JPS60188396A - Production of 9-aminoanthracycline derivative - Google Patents

Abstract

PURPOSE:To obtain the titled compound useful as a carcinostatic agent, economically in high yield, by reacting a 9-aminoanthracyclinone derivative with a 1-acyl saccharide in the presence of a silylsulfonic acid derivative to effect the glycosylation reaction. CONSTITUTION:The objective compound of formula IV can be prepared by reacting (A) the 9-aminoanthracyclinone derivative of formula I with (B) the 1-acyl saccharide of formula II in the presence of (C) the silylsulfonic acid derivative of formula III, usually in a solvent (e.g. methylene chloride) at -20-+20 deg.C. The amount of the component B is usually 1-2 equivalent, and that of the component C is preferably 3-9pts. per 1 unit of the component A. In the formulas I - IV, both R<1> and R<2> are H or one is H and the other is methoxy, etc.; R<3> is H or halogen-substituted lower alkanoyl; R<4> is H or CH3; R<5> is H, lower alkanoyloxy, etc.; R<6> is H, halogen-substituted lower alkanoylamino, etc.; R<7> is lower alkanoyloxy, etc.; R<8>-R<10> are alkyl, etc.; A is alkyl, aryl, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is based on the general formula [wherein R1 and R2 both mean a hydrogen atom, or R-
One of R means a hydrogen atom, the other means a methoxy group or a hydroxy group, 18 means a hydrogen atom or a halogen-substituted lower alkanoyl group, R4 means a hydrogen atom or a methyl group, R5 means a hydrogen atom, It means a lower alkanoyloxy group or an aroyloxy group, and ■ means a hydrogen atom, a lower alkanoyloxy group, or a halogen-substituted lower alkanoylamino group. ] It is related with the manufacturing method of the 9-amino anthracycline derivative represented by these.

9 represented by the general formula (1) obtained by the present invention
-Aminoanthracycline derivatives themselves have side-carcinogenic effects, and it is possible to remove the protecting group of the hydroxyl group or amino group under milder conditions.
No. 2870] (see reference side below).

Conventionally, various glycosylation reactions have been developed for producing anthracycline derivatives having substituents at the 8-position, 4-position and/or 5-position of the sugar moiety. Specifically, (1) a method in which an anthracyclinone derivative and a 1-halo sugar are reacted in the presence of (a) silver trifluoromethanesulfonate (M, J., Broadhurst et al.
,, J, C! hem, Soc'.

Perkin I, 1982.2249; JP-A-57-58497; F, Arcamone et
aVe2 Ezperie? Ltia.

84.1255 (1978), etc.], (b) method carried out in the presence of a mixture of mercury oxide and mercury bromide or a mixture of mercury cyanide and mercury bromide (T, HoSmith
et 211. J,Org,Ohem,,42.
865B (1977); F, Arcamone et
al,, CancerTreat Rep,, so
, 829 (1976); Special Publication No. 58-88880
No.: Special Publication No. 58-40555: Special Publication No. 58-4055
7, etc.], (2) A method of carrying out the reaction of an anthracyclinone derivative and glycal in the presence of (a) an acid catalyst [Japanese Patent Publication No. 58-40556; JP-A No. 50-149668; H. Umezawa et al. y J, Antibi
otics, 138°1581 (1980), etc.]
or (b) a method carried out in the presence of N-iodosuccinimide (5) (D. Horton et al., “Anthracy
c, /ine Anti-bioticq, 11e
d, by HoS, El l [liadem, Ac
ade-mic Press, 1982. p221)
e and (8) a method of reacting an anthracyclinone derivative with a 1-acyl sugar in the presence of rl-)luenesulfonic acid or a Lewis acid catalyst (C, Monneret et al.
,/,, “Anthr-acycline Antib
iotics,” ed, by H,S,E,/Kh
adem, Academic Press, 198
2. p282 ;H.

8, El Khadem, ship 4 I b + d-s 1
982 *T1265; H, S, EeKhadem
etae,, Carbohydr-rate Re5
arch, 101. CI (1982); J, 1
)oi-vin, etal,, Tetrahed
ron, 24.4219 (1981), etc.). However, although method (1) (a) selectively produces only the desired anomer, it uses unstable 1-halo sugars and uses expensive trifluorocarbons for anthracynolinone derivatives. The disadvantage is that it is necessary to use more than an equivalent amount of silver lomethane sulfonate.

Method (1) (b) uses 1-halo sugar as in (a), and in some cases, 1-halo sugar is added (6
) Disadvantages include the need to use 3 to 9 times the amount of the cyclinone derivative, the fact that other unnecessary anomers are usually produced as by-products in addition to the desired anomer, and the use of toxic mercury salts as the glycosylating agent. It is. In method (2), the 1-halo sugar used as a raw material in (1) is further treated with mercury cyanide or silver carbonate, or the 1-hydroxy sugar is treated with p-1-luenesulfonyl chloride viridine. It is necessary to use the glycal obtained by using 2 to 4 times the amount of the anthracyclinone derivative, and as in (1) (b), unnecessary anomer is often produced as a by-product. The disadvantage of method 2) (b) is that a deiodination reaction is essential following the glycosylation reaction. Method (8) uses 1-acyl sugar, which is more stable than 1-halo sugar, but
- The anomer production ratio remains at a maximum of about 9:1, and moreover, when a Lewis acid such as tin tetrachloride is used,
The disadvantage is that it is not easy to separate the raw acid after the reaction. In addition, in all methods (1) to (3), the desired anthracycline derivative is usually obtained at a yield of 50-60%, unreacted anthracyclinone derivative remains, and unnecessary anomer is often produced as a by-product, and separation operations such as column chromatography are essential. For the reasons mentioned above, it is very difficult to apply these methods to the synthesis of 9-aminoanthracycline derivatives, and there are many problems in industrializing them.

The present inventors conducted studies to overcome the shortcomings of the conventional 9-amino-anthracyclytic method, and discovered that it is possible to perform glycosylation using inexpensive reagents and to produce only the desired anomer with high stereoselectivity and in high yield. It is a completed invention.

That is, the present invention, like the method (8) above, allows the use of 1-acyl sugars, which are far more stable and suitable for long-term storage than 1-halo sugars, as a raw material, and produces almost no by-products in the glycosylation reaction. Since only the desired anomer can be selectively obtained, there are advantages such as easy separation operation.

Furthermore, in the present invention, a glycosylation reaction with a sugar in which the 8-, 4-, and 5-positions are all unsubstituted (R4-R5==R6-H) also has the advantage of providing the desired product in high yield.

The present invention is based on the general formula %Formula (1) [wherein, R9 and RIG mean an alkyl group, and A means 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 % formula % ([wherein, B I and Rl! both mean a hydrogen atom, or one of R and H means a hydrogen atom, and the other ( 9) R8 means a methoxy group or a hydroxy group, and R8 means a hydrogen atom or a halogen-substituted lower alkanoyl group.] and a 9-aminoanthracyclinone derivative represented by the general formula or methyl group R6
means a hydrogen atom, a lower alkanoyloxy group, or an aroyloxy group; R6 means a hydrogen atom, a lower alkanoyloxy group, or a halogen-substituted lower alkanoylamino group; R is a lower alkanoyloxy group, a halogen [
means a substituted lower alkanoyloxy group or an aroyloxy group. ] to produce a 9-aminoanthracycline derivative represented by the general formula fI).

Lower alkanoyl oki r 1 ^ in the above general formula
The halogen-substituted lower alkanoyl group means, for example, a 02-C6 alkanoyl group, and the halogen-substituted lower alkanoyl group of a halogen-substituted lower alkanoylamino group means, for example, a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom, It means a 02-C6 alkanoyl group substituted with 8 members. Examples of the aroyloxy group include benzoyloxy and nitro-substituted benzoyloxy groups.

The 9-aminoanthracyclinone derivative represented by the above general formula, which is a raw material of the present invention, can be prepared by a known method [JP-A-5
No. 8-194846, and patent application No. 182870-1982.
It is a compound that can be easily obtained according to the following. R1 and R2 of the 9-aminoanthracyclinone derivative represented by the general formula @) mean a hydrogen atom, a methoxy group or a hydroxy group, and at least one of R1 and R2 is a hydrogen atom. R8 is a hydrogen atom or a halogen-substituted lower alkanoyl group represented by a trifluoroacetyl group.

9 formed by the above general formula [phase] which is a raw material of the present invention
-Aminoanthracyclinone derivatives (78, 98)
body, (711・9R,) body, (78・9几) body, (7R
・98) used as a mixture or any combination thereof.

On the other hand, the 1-acyl sugar represented by the general formula (IV) is a compound that can be easily obtained from the corresponding sugar, such as 2.
8.6-1lysooxy-1゜4-di-p-21-lopenzoyl-8-trifluoroacetamide-lyxo-hexopyranose, 2.8.6-)lysooxy-1,4-di-trifluoroacetyl-8-tri Fluoroacedo turf doryxohexobyranose, 2°8.6-) lysooxy-1,4-diacetyl-8-trifluoroacetamide-lyxo-hexopyranose, 2,6-sibuoxy-1°8.4-) reel -Nitrobenzoyl-lyxo-
Hexopyranose, 2.6-sideoxy-8.4-lytrifluoroacetyl-1-p-nitrobenzoyl-lyxo-hexopyranose, 2.6-sideoxy-1.3
．． 4-trifluoroacetyl-lyxo-hexopyranose, 2,6-sideoxy-8,4-diacetyl-
1-p-nitrobenzoyl-lyxohexobylanose, 2-deoxy-1,3,4-)lytrifluoroacetyl-erythropentapyranose, 2-deoxy-
8,4-Diacetyl-1-p-nitrobenzoyl-erythropentapyranose, 2-deoxy-1,8,4-
Mention may be made of tri-p-nitrobenzoyl-erythropentapyranose, 2,8°4-trideoxy-1-p-nitropenzoyl-pentapyranose, 2,3,4-trithioxy-1-trifluoroacetyl-pentapyranose I can do it.

The amount of 1-acyl sugar used is usually 1 to 2 equivalents relative to the 9-aminoanthracyclinone derivative.

The present invention must be carried out in the presence of the silyl (18) sulfonic acid derivative represented by the general formula (I). Preferred silylsulfonic acid derivatives include trimethylsilyltrifluoromethanesulfonate and triethylsilyltrifluoromethanesulfonate, but others include trimethylsilyldifluoromethanesulfonate, 1,limethylsilylchlorodifluoromethanesulfonate, and trimethylsilyl-1,1,2,2-tetrafluoroethanesulfonate. *-),)! J Ethylsilyltrifluoromethanesulfonate, dimethylisopropylsilyltrifluoromethanesulfonate, t-butyldimethylsilyltrifluoromethanesulfonate, trimethylsilylperfluorobutanesulfonate, trimethylsilylperfluorocutanesulfonate, trimethylsilylmethanesulfonate, trimethylsilylethanesulfonate, trimethylsilylbenzenesulfonate, trimethylsilylp
-Bromotoluenesulfonate, trimethylsilyl p-
Toluenesul(14), honate, etc. can also be used. The amount of the silylsulfonic acid derivative to be used is 0.1 to 4 equivalents relative to the 9-aminoanthracyclinone derivative represented by the general formula @).

When carrying out the present invention, it is preferable to carry out the process in a solvent.
For example, a mixed solvent of a halogen solvent such as methylene chloride or 1,2-dichloroethane and an ether solvent such as diethyl ether or dimethoxyethane can be used.

The reaction normally proceeds smoothly at -20 to 20°C.

The 9-aminoanthracycline derivative in the general formula obtained by the method of the present invention further has a hydroxyl group,
A reaction is performed to remove the protecting group of the amino group, and a commonly used protecting group removal method can be applied to this reaction.

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.

Example 1 Anhydrous dichloromethane (11*l) and anhydrous z-tyl (9m
2.8.6-)lysooxy-1,4 in the mixed solvent of
-Di0-(p-nitrobenzoyl)-8-(trifluoroacetyl)amino-α-L-lyxo-hexopyranose (185Hzg, 0.25mmol) was dissolved, and molecular sieve 4A (1,2f) was present. After purging with argon, trimethylsilyltrifluorosulfonic acid (0.1 vrl) was added at -40°C, and the mixture was stirred at 0°C for 1 hour. The reaction mixture was then cooled to -15°C and (78,98)-9-acetyl-9-amino-6,
7,11-)rihydroxy-7.8.9.10-tetrahydronaphthacene-5,12-dione (7111v,
0.19 mmol) of anhydrous dichloro-methane (12 g/
) solution was added, and the reaction was stirred at 0°C for 5 hours. After the reaction was completed, the reaction solution was poured into saturated NaHCO2 water (150 ml) and ethyl acetate (80 ml) with strong stirring.

The organic layer was separated, washed with saturated Na01 water, and then Na2804
It was dried. After evaporating the solvent, the residue was subjected to silica gel column chromatography (C!H2C&: MeOH=95:
5) Separate and purify to give (78°98)-9-acetyl-9-amino-7-((2',8',6'-)lysooxy-8'-(1-lifluoroacetyl)amino- 4
'-0-p-nitrobenzoyl-α-L-lyxo-hexobyranosyl]oxy)-6,11-dihydro(17) #C7,8,9,10-tetrahydronaphthacene-5,12-dione was obtained .

Yield: 189q (yield: 98%) mp: 159-161°C Ca) Knee 7 a, ao (C = 0.101, C
HOd3)IR':,:JoXlcM-':8B20
．． 17B0.1710e1625.1590.158O NMR (CDC!13): δ (PPm) 1.26 (g
H,d.

J=6H2e CII! 1)-1,96-2,88(
4H, m.

2H2' + 2 Ha) e 2.40 (8He
S * A c ) t8.12 (2H1B1 ■
1G), 4.88-4.80 (2H.

”' p ■s ' + ■5' ) * 5.16
(I IN * rne H4') *5.47
(L H, brs, H,), 5.65 (I H,
brs.

WH=-6Hz, ii+'L 6.67 (2H, d
, NU).

7.80 7.96 (21 (, m, Arc), 8.2
8-8.46 (6H,m, ArH) Reference Example 1 (18) 00HO0OHO (78,98)-9-acetyl-9-amino-7-((
2', 8'', 6'-)lysooxy-8'-(trifluoroacetyl)amino-4'-0-p-nitrobenzoyl-α-L-lyxo-hexopyranosyl)-s, 1
1-dihydroxy-7.8,9.10-tetrahydro-
Naphthacene-5,12-dione (115111y, 0
．． 155 mmol) in dichloromethane (0.9 ml)
Dissolve the solution in water and add methanol (100ml) to the solution. O'
O nite 0. IN-NaOH (1.5 ml) was added and the reaction was stirred for 30 minutes.

Add glacial acetic acid (1 drop) and then add ethyl acetate (100 #
Il), add water (100g/) and extract, wash the organic layer with water,
Washed with saturated Nap/water and dried over anhydrous Na2804.

After evaporating the solvent, the residue was separated and purified by silica gel column chromatography (Cu2Ce2:MeOH=95:5) 17, (7s.

98)-9-acetyl-9-amino-7-((2'*
a' p e'-trideoxy-8'-trifluoroacetyl)amino-α-L-lyxo-hexobyranosyl]oxy)-6,11-dihydroxy-7,8,9,1
0-tetrahydro-naphthacene-5,12-dione was obtained.

Yield: 84# (yield: 92%) mp: 14B ~ 145°C [α): +184° (0 = 0.12.C3HO/,
)IRnuj”cll-’: aooo a2oo,
1710-νmax 1620.1585 Reference Example 2 (78,9S)-9-acetyl-9-amino-'I-
((2', 8', 6'-)lysooxy-8'-
(Trifluoroacetyl)amino-α-L-lyxo-hexopyranosyl]oxy:)-6゜11-dihydroxy-7,8,9,10-tetrahydro-naphthacene-5,
12-dione (80”f*0.185 mmall
) in methanol (12 g/), then cooled on ice for 10
A 2CO3 aqueous solution (5 g/) was added to the mixture and reacted at the same temperature for 12 hours. The reaction solution was made acidic by adding 8%-H (J) water, then made alkaline with saturated Na1ICO3 water, and extracted with chloroform.

r91) The residue obtained from the extraction was chromatographed on silica gel (OH20Jl?2:MoOH"95:5-0
．． (78°98)-9-acetyl-9-amino-7-C (2',8
',6'-)lysooxy-8'-amino-α-L-lyxo-hexopyranosyl)oxy)-6,tl~dihydroxy-7,8,9°10-tetrahydronaphthacene-5
, 12-dione was obtained.

Yield: 82111 (Yield: 47%) 'ol -1°IR:: JaxcM, aeoo-810L1710°1
620.1590 This product was converted into a hydrochloride salt by a conventional method (7s.

98)-9-acetyl-9-amino-7~((2',
8', 6'-trideoxy-8'-amino-α-
L-lyxo-hexopyranosyl)oxycy6.11-
Dihydroxy-L L 9-10-tetrahydronaphthacene-5,12 dione hydrochloride (24W) was prepared.

m p: 176 180'C (dec,)■"1l
iLjaoko3': 8500-8100.172
0°1620.1580 [α几8+149°(Q=Q,l 1. H2O) Example 2 As a raw material (78,98)-9-acetyl-9-amino-6,7,11-)lihydroxy-4-methoxy -7,
Using 8,9,10-tetrahydronaphthacene-5,12-dione 1. N? Thereafter, the reaction (28) was carried out in substantially the same manner as in Example 1 and Reference Examples 1 and 2 to obtain (78,98)-9-acetyl-9-amino-7.
-((2',8',6'-1lysooxy-8'-amino-α-L-lyxo-hexopyranosyl)oxy-6,1
1-dihydroxy-4-methoxy-7-so L 10
-tetrahydronaphthacene-5,12-dione can be obtained.

mp197-200°C (HCl salt) [α); Q0+t4s, 1° (0=Q, l, methanol) (HO [salt) ■ As a raw material (78,98)-9-acetyl-9-amino-6, 7,11-trihydroxy-1-methoxy-7s
L9. i o-tetrahydronaphthacene-5,1
Using 2-dione 1. Substantially the same as in Example 1 except for N. The reaction was carried out in the same manner as in Reference Example 1.2 to produce (78,98)-9-acetyl-9-amino-7-CC2', 8', 6'
-trideoxy-8'-amino-α-L-lyxohexinobyranosyl)oxy-6,11-dihydroxy-1
-Methoxy-7,8,9,10-tetrahydronaphthacene-5,12-dione can be obtained.

mp 198-202℃ (He/salt) [α几0+78.9°(C-θ mountain methanol) (ucl
salt) 0001(0 (25) As a raw material (78,98)-9-acetyl 9-amino-
6,7,11-trihydroxy-4-hydroxy-7,
Example 1 was substantially the same except that 8,9,10-tetrahydronaphthacene-5,12-dione was used. The reaction was carried out in the same manner as in Reference Examples 1 and 2 to produce (78,98)-9-acetyl-9-amino-7-CC2', 8', 6'-1-lysooxy-8'-amino-α-L- -hexopyranosyl)oxy-6,11-dihydroxy-4-hydroxy-7,8,9,10-tetrahydronaphthacene-5,1
2-dione can be obtained.

mp 198-197℃ [α) fi'+102° (c=o, o s, CHal
) (26) mp 278-275°C (HCl salt) Example 3 ■ (7S, 9S)-9-acetyl-9-amino-6,7,11-)dihydroxy-4-methoxy-7,
Substantially, except that 8,9,10-tetrahydronaphthacene-5,12-dione and 2゜6-sideoxy-8,4-diO-acetyl-1-p-nitrobenzoyloxy-α-ri-lyxorhexobilanose were used. The reaction was carried out in the same manner as in Example 1 above to give (78°98)-9-acetyl-9-
Amino-7-((8',4'-di-O-acetyl-2'
, 6'-dideoxy-α-L-lyxo-hexopyranosyl)oxy)-6,11-dihydroxy-4-methoxy-7,8,9,10-tetrahydronaphthacene-
5,12-dione can be obtained.

■ As a raw material (7S, 9S)-9-acetyl-9-amino-6,7,11-)dihydroxy-7,8,9,10-
Tetrahydronaphthacene-5,12-dione, 2,6-
The reaction was carried out in the same manner as in Example 1 except that Sibuoxy-3゜4-di-0-acetyl-1-p-nitrobenzoyloxy-α-L-lyxo-hexobylanose was used (78,
98)-9-acetyl-9-amino-7-((8'4'
-di-0-acetinodo2/, 6/-dideoxy-α
-L-lyxo-hexopyranosyl)oxy)-6,11
-dihydroxy-7,8,9,10-tetrahydronaphthacene-5,12-dione can be obtained.

mp: 155-157°C [α), %78171° (e = 0.21, Cl
IC! /3)(29) 0 α■ 0 As a raw material (78,98)-9-acetyl-9-trifluoroacetamide-6,7,11-trihydroxy-
7,8,9,10-tetrahydronaphthacene-5,12
The reaction was carried out in the same manner as in Example 1 except that 2,6-sideoxy-8,4-di-0-acetyl-t-p-nitrobenzoyloxy-α-L-lyxo-hexobylanose was used (78, 98) -9-acetyl-9-trifluoroacetamide-7-CCB', 4'-di0-
Acetyl-2'.

6'-dideoxy-α-L-lyxo-hexopyranosyl)oxy)-6,1,1-dihydroxy-7,8,9,
10-tetrahydronaphthacene-5,12-dione can be obtained.

(80) m p : 1 8 B -140'CCa) Pan7+
226° (C=0.16.cHe13)cO As a raw material (7S, 98)-9-acetyl-9-amino-6,7,11-)dihydroxy-7,8,9,10-
Same as Example 1 except that tetrahydronaphthacene-5゜12-dione and 2-deoxy-8,4-di-0-acetyl-1-p-nitrobenzoyloxy-β-D-erythropentapyranose were used. The reaction was carried out to produce 01 1 (78,9S L-9-acetyl-9-amino-7-(
(8',4'-di-0-acetyl-2'-deoxy-β
-D-erythropentapyranosyl)oxy)-6,1
1-dihydroxy-7,8,9,10-tetrahydronaphthacene-5,12-dione can be obtained.

mp: 141-148°C Ell: α)j0+t2o°(C:=Q, l, cHC
e3) HCl salt mp: 159-161°C ■ As a raw material (7S, 98)-9-acetyl-9-amino-6,7,11-)dihydroxy-4-methoxy-7,
8,9,10-tetrahydronaphthale-5,12-dione, 2-deoxy-8,4-di-O-acetyl-1-p
The reaction was carried out in substantially the same manner as in Example 1 except that -nitropenzoyloxy-β-D-erythropentapyranose was used (78,98)-9-acetyl-9-amino-7
-((8', 4'-di-O-acetyl-2'-deoxy-β-ri-erythropentapyranosyl)oxy)
-6゜11-dihydroxy-4-methoxy-7,8゜9
．． 10-tetrahydronaphthacene-5,12-dione can be obtained.

mp: 122-124°C (α:): +151.2° (C=0.1.OHO/3)
HCl salt mp: 178-175°C (83) As a raw material (78,98)-9-acetyl-9-amino-6,7,11-1-dihydroxy-1-methoxy 7*
8*9*1O-5-t-lahydronaphthacene-5.12
-dione, 2-deoxy-8,4-di-0-acetyl-
The reaction was carried out in the same manner as in Example 1 except that 1-p-nitrobenzoyloxy-β-D-erythropentapyranose was used (78,98)-g-ace(84)thyl-9-amino-7- ((8', 4'-G〇-
Acetyl-2'-deoxy-β-D-erythropentapyranosyl)oxy)-6゜11-dihydroxy-1-
Methoxy-7,8°9.10-tetrahydronaphthacene-5,12-dione can be obtained.

mp: 128-180°C ■ CI salt mp: 161-164°C ◎ 0HOH As a raw material (78,98)-9-acetyl-9-amino-6,7,11-)dihydroxy-7,8,9, 10-
Tetrahydronaphthacene-5,12-dione, 2.8.
The reaction was carried out in substantially the same manner as in Example 1 except that 4-trideoxy-t-p-nitropenzoyloxy-pentabilanose was used (7S, 9S)-9-acetyl-9-amino-7-0-tetrahydro. Pyranyl-6,11-dihydroxy-7,8,9゜10-tetrahydronaphthacene-
Two types of crystals of 5,12-dione can be obtained.

Crystal A mp: 155-159°C [α] 9° + 84.7° ((!=0.10. CHCl
! s) Crystal B mp: 120-126℃ [α几0+281°(c=0.11.cHc13)(8
6) As a raw material (78,98)-9-acetyl-9-amino-6,7,11-trihydroxy-4-methoxy-7,
Reaction was carried out in the same manner as in Example 1 except that 8,9,10-tetrahydronaphthacene-5,12-dione and 2.8.4(87)-trideoxy-1-p-nitrobenzoyloxy-pentabilanose were used. (78,98)-9-acetyl-9-amino-7-
0-tetrahydropyranyl-6,11-dihydroxy-
Two types of crystals of 4-methoxy-7,8,9,10-tetrahydronaphthacene-5,12-dione can be obtained.

Crystal A mp: 188-140℃ Crystal B mp: 185-188℃ (38 completed) Procedural amendment (voluntary) April 13, 1980 1 Indication of case 1982 Patent Application No. 48648 2, Title of the invention 9-Method for producing aminoanthracycline derivatives 3, Relationship with the case of the person making the amendment Patent applicant address: 5-1 Kitahama, Higashi-ku, Osaka City "Detailed Description" column 6, Contents of amendment 1) The claims on pages 1 to 8 of the specification are corrected as shown in the attached sheet.

2) In the 8th line from the bottom of the 5th page, [etaly j] is corrected to [etat,, J.

8) On page 6, line 16, the text ``1 anthracynolinone'' is corrected to ``anthracyclinone.''

4) Correct the following line from page 12, line 9 to page 13, line 16.

[, for example 2,8,6-drydeoxy-1,4-
di-op-nitropenzoyl-8-trifluoroacetamide-lyxo-hexopyranose, 2.8.6-drideoxy-1,4-di-0-trifluoroacetyl-
8-trifluoroacetamido-lyxo-hexopyranose, 2,8,6-dolideoxy-1,4-di-0-acetyl-8-trifluoroacetamido-lyxo-hexopyranose, 2,6-sideoxy-1,8,4-tri( t)) 10-p-nitrobenzoyl-lyxo-hexopyranose, 2,6-sideoxy-8,4-di-0-trifluoroacetyl-1-〇-p-nitrobenzoyl-lyxo-
Hexopyranose, 2.6-sideoxy-1.8.4-
Tri〇-trifluoroacetyl lyxo-hexopyranose, 2,6-sibuoxy-8゜4-diO-acetyl-1-0-I)-nitropenzoyl lyxohexobyranose, 2-deoxy-1 , 8,4-tri0-trifluoroacetyl-erythropentapyranose, 2
-deoxy-8,4-di-0-acetyl-t-o-p-
Nitropenzoyl-erythropentabilanose, 2-
Deoxy-1゜8.4-triop-nitropenzoyl-erythropentapyranose, 2.8.4-trideoxy-1-0-p-nitrobenzoyl-pentapyranose, 2.8.4-trideoxy -1-0-) Lifluoroacetyl-pentapyranose.

” (Q) 5) On page 14, lines 9 to 11, “Triethylsilyl 00
10. Sulfonates," should be deleted.

6) From the bottom of page 14, in lines 2 to 1, "p-bromotoluenesulfonate" is corrected to "p-bromobenzenesulfonate."

7) On page 17, lines 1 and 2, "trifluorosulfonic acid" is corrected to "trifluoromethanesulfonic acid."

8) From the bottom of page 19, in the 9th line, the text "1 pyranosyl]" is corrected to "1 pyranosyl]oxy".

9) The bottom line of page 22 is corrected as follows.

rm p two 176-180”C (dec,) Jlo
) On page 24, lines 8 to 4, the text ``[pyranosyl)oxy'' is corrected to ``1pyranosyl)oxy]''.

11) On page 25, lines 8-9, the text "1-pyranosyl)oxy" is corrected to "1-pyranosyl)oxy]".

(4) 12) From the bottom of page 26, line 18 is corrected as follows.

"9-amino-4,6,7,11-tetrahydroxy-
13) From the bottom of page 26, line 6 is corrected as follows.

1-lanosyl)oxy')-4,6,11-trihydroxy'' Claims (1) In the presence of a silylsulfonic acid derivative represented by the general formula %, 9-amino acid represented by the general formula A method for producing a 9-aminoanthracycline derivative represented by the general formula, which comprises reacting an anthracyclinone derivative with a 1-acyl sugar represented by the general formula [wherein R1 and R2 both represent a hydrogen atom] Or R1
, one of R2 means a hydrogen atom, the other means a methoxy group or a hydroxy group, R8 means a hydrogen atom or a halogen-substituted lower alkanoyl group, R4 means a hydrogen atom or a methyl group, R is a hydrogen atom , means a lower alkanoyloxy group or an aroyloxy group, R6 means a hydrogen atom, a lower alkanoyloxy group or a halogen-substituted lower alkanoylamino group, and R7 means a lower (2) alkanoyloxy group, a halogen-substituted lower alkanoyloxy group or an aroyloxy group. means Ra,
R9 and RIG mean an alkyl group, and A means an alkyl group, an aryl group, a polyfluoroalkyl group, or a hydrogen atom. ].

(8 complete)

Claims (1)

[Claims] (1) General formula consisting of reacting a 9-aminoanthracyclinone derivative represented by the general formula with a 1-acyl sugar represented by the general formula in the presence of a silylsulfonic acid derivative represented by the general formula %. A method for producing a 9-aminoanthracycline derivative represented by the formula [wherein R1 and R2 both represent a hydrogen atom, or R,
One of R means a hydrogen atom I), the other means a methoxy group or a hydroxy group, R11 means a hydrogen atom or a halogen-substituted lower alkanoyl group, R4 means a hydrogen atom or a methyl group, R and 5 mean a hydrogen atom , means a lower alkanoyloxy group or an aroyloxy group, R
means a hydrogen atom, a lower alkanoyloxy group or a halogen-substituted lower alkanoylamino group, R7 means a lower alkanoyloxy group, a halogen-substituted lower alkanoyloxy group or an aroyloxy group, and R8, R9 and 110 mean an alkyl group. , A means an alkyl group, an aryl group, a polyfluoroalkyl group or a hydrogen atom. ].