

NMR (400MHz, d'-pyridine): 62.3
1 (IH, dd, J=14.2and4.4Hz,
2-Hax), 2.72 (IH.

ddd, J, = 14.2.2.1 and 1.8Hz.

2-Heq), 3.24 (IH, d, J -18,
9Hz, 4-Hax), 3.68 (IH.

dd, J=18.9and1.8Hz, 4-H
eQ), 4.08 (IH, d, J -10
, 8Hz, 13-H), 4.10 (LH.

d, J=10.8Hz, 13-H), 5.
69 (IH, dd, J-4, 4 and 2.1Hz.

1-H), 6.49 (3H, br, 1-O
H.

3-OH, 13-0H), 7.70-7.77 (2
H, m, Aroma tic Hg).

8.33~8.40 (2H, m, Aroma
t icH*), 13.79 (IH
,s, phenolH), 1 4.08 (
LH,s, pheno IH).

IR(K, Br) = 3460. 1625. 1
590°1415, 1405. 1375. 1265
゜1240, 1050. 985cm-'.

Mass hector (m/a): 356 (43, M
''').

357 (10, M”+1).

Elemental analysis 2C+qH+hOy Calculated as 1/4HtO: C, 63,24, H, 4,61%.

Measured values: C, 63,43; H, 4,55%.

Reference example 5 3 (R)-Hydroxymethyl-1(S), 3 (
R).

5.12-tetrahydroxy-1,2,3,4-tetrahydronaphthacene-6,11-dione (29,0w, 0
．． 0814 mmol) in anhydrous pyridine (1.5 ml)
Phenyl isocyanate in pyridine solution (0
,186M/j! , 0.44 ml and 0.082 mm 0 were added dropwise and stirred at room temperature for 3 hours. The reaction solution was further added every 72 hours and stirred at 25° C. for 5 hours. After concentrating the reaction solution under reduced pressure, the residue was dissolved in ethyl acetate, and insoluble materials were filtered off.

The filtrate was washed successively with 3N salt # (twice) and water (twice), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, benzene-ethyl acetate (1:1)), and further purified by 3(R) column chromatography (silica gel, hot chloroform-benzene-ethyl acetate (1:1)). )-phenylcarbamoyloxymethyl-1(
S).

3 (R), 5.12-tetrahydroxy-1,2゜3
．． 4-tetrahydronaphthacene-6,11-dione (2
0.3■, yield 52%) was obtained as an orange solid.

A pure product was obtained by recrystallization from ether-n-hexane.

mp　222-223℃.

[α] et al.”+121′ (c O, 053, dioxane).

(Literature value, mp 225-226℃, [α]; 0+
136.0° (CO, 05, dioxane), JP-A-5
9-80692>.

NMR (90 MHz, CDCIs): δ 1.97 (I
H, dd, J=15.0and5.4Hz.

2-T(ax), 2.46 (IH, ddd, J −
15,0,1,7and ~2Hz, 2-Heq).

2.73 (LH, d, J=18.9Hz, 4-
Hax), 3.30 (LH, dd, J=18.9a
nd1.7Hz, 4-Heq), 3.69(IH,d,
J=4.6Hz, 1-0H).

3.96 (IH, s, 3-0H), 4.33 (2H
, s, 13-H,), 5.36 (IH.

ddd, J"5.4.4.6and~2Hz.

1-H), 6.88 (IH, brs, NH).

7.0-7.5 (5H, m, ph), 7.75-8
．． 0 (2H, m, Aromatic Ht).

8.25~8.5 (2H, m, Aroma t t
cHz), 13.32 (IH,s, pheno
IH), 13.58 (1)(, s, phenolH
).

IR (KBr): 3450, 1735.1715 (sh
), 1625. 1590. 1440°1235
am-'.

Mass spectrum (m/s): 475 (7, M″
″).

476 (2, M”+1).

Elemental analysis: c, hH,, o*N・1/31 (calculated value as to: C, 64,86; H, 4,54.

N, 2.91%.

Measured value: C, 64, 91: H, 4, 43; N,
2.84%.

Claims (1)

[Claims] 2-alkoxycarbonyl-2,5,12 represented by the general formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼-(I) (in the formula, R is an alkyl group)
Formulas characterized by reducing -trihydroxy-1,2,3,4-tetrahydronaphthacene-6,11-dione with a complex metal hydride reducing agent▲There are mathematical formulas, chemical formulas, tables, etc.▼-(II ) A method for producing 2-hydroxymethyl-2,5,12-trihydroxy-1,2,3,4-tetrahydronaphthacene-6,11-dione.