JPS61106590A - Anthracycline glycoside - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to anthracycline glycosides, processes for their production, and pharmaceutical compositions containing them.

The present invention provides an anthracycline glycoside represented by the general formula (I): (wherein R represents a hydrogen atom or a hydroxy group, and X represents a hydrogen atom or a trifluoroacetyl group), and further provides pharmaceutically acceptable acid addition salts thereof.

Anthracycline glycoside CI) is prepared according to the invention in the presence of silver trifluoromethanesulfonate.
Hydroxy-4-demethoxy-11-deoxydaunomycinone (II): l-chloro-N,O-di(trifluoroacetyl)-
condensation with taunosamine, removing the 0-trifluoroacetyl group by methanolysis, optionally removing the trifluoroacetyl group by mild alkaline hydrolysis, and then optionally converting the resulting dau/bisi7FJ conductor to
In formula (I): R-H, can.

Condensation of racemic anthracyclinone (II) was performed using the protected anthracycline α-glycoside 7 according to the method described in U.S. Pat. No. 4,107,323.
S,! 15 and an easily separable mixture of 7R and 9R. Bromination and sodium formate treatment are performed by the method described in US Pat. No. 3,803,124.

l-Hydroxy-4-demethoxy-■-deoxy-daunomycin (n) is a novel anthracyclinone, and two synthetic routes have been developed to obtain it. These routes are shown in the following reaction diagrams A and B. 0 Reaction diagram A
The compounds described in are known compounds (UK Patent No. 84157).
54) and anthracyclinone (II) and 6,7-cyoxycarminomycinone (I4
), and the one described in reaction diagram B shows a route that gives only anthracyclinone (n). Both routes are 2-, which is a precursor of 4-ring C and O rings. It is based on the nucleophilic attack on lithio-1,4,5-)limethoxynaphthalene (6) or on the ester carbonyl group of the cyclohexene derivative which is the precursor of the ^ and B rings.

In the synthetic route of ri41, cis 1,2-dimethoxycarbonyl-4-7cetylcyclohexene (I) [Penco et al. ] in a regiochemical mixture of monoesters of p-nitrophenol (see
Convert to 3). p-nitriphenyl ester is required for the coupling reaction with 6.

The reaction of (6) with (I) yields only a trace amount of the coupling product, whereas the same reaction using the new ester (4) reduces 7 in about 50% yield and p-nitrophenyl ester. attack. In a second synthetic route, trans-1,2-dimethoxycarbonyl-4-ethylidene-cyclohexene 16 is converted to the key intermediate δ-lactone (20), which is coupled with 6 via regiochemical methods to give 21. (attacks exclusively the ester carbonyl group).

・“1 Lj- Li (Ba) (Isl (J Den1 (xMl (↓01 (II) C) Qtl-Here, reaction diagram A will be explained in more detail. Compound 1 is hydrolyzed with dilute alkali. The corresponding monoester 2 is obtained as a mixture of regiochemicals. This is treated with p-nitrophenol and ΩCCI to obtain compound 3. The carbonyl is then protected with ethylene glycol and pyridinium p-toluenesulfonate to obtain 4. The known 3-bromo derivative (
5) [Barbour (8arbsr), xichi Rapapart (H, Rapapart), J.I. Olga Kemj, Or.

a■, mouth, 2153 (I1179)]
Compound (7) is obtained by a coupling reaction between 3-lithio-1,4,5-trimethoxynaphthalene (6) obtained from Compound 4 and Compound 4. The double bond is deketalized and the catalyst is removed to obtain compound (8). The benzylic carbonyl group is reduced using a pyridine:borane complex in trifluoroacetic acid, while the aliphatic keto group is reduced to a secondary alcohol. Hydrolysis of the ester to the corresponding melt gives compound (9), which can be further converted into a tetracyclic system (IO) by treatment with trifluoroacetic anhydride and trifluoroacetic acid
) is converted to This alcohol is triethylamine:
Oxidation with a sulfur trifutide complex gives the corresponding ketone (I1), which is roughly converted to anthraquinone (I2) via oxidative demethylation with aluminum trichloride. The introduction of hydroxyl groups to form enolic acetic acid, epoxidation,
(±) l-Hydroxy-4-demethoxy-7,11-dideoxydaunomycinone (I3) and (±) 4-demethyl-41, which are then achieved by basic hydrolysis and easily separated by silica gel chromatography. ，? -dideoxydaunomycinone (I4) is obtained. lastly,
Introduction of the 7-hydroxy group is carried out by benzylic bromination followed by solvolysis.

Alternatively, according to reaction rg:iB, compound (I6)
was oxidized with acidic permanganic acid to obtain the α-hydroxyketone as a stereo-cold product, which was further treated with p-)luenesulfonic acid and toluene under reflux to give the γ-lactone (I7) and the δ-lactone (I7). -j: Lactone (IB
) give a mixture of Lactone; (I8) is separated on silica gel and then treated with sodium borohydride-rejected alumina to obtain alcohol (I9). After protecting the alcohol as tetrahydropyranyl ether, the obtained compound (20) was converted into a lithium salt (6
) to give (21) which is further converted to anthracyclinone (■) according to the process already described in Figure A.

Anthracyclinone glycosides (CI) have anticancer properties, and therefore the present invention further provides a mixture of anthracyclinone glycosides (CI) or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable diluent or carrier. The present invention provides a pharmaceutical composition comprising:

The invention is illustrated by the following example.

(■) (Figure ^) a)z 400tJL of water and 1N sodium hydroxide aqueous solution 22
01 was added to a methanol 880si solution of 35 g (0.1+s mol) of compound (I). The solution was stirred at room temperature for 2 hours and then! Neutralized with prescribed salt. The methanol was evaporated and the aqueous solution was brought to pH 8. Unreacted starting material was extracted with ethyl acetate. The solution was adjusted to pH 3 with 1N hydrochloric acid.
acidified and then extracted with ethyl acetate to form an oil (2).
(Yield: 94%) 31 g was obtained.

S: m/e 22fi (N”) IR (film): 1730, 1700, 1f180am-
Otori'H4MR (8G) IHz, CDCl3. δ):2
．． 33 (*, C0CH5).

2.55-2.95(m, 11:H2-C=CI-08
2), 3.0O-3,30 (m.

)10COCH, Cl30GOCI(), and 3.8
7 and 3.70 (2g, 88.C00CH3), 8.8
0 (m, 0H-C), 10.4 (g.

coon).

b) A cold solution of 28.33 g of 3°0001 ((I, 137 mol) in 150 mA of anhydrous tetra-L-dolphuran was added to compound (2) 3
1 g (0,137 mol) and p-nitrophenol 1
1 g (0,,1,37 mol) of anhydrous tetrahydrofuran 200 intestines! The solution was quenched at 0°C. The mixture was left at 0° C. for 2 hours and then at room temperature overnight. Filter 0 Ctl;
The solvent was removed under reduced pressure, and the residue was dissolved in ethyl acetate.

The solution was washed with an aqueous sodium bicarbonate solution and an aqueous sodium chloride solution. It was then dried over anhydrous sodium sulfate and evaporated to dryness. The crude material is converted into kieselgel (kisel gel).
35 g (yield near 3%) of compound (3) was obtained as an oil.

NS: -/@347 (M”) fil (film): 1730.1880c Peng→'H-NNR(
80MHz, C[ICl3. δ)': 2.30 and 2
．． 33 (2g, all, CDCl3), 2.55-2.
115(s, CH2C-CM-11:82).

3.00-3.30 (intestine, II:830GOCM0.0
2N-Ph-011:OCM).

3.70 and 3.73 (2g, 8H, GOOCH3)
, 8. flO(s,0H-C).

7.27 (d, aromatic proton), 8.27 (d,
aromatic protons).

c) 50 layers of 4 ethylene glycol and 35 g (4 mmol of I) of p-toluenesulfonic acid pyridinium salt were added to the compound (
3) Added 35 mol (0.1 mol) of anhydrous benzene to 450 ml of a solution. The solution was transferred to a Dean-Stark (Dean-5t)
The reaction mixture was refluxed for 18 hours using an ark) apparatus, cooled, diluted with ethyl acetate, washed with water, and then dried over anhydrous sodium sulfate. The solvent was evaporated and chromatographed on Kieselgel to give an oily compound (4) 3
1.3g (yield: 8G%) was obtained.

MS: ale [1()l”) IR (7ilm): 1730c°118-
NNR (80MHz, (DC+3.δ): Above all 1
．． 5゜(s, C)13-C), 3.75(s, 0)+3
0(0), 3.8(s, 0CH2-C)120), 5
．． 93 (m, CM-C), 7.27 (d, 2 aromatic protons), 8.27 (d, 2 aromatic protons).

d) A solution of 107 mmol of 7 n-butyllithium in 300 sjl of anhydrous tetrahydrofuran was added to a dropping funnel with a side pipe (a double ended ns*) at -78°C under nitrogen pressure.
dl@). After standing for 5 minutes, the generated lithium salt (6) was mixed with 24.3 g of compound (4) (82,3
mmol)), 1: Anhydrous tetrahydrofuran was added to the two Yamami solutions in the same manner. After 1 hour, -78℃
The reaction mixture was quenched with acetic acid and then the solvent was quenched with 'Li
LE removed. The residue was dissolved in ethyl acetate, the solution was washed with saturated aqueous sodium chloride solution, then dried over anhydrous sulfuric acid, and then the solvent was removed under reduced pressure. Chromatography on Kieselgel yielded 10.57 g of compound (7).
(yield: 47%).

Ms: ale 47G (M”) IR (film): 1730, 1880c++
-'184MR (60MHz, 00G+3.δ): Especially 1.45 (s, C) 13-(:), 3.83-4
．． 08 (m, 16H), 5.88 (m, CH-C).

6.11-8.4 (Zeng, 4H).

A solution of Compound (7) IO, 57 g (22.5 mmol) in 800 ml of methanol and 1 tJL of methanol was evaporated under reduced pressure. The residual liquid was dissolved in diethyl ether. The solution was washed with a dilatated aqueous sodium bicarbonate solution and then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. After dissolving 250 ml of methanol, 10% by weight of the crude substance
palladium-supported carbon 1.5Jl'
Hydrogenated in the presence of at room temperature and atmospheric pressure. Remove the tentacles, then evaporate the methanol to form an oily compound (8)
8.78 g (yield: 81%) was obtained.

MS: ale 428 (N”) IR (film): 1730.1710.168
0c fat cap'H-NNR(80)LHz, CrJCI3
．． δ): 2.20 (a, C0CH5), 3.7 among others
-4.05 (m, 1211), 8.1l -7,85 (m
, 4H)f)9 Pyridine:borane complex8. ? sJL to compound (8) 8.
78 g (20,5 mmol) of trifluoroacetic acid! OO
Wear! The solution was quenched with stirring and under a nitrogen atmosphere until -10
Cooled to ℃. After standing at room temperature for 2 hours, the solvent was removed under reduced pressure. 80 ann of 4M aqueous sodium hydroxide solution was added and the mixture was then warmed to 70° C. to completely dissolve. After cooling, the pH was adjusted to 4 with 1N hydrochloric acid. The precipitate that formed was extracted with ethyl acetate. The solution was dried over anhydrous sodium sulfate, and then the solvent was evaporated to give 7.8 g of compound (9) (
Yield: 93%) was obtained.

MS: ale 402 (M”) IR (08G
+3): 3450, 1700cm''H-NMR (
80MHz, CrJCI3. δ): 1.23 among others
(d, J = 4Hz, CH3-(H), 3.8(s,
0 (I3), 3.83 (s.

QCH3n, 3J7(g, 0CH3), 8.5(s, 1
)1), 7.1-8.4 (Maro, 3H).

g)　　　　　　t　.

Compound (9) 7.17g (I7.8 mmol) at 0°C
The mixture was treated with 54% trifluoroacetic anhydride and 27% trifluoroacetic acid for 2 hours. The solution diluted with ethyl acetate and water was neutralized with solid sodium bicarbonate.

The organic layer was washed with brine and then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The crude material was treated with 230 g of methanol in the presence of 4 g of sodium methoxide for 3 hours at room temperature. It was then neutralized with 1N hydrochloric acid, diluted with water and then extracted with ethyl acetate. The a-layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. The residue obtained by evaporation was chromatographed on Kieselgel to obtain compound (I0) 3.
82g (yield: 53%) was obtained.

MS: s/s 384 (N”) IR (KBr): 3450.1880cm-''H-N
MR (80MHz, CDI:, 13.δ): Especially 1.23 (d, J= 4Hz, (H-CH3), 3.8
0 (s, 0CH3), 3.93 (s.

0CH3), 4.00 (s, 0CH3), 6.9-8.
00 (m, 3H).

h) A dimethyl sulfo solution containing 8.82 g (37.7 mmol) of triethylamine:sulfur trioxide complex at room temperature was mixed with compound (
l O ) 3. fi2g (9.42 mmol) of dimethyl sulfoxide ethylamine 13■41 (94.2 mmol)
Added to the solution. 1 hour later. pi ( was adjusted to 3 with 1N hydrochloric acid, and the solution was then allowed to stand for an additional 30 minutes. The reaction mixture was poured into 400 mjL of water, and then extracted with ethyl acetate. The organic phase was diluted with 1N hydrochloric acid, a saturated aqueous sodium bicarbonate solution, and then saturated. It was washed with an aqueous sodium chloride solution and then dried over anhydrous sodium sulfate.The solvent was removed by evaporation, yielding 3.57 g of compound (11) (yield: 87%).
) was obtained.

1,, MS: ale 382 (
N”) IR (in 8r): 1710, 1680cm
-''H-NMR (80MHz, COCH3, δ):
Among them, 2.38 (s, COCH3), 3.8 (s, 0
(:H3), 3.93 (g, OCH3).

4,00 (s, OCH3), 8.9-8.00 (m, 3
H) -i) 3.57 g (9.34 mmol) of l 2 compound (1 1 ) was dissolved in 70 mfL of nitrobenzene. 8.5 g of aluminum trichloride are added and the mixture is heated at 70'O for 3
I left it for a while. The reaction mixture was poured into a saturated aqueous oxalic acid solution and then extracted with dichloromethane. The sample was washed with water and then dried with anhydrous sodium sulfate. The residual liquid obtained by evaporating the solvent was subjected to chromatography on Kieselgel to obtain 1.55 g of compound (1 2 ) (yield: 48%).
) was obtained.

M'J: ale 33B (M") IR (KBr): 2940, 1710, 187
0, 1825cm-'') I-NMR (8ON)
Iz. COCH3. 8): Nakatemo 2.35 (s
, (:OCH3), 7.30-7.83 (m, 48),
12.70 (s, OH).

13, 10 (s, OH).

(see) racemicus l3
A solution of 1.5 g (4.5 mmol) of 14 compound (1 2 ), 32 μm of carbon tetrachloride, 18.8 si of acetic anhydride, and 1 drop of perchloric acid was allowed to stand at room temperature for 15 hours. Add 0.340 g of sodium bicarbonate, then reduce the mixture to 1
Stirred for 0 minutes.

Solid! Filter and remove. The filtrate was evaporated to a syrup, diluted with dichloromethane, washed with cold aqueous sodium bicarbonate, and then evaporated to 11fIiA under reduced pressure.

The residual solution was dissolved in 20 g of dichloromethane and then treated with 0.9 g of dichloroperbenzoic acid in the presence of 28 g of a 5% aqueous solution of disodium orthophosphoric acid-hydrogen. The phases were separated after being left at room temperature for 3 hours, and the organic layer was then washed with dilute aqueous sodium sulfite solution and aqueous sodium bicarbonate solution. The solvent was removed by evaporation. The remaining liquid was diluted with 30*i of tetrahydrofuran.

It was suspended in a mixture of 24 ml of water and 11 ml of 1.5 N aqueous sodium hydroxide solution. After 1 hour at room temperature, the suspension was brought to pH 4 with 4N hydrochloric acid and then extracted with dichloromethane. The organic layer was evaporated to dryness and chromatographed on Kieselgel to yield compound (13)O.
．． 19 g and 0.54 g of compound (14) were obtained. [F. Angslucci
etc., J. Che
m. Soc.

Please refer to ``Wong ■Gongjiang Dangyo'', 530 (I984)]
.

13 Data gut. p. Maro 221-222℃ LIV (Ml!OH) saw: 229, 259,
292, 432nm IR (KBr): 34B5
, 1705 , 1880 , 1805 , 15
80cm-'HR) Is calculated value: [C2o11eOs.
Power: 352.0947 (actual value: 352, H41) 'H-N) IR (200MHz.COCH3.5)
:2.2-1.9(m,2M,8-)1).

2, 38Cs, (:OCH3), 2, 8 1
(dd, J-17.0, 2.3Hz, 10
-Heq).

3, 2-2.8 (m,?-H)J. 32 (d.JllI
7.0Hz, 10-Ha! .

3, 89(x, 9-0)1), 7.211(d
d, J-8.3, 1.2Hz, l'-H
, 2-H).

7, 58 (s, II-H), 7.87 (dd.J=8.
3,7.5Hz. 3) 1), 7.83 (dd.J”7.
5, 1.2Hz, 4H), I2. '88 (s.l-OR
), lff. IQ (s.8-OH).

1. A suspension of 0.158 g (0.45 mmol) of compound (13) in 25 g of benzene, 2.81 g of ethylene glycol and 29 g of PL luenesulfonic acid.
Perfusion was performed using a Teen Stark apparatus for 5 hours. Cool the reaction mixture.

Wash with sodium pylyl 15ate aqueous solution and water. ;i. It was evaporated to dryness. The obtained ketal was dissolved in dichloromethane 70 an
Then, in 2.8 m of a 0.195 molar solution of bromine in dichloromethane, 99 mg of AIBN and 13.5 molar of water were added.
- Treated at room temperature in the presence of bacteria. After 1.5 hours, the two phases were separated, the organic layer was washed with saturated aqueous sodium bicarbonate and sodium chloride, and then the solvent was removed under reduced pressure. The residue was dissolved in 90% DingFA aqueous solution 1, 1 ml.
Stir at 0°C for 45 minutes, then add 3 h of ice/water.
Added l. The mixture was extracted with dichloromethane, washed with aqueous sodium bicarbonate solution, dried over aqueous sodium sulfate, and then evaporated under reduced pressure. Chromatography of the crude product on Kieselgel yields the racemic compound (r
y) Soybean intestine g (yield: 3H%) was obtained.

m, p, -209-210°C UV (XeOH) λwax: 228.25E! , 29
0. 432nmIR(C)12012): 342
0,1705.1880. l825,1805cm-'
HRMS calculation value: [C20H180? ,”]: 388
．． 08i38 (actual value: 388.08911) ・□・・□ 1□-NMR (2008□2...

13.8):2.20(ddj-14,8°4.8H
z, 8-Ham), 2.35 (ddd, J-14, 8,
2, 3,! , 9Hz.

8-Heq), 2.41 (s, GOCH3), 3.01
(dd, J-18,0,2,3H.

1O-Heq), 3.28(d, J-18,0)1z,
1O-Hax), 3.82 (d.

7-0H), 4.57(s, 9-Of(), 5.35(
ddd, J-5,0,4,8°1.9Hz, η0,7.
33 (dd, J-8, 2, 1, 2Hz, 2-H), 7.
66 (s, 1l-H), 7.70 (dd, Jeg. 8.2,
7.5Hz, 3-1(), 7.84(dd, J=7.5
, 1.2Hz, 4-H), 12.80(s, l-0H)
, 13.33 (s, 8-0H).

77 tons, 800 tons of 23 g (I00 mmol) of compound (I6) were mixed with 115 tons of water in which 23 g of potassium peringanate was dissolved and 575 tons of 7 setsone at room temperature with vigorous stirring.
mA, 70 ml of water and 141 ml of acetic acid solution. After 1 hour, 11.5 g of sodium nitrite, ll
I added two sulfuric acid sulfuric acids. The brown precipitate was removed. The colorless solution was diluted with water and then extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium bicarbonate solution and then dried over anhydrous sodium sulfate. Removal of the solvent under reduced pressure gave 25 g of the product, a stereoisomeric mixture of α-hydroxyketones. The product was dissolved in 450 ml of toluene and then diluted with p-)luenesulfone #1.5 in a Dean-Stark apparatus.
The solution was refluxed in the presence of g. After 4 hours, the solution was cooled and then washed with saturated aqueous sodium bicarbonate solution. The solution was dried over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure. Chromatography on Kieselgel yielded 9 g of compound (I7) (yield: 38%) and 8 g of compound (I8).
g (yield: 24%) was obtained.

18 - Even more. p. 82-83℃ MS: ale 228 (M”) IR (KBr)
:1780, 1730, 1710a(”'H-
NMR (80MHz, CDCl3, δ): 1. ll-
2.8(g,5)1).

2, 33 (s, GO (H3), 2.8-3.3 (m, 3
M), 3.7 (s.

coocn3].

b) A solution of 0.226 g (I mmol) of 19 + compound (1 8 ) in 3 mJ1 of tetrahydrofuran was added to 1.5 g 41! of sodium borohydride. The solution was added to a solution of aluminum oxide in 4.5 sJL of tetrahydrofuran at room temperature while stirring. 15
After a few minutes, the solid was removed and washed several times with tetrahydrofuran. Removal of the solvent under reduced pressure yielded compound (I9) 0,19 as a stereoisomer mixture (2 products l:1).
g (yield: 83%) was obtained.

MS: ale 228 (M”) IR (film): 1780. 1740cm-
'')l-MMR(C111G13.2001111z
, δ): 1.1B, 1.19 (2d.

J = 8.7) 1z, 8H. C) 13-OH), 1.5
-2.3 (Peng, 1211.3-CH2.

5-CI (2.8-GO2), 2.9-3.1 (2g,
8H, C00GH3), 3.8? .

3, 88 (2q.2H.J= 8.7, Lee-CH5),
c) 20 r Compound (19) 0.58 g (2.5 mmol), dihydropyran 0.315 g and pyridinium p-toluenesulfonate 0.082 g dichloromethane 1
The seven-layer solution was left at room temperature for 4 hours. After washing with saturated aqueous sodium chloride solution, the product is purified by chromatography on Kieselgel, resulting in a mixture of stereoisomers (
Compound (20) as 4 products 1:l:l:l)
, 57 g (yield near 3%) was obtained.

MS: ■/e 312 (M”) IR (film): 17flo, 174Gc
+++"I') I-NMR (00G13,200MHz
, δ): 1. I-1,3 (4d, J=8.5)1z,1
2) 1jl: I (3-(H) mountain 4-2.5(s, 48H
,3-CH2゜5-(:H2,8Jl;)12,2°-
CI(2,3°-C)12.4°-C)+2), 2.9
-3.1 (m, 8H, 1-CH, 2-fl:)l), 3
．． 4-4.0(m, 12H, (:I(-(:)13.5
'-CH2), 3.72 (g, +2)1. cOOcH
3), 4.72 (sr.

4) 1.1'-H).

d) 21 A solution of 0.58 g (I, 95 mmol) of 3-bromo-1,4,5-trimethoxynaphthalene cooled to 78°C in 511 L of anhydrous tetrahydrofuran was added to 1.8*R of n-butyllithium ( 2.14 mmol) in 8 ml of tetrahydrofuran. After standing for 5 minutes, the formed lithio derivative was cooled to -78°C and the compound (20)
0.53 g (I, 77 mmol) of tetrahydrof 1,
: Run 8■ Added to love solution. After 30 minutes, the reaction was quenched with acetic acid until the solution became acidic. The solution was diluted with dichloromethane and then washed with water. Compound (21) 0.52
g (yield: 59%) was obtained as a diastereomeric mixture (4 products 1:l:1:1).

NS: ■/@4118 (M”) IR (CHCI3): 1750.1670cm→
1) 1-NMR (CDC13,200MHz, δ): 1
．． 1-1.3 (4d, J=6.5Hz, 121C113
-CH), 1.5-2.4(m, 48H, 3-0M2゜5-(:H2, [1-CH2,2-CH2,3°-C)
12.4'-CH2), 2.8-3.1(s, 8H, 1
-CH,2-CH), 3.74! , 3.9B, 4.0
3(x.

3 [IH, 4'-0 (lI3.8"-0CR3,5-〇G) 13), 3..5-4.3 (intestine, 12H, (H-C
)13.5'-CH2), 4.7-4.8(■, 4H1
1°-II), 8.8fl (4j, 4H,?”-H),
8.118(d, J=1.7)1z.

4H, 3”-H), 7.48 (t, J-2, 7Hz, 4
H,2--H),? ,88(d,J=2.7)1g,4
H,1”-H)n (I: R-H,X-GOC
F3) 1-hydroxy-4-demethoxy-1! -Deoxy-daunomycinone II eomg (0.18 mmol) was dissolved in 80 ml of dichloromethane. To 1-chloro-, a 4 sM solution of 0-di(trifluoroacetyl (0.4 mmol) in anhydrous dichloromethane was added to the above solution at 15°C, followed by 80 g (0.3 mmol) of silver trifluoromethanesulfonate. After 20 minutes, sy
s'' collidine was added and the reaction mixture was then allowed to stand for an additional 20 minutes. Saturated aqueous sodium bicarbonate solution was added and stirring continued for 30 minutes. The two phases were separated.

The organic layer was then washed with water and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent was suspended in 60 methanol and then kept at 4°C overnight.

After filtration of unreacted material (40 mg recovered), the filtrate was chromatographed on Kieselgel to yield the title compounds (7S, 9S5, 8 and 7R, SR 5, 8).

H';: m/e 594 (M") UV (Me
O) 1) Input mat: 2G111.228, 258, 29
0,434nmc. n. : Δ ε 231ns+s
i. 33, Δt 211Gam--1.78.

'H-N)IR (200MHz, (:00+3,δ)
:2. l-1.8 (m, 2°082).

2, 14 (dd, Jm14.5, 4.1) 1z. 8-H
at), 2.35 (ddd.

J-14.5, 2.1, 1.9) 1z, 8-Heq),
2.311(s, (:OCH3).

3, 11 (dd.JJ8.0.1.9Hz, 1G-)1
a+i), 3.28(d, J-111, 0Hz, 1Ga
m-H), 3.7-3. fl(m, 4°-11), 4.
3-4.1 (■, 3°-H), 4.28 (s, 9-OH
), 4.2fl(m.5°-1(), 5.28(dd,
Ja4. l, 2.1Hz,? -H), 5.47 (d, J
m3.4Hz.

1'-H), 11.84 (by, NHCOCF3), 7
．． 33(d, Js8.2Hz.

2-H), 7.88CB, 11-[(),? ．． 73(d
, J-7.5) 1z, 3-H).

12, 58 (s, l-OR), 13.32 (s, 8-0
) 1) Prepared 0.1N sodium hydroxide aqueous solution 7S.

+19I-hydroxy-4-demethoxy-11-deoxyto triple oroacetyl-daunorubicin 8B 7
Seven tons of the solution was added at 0°C under nitrogen. 2 at 0℃
After stirring for an hour, the pH was lowered to 4.5 and the neutralized product was extracted with dichloromethane. The acidic aqueous layer was brought to p) 18.5 and then extracted with dichloromethane.

The organic solution was brought to a small volume and then treated with a few drops of methanolic hydrogen chloride. The product was precipitated by addition of diethyl ether. - After that! ! Compound A 4-8 was obtained.

MS (F, D): ale 498 (M”)
Ull(NeOH)λsag: 22B, 258,290
, 432mm HPLC (column RP810p (25
x0.4cm), wavelength 254nm, eluent 85/35
Maha's buffer solution mixture. (KH to 0,025
Prepared with 2PO4.

The pH was adjusted to 4 with H3PO4. ) and CH3CN, elution rate 217 min) Rt-8,02°Rf (TLC on Statacrom)
: Eluent Dikuaa Methane: Methanol: #Brew: Water
80:20 near:3 volume) 30.44'H-NMR (2
00MHz, d4-D) 150.6): especially 1.1
8 (d, J=8.8Hz, CH3), L, S-1,7
(a, 2°-Heq), 1.8-1.9 (m, 2°-1
1am), 2.1-2.3 (+s, 8-H), 2.23
(x.

C0CH5), 3.02-3.1T (qAB, JJ8.
OHz, 1O-H).

4.13 (q broad, Jll[1,8,2Hz,
5°-H), 5.02 (m.

? -H), 5.27 (d, J=3.2Hz, l'-H)
, 5.40(br, 4°-111°1□0 old, 5.56(s, 1l-01(), 7.40
(dd, Js?, 5, 2.0Hz.

3-H),? , 58(s,!+-H), 7.9-7.8
(m,4-H,2-)1).

According to the method described in U.S. Pat. Isolated as a salt.

□

Claims (1)

[Claims] 1. General formula (I): ▲Mathematical formula, chemical formula, table, etc.▼(I) (In the formula, R represents a hydrogen atom or a hydroxy group, and X represents a hydrogen atom or a trifluoroacetyl group. ) or a pharmaceutically acceptable acid addition salt thereof. 2,1-Hydroxy-4-demethoxy-11-deoxy-N-trifluoroacetyl-daunorubicin. 3,1-hydroxy-4-demethoxy-11-deoxy-daunorubicin. 4,1-Hydroxy-4-demethoxy-11-deoxy-N-trifluoroacetyl-doxorubicin. 5,1-hydroxy-4-demethoxy-11-deoxydoxorubicin. 6, (±) 1-hydroxy-4-demethoxy-11-deoxy-daunomycinone. 7. In the presence of silver trifluoromethanesulfonate (±)
1-Hydroxy-4-demethoxy-11-deoxy-daunomycinone was condensed with 1-chloro-N,O-di(trifluoroacetyl)-daunosamine, the 0-trifluoroacetyl group was removed by methanolysis, and the 1-hydroxy-4-demethoxy-11-deoxy-daunomycinone was purified by silica gel column. The desired 7S,9S-N-trifluoroacetyl-α-glycoside is converted to its diastereomeric 7
R,9R derivatives are separated, optionally the N-trifluoroacetyl group is removed by mild alkaline hydrolysis, and then optionally the resulting daunorubicin derivative (
I:R=H, Method. 8. Anthracycline glycoside according to any one of claims 1 to 5 or a pharmaceutically acceptable acid addition salt of such anthracycline glycoside, and a pharmaceutically acceptable diluent or carrier. A pharmaceutical composition characterized in that it is formed by mixing.