JPS62153290A - 2,6-epoxy-3,4,5,6,11,12-hexahydro-2h-naphtahceno (1,2-b)oxocin-9,16-dione derivative - Google Patents

Abstract

NEW MATERIAL:A compound shown by formula I (R<1> is H or hydroxyl-prote cting group; Me is methyl). EXAMPLE:(+)-(2R,3S,4R,5R,6R)-3,5-Diacetoxy-4-dimethylamino-8,10-dihydr oxy-6, 13-dimethyl-2,6-epoxy-3, 4, 5, 6, 11, 12-hexahydro-2-H-naphthaceno[1,2-b]oxocin-9,16- dione. USE:A carcinostatic agent. PREPARATION:For example, a hexan-2-one derivative shownby formula II (t-Bu is t-butyl) is reacted with a tetramethoxynaphthalene shown by formula III, a protecting group is removed, the resultant compound is oxidized, reduced, a protecting group is introduced to the resulting compound, which is successively reduced oxidized to give a compound shown by formula IV (R<2> is hydroxyl protecting group). This compound is subjected to ring formation and reacted witha cyclohexene derivative shown by formula V (R<4>-R<6> are alkyl) and finally protecting group is removed to give a compound shown by formula I.

Description

[Detailed Description of the Invention] [Industrial Application Field] The present invention relates to a novel anthracycline derivative.2 The compound of the present invention itself has anticancer activity, but it can be further subjected to a dehydrogenation reaction. As a result, an optically active nogalene derivative having anticancer activity can be obtained.

[Conventional technology]

There is a strong demand from society for the development of excellent anticancer drugs.
Anthracycline derivatives occupy an important position in medicine as a group of compounds having strong anticancer activity.

Various anthracycline antibiotics have been known in the past, and in recent years one of them, 2,6-nipoxy, 3.
4. 5. 6-Tetrahydro-2H-naftaceno [
1,2-b) Oxocine-9,16-dione derivatives are attracting attention as compounds that exhibit anticancer activity.

±2,569 (1979) iK, Imamur
a.

at al,, J,Antlblot,,
36°1569 (1983); H, Umeza
wa.

et at,, J, Antibiot,, 36+4
51 (1983)] 0 For example, optically active nogalen derivatives are a type of nogaramycin derivatives, which are anthracycline antibiotics that have attracted particular attention in recent years due to their excellent anticancer activity. (P, F.

Wiley, “Anthracycline Antib.
iotics'' ed, by H,S.

EI Khadem, Academic Press;
1982. R97,), which is conventionally derived from naturally occurring nogaramycin by chemically derived CP, F.
,Wi lay,eta l,,J,Org,Chem
, 1 Sat. 4030 (1979); P.F. Wiley
, at al.

J. Med. Chem., 25.560 (1982))
. Generally, the anticancer activity of a compound is highly dependent on its chemical structure, so it is extremely likely that a compound with a structure different from existing compounds will be found that can be put to practical use as an excellent anticancer agent. It would also be very beneficial if these compounds could be easily synthesized directly chemically.

[Problems to be solved by the present invention]

The object of the present invention is to develop a novel 2,6-epoxy-3゜4.5,6 which has anticancer activity and is a precursor of nogalene derivatives.
．． 11.12-hexahydro-28-naphthacene (1
, 2-b) to provide oxosine-9,16-dione derivatives.

[Means for solving problems]

The present invention provides novel 2.6-nipoxy 3.4.5 represented by the general formula (wherein R1 is a hydrogen atom or a hydroxyl group protecting group).
．． 6,11.12-hexahydro-2H-naphthacene (
1,2-b) Oxosine-9°16-dione derivative.

2,6-nipoxy represented by the general formula (1) 3.
4.5,6,11.12-hexahydro-28-naphthacene (1,2-b)oxocine-9,16-dione derivative can be produced according to the following reaction formula.

(In the formula, Rt, R2 are hydroxyl group protecting groups, R4, R
8 and R6 are lower alkyl groups. ) [First step] This step is performed by adding 1°4.5.
6-t-Butyldimethylsilyloxy-4-(N-
Methoxycarbonyl-N-methyl)amino-3,5-dimethoxymethyloxy-hexan-2-one (■) is a compound that can be synthesized by a known method (M., Kawasaki, et al.).

Tetrahedron Lett,, 2G+269
3 (1985)).

The addition reaction in this step is preferably carried out in a solvent, and for example, ether solvents such as tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, and dioxane can be used.

The reaction proceeds smoothly at -78°C to 50°C.

[Second Step] In this step, the t-butyldimethylsilyl group of the 2-hexanol derivative represented by the formula (IV) obtained in the first step is removed, and the 1,5- This method produces hexanediol derivatives.

In removing the protecting group in this step, for example, tetrabutylammonium fluoride, hydrofluoric acid, acetic acid, etc. can be used as a desilylating agent.

This step is preferably carried out in a solvent, such as diethyl ether, tetrahydrofuran, 1.2-
Ether solvents such as dimethoxyethane and dioxane, and halogenated hydrocarbon solvents such as diform and dichloromethane can be used.

The reaction proceeds smoothly at a temperature of 0°C to 100°C.

[Third Process] Woodworking @i is obtained in the second step 41. In the above formula (V), j(''wasarero I, 5-1-xanediol derivative is oxidized and 6-(1,4゜5
．． 8-tetramethoxynaphthalen-2-yl)-3,4
,5,6-tetrahydro-2-pyranone-donor! ! !
It is something that is created.

In the oxidation of this step, for example, dimethyl sulfoquinide/oxalyl chloride/triethylamine mixed oxidizing agent, dimethyl sulfoquinide/trifluoroacetic anhydride/triethylamine mixed oxidizing agent, pyridinium chlorochromate, etc. may be used. I can do it.

This step is preferably carried out in a solvent, and for example, halogenated hydrocarbon solvents such as chloroform, dichloromethane, and dichloroethane can be used.

This step is the 6-(1,4,5,8-tetramethoxynaphthalen-2-yl)-3,4,5,6-tetrahydro-2- represented by the formula (Vl) obtained in the third step.
By reducing the pyranone derivative, 6 represented by the above formula (■)
-(1,4,5,8-tetramethoxynaphthalene-2-
yl)-3,4°5,6-tetrahydro-2H-pyran derivative.

In the reduction of this step, the reducing agent is, for example, 5 diisobutyl hydride, hydrogenated trit
-Butoxyaluminum lithium, etc. can be used.

It is desirable to carry out this step in a solvent, such as diethyl ether, tetrahydrofuran, 1.2-
Ether solvents such as dimethoxyethane and hydrocarbon solvents such as toluene and hexane can be used.

The reaction proceeds smoothly at a temperature of 8°C to 0°C.

[Fifth Step] This step is performed to obtain the 6-(1,4,5,8-tetramethoxynaphthalen-2-yl)-3,4,5,6 represented by the formula (■) obtained in the fourth step. -tetrahydro-2H
- Preservation of water # group at 2-position hydroxyl group of biran derivative 1! By introducing a group, Chikuru 6-(1,4,5,8
-tetramethoxynaphthalen-2-yl)-3,4,5
, G-tetrahydro-2H-bilane derivatives. As protecting groups for hydroxyl groups, methyl group, 1-butyl group, allyl group, 2,2.2-trichloroethyl group,
Benzyl group, p-methoxybenzyl Me silyl group, t-
Trialkylsilyl groups such as butyldimethylsilyl group, t-butyldiphenylsilyl group, methoxymethyl group, 2-
methoxyethoxymethyl group, benzyloxymethyl group,
2-trimethylsilylethoxymethyl group, 2,2.2-
) alkoxymethyl groups such as dichloroethoxymethyl groups,
Examples include alkyl groups such as a methylthiomethyl group and a phenylthiomethyl group, and a phenylthiomethyl group. These protecting groups can be prepared by methods known to those skilled in the art (C, B, Rees
e,' ProtectiveGroups in
OrganlcChemistry'', ed, by
J.F.W.

Me 0nto, Plenum Pres3Lon
Don and New York.

1973, pp95-144; T, W.

Greens,” Protective Groups
in Organic Chamlstry”, J
ohn Wiley&5ons, New York
, 1981. pplO-86; Takeshi Oishi, Yugoka, 36
．． 715 (1978). ) can be introduced by

6-(1,4゜5.8-
Tetramethoxynaphthalen-2-yl)-3,4,5,
What is necessary is to react 6-tetrahydro2H-pyranyl. Examples of the alkoxymethyl halides used include methoxymethyl chloride, methoxymethyl bromide, 2-methoxyethoxymethyl chloride, 2-trimethylnrillethoxymethyl chloride, and pencyloxymethyl chloride.The reaction was carried out in a 1M medium. For example, diethyl ether, tetrahydrofuran, 1.2
-Ether solvents such as dimethoxyethane and dioxane°
It can also be carried out by adding.

The reaction proceeds smoothly at room temperature to 80°C.

(Sixth Step) This step consists of 6-(1,4,5,8-tetramethoxynaphthalen-2-yl)-3,4,5, represented by the formula (■) obtained in the fifth step, 6-tetrahydro-2H-
6-(1,4,5,8-tetramethoxynaphthalene-2) represented by the general formula (IX) by reducing a pyran derivative.
-yl)-3°4.5.6-tetrahydro-2H-bilane derivatives.

Ram etc. can be used.

It is desirable to carry out this step in a solvent, and for example, ether solvents such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, and dioxane can be used.

The reaction proceeds smoothly at a temperature of 0°C to 80°C.

[Seventh step] This step is performed to obtain the 6-(1,4,5,8-tetramethoxynaphthalen-2-yl)-3,4, represented by the general formula (IX) obtained in the sixth step. 5゜6-tetrahydro-
6-(5,8-dimethoxy-1,4-dioxonaphthalen-2-yl)-3,4,5,6-tetrahydro-2H represented by the general formula (X) is obtained by oxidizing 2H-pyran ta8 body. -Produces pyran derivatives. Cerium ammonium nitrate can be selected as the oxidizing agent.

This step is preferably carried out in a solvent, and for example, an atorcohol solvent such as methanol, ethanol, propatool, etc., a polar solvent such as athermal cocitrile, dimethylformamide, dimethylacetamide, etc. can be used.

The reaction proceeds smoothly at a temperature of -50°C to 50°C.

[Eighth Step] This step is performed using 6-(5,8-dimethoxy-1,4-dioxonaphthalen-2-yl)-3゜4 represented by the general formula (X) obtained in the seventh step. .5. The 6-tetrahydro-2H-pyran derivative is reduced with sodium hydrosulfide, and the resulting product is converted into trimethylsilyl bromide,
Treat with trialkylsilyl halide such as trimethylsilyl iodide to perform a ring-closing reaction and remove the protective groups for the 3- and 5-position hydroxyl groups, and then reintroduce protective groups to the two hydroxyl groups generated at the 3- and 5-positions. 9,12-dimethoxy-2゜6-epoxy 3 represented by the general formula (XI)
．． 4,5.6-tetrahydro-2H-naphthaleno (1
, 2-b) for producing oxosin derivatives.

The reduction step of this process is preferably carried out in a two-layer system consisting of an organic layer and an aqueous layer, with the organic layer containing chloroform, dichloromethane, l,2-dij-? =j'z A halogenated hydrocarbon solvent such as ethane is used.

The reaction proceeds smoothly at a temperature of θ°C to 50°C.

The steps of ring closure and removal of the protecting groups for the 3- and 5-position hydroxyl groups in this step are preferably carried out in a solvent; for example, halogenated hydrocarbon solvents such as chloroform, dichloromethane, and 1,2-dichloroethane can be used. .

The reaction proceeds smoothly at a temperature of 30°C to 60°C.

The hydroxyl protecting groups introduced at the 3- and 5-positions in this step include methyl group, t-butyl group, allyl i, 2,2.
Alkyl groups such as 2-trichloroethyl group, benzyl) Lta, p-nitrobenzyl group, p-methoxybenzyl group, and terylmethyl group, trimethylsilyl group, triethylsilyl group, isopropyldimethylsilyl group, t-butyldimethylsilyl group , trialkylsilyl group such as t-butyldiphenylsilyl group, formyl group, acetyl group, trichloroacetyl 5, trifluoroacetyl group, benzoyl group, p-phenylhenshiyla J, p-methoxybenzoyl group, methoxycarbonyl group, Ethoxycarbonyl group, 2,2.2-trichloroethquine carbonyl bottle,
Benzyloxycarbonyl L p-Nitrobenzyloxycarbonyl group, p-methoxybenzyloxycarbonyl group, acyl group such as 1(-phenylcarbamoyl 5, N, N-dimethylcarbamoyl group, methoxymethyl group, 2-methoxyethoxymethyl group, benzyloxymethyl group, 2-trimethylsilylethoxymethyl group, 2.2
．． alkoxymethyl groups such as 2-trichloroethoxymethyl group; alkyl groups such as methylthiomethyl group and phenylthiomethyl group;

Examples include sulfonyl groups such as a mono-ruthiomethyl group, a methanesulfonyl group, a penzenesulfonyl group, and a p-mediensulfonyl group. These retaining groups can be prepared by methods known to those skilled in the art (C, B, Ree ae.

”ProLectlva Groups inQr
Ganic Ci+amLsLry', ed.

by J, F, W, Mc 0m1e, Plen
umPress, London and New
York, 1973. 9995-144;T,
W, Greens,” Pro tec t.
1veGroups in Organi
cChemistry', John Wiley
&5ons, New York, 1981. pp
lQ-86; Takeshi Oishi, Yuika, Kodan, 715 (197
8), ) can be introduced.

When introducing an acetyl group as a protecting group for water #1, use acetic anhydride, acetyl chloride, etc. in the presence of potassium acetate, sodium acetate, etc. without a solvent or in an alcoholic solvent such as methanol, ethanol, propatool, etc. Something will happen.

The reaction proceeds smoothly at a temperature of -20°C to 50°C.

[Ninth Step] This step is performed to prepare the 9,12-dimethoxy-2゜6-epoxy- represented by the general formula (XI) obtained in the eighth step.
3,4,5,6-chitrahydro 2H-natsutaleno (
1,2-b) After reacting the oxosine derivative with boron tribromide, the reaction is terminated with triethylamine, and the resulting product is oxidized with cerium ammonium nitrate to obtain 2,6 represented by the general formula (Xll) above. -Nipoxy 3. 4.
5. 6-tetrahydro-2H-naphthaleno (1,
2-b) Oxocine-9,12-dione derivatives are produced.

The reaction with boron tribromide in this step is preferably carried out in a solvent, such as chloroform, dichloromethane, 1.
This can be carried out using a halogenated hydrocarbon solvent such as 2-dichloroethane.

The reaction proceeds smoothly at a temperature of 0° C. to room temperature.

The oxidation reaction with cerium ammonium nitrate in this step is preferably carried out in a solvent, and can be carried out, for example, in an alcoholic solvent such as methanol, ethanol or propatool.

The reaction proceeds smoothly at a temperature of -78°C to 0°C.

[10th Step] This step is carried out using the 2,6-nipoxy 3.4゜5.6-tetrahydro-2H-naphthaleno (1゜2-b) obtained in the ninth step (represented by Xl). A Diels-Asoder reaction between an oxocin-9,12-dione derivative and a 4-bis(trialkylsilyloxy)methylene-1-methyl-3-methylene-1-cyclohexene derivative represented by the general formula (Xlll) 2,6-Eboxy represented by formula (1.) 3. 4.
5. 6゜11.12-hexahydro-2H-naphthacene (1,2-b)oxocine-9,16-dione derivative is produced.

4-bis(trialkylsilyloxy)methylene-1-methyl-3-methylene- represented by general formula (XIH)
A 1-cyclohexene derivative is a compound that can be synthesized by the following reaction.

(In the formula, R4, R5, R6 represent an alkyl group.) Ethyl-2,4-dimethy group represented by the above formula (XIV),
3-Cyclohexadiene-1-carboxylate is a compound that can be synthesized by a known method (J, P, G55so
n, at at,.

Tetrahadron, earth 0.4743 (Xm), can be obtained by treatment of aluminum bromide in tetrahydrothiophene.

The reaction proceeds smoothly at a temperature of 0°C to room temperature.

The 4-bis(trialkylsilyloxy)methylene-1-methyl-3-methylene-1-cyclohexene derivative represented by the general formula (Xlll) can be obtained by replacing Xm with 2 equivalents of lithium diisopropylamide, lithium hexamethyldi Treating with silazide etc. and reacting the generated dianion with a trialkylsilyl halide such as trimethylsilyl chloride, trimethylsilyl bromide, triethylsilyl chloride, ethyldimethylsilyl chloride, dimethylpropylsilyl chloride, -(-butyldimethylsilyl chloride) It is a compound that can be synthesized by the formula (X
The 4-bis(trialkylsilyloxy)methylene-1-methyl-3-methylene-1-cyclohexene derivative represented by Deals with )
＼l″／ Used for a≠der reaction.

1: Xm and (Xllll) Noddy JL Sua
The reaction is preferably carried out in a solvent, such as an ether solvent such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, or 1,4-dioxane, or a halogenated hydrocarbon solvent such as chloroform, dichloromethane, or 1,2-dichloroethane. As a solvent, a hydrocarbon solvent such as benzene, toluene, xylene, etc. can be used.

The reaction proceeds smoothly at a temperature of -20°C to 50°C.

[11th Step] This step is performed by converting the general formula (r a
) 2,6-Eboxy 3.4°5.6,1
1.12-hexahydro-2H-naphthacene (1,2-
b) By removing the protecting groups for the hydroxyl groups at the 3- and 5-positions from the oxocine-9,16-dione derivative, 3,5-dihydroxy-2,6-eboxy 3 represented by the above formula N b) is obtained.
．． 4.5゜6,11.12-hexahydro-2H-naphthacene (1,2-b) oxosine-9,16-dione can be carried out by using a known method a
(C, B, Reese.

”Protective Groups inOr
ganic Chemistry”, ad.

by J, F, W, Mc 0m1e, Plenum
Pross, London and New York, 1973. pp95-144
;T, W, Graena,” ProtectiveG
roups in OrganicChemist
ry”, John Wiley & 5ons, New
York, 1981. ppt.

-86; Takeshi Oishi, Yuika, 1dan, 715 (197B)
,) Its removal can be carried out by adding an inorganic or organic acid and heating.

The reaction temperature is room/! Proceeds smoothly at 1-100°C.

2,6-epoxy-3°4.5 obtained as above
,6,11.12-hexahydro-2H-naphthacene
The usefulness of the (1,2-b) oxosine-9,16-dione derivative as an anticancer agent was confirmed by conducting a malignant tumor cell growth inhibition test. The test was conducted using mouse lymphocytic leukemia cells (p388) according to a conventional method, and the inhibition rate was determined.

2,6-Eboxy represented by the above general formula (2) of the present invention;3. 4. 5. 6. 11. 12-hexahydro-2H-naphthacene (1,2-b)oxocine-9
, 16-dione derivatives undergo no dehydrogenation reaction (wherein, R1 is a hydrogen atom or a protecting group for a hydroxyl group).

) can lead to optically active nogalene derivatives represented by

The dehydrogenating agent used is 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ), which is easily available industrially, and tetrachloride.

2-benzoquinone (0-chloranil), tetrachloro-
1,4-benzoquinone (chloranil) and the like can be used. The dehydrogenating agent is a raw material, 2,6-epoxy 3.4.5,6. ll, 1
2-hexahydro-2H-su, phtaceno(1,2-b)
2 to 10 for oxosine-9゜16-dione derivatives
It can be used in the current scene.

The reaction is preferably carried out in a solvent, such as a hydrocarbon solvent such as toluene or benzene, an aprotic solvent such as an ether solvent such as diethyl ether, tetrahydrofuran, 2-dimethoxyethane, or dioxane; Although any solvent can be suitably used, toluene is preferably used from an industrial point of view.

The reaction proceeds smoothly at a temperature ranging from room temperature to 110°C.

2,6-epoxy-3°4.5 represented by the general formula (XVI) (wherein, R1 is a hydroxyl protecting group)
．． 6-tetrahydro-2H-naphthaceno(1,2-b)
The above general formula (XVI) from oxocine-9,16-dione derivatives (wherein l'ij+ is a hydrogen atom).
Retention of hydroxyl group to optically active nogalene expressed as t! Removal of one group can be carried out by applying methods known to those skilled in the art depending on the type of protecting group for the hydroxyl group (C, B, Reese, 'Protect
Iv+5Groups in Organic
Chemistry', ad, by J, F,
W.

Me　　　　m1e, Plenum　　Press.

London and New York
.

1973, pp95-144; T, W, Groan
s.

'Protective Qroups in
Organic Chemistry'.

John WILey & 5oz.

New York, 1981. 'pplO-86
; Takeshi Oishi, Yuaika, 1st, 715 (1978),).

When the protecting group for the hydroxyl group is an acetyl group, this can be carried out by adding an inorganic or organic acid to an aqueous solution and heating.

The reaction proceeds smoothly at room temperature to 100°C.

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

Reference example 1 1.4,5.8-tetramethoxynaphthalene (m, p,
1B'? -169℃) 1.74g (7.0mmol)
was dissolved in 180 ml of anhydrous tetrahydrofuran, stirred at 0°C, and then dissolved in n-butyllithium hexane solution (1,
5.51 ml (7.0 mmol) of 27 molar concentration) was added thereto, and stirring was continued at that temperature for 20 minutes. (-)-(
3R,43,53)-6-5-buty, bl, silicate, 3,5-dimethoxymethyloxy-4-(N-methoxycarbonyl-N-methylgemin\-2-hexanone (Tetrahedron Lett, , 2L26
93 (1985)) 2.13 g (
4,9 mmol l) of anhydrous tetrahydrofuran solution 15
m1 was added dropwise over 30 seconds at 0°C. Stirring was further continued at that temperature for 3 minutes. Subsequently, 100 ml of a saturated ammonium chloride aqueous solution was added to stop the reaction. After adding 200 ml of toluene and stirring, the organic layer was separated, washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was passed through a silica gel column (n
-hexane/ethyl acetate-3)*chloroform/
(-)-(2R,3R).

43.53)-6-t-butyldimethylsilyloxy-
3,5-dimethoxymethyloxy-4-(N-methoxycarbonyl-N-methyl)amino-2(1,4,5,8
1.90 g (57% yield) of -tetramethoxynaphthalen-2-yl)-2-hexanol was obtained as a pale yellow caramel.

[α]1·-35,5° (cm1.oo chloroform1] mass) mass spectrum m/a685 (M”).

NMR (CDCIs) δ (ppm): 0.03゜0
．． 05 (6H, 2s, SL (CH,)t).

0.86. 0.90 (98,2s.

S iC (CHs) 3), 1.76 (3H, s.

3H,), 3.02 (3H,s, NCH,).

3.1G, 3.29.3.33, 3.37, 3.55°5.0 (10)1. m, Of(,0CHt×3゜Hs
, H,, Ha), 6.84 (2H, s.

ArH), 7.00 (IH, s, ArH).

IR (nea L): 3450 (OH).

1690 (CO), 1600 (Ar) cm-'.

Elemental analysis value: Cs5HssNO++ Calculated value as Si: C; 57.79. Hi 8.08°N;2.
0494° Analysis value: C; 57.76, Hi 7.93°N, 1
．． 99%.

Reference Example 2 Monobutyldimethylsilyloxy-3,5-dimethoxymethyloxy-4-(N-methoxycarbonyl-N-methyl)amino-2-(1,4,5,8-tetramethoxynaphthalen-2-yl)- 2-hexanol 1.50g
(2,19 mmol) in 5.0 ml of anhydrous tetrahydrofuran solution (1 molar concentration) (5,0 mmol I)
was added and stirring was continued at that temperature for 1 hour. After distilling off the solvent, pass the residue through a silica gel column (ethyl acetate).
-(23゜3S,4R,5R)-3-(N-methoxycarbonyl-N-methyl)amino-2,4-dimethoxymethyloxy-3-(1,4,5,8-tetramethoxynaphthalene-2- )-1,5-hexaftanyl 1.
22 g (98% yield) were obtained as colorless caramel.

[α)"31.4' (c-1,25 chloroform) mass spectrum m/e 571 (M").

NMR (CDCIs) δ (ppm): 1.73 (
3H,s, 3Hh), 2.96 (3H,s.

NCHs), 3.2 4.1 (28H, m.

7 CHs, 2 H+, H1+ Hz,
Ha.

20H), 4.4-5.0 (4H, m.

OCR! Ox 2 ), 6 , 81 (2H
,s.

ArH),? , 05, 7.22 (IH, 2g.

Arc).

IR (naat): 3450 (OH)
.

1680 (Co), 1600 (Ar)cs
-'.

Reference Example 3 (7.0 mmol) in 5 ml of anhydrous dichloromethane solution was added and stirred at that temperature for 2 minutes. (-)-(2S,
33.4R,5R)-3-(N-methoxycarbonyl-
N-methyl)amino-2,4-dimethoxymethyloxy-5-(1,4,5,8-tetramethoxynaphthalene-
0.90g (1,
After adding 5 ml of anhydrous dichloromethane solution of 57 mmol I) and stirring at -60°C for 20 minutes, 1.52 g of triethylamine (15.0 mmol I) was added at this temperature.
was added dropwise, and the reaction temperature was raised to 0° C. over 20 minutes.

100ml of saturated ammonium chloride aqueous solution and 11ml of ethyl acetate
The reaction was stopped by adding 00ml. Separate the organic layer with water i1 [
It was dried over magnesium, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane-2) to obtain 0.82 g (91% yield) of (33
,4R,5R,6R)-4-(N-methoxycarbonyl-N-methyl)amino-3,5-dimethoxymethyloxy-6- was obtained.

Mass spectrum: m/e567 (M').

NMR (CDCIs) δ (ppm): 2.04
(3H,s, 6 CHs), 2.97 (3H.

s, NCHs), 3.20, 3.36 (6H.

2 s, 0CHzx 2), 3.66.3.70°3.
86, 3.90, 3.92 (15H, 5s.

A rOCHsX 4. C0tCHs), 4.56 (2
H, dd, J = 7Hz, 8Hz.

0CR1Oon, 4.92 (2H, dd,
J line 36Hz, 7Hz, 0CHzO), 6.84 (2
H,s,ArH), 7.00 (LH.

s, ArH>.

IR (neat): 174Q (Co).

1695 (Co), 1600 (Ar).

1021025 (-0-) Spirit.

Reference example 4 <33,4R,5R,6R,)-4-(N-methoxycarbonyl-N-methyl)amino-3,5-dimethoxymethyloxy-6-methyl-6-(1°6 is 7) 4.5.8-Tetramethoxynaphthalene 435* (0.77 mmol) was dissolved in anhydrous toluene 3
While stirring at -78° C., 0.92 ml (0.92 mmol) of a hexane solution of diisobutylaluminum pydolide (1.0 molar concentration) was added dropwise, and the mixture was stirred at this temperature for 20 minutes. methanol 0.5m
1 was removed to stop the reaction, 100 ml of a saturated ammonium chloride aqueous solution was added, and the mixture was extracted with ethyl acetate (30 ml x 2). Combine the organic layers and add saturated brine (20ml x 2
), dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure.

Dissolve the residue in 30 ml of methanol and add 2 ml of anhydrous potassium carbonate.
．． After adding Og and heating under reflux for 30 minutes, the reaction solution was filtered, and the filtrate was heated to 1 m under reduced pressure. This product was purified by silica gel column chromatography (ethyl acetate/hexane-2)-(33,4R,5R,6R)-2
-Hydroxy-4-(N-methoxycarbonyl-N-methyl)amino-3,5-dimethoxymethyloxy-6-
Methyl-6-(1,4,5,8-tetramethoxynaphthalen-2-yl)-3,4,5,6-tetrahydro-2
354 ml of H-bilane (82% yield) was obtained as a pale yellow caramel.

(α)"+12.1' (c=1.05 riooform J) mass spectrum m/e569 (M).

NMR (CDCIs) δ (ppm): 1.83°1.91 (3H, 2g, 6 CHs).

2.96. 2.99 (3H, 2s, NCHi).

3.28 (3H, s, 0CHs), 3.37 (
3H,s, 0CHs), 3.4 4.3(19
1(,m, OCH,x4.C0tC)(s.

0) (, Hz, Ha, Hs), 4.4
4.9 (5H, m, 0C11xX 2.Hz)
, 6.80 (2H,s, ArH), 7.72
(IH, s.

ArH).

IR (neat): 3450 (OH)
.

1690 (Co), 1600 (Ar).

IQ 70. 1030 (-0-)clI-
'.

Reference Example 5 Droxy-4-(N-methoxycarbonyl-N-methyl)amino-3,5-dimethoxymethyloxy-6-methyl-6-(1,4,5,8-tetramethoxynaphthalen-2-yl) -3,4,5゜6-tetrahydro-2H-
Dissolve pilaf 350 (0.62 mmol 1) in 5.0 ml of anhydrous tetrahydrofuran, add 4.44 g (34 mmol) of pilaf ethylamine, and 3.18 g (34 mmol) of dichloromethyl methyl ether. After adding (39 mmol 1), the mixture was heated under reflux for 3 hours. Subsequently, 1 ml of triethylamine and 3 ml of methanol were added under stirring while cooling with water, and after leaving at this temperature for 15 minutes, 13 ml of ethyl acetate was added.
Added l. The organic layer was mixed with cold 3NHC1 water, saturated sodium bicarbonate solution,
After washing successively with saturated brine and drying over anhydrous magnesium FMate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane-2) to give (-)-(3S, 4R, 5R.

6R)-4-(N-methoxycarbonyl-N-methyl)
Amino-2,3,5-trimethoxymethyloxy-6-
Methyl-6-(1,4,5,8-tetramethoxynaphthalen-2-yl)3.4,5°6-tetrahydro-2H
-Pyran 343 (91% yield) was obtained as colorless crystals.

m, p, 115-116'.

(α)7). -16,2°C (C-1,10 chloroform) W spectra m/a613 (Mo).

NMR (CDCI,) δ(J+m): 1.82 (3H
, s, 6-CHa), 2.96°3.00 (3H, 2
s, NCHs), 3.23°3.28, 3.40 (9
H, 3s, 0CHsX3), 3.5-4.3 (17H
,nt.

0CHsX 5. Hs, Hs), 4.3-5.3 (2H
, s, ArH), 7.74 (IH, s.

ArH).

IR (KBr): 1700 (Co), 1600 (
A r), 1020 (-0-) cm-'.

Elemental analysis value i Calculated value as C2vH4N O+ x: C; 56.76, Hi 7.06°N; 2.2
8%.

Analysis value: C; 56.63. Hi 7.1? .

N: 2.21%.

(-)-(33,4R,5R,6R)-4-(N-methoxycarbonyl-N-methyl)amino-2,3,5-)
liftoxymethyloxy-6-monomethyl-6-(1,4,
5,8-tetramethoxynaphthalen-2-yl)-3,
Dissolve 4,5,6-tetra in 40 ml of anhydrous ether, add 182 w (4,8 mmol) to hydrogenated aluminum linau, heat under reflux for 1 hour, and then add 1 ml of methanol to stop the reaction. stopped. 100 ml of ethyl acetate was added, and the organic layer was washed with saturated brine (20 ml x 3), dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.

The residue was purified by silica gel column chromatography (ethyl acetate/hexane-2)-)-(3S, 41?,
SR,6R)-4-dimethylamino-2,3,5-)dimethoxymethyloxy-6-methyl-6-(1,4,5
,8-tetramethoxynaphthalen-2-yl)-3,4
,5,6-tetrahydro-2H-pyran 641■ (95
% yield) as colorless crystals.

m, p, 109-110°C.

[α]Ra'O (C-1,08 chloroform) [α]Rahi 10.3' (cm 1.08 chloroform) Mass spectrum m/e: 569 (M'').

NMR (CDC13) δ (ppm): 1.84 (3
H, s, 6 CHs), 2.53 (6H.

s, N (CH3) *), 3.02 (IH, t.

J=8.7Hz, Ha), 3.35 (6H, s.

0CHiX2), 3.38 (3H, s.

OCR, ), 3.71, 3.84.3.90°3.92
(12H14s, Ar0CHsX 4).

3.5-4.2 (2H, m, Hs, Ha).

4.6 5.3 (7H, m, OCH*OX3゜Hm)
, 6.80 (2H,s,ArH).

7.70 (IH, s, ArH).

IR (KBr): 1600 (Ar), 1070°1
040, 1020 (0) cm-'.

Elemental analysis value: Calculated value as Cz* Has N O+ +: C; 59.04. H, 7,61°N; 2.
4G%.

Analysis value: C; 58.86. H; 7.57°N;
2.40%.

Reference Example 7 (-)-(33,4R,SR,6R)-4-dimethylamino-2,3,5-trimethoxymethyloxy-6-methyl-6-(1,4,5,8-tetramethoxy naphthalen-2-yl)-3,4゜5.6-tetrahydro-2H
- Biran 300 ■ Death / (0.53 mmol) Dissolve ≠ 9 ml of tanol and 14
Cerium ammonium nitrate 1.80g (3,28
3 ml of an aqueous solution of 3 mmol) was added and the temperature was raised. After stirring for 10 minutes at 0°C, add 20 ml of ethyl acetate and 20 ml of water.
1 was added thereto, and saturated sodium bicarbonate solution was added dropwise with vigorous stirring to adjust the pH of the aqueous layer to -8. After separating the organic layer, saturated brine (10
After washing with 0.5N) ICI water (20ml
2), and after adjusting the pH to a with saturated sodium bicarbonate solution, extracted again with ethyl acetate (20 ml x 2). After drying the organic layer over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate) -(33,4R).

5R,6R)-6-(5,8-dimethoxy-1゜4-dioxonaphthalen-2-yl)-4-dimethylamine-
2,3,5-trimethoxymethyloxy-6-methyl-
3,4,5,6-tetrahydro-2H-pyran 205■
(72% yield) was obtained as yellow crystals.

m, p, 151-152°C.

(α) ”+ 14.3′ (e-0,28 chloroform) Mass spectrum m/e; 539 (Ml.

NMR (CDCIff) δ (ppm): 1.82
(3H,s, 6 CHs), 2.46 (6H.

s, N (CHs) t), 2.82 (L H, t.

J-6Hz, Ha), 3.31 (3H, s.

○CHs), 3.39 (6H, s.

0CR3X2), 3.78 (LH, d, J=7H2,
Hm), 3.90, 3.94 (6H.

2s, Ar0CH3x2), 4.15 (IHa, J
-6Hz, Hs), 4.5-5.1 (7H, m, OCH
! OX3. Hz).

7.24 (3H,s,ArH).

1020 (0-) cm-'.

Elemental analysis value: Calculated value as CgiHstNO++:
Ci 57.86. H, 6,91°Ni2.60%.

Analysis value: C, 57,46,H; 7.09°N; 2.
50%.

Reference example 8 (+) -(33,4R,5R,6R) -6-(3,
8-dimethoxy-1,4-dioxonaphthalen-2-yl)-4-dimethylamino-2,3°5-trimethoxymethyloxy-6-methyl-3°4, 5. 6-Titrahydro 2H-pyran 100Ql (0,19mmo
I) in chloroform loml (1,44 mmol)
23 ml of an aqueous solution was added thereto, and the mixture was vigorously stirred at room temperature. When the chloroform layer changed from yellow to colorless, it was allowed to stand, the chloroform layer was separated, and the solvent was distilled off under reduced pressure. To this was added 5 ml of anhydrous methylene chloride, heated under reflux, 1 Oml of trimethylsilyl bromide was added, and the mixture was stirred at this temperature for 10 minutes.

After the solvent was distilled off under reduced pressure, 1 m of methanol was separated at -78°C and this was distilled off under reduced pressure at room temperature, which was repeated twice to obtain crude (2R, 33, 4R).

5R,6R)-4-dimethylamino-3,5,8-trihydroxy-9,"2-dimethoxy-6-methyl-2,
6-Eboxy 3.4,5.6-tetrahydro-2H-
Dissolve naphthaleno (1,2-b)oxosine hydrobromide in 3 ml of methanol and 300 w of potassium acetate (
3.1 mmol), acetic anhydride 2.0 ml (21 m
After stirring at 30° C. for 1 hour, the solvent was distilled off under reduced pressure. This product was purified by silica gel column chromatography (ethyl acetate).+)-(2R,33,4R
,5R.

6R)-3,5-diacetoxy-4-dimethylamino-
8-hydroxy-9,12-dimethoxy-6-methyl-
2,6-epoxy-3,4,5,6-titrahydro 2
H-Naphthalene (1,2-b)oxosine 69■ (7
8% yield) was obtained as colorless crystals.

m, p, 182-183°C.

[α) ”+79.7° (c-0,31 chlorophor (
3H,s, 6-CHs), 2.0? .

2.13 ((iH, 2s, C0CHaX 2).

2.26 (6Hl s, N (CHs)x>
.

2.76 (I H,t, J = 10.3Hz
, Ha).

3.86.4.02 (6H, 2s, 0CHsx
2), 5.12 (IH, d, J-10, 3
Hz.

Hs), 5.15 (IH, dd, J-10
, 3Hz, 4.4Hz, Hs), 5.85
(IH.

d, J=4.411z, Ha), 6.61
(IH.

3,8rH), 6.77 (2H,s, ArH)
.

9.35 (IH, s, 0) ().

IR (KBr) = 3440 (OH), 1
745(Co), 1250. 1235. 122
0 (cot), 1040 (CO-C0-C) (J-'.

Calculated value as elemental analysis value 'Cg4H□q N O*:
C; 60.62. H; 6.15°N; 2.95%.

Analysis value: C; 60.21. H; 6.13°N;
2.88%.

Reference example 9 (+) −(2R, 33, 4R, 5R, 6R) −3,
5-diacetoxy-4-dimethylamino-9゜12-damine-1xy-6-methyl-2.6-epoxy3. 4.
5. 6-tetrahydro-2H-naphucleno (l,
2-b) Oxocin 45μ (0,095mmol) in anhydrous dichloromethane 4.5ml! 0.90 + n l of a 1.0M solution of boron tribromide in methylene chloride at 0°C.
(0.90 rnmol) was added dropwise, and the mixture was stirred at this temperature for 30 minutes. After distilling off the solvent and excess boron tribromide under reduced pressure at 0°C, 5 ml of triethylamine Q and 3 ml of methanol were added at -78°C, and the mixture was distilled off under reduced pressure at room temperature. The residue was dissolved in 12 ml of ethanol at -78°C, and cerium ammonium nitrate 270QI (0.49 mmol) was dissolved in 12 ml of ethanol.
A solution of 0.3 ml of water + 1.5 ml of ethanol was added dropwise and stirred at this temperature for 10 minutes, followed by 0.2 ml of triethylamine.
The reaction was stopped by adding 7 ml of the solution dropwise. This and 50m of water! was added, and then extracted with chloroform (50 ml x 2). The chloroform layers were combined, washed successively with saturated brine, INMCI water, saturated sodium bicarbonate water, and saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane-2)-(2R,35,4R,5R,6R)-3
,5-diacetoxy-4-dimethylamino-8-hydroxy-6-methyl-2,6-epoxy3.4.5.6
-Tetrahydro-2H-naphthaleno(1,2-b)oxosine-9,12-dione (30 µm (71% yield)) was obtained as red-orange crystals.

m, p, 153-155°C.

[α)j'+420' (e-0,050 chloroform) mass spectrum m/e: 445 (M'').

NMR(CDCls)δ(ppm):
1.5B (3H, s, 6 CHs), 2.12゜2
．． 15 (6H, 2s, C0CHsX 2).

2.28 (6H, s, N (CHs) meaning)・2
．． 65 (11(,t, J = 10JHz,
Ha).

5.11 (I H, d, J ” l O, 8Hz,
Hs).

5.19 (LH, dd, J-LQ, 8Hz.

4.0Hz, H3), 5.85 (LH, d.

J-4,0Hz+Hz), 6.89 (2H
,s.

ArH), 12.40 (LH, s, OH).

I R (KI3r): 3460 (OH),
1745 (Co), 1640 (Co), 1
220 (Co, 1040 (CO-C0-C) c+a-'.

Elemental analysis value: CttHtsNOq” Calculated value assuming 0.5H*O: C; 58.15.H: 5.32°N, 3
．． 08%.

Analysis value: C; 58.36, H; 5.26°N; 3.0
1%.

Reference Example 10 Ethyl 2,4-dimethyl-1,3-cyclohexitodiene-1-carboxylate (Tetrahedron, ±0.4743 (1984
) Synthesized by the method of
Add to 5 ml of tetrahydrothiophene solution at 30°C.
．． The 0 reaction solution reacted for 5 hours was poured into a mixture of 3N HCl, 5Qml of water and ice, extracted with ethyl acetate (20ml x 3), the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate-4), and m, I)
, 92-94°C.

Quality M Spectrum m/6152 (M”).

NMR(CDCls)δ(ppm): 1.
87 (3H,s, CHs), 2.19 (3H,s.

CHs), 1.9 2.3 (2H, m, 2Hs).

2.3 2.7 (2B, m, 2H&), 5.6 -5.
8 (I H, m, I(s).

IR (KBr): 3430 (OH), 1670°16
35 (Co).

As elemental analysis value jc*H+mox Calculated value: C, 71,03, Hi 7.95%.

Analysis value j　C; 70.90. H: 7.79%.

Reference Example 11 Diisopropylamine 0.17ml (1,2m-m
1) was dissolved in 0.5 ml of anhydrous tetrahydrofuran, and 0.61 ml (1.0 mmol) of a 1,64 mol hexane solution of n-butyllithium was added dropwise at -40°C.

After stirring at this temperature for 10 minutes, at -78°C 76 g of 2,4-dimethyl-1,3-cyclohexadienecarboxylic acid
(0,50mmol I) of anhydrous tetrahydrofuran Q
, 5ml liquid and 0.32ml trimethylsilyl chloride
(2.5 mmol) was added, the reaction temperature was raised to 30°C, and after stirring at this temperature for 30 minutes, the solvent was distilled off under reduced pressure. To this was added 2 ml of anhydrous hexane, stirred and allowed to stand, and the supernatant was transferred to another container and distilled off under reduced pressure to obtain 4-bis(trimethylsilyloxy)methylene-1-methyl-3.
-Methylene-1-cyclohexene was obtained as a pale yellow caramel.

NMR(CDCls)δ(ppm): 0.
18 (9H,s, S l (CHs)s), 0.24
(9H,s, S l (CHs)s), 1.76(3
H, s, I CHs), 1.9 2.5 (4H, m,
2H8, 2H &), 4.87 (IH, d, J-2, 6H
z, C-CH).

5.21 (LH, d, J-2, 6Hz, C=CH)
, 5.84 (IH, broad s.

H).

Example 1 (Jl-1li O8iMe 5 Ac 4-bis(trimethylsilyloxy)methylene-1-methyl-3-methylene-1-cyclohexene 148 mg
(0.50 mmo I) in anhydrous tetrahydrofuran 1.
Dissolve in 0 ml of (+)-(2R,33,4
R,5R,6R) -3,5-diacetoxy-4-dimethylamitor8-hydroxy-6-methyl-2,6-epoxy3.4,5°6-tetrahydro-2H-naphthaleno (1,2-b ]Oxocin-9,12-ψone 5
0 ■ (0.11 mmol) of anhydrous tetrahydrofuran 3
Add 1Qml of ethyl acetate solution and 1Qml of ethyl acetate and add saturated sodium bicarbonate solution while stirring vigorously to adjust the pH of the aqueous layer to 8.The organic layer is separated, and the aqueous layer is further diluted with ethyl acetate (20ml).
The extracts were extracted with 1) and combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane-1) to give (+)-(2R,3S,4R,5R
,6R)-3゜5-diacetoxy-4-dimethylami'
A-a.

lO-dihydroxy-6,13-dimethyl-2゜6-epoxy3.4,5,6,11.12-hexahydro-
2H-naphthacene(1,2-b)oxosine-9,16
55 g (85% yield) of -dione were obtained as orange crystals.

m, p, t71-172°C.

(α)”+468: (c=0.112 chloroform)
Mass hector m/e: 57? (M”)
.

NMR (CDCIs) δ (ppm): 1,59 (3H
, s, 6 CHs), 1.99 (3H.

broad s, 13-CHs), 2.13°2.1
6 (6H, 23, COCH3X2).

2.28 (6H, s, N (CH=)t).

2.2 2.5 (2H, m, 21(z), 2
．． 69 (IH, t, J=10.8Hz, H4), 2.8
3.1 (2H, m, 2 Ho), 5.13
(IH, d, J=10.8Hz, Hs).

5.21 (IH, dd, J-10, 8Hz.

4.0Hz, Hs), 5.88 (IH, d
.

J=4.01 (z, Hg), 6.32 (I
H.

broads, H+a), 7.02 (IH.

! , Has), 7.44 (I H,s, H
t).

12.26. 12.53 (2H, 2s, 0H
x2).

IR (KBr): 3460 (OH), 1
750 (Go), 1620 (Co), 12
20 (Co, ), 1040 (C0-C-0-C)cs-'.

Elemental analysis value: Cs+Hs+NO+e+0.5H10.

Calculated value: Ci 63.46. H; 5.50°N; 2
．． 39%.

Analysis value: C, 63,75,H; 5.40°N i
2.32%.

Example 2 3.5-Diacetoxy-4-dimethylami9-a.

10-dihydroxy-6,13-dimethyl-2°6-epoxy3. 4. 5. 6. 11. 12-hexahydro-2H-naphthacene (1,2-b)oxocine-9,16-dione 12.0■ (0,021 mmol
) was suspended in 10 ml of 1N HCl water, heated under reflux for 15 hours, neutralized with saturated sodium bicarbonate solution under cooling with water, and dissolved in chloroform (15
mlx2).

After drying the chloroform layer over anhydrous magnesium viate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol-9) to give (+) -(2R, 33° 4R, 5R, 6R)-4
-dimethylamino-3゜5, 8. to-tetrahydroxy-6゜13-dimethyl-2,6? -Epoxy-
3,4,5,6°11.12-hexahydro-2H-naphthacene(1,2-b)oxocine-9,16-dione 9, θ■ (88% yield) was obtained as orange crystals.

m, p, 251 257°C (decomp, ) [α] cabinet + 571" CC = 0.070 chloroform) mass s hectare m/e: 493 (M").

NMR (CDCa/DtO) δ (ppm): 1.
75 (3H,s, 6 CH3), 2.
01 (3H, s, 13 Hz), 2.2
2.5(2H,m, -CHs), 2.7
3.0 (3H, m, -CH2-, Ha), 3.5
7 (I H, d, J = 10.5Hz, Hs
).

4.15 (IH, dd, J=10.5) (z.

3.5Hz, Hs), 5.91 (IH,s
.

H,,), 5.93÷(IH, d, J=3.5
H2, Hri, 6.43 (IH, broad (C
o) am″1° element g analysis M: Calculated value as CxtHxyNOs+0.5H!O: C, 64,53,H; 5.62°N, 2.
79%, analysis value: C; 64.30. H; 5.57°N; 2
．． 62%.

Reference Example 12 5.6,11.12-hexahydro-2H-naphthacene (1,2-b) Oxocin-9, Dissolved in 16-ml, diluted with D and monocamphorsulfonic acid 15w (Q, 065
mmo 1), 2,3-dicoo-5゜6-dicyano-p-benzoquinone (DD'Q) 60■ (No. 0,26 m
mol) was added and heated under reflux for 5 hours. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate/n-hexane~2)-(2R,3S).

4R,5R,6R)-3,5-diacetoxy-4-dimethylamino8.10-dihydroxy-6°13-dimethyl-2,6-eboxy3. 4. 8.5 μm (85% yield) of 5°6-tetrahydro-2H-naphthaceno (1,2-b)oxosine-9,16-sion was obtained as orange crystals.

m, p, 17? -179℃.

[α)”+445° (c=0.062 chloroform)
M amount spectrum m/e: 575 (M”).

NMR (CDCIs/↑MS) δ (pPmll, 6
1 (3H,s, 6 CHs), 2.15°2.2
0 (6H, 2s, C0CHsX2).

2.29 (6H, s, N (CHs)*).

2.59 (3H, s, 13 CHs).

2.72 (LH, L, J=10.8Hz, Ha)
.

5.15 (IH, d, J=IQ, 8Hz, Hs).

5.24 (IH, dd, J-10, 8Hz.

4.0Hz, Hs), 5.92 (LH, d.

J=4.0Hz, Hz), 7.06 (IH
,s.

8.4), 7.52 (2M, ct, J=8
．． 6Hz.

2H, t), 7.77 (IH, s, H+s).

8.19 (l H, s, Hw), 8.41
(2H.

d, J=8.6Hz, 2Ht+), l 2
．． 6.5°13.73 (2H, 2s, 0Hx2).

Summer R (KBr): 3450 (OH)
, 1 750 (Co), 1620 (Co)
, 1220(C0t)cs-'.

Elemental analysis values: C31H□, NOo. Calculated value for closing:
C; 64.69. Hi 5.08°N, 2.43%
.

Analysis (IC; 64.50.H; 5.10°N; 2.
32%.

Reference example 13 3.5-diacetoxy-4-dimethylamino-8°10
-dihydroxy-6,13-dimethyl-2゜6-epoxy3.4.5.6-tetrahydro2H-naphthacene(1,2-b)oxocine-9゜16-sion 7,O
QI (0,012 mmo I) was suspended in 1N HCl water and heated under reflux for 12 hours. This was neutralized by adding 30 ml of chloroform under water cooling and stirring with saturated sodium bicarbonate solution, and the chloroform layer was separated. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (chloroform/methanol = 9)-i? Purification W, (+)-/ka'L/7 (
(+) −(2R, 33, 4R, SR, 6R) −4−
Dimethylamino-3,5,8,to-tetrahydroxy-6,13-dimethyl-2,6-epoxy-3°4.5
．． 6-tetrahydro-2H-naphthaceno(1,2-b)
5.2 (87% yield) of oxosine-9,16-sion was obtained as orange crystals.

m, p, 277-281°C (decomp, ) [α] +946” (c-0,070 chlorophor → mass spectrum m/e: 491 (M').

NMR (CDCIt/DtO) δ (pppm):
1.78 (3H,s, 6-CHs), 2.
56(6H,s,N(CHi)x), 2.60
(3H,s, 13 CH,), 2.93(
LH, t, J=10.5Hz, H4).

3.62 (IH, d, J=1 0.5Hz,
Hs), 4.19 (LH, dd, J=I
O, 5Hz.

3.5Hz, Hs), 5.96 (IH, d
.

J-3,5Hz, H 寞), 7.10, ? ,2
6°7.29 (3H, 3s, H?, HI4
．． Has).

7.50 (IH, d, J=8.4Hz, H
Ia).

8.27 (IH, d, J”'8.4Hz,
H,).

IR (KBr) = 3450 (OH), 1
660°1 6 1 5 (Co) ca-'.

The physical properties of standard (+)-nogalene are shown below.
p, 276-279' (decomp,) [α)"
+970°C (C-0,100 chlorophor 7!-) Mass spectrum m/e: 491 (M').

NMR(CD Cl x/DzO) δ(ppm1
1.78 (3H,s, 6-CHs), 2.58 (98
,2s,N(CH3)t,l 3-Cnee1*),2
．． 99 (IH, t, J=10.5H2,H,), 3.
63 (IH, d, J=10.5Hz, Hs),
4.19 (I H, d d.

J = 10.5Hz, 3.5Hz, H3).

5.97 (L H, d, J-3,5Hz, Hz)
.

7.02. 7.26. 7.29. (3H, 3s
.

H? , HIa, HIa), 7.47 (I H,
d.

J=8.4Hz, HIa), 8.24 (I
H,d.

J-8, 41 (Z, Hll).

IR (KBr): 3450 (OH), 1
660. '1 6 1 5 (Co) cs-'.

When the synthesized (+)-nogalene and standard (+)-nogalene were mixed and melted, m was 9.276-279°C (dec
omp, ), and no decrease in melting point was observed.

Test example (cancer cell growth inhibition effect) Mouse lymphoid hus cells (p 388) were increased by 10%, the number of cultured husks was adjusted to 5 x 10' cells/l ml, and the novel 2.6-eboxy 3 of the present invention was prepared. .4,5,6゜11.12
--hexahydro-2[1-naphthacene 1:1.2-b
]Oxocine-9,16-dione derivative (Ia%- and I
h) from the growth inhibition rate to a predetermined concentration, 50% growth inhibition H'j I C++. Table 1 shows the results.

Table 1

Claims (1)

[Claims] 2,6-epoxy-3,4,5,6,11 represented by the general formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼-(I)
, 12-hexahydro-2H-naphthaceno[1,2-b
] Oxocine-9,16-dione derivative (wherein R^1
is a protecting group for a hydrogen atom or a hydroxyl group. ).