JPH03876B2 - - Google Patents

Description

[Detailed Description of the Invention] The present invention relates to the general formula [In the formula, R ¹ is an acyl group, X ¹ and X ² are hydrogen atoms, methoxy groups, hydroxyl groups, halogen atoms or lower alkyl groups, Y ¹ and Y ² are hydrogen atoms, alkoxy groups or hydroxyl groups, and Z Atom or protected hydroxyl group. ] The present invention relates to a method for producing an anthracycline derivative represented by the following. The anthracycline derivative represented by the general formula () obtained by the present invention is an anthracycline antibiotic having excellent anticancer activity by removing the protecting group of the hydroxyl group or amino group under mild conditions, such as daunomycin, 4-demethoxydaunomycin, adriamycin, 4-demethoxyadriamycin, 4-demethoxy-11
- It can be easily led to deoxyadriamycin, etc. Conventionally, various glycosylation reactions have been developed for producing anthracycline derivatives represented by the above general formula (). Specifically, (1) the reaction between an anthracyclinone derivative and 1-halo sugar (a)
Method carried out in the presence of silver trifluoromethanesulfonate [MJ Broadhurst et al., J.Chem.Soc.
Perkin I, 1982 , 2249; JP-A No. 57-53497;
F.Arcamone et al., Experientia, 34 , 1255
(1978) etc. and the comparative examples below], (b) a method carried out in the presence of a mixture of mercury oxide and mercury bromide or a mixture of mercury cyanide and mercury bromide (THSmith
et al., J.Org.Chem., 42 , 3653 (1977); F.
Arcamone et al., Cancer Treat.Rep., 60 ,
829 (1976); Special Publication No. 58-33880; Special Publication No. 58-
40555; see Japanese Patent Publication No. 58-40557, etc.], (2) a method of reacting an anthracyclinone derivative with glycal in the presence of (a) an acid catalyst [Japanese Patent Publication No. 59-40556;
JP-A-50-149663; H. Umezawa et al., J.
Antibiotics, 33 , 1581 (1980), etc.] or
(b) Method carried out in the presence of N-iodosuccinimide [D. Horton et al., “Anthracycline
Antibiotics, “ed.by HSEI Khadem,
Academic Press, 1982 , p221], and (3) a method of reacting an anthracyclinone derivative with a 1-acyl sugar in the presence of p-toluenesulfonic acid or a Lewis acid catalyst [C. Monneret et al.,
“Anthracycline Antibiotics,”ed.by HSEl
Khadem, Academic Press, 1982 , p232; HS
El Khadem, et al . , Ibid . , 1982 , P265; HS
El Khadem et al., Carbohydrate Research,
101, C1 (1982); J. Boivin, et al.,
Tetrahedron, 24 , 4219 (1981), etc., and see Comparative Examples below]. However(1)
Although method (a) selectively produces only the desired α-anomer, it uses an unstable 1-halo sugar and uses more than an equivalent amount of expensive silver trifluoromethanesulfonate relative to the anthracyclinone derivative. The disadvantage is that it needs to be used. (1) (b)
The method uses 1-halo sugar as in (a), and
In some cases, it is necessary to use 1-halo sugar in an amount 3 to 9 times the amount of the anthracyclinone derivative, and in addition to the desired α-anomer, unnecessary β-
- Disadvantages include that anomers are usually produced as by-products and that toxic mercury salts are used as glycosylation agents.
In method (2), the 1-halo sugar used as a raw material in (1) is further treated with mercuric cyanide or silver carbonate, or the 1-hydroxy sugar is treated with p-toluenesulfonyl chloride-pyridine. The glycal obtained must be used in an amount 2 to 4 times the amount of the anthracyclinone derivative, and (1)
Similar to (b), β-anomer is often produced as a by-product, and the method (b) of (2) has the disadvantage that a deiodination reaction is essential following the glycosylation reaction. Method (3) uses 1-halosugar, which is more stable than 1-halosugar.
Although acyl sugars are used, α-anomer and β
-The production ratio of the anomer remains at a maximum of about 9:1, and furthermore, when a Lewis acid such as tin tetrachloride is used, the disadvantage is that it is not easy to separate the product after the reaction. In addition, in all methods (1) to (3), the target anthracycline derivative is usually 50%
The yield is only ~60%, unreacted anthracyclinone derivative remains, and β-
Anomers are often produced as by-products, and separation operations such as column chromatography are essential. For the above reasons, it is very difficult to apply these methods to the synthesis of anthracycline derivatives.
There are many problems with industrialization. As a result of studies to overcome the drawbacks of conventional methods, the present inventors discovered that it is possible to perform glycosylation using inexpensive reagents and to produce only the α-anomer with high stereoselectivity and in high yield, and have completed the present invention. It is something. That is, the present invention, like the method (3) above,
1-acyl sugar, which is much more stable than halo sugar and suitable for long-term storage, can be used as a raw material, and there are almost no by-products in the glycosylation reaction.
- Since only the anomer can be selectively obtained, there are advantages such as easy separation operation. The present invention is based on the general formula R ⁵ R ⁴ R ³ SiOSO ₂ A −() [wherein R ³ , R ⁴ and R ⁵ are alkyl groups,
A is an alkyl group, an aryl group, a polyfluoroalkyl group, or a hydrogen atom. ) In the presence of a silylsulfonic acid derivative represented by the general formula (In the formula, R is a hydrogen atom or a trialkylsilyl group, X ¹ and X ² are a hydrogen atom, a methoxy group, a hydroxyl group,
A halogen atom or a lower alkyl group, Y ¹ and Y ² are a hydrogen atom, an alkoxy group or a hydroxyl group, and Z is a hydrogen atom or a protected hydroxyl group. ) and the anthracyclinone derivative represented by the general formula (In the formula, R ¹ and R ² are acyl groups.) is reacted with a 1-acyl sugar represented by the following in a mixed solvent of a halogen solvent and an ether solvent to produce an anthracycline represented by the general formula (). It is used to produce derivatives. Among the anthracyclinone derivatives represented by the general formula (), which are raw materials of the present invention, compounds in which R is a hydrogen atom can be prepared by a known method [F.Arcamone, at
al., Experientia, 34 , 1255 (1978); H.
Umezawa, et al., J. Antibiotics, 33 , 1581
(1980); S.Terashima, et al., Chem.Pharm.
Bill., 31 , 811, 821 (1983); S. Terashima, et al.
al., Tetrahedron Letters, 23 , 4107 (1982); S.
Terashima, et al., 43rd Synthetic Organic Chemistry Comprehensive Research Conference Abstracts, 1983 , p. 94, etc.]. Also, R is -
The compound represented by SiR ³ R ⁴ R ⁵ is a compound in which R is a hydrogen atom, or a ketene silylacetal or 1,3
-It is a compound easily obtained by reacting with diketone silyl enol ether. Ketensilyl acetal is a compound obtained by reacting R ⁵ R ⁴ R ³ SiCl with lithium enolate, which is produced by reacting a carboxylic acid ester with a strong base such as lithium diisopropylamide.
1,3-diketone silyl enol ether is 1,
3-diketone in the presence of imidazole R ⁵ R ⁴ R ³ SiCl
This is a compound obtained by reacting with
Examples of R ³ , R ⁴ and R ⁵ include lower alkyl groups such as methyl, ethyl, propyl and butyl. X ¹ and X ² of the anthracyclinone derivative represented by the above general formula () are hydrogen atoms,
Examples include methoxy groups, hydroxyl groups, halogen atoms such as chlorine atoms and bromine atoms, lower alkyl groups such as methyl groups and ethyl groups, and Y ¹ and Y ² are hydrogen atoms,
Examples include alkoxy groups such as methoxy groups and ethoxy groups, and hydroxyl groups. Z is a hydrogen atom, a protected hydroxyl group, such as an acyloxy group such as an acetoxy group, a t-butoxycarbonyloxy group, or a benzoyloxy group, a methoxy group, a benzyloxy group, a tetrahydropyranyloxy group, or a 2-methoxyethoxy group. In addition to alkoxy groups such as , (2-methoxyethoxy)methoxy groups, trialkylsilyloxy groups such as trimethylsilyloxy groups and dimethyl-t-butylsilyloxy groups, protection of hydroxyl groups and simultaneous protection of adjacent carbonyls [ Protective groups such as the formula (R is a lower alkyl group) can also be exemplified.
In addition, the hydroxyl group at the 9th position and the hydroxyl group at the 14th position are, for example, They can also be simultaneously protected within the molecule, as in (R is a lower alkyl group). On the other hand, the 1-acyl sugar represented by the general formula () is a compound easily obtained from the corresponding amino sugar, and R ¹ and R ² include p-nitrobenzoyl group, trifluoroacetyl group, acetyl group, benzoyl group, etc. An example is an acyl group.
The amount of 1-acyl sugar used is usually 1.1 to 1.5 equivalents based on the anthracyclinone derivative. The present invention must be carried out in the presence of the silylsulfonic acid derivative represented by the general formula (). Silylsulsonic acid derivatives include trimethylsilyltrifluoromethanesulfonate, trimethylsilyldifluoromethanesulfonate, trimethylsilichlorodifluoromethanesulfonate, trimethylsilyl-1,1,2,2-tetrafluoroethanesulfonate, triethylsilyltrifluoromethanesulfonate, dimethylisopropylsilyltrifluoromethanesulfonate, t-Butyldimethylsilyltrifluoromethanesulfonate, trimethylsilylperfluorobutanesulfonate, trimethylsilylperfluorooctanesulfonate, trimethylsilylmethanesulfonate, trimethylsilylethanesulfonate, trimethylsilylbenzenesulfonate, trimethylsilyl p-bromobenzenesulfonate, trimethylsilyl p-toluenesulfonate, etc. can be used. . The amount of the silylsulfonic acid derivative to be used is 0.1 to 4 equivalents relative to the anthracyclinone derivative when using a compound represented by the above general formula () in which R is a hydrogen atom, When using a compound in which R of the anthracyclinone derivative represented by the above general formula () has a trialkylsilyl group, a catalyst amount of 0.05 to 0.3 equivalent to the anthracyclinone derivative is used. The present invention is carried out in a mixed solvent of a halogen-based solvent and an ether-based solvent, such as a mixed solvent of a halogen-based solvent such as methylene chloride or 1,2-dichloroethane and an ether-based solvent such as diethyl ether or dimethoxyethane. can be used. The reaction normally proceeds smoothly at -20 to 20°C. EXAMPLES Hereinafter, the present invention will be explained in more detail with reference to Examples and Reference Examples, but the present invention is not limited to the Examples in any way. 2,3,6-trideoxy-1,4-di-O-
p-Nitrobenzoyl-3-trifluoroacetamide-α-L-lyxohexopyranose [J.
Org.Chem., 42 , 3653 (1977). Synthesized by the method of
mp: 202-203℃ (mp 203-204℃)〕82.8mg
(0.15 mmol), 400 mg of Molecular Sheep 4A, 4 ml of anhydrous methylene chloride, and 4 ml of anhydrous ether were added with 0.06 ml (0.31 mmol) of trimethylsilyltrifluoromethanesulfonate at -40°C.
Stirred at -5°C for 0.5 hour. -15 to -20
After cooling to ℃, 4-demethoxydaunomycinone
4.20 mg (0.11 mmol) of anhydrous methylene chloride solution 14
ml was added dropwise over 10 minutes. Stirring was continued at that temperature for an additional 20 minutes. The reaction solution was poured into a vigorously stirred mixture of 50 ml of saturated sodium bicarbonate solution and 50 ml of ethyl acetate at 0°C to stop the reaction. After separating the organic layer, it was washed with saturated sodium chloride solution,
After drying over anhydrous magnesium sulfate, the solvent was distilled off.
TLC of the residue showed complete disappearance of 4-demethoxydaunomycinone. This was applied to a silica gel shoto column (benzene/ethyl acetate =
4) to give 4′-O-p-nitrobenzoyl-
80.0 mg (98% yield) of 3'-N-trifluoroacetyl-4-demethoxydaunomycin was obtained as orange crystals. mp: 165-170℃. [α] ²⁰ _D −88.6° (c = 0.10, dioxane) (lit, mp 171-175°C, [α] ²⁰ _D −89.8° (c = 0.1 dioxane); MJ Broadhurst et al,
J. Chem, Soc., Perkin I, 1982, 2249). NMR (CDCl ₃ ) δ (ppm): 1.25 (3H, d, J
=6Hz, 6'- _CH3 ), 1.98~2.38 (4H, m,
2H ₂ ′+22H ₈ ), 2.45 (3H, s, COCH ₃ ),
3.00 (1H, d, J = 19Hz, H _10ax ), 3.36 (1H,
d, J = 19Hz, H _10eq ), 4.22 (1H, s, 9-
OH), 4.34 to 4.66 (2H, m, H ₃ ′ + H ₅ ′), 5.36
(1H, brs, H ₇ ), 5.51 (1H, m, H ₄ ′), 5.70
(1H, brs, W _H = 6Hz, H ₁ ′), 6.24 (1H,
brd, J=7Hz, NH), 7.76-7.94 (2H, m,
ArH), 8.20-8.48 (6H, m, ArH), 13.35
(1H, s, ArOH), 13.68 (1H, s,
ArOH). Dissolve 74.3 mg (0.10 mmol) of 4'-O-p-nitrobenzoyl-3'-N-trifluoroacetyl-4-demethoxydaunomycin in 1 ml of methylene chloride and 100 ml of methanol, and add 2 ml of 0.1N sodium hydroxide solution to ℃ and stirred for 20 minutes. After neutralizing with glacial acetic acid until the reaction solution turned orange,
Added 100ml of water and extracted with ethyl acetate (2x
50ml). The extract was washed with saturated brine (30 ml), dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/acetone = 15) to obtain 55.4 mg (98%) of 3'-N-trifluoroacetyl-4-demethoxydaunomycin. mp 150-154℃. [α] ²⁰ _D +190° (c0.10 dioxane) (lit, mp 155-156℃, [α] ²⁰ _D +190° (c0.1
dioxane); MJ Broadhurst, et al., J.
Chem, Soc., Perkin I, 1982, 2249). NMR (CDCl ₃ ) δ (ppm): 1.34 (3H, d, J
=7Hz, 6'- _CH3 ), 1.80~2.38 (4H, m,
2H ₈ +2H ₂ ′), 2.43 (3H, s, COCH ₃ ), 2.99
(1H, d, J = 19Hz, H _10ax ), 3.34 (1H,
dd, J=19, 1.5Hz, _H10eq ), 3.62~3.78
(1H, m, H ₄ ′), 4.32 (1H, s, 9-OH),
4.10~4.42 (2H, m, H ₃ ′ + H ₅ ′), 5.30 (1H,
bd, J = 4.2Hz, H ₇ ), 5.54 (1H, brd, J =
3Hz, H ₁ ′), 6.67 (1H, brd, J=8Hz,
NH), 7.81~7.93 (2H, m, ArH), 8.35~
8.47 (2H, m, ArH), 13.38 (1H, s,
ArOH), 13.66 (1H, s, ArOH). IR (KBr): 3530 (NH), 3475 (OH), 1720 (CO)
cm ^-1 . 77.0 mg (0.14 mmol) of 3'-N-trifluoroacetyl-4-demethoxydaunomycin was dissolved in 15 ml of 0.1N sodium hydroxide solution at 30°C under an argon atmosphere.
Stir for a minute. Adjust the reaction solution to PH8 with 5NHCl,
Extracted with chloroform (5x30ml). extract liquid
After washing with 50 ml of water and drying over anhydrous magnesium sulfate, the solvent was distilled off. Pour the residue into a small amount of methanol.
After dissolving in chloroform (1:10) and adding 0.6 ml of 0.25NHCl methanol solution, the mixture was diluted with 20 ml of ether to precipitate crystals of 4-demethoxydaunomycin hydrochloride. Yield 45.2 mg (65%). mp: 184~187℃ (decomposition) (lit, 183~185
℃：F.Arcamone, et al., Cancer Treatment
Rep. 60 , 829 (1976). ). [α] ²⁰ _D +188° (c0.10 CH ₃ OH) (lit, +187° (c0.
1
CH ₃ OH): MJ Broadhurst, et al, J.Chem,
Soc., Perkin I, 1982, 2249). NMR (d ₆ -DMSO) δ (ppm): 1.15 (3H, d,
J=6Hz, 6'6'- _CH3 ), 1.60~2.22 ( _4H1 ,
m, 2H ₂ ′ + 2H ₈ ), 2.30 (3H, s, COCH ₃ ),
2.97 (2H, brs, 2H ₁₀ ), 3.50~3.73 (1H,
brs, H ₄ ′), 4.22 (1H, brd, J=6Hz,
H ₅ ′), 4.95 (1H, brs, H ₇ ), 5.33 (1H, brs,
W _H = 6Hz, H ₁ '), 5.36~5.62 (2H, m, 9-
OH+4'-OH), 7.85-8.12 (2H, brs,
ArH), 8.18-8.34 (2H, brs, ArH). 2,3,6-trideoxy-1,4-di-O-
Trifluoroacetyl-3-trifluoroacetamide-α-L-lyxohexopyranose [(Synthesized by the method of Japanese Patent Publication No. 58-33880) mp133-135℃
(lit, 132-134℃)〕6.10mg (0.15mmol), Molecular Sieve 4A 400mg, Anhydrous methylene chloride 4ml,
0.06 ml of trimethylsilyl trifluoromethanesulfonate at -40 °C in a mixture of 4 ml of anhydrous ether.
(0.31 mmol) was added and stirred at -40°C for 0.5 hour.
41.5 mg of 4-demethoxydaunomycin in the reaction solution
(0.11 mmol) of methylene chloride solution was added dropwise over 10 minutes, and after further stirring for 20 minutes, the temperature of the reaction solution was raised to -2°C and stirred at that temperature for 2 hours. It was treated in the same manner as in Example 1 to obtain 3',4'-N,O-bistrifluoroacetyl-4-demethoxydaunomycin. 3',4'-N,O-bistrifluoroacetyl-4-demethoxydaunomycin is N-
It was induced into trifluoroacetyl-4-demethoxydaunomycin and its structure was confirmed. That is, 3′,
4'-N,O-bistrifluoroacetyl-4-demethoxydaunomycin was dissolved in 30 ml of methanol and hydrolyzed with 2 ml of 0.1N NaOH at 0°C (20
minutes), neutralized with glacial acetic acid, extracted, washed with water,
After drying, it was purified by silica gel column chromatography (chloroform/acetone = 15),
40.0 mg (61%) N-trifluoroacetyl-4
- Demethoxydaunomycin was obtained. the
The NMR and IR spectra matched those of Reference Example 1. 2,3,6-trideoxy-1,4-di-O-
p-Nitrobenzoyl-3-trifluoroacetamide-α-L-lyxohexopyranose 40.0mg
(0.074 mmol), 200 mg of Molecular Sieve 4A, 2 ml of anhydrous methylene chloride, and 2 ml of anhydrous ether were added with 0.03 ml of trimethylsilyltrifluoromethanesulfonate at -40°C, stirred for 0.5 hour at -3°C, and then heated to -15°C with daunomycin 21.3 mg (0.056mmol)
6 ml of methylene chloride solution was added and reacted for 30 minutes. Thereafter, treatment was carried out in the same manner as in Example 1 to obtain 4'-O-P nitrobenzoyl-3'-N-trifluoroacetyldaunomycin. Yield 41.0 mg (95%). 4′−
O-p-nitrobenzoyl-3'-N-trifluoroacetyldaunomycin in methanol;
It was hydrolyzed with 0.1N NaOH, converted to N-trifluoroacetyldaunomycin, and its structure was confirmed. mp: 170~172℃, [α] ²³ _D = +214゜ (c0.10CHCl ₃ ) (lit, mp170~171℃, [α] ²³ _D = +
235° (c0.1 CHCl ₃ ): see Special Publication No. 1984-40556). NMR (CDCl ₃ ) δ (ppm): 1.33 (3H, d, J=
7Hz, CH ₃ ) 1.95 to 2.35 (4H, m, 2H ₈ +
2H ₂ ′), 2.41 (1H, s, COCH ₃ ), 2.98 (1H,
d, J=19Hz, H _10ax ), 3.34(1H, dd, J=
19, 1.5Hz, H _10eq ), 3.62~3.77 (1H, m,
H ₄ ′), 4.02 (1H, s, 9-OCH ₃ ), 4.33
(1H, S, 9-OH), 4.11~4.42 (2H, m,
H ₃ ′ + H ₅ ′), 5.15 (1H, brs, H ₇ ), 5.40 (1H,
brd, J=3Hz, H ₁ ′), 6.70(1H, brd, J=
8Hz, NH), 7.24~8.00 (3H, m, ArH),
12.90 (1H, s, ArOH), 13.65 (1H, s,
ArOH). 2,3,6-trideoxy-1,4-di-O-
p-Nitrobenzoyl-3-trifluoroacetamide-α-L-lyxohexopyranose 35.5mg
(0.066mmol), methylene chloride 2ml, ether 2ml
Add 0.04 ml of trimethylsilyltrifluoromethanesulfonate to the mixture at -40℃ and mix between 0℃ and -3℃.
The mixture was stirred for 30 minutes. 14-acetoxy-4-demethoxydaunomycinone (synthesized according to Reference Example 2)
8 ml of a 22.0 mg (0.052 mmol) methylene chloride solution was added dropwise at -15°C, followed by stirring for 1 hour. Treated as in Example 1, 38.1 mg (92%) of 4'-O-
p-Nitrobenzoyl-3'-N-trifluoroacetyl-14-acetoxy-4-demethoxydaunomycin was obtained. mp: 168-172℃. NMR (CDCl ₃ ) δ (ppm): 1.30 (3H, d, J = 6
Hz, 6′−CH ₃ ) 2.00–2.68 (4H, m, 2H ₂ ′+
2H ₈ ), 2.22 (3H, s, COCH ₃ ), 3.10 (1H,
d, J=19Hz, H _10ax ), 3.44(1H, dd, J=
19, 1.5Hz, H _10eq ), 4.39(1H, s, 9-
OH), 4.35 to 4.60 (2H, m, H ₃ ′ + H ₅ ′), 5.10
(1H, d, J=19Hz, H ₁₄ ), 5.40 (1H, brs,
H ₇ ), 5.44 (1H, d, J = 19Hz, H ₁₄ ), 5.54
(1H, brs, H ₄ ′), 5.74 (1H, brs, W _H = 6
Hz, H ₂ ′), 6.31 (1H, brs, J=8Hz, NH)
7.80~7.98 (2H, m, ArH), 8.20~8.50 (6H,
m, ArH), 13.33 (1H, s, ArOH), 13.69
(1H,s,ArOH). IR (KBr): 3500 (NH), 3350 (OH), 1730 (CO)
cm ^-1 . Elemental analysis value: C ₃₇ H ₃₁ F ₃ N ₂ O ₁₅・2H ₂ O Calculated value: C; 53.11, H; 4.19, N; 3.35% Analysis value: C; 53.06, H; 3.96, N: 3.56% 4-demethoxydaunomycinone 74.0mg
(0.20 mmol) was dissolved in 7.5 ml of THF, 74.0 mg (0.23 mmol) of pyridinium bromide perbromide was added, and the mixture was stirred for 2.5 hours. Add 7.5ml of acetone to the reaction solution.
was added and stirred for 15 minutes, and then anhydrous potassium acetate was added.
225 mg (2.30 mmol) was added and stirred for 1.5 hours.
The solvent was distilled off under reduced pressure, 25 ml of water was added to the residue, and the mixture was extracted with methylene chloride (3 x 20 ml). The extract was washed successively with water and saturated brine, and then dried over anhydrous magnesium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography (benzene/ethyl acetate = 4) to obtain 60 mg of a red solid.
(70% yield). To obtain analytical samples, benzene-ether
It was recrystallized from a mixed solvent of hexane. mp: 187-188.5℃. [α] ²⁰ _D +181° (c0.10 dioxane). NMR (CDCl ₃ ) δ (ppm): 2.08 (1H, dd, J=
15, 4.5Hz, H _8ax ), 2.21 (3H, s, OCH ₃ ),
2.51 (1H, dt, J=15, 2Hz, _H8eq ), 3.00
(1H, d, J = 19Hz, H _10ax ), 3.31 (1H,
dd, J=19, 1.5Hz, H _10eq ), 3.43(1H, brs,
7-OH), 4.69 (1H, s, 9-OH), 5.17
(1H, d, J=18Hz, H ₁₂ ), 5.38 (1H, brs,
H ₇ ), 5.42 (1H, d, J = 18Hz, H ₁₂ ), 7.76
~8.01 (2H, m, ArH), 8.24 ~ 8.48 (2H,
m, ArH), 13.19 (1H, s, ArOH), 13.52
(1H,s,ArOH). IR (KBr): 3500 (NH), 3450 (OH), 1745 (CO)
1735 (CD) cm ^-1 . Ms m/e 426 (M ⁺ ). Elemental analysis value: Calculated value as C ₂₂ H ₁₈ O ₉ : C: 61.97, H: 4.26%. Analysis value: C; 61.86, H; 4.28%. 4-demethoxydaunomycinone 90mg
(0.24 mmol) was dissolved in anhydrous methylene chloride to obtain methyl ketene methyl trimethyl serial acetal [Y. Kita et al, Tetrahedron Lett., 1979, 4311
It was synthesized by bp45~47℃/23mmHg (lit,
bp46.3-46.5℃/23mmHg)〕220mg (1.38mmol)
was added, and the mixture was refluxed for 3 hours under an argon stream. After cooling the reaction solution, the solvent and unreacted ketenemethyltrimethylsilyl acetal were distilled off under reduced pressure.
The residue was purified by silica gel column chromatography (benzene/ethyl acetate = 4) to give 92.3 mg (86
%) of 7-trimethylsilyl-4-demethoxydaunomycin was obtained. To obtain analytical samples7
-Trimethylsilyl-4-demethoxydaunomycin was recrystallized from hexane/benzene=4. mp: 164-165℃. [α] ²⁰ _D +210° (c 0.10 dioxane). NMR (CDCl ₃ ) δ (ppm): 0.30 (9H, s,
(CH ₃ ) ₃ Si), 1.88-2.20 (2H, m, 2H ₈ ),
2.45 (3H, s, COCH ₃ ), 2.95 (1H, d, J
= 18Hz, H _10ax ), 3.30 (1H, d, J = 1.8Hz,
H _10eq ), 5.43 (2H, brs, H ₇ +9-OH),
7.73~7.95 (2H, m, ArH), 8.22~8.42 (2H,
m, ArH), 13.33 (1H, s, ArOH), 13.60
(1H,s,ArOH). Elemental analysis value: Calculated value as C ₂₃ H ₂₄ O ₇ Si: C: 62.70, H: 5.49%. Analysis value: C; 62.63, H; 5.49%. 4-demethoxydaunomycin 40.0mg
(0.109 mmol) was dissolved in 8 ml of anhydrous methylene chloride,
2,4-pentanedione trimethylsilyl enol ether [T. Veysoglu et al, Tetrahedron
Synthesized according to the method of Letter 22 , 1303 (1981)] 140mg
(0.81 mmol) was added and refluxed for 2 hours. After distilling off the volatile fraction from the reaction solution under vacuum, it was passed through a silica gel shoto column (benzene and then benzene/ethyl acetate=4) to obtain 7-trimethylsilyl-4-demethoxydaunomycinone. Yield 43.6mg
(92%). The NMR spectrum matched that of Reference Example 3. 7-trimethylsilyl-4-demethoxydaunomycinone 48.4 mg (0.11 mmol), 2,3,6-trideoxy-1,4-di-O-p-nitrobenzoyl-3-trifluoroacetamide-α-L-
After dissolving 80.0 mg (0.15 mmol) of lyxohexopyranose in 15 ml of a mixed solvent of anhydrous methylene chloride and ether (3:1), the reaction solution was cooled to -3°C, and a methylene chloride solution of 0.1 M trimethylsilyl trifluoromethanesulfonate was added. 0.2ml
(0.02 mmol) and stirred for 45 minutes. The reaction mixture was poured into a vigorously stirred mixture of saturated sodium bicarbonate solution (50 ml) and ethyl acetate (50 ml) at 0°C, and the organic layer was separated. After washing it with saturated saline (30ml) and drying it with anhydrous magnesium sulfate,
The solvent was distilled off to obtain 61.2 mg (7.5%) of glycoside. The spectral data of the product was consistent with Example 1. 1g of diisopropylamine in 7.5ml of THF at 0℃
Dissolve 1.6M BuLi in hexane solution and dropwise add 7ml of 1.6M BuLi hexane solution.
Stirred at 0°C for 15 minutes. After cooling the reaction solution to -78°C, 0.88 g (10 mmol) of methyl propionate was added, and after 30 minutes, 1.64 g (12 mmol) of dimethylisopropylsilyl chloride was added, and the mixture was further stirred for 30 minutes. After adding 1.9 ml of methyl iodide and 5 ml of pentane to the reaction mixture at -78°C, the mixture was placed in an ice bath and heated to 0°C for 30 min.
After stirring for a minute, it was left in the refrigerator overnight. After filtering the reaction mixture, the liquid was distilled off under reduced pressure.
1.24g (66%) of crude methylketene methyldimethylisopropylsilylacetal was obtained. NMR (CCl ₄ ) δ (ppm): 0.12 (6H, g,
(CH ₃ ) ₂ Si) 0.96 (6H, s, CH(3H ₃ ) ₂ ), 0.99
(1H, s, CH(CH ₃ ) ₂ ), 1.40 (3H, d, J=
6Hz= _CHCH3 ), 3.45(3H,s, _OCH3 ),
3.57 (1H, q, J=6Hz, CH ₃ CH=). This product was used in the reaction of Reference Example 6 without being purified. 4-demethoxydaunomycinone 10.2mg
(0.028 mmol) was dissolved in 2 ml of anhydrous methylene chloride,
Methyl ketene methyl dimethyl isopropyl silylacetal [synthesized according to Reference Example 5] 36.0 mg
(0.192 mmol) was added and refluxed for 2 hours. The treatment was carried out in the same manner as in Example 5, and the residue was purified by silica gel column chromatography (benzene/ethyl acetate = 50) to give 7-dimethylisopropylsilyl-4-
9.0 mg (69%) of demethoxydaunomycinone was obtained. NMR (CDCl ₃ ) δ (ppm): 0.29 (6H, s,
(CH ₃ ) ₃ Si), 0.96 (6H, s, CH(CH ₃ ) ₂ ),
0.99 (1H, s, CH( _CH3 ) ₂ ), 1.88~2.20 (2H,
m, 2H ₈ ), 2.43 (3H, s, COCH ₃ ), 2.95
(1H, d, J = 18Hz, H _10ax ), 3.30 (1H, d,
J = 18Hz, H _10eq ), 5.44 (2H, brs, H ₇ + 9
-OH), 7.73~7.95 (2H, m, ArH), 8.22~
8.42 (2H, m, ArH), 13.30 (1H, s,
ArOH), 13.60 (1H, s, ArOH). 7-dimethylisopropylsilyl-4-demethoxydaunomycinone 48.0mg (0.11mmol), 2,
3,6-trideoxy-1,4-di-O-p-nitrobenzoyl-3-trifluoroacetamide-α-L-lyxohexopyranose 80.0mg
(0.15 mmol) was dissolved in 15 ml of anhydrous methylene chloride-ether (3:1) mixed solvent and heated at -3℃.
0.2 ml (0.02 mmol) of 0.1 M trimethylsilyl trifluoromethanesulfonate methylene chloride solution was added, and the mixture was reacted for 1 hour. A glycoside was obtained by processing in the same manner as in Example 5. Yield 58.8 mg (72%). mp: 166~170℃ Dissolve 46.0 mg (0.12 mmol) of daunomycinone in 30 ml of anhydrous methylene chloride, and dissolve 105 mg (0.66 mmol) of methylketene methyltrimethylsilyl acetal).
was added, and the mixture was refluxed for 3 hours under an argon stream. The volatile fraction was distilled off from the reaction solution under vacuum, and the residue was purified by silica gel column chromatography to obtain 7-trimethylsilyldaunomycinone. Yield 47.7
mg (84%). NMR (CDCl ₃ ) δ (ppm): 0.30 (9H, s,
(CH ₃ ) ₃ Si), 1.89-2.20 (2H, m, 2H ₈ ),
2.45 (3H, s, COCH ₃ ), 2.97 (1H, d, J
= 18Hz, H _10ax ), 3.32 (1H, d, J = 18Hz,
H _10eq ), 4.02 (1H, s, OCH ₃ ) 5.44 (2H,
brs, H ₇ +9-OH), 7.25-8.03 (3H, m,
ArH), 12.85 (1H, s, ArOH), 13.54 (1H,
s, ArOH). 7-trimethylsilyldaunomycinone 30.0mg
(0.063mmol), 2,3,6-trideoxy-1,
After dissolving 46.0 mg (0.085 mmol) of 4-di-O-p-nitrobenzoyl-3-trifluoroacetamide-α-L-lyxohexopyranose in 10 ml of a mixed solvent of anhydrous methylene chloride-ether (3:1), After cooling the reaction solution to -3°C, 0.15 ml (0.015 mmol) of 0.1 M trimethylsilyltrifluoromethanesulfonate methylene chloride solution was added, and the mixture was reacted for 1 hour. The reaction solution was treated in the same manner as in Example 5 and purified by silica gel column chromatography to give 37.4
mg (77%) of glycosides were obtained. This was hydrolyzed with 0.1N NaOH in methanol and quantitatively converted to N-trifluoroacetyldaunomycin. mp: 169-171゜〔α〕 ²³ _D +210゜C0.10 dioxane). 4-demethoxydaunomycin 20.9mg
(0.057 mmol) and 1-chloro-N-trifluoroacetyl-O-p-nitrobenzoyldaunosamine 26.7 mg (0.075 mmol) [2,3,6-trideoxy-1,4-di-O-p-nitro benzoyl
[obtained by treating 3-trifluoroacetamido-α-L-lyxohexopyranose with hydrogen chloride] was dissolved in 4 ml of anhydrous THF, and 1 ml of a solution of 22.0 mg (0.086 mmol) of silver trifluoromethanesulfonate in anhydrous ether was added with stirring. added. The reaction solution was stirred at room temperature for 1 hour with the exclusion of light, then diluted with 20 ml of ethyl acetate and washed with excess saturated sodium bicarbonate solution. The organic layer was separated, dried and passed through Celite, and the solvent was distilled off. 4'-O-p-nitrobenzoyl-3'-N-trifluoroacetyl-4
An approximately 1:1 mixture of -demethoxydaunomycin and 4-demethoxydaunomycinone was obtained.
Without separating 4'-O-p-nitrobenzoyl-3'-N-trifluoroacetyl-4-demethoxydaunomycin, the reaction residue was dissolved in a small amount of methylene chloride, 20 ml of methanol was added, and the mixture was cooled on ice. The mixture was treated with 0.5 ml of 0.1N NaOH solution, neutralized with glacial acetic acid, and extracted with ethyl acetate. The extract was washed with water, dried, and then separated and purified using silica gel column chromatography (benzene/ethyl acetate = 4).
9.8 mg of unreacted 4-demethoxydaunomycinone
16.5 mg (51%) of N- with recovery of (47%)
Trifluoroacetyl-4-demethoxydaunomycin was obtained. 4-demethoxydaunomycinone 10.3mg
(0.028mmol), 2,3,6-trideoxy-1,
20.0 mg (0.037 mmol) of 4-di-O-p-nitrobenzoyl-3-trifluoroacetamide-α-L-lyxohexopyranose was dissolved in 3 ml of anhydrous methylene chloride and 0.5 ml of ether, and dissolved in anhydrous tin tetrachloride of approx. 20 mg (0.08 mmol) was added and stirred at room temperature for 1 hour. (The yield of the product did not improve even after 3 hours of reaction.) The reaction solution was poured into a mixture of saturated sodium hydrogen carbonate solution and ethyl acetate, and the resulting emulsion was washed several times with saturated brine. It was dried and the solvent was distilled off. TLC of the residue showed the presence of approximately 50% glycosides and raw aglycones. The produced glycoside was hydrolyzed with 0.1N NaOH without separation, and then separated by column chromatography to obtain 8.8 mg (56%) of N-trifluoroacetyl-4-demethoxydaunomycin.

Claims (1)

[Claims] 1. In the presence of a silylsulsonic acid derivative represented by the general formula R ⁵ R ⁴ R ³ SiOSO ₂ A, the general formula Anthracyclinone derivatives represented by and general formula A general formula consisting of reacting a 1-acyl sugar represented by in a mixed solvent of a halogen solvent and an ether solvent. A method for producing an anthracycline derivative represented by [where R ³ , R ⁴ and R ⁵ are an alkyl group, A is an alkyl group, aryl group, polyfluoroalkyl group or a hydrogen atom, and R is a hydrogen atom or trialkylsilyl] group, R ¹ and R ² are acyl groups, X ¹ and X ² are hydrogen atoms, methoxy groups, hydroxyl groups, halogen atoms, or lower alkyl groups, Y ¹ and Y ² are hydrogen atoms, alkoxy groups, or hydroxyl groups, Z is a hydrogen atom or a protected hydroxyl group. ].